WO2017210545A1 - Potassium channel modulators - Google Patents

Potassium channel modulators Download PDF

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WO2017210545A1
WO2017210545A1 PCT/US2017/035662 US2017035662W WO2017210545A1 WO 2017210545 A1 WO2017210545 A1 WO 2017210545A1 US 2017035662 W US2017035662 W US 2017035662W WO 2017210545 A1 WO2017210545 A1 WO 2017210545A1
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Prior art keywords
alkyl
alkylene
compound
heterocyclyl
difluorocyclohexyl
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PCT/US2017/035662
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French (fr)
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WO2017210545A8 (en
Inventor
Birgitte Langer ERIKSEN
Magnus Gustafsson
Charlotte Hougaard
Thomas Amos JACOBSEN
Martin R. Jefson
Jessica KLEIN
Janus Schreiber LARSEN
John A. Lowe, Iii
John M. Mccall
Dorte STROØBÆK
Nadia Lybøl VON SCHOUBYE
Gregg F. Keaney
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Cadent Therapeutics, Inc.
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Priority to AU2017275657A priority Critical patent/AU2017275657B2/en
Priority to CA3026149A priority patent/CA3026149A1/en
Priority to US15/749,325 priority patent/US10774064B2/en
Publication of WO2017210545A1 publication Critical patent/WO2017210545A1/en
Publication of WO2017210545A8 publication Critical patent/WO2017210545A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • potassium channels are the largest and most diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP- sensitivity.
  • the small conductance calcium-activated potassium channels are a subfamily of Ca 2+ -activated K + channels and the SK channel family contains 4 members - SKI, SK2, SK3, and SK4 (often referred to as intermediate conductance).
  • the physiological roles of the SK channels have been especially studied in the nervous system, where for example they are key regulators of neuronal excitability and of neurotransmitter release, and in smooth muscle, where they are crucial in modulating the tone of vascular, broncho- tracheal, urethral, uterine or gastro-intestinal musculature.
  • R 1 , R 3 , R 5 , R 4a , R 4b , X 1 , X 2 , and A are defined and described herein.
  • FIG. 1 is a diagram illustrating the effect of Compound 359 following oral (PO) dosing on harmaline induced tremor.
  • FIG. 2 is a diagram illustrating the %SK2 SCioo of Compound 359 compared with chlorzoxazone (CHZ).
  • X 1 is selected from C(R a ) and N;
  • X 2 is selected from C(R b ) and N, wherein X 1 and X 2 are not simultaneously nitrogen; each of R a and R b is independently selected from hydrogen, halo, -CN, optionally substituted C 1 -C 4 alkyl, optionally substituted -0-(Ci-C 4 alkyl), -OH, -NH 2 , optionally substituted -NH(Ci-C 4 alkyl), optionally substituted -N(Ci-C 4 alkyl) 2 , optionally
  • each R 1 if present, is independently selected from halo, -CN, optionally
  • each R is independently selected from halo, -CN, optionally substituted C3-C6 cycloalkyl, optionally substituted -Ci-C 6 alkyl, optionally substituted -0-(Ci-C 4 alkyl), optionally substituted -NH(Ci-C 4 alkyl), optionally substituted -S-(Ci-C 4 alkyl), optionally substituted -S(0)-(Ci-C 4 alkyl), and optionally substituted -S(0) 2 -Ci-C 4 alkyl;
  • R 4a is selected from fluoro and -CF 3 ;
  • R 4b is selected from hydrogen and fluoro
  • R 5 is selected from hydrogen and optionally substituted Q-C 4 alkyl
  • each R 6 is independently selected from hydrogen and optionally substituted C1-C 4 alkyl
  • n 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
  • n 1, 2 or 3;
  • o 1 or 2;
  • p 1, 2, 3 or 4
  • halo and halogen as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
  • alkyl used alone or as part of a larger moiety, such as “alkoxy”, “haloalkyl”, “aralkyl”, “heteroaralkyl” and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., (Ci-C 6 )alkyl. As used herein, a “(Ci-C 6 )alkyl” group is means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
  • haloalkyl includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl.
  • (Ci-C 4 )alkoxy includes methoxy, ethoxy, proproxy, and butoxy.
  • aryloxy refers to an aromatic monocyclic or bicyclic carbon ring system having, unless otherwise specified, a total of 6 to 14 ring members.
  • aryl may be used interchangeably with the term “aryl ring”, “aryl group”, “aryl moiety,” or “aryl radical”. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic carbon ring is fused to one or more carbocyclyl rings, e.g.,
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as "Ph”), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group (e.g., in the case of an optionally substituted aryl or aryl which is optionally substituted) may be present on any substitutable position, i.e., any ring carbon substituted with hydrogen.
  • cycloaliphatic means a monocyclic, bicyclic (e.g., a bridged or spiro bicyclic ring), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system that is completely saturated or that contains one or more units of partial unsaturation, but where there is no aromatic ring.
  • Cycloalkyl is a completely saturated carbocycle.
  • Monocyclic carbocyclyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl.
  • Bridged bicyclic carbocyclyl groups include, without limitation, bicyclo[3.2.1]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.0]hexane, and the like.
  • Spiro bicyclic carbocyclyl groups include, e.g., spiro[3.6]decane, spiro[4.5]decane, and the like.
  • Fused carbocyclyl rings include, e.g., decahydronaphthalene, octahydropentalene, and the like.
  • optional substituents on a carbocyclyl may be present on any substitutable position and, include, e.g., the position at which the carbocyclyl group is attached.
  • heteroaryl used alone or as part of a larger moiety as in
  • heteroarylalkyl refers to a 5- 10 -membered aromatic radical containing 1-4 heteroatoms selected from N, quaternary ammonium cation, O, and S, and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring", “heteroaryl group”, or “heteroaromatic”.
  • Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrrolopyridinyl, quinolyl, quinazolinyl, and quinoxalinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position (carbon and nitrogen).
  • heterocyclyl means a 3- 12 membered (e.g., a 4-, 5-, 6- and 7- membered) saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be mononcyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic.
  • heterocycle e.g., a bridged, fused, or spiro bicyclic ring
  • heterocyclyl ring refers to “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein.
  • a heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl,
  • heterocyclyl also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole,
  • heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or heterocyclyl which is optionally substituted).
  • spiro refers to two rings that share one ring atom (e.g., carbon).
  • fused refers to two rings that share two adjacent ring ring atoms.
  • bridged refers to two rings that share at least three ring atoms.
  • compounds herein may contain “optionally substituted” moieties. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent that results in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • the terms "subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • treatment refers to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment.
  • treatment may be administered in the absence of symptoms.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
  • an effective amount or “therapeutically effective amount” includes an amount of a compound described herein that will elicit a biological or medical response of a subject.
  • Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimpo sable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
  • Enantiomer means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more
  • “Geometric isomer” are stereoisomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclyl ring, or to a bridged bicyclic system.
  • Racemate or “racemic mixture” means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
  • the compounds of the invention may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomeric ally enriched mixture.
  • Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by
  • the stereochemistry of a disclosed compound is named or depicted by structure
  • the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers.
  • Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisiomer over the weight of the the other stereoisomers.
  • the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure.
  • Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • stereoisomers mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s).
  • name or structure may encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).
  • one or more hydrogens can be replaced by deuterium.
  • Isotopic enrichments include e.g., at least 10%, 25%, 50%, 75%, 80%,85%, 90&, 95%, 87%, 98%, 99.0%, 99.5% and 99.8%".
  • all hydrogen atoms represented in Formula I, la, II, III, IV, V, VI, and VII are present in natural abundance.
  • specific compounds disclosed herein, such as those in Table 1 and in the Exemplification section all hydrogen atoms are present in natural abundance unless otherwise specified.
  • the compounds described herein may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids).
  • Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).
  • Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like.
  • Other examples of such salts include hydrochlorides,
  • the resent disclosure provides a compound of Formula I:
  • the compound of Formula I is of the Formula la:
  • the compound of Formula I or Formula la is of the Formula II or III:
  • the optional substituents for each occurrence of an optionally group for the compounds of Formulas I, la, II, or III are 1 to 3 groups independently selected from R as defined in the sixth
  • alkylene)carbocyclyl -S(0) 2 (Co-C 4 alkylene)heterocyclyl, -S(0) 2 (Co-C 4 alkylene)heteroaryl, -S(0) 2 (Co-C 4 alkylene)aryl, -NH(Ci-C 4 alkyl), -S-(Ci-C 4 alkyl), -S(0)-(Ci-C 4
  • alkylene)carbocyclyl -0(Co-C 4 alkylene)heterocyclyl, -0(Co-C 4 alky lene)hetero aryl, -O(C 0 - C 4 alkylene)aryl, -S(Co-C 4 alkylene)carbocyclyl, -S(Co-C 4 alkylene)heterocyclyl, -S(Co-C 4 alkylene)heteroaryl, -S(Co-C 4 alkylene)aryl, -S(0)(Co-C 4 alkylene)carbocyclyl, -S(0)(Co-C 4 alkylene)heterocyclyl, -S(0)(Co-C 4 alkylene)heteroaryl, -S(0)(Co-C 4 alkylene)aryl, -S(O) 2 (C 0 -C 4 alkylene)carbocyclyl, -S(O) 2 (C 0 -C 4
  • each of said heterocyclyl, heteroaryl, carbocyclyl, aryl, d- C 4 alkylene, and Ci-C 4 alkyl for R in the first, second, third, or fourth embodiment are
  • R 7 7 optionally substituted with 1 to 3 groups independently selected from R , where R is halogen,
  • R c is hydrogen or (Ci-C 6 )alkyl optionally substituted with 1 to 3 halogen;
  • R d and R e are each independently selected from hydrogen and (Ci-C 6 )alkyl; and k is 0, 1 or 2, wherein the remaining
  • alky lene)thiomorpholinyl- 1,1 -dioxide -0(C 1 -C 2 alkylene)oxazolyl, -0(C 1 -C 2
  • hydroxyalkylene)oxazolyl -0(C 1 -C 2 alkylene)phenyl, and -0(C 1 -C 2 alkylene)cyclobutyl each of said morpholinyl, piperazinyl, azetidinyl, triazolyl, pyrrolidinyl, oxadiazole,
  • R c is hydrogen or (Ci-C 4 )alkyl optionally substituted with 1 to 3 halogen;
  • R d and R e are each independently selected from hydrogen and (Ci-C 4 )alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, or sixth embodiment.
  • R in Formulas I, la, II, or III is independently selected from halo, -CN, -0(Ci-C 4 alkyl), Ci-C 4 alkyl, C 3 -C 4 cycloalkyl, cyanoCi-C 4 alkyl, haloCi-C 4 alkyl, and hydroxyCi-C 4 alkyl, wherein the remaining variables are as described in Formula I or Formula la, or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
  • R in Formulas I, la, II, or III is independently selected from chloro, bromo, fluoro, -CN, -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 3 , -
  • each of n, o, and p in Formulas I, la, II, or III is 1 or 2, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
  • each of R a and R b in Formula I or Formula la is independently selected from hydrogen and Ci-C 4 alkyl, or wherein R 3 and R a or R 3 and R b taken together with the atoms they are attached form an optionally substituted 5-6 membered, nitrogen-containing heterocyclyl, wherein the remaining variables are as described in
  • R a in Formula I or Formula la is selected from hydrogen, methyl, and ethyl; or R a and R 3 are taken together with the atoms they are attached form an optionally substituted piperidinyl or an optionally substituted lH-imidazolyl, wherein the remaining variables are as described in Formula I or Formula la, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.
  • the piperidinyl or lH-imidazolyl in the eleventh embodiment is optionally substituted at a ring nitrogen, wherein the remaining variables are as described in Formula I or Formula la, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.
  • R in Formulas I, la, II, or III is selected from halo, -CN, alkyl, -NH-(Ci-C 6 alkyl), alkyl-NH(R 7 ), -C(0)NH(R 7 ), carbocyclyl,
  • heterocyclyl -O-heterocyclyl, -NH-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene- carbocyclyl, -NH-alkylene-carbocyclyl, and -NH-alkylene-heterocyclyl, or R is taken together with R a to form an optionally substituted heterocyclyl, wherein R 7 is selected from hydrogen and Ci-C 4 alkyl; and any alkyl, alkylene, carbocyclyl, or heterocyclyl portion of R is optionally substituted, wherein the remaining variables are as described in Formula I or the second, third, ninth, tenth, eleventh, or twelfth embodiment.
  • R in Formulas I
  • R 5 in Formulas I, la, II, or III is selected from hydrogen, methyl and ethyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.
  • R 4a and R 4b in Formulas I, la, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.
  • R 4a is -CF 3 and R 4b hydrogen in Formulas I, la, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.
  • m in Formulas I, la, II, or III is 0, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth
  • R in Formulas I, la, II, or III is selected from:
  • R in Formulas I, la, II, or III is selected from:
  • R in Formulas I, la, II, or III is or , wherein the remaining variables are as described in
  • the compound of Formula I, la, II, or III is of Formula IV or V
  • the compound of Formula I, la, II, or III is of the Formula VI or VII:
  • ring A in Formulas I, la, II, III, IV, V, VI, or VII is or 5 wherein the remaining variables are as described in
  • R in Formulas I, la, II, III, IV, V, VI, or VII is independently selected from C 1 -C4 alkyl, haloCi-C4 alkyl, and hydroxyCi-C 4 alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.
  • R in Formulas I, la, II, III, IV, V, VI, or VII is independently selected from CH 3 , CHF 2 , CH 2 F, -CH(CH 3 )OH, and -CH 2 OH, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.
  • R 5 in Formulas I, la, II, III, IV, V, VI, or VII is hydrogen or Ci-C 4 alkyl, wherein the remaining variables are as described in Formula I or or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty- first embodiment.
  • R 5 in Formulas I, la, II, III, IV, V, VI, or VII is hydrogen, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty- first embodiment.
  • compositions are provided.
  • this disclosure provides a composition
  • a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in compositions is such that is effective to measurably modulate potassium channels in a biological sample or in a patient.
  • a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.
  • compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxy
  • compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions described herein may also be prepared in injectable form.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
  • compositions described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1 - 100 mg/kg body weight/day, can be
  • compositions administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound described herein in the composition will also depend upon the particular compound in the composition.
  • compounds and compositions described herein are useful in treating diseases and/or disorders associated with the activity of potassium channels.
  • diseases and/or disorders include e.g., neurodegenerative and neurological conditions (e.g., Parkinson's disease, tremors, Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS) ataxia, anxiety, depression, mood disorders, memory and attention deficits, bipolar disorder, psychosis, schizophrenia, traumatic brain injury, and narcolepsy), heart disease and realted conditions (e.g., ischaemic heart disease, coronary heart disease, angina pectoris, and coronary artery spasms), metabolic disease and bladder diseases (e.g., bladder spasms, urinary incontinence, bladder outflow obstruction, gastrointestinal dysfunction, irritable bowel syndrome, and diabetes), withdrawal symptoms associated with termination of addiction, and other conditions associated with the modulation of potassium channels such as e.g., respiratory diseases, epilepsy, convulsions, seizures, absence seizures,
  • the present disclosure provides a method of modulating the activity of a potassium channel in a subject comprising the step of administering a compound of Formula I, or a composition comprising any of the compounds herein.
  • the present disclosure provides a method of positively modulating a SK2 channel in a cell comprising the step of contacting the cell with a compound of Formula I, or a composition comprising any of the compounds herein.
  • the present disclosure further provides a method of treating essential tremor in a subject comprising the step of administering a compound or pharmaceutically acceptable salt or composition described herein.
  • the present disclosure provides a method of treating a disease or condition selected from a neurodegenerative disease, dementia, heart disease, withdrawal symptoms associated with termination of addiction, metabolic disease, and bladder disease.
  • a disease or condition selected from ataxia, dystonia, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.
  • a provided compound is one or more compounds selected from those exemplified in the
  • compounds of Formula I can be prepared according to Scheme 1, where the variables R 1 , R 3 , R 5 , R 4a , R 4b , X 1 , X 2 , and A are defined for Formula I.
  • compounds of Formula I can be prepared by reacting a compound of Formula 600 with a compound of Formula 601 in the presence of base, such as, e.g.,
  • Step 1 To a stirred solution of methyl 2,4-dichloropyrimidine-6- carboxylate [0001] (5 g, 24.16 mmol) in acetonitrile (50 mL) was added 4,4- difluorocyclohexylamine hydrochloride [0002] (4.1 g, 24.158 mmol) and N,N-diisopropyl ethylamine (8.8 mL, 50.72 mmol) at rt and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure.
  • Step 2[0004] To a stirred solution of methyl 2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate [0003] (0.5 g, 1.635 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride in
  • Step 3 [0006 and 0007] : To a stirred solution of (2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methanol [0004] (1.7 g, 6.12 mmol) in acetonitrile (20 mL) were added ethyl- lH-pyrazole-3-carboxylate [0005] (0.87 g, 6.12 mmol) and cesium carbonate (2.99 g, 9.18 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure.
  • Step 4[0007] To a stirred solution of a mixture of l-(4-((4,4- difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylic acid [0006] and its ester [0007] (3 g, 8.4 mmol) in ethanol (30 mL) was added cone, sulfuric acid (0.923 mL, 16.98 mmol). The reaction mixture was refluxed at 85 °C for 5 h and
  • Step 1[0010] To a stirred solution of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] (0.45 g, 1.01 mmol) in tetrahydrofuran (10 mL) were added 4-isopropyl-2-azetidinone [0009] (0.126 g,) and sodium ie/t-butoxide (0.146 g, 1.52 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 30 min.
  • Step 2 [0085]: To a stirred solution of ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 6-((2-isopropyl-4-oxoazetidin-l-yl)methyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate
  • Step 3[0016] The procedure is similar to step 3[0012] in example 2. 0.2 g of 1- ((6-((4, 4-difluorocyclohexyl) amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4- yl) methyl) pyrrolidin-2-one [0015] gave 0.035 g of l-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)pyrrolidin-2-one [0016],
  • reaction mixture was irradiated in microwave at 100 °C for 1 h, added water (10 mL) and extracted with ethyl acetate (2x15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Step 2[0019] To a stirred solution of ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 6-((3,5-dimethyl-lH-pyrazol-l-yl)methyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0018] (0.220 g, 0.478 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium aluminium hydride in tetrahydrofuran (478 mL, 2 M, 0.957 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h.
  • Step 3[0020] The procedure is similar to step 3 [0012] in example 2.
  • [0019] gave 0.036 g of N-(4,4-difluorocyclohexyl)-6-((3,5- dimethyl- IH-pyrazol- l-yl)methyl)-2-(3-(fluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-amine [0020], Compound 300 as an off-white solid.
  • Step 2[0023] The procedure is similar to step 2 [0019] in example 4. 0.830 g of ethyl l-(4-(((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0022] gave 0.570 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)methoxy)azetidine-l-carboxylate [0023] as an off-white solid.
  • Step 3 The procedure is similar to step 3 [0012] in example 2.
  • Step 4 To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methoxy)azetidine-l-carboxylate [0024] (0.2 g, 0.402 mmol) in dichloromethane (5 mL) was added trifluoro acetic acid (0.468 mL, 6.042 mmol) at 0 °C and the mixture was stirred at rt for 2 h.
  • Step 5 To a stirred solution of 6-((azetidin-3-yloxy)methyl)-N-(4,4- difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0025] (0.180 g, 0.454 mmol) in dichloromethane (5 mL) were added triethylamine (0.17 mL, 1.20 mmol) and methyl chloroformate (0.180 g, 0.81 mmol) at 0 °C.
  • Step 1[0028] To a stirred solution of methyl-2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate [0003] (6.6 g, 21.589 mmol) in methanol was added methanolic ammonia (60 mL) at rt. After 2 h the reaction mixture was purged with nitrogen to remove excess ammonia and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and stirred for 10 min.
  • Step 2[0029] To a suspension of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carboxamide [0028] (5.5 g, 18.92 mmol) in dichloromethane was added triethylamine (9.57 g, 94.6 mmol) and phosphorus oxychloride (7.25 g, 47.3 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h the reaction mixture was quenched with ice (100 g) and extracted with dichloromethane (2x100 mL).
  • Step 3 To a solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile [0029] (3.6 g, 13.302 mmol) in tetrahydrofuran was added a solution of lithium aluminium hydride in tetrahydrofuran (9.9 mL, 2M solution, 19.803 mmol) at -15 °C and the reaction mixture was stirred at same temperature. Reaction turned dark brown after LAH addition. After 10 min, the reaction mixture was quenched with saturated aqueous sodium sulfate solution at 0 °C and stirred at rt.
  • Step 4[0031] To a solution of 6-(aminomethyl)-2-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine [0030] (4.2 g, 15.178 mmol) in dichloromethane were added triethylamine (2.3 g, 22.76 mmol) and boc-anhydride (3.9 g, 18.213 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with dichloromethane (2x100 mL).
  • Step 5 To a solution of tert-butyl ((2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methyl)carbamate [0031] (4.2 g, 15.178 mmol) and ethyl- lH-pyrazole-3-carboxylate [0005] (4.2 g, 15.178 mmol) in acetonitrile was added cesium carbonate (4.2 g, 15.178 mmol) and the reaction mixture was heated at 85 °C in sealed tube. After 2 h, the reaction mixture was filtered, washed with chloroform (50 mL).
  • Step 6 [00107]: To a solution of ethyl l-(4-(((tert-butoxycarbonyl)amino)methyl)-6- ((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0032] (2.2 g, 4.578 mmol) in tetrahydrofuran was added a solution of lithium aluminum hydride in tetrahydrofuran (3.43 mL, 2 M, 6.867 mmol) at -20 °C and the reaction mixture was stirred at rt.
  • Step 7[0034] To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0033] (1.9 g, 4.333 mmol) in dichloro methane was added diethylamino sulfur trifluoride (1.0 g, 6.499 mmol) at - 20 °C and the reaction mixture was stirred at same temperature for 15 min, quenched with saturated aqueous sodium bicarbonate solution at 0 °C and extracted with dichloro methane (2x50 mL).
  • Step 8[0036] To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0034] (0.15 g, 0.340 mmol) in dichloro methane was added dry hydrogen chloride in dioxane (4M) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and the residue was diluted with dichloro methane (20 mL).
  • Step l[0038] To a solution of cyclobutanecarboxylic acid (0.3 g, 2.99 mmol) in dichloromethane was added oxalyl chloride (1.14 g, 8.98 mmol) and N,N-dimethylformamide (0.02 g, 0.3 mmol) at 0 °C and the reaction mixture was stirred rt. After 1 h, the reaction mixture was concentrated under reduced pressure to afford cyclobutanecarbonyl chloride [0038] as brown oil (0.4 g). This was taken as such to next step.
  • Step 2[0039] The procedure is similar to Step 8[0036] in example 6. 0.3 g of tert- butyl ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4- yl)methyl)carbamate[0034] gave 0.098 g of N-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)cyclobutanecarboxamide [0039], Compound 328 as pale brown solid.
  • Step 1[0040] To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0034] (0.3 g, 0.68 mmol) in dichloromethane was added 4M HCl in dioxane (5 mL) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure to afford 6- (armnomethyl)-N-(4,4-difluorocy
  • Step 1[0044] The procedure is similar to step 1[0003] in Example 1. 1 g of methyl-2,4-dichloropyrimidine-6-carboxylate [0001] gave 1.1 g of methyl 2-chloro-6-((3,3- difluorocyclohexyl)amino)pyrimidine-4-carboxylate [0044] as a white solid.
  • Step 3[0046] Compound 350: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylicacid [0045] (1.9 g, 5.407 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.74 g, 21.63 mmol) and N,N-dimethylformamide (0.04 g, 0.54 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 1 h.
  • Step 4 [0047] Compound 351: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxamide
  • Step 2[0049] Compound 352:To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N-methoxy-N- methylpyrimidine-4-carboxamide [0045] (0.33 g, 0.836 mmol) in tetrahydrofuran (7 mL) at - 70 °C was added methyl magnesium bromide ((3 M solution in tetrahydrofuran) 2.23 mL, 6.69 mmol) drop wise. The reaction mixture was stirred at rt for 10 min.
  • Step 3[0050] Compound 353: To a cooled solution of l-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- 1-one [0049] (0.17 g, 0.486 mmol) in methanol (3 mL) was added sodium borohydride (0.018 g, 0.486 mmol). The reaction mixture was stirred at rt for 10 min, concentrated under reduced pressure, dissolved in water (5 mL), neutralized with 1.5 N HC1 solutions (10 mL) and extracted with ethyl acetate (2x20 mL).
  • Step 4 [0051 and 0052] Compound 354 and 355: The isomers were separated by Supercritical Fluid Chromatography (SFC) to afford 0.040 g of (+)-l-(6-(((S)-3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- l-ol
  • Step 1[0056] Compound 358: To a solution of (6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)methanol [0055] (0.1 g, 0.296 mmol) in dichloromethane (10 mL) was added diethylamino sulfur trifluoride (0.095 g, 0.592 mmol) drop-wise at 0 °C, after addition the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with dichloromethane (20 mL).
  • Step 3 The procedure is similar to step 2[0049] in example 10. 0.65 g of methyl 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0058] gave 0.13 g of 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)propan-2-ol [0059], Compound 152.
  • Step 1 [0060 and 0061] Lithium aluminum hydride (2M THF solution, 31.62 mmol) was added drop- wise at -78 °C to a solution of ethyl 6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylate
  • Step 2[0062] The procedure is similar to step 3 [0012] in example 2. 0.25 g of (6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)methanol [0061] gave 0.05 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- (fluoromethyl)pyrimidin-4-amine [0062], Compound 165 as an off-white solid.
  • Step 1[0063] The procedure is similar to step 2[0049] in example 10. 2.8 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0060] gave 0.48 g of racemate l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0063], as an off-white solid.
  • Step 2 [00142] Step 2[0064 and 0065]: 0.48 g of l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [63] was purified by chiral preparative HPLC to afford 0.12 g of (-)l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0064], Compound 198 as an off-white solid.
  • Step 1[0066] The procedure is similar to step 3 [0012] in example 2. 0.21 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [11] gave 0.06 g of N-(4,4-difluorocyclohexyl)-6-(difluoromethyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0066], Compound 142 as an off-white solid.
  • Step 1 To a solution of (6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)methanol [0061] (1.4 g, 4.14 mmol) in
  • NSSY5107.0001 0.4 g of 6-(bromomethyl)-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0069] and N,N- dimethylamine [0070] (0.18 g, 3.99 mmol) in tetrahydrofuran was heated at 80 °C to afford 0.028 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazo 1-1 -yl)-6- ((dimethylamino)methyl)pyrimidin-4-amine [0071], Compound 177 as an off-white solid.
  • Step 1 0.35 g of 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0069] and 1-methylpiperazine [0072] (0.096 g, 0.9618 mmol) in acetonitrile was added triethylamine (2 eq) and stirred at rt to afford 0.04 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-6-((4-methylpiperazin- 1- yl)methyl)pyrimidin-4-amine [0073], Compound 178 as an off-white solid.
  • Step 1[0076] The procedure is similar to step 1[0003] in example 1. 2.0 g of methyl 2,6-dichloropyrimidine-4-carboxylate [0001] gave 2.56 g of methyl 2-chloro-6-((3,3- difluorocyclopentyl)amino)pyrimidine-4-carboxylate [0076] as a pale brown solid.
  • Step 4[0079] The procedure is similar to Step 4[0047] in example 09. 0.18 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carboxamide [0078] gave 0.1 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carbonitrile [0079], Compound 184 as an off-white solid.
  • Step 2[0081] The procedure is similar to step 2[049] in example 10. 0.25 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0080] gave 0.03 g of 2-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)propan-2-ol [0081], Compound 214 as a yellow solid.
  • Step 1[0082] The procedure is similar to step 2 [0019] in Example 4. 0.18 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0080] gave 0.04 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)methanol [0082], Compound 192 as a white solid.
  • Step 2 [00164] :0.3 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)methanol [0082] gave 0.3 g of 6-((3,3- difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carbaldehyde [0083] as a yellow solid (using Dess-Martin periodinane (2 eq) in dichloro methane).
  • Step 3 The procedure is similar to step 3[0012] in example 2.
  • 0.2 g of 6- ((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0083] gave 0.02 g of N-(3,3-difluorocyclopentyl)-6-(difluoromethyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0084], Compound 168 as a white solid.
  • Step 1[0085] The procedure is similar to step 2[049] in example 10. 0.22 g of 6- ((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0083] gave 0.05 g of l-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0085], Compound 225 as a pale yellow solid.
  • Step 1 [00169] Step 1[0087A and 0087B] : To a solution of 2,4-dichloro-6-methylpyrimidine [0086] (5 g, 30.67 mmol) in tetrahydrofuran (20 mL) was added 4,4- difluorocyclohexylamine hydrochloride [0002] (5.26 g, 30.67 mmol) and cesium carbonate (19.9 g, 61.3 mmol), then the reaction mixture was heated at 60 °C for 16 h.
  • reaction mixture was filtered to remove cesium carbonate, the filtrate was concentrated under reduced pressure to afford as an yellow gum and which was purified by column chromatography silica gel (60-120 mesh) using 40% ethyl acetate in pet ether as a eluent to afford 3.5 g of 2-chloro- N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] as an off-white solid and 2.8 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine
  • Step 2[0088] The procedure is similar to Step3 [0515] in example 188.
  • 2.5 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 1.5 g of 4- ((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0088] at 80 °C for 16 h using sodium cyanide (1.1 eq), DABCO (1.1 eq) in dimethylsulfoxide.
  • MS(M+1) + 243.
  • Step 3[0089] The procedure is similar to Step4 [0516] in example 188.
  • 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0088] gave 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbothioamide [0089] using ammonium sulfide (3 eq), triethylamine (2 eq) in ⁇ , ⁇ -dimethylformamide.
  • MS(M+1) + 287.
  • reaction mixture was concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh) using 3% methanol in chloroform as eluent to afford as an off-white solid 0.700 g, as an HBr salt, which was dissolved in saturated bicarbonate solution and extracted with ethyl acetate (2x70 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum to afford 0.41 g of N-(4,4-difluorocyclohexyl)-6-methyl-2-(4-methylthiazol-2-yl)pyrimidin-
  • Step 1[0092] The procedure is similar to step 3 [0006] in Example 1. 4 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 2.6 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine
  • Step 2[0094] The procedure is similar to step 3 [0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.26 g of l-(4- ((4,4-difluorocyclohexyl)amino)-6-methyl pyrimidin-2-yl)-lH-pyrazole-3-carbonitrile
  • Step 1[0096]: The procedure is step 3[0006] in Example 1. 0.3 g of 2-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.21 g of 2-(3- cyclopropyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine
  • Step 1[0098] The procedure is step 3[0006] in Example 1. 0.3 g of 4-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine [0087B] gave 0.14 g of N-(4,4- difluorocyclohexyl)-4-methyl-6-(3-methyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0098],
  • Step 1[0099] To a stirred solution of 2,4-Dichloro-6-methylpyrimidine [0086] (5 g, 30.674 mmol) in tetrahydrofuran (50 mL) was added sodium thiomethoxide (2.14 g, 30.67 mmol) in portions at -10 °C under nitrogen. The mixture was stirred at -10 °C for 3 h. The solid precipitate was filtered, washed with methanol (20 mL) and dried under vacuum to afford 2-chloro-4-methyl-6-(methylthio)pyrimidine [0099] as an yellow solid (5 g).
  • Step 1[0108] The procedure is similar to step 1[0106] in example 34. 0.15 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylsulfonyl)pyrimidine [0101] gave 0.08 g of N- ((lR,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-6-methyl-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-amine [0108], Compound 245 as an off-white solid.
  • Step 1[0114] The procedure is similar to step 1[0102] in example 32. 0.12 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylsulfonyl)pyrimidine [0101] gave 0.06 g of 6- methyl-2-(3-methyl-lH-pyrazol-l-yl)-N-(4-(trifluoromethyl)cyclohexyl)pyrimidin-4-amine [0114], Compound 144 as a yellow solid.
  • Step 1[0115] The procedure is similar to step 3 [0006] in example 1. 2.0 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.9 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0115], Compound 148 as an off-white solid.
  • Step 1[0117] The procedure is similar to step 3[0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.18 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- amine [0117], Compound 200 as an off-white solid.
  • Step 1[0119] The procedure is similar to step 3 [0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.12 g of N- (4,4-difluorocyclohexyl)-2-(4-fluoro-3,5-dimethyl- lH-pyrazol-l-yl)-6-methylpyrimidin-4- amine [0119], Compound 201 as a white solid.
  • Step 1[0123] The procedure is similar to step 3[0006] in example 1. 0.300 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] and 0.148 g of 4- fluoro pyrazole [0122] gave 0.150 g of N-(4,4-difluorocyclohexyl)-2-(4-fluoro-lH-pyrazol-l- yl)-6-methylpyrimidin-4-amine [0123], Compound 196 as an light yellow solid,
  • Step 1[0125] The procedure is similar to step 3[0006] in example 1. 0.15 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.1 g of 2-(l- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)acetonitrile [0125], Compound 208 as a white solid.
  • Step 2[0128A & 0128B] The procedure is similar to step 1[0106] in example 34 (75 °C, acetonitrile).
  • 1.2 g of 2,4-dichloro-6-methylpyrimidine [0127] gave 0.6 g of 2-chloro- N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-4-amine [0128A] as white solid and 0.28 g of 4-chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-2-amine [0128B] as yellow solid.
  • MS(M+l)+ 290.3.
  • Step 1[0132] To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.3 g, 1.146 mmol) in acetonitrile (10 mL) was added 3- bromo-5-methyl-lh-pyrazole (0.276 g, 1.719 mmol) and cesium carbonate (0.74 g, 2.29 mmol). The reaction mixture was irradiated in microwave at 150 °C for 2 h. The reaction mixture was filtered to remove cesium carbonate.
  • reaction mixture was degassed for 10 min, added l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.026 g, 0.032 mmol) and irradiated in microwave at 110 °C for 2 h. After completion the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.021 g of 2-(3-cyclopropyl-5-methyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0134], Compound 221 as an off-white solid.
  • Step 1[0143] The procedure is similar to step 3[0006] in example 1. 0.250 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.210 g of 3- isopropyl-lH-pyrazole [0142] gave 0.200 g of N-(4,4-difluorocyclohexyl)-2-(3-isopropyl- lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0143], Compound 218 as an off-white solid which was purified by prep HPLC.
  • Step 2 0.25 g of 2-chloro-N-(3,3-difluorocyclopentyl)-6-methylpyrimidin- 4-amine [0144] and 0.145 g of 3, 5-dimethyl pyrazole in acetonitrile was irradiated at 150 °C to afford 0.1 g of N-(3, 3-difluorocyclopentyl)-2-(3, 5-dimethyl- lH-pyrazol- l-yl)-6- methylpyrimidin-4-amine [0145] as a white solid.
  • Step 2[0147] The procedure is similar to step 2[049] in example 10. 0.15 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0146] gave 0.015 g of 2-(l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-lH-pyrazol-3-yl)propan-2-ol [0147], Compound 215 as a white solid.
  • Step 1[0154] To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0150] (1 g, 2.63 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.2 g, 5.27 mmol) at -78 °C and the reaction mixture was stirred at same temperature. After 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at -78 °C, brought to rt and stirred for 15 min. The white precipitate formed was filtered off through celite bed and washed with ethyl acetate.
  • the procedure is similar to step 3 [0012] in Example 2.
  • 0.5 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4- methyl-lH-pyrazol-3-yl)methanol [0154] gave 0.15 g of N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-4-methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0156], Compound 258 as white solid.
  • Step 2[0160] The procedure is similar to step 3[0050] in example 10. 0.15 g of 1- (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)ethan- 1-one [0159] gave 0.1 g of l-(l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH- pyrazol-3-yl)ethan-l-ol [0160], Compound 202 as an off-white solid.
  • Step l[0161] The procedure is similar to step 2 [0019] in Example 4. 1.4 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0146] gave 0.98 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0161] Compound 204 as an off-white solid.
  • Step 2[0162]:0.9 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0161] gave 0.62 g of l-(4-((4,4-difluorocyclohexyl)amino)- 6-methylpyrimidin-2-yl)-lH-pyrazole-3-carbaldehyde [0162] as a white solid, using manganese dioxide (5 eq) in dichloromethane. MS(M+l)+ 322.3.
  • Step 3[0163] The procedure is similar to step 3 [0012] in Example 2. 0.7 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3-carbaldehyde [0162] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-lH-pyrazol-l-yl)- 6-methylpyrimidin-4-amine [0163] as an off-white solid.
  • Step 1 Thionyl chloride (0.49 g, 4.17 mmol) was added to a solution of (l-(4- ((4,4-difluorocyclohexyl)arnino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0161] (0.45 g, 1.39 mmol) in dichloromethane and the reaction mixture was heated at 50°C.
  • Step 2 [0168 and 0169]: The procedure is similar to step 2[0019] in example 4. 0.7 g ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-lH- pyrazole-3-carboxylate [0167] gave 0.1 g of l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3-carbaldehyde [0168] as an off-white solid.
  • Step 3[0170] The procedure is similar to step 3 [0012] in example 2, 0.1 g l-(4- ((4,4-difluorocyclohexyl)arriino)-6-methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3- carbaldehyde [0169] gave 0.018 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-5- methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0170], Compound 256 as a grey solid.
  • Step 1[0171] The procedure is similar to step 3 [0012] in example 2. 0.15 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3- carbaldehyde [0168] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-5- methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0171], Compound 237 as a white solid.
  • Step 1[0175] The procedure is similar to step 2[0177] in example 62.
  • 0.2 g of 4- chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine [0173] gave 0.1 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0175], Compound 163 as an off-white solid.
  • Step 2[0178] The procedure is similar to step 2[0174] in Example 62 (without base). 0.25 g of 2-chloro-N-(4,4-difluorocyclohexyl)-5-ethylpyrimidin-4-amine [0177] gave 0.03 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)-5-ethylpyrimidin-4- amine [0178], Compound 111 as an off-white solid.
  • Step 1 [0180A & 0180B]: To a solution of 2,4-Dichloro-6-ethylpyrimidine [0179] (1 g, 5.64 mmol) and 4,4-Difluorocyclohexylamine Hydrochloride (0.96 g, 5.64 mmol) in acetonitrile was added cesium carbonate (3.68 g, 11.29 g ) and the reaction mixture was heated at 65 °C in sealed tube.
  • Step 1 [0187 A and 0187B]: The procedure is similar to Step 1 [0180 A & 0180B] in example 66.
  • 0.5 g of 2,4-dichloro-6-cyclopropyl pyrimidine [0186] gave 0.3 g of 2-chloro- 6-cyclopropyl-N-(3,3-difluorocyclopentyl) pyrimidin-4-amine [0187 A] and 0.125 g of 4- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-2-amine [0187B] both as colorless gums.
  • MS(M+l)+ 274.0.
  • Step 2[0188] The procedure is similar to step 3[0006] in Example 1.0.3 g of 2- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-4-amine [0187 A] gave 0.175 g of 6-cyclopropyl-N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4- amine [0188], Compound 217 as white solid.
  • Step 1[0195] To a solution of 4-chloro-2-(methylsulfanyl)-6-(trifluoromethyl) pyrimidine [0194] (1 g, 4.374 mmol) in acetonitrile (10 mL) was added N,N-diisopropyl ethylamine (0.84 g, 6.56 mmol), followed by 4,4-difluorocyclohexylamine hydrochloride [0002] (0.75 g, 4.374 mmol). The reaction mixture was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL).
  • Step 2[0196] To a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- (trifluoromethyl)pyrimidin-4-amine [0195] (0.55 g, 1.68 mmol) in dichloro methane (10 mL), 3-chloroperbenzoic acid (0.86 g, 5.04 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with dichloro methane (50 mL).
  • Step 3[0203] The procedure is similar to Step 3[0197] in example 69. 0.2 g N- (3,3-difluorocyclopentyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine [0202] gave 0.07 g of N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- (trifluoromethyl)pyrimidin-4-amine [0203], Compound 167 as a white solid.
  • Step 1[0204] The procedure is similar to Step 1 [0195] in example 69. 1.0 g of 4- chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine [0190] gave 0.8 g 4-(difluoromethyl)-6- (3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidine [0204] as an off-white solid.
  • Step 3[0206] The procedure is similar to Step 3[0197] in example 69 (DIPEA as base). 0.4 g of 4-(difluoromethyl)-6-(3,5-dimethyl- lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidine [0205] gave 0.2 g of N-(4,4-difluorocyclohexyl)-4- (difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0206] as a white solid.
  • Step 3[0207] The procedure is similar to Step 3[0197] in example 69 (DIPEA as base). 0.25 g of 4-(difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidine [0205] gave 0.2 g N-(3,3-difluorocyclopentyl)-4- (difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0207], Compound 181 as a white solid.
  • Step 2[0209] The procedure is similar to Step 3[0197] in example 69. 0.2 g 4- chloro-6-cyclopropyl-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine [0208] gave 0.04 g of 4- cyclopropyl-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0209], Compound 226 as a white solid.
  • Step 1[0211] To a solution of 2-Bromo-4-Hydroxymethylthiazole [0210] (2 g, 10.30 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyl dimethylsilyl chloride (3.2 g, 20.6 mmol) and imidazole (2.80 g, 41.2 mmol), then the reaction mixture was stirred at rt for 5h.
  • Step 3[0213] To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.3g, 1.14 mmol) in toluene (10 mL) was added 4- (((tert-butyldimethylsilyl)oxy) methyl)-2-(tributylstannyl) thiazole [00212] (0.7 lg,
  • Step 4[0214] To an ice cooled solution of 2-(4-(((tert-butyldimethylsilyl) oxy)methyl)thiazol-2-yl)-N-(4,4-difluoro cyclohexyl)-6-methylpyrimidin-4-amine [0213] (0.12g, 0.26mmoll.) in diethyl ether (10 mL) was added hydrogenchloride (gas) in dioxane, After the completion of the reaction, the solid was filtered and washed with hexane to afford as off-white solid and which was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (2x25 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless gum and which was purified by column of silica gel (60-120 mesh), using ethyl acetate as eluent to afford 0.055 g of (2-(2-(tert-but
  • Step 2[00217] The procedure is similar to step 3 [0012] in example 2. 0.080 g of 2-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazole-4-carbaldehyde
  • Stepl[219] To a solution of 2-bromo-4-(trifluoromethyl)thiazole in
  • Step 1[0220] To a solution of 0.2 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] and 0.7 g of 2-(tributylstannyl)-4- (trifluoromethyl)thiazole in toluene (8 mL), was degassed with nitrogen for 10 min and tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture and irradiated in microwave at 130 °C.
  • Step 1[0223] To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.8 g, 3.056 mmol) and l,4-diazabicyclo[2.2.2]octane (0.342 g, 3.056 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at rt for lh. To the resultant reaction mixture was added sodium cyanide (0.151 g, 3.056 mmol) and stirred at 80°C for 24h.
  • Step 1[0282] The procedure is similar to step 1[0220] in example 78. 0.500 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 1.1 g of 2- chloro-6-(tributylstannyl) pyridine [0227] gave 0.040 g of 2-(6-chloropyridin-2-yl)-N-(4,4- difluorocyclohexyl)-6-methyl pyrimidin-4-amine [0282], Compound 230 as a light yellow solid, which was purified by column of silica gel (60-120 mesh) using 60% ethyl acetate in hexane as eluent.
  • Step 1[0230] The procedure is similar to step 1[0220] in example 78.
  • Step 1[0232] To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.15 g, 0.573 mmol) in a mixture (1: 1 ratio) of 1,2- dimethoxyethane and water, were added 6-methoxypyridine-2-boronic acid [0231] (0.18 g, 1.146 mmol), potassium phosphate- tribasic (0.243 g, 1.146 mmol) in a microwave vial.
  • reaction mixture was irradiated in microwave at 100 °C for 2 h. After cooling to rt, reaction mixture was diluted with ethyl acetate (20 mL).
  • Step 3[0242] To a stirred solution of 4,6-dichloro-2-(3, 5-dimethyl-lh-pyrazol-l- yl) pyrimidine [0241] (4.9 g, 20.156 mmol) in acetonitrile (50 rriL), was added 4,4- difluorocyclohexylamine hydrochloride [0002] (3.45 g, 20.16 mmol) and N,N-diisopropyl ethylamine (7.01 mL, 40.31 mmol). The reaction mixture was heated at 60 °C for 16 h and concentrated under reduced pressure.
  • Step 4[0244] To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lh-pyrazol-l-yl)pyrimidin-4-amine [0242] (0.400 g, 1.17 mmol) in dioxane (10 mL), were added 3-oxetanamine (0.171 g, 2.34 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (0.135 g, 0.234 mmol) and cesium carbonate (0.764 g, 2.34 mmol). The reaction mixture was degassed with nitrogen for 10 min, before adding
  • Step 1[0246] The procedure is similar to step 2[174] in example 62. 0.350 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
  • Step 1[0248] The procedure is similar to step 2[0174] in example 62. 0.350 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] gave 0.075 g of 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl) amino)- l-methylpyrrolidin-2-one [0248], Compound 125 as a yellow solid.
  • Step 2[0249 and 0250] 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl) amino)- l-methylpyrrolidin-2-one [0248] which was purified by chiral preparative to afford 0.012 g of (+)-3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)amino)-l-methylpyrrolidin-2-one [0249],
  • Step 1[0251] To a solution of indium(III)chloride (0.51 g, 2.34 mmol) in tetrahydrofuran was added cyclopropyl magnesium bromide (1.02 g, 7.02 mmol) at -78 °C and stirred at same temperature.
  • reaction mixture was brought to rt and cannulated to a vial containing 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-amine [0242] (0.8 g, 2.34 mmol) in tetrahydrofuran and heated at 90 °C. After 16 h, the reaction mixture was quenched with few drops of methanol, stirred for 10 min, filtered through celite bed which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was again dissolved in ethyl acetate and washed with water and brine solution.
  • the mixture was stirred at rt for 30 min and then heated at 80 °C for 24 h.
  • the reaction mixture was diluted with ethyl acetate (250 mL) and water (100 mL). Aqueous layer was extracted with ethyl acetate (2x100 mL).
  • Step 1 The procedure is similar to Step 2[0174] in example 62. 0.3 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.348 g of (lS,4S)-(-)-2-Boc-2,5-diazabicyclo[2.2.1]heptane [0254] gave 0.075 g of tert-butyl (lR)-5-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0255] as an white solid.
  • Step 2 [0256]: tert-Butyl (lR)-5-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate [0255] was acidified by using Hydrochloric acid in dioxane to afford 6-((4R)-2,5- diazabicyclo[2.2.
  • Step 1 The procedure is similar to Step 2[0174] in example 62. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.22g of piperazine-2-carboxamide [0258] gave 0.055 g of 4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)piperazine-2- carboxamide [0258], Compound 100.
  • Step 1[0262] The procedure is similar to Step 3 [0006] in example 1 (solvent dimethyl sulfoxide at 100 °C). 0.6 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.309 g of 2-aminopropanamide [0262] gave 0.038 g of 2-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)amino)propanamide, Compound 109 using Cesium carbonate and dimethylsulphoxide at 100 °C for 48h.
  • Step 1[0264] The procedure is similar to Step 3[0006] in example 1(100 °C, dimethylsulfoxide ). 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.102 g of morpholin-2-ylmethanol [0263] gave 0.14 g of racemate (4-(6-((4,4-difluorocyclohexyl) amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)morpholin-2-yl)methanol [0264], Compound 110.
  • Step 2 [00333] Step 2[0265 & 0266] : 0.14 g of racemate (4-(6-((4,4-difluorocyclohexyl) amino)- 2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)morpholin-2-yl)methanol [0264] was separated by chiral Prep HPLC to afford 0.050 mg of (+)-(4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morphoU ⁇ yl)methanol [0265], Compound 112.
  • Step 1[0270] To a solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (lg, 4.11 mmol) and morpholine-2-carboxamide [0269] (0.53g, 4.11 mmol) in dimethylsulfoxide (8 mL) was added cesium carbonate (2.68g, 8.22 mmol) under N2 atmosphere. The resultant reaction mixture was heated at 80 °C in a closed vial for 8 h, quenched with water and extracted with ethyl acetate (2x200 mL).
  • Step 1[0273] A stirred solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (1.3 g, 5.348 mmol), 1-acetylpiperazine [0272] (0.685 g, 5.348 mmol) and triethylamine (0.82 mL, 5.883 mmol) in acetonitrile (50 mL) was heated at 55 °C for 16 h.
  • Step 2[0274] A stirred suspension of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one [0273] (0.22 g, 0.657 mmol), 4,4- difluorocyclohexylamine hydrochloride [0002] (0.135 g, 0.788 mmol) and cesium carbonate (0.535 g, 1.642 mmol) in acetonitrile was heated at 150 °C in MW for 5 h.
  • Step 1 The procedure is similar to Step 2[0274] in example 99. 0.2 g of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0273] and 0.1 g of 4-(Trifluoromethyl)Cyclohexanamine [0113] gave 0.06 g of l-(4-(2-(3,5- dimethyl-lH-pyrazol-l-yl)-6-((4-(trifluoromethyl)cyclohexyl)amino)pyrimidin-4- yl)piperazin-l-yl)ethan- 1-one [0275], Compound 149.
  • Step 1 The procedure is similar to Step 2[0274] in example 99 ( Using DIPEA, MW, 180 °C). 0.2 g of l-(4-(6-chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4- yl)piperazin-l-yl)ethan- 1-one [0273] and 0.108 g of 3,3-difluorocyclopentan-l-amine [0075] gave 0.065 g of l-(4-(6-((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)piperazin-l-yl)ethan- 1-one [0276], Compound 130.
  • Step 2[0280] 0.4 g of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin- 4-yl)piperazin-l-yl)ethan-l-one [0273] and 0.44 g of 4,4-difluoro-N-methylcyclohexan-l- amine [0279] gave 0.190 g of l-(4-(6-((4,4-difluoro cyclohexyl)(methyl)amino)-2-(3,5- dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0280], Compound 132 using ⁇ , ⁇ -diisopropyl ethylamine and acetonitrile in MW at 180 °C for 3h.
  • Step 2[0282] To a stirred solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)-N'-hydroxypyrimidine-4-carboximidamide [0281] (1.8 g, 5.88 mmol) in acetic anhydride (20 mL) was heated at 100 °C in sealed tube for 24 h.
  • Step 3[0283]: 0.9 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-(5-methyl- 1,2,4- oxadiazol-3-yl)pyrimidin-4-amine [56] gave 1.0 g of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-(5-methyl-l,2,4-oxadiazol-3-yl)pyrimidin-2-yl)-lH-pyrazole-3- carboxylate [57] as an off-white solid using CS2C03, ACN 80 °C 2h. MS(M+l)+ 434.
  • Step 1[0284] The procedure is similar to step 2[0011] in example 2.
  • Step 2 The procedure is similar to step 3 [0012] in example 2. 0.45 g of (1- (4-((4,4-difluorocyclohexyl)amino)-6-(5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0284] gave 0.24 g of N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)-6-(5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin-4- amine [0285], Compound 331 as a white solid.
  • Step 3 [0290 and 0291]: To a solution of tert-butyl (4,4-difluorocyclohexyl)(2- (3,5-dimethyl-lH-pyrazol-l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0289] (0.5 g, 1.01 mmol) in methanol (5 mL) was added sodium borohydride (38.5 g, 1.01 mmol). The reaction mixture was stirred at rt for 10 min. The reaction mixture was concentrated under reduced pressure.
  • Step 1[0292] To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-((+)-4- hydroxytetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0290] (0.80 g, 0.157 mmol) in dioxane (5 mL) was added hydrogen chloride gas (5 mL) in dioxane. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL).
  • Step 5[23] The procedure is similar to step 1 [0292] in example 107.
  • [0291] gave 0.042 g of (-)-3-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)tetrahydro-2H- pyran-4-ol [0293], Compound 257 as a white solid.
  • Step 1 [0294 and 0295] : To an ice-cold solution of tert-butyl (4,4- difluorocyclohexyl)(2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(-4-hydroxytetrahydro-2H-pyran-3- yl)pyrimidin-4-yl)carbamate [0291] (0.240 g, 0.472 mmol) in dichloromethane (5 mL) was added diethylamino sulfur trifluoride (0.152 g, 0.945 mmol) drop wise. The reaction mixture was slowly warmed to rt and stirred for 2 h.
  • Step 2[0296] To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(5,6- dihydro-2H-pyran-3-yl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)carbamate [0295] (0.08 g, 0.18 mmol) in dioxane (3 mL) was added hydrogen chloride gas in dioxane (3 niL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL). It was then neutralized with 10% sodium bicarbonate solution.
  • Step 1 [0301]: To a stirred solution of 0.500 g of 6-chloro-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] in 50% aqueous sodium hydroxide solution (2 mL), was added 0.331 g of (2-methyl-2H- 1,2,3- triazol-4-yl)methanol [0300] and tetra butyl ammonium hydrogen sulfate (0.200 g, 0.586 mmol). The reaction mixture was heated at 110 °C for 16 h.
  • Step 1[0303] The procedure is similar to step 1 [0301] in example 111. 0.250 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0242] and 0.165 g of (l-methyl-lH-l,2,3-triazol-5-yl)methanol [0302] gave 0.150 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l-methyl-lH-l,2,3-triazol-5- yl)methoxy)pyrimidin-4-amine [0303], Compound 126 as an white solid.
  • Step 1[0305] The procedure is similar to step 1[0301] in example 111. 0.150 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] gave 0.030 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l- methyl- 1 H- 1 ,2,4-triazol-5-yl)methoxy)pyrimidin-4-amine[0305] , Compound 274.
  • Step 1[0307] The procedure is similar to step 2[0274] in Example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.09 g of (2-methyl-2H-l,2,3-triazol-4-yl)methanamine [0306] gave 0.03 g of N4- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6-((2-methyl-2H-l,2,3-triazol- 4-yl)methyl)pyrimidine-4,6-diamine [0307], Compound 235 as a light yellow solid.
  • Step 1[0309] The procedure is similar to step 2[0274] in Example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.09 g of (l-methyl-lH-l,2,3-triazol-4-yl)methanamine [0308] gave 0.04 g of N4- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6-((l-methyl-lH-l,2,3-triazol- 4-yl)methyl)pyrimidine-4,6-diamine [0309], Compound 233 as an off-white solid.
  • Step 1[0310] To a stirred solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (2 g, 8.227 mmol) in a mixture of solvent (tetrahydrofuran (20 mL) and water (2 mL)) was added sodium hydroxide (0.65 g, 16.454 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, neutralized with 1.5 N HCl solution (-0.5 mL), and extracted with ethyl acetate (3x50 mL).
  • Step 2[0312] To a stirred solution of 6-chloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidin-4-ol [0310] (0.50 g, 0.2226 mmol) in acetonitrile (2 mL) was added sodium chlorodifluoroacetate [0311] (0.54 g, 0.356 mmol) and sodium carbonate (0.47 g, 0.445 mmol). The reaction mixture was heated at 90 °C for 5 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (5 mL).
  • Step 1[55] The procedure is similar to step 3[0313] in example 116. 0.5 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
  • Stepl[0317] The procedure is similar to step 3[0313] in example 116. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
  • Step-1 To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] (15g, 43.88 mmol) in acetonitrile (200 mL) was added morpholine [0067] (15.29 g, 175.54 mmol) and the resultant reaction mixture was heated at 75 °C in sealed tube.
  • Step 1 The procedure is similar to step 3[0313] in example 116. 0.15 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
  • Step 1 The procedure is similar to Step 2[0274] in example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.101 g of 2,6-dimethyl morpholine [0321] gave 0.07 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(2,6- dimethylmorpholino)pyrimidin-4-amine [0322], Compound 190.
  • Step 1 The procedure is similar to Step 2[0274] in example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.127 g of 2-(morpholin-2-yl)propan-2-ol [0323] gave 0.050 g of 2-(4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholin-2- yl)propan-2-ol [0324], Compound 227.
  • Step 1[0326] The procedure is similar to Step 2[0274] in example 99. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
  • Step 1[0328] The procedure is similar to step 1[0301] in example 111. 0.25 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.16 g of (l-methyl-lH-l,2,3-triazol-5-yl)methanol [0327] gave 0.15 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l-methyl-lH-l,2,3-triazol-5- yl)methoxy)pyrimidin-4-amine [0328], Compound 189 as an white solid,
  • reaction mixture was quenched with water at -78 °C, slowly brought to rt and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford a yellow solid, which
  • Step 3[0335] The procedure is similar to step 4 [0244] in example 87. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] gave 0.11 g of l-(6-((4,4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)-3-methylazetidin-3-ol [0335], Compound 140 as white solid.
  • Step 1[0340] A stirred solution of maleic anhydride [0338] (10 g, 101.981 mmol) and benzyl amine [0339] (11.15 g, 101.981 mmol) in acetic acid (100 mL) was heated at 120 °C for 18 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to obtain l-benzyl-lH-pyrrole-2,5-dione [0340] as off-white solid (10 g, 52%).
  • Step 5 [00413] Step 5[0345].
  • 0.5 g of 3-benzyl-3-azabicyclo[3.1.0]hexan-6-amine [0344] gave 0.5 g of tert-Butyl(3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)carbamate [0345], using triethylamine, boc-anhydride in tetrahydrofuran.
  • MS(M+1)+ 289.1.
  • Step 6[0346] To a degassed solution of tert-Butyl (3-benzyl-3- azabicyclo[3.1.0]hexan-6-yl) carbamate [0345] (0.2 g, 0.694 mmol) in methanol (10 mL) was added palladium on carbon (0.04 g, 10% WAV) in a tiny clave hydrogen reactor. The mixture was hydrogenated under 50 psi hydrogen gas pressure for 18 h. The reaction mixture was filtered through a bed of celite and washed with methanol (20 mL).
  • Step 2[0348] A stirred solution of tert-Butyl (3-(6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)-3- azabicyclo[3.1.0]hexan-6-yl)carbamate [0347] (0.2 g, 0.409 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Trifluoro acetic acid (0.235 g, 2.042 mmol) was added and the mixture was stirred at rt for 18 h.
  • Step 1[0351] To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0333] (4.1 g, 12.509 mmol) and tert-butyl 3- hydroxyazetidine-l-carboxylate [0021] (4.3 g, 25.018 mmol) in dioxane (40 mL) was added cesium carbonate (6.11 g, 18.763 mmol). The reaction mixture was heated at 100 °C in a sealed tube for 18 h. The reaction mixture was concentrated under reduced pressure.
  • Step 2[0352] To a cooled solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0351] (2.1 g, 4.52 mmol) in dioxane (10 mL) was added hydrogen chloride gas in dioxane (10 mL). The reaction mixture was stirred at rt for 1 h.
  • Step 3[0354] To a cooled solution of 6-(azetidin-3-yloxy)-N-(4,4- difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0352] (0.25 g, 0.686 mmol) in dichloro methane (3 mL) was added triethylamine (0.1 mL, 0.754 mmol), followed by iso-butyryl chloride [0353] (73 g, 0.686 mmol). The reaction mixture was stirred at rt for 1 h and diluted with dichloro methane (20 mL).
  • Step 1[77] The procedure is similar to step 3[0354] in example 133. 0.8 g of 6- (azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0352] and 0.2 g of methyl chloroformate [0026] gave 0.32 g of 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0355], Compound 205 as a white solid.
  • Step 1[0357] The procedure is similar to step 3[0354] in example 133. 0.8 g of 6-(azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0352] and 0.26 g of pivaloyl chloride [0356] gave 0.4 g of l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- 1-yl)- 2,2-dimethylpropan-l-one [0357], Compound 211 as a white solid.
  • Step 1[45] The procedure is similar to step 4 [0244] in example 87. 0.4 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.178 g of 3-Oxetanamine [0243] gave 0.07 g of N4-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)-N6-(oxetan-3-yl)pyrimidine-4,6-diamine [0358], Compound 141 as yellow solid.
  • Step 1[0360] The procedure is similar to step 4 [0244] in example 87. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.22 g of N,N-dimethylazetidin-3-amine dihydrochloride [0359] gave 0.08 g of N-(4,4- difluorocyclohexyl)-6-(3-(dimethylamino)azetidin- l-yl)-2-(3-methyl- IH-pyrazol- 1- yl)pyrimidin-4-amine [0360], Compound 143 as a yellow solid.
  • Step 2[0362] 0.3 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- 1H- pyrazol-l-yl)pyrimidin-4-amine [0333] and 0.3 g of tert-butyl 3-hydroxyazetidine-l- carboxylate [0021] gave 0.05 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0362], Compound 151 as a yellow solid.
  • Step 1[0364] The procedure is similar to step 1[0361] in example 138. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.156 g of 1- (aminomethyl)-N,N-dimethylcyclobutane-l-amine[0363] gave 0.08 g of N4-(4,4-difluorocyclohexyl)-N6-((l-(dimethylamino)cyclobutyl)methyl)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidine-4,6-diamine [0364], Compound 157 as a white solid.
  • Step 1[0366]: To a solution of dl-a-amino-e-caprolactam [0365] (3 g, 23.405 mmol) in dichloro methane (30 mL) was added triethylamine (2.36 g, 23.405 mmol) and followed by slow addition of boc-anhydride (5.1 g, 23.405 mmol) at 0°C under N2 atm. The resultant reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to afford 4.2 g of tert-butyl (2-oxoazepan-3-yl)carbamate [0366] as a white solid. MS(M+1)+ 229.
  • Step 1[0370] The procedure is similar to step 1[0361] in example 138. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.17 g of l-ethylazepan-3-amine [0369] gave 0.02 g of N4-(4,4-difluorocyclohexyl)-N6- (l-ethylazepan-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidine-4,6-diamine [0370],
  • Step 1 [0371] : To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0333] (0.5 g, 1.52 mmol) in tetrahydrofuran (50 mL) was added boc-anhydride (998 g , 4.57 mmol) followed by 4-N,N-dimethylamino pyridine (35 g, 0.289 mmol). The reaction mixture was heated at 85 °C for 1 h.
  • Step 2[0372] To a solution of tetrahydro-4h-pyran-4-One [0288] (0.46 g, 4.67 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl) amide (1 M solution in tetrahydrofuran ) (4.6 mL, 4.67 mmol) at 0 °C.
  • tert-butyl (6-chloro-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)(4,4-difluorocyclohexyl)carbamate [0371] (0.5 g, 1.168 mmol) was added to the reaction mixture at 0 °C, drop wise in tetrahydrofuran (5 mL). After addition the reaction was stirred at rt for 18 h, quenched with water (5 mL) and extracted with ethyl acetate (2 x 50 mL).
  • Step 3 [0373] : To a solution of tert-butyl (4,4-difluorocyclohexyl)(2-(3-methyl- lH-pyrazol-l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0372] (0.5 g, 0.101 mmol) in methanol (1 mL) was added sodium borohydride (0.038 g, 0.101 mmol). The reaction mixture was stirred at rt for 10 min, concentrated under reduced pressure, added with 10% sodium bicarbonate (5 mL) and extracted with ethyl acetate (2 x 10 mL).
  • Step 4[0374] To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(4- hydroxytetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0373] (0.05 g, 0.101 mmol) in dioxane (2 mL) was added hydrogen chloride gas in dioxane (2 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL) and neutralized with 10% sodium bicarbonate (5 mL) solution.
  • Step 1[0375] To an ice-cold solution of tert-butyl (4,4-difluorocyclohexyl)(2-(3- methyl- IH-pyrazol- l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0372] (0.08 g, 0.162 mmol) in dichloromethane (1 mL) was added diethylamino sulfur trifluoride (0.043 mL, 0.325 mmol) drop wise.
  • Step 2[0376] To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(4,4- difluorotetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0375] (0.04 g, 0.077 mmol) in dioxane (2 mL) was added hydrogen chloride gas in dioxane (2 mL). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and neutralized with 10% sodium bicarbonate solution (10 mL).
  • Step 1[0377] To a suspension of 4,6-dichloro-2-(methylthio)pyrimidine [0029] (10 g, 51.26 mmol) in N,N-dimethylformamide (50 mL) was added 3,5-dimethyl pyrazole [0017] (4.9 g, 51.26 mmol), followed by cesium carbonate (25.05 g, 76.89 mmol) and the reaction mixture was heated at 80 °C . After 16 h, the reaction mixture was filtered and washed with chloroform. The filtrate was concentrated under reduced pressure and the residue was triturated with water.

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Abstract

Provided are novel compounds of Formula (I): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions which can be affected by potassium channel modulation. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with potassium channels.

Description

POTASSIUM CHANNEL MODULATORS
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 62/344513, filed June 2, 2016, and U.S. Provisional Application No. 62/449309, filed January 23, 2017, each of which are incorporated herein by reference.
BACKGROUND
[0002] Among the ion channels, potassium channels are the largest and most diverse, being found in a variety of animal cells such as nervous, muscular, glandular, immune, reproductive, and epithelial tissue. These channels allow the flow of potassium in and/or out of the cell under certain conditions. These channels are regulated, e.g., by calcium sensitivity, voltage-gating, second messengers, extracellular ligands, and ATP- sensitivity.
[0003] Dysfunction of potassium channels, as well as other ion channels, generates loss of cellular control and results in altered physiological functioning and disease conditions. Because of their ability to modulate ion channel function and/or regain ion channel activity in acquired or inherited channelopathies, potassium channel modulators are being used in the pharmacological treatment of a wide range of pathological diseases and have the potential to address an even wider variety of therapeutic indications.
[0004] The small conductance calcium-activated potassium channels (SK channel) are a subfamily of Ca2+-activated K+ channels and the SK channel family contains 4 members - SKI, SK2, SK3, and SK4 (often referred to as intermediate conductance). The physiological roles of the SK channels have been especially studied in the nervous system, where for example they are key regulators of neuronal excitability and of neurotransmitter release, and in smooth muscle, where they are crucial in modulating the tone of vascular, broncho- tracheal, urethral, uterine or gastro-intestinal musculature.
[0005] Given these implications, small molecule modulators of potassium ion channels could have potentially powerful influence in the modulation and control of numerous consequences of a variety of conditions.
SUMMARY
[0006] Disclosed are compounds and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases associated with the modulation of ion channels, such as potassium ion channels. (See e.g., Table 2). Such compounds include those of structural Formula I:
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, R4a, R4b, X1, X2, and A are defined and described herein.
[0007] Compounds described herein, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with the modulation of potassium channels. Such diseases, disorders, or conditions include those described herein.
BRIEF DESCRIPTION OF THE FIGURES
[0001] FIG. 1 is a diagram illustrating the effect of Compound 359 following oral (PO) dosing on harmaline induced tremor.
[0008] FIG. 2 is a diagram illustrating the %SK2 SCioo of Compound 359 compared with chlorzoxazone (CHZ).
DETAILED DESCRIPTION
General Description of Compounds of the Invention
[0009] In certain embodiments provided herein is a compound of Formula I:
Figure imgf000003_0002
or a pharmaceutically acceptable salt thereof, wherein: selected from "(R2)P (R2)n
Figure imgf000004_0001
Figure imgf000004_0002
X1 is selected from C(Ra) and N;
X2 is selected from C(Rb) and N, wherein X1 and X2 are not simultaneously nitrogen; each of Ra and Rb is independently selected from hydrogen, halo, -CN, optionally substituted C1-C4 alkyl, optionally substituted -0-(Ci-C4 alkyl), -OH, -NH2, optionally substituted -NH(Ci-C4 alkyl), optionally substituted -N(Ci-C4 alkyl)2, optionally
substituted -S-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
each R1, if present, is independently selected from halo, -CN, optionally
substituted -Ci-C6 alkyl, optionally substituted -0-(Ci-C4 alkyl), optionally
substituted -NH(Ci-C4 alkyl), optionally substituted -N(Ci-C4 alkyl)2, optionally
substituted -S-(Ci-C4 alkyl), optionally substituted -S(0)-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
each R is independently selected from halo, -CN, optionally substituted C3-C6 cycloalkyl, optionally substituted -Ci-C6 alkyl, optionally substituted -0-(Ci-C4 alkyl), optionally substituted -NH(Ci-C4 alkyl), optionally substituted -S-(Ci-C4 alkyl), optionally substituted -S(0)-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
R3 is selected from halo, -C(=0)NH2, -OH, -CN, -(C0-C4 alkylene)- carbocyclyl, -(C0-C4 alkylene)-heteroaryl, -(C0-C4 alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, -N(R6)-carbocyclyl, -N(R6)-heterocyclyl, -N(R6)-heteroaryl, -N(R6)-aryl, - 0(Co-C4 alkyl)carbocyclyl, -0(Co-C4 alkylene)heterocyclyl, -0(Co-C4 alkylene)heteroaryl, - 0(Co-C4 alkylene)aryl, -S(Co-C4 alkylene)carbocyclyl, -S(Co-C4 alkylene)heterocyclyl, - S(Co-C4 alkylene)heteroaryl, -S(Co-C4 alkylene)aryl, -S(0)(Co-C4 alkylene)carbocyclyl, - S(0)(Co-C4 alkylene)heterocyclyl, -S(O)(C0-C4 alkylene)heteroaryl, -S(O)(C0-C4 alkylene)aryl, -S(0)2(Co-C4 alkylene)carbocyclyl, -S(0)2(Co-C4 alkylene)heterocyclyl, - S(O)2(C0-C4 alkylene)heteroaryl, -S(O)2(C0-C4 alkylene)aryl, -0-(Ci-C4 alkyl), -NH(Ci-C4 alkyl), -S-(Ci-C4 alkyl), -S(0)-(Ci-C4 alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, alkylene, and alkyl are optionally substituted; or R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl;
R4a is selected from fluoro and -CF3;
R4b is selected from hydrogen and fluoro;
R5 is selected from hydrogen and optionally substituted Q-C4 alkyl;
each R6 is independently selected from hydrogen and optionally substituted C1-C4 alkyl;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
n is 1, 2 or 3;
o is 1 or 2; and
p is 1, 2, 3 or 4,
provided the com ound of Formula I is not
Figure imgf000005_0001
, or a pharmaceutically acceptable salt thereof.
2. Compounds and Definitions
[0010] The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -CI), bromine (bromo, -Br), and iodine (iodo, -I).
[0011] The term "alkyl" used alone or as part of a larger moiety, such as "alkoxy", "haloalkyl", "aralkyl", "heteroaralkyl" and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1-6 carbon atoms, i.e., (Ci-C6)alkyl. As used herein, a "(Ci-C6)alkyl" group is means a radical having from 1 to 6 carbon atoms in a linear or branched arrangement.
[0012] The term "haloalkyl" includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.
[0013] "Alkoxy means an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(Ci-C4)alkoxy" includes methoxy, ethoxy, proproxy, and butoxy.
[0014] The term "aryl" used alone or as part of a larger moiety as in "aralkyl",
"aralkoxy", or "aryloxyalkyl", refers to an aromatic monocyclic or bicyclic carbon ring system having, unless otherwise specified, a total of 6 to 14 ring members. The term "aryl" may be used interchangeably with the term "aryl ring", "aryl group", "aryl moiety," or "aryl radical". Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic carbon ring is fused to one or more carbocyclyl rings, e.g.,
tetrahydronaphthalenyl. In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but is not limited to, phenyl (abbreviated as "Ph"), naphthyl and the like. It will be understood that when specified, optional substituents on an aryl group (e.g., in the case of an optionally substituted aryl or aryl which is optionally substituted) may be present on any substitutable position, i.e., any ring carbon substituted with hydrogen.
[0015] The term "carbocyclyl" (also referred to herein as "carbocycle" or
"cycloaliphatic", as used herein, means a monocyclic, bicyclic (e.g., a bridged or spiro bicyclic ring), polycyclic (e.g., tricyclic), or fused hydrocarbon ring system that is completely saturated or that contains one or more units of partial unsaturation, but where there is no aromatic ring. Cycloalkyl is a completely saturated carbocycle. Monocyclic carbocyclyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bridged bicyclic carbocyclyl groups include, without limitation, bicyclo[3.2.1]octane, bicyclo[2.2.1]heptane, bicyclo[3.1.0]hexane, and the like. Spiro bicyclic carbocyclyl groups include, e.g., spiro[3.6]decane, spiro[4.5]decane, and the like. Fused carbocyclyl rings include, e.g., decahydronaphthalene, octahydropentalene, and the like. It will be understood that when specified, optional substituents on a carbocyclyl (e.g., in the case of an optionally substituted carbocyclyl or carbocyclyl which is optionally substituted) may be present on any substitutable position and, include, e.g., the position at which the carbocyclyl group is attached.
[0016] The term "heteroaryl" used alone or as part of a larger moiety as in
"heteroarylalkyl", "heteroarylalkoxy", or "heteroarylaminoalkyl", refers to a 5- 10 -membered aromatic radical containing 1-4 heteroatoms selected from N, quaternary ammonium cation, O, and S, and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, pyrrolopyridinyl, quinolyl, quinazolinyl, and quinoxalinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position (carbon and nitrogen).
[0017] The term "heterocyclyl" means a 3- 12 membered (e.g., a 4-, 5-, 6- and 7- membered) saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be mononcyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. The terms "heterocycle", "heterocyclyl",
"heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl,
dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, 3- azabicyclo[3.1.0]hexanyl, 2-oxa-6-azaspiro[3.3]heptanyl, l-azaspiro[4.5]decane, and tetrahydropyrimidinyl. The term "heterocyclyl" also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole,
imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (e.g., in the case of an optionally substituted heterocyclyl or heterocyclyl which is optionally substituted).
[0018] The term "spiro" refers to two rings that share one ring atom (e.g., carbon).
[0019] The term "fused" refers to two rings that share two adjacent ring ring atoms.
[0020] The term "bridged" refers to two rings that share at least three ring atoms.
[0021] As described herein, compounds herein may contain "optionally substituted" moieties. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent that results in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
[0022] In one embodiment, suitable substituents for an optionally substituted alkyl, carbocyclyl, heterocyclyl, aryl group and heteroaryl group are those which do not substantially diminish the potassium ion channel activity of the compound. Examples include halogen, CN, -ORc, -NRdRe, -S(0)iRc, -NRcS(0)2Rc, -S(0)2NRdRe, -C(=0)ORc, -OC(=0)ORc,- OC(=0)Rc, -
OC(=S)ORc, -C(=S)ORc, -0(C=S)Rc, -C(=0)NRdRe, -NRcC(=0)Rc, -C(=S)NRdRe, -NRCC(= S)RC, -NRc(C=0)ORc, -0(C=0)NRdRe, -NRc(C=S)ORc, -0(C=S)NRdRe, -NRc(C=0)NRdRe, - NRc(C=S)NRdRe, -C(=S)RC, -C(=0)Rc, (Ci-C6)alkyl, cycloalkyl, -(CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4-heterocyclyl, aryl, -NHC(=0)-heterocyclyl, -NHC(=0)-cycloalkyl, - (CH2)i-4-aryl, heteroaryl or -(CH2)i-4-heteroaryl, wherein each of said (Ci-C6)alkyl, cycloalkyl, -(CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4-heterocyclyl, aryl, -(CH2)i-4-aryl, heteroaryl and -(CH2)i-4-heteroaryl are optionally substituted with halogen,
ORc, -N02, -CN, -NRcC(=0)Rc, -NRdRe, -S(0)kRc, -C(=0)ORc, -C(=0)NRdRe, -C(=0)Rc, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkoxy, and halo(Ci- C3)alkoxy, wherein Rc is hydrogen or (Ci-C6)alkyl optionally substituted with 1 to 3 halogen; Rd and Re are each independently selected from hydrogen and (Ci-C6)alkyl; and k is 0, 1 or 2. Suitable substituents for optionally substituted alkyl, carbocyclyl, and heterocyclyl also include =0.
[0023] In another embodiment, suitables substituents are selected from halo, - NHC(=0)0(Ci-C4 alkyl), -NHC(=0)-Ci-C4 alkyl, -CN, -NHC(=0)-cyclobutyl, -NHC(=0)- oxetanyl, C=0, -C(=0)NRdRe, -C(=0)Rc, ORc, -C(=0)ORc, -NRdRe, or (Ci-C4)alkyl optionally substituted with -C(=0)ORc or ORc, wherein Rc is hydrogen or (Ci-C4)alkyl optionally substituted with 1 to 3 halogen; and Rd and Re are each independently selected from hydrogen and (Ci-C4)alkyl.
[0024] As used herein the terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.
[0025] The terms "treatment," "treat," and "treating" refer to reversing, alleviating, reducing the likelihood of developing, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
[0026] The term "effective amount" or "therapeutically effective amount" includes an amount of a compound described herein that will elicit a biological or medical response of a subject.
[0027] Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror images are not superimpo sable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center.
"Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that contain two or more
asymmetrically substituted carbon atoms. "Geometric isomer" are stereoisomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a carbocyclyl ring, or to a bridged bicyclic system.
[0028] "Racemate" or "racemic mixture" means a compound of equimolar quantities of two enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane of polarized light.
[0029] The compounds of the invention may be prepared as individual enantiomers by either enantio-specific synthesis or resolved from an enantiomeric ally enriched mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an enantiomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the enantiomers of an enantiomeric pair using an optically pure acid, amine or alcohol (followed by
chromatographic separation and removal of the chiral auxiliary), or resolving an enantiomeric mixture of either a starting material or a final product using various well known
chromatographic methods.
[0030] When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. Percent by weight pure relative to all of the other stereoisomers is the ratio of the weight of one stereoisiomer over the weight of the the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight optically pure. Percent optical purity by weight is the ratio of the weight of the enantiomer over the weight of the enantiomer plus the weight of its optical isomer.
[0031] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight pure relative to all of the other stereoisomers. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
[0032] When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has one chiral center, it is to be understood that the name or structure encompasses one enantiomer of compound free from the corresponding optical and geometric isomer, a racemic mixture of the compound, and mixtures enriched in one enantiomer relative to its corresponding optical isomer.
[0033] When a disclosed compound is named or depicted by structure without indicating the stereochemistry and e.g, the compound has at least two chiral centers, it is to be understood that the name or structure encompasses one stereoisomer free of other
stereoisomers, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers is enriched relative to the other stereoisomer(s). For example, the name or structure may encompass one stereoisomer free of other diastereomers, mixtures of stereoisomers, and mixtures of stereoisomers in which one or more diastereomers is enriched relative to the other diastereomer(s).
[0034] With respect to the generic Formula I, la, II, III, IV, V, VI, and VII, unless otherwise specified, one or more hydrogens can be replaced by deuterium. Isotopic enrichments include e.g., at least 10%, 25%, 50%, 75%, 80%,85%, 90&, 95%, 87%, 98%, 99.0%, 99.5% and 99.8%". In one embodiment, all hydrogen atoms represented in Formula I, la, II, III, IV, V, VI, and VII are present in natural abundance. With respect to specific compounds disclosed herein, such as those in Table 1 and in the Exemplification section, all hydrogen atoms are present in natural abundance unless otherwise specified.
[0035] The compounds described herein may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides,
hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.
3. Description of Exemplary Compounds
[0036] In a first embodiment, the resent disclosure provides a compound of Formula I:
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.
[0037] In a second embodiment, the compound of Formula I is of the Formula la:
Figure imgf000011_0002
or a pharmaceutically acceptable salt thereof, wherein the variables in Formula la are as described in Formula I. [0038] In a third embodiment, the compound of Formula I or Formula la is of the Formula II or III:
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof, wherein the variables in Formula II and III are as described in Formula I. In one alternative to the second embodiment, the optional substituents for each occurrence of an optionally group for the compounds of Formulas I, la, II, or III are 1 to 3 groups independently selected from R as defined in the sixth
embodiment.
[0039] In a fourth embodiment, R in Formulas I, la, II, or III is selected from - C(=0)NH2, -(C0-C4 alkylene)-heteroaryl, -(C0-C4 alkylene)-aryl, -N(R6)-carbocyclyl, -N(R6)- heterocyclyl, -N(R6)-heteroaryl, -N(R6)-aryl, -O(C0-C4 alkylene)carbocyclyl, -O(C0-C4 alkylene)heterocyclyl, -0(Co-C4 alkylene)heteroaryl, -0(Co-C4 alkylene)aryl, -S(Co-C4 alkylene)carbocyclyl, -S(Co-C4 alkylene)heterocyclyl, -S(Co-C4 alkylene)heteroaryl, -S(Co-C4 alkylene)aryl, -S(0)(Co-C4 alkylene)carbocyclyl, -S(0)(Co-C4 alkylene)heterocyclyl, - S(0)(Co-C4 alkylene)heteroaryl, -S(O)(C0-C4 alkylene)aryl, -S(O)2(C0-C4
alkylene)carbocyclyl, -S(0)2(Co-C4 alkylene)heterocyclyl, -S(0)2(Co-C4 alkylene)heteroaryl, -S(0)2(Co-C4 alkylene)aryl, -NH(Ci-C4 alkyl), -S-(Ci-C4 alkyl), -S(0)-(Ci-C4
alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, Ci-C4 alkylene, and Ci-C4 alkyl are optionally substituted, and wherein said (Ci-C6)alkyl is substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)-0-(Ci-C4 alkyl), -NHC(=0)-(Ci-C4 alkyl), -CN, -NHC(=0)-cycloalkyl, -NHC(=0)-heterocyclyl, -OH, or -0(Ci-C4 alkyl); or R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl, wherein the remaining variables are as described in Formula I or the second or third embodiment.
[0040] In a fifth embodiment, R in Formulas I, la, II, or III is selected from - C(=0)NH2, -(C0-C4 alkylene)-heteroaryl, -(C0-C4 alkylene) -aryl, -O(C0-C4
alkylene)carbocyclyl, -0(Co-C4 alkylene)heterocyclyl, -0(Co-C4 alky lene)hetero aryl, -O(C0- C4 alkylene)aryl, -S(Co-C4 alkylene)carbocyclyl, -S(Co-C4 alkylene)heterocyclyl, -S(Co-C4 alkylene)heteroaryl, -S(Co-C4 alkylene)aryl, -S(0)(Co-C4 alkylene)carbocyclyl, -S(0)(Co-C4 alkylene)heterocyclyl, -S(0)(Co-C4 alkylene)heteroaryl, -S(0)(Co-C4 alkylene)aryl, - S(O)2(C0-C4 alkylene)carbocyclyl, -S(O)2(C0-C4 alkylene)heterocyclyl, -S(O)2(C0-C4 alkylene)heteroaryl, -S(O)2(C0-C4 alkylene)aryl, -S-(Ci-C4 alkyl), -S(0)-(Ci-C4
alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each of said heterocyclyl, carbocyclyl, heteroaryl, aryl, Ci-C4 alkylene, and Ci-C4 alkyl are optionally substituted, and wherein said (Ci-C6)alkyl is substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)-0-(Ci-C4 alkyl), NHC(=0)-(Ci-C4 alkyl), -CN, -NHC(=0)-cycloalkyl, -NHC(=0)-heterocyclyl, -OH, or - 0(Ci-C4 alkyl); or R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl, wherein the remaining variables are as described in Formula I or the second, third or fourth embodiment.
[0041] In a sixth embodiment, each of said heterocyclyl, heteroaryl, carbocyclyl, aryl, d- C4 alkylene, and Ci-C4 alkyl for R in the first, second, third, or fourth embodiment are
7 7 optionally substituted with 1 to 3 groups independently selected from R , where R is halogen,
CN, -ORc, -NRdRe, -S(0)iRc, -NRcS(0)2Rc, -S(0)2NRdRe, -C(=0)ORc, -OC(=0)ORc,- OC(=0)Rc, -
OC(=S)ORc, -C(=S)ORc, -0(C=S)Rc, -C(=0)NRdRe, -NRcC(=0)Rc, -C(=S)NRdRe, -NRCC(= S)RC, -NRc(C=0)ORc, -0(C=0)NRdRe, -NRc(C=S)ORc, -0(C=S)NRdRe, -NRc(C=0)NRdRe, - NRc(C=S)NRdRe, -C(=S)RC, -C(=0)Rc, (Ci-C6)alkyl, cycloalkyl, -(CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4-heterocyclyl, aryl, -(CH2)i-4-aryl, heteroaryl or -(CH2)i-4-heteroaryl, wherein each of said (Ci-C6)alkyl, cycloalkyl, -(CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4- heterocyclyl, aryl, -(CH2)i-4-aryl, heteroaryl and -(CH2)i-4-heteroaryl for R are optionally substituted with halogen,
ORc, -N02, -CN, -NRcC(=0)Rc, -NRdRe, -S(0)kRc, -C(=0)ORc, -C(=0)NRdRe, -C(=0)Rc, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy(Ci-C3)alkyl, (Ci-C3)alkoxy, and halo(Ci- C3)alkoxy; or two instances of R7 are taken together on the same atom to form =0; Rc is hydrogen or (Ci-C6)alkyl optionally substituted with 1 to 3 halogen; Rd and Re are each independently selected from hydrogen and (Ci-C6)alkyl; and k is 0, 1 or 2, wherein the remaining variables are as described in Formula I or the second, third, fourth, or fifth embodiment.
[0042] In a seventh embodiment, R in Formulas I, la, II, or III is selected from 1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5- dihydro-l,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 3 groups selected from R ; 2) -S-(C1-C2 alkyl), -0-(C1-C2 haloalkyl), - C(=0)NH2, -(Ci-C2 alkylene)-morpholinyl, -(C1-C2 alkylene)-piperazinyl, -0(C1-C2 alkylene)azetidinyl, -0(C1-C2 alkylene)triazolyl, -0(C1-C2 alkylene)pyrrolidinyl, -0(C1-C2 alkylene)oxadiazole, -0(C1-C2 alkylene)thiomorpholinyl, -0(C1-C2
alky lene)thiomorpholinyl- 1,1 -dioxide, -0(C1-C2 alkylene)oxazolyl, -0(C1-C2
hydroxyalkylene)oxazolyl, -0(C1-C2 alkylene)phenyl, and -0(C1-C2 alkylene)cyclobutyl each of said morpholinyl, piperazinyl, azetidinyl, triazolyl, pyrrolidinyl, oxadiazole,
thiomorpholinyl, thio morpholinyl- 1,1 -dioxide, oxazolyl, phenyl, and eye lo butyl being optionally substituted with 1 to 3 groups selected from R ; and 3) (Ci-C4)alkyl substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)0(Ci-C4 alkyl), -NHC(=0)-C1-C4 alkyl, - CN, -NHC(=0)-cyclobutyl, -NHC(=0)-oxetanyl, -OH, or -0(Ci-C4 alkyl); R7 is
halo, -C(=0)NRdRe, -C(=0)Rc, ORc, -C(=0)ORc, -NRdRe, or (Ci-C4)alkyl optionally substituted with -C(=0)ORc or ORc; or two instances of R7 are taken together on the same atom to form =0; Rc is hydrogen or (Ci-C4)alkyl optionally substituted with 1 to 3 halogen; Rd and Re are each independently selected from hydrogen and (Ci-C4)alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, or sixth embodiment.
[0043] In an eighth embodiment, R in Formulas I, la, II, or III is selected from 1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5- dihydro- 1,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 2 groups selected from R ; 2) -S-(C1-C2 alkyl), -0-(C1-C2 haloalkyl), - C(=0)NH2, -(Ci-C2 alkylene)-morpholinyl, -(C1-C2 alkylene)-piperazinyl, -0(Ci-C2 alky lene) azetidinyl, -0(Ci-C2 alkylene)triazolyl, -0(Ci-C2 alkylene)pyrrolidinyl, -0(Ci-C2 alkylene)oxadiazole, -0(Ci-C2 alkylene)thiomorpholinyl, -0(Ci-C2
alky lene)thio morpholinyl- 1,1 -dioxide, -0(Ci-C2 alkylene)oxazolyl, -0(Ci-C2
hydroxyalkylene)oxazolyl, -0(Ci-C2 alkylene)phenyl, and -0(Ci-C2 alkylene)cyclobutyl, each of said azetidinyl, triazolyl, pyrrolidinyl, oxadiazole, phenyl, and cyclobutyl being optionally substituted with 1 to 2 groups selected from R ; and 3) (Ci-C4)alkyl substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)0-Ci-C4 alkyl, -NHC(=0)-C1-C4 alkyl, - CN, -NHC(=0)-cyclobutyl, -NHC(=0)-oxetanyl, -OH, or -0(Ci-C4 alkyl), wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, or seventh embodiment.
[0044] In a ninth embodiment, R in Formulas I, la, II, or III is independently selected from halo, -CN, -0(Ci-C4 alkyl), Ci-C4 alkyl, C3-C4 cycloalkyl, cyanoCi-C4 alkyl, haloCi-C4 alkyl, and hydroxyCi-C4 alkyl, wherein the remaining variables are as described in Formula I or Formula la, or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
Alternatively, R in Formulas I, la, II, or III is independently selected from chloro, bromo, fluoro, -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2OH, -CH2CH3, -
CH2CN, -CH(CH3)CH3, -CH(CH3)OH, -C((CH3)2)OH, -OCH3, and cyclopropyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
[0045] In a tenth embodiment, each of n, o, and p in Formulas I, la, II, or III is 1 or 2, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment.
[0046] In an eleventh embodiment, each of Ra and Rb in Formula I or Formula la is independently selected from hydrogen and Ci-C4 alkyl, or wherein R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered, nitrogen-containing heterocyclyl, wherein the remaining variables are as described in
Formula I or the fourth, fifth, sixth, seventh, eighth, ninth, or tenth embodiment.
[0047] In a twelfth embodiment, Ra in Formula I or Formula la is selected from hydrogen, methyl, and ethyl; or Ra and R3 are taken together with the atoms they are attached form an optionally substituted piperidinyl or an optionally substituted lH-imidazolyl, wherein the remaining variables are as described in Formula I or Formula la, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment. In one alternative, the piperidinyl or lH-imidazolyl in the eleventh embodiment is optionally substituted at a ring nitrogen, wherein the remaining variables are as described in Formula I or Formula la, or the fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.
[0048] In a thirteenth embodiment, R in Formulas I, la, II, or III is selected from halo, -CN, alkyl, -NH-(Ci-C6 alkyl), alkyl-NH(R7), -C(0)NH(R7), carbocyclyl,
heterocyclyl, -O-heterocyclyl, -NH-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene- carbocyclyl, -NH-alkylene-carbocyclyl, and -NH-alkylene-heterocyclyl, or R is taken together with Ra to form an optionally substituted heterocyclyl, wherein R7 is selected from hydrogen and Ci-C4 alkyl; and any alkyl, alkylene, carbocyclyl, or heterocyclyl portion of R is optionally substituted, wherein the remaining variables are as described in Formula I or the second, third, ninth, tenth, eleventh, or twelfth embodiment. Alternatively, R in Formulas I,
Figure imgf000016_0001
remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.
[0049] In a fourteenth embodiment, R5 in Formulas I, la, II, or III is selected from hydrogen, methyl and ethyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.
[0050] In a fifteenth embodiment, R4a and R4b in Formulas I, la, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment. Alternatively, R4a is -CF3 and R4b hydrogen in Formulas I, la, II, or III are simultaneously fluoro, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.
[0051] In a sixteenth embodiment, m in Formulas I, la, II, or III is 0, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth
embodiment.
[0052] In a seventeenth embodiment, R in Formulas I, la, II, or III is selected from:
Figure imgf000018_0001
-S02Me, CH2NH2, and -CH2NMe2, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eig
Figure imgf000018_0002
I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment. In another alternative, R in Formulas I, la, II, or III is selected from:
Figure imgf000019_0001
, and , wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth
embodiment. In yet another alternative, R in Formulas I, la, II, or III is
Figure imgf000019_0002
or , wherein the remaining variables are as described in
Formula I or the second, third, fourth, fifth, sixth, seventh, or eighth embodiment.
[0053] In an eighteenth embodiment, the compound of Formula I, la, II, or III, is of Formula IV or V
Figure imgf000019_0003
or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or seventeenth embodiment. [0054] In a ninteenth embodiment, the compound of Formula I, la, II, or III, is of the Formula VI or VII:
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, or sixteenth embodiment.
twentieth embodiment, ring A in Formulas I, la, II, III, IV, V, VI, or VII is
Figure imgf000020_0002
or 5 wherein the remaining variables are as described in
Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, or nineteenth embodiment. Alternatively, ring A in Formulas I, la, II, III, IV, V, VI, or VII is
Figure imgf000020_0003
, or , wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, or nineteenth embodiment.
[0056] In a twenty-first embodiment, R in Formulas I, la, II, III, IV, V, VI, or VII is independently selected from C1-C4 alkyl, haloCi-C4 alkyl, and hydroxyCi-C4 alkyl, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment. Alternatively, R in Formulas I, la, II, III, IV, V, VI, or VII is independently selected from CH3, CHF2, CH2F, -CH(CH3)OH, and -CH2OH, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, or twentieth embodiment.
[0057] In a twenty- second embodiment, R5 in Formulas I, la, II, III, IV, V, VI, or VII is hydrogen or Ci-C4 alkyl, wherein the remaining variables are as described in Formula I or or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty- first embodiment. Alternatively, R5 in Formulas I, la, II, III, IV, V, VI, or VII is hydrogen, wherein the remaining variables are as described in Formula I or the second, third, fourth, fifth, sixth, seventh, eighth, seventeenth, eighteenth, nineteenth, twentieth, or twenty- first embodiment.
[0058] Specific examples of compounds are provided in Table 1 and Table 2 as well as the EXEMPLIFICATION section and are included as part of a twenty-third embodiment herein. Pharmaceutically acceptable salts as well as the neutral forms of the compounds in Table 1 and the EXEMPLIFICATION are also included.
Table 1
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Table 2 - Continued
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Table 2 - Continued
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
NSSy6514 368.4099
NSSy6473 421 .4208
NSSy6563 406.455
NSSy6435 393.3672
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
NSSy5674 421.5135
NSSy6374 395.4717
NSSy5959 423.4177
NSSy5957 379.4087
NSSy6044 322.421
NSSy5808 402.4466 o
NSSy5934 420.4574
NSSy5972 437.5085
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000116_0002
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Table 2 - Continued
Figure imgf000144_0002
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Table 2 - Continued
Figure imgf000156_0001
Figure imgf000157_0001
4. Uses, Formulation and Administration
Pharmaceutically acceptable compositions
[0059] According to another embodiment, this disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions is such that is effective to measurably modulate potassium channels in a biological sample or in a patient.
[0060] In certain embodiments, a composition described herein is formulated for administration to a patient in need of such composition. In some embodiments, a composition described herein is formulated for oral administration to a patient.
[0061] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
[0062] Pharmaceutically acceptable compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
[0063] Pharmaceutically acceptable compositions described herein may also be prepared in injectable form. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
[0064] Pharmaceutically acceptable compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically- transdermal patches may also be used.
[0065] The amount of compounds described herein that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor, such as e.g., 0.1 - 100 mg/kg body weight/day, can be
administered to a patient receiving these compositions.
[0066] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the composition. Uses of Compounds and Pharmaceutically Acceptable Compositions
[0067] In some embodiments, compounds and compositions described herein are useful in treating diseases and/or disorders associated with the activity of potassium channels. Such diseases and/or disorders include e.g., neurodegenerative and neurological conditions (e.g., Parkinson's disease, tremors, Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS) ataxia, anxiety, depression, mood disorders, memory and attention deficits, bipolar disorder, psychosis, schizophrenia, traumatic brain injury, and narcolepsy), heart disease and realted conditions (e.g., ischaemic heart disease, coronary heart disease, angina pectoris, and coronary artery spasms), metabolic disease and bladder diseases (e.g., bladder spasms, urinary incontinence, bladder outflow obstruction, gastrointestinal dysfunction, irritable bowel syndrome, and diabetes), withdrawal symptoms associated with termination of addiction, and other conditions associated with the modulation of potassium channels such as e.g., respiratory diseases, epilepsy, convulsions, seizures, absence seizures, vascular spasms, renal disorders (e.g., polycystic kidney disease), erectile dysfunction, secretory diarrhoea, ischaemia, cerebral ischaemia, dysmenorrhea, Reynaud's disease, intermittent claudication, Sjorgren's syndrome, arrhythmia, hypertension, myotonic muscle dystrophia, spasticity, xerostomi, hyperinsulinemia, premature labour, baldness, cancer, immune suppression, migraine and pain.
[0068] In one, the present disclosure provides a method of modulating the activity of a potassium channel in a subject comprising the step of administering a compound of Formula I, or a composition comprising any of the compounds herein. In another embodiment, the present disclosure provides a method of positively modulating a SK2 channel in a cell comprising the step of contacting the cell with a compound of Formula I, or a composition comprising any of the compounds herein.
[0069] The present disclosure further provides a method of treating essential tremor in a subject comprising the step of administering a compound or pharmaceutically acceptable salt or composition described herein.
[0070] In some embodiments, the present disclosure provides a method of treating a disease or condition selected from a neurodegenerative disease, dementia, heart disease, withdrawal symptoms associated with termination of addiction, metabolic disease, and bladder disease. In other embodiments, the present disclosure provides a method of treating a disease or condition selected from ataxia, dystonia, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.
[0071] Certain exemplary provided compounds, e.g. , having structural formula I are set forth in the EXEMPLIFICATION section below. In some embodiments, a provided compound is one or more compounds selected from those exemplified in the
EXEMPLIFICATION section below, or a pharmaceutically acceptable salt thereof.
EXEMPLIFICATION
[0072] The representative examples that follow are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples that follow and the references to the scientific and patent literature cited herein. It should further be appreciated that the contents of those cited references are incorporated herein by reference to help illustrate the state of the art.
[0073] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the synthetic methods and Schemes depict the synthesis of certain compounds of the present invention, the following methods and other methods known to one of ordinary skill in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.
[0074] General Synthetic Scheme:
Scheme 1.
Et
Figure imgf000161_0001
Figure imgf000161_0002
[0075] In one aspect, compounds of Formula I can be prepared according to Scheme 1, where the variables R1, R3, R5, R4a, R4b, X1, X2, and A are defined for Formula I. For example, compounds of Formula I can be prepared by reacting a compound of Formula 600 with a compound of Formula 601 in the presence of base, such as, e.g.,
diisopropylethylamine to form intermediate 602. Reduction with e.g., a reducing agent such as lithium aluminum hydride forms a compound of Formula 603. Reaction with a nitrogen atom on ring A affords 604 followed by halogenation with e.g., phosphorous tribromide gives 605. Treatment with amine reagent having the formula R -N in the presence of base, such as e.g., sodium t-butoxide gives 606. Scheme 1 is in no way limiting and represents only one method by which certain compounds described herein can be made. Other methods of making compounds of Formula I would be apparent to one of skill in the art.
PREPARATION OF COMPOUNDS OF FORMULA I
[0076] Compounds of Formula I were prepared according to the general procedures outlined below. [0077] Example 1
Figure imgf000162_0001
[0078] Step 1 [0003]: To a stirred solution of methyl 2,4-dichloropyrimidine-6- carboxylate [0001] (5 g, 24.16 mmol) in acetonitrile (50 mL) was added 4,4- difluorocyclohexylamine hydrochloride [0002] (4.1 g, 24.158 mmol) and N,N-diisopropyl ethylamine (8.8 mL, 50.72 mmol) at rt and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure. To the residue water (25 mL) was added, the solid thus formed was filtered and dried by suction to afford 4 g of crude which was purified by column chromatography using 15% ethyl acetate in pet ether as eluent to afford 2.8 g of methyl 2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxylate [0003] as a white solid. MS(M+l)+=306.0.
[0079] Step 2[0004] : To a stirred solution of methyl 2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate [0003] (0.5 g, 1.635 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium aluminum hydride in
tetrahydrofuran (2 M, 1.63 mL, 3.27 mmol) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (2 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.4 g of crude (2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)methanol [0004] as a brown gum. MS(M+l/M+3)+=278.2/280.2.
[0080] Step 3[0006 and 0007] : To a stirred solution of (2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methanol [0004] (1.7 g, 6.12 mmol) in acetonitrile (20 mL) were added ethyl- lH-pyrazole-3-carboxylate [0005] (0.87 g, 6.12 mmol) and cesium carbonate (2.99 g, 9.18 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was quenched with water (15 mL), acidified with 4 N HC1 solutions (25 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.5 g as a mixture of l-(4- ((4,4-difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-lH-pyrazole-3- carboxylic acid [0006] MS(M+1)+=354.1 and its ethyl ester [0007] MS(M+l)+=382.2.
[0081] Step 4[0007] : To a stirred solution of a mixture of l-(4-((4,4- difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylic acid [0006] and its ester [0007] (3 g, 8.4 mmol) in ethanol (30 mL) was added cone, sulfuric acid (0.923 mL, 16.98 mmol). The reaction mixture was refluxed at 85 °C for 5 h and
concentrated under reduced pressure. The residue was quenched with water (15 mL), neutralized with saturated aqueous sodium bicarbonate solution (20 mL), extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3.3 g of crude which was purified by column chromatography using 65% ethyl acetate in pet ether as eluent to afford 2 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(hydroxymethyl)pyrimidin-2-yl)-lH-pyrazole- 3-carboxylate [0007] as an off-white solid. MS(M+1)+=381.8.
[0082] Step 5[0008]: To a stirred solution of ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 6-(hydroxymethyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0007] (2 g, 5.24 mmol) in dichloromethane (10 mL) was added phosphorus tribromide (1.41 g, 5.24 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with ice cold water (50 mL) and extracted with dichloromethane (2x50 mL). The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 35% ethyl acetate in pet ether as eluent to afford 0.7 g of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] as a white solid. MS(M+l/M+3)+ = 444.2/446.1. [0083] Example 2
Figure imgf000164_0001
[0084] Step 1[0010] : To a stirred solution of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] (0.45 g, 1.01 mmol) in tetrahydrofuran (10 mL) were added 4-isopropyl-2-azetidinone [0009] (0.126 g,) and sodium ie/t-butoxide (0.146 g, 1.52 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 30 min. The reaction mixture was quenched with water (15 mL) and extracted with ethyl acetate (2x50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 28% ethyl acetate in pet ether as eluent to afford ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-((2-isopropyl-4-oxoazetidin-l-yl)methyl)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0010] as an off-white solid (0.28 g). MS(M+l)+= 476.8.
[0085] Step 2[0011]: To a stirred solution of ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 6-((2-isopropyl-4-oxoazetidin-l-yl)methyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate
[0010] (0.28 g, 0.58 mmol) in tetrahydrofuran (5 mL) was added lithium borohydride (0.038 g, 1.76 mmol) at 0 °C. The reaction mixture was stirred at rt for 1.5 h, quenched with ice and extracted with ethyl acetate (2x15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol- l-yl)pyrimidin-4-yl)methyl)-4-isopropylazetidin-2-one [0011] as a white solid (0.220 g). MS(M+1)+ = 434.9.
[0086] Step 3[0012]: To a stirred solution of l-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)methyl)-4-isopropylazetidin-2-one [0011] (0.22 g, 0.506 mmol) in dichloromethane (5 mL) was added diethylamino sulfur trifluoride (0.133 mL, 1.01 mmol) at 0 °C. The reaction mixture was stirred at rt for 15 min, quenched with 10% sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2x20 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude which was purified by column chromatography using 32% ethyl acetate in pet ether as eluent to obtain l-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)-4- isopropylazetidin-2-one [0012], Compound 325 as a white solid (0.037 g).
MS(M+l)+=437.2, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 6.4 Hz, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 4.35 (d, J = 16.8 Hz, 1H), 4.11 (d, J = 16.1 Hz, 2H), 3.59 (s, 1H), 3.55 (m, 1H), 2.92 (dd, J = 14.8, 5.2 Hz, 1H), 2.65 (m, 1H), 2.18 - 1.90 (m, 6H), 1.70 - 1.60 (m, 2H), 0.88 (dd, J = 24 Hz, 6.8 Hz, 6H).
[0087] Ex mple 3
Figure imgf000165_0001
[0088] Step 1[0014]: To a stirred solution of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] (0.5 g, 1.012 mmol) in tetrahydrofuran (5 mL) was added 2-pyrrolidone [0013] (0.478 g, 5.63 mmol) and potassium ie/t-butoxide (0.151 g, 1.351 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 15 min. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x25 mL). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue of was purified by column chromatography using 65% ethyl acetate in pet ether as eluent to afford ethyl l-(4-((4,4-difluorocyclohexyl)arnino)-6-((2-oxopyrrolidin- 1- yl)methyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0014] as a white solid (0.25 g).
MS(M+l)+= 449.3. [0089] Step 2[0015]: The procedure is similar to step 2[0011] in example 2. 0.25 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-((2-oxopyrrolidin-l-yl)methyl)pyrimidin-2-yl)- lH-pyrazole-3-carboxylate [0014] gave 0.2 g of l-((6-((4, 4-difluorocyclohexyl) amino)-2- (3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) methyl) pyrrolidin-2-one [0015] as a brown solid. MS(M+l)+=407.4.
[0090] Step 3[0016]: The procedure is similar to step 3[0012] in example 2. 0.2 g of 1- ((6-((4, 4-difluorocyclohexyl) amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4- yl) methyl) pyrrolidin-2-one [0015] gave 0.035 g of l-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)pyrrolidin-2-one [0016],
Compound 321 as a white solid. MS(M+l)+=409.2, 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 6.66 (dd, J = 2.6, 1.3 Hz, 1H), 6.20 (s, 1H), 5.45 (d, JF = 48.0 Hz, 2H), 4.27 (s, 2H), 4.18 (bs, 1H), 3.42 (t, J = 6.84 Hz, 2H), 2.33 (t, J = 8.0 Hz, 2H), 2.15 - 1.90 (m, 8H), 1.65-1.5 (m, 2H).
[0091] Example 4
Figure imgf000166_0001
[0092] Step 1[0018]: To a stirred solution of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] (0.5 g, 1.126 mmol) in acetonitrile (10 mL) were added 3,5-dimethyl pyrazole [0017] (0.119 g, 1.23 mmol) and cesium carbonate (0.550 g, 1.69 mmol). The reaction mixture was irradiated in microwave at 100 °C for 1 h, added water (10 mL) and extracted with ethyl acetate (2x15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using 55% ethyl acetate in pet ether as eluent to afford 0.23 g of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-((3,5-dimethyl- IH-pyrazol- l-yl)methyl)pyrimidin-2-yl)- 1H- pyrazole-3-carboxylate [0018] as an off-white solid. MS(M+l)+ = 460.2.
[0093] Step 2[0019] : To a stirred solution of ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 6-((3,5-dimethyl-lH-pyrazol-l-yl)methyl)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0018] (0.220 g, 0.478 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium aluminium hydride in tetrahydrofuran (478 mL, 2 M, 0.957 mmol) at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (3 mL) and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford N-(4,4- difluorocyclohexyl)-6-((3,5-dimethyl- IH-pyrazol- l-yl)methyl)-2-(3-(fluoromethyl)- 1H- pyrazol-l-yl)pyrimidin-4-amine [0019] as an off-white solid (0.2 g). MS(M+1)+=418.2.
[0094] Step 3[0020] : The procedure is similar to step 3 [0012] in example 2. 0.2 g of N- (4,4-difluorocyclohexyl)-6-((3,5-dimethyl- IH-pyrazol- l-yl)methyl)-2-(3-(fluoromethyl)- 1H- pyrazol-l-yl)pyrimidin-4-amine [0019] gave 0.036 g of N-(4,4-difluorocyclohexyl)-6-((3,5- dimethyl- IH-pyrazol- l-yl)methyl)-2-(3-(fluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-amine [0020], Compound 300 as an off-white solid. MS(M+l)+=420.2/421.2, 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.82 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 5.93 (s, 1H), 5.66 (s, 1H), 5.52 - 5.40 (d, JF = 49.96 Hz, 2H), 5.09 (s, 2H), 4.16 (s, 1H), 2.21 (s, 3H), 2.13 (s, 3H), 2.04 - 1.92 (m, 6H), 1.54-1.51 (m, 2H).
Figure imgf000168_0001
Figure imgf000168_0002
[0096] Step 1[0022]: 0.850 g of ethyl l-(4-(bromomethyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0008] gave 0.830 g of ethyl l-(4-(((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0022] as a white solid. (Potassium tert-butoxide in tetrahydrofuran at rt, 10 min) MS(M+l)+=537.9.
[0097] Step 2[0023]: The procedure is similar to step 2 [0019] in example 4. 0.830 g of ethyl l-(4-(((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0022] gave 0.570 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)methoxy)azetidine-l-carboxylate [0023] as an off-white solid.
MS(M+l)+=494.8.
[0098] Step 3 [0024]: The procedure is similar to step 3 [0012] in example 2. 0.560 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)methoxy)azetidine-l-carboxylate [0023] gave 0.225 g of tert-butyl 3-((6- ((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methoxy)azetidine-l-carboxylate [0024] as a white solid. MS(M+l)+=496.9. [0099] Step 4 [0025] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methoxy)azetidine-l-carboxylate [0024] (0.2 g, 0.402 mmol) in dichloromethane (5 mL) was added trifluoro acetic acid (0.468 mL, 6.042 mmol) at 0 °C and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford 0.180 g of 6-((azetidin-3-yloxy)methyl)-N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-amine [0025] as an off-white solid. MS(M+1)+ = 397.3
[00100] Step 5 [0027] : To a stirred solution of 6-((azetidin-3-yloxy)methyl)-N-(4,4- difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0025] (0.180 g, 0.454 mmol) in dichloromethane (5 mL) were added triethylamine (0.17 mL, 1.20 mmol) and methyl chloroformate (0.180 g, 0.81 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 10 min., partitioned between dichloromethane (10 mL) and water (3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography using 75% ethyl acetate in pet ether as eluent to afford 0.125 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methoxy)azetidine-l-carboxylate [0027], Compound 335 as a white solid.
MS(M+l)+=455.2, 1H-NMR (400 MHz, DMSO-d6): δ 8.61 (s, 1H), 7.85 (d, J = 6.84 Hz, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 5.45 (d, JF = 48.0 Hz, 2H), 4.46 (s, 1H), 4.39 (s, 2H), 4.16- 4.14 (m, 3H), 3.82 (s, 2H), 3.56 (s, 3H) 2.15-1.88 (m, 6H), 1.65-1.5 (m, 2H).
Figure imgf000170_0001
Figure imgf000170_0002
Figure imgf000170_0003
[00102] Step 1[0028] : To a stirred solution of methyl-2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyrimidine-4-carboxylate [0003] (6.6 g, 21.589 mmol) in methanol was added methanolic ammonia (60 mL) at rt. After 2 h the reaction mixture was purged with nitrogen to remove excess ammonia and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and stirred for 10 min. The solid formed was filtered, washed with water (25 mL) and dried under vacuum to afford 2-chloro- 6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxamide [0028] as a white solid (5.5 g MS(M+1)+=291.1) and was taken as such to next step.
[00103] Step 2[0029] : To a suspension of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carboxamide [0028] (5.5 g, 18.92 mmol) in dichloromethane was added triethylamine (9.57 g, 94.6 mmol) and phosphorus oxychloride (7.25 g, 47.3 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h the reaction mixture was quenched with ice (100 g) and extracted with dichloromethane (2x100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to afford 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile [0029] as a pale yellow solid (3.6 g, 70 % yield). MS(M+1)+=273.1.
[00104] Step 3 [0030] : To a solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile [0029] (3.6 g, 13.302 mmol) in tetrahydrofuran was added a solution of lithium aluminium hydride in tetrahydrofuran (9.9 mL, 2M solution, 19.803 mmol) at -15 °C and the reaction mixture was stirred at same temperature. Reaction turned dark brown after LAH addition. After 10 min, the reaction mixture was quenched with saturated aqueous sodium sulfate solution at 0 °C and stirred at rt. The suspension was passed through celite bed, washed with chloroform (50 mL). The filtrate was concentrated under reduced pressure to afford 6-(aminomethyl)-2-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine [0030] as red oil (4.2 g, MS(M+l)+=277.2) and it was taken as such to next step.
[00105] Step 4[0031] : To a solution of 6-(aminomethyl)-2-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine [0030] (4.2 g, 15.178 mmol) in dichloromethane were added triethylamine (2.3 g, 22.76 mmol) and boc-anhydride (3.9 g, 18.213 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with dichloromethane (2x100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford as brown oil, which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to afford te/t-butyl ((2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methyl)carbamate [0031] as a pale yellow solid (2.3 g). MS(M+l)+=377.2.
[00106] Step 5 [0032] : To a solution of tert-butyl ((2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)methyl)carbamate [0031] (4.2 g, 15.178 mmol) and ethyl- lH-pyrazole-3-carboxylate [0005] (4.2 g, 15.178 mmol) in acetonitrile was added cesium carbonate (4.2 g, 15.178 mmol) and the reaction mixture was heated at 85 °C in sealed tube. After 2 h, the reaction mixture was filtered, washed with chloroform (50 mL). The combined filtrate was concentrated under reduced pressure to afford pale brown oil which was purified by column chromatography using 35% ethyl acetate in hexane as eluent to afford ethyl l-(4-(((tert-butoxycarbonyl)amino)methyl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0032] as a pale yellow solid (2.2 g). MS(M+1)+=481.3.
[00107] Step 6[0033]: To a solution of ethyl l-(4-(((tert-butoxycarbonyl)amino)methyl)-6- ((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0032] (2.2 g, 4.578 mmol) in tetrahydrofuran was added a solution of lithium aluminum hydride in tetrahydrofuran (3.43 mL, 2 M, 6.867 mmol) at -20 °C and the reaction mixture was stirred at rt. After 30 min, the reaction mixture was quenched with saturated aqueous sodium sulfate solution at 0 °C and stirred at rt for 10 min. The mixture was passed through celite bed, washed with ethyl acetate (50 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0033] as an off-white solid (1.9 g).
MS(M+1)+=439.1.
[00108] Step 7[0034] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0033] (1.9 g, 4.333 mmol) in dichloro methane was added diethylamino sulfur trifluoride (1.0 g, 6.499 mmol) at - 20 °C and the reaction mixture was stirred at same temperature for 15 min, quenched with saturated aqueous sodium bicarbonate solution at 0 °C and extracted with dichloro methane (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a red solid which was purified by column chromatography using 35% ethyl acetate in hexane as eluent to afford tert-butyl ((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methyl)carbamate[0034] as off-white solid (0.75 g). MS(M+1)+=441.2.
[00109] Step 8[0036] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0034] (0.15 g, 0.340 mmol) in dichloro methane was added dry hydrogen chloride in dioxane (4M) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure and the residue was diluted with dichloro methane (20 mL). To the solution was added triethylamine (- 1.5 mL) at 0 °C followed by acetyl chloride (0.054 g, 0.68 mmol). After 10 min, the reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)acetamide [0036], Compound 327 as an off-white solid (0.055 g). MS(M+l)+=383.2, 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.49 (s, 1H), 7.81 (s, 1H), 6.65 (s, 1H), 6.28 (s, 1H), 5.42 (d, JF = 48 Hz, 2H), 4.13 (bs, 3H), 2.15 -1.90 (m, 9H), 1.62 - 1.45 (m, 2H). [00110] Example 7:
J 0037
Figure imgf000173_0001
0034 0039
[00111] Step l[0038]:To a solution of cyclobutanecarboxylic acid (0.3 g, 2.99 mmol) in dichloromethane was added oxalyl chloride (1.14 g, 8.98 mmol) and N,N-dimethylformamide (0.02 g, 0.3 mmol) at 0 °C and the reaction mixture was stirred rt. After 1 h, the reaction mixture was concentrated under reduced pressure to afford cyclobutanecarbonyl chloride [0038] as brown oil (0.4 g). This was taken as such to next step.
[00112] Step 2[0039]: The procedure is similar to Step 8[0036] in example 6. 0.3 g of tert- butyl ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4- yl)methyl)carbamate[0034] gave 0.098 g of N-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)cyclobutanecarboxamide [0039], Compound 328 as pale brown solid. MS(M+l)+=423.2; 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H), 6.64 (s, 1H), 6.21 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 4.12 (bs, 3H), 3.19 - 3.07 (m, 1H), 2.25 - 2.13 (m, 2H), 2.12 - 1.85 (m, 9H), 1.85 - 1.75 (m, 1H), 1.65 - 1.50 (m, 2H).
[00113] Example 8:
Figure imgf000173_0002
0034 0040 0042
[00114] Step 1[0040] : To a solution of tert-butyl ((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)methyl)carbamate [0034] (0.3 g, 0.68 mmol) in dichloromethane was added 4M HCl in dioxane (5 mL) at 0 °C and the reaction mixture was stirred at rt for 1 h, concentrated under reduced pressure to afford 6- (armnomethyl)-N-(4,4-difluorocy
4-amine [0040] as an off-white solid. This was taken as such to next step.
[00115] Step 2[0042]: To a solution of 3-oxetanecarboxylic acid [0041] (0.140 g, 1.38 mmol) in Ν,Ν-dimethylformamide was added 1-propanephosphonic acid cyclic anhydride ((1.317 g, 2.07 mmol), triethylamine (0.209 g, 2.07 mmol) at 0 °C and the reaction mixture was stirred at rt. After 15 min, 6-(aminomethyl)-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0040] (0.26 g, 0.69 mmol) was added to the reaction mixture at 0 °C and stirred at rt for 16 h. The reaction mixture was quenched with water, extracted with ethyl acetate, washed with water and brine. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil, which was purified in the Reveleris flash system using ethyl acetate in hexane followed by methanol in chloroform as eluents in 12 g column. The product was isolated at 07 % methanol in chloroform as eluent to afford N-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)methyl)oxetane-3-carboxamide, Compound 333 [0042] as a white solid (0.05 g).
MS(M+l)+=425.2; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (bs, 1H), 8.54 (bs, 1H), 7.82 (s, 1H), 6.66 (s, 1H), 6.24 (s, 1H), 5.45 (d, JF = 48 Hz, 1H), 4.69 (d, J = 7.9 Hz, 4H), 4.19 (s, 3H), 3.92 - 3.82 (m, 1H), 2.12 - 1.92 (m, 7H), 1.57 (bs, 2H).
[00116] Exam le 9:
Figure imgf000174_0001
[00117] Step 1[0044]: The procedure is similar to step 1[0003] in Example 1. 1 g of methyl-2,4-dichloropyrimidine-6-carboxylate [0001] gave 1.1 g of methyl 2-chloro-6-((3,3- difluorocyclohexyl)amino)pyrimidine-4-carboxylate [0044] as a white solid.
MS(M+l)+=306.7.
[00118] Step 2[0045]: The procedure is similar to step 3[0004] in Example 1. 1.1 g of methyl 2-chloro-6-((3,3-difluorocyclohexyl)arnino)pyrimidine-4-carboxylate [0044] gave 2 g of 6-((3,3-difluoro cyclohexyl)amino)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidine-4- carboxylic acid [0045] as yellow solid. MS(M-1)"=350.0. This was taken as such to next step.
[00119] Step 3[0046] Compound 350: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylicacid [0045] (1.9 g, 5.407 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.74 g, 21.63 mmol) and N,N-dimethylformamide (0.04 g, 0.54 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure under N2 atm to afford 2.2 g of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5- dimethyl- IH-pyrazol- l-yl)pyrimidine-4-carbonyl chloride. 6-((3,3- difluorocyclopentyl)amino)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidine-4-carbonyl chloride was dissolved in tetrahydrofuran (10 mL) and the reaction mixture was purged with ammonia gas at -10 °C for 15 min. The reaction mixture was concentrated under reduced pressure to afford crude was purified by column chromatography using 6% methanol in chloroform as a solvent to afford 0.4 g of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidine-4-carboxamide (Compound 350) [0046] as an off-white solid.
MS(M+1)+=351.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 7.60 Hz, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 6.97 (s, 1H), 6.09 (s, 1H), 4.09 (bs, 1H), 2.54 (s, 3H), 2.44 (bs, 1H), 2.18 (s, 3H), 2.12 - 1.70 (m, 5H), 1.55 - 1.30 (m, 2H).
[00120] Step 4[0047] Compound 351: To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxamide
[0046] (0.35 g, 0.99 mmol) in dichloromethane was added triethylamine (0.50 g, 4.99 mmol) and trifluoromethanesulfonic anhydride (0.71 g, 2.49 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with chloroform, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale brown solid, was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 24 g column to afford 0.24 g of 6-((3,3- difluorocyclo hexyl)amino)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidine-4-carbonitrile
(Compound 351) [0047] as an off-white solid. MS(M+l)+=333.2. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.12 (s, 1H), 4.07 (bs, 1H), 2.54 (s, 3H), 2.42 - 2.32 (m, 1H), 2.17 (s, 3H), 2.03 - 1.70 (m, 5H), 1.50 - 1.32 (m, 2H).
[00121] Example 10:
Figure imgf000176_0001
0052 0051
[00122] Step 1[0048]: To a solution of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylic acid [0045](0.52 g, 1.48 mmol) in N,N- dimethylformamide (5 mL) was added Ν,Ν-diisopropyl ethylamine (1.28 mL, 7.4 mmol), followed by N,0-dimethylhydroxylamine (0.22 g, 2.22 mmol) hydrochloride and HBTU (0.67 g, 1.776). The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice, extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (20 mL), followed by brine (20 mL), dried over anhydrous sodium sulfate to afford 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-N-methoxy- N-methylpyrimidine-4-carboxamide [0048] as a yellow solid (0.6 g). MS(M+1)+ = 395.0
[00123] Step 2[0049] Compound 352:To a solution of 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N-methoxy-N- methylpyrimidine-4-carboxamide [0045] (0.33 g, 0.836 mmol) in tetrahydrofuran (7 mL) at - 70 °C was added methyl magnesium bromide ((3 M solution in tetrahydrofuran) 2.23 mL, 6.69 mmol) drop wise. The reaction mixture was stirred at rt for 10 min. The reaction mixture was quenched with saturated solution of ammonium chloride (5 mL), extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine(10 mL) and dried over anhydrous sodium sulfate to afford 0.6 g of crude product which was purified by column chromatography using 56% ethyl acetate in pet ether as eluent to afford l-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- 1-one (Compound 352) [0049] of as a white solid (0.150 g). MS(M+l)+=350.2, 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.6 Hz, IH), 6.84 (s, IH), 6.12 (s, IH), 4.13 (s, IH), 2.56 (d, J = 9.1 Hz, 6H), 2.20 (s, 3H), 2.05 - 1.73 (m, 6H), 1.52 - 1.31 (m, 2H).
[00124] Step 3[0050] Compound 353: To a cooled solution of l-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- 1-one [0049] (0.17 g, 0.486 mmol) in methanol (3 mL) was added sodium borohydride (0.018 g, 0.486 mmol). The reaction mixture was stirred at rt for 10 min, concentrated under reduced pressure, dissolved in water (5 mL), neutralized with 1.5 N HC1 solutions (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate to afford l-(6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- l-ol
(Compound 353) [0050] as a white solid (0.160 g). MS(M+l)+=352.2, 1H-NMR (400 MHz, DMSO-d6): δ 7.70 (s, IH), 6.51 (s, IH), 6.03 (s, IH), 5.36 (s, IH), 4.46 (s, IH), 4.07 (s, 2H), 3.32 (m, IH), 2.16 (s, IH), 1.99 (s, 3H), 1.95-1.91 (m, 3H), 1.80-1.73 (m, 5H), 1.44-1.38 (m, 2H), 1.34-1.28 (m, 5H),
[00125] Step 4[0051 and 0052] Compound 354 and 355: The isomers were separated by Supercritical Fluid Chromatography (SFC) to afford 0.040 g of (+)-l-(6-(((S)-3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- l-ol
(Compound 354) [0051] as a yellow solid MS(M+l)+=352.2, 1H-NMR (400 MHz, DMSO- d6): δ 7.70 (d, J = 6.76 Hz, IH), 6.51 (s, IH), 6.03 (s, IH), 5.36 (d, J = 4.12 Hz, IH), 4.46 (t, J = 5.36 Hz, IH), 4.07 (bs, 1H),2.56 (s, 2H), 2.49 - 2.48 (m, IH), 2.16 (s, 3H), 2.10 - 1.56 (m, 6H), 1.50 -1.49 (m, IH), 1.48 -1.35 (m, 4H). and (-)-l-(6-(((S)-3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)ethan- l-ol
(Compound 355) [0052] as a yellow solid. MS(M+l)+=352.2, 1H-NMR (400 MHz, DMSO- d6): δ 7.70 (bs, IH), 6.51 (s, IH), 6.03 (s, IH), 5.36 (s, IH), 4.46 (bs, IH), 4.07 (bs, 2H), 3.32 (m, IH), 2.48 - 2.47 (m, IH), 2.16 (s, 2H), 2.01 - 1.99 (m, 3H), 1.99-1.56 (m, 4H), 1.56 -1.49 (m, IH), 1.49 -1.30 (m, 4H). [00126] Example 11:
Figure imgf000178_0001
0045 0053 0054
[00127] Step 1[0053]: Concentrated sulfuric acid (5 mL, 93.80 mmol) was added to a solution of 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine- 4-carboxylicacid [0045] (1.1 g, 3.130 mmol) in ethanol (20 mL), after addition the reaction mixture was heated at 75 °C for 5 h, concentrated under reduced pressure, diluted with water (20 mL), cooled to 5 °C, basified with solid sodium carbonate till pH~ 10 and extracted with ethyl acetate (2x100 mL). The combined organic layers were washed with brine (3 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford 1.2 g of ethyl 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4- carboxylate. This was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford ethyl 6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carboxylate [0053] as a yellow solid (0.660 g). MS(M+l)+=380.0
[00128] Step 2[0054] Compound 356:To a solution of ethyl 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylate
[0053] (0.15 g, 0.395 mmol) in tetrahydrofuran (2 mL), was added methyl magnesium bromide (3 M solution in tetrahydrofuran) 0.32 mL, 0.988 mmol)) drop- wise at 0 °C after addition the reaction mixture was stirred at rt for 3 h. The reaction mixture was cooled to 0 °C and quenched with (1.5 N) HC1 solutions (5 mL). It was then extracted with ethyl acetate (2 x 30 mL). The combined organic layer was washed with water (20 mL), followed by brine (20 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by preparative HPLC to afford 2-(6-((3,3-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)propan-2-ol (Compound 356) [0054] as an off-white solid (0.070 g). MS(M+l)+=366.2, 1H NMR (400 MHz, DMSO-d6) δ 7.68 (bs, 1H), 6.64 (s, 1H), 6.04 (s, 1H), 5.18 (s, 1H), 4.10 (bs, 1H), 2.48 (s, 3H), 2.58 - 2.45 (m, 1H), 2.17 (s, 3H), 2.08 - 1.89 (m, 2H), 1.89 - 1.65 (m, 3H), 1.55 - 1.43 (m, 1H), 1.37 (s, 6H), 1.33 - 1.29 (m, 1H). [00129] Examp
Figure imgf000179_0001
[00130] Step 1[0055]: Compound 357 To a solution of ethyl 6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylate
[0053] (220 g, 0.579 mmol) in tetrahydrofuran (6 mL), was added lithium aluminium hydride (2 M solution in tetrahydrofuran, 0.579 mL, 1.159 mmol) drop-wise at -78 °C, after addition the reaction mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with saturated solution of ammonium chloride solution (10 mL). It was then extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (10 mL), followed by brine and dried over anhydrous sodium sulfate to afford (6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)methanol
(Compound 357) [0055] as an off- white solid (0.150 g). MS(M+l)+=338.2, 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 7.6 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.45 (t, J = 5.8 Hz, 1H), 4.35 (d, J = 5.6 Hz, 2H), 4.07 (s, 1H), 2.40 (s, 1H), 2.16 (s, 4H), 2.04 - 1.91 (m, 2H), 1.88 - 1.69 (m, 3H), 1.46 (d, J = 13.6 Hz, 1H), 1.35 (d, J = 7.7 Hz, 1H).
[00131] Example 1
Figure imgf000179_0002
0055 0056
[00132] Step 1[0056] Compound 358: To a solution of (6-((3,3- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)methanol [0055] (0.1 g, 0.296 mmol) in dichloromethane (10 mL) was added diethylamino sulfur trifluoride (0.095 g, 0.592 mmol) drop-wise at 0 °C, after addition the reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with 10 % sodium bicarbonate solution (15 mL) to afford crude product which was purified by preparative HPLC to afford N-(3,3-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)-6-(fluoromethyl)pyrimidin-4-amine (Compound 358) [0056] as a yellow solid (0.050 g). MS(M+l)+=340.2, 1H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 7.5 Hz, IH), 6.43 (s, IH), 6.07 (s, IH), 5.31 (d, JF = 46.3 Hz, 2H), 4.09 (bs, IH), 2.53 (s, 3H), 2.49 - 2.40 (m, IH), 2.16 (s, 3H), 2.08 - 1.92 (m, 2H), 1.92 - 1.65 (m, 3H), 1.55 - 1.25 (m, 2H).
[00133] Example 14:
Figure imgf000180_0001
0058 0059
[00134] Step 1[0057]: The procedure is similar to step 3[0006] in example 1. 2.2 g of methyl 2-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidine-4-carboxylate [0003] gave 2.8 g of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylic acid [0057] as a yellowish solid. MS(M+l)+=352.0.
[00135] Step 2[0058]: The procedure is similar to step 4[0007] in example 1, 0.9 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4-carboxylic acid [0057] gave 0.71 g of methyl 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carboxylate [0058] as an yellow solid. MS(M+l)+=366.2.
[00136] Step 3 [0059] The procedure is similar to step 2[0049] in example 10. 0.65 g of methyl 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0058] gave 0.13 g of 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)propan-2-ol [0059], Compound 152. MS(M+l)+=366.2, 1H- NMR (400 MHz, DMSO-d6): δ 7.62 (s, IH), 6.64 (s, IH), 6.03 (s, IH), 5.17 (s, IH), 4.05 (bs, IH), 2.56 (s, 3H), 2.15 (s, 3H), 2.07-1.94 (m, 6H), 1.58-1.55 (m, 2H), 1.37 (s, 6H). [00137] Example 15:
Figure imgf000181_0001
0058 0060 0061 0062
[00138] Step 1[0060 and 0061] Lithium aluminum hydride (2M THF solution, 31.62 mmol) was added drop- wise at -78 °C to a solution of ethyl 6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylate
[0058] (6 g, 15.814 mmol) in tetrahydrofuran (85 mL). After addition the reaction mixture was stirred at -78 °C for 3 h, quenched with water (25 mL) and extracted with ethyl acetate (3x500 mL). The combined organic layer was washed with brine (3x300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford mixture an which was purified by column chromatography using 50% ethyl acetate in pet ether as eluent to afford of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidine-4-carbaldehyde [0060] as an yellow solid (1.2 g MS(M+l)+=338.0) and (6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)methanol [0061], Compound 137 as an yellow solid (2.1 g). MS(M+l)+=336.2, 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.7 Hz, 1H), 6.52 (s, 1H), 6.04 (s, 1H), 5.44 (t, J = 5.9 Hz, 1H), 4.35 (d, J = 5.6 Hz, 2H), 4.04 (bs, 1H), 2.56 (s, 3H),2.16 (s, 3H), 2.10 - 1.85 (m, 6H), 1.65 - 1.56 (m, 2H).
[00139] Step 2[0062]: The procedure is similar to step 3 [0012] in example 2. 0.25 g of (6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)methanol [0061] gave 0.05 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- (fluoromethyl)pyrimidin-4-amine [0062], Compound 165 as an off-white solid.
MS(M+l)+=340.2, 1H-NMR (400 MHz, DMSO-d6): δ 7.83 (d, J = 6.96 Hz, 1H), 6.41 (s, 1H), 6.05 (s, 1H), 5.30 (d, JF = 46.3 Hz, 2H), 4.04 (bs, 1H), 2.52 (s, 3H), 2.14 (s, 3H), 2.07- 1.94 (m, 6H), 1.57-1.54 (m, 2H), [00140] Example 16:
Figure imgf000182_0001
[00141] Step 1[0063]: The procedure is similar to step 2[0049] in example 10. 2.8 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0060] gave 0.48 g of racemate l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0063], as an off-white solid.
MS(M+l)+=352.2, 1H-NMR (400 MHz, DMSO-d6): δ 7.64 (d, J = 7.20 Hz, IH), 6.53 (s, IH), 6.03 (s, IH), 5.37 (s, IH), 4.34 (bs, IH), 4.10 (bs, IH), 2.13 (s, 3H), 2.06 - 1.85 (m, 6H), 1.65 - 1.49 (m, 2H), 1.39-1.22 (m, 6H).
[00142] Step 2[0064 and 0065]: 0.48 g of l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [63] was purified by chiral preparative HPLC to afford 0.12 g of (-)l-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0064], Compound 198 as an off-white solid.
MS(M+l)+=352.2. SOR: -9.5°, solvent-methanol, concentration = 0.2, Temp-27.5 °C. 1H- NMR (400 MHz, DMSO-d6): δ 7.67 (d, J = 7.48 Hz, IH), 6.54 (s, IH), 6.04 (s, IH), 5.39 (s, IH), 4.47 (s, IH), 4.05 (bs, IH), 2.52 (s, 3H), 2.16 (s, 3H), 2.06-1.94 (m, 6H), 1.58-1.55 (m, 2H), 1.31 (d, J = 0.60 Hz, 3H), and 0.12 g of (+)l-(6-((4,4-difluorocyclohexyl)amino)-2- (3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0065], Compound 199 as an off- white solid. MS(M+l)+=352.2. SOR: +2.5, Solvent-methanol, Concentration=0.200, Temp- 27.3 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.4 Hz, IH), 6.54 (s, IH), 6.04 (s, IH), 5.39 (s, IH), 4.47 (bs, IH), 4.05 (bs, IH), 2.52 (s, 3H), 2.17 (s, 3H), 2.17 - 1.85 (m, 6H), 1.65 - 1.57 (m, 2H), 1.33 (d, J = 6.6 Hz, 3H).
[00143] Example 17:
Figure imgf000182_0002
[00144] Step 1[0066]: The procedure is similar to step 3 [0012] in example 2. 0.21 g of 6- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [11] gave 0.06 g of N-(4,4-difluorocyclohexyl)-6-(difluoromethyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0066], Compound 142 as an off-white solid. MS(M+l)+=358.2, 1H-NMR (400 MHz, DMSO-d6): δ 8.10 (d, J = 7.04 Hz, 1H), 6.77 (t, JF = 54.7 Hz, 1H), 6.60 (s, 1H), 6.10 (s, 1H), 4.08 (bs, 1H), 2.56 (s, 3H), 2.16 (s, 3H), 2.12 - 1.88 (m, 6H), 1.62-1.53 (m, 2H).
[00145] Exam le 18:
Figure imgf000183_0001
0060 0068
[00146] Step 1[0068]: To a solution of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carbaldehyde [0060] (0.35 g, 1.043 mmol) and morpholine [0067] (0.09 g, 1.047 mmol) in tetrahydrofuran (15 mL), was added
titanium(IV)isopropoxide (0.61 g, 2.08 mmol) at 0 °C. After addition the reaction mixture was stirred at rt for 4 h, cooled to 0°C, added ethanol (4 mL) and sodium borohydride in portions. After 16 h the reaction mixture was concentrated under reduced pressure and the residue was basified with sodium bicarbonate solution (25 mL) till pH~ 10, extracted with ethyl acetate (3x100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column
chromatography using 2% methanol in chloroform as eluent to afford of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethy 1-1 H-pyrazo 1-1 -yl)-6-(morpho lino methyl)pyrimidin-4- amine [0068], Compound 176 as an off-white solid (0.042 g). MS(M+l)+=407.2, 1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 7.4 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 4.03 (bs, 1H), 3.62 (t, J = 4.7 Hz, 4H), 3.38 (s, 2H), 2.48 (s, 3H), 2.45 (s, 4H), 2.16 (s, 3H), 2.15 - 1.88 (m, 6H), 1.65 - 1.56 (m, 2H). [00147] Exam le 19:
Figure imgf000184_0001
[00148] Step 1 [0069]: To a solution of (6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)methanol [0061] (1.4 g, 4.14 mmol) in
dichloromethane (55 mL) was added carbon tetrabromide (1.5 g, 4.564 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (25 mL) and extracted with dichloromethane (2x300 mL). the combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol- l-yl)pyrimidin-4-amine [0069] as a brownish gum (1.25 g). MS(M+1 and
M+3)+=400.2/402.2
[00149] Step 2 [0071] NSSY5107.0001: 0.4 g of 6-(bromomethyl)-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0069] and N,N- dimethylamine [0070] (0.18 g, 3.99 mmol) in tetrahydrofuran was heated at 80 °C to afford 0.028 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazo 1-1 -yl)-6- ((dimethylamino)methyl)pyrimidin-4-amine [0071], Compound 177 as an off-white solid. MS(M+l)+=365.2, 1H NMR (400 MHz, Chloroform-d) δ 6.44 (s, 1H), 5.99 (s, 1H), 5.21 (bs, 1H), 3.89 (bs, 1H), 3.54 (s, 2H), 2.63 (s, 3H), 2.36 (s, 6H), 2.31 (s, 3H), 2.15 - 2.07 (m, 4H), 1.99 - 1.83 (m, 2H), 1.72 - 1.55 (m, 2H).
[00150] Exam le 20:
Figure imgf000184_0002
0069 0073
[00151] Step 1 [0073]: 0.35 g of 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0069] and 1-methylpiperazine [0072] (0.096 g, 0.9618 mmol) in acetonitrile was added triethylamine (2 eq) and stirred at rt to afford 0.04 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-6-((4-methylpiperazin- 1- yl)methyl)pyrimidin-4-amine [0073], Compound 178 as an off-white solid.
MS(M+1)+=420.1, 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 7.5 Hz, IH), 6.49 (s, IH), 6.04 (s, IH), 4.03 (s, IH), 3.37 (s, 2H), 2.56 (s, 3H), 2.39 (bs, 8H), 2.19 (s, 3H), 2.16 (s, 3H), 2.11 - 1.88 (m, 6H), 1.65 - 1.56 (m, 2H).
[00152] Example 21:
Figure imgf000185_0001
0069 0074
[00153] Step 1[0074]: Sodium methoxide (0.33 g, 6.24 mmol) was added to a solution of 6-(bromomethyl)-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0069] (1.25 g, 3.122 mmol) in methanol (60 mL). After addition the reaction mixture was stirred at rt for 48 h, concentrated under reduced pressure, added saturated ammonium chloride solution (25 mL) and extracted with ethyl acetate (3x300 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude and which was purified by preparative HPLC to afford N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- (methoxymethyl)pyrimidin-4-amine [0074] as an off-white solid (0.71 g). MS(M+l)+=352.0,
1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 7.6 Hz, IH), 6.43 (s, IH), 6.05 (s, IH), 4.30 (s, 2H), 4.04 (bs, IH), 3.40 (s, 3H), 2.52 (s, 3H), 2.16 (s, 3H), 2.12 - 1.88 (m, 6H), 1.62 - 1.56
(m, 2H).
[00154] Example 22.
Figure imgf000186_0001
[00155] Step 1[0076]: The procedure is similar to step 1[0003] in example 1. 2.0 g of methyl 2,6-dichloropyrimidine-4-carboxylate [0001] gave 2.56 g of methyl 2-chloro-6-((3,3- difluorocyclopentyl)amino)pyrimidine-4-carboxylate [0076] as a pale brown solid.
MS(M+l)+=292.
[00156] Step 2[0077]: The procedure is similar to step 3[0006] in example 1. 2.0 g of methyl 2-chloro-6-((3,3-difluorocyclopentyl)arnino)pyrimidine-4-carboxylate [0076] gave 2.1 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4- carboxylic acid [0077] as a yellow solid. MS(M+l)+=338.
[00157] Step 3[0078]: To a solution of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylic acid [0076] (0.5 g, 1.482 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.313 g, 3.70 mmol) and N,N- dimethylformamide (0.010 g, 0.148 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 1 h and concentrated under reduced pressure under N2 atm to afford 0.56 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carbonyl chloride. 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carbonyl chloride (0.51 g, 1.40 mmol) was dissolved in tetrahydrofuran (10 mL) and purged with ammonia gas at -10 °C for 15 min. The reaction mixture was then concentrated under reduced pressure to afford crude which was purified by column chromatography using 6% methanol in chloroform as a eluent to afford 6-((3,3-difluorocyclopentyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxamide [33], Compound 183 as a pale brown solid (0.21 g). MS(M+l)+=337, 1H NMR (400 MHz, DMSO-d6): δ 8.27 (d, = -6.80 Hz, IH), 7.81 (s, IH), 7.70 (s, IH), 6.97 (s, IH), 6.09 (s, IH), 4.49-4.50 (m, IH), 2.58-2.67 (m, 4H), 2.21-2.32 (m, 7H), 1.92-1.82 (m, IH),
[00158] Step 4[0079]: The procedure is similar to Step 4[0047] in example 09. 0.18 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carboxamide [0078] gave 0.1 g of 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carbonitrile [0079], Compound 184 as an off-white solid.
MS(M+1)+=319, 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 2.4 Hz, IH), 6.90 (s, IH), 6.09 (s, IH), 4.46 (bs, IH), 2.80-257 (m, IH), 2.55(s, 3H), 2.35-2.28 (m 2H), 2.18(s, 3H), 2.11-2.20 (m, 2H), 1.87 - 1.70 (m, IH).
[00159] Example 23:
Figure imgf000187_0001
[00160] Step 1[0080] : The procedure is similar to step 4[0007] in example 1. 2.1 g of 6- ((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4-carboxylic acid [0077] gave 1.56 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carboxylate [0080] as a yellow gummy solid. MS(M+l)+=366.
[00161] Step 2[0081]: The procedure is similar to step 2[049] in example 10. 0.25 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0080] gave 0.03 g of 2-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)propan-2-ol [0081], Compound 214 as a yellow solid.
MS(M+l)+=352, 1H NMR (400 MHz, DMSO-d6) δ 7.87 (bs, IH), 6.64 (s, IH), 6.05 (s, IH), 5.20 (s, IH), 4.49 (bs, IH), 2.59 (m, 2H), 2.34 - 2.30 (m, IH), 2.29 (s, 3H), 2.28-2.00 (m, 3H) 1.75 (m, IH), 1.38 (s, 3H), 1.37 (s, 3H), 1.23 (m, 2H).
162] Example 24:
[00163] Step 1[0082]: The procedure is similar to step 2 [0019] in Example 4. 0.18 g of ethyl 6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidine-4- carboxylate [0080] gave 0.04 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)methanol [0082], Compound 192 as a white solid.
MS(M+l)+=324, 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 7.0 Hz, IH), 6.51 (s, IH), 6.04 (s, IH), 5.45 (t, J = 5.8 Hz, IH), 4.46 (bs, IH), 4.36 (d, J = 5.8 Hz, 2H), 2.58 (s, 3H), 2.37 - 2.19 (m, 2H), 2.16 (s, 3H), 2.35-1.98 (m, 3H), 1.75 (m, IH).
[00164] Step 2 [0083] :0.3 g of (6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)methanol [0082] gave 0.3 g of 6-((3,3- difluorocyclopentyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carbaldehyde [0083] as a yellow solid (using Dess-Martin periodinane (2 eq) in dichloro methane).
MS(M+l)+=322.
[00165] Step 3 [0084] The procedure is similar to step 3[0012] in example 2. 0.2 g of 6- ((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0083] gave 0.02 g of N-(3,3-difluorocyclopentyl)-6-(difluoromethyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0084], Compound 168 as a white solid. MS(M+l)+=344, 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (d, J = 6.80 Hz, IH), 6.78 (t, JF = 54.40 Hz, IH), 6.61 (s, IH), 6.11 (s, IH), 4.47-4.53 (m, IH), 2.67-2.68 (m, IH), 2.52 (s, 3H), 2.22-2.34 (m, 7H), 1.92-1.85 (m, IH),
[00166] Example 25:
Figure imgf000188_0001
[00167] Step 1[0085]: The procedure is similar to step 2[049] in example 10. 0.22 g of 6- ((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidine-4- carbaldehyde [0083] gave 0.05 g of l-(6-((3,3-difluorocyclopentyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol [0085], Compound 225 as a pale yellow solid. MS(M+l)+=338, 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, IH), 6.54 (s, IH), 6.05 (s, IH), 5.39 (d, J = 4.6 Hz, IH), 4.49 (d, J = 6.9 Hz, 2H), 2.65 - 2.55 (m, 2H), 2.35 - 2.22 (m, 2H), 2.16 (s, 3H), 2.17 (s, 3H) 1.75 (s, IH), 1.33 (d, J = 6.7 Hz, 3H), 1.23 (d, J = 3.8 Hz, IH). [00168] Example 26:
Figure imgf000189_0001
1
[00169] Step 1[0087A and 0087B] : To a solution of 2,4-dichloro-6-methylpyrimidine [0086] (5 g, 30.67 mmol) in tetrahydrofuran (20 mL) was added 4,4- difluorocyclohexylamine hydrochloride [0002] (5.26 g, 30.67 mmol) and cesium carbonate (19.9 g, 61.3 mmol), then the reaction mixture was heated at 60 °C for 16 h. the reaction mixture was filtered to remove cesium carbonate, the filtrate was concentrated under reduced pressure to afford as an yellow gum and which was purified by column chromatography silica gel (60-120 mesh) using 40% ethyl acetate in pet ether as a eluent to afford 3.5 g of 2-chloro- N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] as an off-white solid and 2.8 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine
[0087B]. MS(M+l)+ =262.
[00170] Step 2[0088]: The procedure is similar to Step3 [0515] in example 188. 2.5 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 1.5 g of 4- ((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0088] at 80 °C for 16 h using sodium cyanide (1.1 eq), DABCO (1.1 eq) in dimethylsulfoxide. MS(M+1)+ =243.
[00171] Step 3[0089]: The procedure is similar to Step4 [0516] in example 188. 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0088] gave 1.5 g of 4-((4,4-difluoro cyclohexyl)amino)-6-methylpyrimidine-2-carbothioamide [0089] using ammonium sulfide (3 eq), triethylamine (2 eq) in Ν,Ν-dimethylformamide. MS(M+1)+ =287. [00172] Step 4[0091]: To a solution of 4-((4,4-difluoro cyclohexyl)amino)-6- methylpyrimidine-2-carbothioamide [0089] (1.5 g, 5.23 mmol) in ethanol (15 niL) was added bromoacetone (0.86 g, 6.28 mmoll.), then the reaction mixture was stirred at rt in a closed vial for 16 h. the reaction mixture was concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh) using 3% methanol in chloroform as eluent to afford as an off-white solid 0.700 g, as an HBr salt, which was dissolved in saturated bicarbonate solution and extracted with ethyl acetate (2x70 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under high vacuum to afford 0.41 g of N-(4,4-difluorocyclohexyl)-6-methyl-2-(4-methylthiazol-2-yl)pyrimidin-
4-amine [0091], Compound 231 as an off-white solid. MS(M+l)+ =325, 1H NMR (400 MHz, DMSO-d6) δ 7.52 (bs, 1H), 7.39 (d, J = 1.1 Hz, 1H), 6.35 (bs, 1H), 4.01 (bs, 1H), 2.43 (s, 3H), 2.29 (s, 3H), 2.07-1.95 (m, 6H), 1.59-1.52 (m, 2H).
[00173] Example 27:
Figure imgf000190_0001
0087A 0092
[00174] Step 1[0092]: The procedure is similar to step 3 [0006] in Example 1. 4 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 2.6 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine
[0092], Compound 247 as white solid. MS(M+l)+=322.2, 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 6.03 (s, 1H), 4.01 (bs, 1H), 2.48 (s, 3H), 2.23 (s, 3H), 2.15 (s, 3H), 2.13 - 1.85 (m, 6H), 1.62 - 1.47 (m, 2H).
[00175] Example 28:
Figure imgf000190_0002
0087A 0094 [00176] Step 2[0094]: The procedure is similar to step 3 [0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.26 g of l-(4- ((4,4-difluorocyclohexyl)amino)-6-methyl pyrimidin-2-yl)-lH-pyrazole-3-carbonitrile
[0094], Compound 212 as white solid. MS(M+1)+=319.2, 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.81 (s, 1H), 7.19 (s, 1H), 6.32 (s, 1H), 4.16 (bs, 1H), 2.28 (s, 3H), 2.19 - 1.86 (m, 6H), 1.60 - 1.45 (m, 2H).
[00177] Example 29:
Figure imgf000191_0001
0087A 0096
[00178] Step 1[0096]:. The procedure is step 3[0006] in Example 1. 0.3 g of 2-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.21 g of 2-(3- cyclopropyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine
[0096], Compound 203 as off-white solid. MS(M+l)+=334.4, 1H NMR (400 MHz, DMSO- d6) δ 8.42 (s, 1H), 7.55 (s, 1H), 6.19 (s, 2H), 4.13 (bs, 1H), 2.25 (s, 3H), 2.14 - 1.92 (m, 7H), 1.65 - 1.45 (m, 2H), 1.01 - 0.87 (m, 2H), 0.79 - 0.63 (m, 2H).
[00179] Example 30:
Figure imgf000191_0002
[00180] Step 1[0098]: The procedure is step 3[0006] in Example 1. 0.3 g of 4-chloro-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-2-amine [0087B] gave 0.14 g of N-(4,4- difluorocyclohexyl)-4-methyl-6-(3-methyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0098],
Compound 120 as a white solid. MS(M+l)+=308, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (bs, 1H), 7.35 (bs, 1H), 6.86 (s, 1H), 6.38 (d, J = 2.6 Hz, 1H), 3.99 (d, J = 9.8 Hz, 1H), 2.29 (s, 3H), 2.26(s, 3H), 2.10 - 1.87 (m, 6H), 1.68-1.50 (m, 2H). [00181] Example 31:
Figure imgf000192_0001
0086 0099 0100 0101
[00182] Step 1[0099] : To a stirred solution of 2,4-Dichloro-6-methylpyrimidine [0086] (5 g, 30.674 mmol) in tetrahydrofuran (50 mL) was added sodium thiomethoxide (2.14 g, 30.67 mmol) in portions at -10 °C under nitrogen. The mixture was stirred at -10 °C for 3 h. The solid precipitate was filtered, washed with methanol (20 mL) and dried under vacuum to afford 2-chloro-4-methyl-6-(methylthio)pyrimidine [0099] as an yellow solid (5 g).
MS(M+1)+=175.
[00183] Step 2[0100]: The procedure is step 3[0006] in Example 1. 2.5 g of 2-chloro-4- methyl-6-(methylthio)pyrimidine [0099] gave 3.0 g of 4-methyl-2-(3-methyl-lH-pyrazol-l- yl)-6-(methylthio) pyrimidine [0100] as a yellow liquid. MS(M+1)+=221.
[00184] Step 3[0101]: The procedure is similar to step 2[0378] in example 145. 3.0 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylthio) pyrimidine [0100] gave 1.3 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylsulfonyl)pyrimidine [0101] as a yellow solid using 3-chloroperbenzoic acid (3 eq) in dichloromethane. MS(M+l)+=253.
[00185] Example 32:
Figure imgf000192_0002
[00186] Step 1[0102]: To a solution of 4-methyl-2-(3-methyl-lH-pyrazol-l-yl)-6- (methylsulfonyl)pyrimidine [0101] (0.1 g, 0.396 mmol) in dry tetrahydrofuran (8 mL) was added 3,3-difluoro-N-methylcyclopentan-l-amine [0075] (0.096 g, 0.792 mmol) under N2 atm. The reaction mixture was heated at 100 °C in sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude and which was purified by column chromatography using 30% ethyl acetate in hexane as a eluent to afford N-(3,3- difluorocyclopentyl)-6-methyl-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine, Compound 150 as a white solid (0.04 g). MS(M+l)+=294, 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.79 (bs, 1H), 6.28 (d, J = 2.5 Hz, 1H), 6.2 (bs, 1H), 4.51 (bs, 1H), 2.67-2.58 (m, 1H), 2.24 (s, 3H), 2.24 (s, 3H), 2.20 (m, 2H), 2.10-2.06 (m, 2H), 1.77-1.74 (m, 1H).
[00187] Example 35:
Figure imgf000193_0001
0101 0108
[00188] Step 1[0108]: The procedure is similar to step 1[0106] in example 34. 0.15 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylsulfonyl)pyrimidine [0101] gave 0.08 g of N- ((lR,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)-6-methyl-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-amine [0108], Compound 245 as an off-white solid. MS(M+l)+=306, 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.65 (bs, 1H), 6.30 (d, J = 2.6 Hz, 1H), 6.16 (bs, 1H), 4.36 (bs, 1H), 2.45-2.30 (m, 2H), 2.28 - 2.12 (m, 2H), 2.25 (s, 3H), 2.21 (s, 3H) 1.91 (bs, 2H).
[00189] Example 38:
Figure imgf000193_0002
0101 01 14
[00190] Step 1[0114]: The procedure is similar to step 1[0102] in example 32. 0.12 g of 4- methyl-2-(3-methyl-lH-pyrazol-l-yl)-6-(methylsulfonyl)pyrimidine [0101] gave 0.06 g of 6- methyl-2-(3-methyl-lH-pyrazol-l-yl)-N-(4-(trifluoromethyl)cyclohexyl)pyrimidin-4-amine [0114], Compound 144 as a yellow solid. MS(M+l)+=340, 1H NMR (400 MHz, DMSO-d6) δ 8.42 (bs, 1H), 7.50 (bs, 1H), 6.27 (d, J = 2.5 Hz, 1H), 6.15 (bs, 1H), 3.89 (bs, 1H), 2.58 (bs, 1H), 2.44 (s, 3H), 2.42 (s, 3H), 2.10-1.95 (m, 2H), 1.91 (d, J = 12.2 Hz, 2H), 1.50 - 1.37 (m, 2H), 1.36-1.20 (m, 2H). [00191] Example 39:
Figure imgf000194_0001
0087A 01 15
[00192] Step 1[0115]: The procedure is similar to step 3 [0006] in example 1. 2.0 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.9 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0115], Compound 148 as an off-white solid. MS(M+l)+=308, 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (bs, IH), 7.79 (bs, IH), 6.29-6.19 (m, 2H), 4.13-4.08 (m, IH), 2.25 (s, 3H), 2.24 (s, 3H), 2.05-1.95 (m, 6H), 1.60-1.54 (m, 2H).
[00193] Example 40:
Figure imgf000194_0002
0087A 01 17
[00194] Step 1[0117]: The procedure is similar to step 3[0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.18 g of N- (4,4-difluorocyclohexyl)-6-methyl-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- amine [0117], Compound 200 as an off-white solid. MS(M+l)+=362.0, 1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 2.5 Hz, IH), 7.57 (d, J = 7.6 Hz, IH), 6.90 (d, J = 2.7 Hz, IH), 6.40 (s, IH), 4.04 (bs, IH), 2.33 (s, 3H), 2.13 - 1.94 (m, 6H), 1.65 (qd, J = 12.2, 11.3, 4.3 Hz, 2H). [00195] Example 41:
Figure imgf000195_0001
[00196] Step 1[0119]: The procedure is similar to step 3 [0006] in example 1. 0.2 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.12 g of N- (4,4-difluorocyclohexyl)-2-(4-fluoro-3,5-dimethyl- lH-pyrazol-l-yl)-6-methylpyrimidin-4- amine [0119], Compound 201 as a white solid. MS(M+l)+=340.2, 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 7.6 Hz, 1H), 6.22 (s, 1H), 4.00 (s, 1H), 2.48 (s, 3H), 2.34 - 2.14 (m, 6H), 2.12 - 1.88 (m, 6H), 1.55 (t, J = 11.5 Hz, 2H).
[00197] Example 42:
Figure imgf000195_0002
[00198] Step 1[0121]: The procedure is similar to The procedure is similar to step 3 [0006] in example 1. 0.300 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.220 g of 3-ethyl pyrazole [0120] gave 0.08 g of N-(4,4-difluorocyclohexyl)- 2-(3-ethyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0121], Compound 197 as an white solid, MS(M+l)+=336. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (bs, 1H), 7.56 (bs, 1H), 6.34 (d, J = 2.5 Hz, 1H), 6.20 (bs, 1H), 4.14 (s, 1H), 2.63 (q, J = 7.6 Hz, 2H), 2.26 (s, 3H), 2.12 - 1.91 (m, 6H), 1.60-1.52 (m, 2H), 1.21 (t, J = 7.7 Hz, 3H). [00199] Example 43:
Figure imgf000196_0001
[00200] Step 1[0123]: The procedure is similar to step 3[0006] in example 1. 0.300 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] and 0.148 g of 4- fluoro pyrazole [0122] gave 0.150 g of N-(4,4-difluorocyclohexyl)-2-(4-fluoro-lH-pyrazol-l- yl)-6-methylpyrimidin-4-amine [0123], Compound 196 as an light yellow solid,
MS(M+1)+=312. 1H NMR (400 MHz, DMSO-d6) δ 8.64 (bs, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.66 (bs, 1H), 6.23 (bs, 1H), 4.17 (bs, 1H), 2.26 (s, 3H), 2.10-1.95 (m, 6H), 1.60-1.52 (s, 2H).
[00201] Example 44:
Figure imgf000196_0002
0087A 0125
[00202] Step 1[0125]: The procedure is similar to step 3[0006] in example 1. 0.15 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.1 g of 2-(l- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)acetonitrile [0125], Compound 208 as a white solid. MS(M+1)+=333.1, 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.68 (s, 1H), 6.50 (d, J = 2.6 Hz, 1H), 6.24 (s, 1H), 4.11 (s, 3H), 2.28 (s, 3H), 2.01 (d, J = 42.1 Hz, 6H), 1.56 (s, 2H). [00203] Example 45:
Figure imgf000197_0001
[00204] Step 1[0127]: To a mixture of 4,4-difluorocyclohexanone [0126] (2 g, 14.911 mmol), ethylamine (1.34 g, 29.82 mmol) and acetic acid (2.68 g, 44.73 mmol) in 1,2- dichloroethane under N2 atmosphere was added sodium triacetoxyborohydride (6.32 g, 29.82 mmol) portion wise at 0°C. The resultant reaction mixture was slowly warmed to rt. After 16 h, the reaction mixture was basified with 1 N sodium hydroxide solution and extracted with 10% methanol in chloroform. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-ethyl- 4,4-difluorocyclohexan-l -amine [0127], as brown oil. (1.5 g, 63% yield), MS(M+1)+=164.2. This is taken as such to next step.
[00205] Step 2[0128A & 0128B]: The procedure is similar to step 1[0106] in example 34 (75 °C, acetonitrile). 1.2 g of 2,4-dichloro-6-methylpyrimidine [0127] gave 0.6 g of 2-chloro- N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-4-amine [0128A] as white solid and 0.28 g of 4-chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-2-amine [0128B] as yellow solid. MS(M+l)+=290.3.
[00206] Step 3[0129]: The procedure is similar to step 3[0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-4-amine [0128A] gave 0.17 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-N-ethyl-6-methylpyrimidin- 4-amine [0129], Compound 161 as yellow gum. MS(M+l)+=350.4. 1H NMR (400 MHz, DMSO-d6) δ 6.52 (bs, 1H), 6.05 (s, 1H), 4.58 (bs, 1H),3.43 (bs, 2H), 2.53 (s, 3H), 2.32 (s, 3H), 2.17 (s, 3H), 2.15 - 1.85 (m, 4H), 1.83 - 1.73 (m, 4H), 1.14 (t, J = 6.9 Hz, 3H).
[00207] Step 4[0130]:. The procedure is similar to step 3 [0006] in Example 1. 0.2 g 4- chloro-N-(4,4-difluorocyclohexyl)-N-ethyl-6-methylpyrimidin-2-amine [0128B] gave 0.08 g of N-(4,4-difluorocyclohexyl)-4-(3,5-dimethyl- lH-pyrazol- l-yl)-N-ethyl-6- methylpyrimidin-2-amine [0130], Compound 160 as yellow gum. MS(M+l)+=350.4. 1H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 1H), 6.14 (s, 1H), 4.64 (bs, 1H), 3.49 (q, J = 6.9 Hz, 2H), 2.66 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H), 2.12 (bs, 2H), 2.05 - 1.75(m, 6H), 1.14 (t, J = 6.9 Hz, 3H).
[00208] Example 46
Figure imgf000198_0001
0087A 0132
[00209] Step 1[0132] : To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.3 g, 1.146 mmol) in acetonitrile (10 mL) was added 3- bromo-5-methyl-lh-pyrazole (0.276 g, 1.719 mmol) and cesium carbonate (0.74 g, 2.29 mmol). The reaction mixture was irradiated in microwave at 150 °C for 2 h. The reaction mixture was filtered to remove cesium carbonate. Filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford 0.400 g of 2-(3-bromo-5-methyl-lH-pyrazol-l- yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0132], Compound 220 as an off-white solid. MS(M+l)+= 386.0. 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J = 7.7 Hz, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 4.04 (s, 1H), 2.55 (s, 3H), 2.24 (s, 3H), 2.07 - 1.92 (m, 6H), 1.59 - 1.53 (m, 2H).
[00210] Exampl
Figure imgf000198_0002
0132 0134
[00211] Step 1[0134]: To a stirred solution of 2-(3-bromo-5-methyl-lH-pyrazol-l-yl)-N- (4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0132] (0.25 g, 0.647 mmol) in dioxane (5 mL), was added cyclopropylboronic acid [0133] (0.111 g, 1.29 mmol) and potassium phosphate tribasic (0.274 g, 1.29 mmol). The reaction mixture was degassed for 10 min, added l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.026 g, 0.032 mmol) and irradiated in microwave at 110 °C for 2 h. After completion the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.021 g of 2-(3-cyclopropyl-5-methyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0134], Compound 221 as an off-white solid. MS(M+l)+=348.2, 1H NMR (400 MHz, DMSO-d6): δ 7.52 (d, J = 7.64 Hz, 1H), 6.20 (m, 1H), 5.90 (s, 1H), 3.98 (m, 1H), 2.30 (s, 3H), 1.93 (s, 3H), 1.84-1.91 (m, 6H), 1.50-1.57 (m, 2H), 0.88 (t, J = 6.40 Hz, 2H), 0.85 (t, J = 4.48 Hz, 2H).
[00212] Example 48:
O O
Figure imgf000199_0001
[00213] Step 1[0064]: To a stirred solution of hexane-2, 4-dione [0135] (1 g, 8.760 mmol) in ethanol (25 mL) was added hydrazine hydrate (0.526 g, 10.51 mmol) drop-wise. The reaction mixture was refluxed at 85 °C for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) washed with water (20 mL). The organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.8 g of 3-ethyl-5-methyl-lH-pyrazole [0136] as colorless liquid. MS(M+1)+=110.8.
[00214] Step 2[0137]: To a stirred solution of 3-ethyl-5-methyl-lH-pyrazole [0136] (0.5 g, 4.53 mmol) in acetonitrile (5 mL), was added 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.59 g, 2.269 mmol) and cesium carbonate (1.47 g, 4.53 mmol). The reaction mixture was irradiated in microwave at 140 °C for 2 h, filtered to remove cesium carbonate and washed several times with chloroform (3x20 mL). The solvent was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.050 g of N-(4,4-difluorocyclohexyl)-2-(3-ethyl-5-methyl-lH- pyrazol-l-yl)-6-methyl pyrimidin-4-amine [0137], Compound 249 as an off-white solid
[MS(M+1)+ = 336.0. 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 7.20 Hz, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 4.02 (s, 1H), 2.56 - 2.54 (m, 2H), 2.56 (s, 3H), 2.33 (s, 3H), 2.17-1.88 (m, 6H), 1.59-1.51 (m, 2H), 1.17 - 1.85 (t, J = 7.20 Hz, 3H) and 0.065 g of N-(4,4- difluorocyclohexyl)-2-(5-ethyl-3-methyl-lH-pyrazol-l-y^
[0138], Compound 260 as an off-white solid MS(M+l)+=336.0/337.0. 1H NMR (400 MHz, DMSO-d6) δ 7.55 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 6.06 (s, 1H), 3.98 (s, 1H), 3.01 - 2.95 (q, J = 7.44 Hz, 2H), 2.24 (s, 3H), 2.17 (s, 3H), 2.08 - 1.87 (m, 6H), 1.58 - 1.53 (m, 2H), 1.17 (t, J = 7.4 Hz, 3H).
[00215] Example 50:
Figure imgf000200_0001
[00216] Step 1[0143]: The procedure is similar to step 3[0006] in example 1. 0.250 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 0.210 g of 3- isopropyl-lH-pyrazole [0142] gave 0.200 g of N-(4,4-difluorocyclohexyl)-2-(3-isopropyl- lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0143], Compound 218 as an off-white solid which was purified by prep HPLC. MS(M+l)+=336, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.66 (s, 1H), 6.39 (d, J = 2.7 Hz, 1H), 6.21 (bs, 1H), 4.15 (s, 1H), 3.00-2.95 (m, 1H), 2.27 (s, 3H), 2.14 - 1.88 (m, 6H), 1.60-1.52 (m, 2H), 1.24 (d, J = 6.9 Hz, 6H).
[00217] Ex mple 51:
Figure imgf000200_0002
[00218] Step 1[0144]: The procedure is similar to step 1[0003] in example 1. 0.3 g of 2,4- dichloro-6-methylpyrimidine [0086] gave 0.2 g of 2-chloro-N-(3,3-difluorocyclopentyl)-6- methylpyrimidin-4-amine [0144] as an off-white solid. MS(M+l)+=247.9.
[00219] Step 2 [0145] : 0.25 g of 2-chloro-N-(3,3-difluorocyclopentyl)-6-methylpyrimidin- 4-amine [0144] and 0.145 g of 3, 5-dimethyl pyrazole in acetonitrile was irradiated at 150 °C to afford 0.1 g of N-(3, 3-difluorocyclopentyl)-2-(3, 5-dimethyl- lH-pyrazol- l-yl)-6- methylpyrimidin-4-amine [0145] as a white solid. MS(M+l)+=308.2, 1H NMR (400 MHz, Chloroform-d) δ 6.13 (s, IH), 6.01 (s, IH), 5.50 (s, IH), 4.39 (s, IH), 2.74 - 2.54 (m, 4H), 2.44 (d, J = 0.6 Hz, 3H), 2.33 (s, 4H), 2.25 - 1.99 (m, 2H), 1.84 (dq, J = 12.5, 7.6 Hz, 2H).
[00220] Example 52:
Figure imgf000201_0001
[00221] Step 1[0146]: The procedure is similar to step 3 [0006] in example 1. 1 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.7 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0146] as a pale yellow solid. MS(M+1)+=366.1.
[00222] Step 2[0147]: The procedure is similar to step 2[049] in example 10. 0.15 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0146] gave 0.015 g of 2-(l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-lH-pyrazol-3-yl)propan-2-ol [0147], Compound 215 as a white solid. MS(M+l)+=352.39, 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.55 (s, IH), 6.45 (t, J = 2.60 Hz, IH), 6.19 (s, IH), 5.03 (s, IH), 4.10-4.09 (m, IH), 2.26 (s, 3H), 2.05-1.95 (m, 6H), 1.57-1.54 (m, 2H), 1.45 (s, 6H).
[00223] Example 53:
Figure imgf000201_0002
[00224] Step 1[0149 & 0150]: The procedure is similar to step 3 [0006] in Example 1. 2 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 1.7 g of methyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate [0149] as an off-white solid MS(M+l)+=380.0 and 0.4 g of l-(4- ((4,4-difluorocyclohexyl)arnino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carboxylicacid [0150] as a brown solid. MS(M+l)+=352.3.
[00225] Step 2[0151]: To a solution of l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carboxylic acid [0149] (0.7 g, 1.99 mmol) in dichloromethane was added oxalyl chloride (1.0 g, 7.96 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h, the reaction mixture was concentrated under reduced pressure in nitrogen atmosphere to afford 1 g of l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carbonyl chloride as a brown solid [0151]. MS(M+l)+=366.6 (methyl ester mass). This was taken as such to next step.
[00226] Step 3[0152]: Ammonia gas was purged to a solution of l-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carbonyl chloride [0151] (0.7 g, 1.99 mmol) in tetrahydrofuran at -10 °C for 15 min. After 0.5 h, the reaction mixture was brought to rt and purged with nitrogen for 10 min. The reaction mixture was concentrated under reduced pressure to afford a pale brown solid, which
was purified in the Reveleris flash system instrument using methanol in chloroform as solvent in 24 g column. The product spot was isolated at 4 % Methanol in chloroform as solvent to afford 0.650 g of l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4- methyl-lH-pyrazole-3-carboxamide [0152], as white solid. MS(M+1)+=351.2.
[00227] Step 4[0153]:NSSY5282.0001. To a solution of l-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carboxamide [0152] (0.35 g, 0.85 mmol) in dichloromethane was added triethylamine (0.43 g, 4.28 mmol) and trifluoromethanesulfonic anhydride (0.61 g, 2.14 mmol) at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was quenched with ice and extracted with chloroform, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale brown solid which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as eluent in 24 g column to afford 0.21 g of l-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carbonitrile [0153], Compound 253 as white solid. MS(M+1)+ = 333.2. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.52 (d, J = 7.2 Hz, 1H), 6.37 (s, 1H), 4.05 (bs, 1H), 2.30 (s, 3H), 2.22 (s, 3H), 2.11 - 1.87 (m, 6H), 1.72 - 1.56 (m, 2H). [00228] Example 54:
Figure imgf000203_0001
0150 0154 0155
[00229] Step 1[0154] : To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0150] (1 g, 2.63 mmol) in tetrahydrofuran was added lithium aluminum hydride (0.2 g, 5.27 mmol) at -78 °C and the reaction mixture was stirred at same temperature. After 2 h, the reaction mixture was quenched with saturated aqueous ammonium chloride at -78 °C, brought to rt and stirred for 15 min. The white precipitate formed was filtered off through celite bed and washed with ethyl acetate. The filtrate was washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a pale yellow solid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 24 g column to afford 0.07 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-4-methyl-lH-pyrazol-3-yl)methanol [0154], Compound 236 as a white solid
[MS(M+l)+=338.0. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.23 (s, 1H), 4.68 (t, J = 5.7 Hz, 1H), 4.48 (d, J = 5.7 Hz, 2H), 4.02 (bs, 1H), 2.32 (s, 3H), 2.10 (s, 3H), 2.12 - 1.89 (m, 6H), 1.70 - 1.55 (m, 2H). and 0.4 g of l-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carbaldehyde
[0155] as a white solid. MS(M+1)+ =336.0.
[00230] Example 55:
Figure imgf000203_0002
0154 0156
[00231] Step 2[0156]:NSSy5293.0001. The procedure is similar to step 3 [0012] in Example 2. 0.5 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4- methyl-lH-pyrazol-3-yl)methanol [0154] gave 0.15 g of N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-4-methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0156], Compound 258 as white solid. MS(M+l)+=340.2, 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 6.28 (s, 1H), 5.49 (s, 1H), 5.37 (s, 1H), 4.04 (bs, 1H), 2.26 (s, 3H), 2.13 (s, 3H), 2.11 - 1.84 (m, 6H), 1.72 - 1.58 (m, 2H).
[00232] Example 56:
Figure imgf000204_0001
[00233] Step 3[0157]: The procedure is similar to step 3 [0012] in Example 2. 0.4 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carbaldehyde [0155], Compound 246 gave 0.175 g of N-(4,4-difluorocyclohexyl)-2-(3- (difluoromethyl)-4-methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0157] as white solid. MS(M+l)+=358.0. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.41 (d, J = 7.20 Hz, 1H), 7.00 (t, JF = 53.60 Hz, 1H), 6.32 (s, 1H), 4.01 (bs, 1H), 2.29 (s, 3H), 2.19 (s, 3H), 2.15 - 1.90 (m, 6H), 1.72 - 1.58 (m, 2H).
[00234] Example 57:
Figure imgf000204_0002
[00235] Step 1[87]: The procedure is similar to step 3[0006] in example 1. 0.5 g 2-chloro- N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] gave 0.3 g of l-(l-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)ethan- 1-one [0159] as a white solid. MS(M+l)+=336.0.
[00236] Step 2[0160]: The procedure is similar to step 3[0050] in example 10. 0.15 g of 1- (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)ethan- 1-one [0159] gave 0.1 g of l-(l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH- pyrazol-3-yl)ethan-l-ol [0160], Compound 202 as an off-white solid. MS(M+l)+=338.0, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.58 (s, 1H), 6.44 (d, J = 2.7 Hz, 1H), 6.21 (s, 1H), 5.20 (d, J = 4.8 Hz, 1H), 4.88 - 4.58 (m, 1H), 4.15 (s, 1H), 2.26 (s, 3H), 2.01 (d, J = 41.4 Hz, 6H), 1.56 (d, J = 9.3 Hz, 2H), 1.39 (d, J = 6.5 Hz, 3H).
[00237 Example 58:
Figure imgf000205_0001
[00238] Step l[0161].The procedure is similar to step 2 [0019] in Example 4. 1.4 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0146] gave 0.98 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0161] Compound 204 as an off-white solid.
MS(M+l)+=324, 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.59 (bs, 1H), 6.45 (s, 1H), 6.21 (bs, 1H), 5.20 (s, 1H), 4.49 (d, J = 5.7 Hz, 2H), 4.16 (bs, 1H), 2.26 (s, 3H), 2.15 - 1.88 (m, 6H), 1.65- 1.48 (m, 2H).
[00239] Step 2[0162]:0.9 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0161] gave 0.62 g of l-(4-((4,4-difluorocyclohexyl)amino)- 6-methylpyrimidin-2-yl)-lH-pyrazole-3-carbaldehyde [0162] as a white solid, using manganese dioxide (5 eq) in dichloromethane. MS(M+l)+=322.3.
[00240] Step 3[0163]: The procedure is similar to step 3 [0012] in Example 2. 0.7 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3-carbaldehyde [0162] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-lH-pyrazol-l-yl)- 6-methylpyrimidin-4-amine [0163] as an off-white solid. MS(M+l)+=344.2, 1H NMR (400 MHz, DMSO-d6) δ 8.69 (bs, 1H), 7.72 (bs, 1H), 7.12 (t, JF = 54.16 Hz, 1H), 6.77 (s, 1H), 6.29 (bs, 1H), 4.18 (bs, 1H), 2.28 (s, 3H), 2.17 - 1.83 (m, 6H), 1.65 - 1.57 (m, 2H).
[00241 Example 59:
Figure imgf000205_0002
0161 0164 0165 [00242] Step 1: Thionyl chloride (0.49 g, 4.17 mmol) was added to a solution of (l-(4- ((4,4-difluorocyclohexyl)arnino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0161] (0.45 g, 1.39 mmol) in dichloromethane and the reaction mixture was heated at 50°C. After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was triturated with hexane and dried vacuum to afford 0.41 g of 2-(3-(chloromethyl)-lH-pyrazol- l-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0164] as off-white solid. MS(M+l)+= 342.2. This was taken as such to next step.
[00243] Step 2[0165]: A solution of Potassium fluoride (1.08 g, 18.72 mmol), 18-crown-6 (0.12 g, 0.46 mmol) and 2-(3-(chloromethyl)-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0164] (1.6 g, 4.68 mmol), in acetonitrile was heated at 100 °C in sealed tube. After 24 h, the reaction mixture was quenched with 10% sodium bicarbonate solution until the pH around- 10 and extracted with dichloromethane (3x400 mL), combined organic layer was washed with brine (2x200 mL), dried with anhydrous sodium sulfate, filtrate was concentrated to afford a crude product, which was purified by column
chromatography to afford 0.81 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)-6-methylpyrimidin-4-amine [0165], Compound 233 as off-white solid.
MS(M+l)+=326.2, 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.66 (bs, 1H), 6.64 (s, 1H), 6.26 (bs, 1H), 5.45(d, JF = 48 Hz, 2H), 4.17 (bs, 1H), 2.27 (s, 3H), 2.13 - 1.87 (m, 6H), 1.62 - 1.57 (m, 2H).
[00244] Example 60:
Figure imgf000206_0001
0087A 0167 0168 0169 °170
[00245] Step 1[0167]: The procedure is similar to step 3[0006] in example 1. 0.5 g 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] and ethyl 5-methyl- lH-pyrazole-3-carboxylate [0166] (0.35 g, 2.29 mmol) gave 0.7 g of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3-carboxylate [0167] as a white solid. MS(M+l)+=348.2.
[00246] Step 2 [0168 and 0169]: The procedure is similar to step 2[0019] in example 4. 0.7 g ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-lH- pyrazole-3-carboxylate [0167] gave 0.1 g of l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3-carbaldehyde [0168] as an off-white solid. MS(M+l)+=338.38 and 0.035 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)-5-methyl-lH-pyrazol-3-yl)methanol [0169], Compound 241 as a white solid. MS(M+l)+=336.35, 1H NMR (400 MHz, DMSO-d6) δ 7.57 (d, J = 7.7 Hz, 1H), 6.24 (s, 1H), 6.20 (s, 1H), 5.09 (t, J = 5.9 Hz, 1H), 4.41 (d, J = 6.0 Hz, 2H), 4.02 (s, 1H), 2.54 (s, 3H), 2.25 (s, 3H), 2.12 - 2.02 (m, 2H), 1.95 (d, J = 14.0 Hz, 4H), 1.56 (d, J = 11.9 Hz, 2H).
[00247] Step 3[0170]: The procedure is similar to step 3 [0012] in example 2, 0.1 g l-(4- ((4,4-difluorocyclohexyl)arriino)-6-methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3- carbaldehyde [0169] gave 0.018 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-5- methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0170], Compound 256 as a grey solid. MS(M+l)+=340.4, 1H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 7.8 Hz, 1H), 6.33 (s, 2H), 5.33 (d, JF = 48 Hz, 2H), 3.97 (bs, 1H), 2.56 (s, 3H), 2.28 (s, 3H), 2.13 - 1.88 (m, 6H), 1.62 (q, J = 11.6, 9.6 Hz, 2H).
[00248] Example 61:
Figure imgf000207_0001
0168 0171
[00249] Step 1[0171]: The procedure is similar to step 3 [0012] in example 2. 0.15 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl-lH-pyrazole-3- carbaldehyde [0168] gave 0.075 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-5- methyl-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine [0171], Compound 237 as a white solid. MS(M+l)+=358.35, 1H NMR (400 MHz, DMSO-d6) δ 7.72 (d, J = 7.6 Hz, 1H), 7.02 (t, JF = 54 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 2.58 (s, 3H), 2.28 (s, 3H), 2.09 - 1.89 (m, 6H), 1.56 (d, J = 12.0 Hz, 2H), 1.25 (d, J = 6.2 Hz, 1H). [00250] Example 63:
Figure imgf000208_0001
0173 0175
[00251] Step 1[0175]: The procedure is similar to step 2[0177] in example 62. 0.2 g of 4- chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine [0173] gave 0.1 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0175], Compound 163 as an off-white solid. MS(M+l)+=308.2, 1H-NMR (400 MHz, CDC13): δ 8.20 (d, J = 5.60 Hz, 1H), 6.29 (d, J = 5.60 Hz, 1H), 6.02 (s, 1H), 5.53 (s, 1H), 3.88 (s, 1H), 3.22 (s, 3H), 2.34 (s, 3H), 1.97-1.90 (m, 4H), 1.86-1.73 (m, 2H), 1.71-1.65 (m, 2H),
[00252] Example 64:
Figure imgf000208_0002
0176 0177 0178
[00253] Step 1[0177]: The procedure is similar to step 3[0006] in Example 1. 0.5 g of 2,4- dichloro-5-ethylpyrimidine [0176] gave 0.25 g of 2-chloro-N-(4,4-difluorocyclohexyl)-5- ethylpyrimidin-4-amine [0177] as a light brown gum. MS(M+l)+=276.
[00254] Step 2[0178]: The procedure is similar to step 2[0174] in Example 62 (without base). 0.25 g of 2-chloro-N-(4,4-difluorocyclohexyl)-5-ethylpyrimidin-4-amine [0177] gave 0.03 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)-5-ethylpyrimidin-4- amine [0178], Compound 111 as an off-white solid. MS(M+1)+=336.1, 1H NMR (400 MHz, Chloroform-d) δ 8.09 (s, 1H), 6.01 (s, 1H), 4.70 (d, J = 7.4 Hz, 1H), 4.17 (d, J = 9.8 Hz, 1H), 2.66 (s, 3H), 2.42 (q, J = 7.5 Hz, 2H), 2.33 (s, 3H), 2.18 (d, J = 10.3 Hz, 4H), 2.01 - 1.80 (m, 2H), 1.75 - 1.60 (m, 2H), 1.27 (t, J = 7.5 Hz, 3H). [00255] Example 65:
Figure imgf000209_0001
[00256] Step 1[0180A & 0180B]: To a solution of 2,4-Dichloro-6-ethylpyrimidine [0179] (1 g, 5.64 mmol) and 4,4-Difluorocyclohexylamine Hydrochloride (0.96 g, 5.64 mmol) in acetonitrile was added cesium carbonate (3.68 g, 11.29 g ) and the reaction mixture was heated at 65 °C in sealed tube. After 16 h, the reaction mixture was filtered and the filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford 0.8 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-4-amine [0180A] as colorless oil and 0.5 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-2-amine [0180B] as colorless oil. MS(M+l)+= 276.0.
[00257] Step 2[0181]: The procedure is similar to step 3[0006] in Example 1. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-4-amine [0180A] gave 0.05 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-ethylpyrimidin-4-amine [0181], Compound 171 as off-white solid. MS(M+l)+=336.4. 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 6.04 (s, 1H), 4.03 (bs, 1H), 3.28 (m, 2H), 2.48 (s, 3H), 2.16 (s, 3H), 2.15 - 1.85 (m, 6H), 1.62 - 1.49 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H).
[00258] Step 3[0182]: The procedure is similar to step 3[0006] in Example 1. 0.3 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-ethylpyrimidin-2-amine [0180B] gave 0.95 g of N-(4,4- difluorocyclohexyl)-4-(3,5-dimethyl-lH-pyrazol-l-yl)-6-ethylpyrimidin-2-amine [0182], Compound 169 as white solid. MS(M+1)+ = 336.4. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (bs, 1H), 6.88 (s, 1H), 6.12 (s, 1H), 3.84 (bs, 1H), 2.64 (s, 3H), 2.60 - 2.53 (m, 2H), 2.18 (s, 3H), 2.10 - 1.75 (m, 6H), 1.64 - 1.52 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H). [00259] Example 67:
Figure imgf000210_0001
[00260] Step 1 [0187 A and 0187B]: The procedure is similar to Step 1 [0180 A & 0180B] in example 66. 0.5 g of 2,4-dichloro-6-cyclopropyl pyrimidine [0186] gave 0.3 g of 2-chloro- 6-cyclopropyl-N-(3,3-difluorocyclopentyl) pyrimidin-4-amine [0187 A] and 0.125 g of 4- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-2-amine [0187B] both as colorless gums. MS(M+l)+=274.0.
[00261] Step 2[0188]: The procedure is similar to step 3[0006] in Example 1.0.3 g of 2- chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-4-amine [0187 A] gave 0.175 g of 6-cyclopropyl-N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4- amine [0188], Compound 217 as white solid. MS(M+l)+=334.2, 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.45 (s, 1H), 2.58 (dt, J = 13.6, 6.5 Hz, 1H), 2.45 (s, 3H), 2.31 - 2.17 (m, 2H), 2.15 (s, 3H), 2.06 (dq, J = 16.2, 9.1, 8.0 Hz, 2H), 1.93 (s, 1H), 1.72 (dq, J = 12.2, 8.5 Hz, 1H), 0.98 - 0.90 (m, 3H).
[00262] Step 3[0189]: The procedure is similar to step 3[0006] in Example 1. 0.125 g of 4-chloro-6-cyclopropyl-N-(3,3-difluorocyclopentyl)pyrimidin-2-amine [0187B] gave 0.045 g 4-cyclopropyl-N-(3,3-difluorocyclopentyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2- amine [0189], Compound 222 as white solid, MS(M+l)+=334.2. 1H-NMR (400 MHz, DMSO-d6): δ 7.39 (bs, 1H), 6.99 (s, 1H), 6.13 (s, 1H), 4.29 (q, J = 7.20 Hz, 1H), 2.64 (s, 3H), 2.35 - 2.25 (m, 2H), 2.20 (s, 3H), 2.15-1.98 (m, 4H), 1.85-1.73 (m, 1H), 1.12 - 0.90 (m, 4H). 263] Example 69:
Figure imgf000211_0001
[00264] Step 1[0195] : To a solution of 4-chloro-2-(methylsulfanyl)-6-(trifluoromethyl) pyrimidine [0194] (1 g, 4.374 mmol) in acetonitrile (10 mL) was added N,N-diisopropyl ethylamine (0.84 g, 6.56 mmol), followed by 4,4-difluorocyclohexylamine hydrochloride [0002] (0.75 g, 4.374 mmol). The reaction mixture was stirred at rt for 36 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate to afford 1.4 g of N-(4,4- difluorocyclohexyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine [0195] as a yellow gum. MS(M+l)+=328.3
[00265] Step 2[0196] : To a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- (trifluoromethyl)pyrimidin-4-amine [0195] (0.55 g, 1.68 mmol) in dichloro methane (10 mL), 3-chloroperbenzoic acid (0.86 g, 5.04 mmol) was added portion-wise at 0 °C. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with dichloro methane (50 mL). The organic layer was stirred with saturated solution of sodium thio sulfate solution (20 mL), followed by 10% sodium bicarbonate solution (10 mL), water (10 mL) and brine water (10 mL). The organic layer was dried over anhydrous sodium sulfate to afford 0.6 g of N- (4,4-difluorocyclohexyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine [0196] as a yellow solid. MS(M+l)+=359.9
[00266] Step 3[0197]: To a solution of N-(4,4-difluorocyclohexyl)-2-(methylsulfonyl)-6- (trifluoromethyl)pyrimidin-4-amine [0196] (0.55 g, 1.53 mmol) in acetonitrile (6 mL), was added 3,5-dimethyl pyrazole [0017] (0.22 g, 2.296 mmol) and cesium carbonate (0.748 g, 2.296 mmol). The reaction mixture was irradiated in microwave at 130 °C for 2 h and concentrated under reduced pressure to afford 0.55 g of N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)-6-(trifluoromethyl)pyrimidin-4-amine. This was purified by column chromatography using 60% ethyl acetate in pet ether as solvent to afford 0.090 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-6-(trifluoromethyl) pyrimidin- 4-amine [0197], Compound 162 as a white solid. MS(M+l)+=376.6. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 7.5 Hz, IH), 6.74 (s, IH), 6.13 (s, IH), 4.09 (bs, IH), 2.57 (s, 3H), 2.19 (s, 3H), 2.15 - 1.90 (m, 6H), 1.65 - 1.52 (m, 2H).
00267] Example 71:
Figure imgf000212_0001
[00268] Step 1[0201] : The procedure is similar to Step 1 [0195] in example 69. 0.5 g of 4- chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine [0194] gave 0.4 g of N-(3,3- difluorocyclopentyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine [0201] as an off- white solid. MS(M+1)+=314.1.
[00269] Step 2[0202]: The procedure is similar to Step 2[0196] in example 69. 0.4 g N- (3,3-difluorocyclopentyl)-2-(methylthio)-6-(trifluoromethyl)pyrimidin-4-amine [0201] gave 0.35 g of N-(3,3-difluorocyclopentyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4- amine [0202] as an off-white solid. MS(M+l)+=346.2.
[00270] Step 3[0203]: The procedure is similar to Step 3[0197] in example 69. 0.2 g N- (3,3-difluorocyclopentyl)-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidin-4-amine [0202] gave 0.07 g of N-(3,3-difluorocyclopentyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- (trifluoromethyl)pyrimidin-4-amine [0203], Compound 167 as a white solid.
MS(M+l)+=362.2, IH NMR (400 MHz, CDC13): δ 6.52 (s, IH), 6.06-5.99 (m, 2H), 4.36 (m, IH), 2.70-2.65 (m, 4H), 2.39-2.29 (m, 5H), 2.23-2.16 (m, 2H), 2.12-2.09 (m, IH).
[00271] Example 72:
Figure imgf000212_0002
[00272] Step 1[0204] : The procedure is similar to Step 1 [0195] in example 69. 1.0 g of 4- chloro-6-(difluoromethyl)-2-(methylthio)pyrimidine [0190] gave 0.8 g 4-(difluoromethyl)-6- (3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidine [0204] as an off-white solid.
MS(M+1)+=271.2.
[00273] Step 2[0205]: The procedure is similar to Step 2[0196] in example 69. 1.0 g 4- (difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidine [0204] gave 0.7 g of 4-(difluoromethyl)-6-(3,5-dimethyl- lH-pyrazol- l-yl)-2-(methylsulfonyl)pyrimidine [0205] as an off-white solid.MS(M+l)+=303.1.
[00274] Step 3[0206]: The procedure is similar to Step 3[0197] in example 69 (DIPEA as base). 0.4 g of 4-(difluoromethyl)-6-(3,5-dimethyl- lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidine [0205] gave 0.2 g of N-(4,4-difluorocyclohexyl)-4- (difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0206] as a white solid. MS(M+l)+=358.2, 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 7.4 Hz, 1H), 7.19 (s, 1H), 6.76 (t, JF = 54 Hz, 1H), 6.21 (s, 1H), 2.68 (s, 3H), 2.21 (s, 3H), 2.12 - 1.89 (m, 6H), 1.60 (d, J = 11.8 Hz, 3H).
[00275] Example 73:
Figure imgf000213_0001
0205 0207
[00276] Step 3[0207]: The procedure is similar to Step 3[0197] in example 69 (DIPEA as base). 0.25 g of 4-(difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidine [0205] gave 0.2 g N-(3,3-difluorocyclopentyl)-4- (difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0207], Compound 181 as a white solid. MS(M+l)+=344.4, 1H NMR (400 MHz, DMSO-d6) δ 8.25 - 7.72 (m, 1H), 7.22 (s, 1H), 6.77 (t, JF = 54.5 Hz, 1H), 6.20 (s, 1H), 4.35 (s, 1H), 2.67 (s, 3H), 2.55 (d, J = 8.1 Hz, 1H), 2.42 - 1.90 (m, 7H), 1.82 (q, J = 9.0 Hz, 1H). [00277] Example 74:
Figure imgf000214_0001
[00278] Step 1[0208]: The procedure is similar to Step 3[0197] in example 69. 0.3 g 2,4- dichloro-6-cyclopropylpyrimidine [0186] gave 0.2 g of 4-chloro-6-cyclopropyl-N-(4,4- difluorocyclohexyl)pyrimidin-2-amine [0208] as an off-white solid. MS(M+l)+=288.2.
[00279] Step 2[0209]: The procedure is similar to Step 3[0197] in example 69. 0.2 g 4- chloro-6-cyclopropyl-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine [0208] gave 0.04 g of 4- cyclopropyl-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0209], Compound 226 as a white solid. MS(M+l)+=348.2, IH NMR (400 MHz, DMSO- d6): δ 7.91 (m, IH), 7.60 (m, IH), 5.82 (s, IH), 5.06 (m, IH), 3.55 (s, 2H), 2.57 (m, IH), 2.43 (s, 3H), 1.51-1.46 (m, 6H), 1.31-1.32 (m, 2H), 1.29 (s, 6H).
[ le 75:
Figure imgf000214_0002
[00281] Step 1[0211] : To a solution of 2-Bromo-4-Hydroxymethylthiazole [0210] (2 g, 10.30 mmol) in N,N-dimethylformamide (20 mL) was added tert-butyl dimethylsilyl chloride (3.2 g, 20.6 mmol) and imidazole (2.80 g, 41.2 mmol), then the reaction mixture was stirred at rt for 5h. After the completion of the reaction, to the reaction mixture was added ice cold water and extracted with ethyl acetate (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless liquid and which was purified by column of silica gel (60-120 mesh) using 15% ethyl acetate in hexane as eluent to afford 3 g of 2-bromo-4-(((tert-butyl dimethylsilyl)oxy)methyl)thiazole [0211] as an colorless liquid. [00282] Step 2[0212] : To a solution of 2-bromo-4-(((tert-butyl
dimethylsilyl)oxy)methyl)thiazole [0211] (0.3 g, 0.97 mmol) in tetrahydrofuran (10 niL) at - 78 °C under N2 was added n-BuLi (2.5 M in hexane) (0.06, 1.07, 1.) and the resulting brown solution was stirred for 30 min before adding tributyltin chloride (0.38 g, 1.16 mmol) and the reaction mixture was allowed to warm to rt and left overnight. After completion, the reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.7 g of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2- (tributylstannyl)thiazole [0212] as a light yellow liquid.
[00283] Step 3[0213] : To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.3g, 1.14 mmol) in toluene (10 mL) was added 4- (((tert-butyldimethylsilyl)oxy) methyl)-2-(tributylstannyl) thiazole [00212] (0.7 lg,
1.37mmoll.) and purged nitrogen for 5 min, then
added tetrakis(triphenylphosphine)palladium(0) (0.26g, 0.22mmol0.) to the reaction mixture and was irradiated in microwave at 130 °C for 2 h. the reaction mixture was filtered through celite bed and the filtrate was concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh), using 50% ethyl acetate in hexane as eluent to afford 0.140 g of 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-N-(4,4-difluoro cyclohexyl)-6-methylpyrimidin-4-amine[0213] as an colorless gum. MS(M+1)+ = 455.
[00284] Step 4[0214] : To an ice cooled solution of 2-(4-(((tert-butyldimethylsilyl) oxy)methyl)thiazol-2-yl)-N-(4,4-difluoro cyclohexyl)-6-methylpyrimidin-4-amine [0213] (0.12g, 0.26mmoll.) in diethyl ether (10 mL) was added hydrogenchloride (gas) in dioxane, After the completion of the reaction, the solid was filtered and washed with hexane to afford as off-white solid and which was dissolved in saturated sodium bicarbonate solution and extracted with ethyl acetate (2x25 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an colorless gum and which was purified by column of silica gel (60-120 mesh), using ethyl acetate as eluent to afford 0.055 g of (2-(4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazol-4-yl)methanol [0214], Compound 270 as an white solid. MS(M+1)+ =341, 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 2H), 6.35 (s, 1H), 5.39 (t, J = 5.7 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 4.09 (s, 1H), 2.29 (s, 3H), 2.07-1.95 (m, 6H), 1.59-1.52 (m, 2H).
[00285] Step 5[0215]: The procedure is similar to step 3 [0012] in example 2. 0.32 g of (2- (4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazol-4-yl)methanol [0214] gave 0.18 g of N-(4,4-difluorocyclohexyl)-2-(4-(fluoromethyl)thiazol-2-yl)-6- methylpyrimidin-4-amine [0215], Compound 273 as an light yellow solid, MS(M+l)+=343. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, J = 3.4 Hz, 1H), 7.57 (bs, 1H), 6.38 (bs, 1H), 5.50 (d, JF =48.5 Hz, 2H), 4.10 (bs, 1H), 2.30 (s, 3H), 2.02-1.95 (m, 6H), 1.61-152 (m, 2H).
[002 Example 76:
Figure imgf000216_0001
[00287] Step 1[0216]:0.080 g of (2-(4-((4,4-difluorocyclohexyl)amino)-6- methylpyrimidin-2-yl)thiazol-4-yl)methanol [0214] gave 0.080 g of 2-(4-((4,4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazole-4-carbaldehyde [0216] as an light brownish gum, using Dess-Martin periodinane(2 eq) in dichloro methane.
MS(M+l)+=338 and it was taken as such for next step.
[00288] Step 2[00217]: The procedure is similar to step 3 [0012] in example 2. 0.080 g of 2-(4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)thiazole-4-carbaldehyde
[0216] gave 0.032 g of N-(4,4-difluorocyclohexyl)-2-(4-(difluoromethyl)thiazol-2-yl)-6- methylpyrimidin-4-amine [0217], Compound 277 as an light yellow gummy solid.
MS(M+l)+=338. 1H-NMR (400 MHz, DMSO-d6): δ 8.22 (t, J = 1.40 Hz, 1H), 7.50 (s, 1H), 7.14 (t, JF = 54.52 Hz, 1H), 6.41 (bs, 1H), 4.05 (bs, 1H), 2.32 (s, 3H), 2.09-1.99-1.90 (m, 6H), 1.63-1.57 (m, 2H).
[00289] Example 77:
Figure imgf000216_0002
[00290] Stepl[219] : To a solution of 2-bromo-4-(trifluoromethyl)thiazole in
tetrahydrofuran (10 mL) at -78 °C under N2 atmosphere was added n-Butyl lithium (2.5 M in hexane) and the reaction mixture was stirred at same temperature. After 30 min, tributyltin chloride was added to the reaction mixture at -78 °C and stirred at rt. After 16 h, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2*25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 2-(tributylstannyl)-4-(Rs)-thiazole [219A to C] as a yellow liquid. LCMS inconclusive and it was taken as such for next step.
[00291] Example 78
Figure imgf000217_0001
[00292] Step 1[0220] : To a solution of 0.2 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] and 0.7 g of 2-(tributylstannyl)-4- (trifluoromethyl)thiazole in toluene (8 mL), was degassed with nitrogen for 10 min and tetrakis(triphenylphosphine)palladium(0) was added to the reaction mixture and irradiated in microwave at 130 °C. After 2 h, the reaction mixture was passed through celite bed and the filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford 0.025 g of N-(4,4-difluoro cyclohexyl)-6-methyl-2-(4- (trifluoromethyl)thiazol-2-yl)pyrimidin-4-amine [0220], Compound 269 as an light yellow solid. MS(M+l)+=379. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.67 (bs, 1H), 6.41 (bs, 1H), 3.88 (bs, 1H), 2.32 (s, 3H), 2.03-1.95 (d, 6H), 1.60-1.52 (m, 2H).
[00293] Example 79:
Figure imgf000217_0002
[00294] Step 1[0221]: The procedure is similar to step 1[0220] in example 78. 0.2 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.016 g of 2- (4-cyclopro pylthiazol-2-yl)-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0221], Compound 267 as an yellow solid which was purified by Prep HPLC, MS(M+1)+ =351. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (bs, 1H), 7.38 (s, 1H), 6.35 (bs, 1H), 4.04 (bs, 1H), 3.01 (bs, 1H), 2.29 (s, 3H), 2.13 - 1.91 (m, 6H), 1.60-1.52 (m, 2H), 0.93 (dt, J = 8.3, 2.9 Hz, 2H), 0.85 (dt, J = 5.2, 2.8 Hz, 2H).
[00295] Example 80:
Figure imgf000218_0001
0087A 0222
[00296] Step 1[0222]: The procedure is similar to step 1[220] in example 78. 0.3 g of 2- chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087 A] gave 0.065 g of N- (4,4-difluorocyclohexyl)-2-(4-isopropylthiazol-2-yl)-6-methylpyrimidin-4-amine [0222], Compound 278 as an off-white solid which was purified by Prep HPLC, MS(M+l)+=353. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (bs, 1H), 7.39 (s, 1H), 6.36 (bs, 1H), 4.04 (bs, 1H), 3.12-3.05 (m, 1H), 2.30 (s, 3H), 2.14 - 1.91 (m, 6H), 1.59-1.52 (m, 2H), 1.28 (d, J = 6.9 Hz, 6H).
[00297] Example 81:
Figure imgf000218_0002
[00298] Step 1[0223] : To a solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.8 g, 3.056 mmol) and l,4-diazabicyclo[2.2.2]octane (0.342 g, 3.056 mmol) were dissolved in dimethyl sulfoxide (10 mL) and stirred at rt for lh. To the resultant reaction mixture was added sodium cyanide (0.151 g, 3.056 mmol) and stirred at 80°C for 24h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x400 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.500 g of 4- ((4,4-difluorocyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0223] as an off-white solid. MS(M+1)+ = 253.
[00299] Step 2[0224]: The procedure is similar to step 4[0516] in Example 188. 0.4 g of 4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidine-2-carbonitrile [0223] gave 0.4 g of 4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidine-2-carbothioarnide [0224] as an off- white solid, ammonium sulfide, triethylamine in η,η-dimethylformamide.. MS(M+l)+=287.2
[00300] Step 3[0225] : 0.3 g of 4-((4,4-difluorocyclohexyl)amino)-6-methylpyrimidine-2- carbothioamide [0224] and 1.89 g l-bromobutan-2-one in tetrahydrofuran was heated at 70 °C to afford 0.4 g N-(4,4-difluorocyclohexyl)-2-(4-ethylthiazol-2-yl)-6-methylpyrimidin-4- amine [0225], Compound 279 as a yellow solid. MS(M+l)+=339.0. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H), 7.40 (s, 1H), 6.35 (s, 1H), 4.07 (bs, 1H), 2.79 (q, J = 7.5 Hz, 2H), 2.29 (s, 3H), 2.16 - 1.86 (m, 6H), 1.65 - 1.46 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H).
[00301] Exampl
Figure imgf000219_0001
[00302] Step 1[0282]: The procedure is similar to step 1[0220] in example 78. 0.500 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 1.1 g of 2- chloro-6-(tributylstannyl) pyridine [0227] gave 0.040 g of 2-(6-chloropyridin-2-yl)-N-(4,4- difluorocyclohexyl)-6-methyl pyrimidin-4-amine [0282], Compound 230 as a light yellow solid, which was purified by column of silica gel (60-120 mesh) using 60% ethyl acetate in hexane as eluent. MS(M+1)+ =339, 1H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 7.7 Hz, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.59 (d, J = 7.7 Hz 1H), 7.48 (bs, 1H), 6.40 (bs, 1H), 4.06 (bs, 1H), 2.33 (s, 3H), 2.17 - 1.90 (m, 6H), 1.60-1.52 (m, 2H). [00303] Example 83:
Figure imgf000220_0001
[00304] Step 1[0230]: The procedure is similar to step 1[0220] in example 78. 0.400 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-methylpyrimidin-4-amine [0087A] and 1.16 g of 2- chloro-6-(tributylstannyl) pyridine [0229] gave 0.200 g of N-(4,4-difluorocyclohexyl)-6- methyl-2-(6-methylpyridin-2-yl)pyrimidin-4-amine [0230], Compound 224 as an off-white solid, which was purified by column of silica gel (60-120 mesh) using ethyl acetate as eluent, MS(M+1)+=319, 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 7.7 Hz, 1H), 7.36 (bs, 1H), 7.30 (d, J = 7.5 Hz, 1H), 6.36 (bs, 1H), 4.09 (bs, 1H), 2.53 (s, 3H), 2.31 (s, 3H), 2.10-1.95 (m, 6H), 1.60-1.52 (m, 2H).
[00305] Example 84:
Figure imgf000220_0002
[00306] Step 1[0232] : To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)-6- methylpyrimidin-4-amine [0087 A] (0.15 g, 0.573 mmol) in a mixture (1: 1 ratio) of 1,2- dimethoxyethane and water, were added 6-methoxypyridine-2-boronic acid [0231] (0.18 g, 1.146 mmol), potassium phosphate- tribasic (0.243 g, 1.146 mmol) in a microwave vial. After 5 min added bis(triphenylphosphine)palladium(II) dichloride (0.04 g, 0.057 mmol) in one portion and the reaction mixture was irradiated in microwave at 100 °C for 2 h. After cooling to rt, reaction mixture was diluted with ethyl acetate (20 mL). The insoluble were filtered and filtrate was washed with water (2x50 mL), brine (2x50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.11 g of N-(4,4-difluorocyclohexyl)-2-(6-methoxypyridin-2-yl)- 6-methylpyrimidin-4-amine [0232], Compound 219 as an off-white solid.
MS(M+l)+=335.2, 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 7.6 Hz, 1H), 6.84 (s, 1H), 6.12 (s, 1H), 4.13 (s, 1H), 4.01 (s, 1H), 2.56 (d, J = 9.1 Hz, 6H), 2.20 (s, 3H), 2.05 - 1.73 (m, 6H), 1.52 - 1.31 (m, 2H).
[00307] Example 87
Figure imgf000221_0001
[00308] Step 1[0239]: The procedure is similar to step 1[0191] in example 68. 10 g of 4,6- dichloro-2-(methylthio)pyrimidine [0239] gave 8 g of 4,6-dichloro-2- (methylsulfonyl)pyrimidine [0240] as an off-white solid. MS(M+l)+=228.
[00309] Step 2[0241]: To a suspension of sodium hydride (35.2 g) in dichloromethane was added 84.6 g of 3,5-dimethyl pyrazole at 0 °C and the reaction mixture was stirred at rt. After 30 min, 200 g of 4,6-dichloro-2-(methylsulfonyl)pyrimidine [0239] (dissolved in
dichloromethane) was added drop wise to the reaction mixture at -78 °C and the reaction mixture was stirred at same temperature. After 2 h, the reaction mixture was quenched with water at -78 °C and diluted with dichloromethane. After 5 min, dichloromethane was decanted and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography to afford 138 g of 4,6-dichloro-2-(3, 5-dimethyl-lh-pyrazol-l-yl) pyrimidine [0241] as an off-white solid. MS(M+l)+=244.2.
[00310] Step 3[0242] : To a stirred solution of 4,6-dichloro-2-(3, 5-dimethyl-lh-pyrazol-l- yl) pyrimidine [0241] (4.9 g, 20.156 mmol) in acetonitrile (50 rriL), was added 4,4- difluorocyclohexylamine hydrochloride [0002] (3.45 g, 20.16 mmol) and N,N-diisopropyl ethylamine (7.01 mL, 40.31 mmol). The reaction mixture was heated at 60 °C for 16 h and concentrated under reduced pressure. Water (50 mL) was added to the residue and the solid formed was filtered to afford a crude product which was purified by column chromatography using 25% ethyl acetate in pet ether as solvent to afford 3.8 g of 6-chloro-N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lh-pyrazol-l-yl)pyrimidin-4-amine [0242] as a pale brown solid. MS(M+l)+=342.0.
[00311] Step 4[0244] : To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lh-pyrazol-l-yl)pyrimidin-4-amine [0242] (0.400 g, 1.17 mmol) in dioxane (10 mL), were added 3-oxetanamine (0.171 g, 2.34 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (0.135 g, 0.234 mmol) and cesium carbonate (0.764 g, 2.34 mmol). The reaction mixture was degassed with nitrogen for 10 min, before adding
tris(dibenzylideneacetone)dipalladium(0) (0.38 g, 0.117 mmol) and heated at 95 °C for 16 h. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to afford crude product which was purified by preparative HPLC to afford 0.065 g of N4-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6-(oxetan-3-yl)pyrimidine- 4,6-diamine [0244], Compound 243 as an off-white solid. MS(M+l)+ = 379.0. 1H NMR (400 MHz, DMSO-d6) δ 7.63 (s, 1H), 6.99 (d, J = 7.9 Hz, 1H), 5.99 (s, 1H), 5.25 (s, 1H), 4.78 (s, 3H), 4.47 (s, 2H), 3.82 (s, 1H), 2.55 (s, 3H), 2.14 (s, 3H), 2.07 - 1.89 (m, 6H), 1.54 - 1.51 (m, 2H).
[00312] Exampl
Figure imgf000222_0001
0242 0246
[00313] Step 1[0246]: The procedure is similar to step 2[174] in example 62. 0.350 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0242] gave 0.015 g of N4-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6- (l-(thiazol-2-yl)ethyl)pyrimidine-4,6-diamine[0246], Compound 124 as a yellow solid. MS(M+l)+=434.7, 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 7.66 (d, J = 7.3 Hz, 1H), 7.56 (s, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.96 (s, 1H), 5.40 (bs, 2H), 3.72 (bs, 1H), 2.37 (s, 3H), 2.12 (s, 3H), 2.07 - 1.88 (m, 6H), 1.55 (d, J = 6.9 Hz, 5H). [00314] Example 89:
Figure imgf000223_0001
[00315] Step 1[0248]: The procedure is similar to step 2[0174] in example 62. 0.350 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] gave 0.075 g of 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl) amino)- l-methylpyrrolidin-2-one [0248], Compound 125 as a yellow solid. MS(M+1)+ = 420.8 IH NMR (400 MHz, DMSO-d6) δ 7.10 (s, IH), 6.92 (d, J = 7.8 Hz, IH), 5.99 (s, IH), 5.42 (s, IH), 4.50 (s, IH), 3.83 (s, IH), 2.76 (s, 3H), 2.48 (s, 3H), 2.14 (s, 3H), 2.06 (s, 2H), 1.91 (d, J = 13.4 Hz, 5H), 1.53 (d, J = 11.9 Hz, 2H).
[00316] Step 2[0249 and 0250] : 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl) amino)- l-methylpyrrolidin-2-one [0248] which was purified by chiral preparative to afford 0.012 g of (+)-3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)amino)-l-methylpyrrolidin-2-one [0249],
Compound 128 as an off-white solid [MS(M+l)+=420.8, IH NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 7.48 Hz, IH), 6.92 (d, J = 7.8 Hz, IH), 5.99 (s, IH), 5.41 (s, IH), 4.49 (bs, IH), 3.83 (bs, IH), 2.76 (s, 3H), 2.48 (s, 3H), 2.44 (m, 3H), 2.14 (s, 3H), 2.07 - 1.78 (m, 7H), 1.54 - 1.50 (m, 2H) and 0.0115 g of (-)-3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)amino)-l-methylpyrrolidin-2-one [0250], Compound 129 as an off-white solid. MS(M+l)+=420.8, 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, IH), 6.92 (d, J = 7.9 Hz, IH), 5.99 (s, IH), 5.41 (s, IH), 4.50 (s, IH), 3.81 (s, IH), 2.75 (s, 3H), 2.52 (s, 3H), 2.44 (m, 3H) 2.14 (s, 3H), 2.06 - 1.82 (m, 7H), 1.62 - 1.48 (m, 2H).
[00317] Exam le 9
Figure imgf000223_0002
0242 0251 [00318] Step 1[0251] : To a solution of indium(III)chloride (0.51 g, 2.34 mmol) in tetrahydrofuran was added cyclopropyl magnesium bromide (1.02 g, 7.02 mmol) at -78 °C and stirred at same temperature. After 30 min, the reaction mixture was brought to rt and cannulated to a vial containing 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-amine [0242] (0.8 g, 2.34 mmol) in tetrahydrofuran and heated at 90 °C. After 16 h, the reaction mixture was quenched with few drops of methanol, stirred for 10 min, filtered through celite bed which was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was again dissolved in ethyl acetate and washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 25 g column, to afford 0.08 g of 6-cyclopropyl-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0251], Compound 186 as a white solid.
MS(M+l)+=348.2, 1H-NMR (400 MHz, DMSO-d6): δ 7.49 (s, 1H), 6.31 (s, 1H), 6.02 (s, 1H), 3.99 (bs, 1H), 2.46 (s, 3H), 2.15 (s, 3H), 2.05-1.92 (m, 7H), 1.62 - 1.50 (m, 2H), 0.99 - 0.85 (m, 4H).
[00319] Example 91:
Figure imgf000224_0001
[00320] Step 1[0252]: To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2- (3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] (1.5 g, 4.388 mmol) and potassium cyanide (0.583 mmol) in acetonitrile (40 mL) were added tributyltin chloride (0.085 g, 0.263 mmol) followed by 'l,l'-bis(diphenylphosphino)ferrocene (0.32 g, 0.438 mmol) and tris(dibenzylidene acetone)dipalladium(0) (0.4 g, 0.438 mmol). The mixture was stirred at rt for 30 min and then heated at 80 °C for 24 h. The reaction mixture was diluted with ethyl acetate (250 mL) and water (100 mL). Aqueous layer was extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with water (250 mL), brine solution (100 mL), dried over anhydrous sodium sulfate, filtered and the concentrated under reduced pressure to afford crude and which was purified by column chromatography using 12% ethyl acetate in pet ether as solvent to afford 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol- l-yl)pyrimidine-4-carbonitrile [0252] of as an off-white solid (0.43 g). MS(M+l)+= 333.2, 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 6.99 (s, 1H), 6.10 (s, 1H), 2.55 (s, 3H), 2.19 (s, 3H), 2.02 (d, J = 39.6 Hz, 6H), 1.58 (d, J = 11.9 Hz, 2H).
[00321] Step 2[0253]: To a stirred solution of 6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carbonitrile [0252] (0.15 g, 0.451 mmol) in a mixture of methanol (5 mL) and water (15 mL) was added potassium hydroxide (0.025 g, 0.451 mmol). The reaction mixture was stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (75 mL) and two layers were separated. Organic layer was washed with water (2x50 mL), brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude and which was purified by column chromatography using 4% methanol in chloroform as solvent to afford 6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidine-4-carboxamide [0253], Compound 131 as an off-white solid (0.032 g). MS(M+1)+=351.2, 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 7.4 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 6.99 (s, 1H), 6.10 (s, 1H), 4.10 (bs, 1H), 2.55 (s, 3H), 2.19 (s, 3H), 2.10 - 1.90 (m, 6H), 1.58 - 1.53 (m, 2H).
[00 22] Example 92:
Figure imgf000225_0001
[00323] Step 1 [0255]: The procedure is similar to Step 2[0174] in example 62. 0.3 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.348 g of (lS,4S)-(-)-2-Boc-2,5-diazabicyclo[2.2.1]heptane [0254] gave 0.075 g of tert-butyl (lR)-5-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0255] as an white solid.
[00324] Step 2 [0256]: tert-Butyl (lR)-5-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate [0255] was acidified by using Hydrochloric acid in dioxane to afford 6-((4R)-2,5- diazabicyclo[2.2. l]heptan-2-yl)-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- IH-pyrazol- 1- yl)pyrimidin-4-amine hydrochloride salt [0256], Compound 103 as an light yellow solid (55 mg). MS(M+l)+=404, MS(M+l)+=404, 1H NMR (400 MHz, Methanol-d4) δ 6.30 (s, 1H), 5.21(s, 1H) 4.66 (s, 1H), 3.99-3.78 (m, 3H), 3.52 (s, 2H), 2.72 (s, 3H), 2.33 (s, 4H), 2.20 - 2.01 (m, 6H), 1.82-1.65 (m, 2H).
[00325] Exampl
Figure imgf000226_0001
[00326] Step 1 [0258]: The procedure is similar to Step 2[0174] in example 62. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.22g of piperazine-2-carboxamide [0258] gave 0.055 g of 4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)piperazine-2- carboxamide [0258], Compound 100. MS(M+l)+=435, 1H NMR (400 MHz, DMSO-d6) δ 7.34 (s, 1H), 7.18 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.00 (s, 1H), 5.57 (s, 1H), 4.08 (b, 1H), 3.95-3.80 (m, 2H), 3.19 (dd, J = 9.3, 3.4 Hz, 1H), 3.05-2.85 (m, 3H), 2.70-2.60(m, 2H), 2.49 (s, 3H), 2.15 (s, 3H), 2.07 - 1.89 (m, 6H), 1.45-1.60 (m, 2H).
[00327] Example 94:
Figure imgf000226_0002
[00328] Step 1 [0260] The procedure is similar to Step 3 [0006] in example 1 (solvent dimethyl sulfoxide at 100 °C). 0.12 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.069 g of 2-oxa-6-azaspiro(3,3) heptane [0260] gave 0.08 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH pyrazol-l-yl)- 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-amine, Compound 105 MS(M+l)+=405, 1H NMR (400 MHz, DMSO-d6) δ 7.07 (d, J = 8.0 Hz, IH), 6.00 (s, IH), 5.19 (s, IH), 4.72 (s, 4H), 4.11 (s, 4H), 3.86 (bs, IH), 2.50 (s 3H), 2.14 (s, 3H), 2.15-1.80 (m, 6H), 1.40-1.35 (m, 2H).
[00329] Exampl 95:
Figure imgf000227_0001
0242 0262
[00330] Step 1[0262]: The procedure is similar to Step 3 [0006] in example 1 (solvent dimethyl sulfoxide at 100 °C). 0.6 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.309 g of 2-aminopropanamide [0262] gave 0.038 g of 2-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)amino)propanamide, Compound 109 using Cesium carbonate and dimethylsulphoxide at 100 °C for 48h. MS(M+l)+=394, 1H NMR (400 MHz, DMSO-d6) δ 7.38 (s, IH), 6.85-7.05 (m, 3H), 5.99 (s, IH), 5.39 (bs, IH), 4.24 (bs, IH), 3.78 (bs, IH), 2.49 (s, 3H), 2.14 (s, 3H), 2.12-2.00- (m, 2H), 2.0-1.85 (m 4H), 1.61-1.49 (m, 2H), 1.28 (d, J = 7.0 Hz, 3H).
[00331] Example 96:
Figure imgf000227_0002
[00332] Step 1[0264]: The procedure is similar to Step 3[0006] in example 1(100 °C, dimethylsulfoxide ). 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.102 g of morpholin-2-ylmethanol [0263] gave 0.14 g of racemate (4-(6-((4,4-difluorocyclohexyl) amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)morpholin-2-yl)methanol [0264], Compound 110. MS(M+l)+=423, 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 8.0 Hz, IH), 6.01 (s, IH), 5.57 (s, IH), 4.85 (t, J = 5.5 Hz, IH), 4.19-3.96 (m, 2H), 4.07 - 3.87 (m, 2H), 3.55 - 3.40 (m, 4H), 2.95-2.85 (m, IH), 2.66 - 2.59 (m, IH), 2.49 (s, 3H), 2.15 (s, 3H), 2.15-1.85 (m, 6H), 1.60-145 (m, 2H). [00333] Step 2[0265 & 0266] : 0.14 g of racemate (4-(6-((4,4-difluorocyclohexyl) amino)- 2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)morpholin-2-yl)methanol [0264] was separated by chiral Prep HPLC to afford 0.050 mg of (+)-(4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morphoU^ yl)methanol [0265], Compound 112. MS(M+l)+=423. SOR: +20.909°, C = 0.110, S = MeOH, T=23.4 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 4.85 (t, J = 5.5 Hz, 1H), 4.19-3.96 (m, 2H), 4.07 - 3.87 (m, 2H), 3.55 - 3.40 (m, 4H), 2.95-2.85 (m, 1H), 2.66 - 2.59 (m, 1H), 2.49 (s, 3H), 2.15 (s, 3H), 2.15-1.85 (m, 6H), 1.60-145 (m, 2H) and 55 mg of (-)-(4-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)morpholin-2-yl)methanol [0266], Compound 113.
MS(M+l)+=423. SOR: -13.889°, C=0.108, S=MeOH, T=23.8 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 4.85 (t, J = 5.5 Hz, 1H), 4.19-3.96 (m, 2H), 4.07 - 3.87 (m, 2H), 3.55 - 3.40 (m, 4H), 2.95-2.85 (m, 1H), 2.66 - 2.59 (m, 1H), 2.49 (s, 3H), 2.15 (s, 3H), 2.15-1.85 (m, 6H), 1.60-145 (m, 2H).
00334] Example 98
Figure imgf000228_0001
[00335] Step 1[0270] : To a solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (lg, 4.11 mmol) and morpholine-2-carboxamide [0269] (0.53g, 4.11 mmol) in dimethylsulfoxide (8 mL) was added cesium carbonate (2.68g, 8.22 mmol) under N2 atmosphere. The resultant reaction mixture was heated at 80 °C in a closed vial for 8 h, quenched with water and extracted with ethyl acetate (2x200 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford as a yellow gum and which was purified by column chromatography using 5% methanol in chloroform as eluent to afford 4-(6-chloro-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholine-2-carboxamide [0270] as an off-white solid (0.77 g), MS(M+l)+=337. [00336] Step 2[271]:. To a solution of 4-(6-chloro-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)morpholine-2-carboxamide [0270] (0.28 g, 0.831 mmol) and 4,4- Difluorocyclohexylamine hydrochloride [0002] (0.28 g, 1.66 mmol) in dimethylsulfoxide (6 mL) was added cesium carbonate (0.541 g, 1.66 mmol) under N2 atmosphere. The resultant reaction mixture was heated at 90 °C in a closed vial for 4 days. The reaction mixture was quenched with water, the solid formed was filtered and dried to afford as brown solid and which was purified by prep HPLC to afford 4-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholine-2-carboxamide [271], Compound 115 as an off-white solid (0.05 g). MS(M+l)+=436. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H), 7.12 (s, 1H), 7.10 (bs 1H), 6.00 (s, 1H), 5.51 (s, 1H), 4.74 (bs, 1H), 4.30 (d, J = 11.8 Hz, 1H), 4.01 - 3.83 (m, 2H), 3.65 (dd, J = 11.8, 3.8 Hz, 2H), 3.55 - 3.35 (m, 2H), 2.47 (s, 3H), 2.14 (s, 3H), 2.09 - 1.85 (m, 6H), 1.62-1.49 (m, 2H).
[00337] Example 99:
Figure imgf000229_0001
0241 0273 0274
[00338] Step 1[0273] : A stirred solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (1.3 g, 5.348 mmol), 1-acetylpiperazine [0272] (0.685 g, 5.348 mmol) and triethylamine (0.82 mL, 5.883 mmol) in acetonitrile (50 mL) was heated at 55 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude product and which was purified by column chromatography using 5% ethyl acetate in hexane as eluent to afford l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0273] as an white solid (1.1 g, 64%). MS(M+l)+=335.2.
[00339] Step 2[0274] : A stirred suspension of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one [0273] (0.22 g, 0.657 mmol), 4,4- difluorocyclohexylamine hydrochloride [0002] (0.135 g, 0.788 mmol) and cesium carbonate (0.535 g, 1.642 mmol) in acetonitrile was heated at 150 °C in MW for 5 h. The reaction mixture was concentrated under reduced pressure, added water (10 mL), extracted with chloroform (3* 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude which was purified by column chromatography using 2% methanol in chloroform as eluent to afford l-(4-(6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one [0274], Compound 102 as an off-white solid (0.043 g, 15%). MS(M+l)+=434, 1H NMR (400 MHz, DMSO-d6) δ 7.09 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 3.88 (bs, 1H ,) 3.65 - 3.42 (m, 8H), 2.48 (s, 3H), 2.15 (s, 3H), 2.05 (s, 6H), 1.95 - 1.85 (m, 3H), 1.65 - 1.48 (m, 2H).
[00340] Examp
Figure imgf000230_0001
[00341] Step 1 [0275]: The procedure is similar to Step 2[0274] in example 99. 0.2 g of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0273] and 0.1 g of 4-(Trifluoromethyl)Cyclohexanamine [0113] gave 0.06 g of l-(4-(2-(3,5- dimethyl-lH-pyrazol-l-yl)-6-((4-(trifluoromethyl)cyclohexyl)amino)pyrimidin-4- yl)piperazin-l-yl)ethan- 1-one [0275], Compound 149. MS(M+l)+=466, 1H NMR (400 MHz, DMSO-d6) δ 7.02 (d, J = 7.0 Hz, 1H), 6.00 (s, 1H), 5.56 (s, 1H), 3.54 - 3.45 (m, 9H), 2.48 (s, 3H), 2.34 - 2.27 (m, 1H), 2.16 (s, 3H), 2.05 (s, 3H), 2.02 - 1.86 (m, 4H), 1.42 - 1.23 (m, 4H).
[00342] Exam le 101:
Figure imgf000230_0002
0273 0276
[00343] Step 1 [0276]: The procedure is similar to Step 2[0274] in example 99 ( Using DIPEA, MW, 180 °C). 0.2 g of l-(4-(6-chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4- yl)piperazin-l-yl)ethan- 1-one [0273] and 0.108 g of 3,3-difluorocyclopentan-l-amine [0075] gave 0.065 g of l-(4-(6-((3,3-difluorocyclopentyl)arnino)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-yl)piperazin-l-yl)ethan- 1-one [0276], Compound 130. MS(M+l)+=420, 1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 7.2 Hz, 1H), 6.03 (s, 1H), 5.58 (d, J = 2.3 Hz, 1H), 4.32 (s, 1H), 3.58 (bs, 2H), 3.53 (s, 6H), 2.74 - 2.56 (m, 1H), 2.48 (s, 3H) 2.35 - 2.22 (m, 1H), 2.10 (dd, J = 45.1, 2.5 Hz, 9H), 1.72 (dt, J = 11.9, 8.4 Hz, 1H).
[00344] Example 103:
Figure imgf000231_0001
[00345] Step 1[0279]: The procedure is similar to Step 1[127] in example 45. 0.5 g of 4,4- Difluoro cyclohexanone [0126] and 0.173 g of methylamine, 2M solution in tetrahydrofuran gave 0.52 g of 4,4-difluoro-N-methylcyclohexan-l -amine [0279]. MS(M+1)+=150.
[00346] Step 2[0280] : 0.4 g of l-(4-(6-chloro-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin- 4-yl)piperazin-l-yl)ethan-l-one [0273] and 0.44 g of 4,4-difluoro-N-methylcyclohexan-l- amine [0279] gave 0.190 g of l-(4-(6-((4,4-difluoro cyclohexyl)(methyl)amino)-2-(3,5- dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0280], Compound 132 using Ν,Ν-diisopropyl ethylamine and acetonitrile in MW at 180 °C for 3h.
MS(M+1)+=150, 1H NMR (400 MHz, Chloroform-d) δ 6.0 (s, 1H), 5.34 (s, 1H) 4.81 (s, 1H), 3.83 (dd, J = 6.5, 4.1 Hz, 2H), 3.75 (dd, J = 6.6, 4.2 Hz, 2H), 3.58 (td, J = 7.4, 5.2 Hz, 4H), 2.89 (s, 3H), 2.62-2.33 (m, 6H), 2.21 (m, 2H), 2.15 (s, 3H), 1.78 (s, 6H).
[00347] Example 104:
Figure imgf000231_0002
[00348] Step 1[0281]: To a solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidine-4-carbonitrile [0029] (1.8 g, 6.601 mmol) in tetrahydrofuran (15 mL) was added triethylamine (0.7 g, 6.931 mmol) and followed by slow addition of hydro xylamine hydrochloride (0.486 g, 6.931 mmol) under N2 atm. The resultant reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2x 200 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-6-((4,4-difluorocyclohexyl)amino)-N'- hydroxypyrimidine-4-carboximidamide [0281] as an off-white solid (1.99 g).
MS(M+l)+=306.
[00349] Step 2[0282] : To a stirred solution of 2-chloro-6-((4,4- difluorocyclohexyl)amino)-N'-hydroxypyrimidine-4-carboximidamide [0281] (1.8 g, 5.88 mmol) in acetic anhydride (20 mL) was heated at 100 °C in sealed tube for 24 h. The reaction mixture was concentrated under reduced pressure to afford crude and which was purified by column chromatography using 30% ethyl acetate in pet-ether as a solvent to afford 2-chloro-N-(4,4-difluorocyclohexyl)-6-(5-methyl-l,2,4-oxadiazol-3-yl)pyrimidin-4- amine [0282] as an white solid (0.9 g). MS(M+l)+=330.
[00350] Step 3[0283]: 0.9 g of 2-chloro-N-(4,4-difluorocyclohexyl)-6-(5-methyl- 1,2,4- oxadiazol-3-yl)pyrimidin-4-amine [56] gave 1.0 g of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-(5-methyl-l,2,4-oxadiazol-3-yl)pyrimidin-2-yl)-lH-pyrazole-3- carboxylate [57] as an off-white solid using CS2C03, ACN 80 °C 2h. MS(M+l)+=434.
[00351] Example 105:
Figure imgf000232_0001
[ , Α
0283 0284 0285 0286
[00352] Step 1[0284]: The procedure is similar to step 2[0011] in example 2. 0.8 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(5-methyl-l,2,4-oxadiazol-3-yl)pyrimidin-2- yl)-lH-pyrazole-3-carboxylate [0283] gave 0.9 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6- (5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol
[0284] as an white solid. MS(M+l)+=394.
[00353] Step 2 [0285]: The procedure is similar to step 3 [0012] in example 2. 0.45 g of (1- (4-((4,4-difluorocyclohexyl)amino)-6-(5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin- 2-yl)-lH-pyrazol-3-yl)methanol [0284] gave 0.24 g of N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)-6-(5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin-4- amine [0285], Compound 331 as a white solid. MS(M+l)+=396, 1H-NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 8.05 (bs, 1H), 7.54 (bs, 1H), 6.83 (d, J = 11.52 Hz, 1H), 6.70 (s, 1H), 5.76 (s, 1H), 5.46 (d, JF =48.5 Hz, 2H), 4.22 (bs, 1H), 2.07-1.98 (m, 6H), 1.61-1.59 (m, 2H), 1.39 (d, J = 4.0 Hz, 3H).
[00354] Step 3[0286]:0.15 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)-6-(5-methyl-4,5-dihydro-l,2,4-oxadiazol-3-yl)pyrimidin-4-amine [0285] gave 0.11 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)-6-(5-methyl- l,2,4-oxadiazol-3-yl)pyrimidin-4-amine [0286], Compound 334 as an off-white solid, using manganese dioxide in dichloro methane. MS(M+l)+=394, 1H-NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.22 (d, J = 7.32 Hz, 1H), 7.14 (s, 1H), 6.70 (s, 1H), 5.48 (d, JF =48.5 Hz, 2H), 4.26 (bs, 1H), 2.70 (s, 3H), 2.09-2.01 (m, 6H), 1.63-1.61 (m, 2H).
[00355] Example 106:
Figure imgf000233_0001
0242 0287 0289 0290
[00356] Step 1[0287]: To a solution 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0242] (1 g, 2.92 mmol) in tetrahydrofuran (50 mL) was added boc-anhydride (1.91 g, 8.777 mmol) followed by 4-N,N-dimethylamino pyridine (0.067 g, 0.555 mmol). The reaction mixture was heated at 85 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet ether as solvent to afford 1.2 g of tert-butyl (6-chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)(4,4- difluorocyclohexyl)carbamate [0287] as a white solid. MS(M+l)+=342.2
[00357] Step 2[0289]: To a solution of tetrahydro-4h-Pyran-4-One [0288] (1.35 g, 13.577 mmol ) in tetrahydrofuran (25 mL) was added lithium bis(trimethylsilyl) amide ((1 M solution in tetrahydrofuran ) (13.57 mL, 13.577 mmol) at 0 °C. After 30 min tert-butyl (6-chloro-2- (3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)(4,4-difluorocyclohexyl)carbamate [0287] (1.5 g, 3.394 mmol) was added to the reaction mixture at 0 °C drop wise in tetrahydrofuran (5 mL). After addition the reaction was stirred at rt for 1 h. The reaction mixture was quenched with water (25 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (20 mL), followed by brine (20 mL), dried over anhydrous sodium sulfate to afford 2.1 g of tert-butyl (4,4-difluorocyclohexyl)(2-(3,5-dimethyl-lH-pyrazol-l- yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0289] as a yellow solid. MS(M+l)+= 506.3
[00358] Step 3[0290 and 0291]: To a solution of tert-butyl (4,4-difluorocyclohexyl)(2- (3,5-dimethyl-lH-pyrazol-l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0289] (0.5 g, 1.01 mmol) in methanol (5 mL) was added sodium borohydride (38.5 g, 1.01 mmol). The reaction mixture was stirred at rt for 10 min. The reaction mixture was concentrated under reduced pressure. The residue was neutralized with 10% sodium bicarbonate solution (15 mL, extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by preparative HPLC to afford 0.045 g of tert-butyl (4,4-difluorocyclohexyl)(6-((+)-4-hydroxytetrahydro-2H-pyran-3- yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0290] as a yellow solid and 0.130 g of tert-butyl (4,4-difluorocyclohexyl)(6-((-)-4-hydroxytetrahydro-2H-pyran-3-yl)-2- (3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)carbamate [0291] . MS(M+l)+=494.2
[00359] Example 107:
Figure imgf000234_0001
0290 0292
[00360] Step 1[0292] : To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-((+)-4- hydroxytetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0290] (0.80 g, 0.157 mmol) in dioxane (5 mL) was added hydrogen chloride gas (5 mL) in dioxane. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL). It was then neutralized with 10% sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford 0.055 g of (+)-3-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)tetrahydro-2H- pyran-4-ol [0292], Compound 254 as a white solid. MS(M+l)+=408.4, 1H NMR (400 MHz, DMSO-d6) δ 7.60 (bs, 1H), 6.29 (bs, 1H), 6.03 (s, 1H), 4.85 (d, J = 5.5 Hz, 1H), 4.04 (bs, 1H), 3.95 - 3.80 (m, 3H), 3.39 (t, J = 11.2, 2H), 2.48 (s, 3H), 2.16 (s, 3H), 2.05 - 1.80 (m, 7H), 1.63 - 1.36 (m, 3H).
[00361] Example 108
Figure imgf000235_0001
0291 0293
[00362] Step 5[23]: The procedure is similar to step 1 [0292] in example 107. 0.060 g of tert-butyl (4,4-difluorocyclohexyl)(6-((-)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0291] gave 0.042 g of (-)-3-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)tetrahydro-2H- pyran-4-ol [0293], Compound 257 as a white solid. MS(M+1)+ = 408.4, 409.4. 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J = 7.7 Hz, 1H), 6.24 (bs, 1H), 6.06 (s, 1H), 5.39 (bs, 1H), 4.24 (s, 1H), 4.02 (bs, 1H), 3.97 - 3.80 (m, 1H), 3.80 - 3.54 (m, 3H), 2.82 (bs, 1H), 2.53 (s, 3H), 2.16 (s, 3H), 2.10 - 1.7 (m, 7H), 1.57 - 1.50 (m, 3H).
[00363] Example 109:
Figure imgf000235_0002
0291 0294 0295 0296
[00364] Step 1[0294 and 0295] : To an ice-cold solution of tert-butyl (4,4- difluorocyclohexyl)(2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(-4-hydroxytetrahydro-2H-pyran-3- yl)pyrimidin-4-yl)carbamate [0291] (0.240 g, 0.472 mmol) in dichloromethane (5 mL) was added diethylamino sulfur trifluoride (0.152 g, 0.945 mmol) drop wise. The reaction mixture was slowly warmed to rt and stirred for 2 h. The reaction mixture was diluted with dichloromethane (20 mL). The organic layer was washed with 10% sodium bicarbonate solution (10 mL), washed with water (10 mL), followed by brine (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by preparative HPLC to afford 0.050 g of tert-butyl (4,4- difluorocyclohexyl)(2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((3S,4R)-4-fluorotetrahydro-2H- pyran-3-yl)pyrimidin-4-yl)carbamate [0294] as a white solid. MS(M+1)+ = 410.4 and 0.08 g of tert-butyl (4,4-difluorocyclohexyl)(6-(5,6-dihydro-2H-pyran-3-yl)-2-(3,5-dimethyl- 1H- pyrazol-l-yl)pyrimidin-4-yl)carbamate [0295] as a white solid. MS(M+1)+ = 390.0
[00365] Step 2[0296] : To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(5,6- dihydro-2H-pyran-3-yl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)carbamate [0295] (0.08 g, 0.18 mmol) in dioxane (3 mL) was added hydrogen chloride gas in dioxane (3 niL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL). It was then neutralized with 10% sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford 0.060 g of N-(4,4- difluorocyclohexyl)-6-(5,6-dihydro-2H-pyran-3-yl)-2-(3,5-dimethyl-lH-pyrazol-l- yl)pyrimidin-4-amine [0296], Compound 262 as a white solid. MS(M+l)+=390.2, 391.2. 1H NMR (400 MHz, DMSO-d6) δ 7.66 (bs, 1H), 6.93 (bs, 1H), 6.27 (bs, 1H), 6.05 (s, 1H), 4.42 (s, 2H), 4.05 (bs, 1H), 3.74 (t, J = 5.4 Hz, 2H), 2.46 (s, 3H), 2.31 (bs, 2H), 2.17 (s, 3H), 2.10 - 1.85 (m, 6H), 1.60 - 155 (m, 2H).
[00366 Example 110
Figure imgf000236_0001
0241 0298 0299
[00367] Step 1[0298]: The procedure is similar to Step2 [0271] in example 98 (16 h). 0.4 g of 4,6-dichloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine [0241] gave 0.350 g of 4- chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(lH-pyrazol-l-yl)pyrimidine [0298] as an off- white solid.. MS(M+1)+ =275.
[00368] Step 2[0299]: The procedure is similar to Step2 [0271] in example 98 (16 h). 0.15 g of 4-chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(lH-pyrazol-l-yl)pyrimidine [0298] gave 0.04 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(lH-pyrazol- l-yl)pyrimidin-4-amine [0299], Compound 117 as an off-white solid. MS(M+l)+=374. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 6.85 (s, 1H), 6.59 (s, 1H), 6.13 (d, J = 2.8 Hz, 1H), 4.12 (bs, 1H), 2.61 (s, 3H), 2.20 (s, 3H), 2.15-1.85 (m, 6H), 1.68-1.50 (m, 2H).
[00369] Exam le 111:
Figure imgf000237_0001
[00370] Step 1[0301]: To a stirred solution of 0.500 g of 6-chloro-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] in 50% aqueous sodium hydroxide solution (2 mL), was added 0.331 g of (2-methyl-2H- 1,2,3- triazol-4-yl)methanol [0300] and tetra butyl ammonium hydrogen sulfate (0.200 g, 0.586 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction mixture was extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography to afford 0.22 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol- l-yl)-6-((2-methyl-2H-l,2,3-triazol-4-yl)methoxy)pyrimidin-4-amine [0301], Compound
191 as an white solid. MS(M+1)+ =419. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (bs, 1H), 7.51 (bs, 1H), 6.09 (s, 1H), 5.70 (bs, 1H), 5.36 (s, 2H), 4.14 (s, 3H), 4.01 (bs, 1H), 2.57 (s, 3H), 2.19 (s, 3H), 2.10 - 1.90 (m, 6H), 1.60-1.53 (m, 2H).
[00371] Exam le 112:
Figure imgf000237_0002
[00372] Step 1[0303] : The procedure is similar to step 1 [0301] in example 111. 0.250 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0242] and 0.165 g of (l-methyl-lH-l,2,3-triazol-5-yl)methanol [0302] gave 0.150 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l-methyl-lH-l,2,3-triazol-5- yl)methoxy)pyrimidin-4-amine [0303], Compound 126 as an white solid. MS(M+1)+=419. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (bs, 1H), 7.48 (bs, 1H), 6.09 (s, 1H), 5.70 (s, 1H), 5.36 (bs, 2H), 4.04 (s, 3H), 4.03 (m, 1H), 2.58 (s, 3H), 2.20 (s, 3H), 2.08 - 1.91 (m, 6H), 1.50-1.45 (m, 2H).
[00373] Ex mple 113:
Figure imgf000238_0001
0242 0305
[00374] Step 1[0305]: The procedure is similar to step 1[0301] in example 111. 0.150 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] gave 0.030 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l- methyl- 1 H- 1 ,2,4-triazol-5-yl)methoxy)pyrimidin-4-amine[0305] , Compound 274.
MS(M+1)+=418.2, 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.56 (bs, 1H), 6.08 (s, 1H), 5.76 (bs, 1H), 5.47 (s, 2H), 3.99 (s, 4H), 2.55 (s, 3H), 2.17 (s, 3H), 2.12 - 1.85 (m, 6H), 1.62 - 1.45 (m, 2H).
[00375] Exam le 114:
Figure imgf000238_0002
0242 0307
[00376] Step 1[0307] : The procedure is similar to step 2[0274] in Example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.09 g of (2-methyl-2H-l,2,3-triazol-4-yl)methanamine [0306] gave 0.03 g of N4- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6-((2-methyl-2H-l,2,3-triazol- 4-yl)methyl)pyrimidine-4,6-diamine [0307], Compound 235 as a light yellow solid.
MS(M+1)+=418, 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.32 (t, J = 5.8 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 5.98 (s, 1H), 5.35 (s, 1H), 4.43-4.39 (m, 2H), 4.08 (s, 3H), 3.80 (bs, 1H), 2.46 (s, 3H), 2.13 (s, 3H), 2.15-1.80 (m, 6H), 1.60-1.43 (m, 2H).
[00377] Exam le 115:
Figure imgf000239_0001
[00378] Step 1[0309] : The procedure is similar to step 2[0274] in Example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.09 g of (l-methyl-lH-l,2,3-triazol-4-yl)methanamine [0308] gave 0.04 g of N4- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-N6-((l-methyl-lH-l,2,3-triazol- 4-yl)methyl)pyrimidine-4,6-diamine [0309], Compound 233 as an off-white solid.
MS(M+1)+=418, 1H NMR (400 MHz, DMSO-d6) δ 8.09 (bs, 1H), 7.33 (t, J = 5.9 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.00 (s, 1H), 5.37 (s, 1H), 4.42 (d, J = 5.8 Hz, 2H), 4.00 (s, 3H), 3.81 (bs, 1H), 2.48 (s, 3H), 2.16 (s, 3H), 2.08 - 1.87 (m, 6H), 1.53-1.48 (m, 2H).
[00379] Example 116
Figure imgf000239_0002
0241 0310 0312 0313
[00380] Step 1[0310] : To a stirred solution of 4,6-dichloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidine [0241] (2 g, 8.227 mmol) in a mixture of solvent (tetrahydrofuran (20 mL) and water (2 mL)) was added sodium hydroxide (0.65 g, 16.454 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, neutralized with 1.5 N HCl solution (-0.5 mL), and extracted with ethyl acetate (3x50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.550 g of 6-chloro-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-ol [0310] as a white solid.
MS(M+1)+ = 225.2. [00381] Step 2[0312] : To a stirred solution of 6-chloro-2-(3,5-dimethyl- lH-pyrazol- 1- yl)pyrimidin-4-ol [0310] (0.50 g, 0.2226 mmol) in acetonitrile (2 mL) was added sodium chlorodifluoroacetate [0311] (0.54 g, 0.356 mmol) and sodium carbonate (0.47 g, 0.445 mmol). The reaction mixture was heated at 90 °C for 5 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 0.110 g of 4-chloro-6-(difluoromethoxy)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidine
[0312] as an off-white solid. MS(M+1)+ = 275.2/276.2.
[00382] Step 3[0313]: To a stirred solution of 4-chloro-6-(difluoromethoxy)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidine [0312] (0.1 g, 0.364 mmol) in acetonitrile (3 mL) was added 4,4-difluorocyclohexylamine hydrochloride (0.125 g, 0.728 mmol) and N,N- diisopropyl ethylamine (0.117 g, 0.91 mmol). The reaction mixture was irradiated in microwave at 130 °C for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 35% ethyl acetate in pet ether as solvent to afford 0.035 g of N-(4,4-difluorocyclohexyl)-6-(difluoromethoxy)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin- 4-amine [0313], Compound 209 as a white solid. MS(M+1)+ = 336.0/337.0. 1H NMR (400 MHz, DMSO-d6) δ 7.76- 7.40 (t, JF = 72.8 Hz, 1H), 7.65 (d, 8 Hz, 1H),6.07 (s, 1H), 5.94 (s, 1H), 3.94 (s, 1H),2.55 (s, 3H), 2.18 (s, 3H), 2.07 - 1.95 (m, 6H), 1.63- 1.61 (m, 2H).
[00383] Ex mple 117:
Figure imgf000240_0001
0242 0315
[00384] Step 1[55]: The procedure is similar to step 3[0313] in example 116. 0.5 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0242] gave 0.28 g of (R)-2-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-yl)amino)-3-methylbutanamide [0315], Compound 164 0.28 g of as a white solid. MS(M+l)+= 422.2. 1H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 7.01 (bs, 1H), 6.93 (bs, 1H), 6.71 (bs, 1H), 5.97 (s, 1H), 5.48 (bs, 1H), 4.23 (bs, 1H), 3.74 (bs, 1H), 2.47 (s, 3H), 2.12 (s, 3H), 2.10-2.00 (m, 3H), 2.00-1.80 (m, 4H), 1.62 - 1.48 (m, 2H), 0.95 (d, J = 0.68 Hz, 6H).
[00385] Example 118
Figure imgf000241_0001
0242 0317
[00386] Stepl[0317]: The procedure is similar to step 3[0313] in example 116. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0242] gave 0.020 g of N4-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- lH-pyrazol- l-yl)-N6- (oxazol-2-ylmethyl)pyrimidine-4,6-diamine [0317], Compound 145 as an light brown solid. MS(M+l)+=404, 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.48 (t, J = 6.0 Hz, 1H), 7.15 (s, 1H), 7.02 (d, J = 7.9 Hz, 1H), 5.98 (s, 1H), 5.43 (s, 1H), 4.55 (d, J = 5.9 Hz, 2H), 3.81 (bs, 1H), 2.42 (s, 3H), 2.13 (s, 3H), 2.06-1.90 (m, 6H), 1.50-1.60 (m, 2H).
[00387] Example 119:
Figure imgf000241_0002
0242 0318
[00388] Step-1 [0318]: To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] (15g, 43.88 mmol) in acetonitrile (200 mL) was added morpholine [0067] (15.29 g, 175.54 mmol) and the resultant reaction mixture was heated at 75 °C in sealed tube. The reaction mixture was quenched with water, the obtained solid was filtered dried under vacuum to afford N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine [0318] Compound 187 as an off-white solid (13.8 g). MS(M+l)+=393, 1H-NMR (400 MHz, DMSO-d6): δ 7.09 (d, J = 7.92 Hz, 1H), 6.00 (s, 1H), 5.56 (s, 1H), 3.86 (bs, 1H), 3.66 (m, 4H), 3.50 (m, 4H), 2.50 (s, 3H), 2.14 (s, 3H), 2.08-1.89 (m, 6H), 1.54-1.51 (m, 2H). [00389] Example 120:
Figure imgf000242_0001
[00390] Step 1: The procedure is similar to step 3[0313] in example 116. 0.15 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0242] and 0.088 g of 2-methyl morpholine [0319] gave 0.07 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(2-methylmorpholino)pyrimidin-4- amine [0320], Compound 188. MS(M+l)+=407, 1H-NMR (400 MHz, DMSO-d6): δ 7.07 (d, J = 8.00 Hz, IH), 6.01 (bs, IH), 5.57 (s, IH), 4.07-3.89 (m, 2H), 3.89-3.88 (m, 2H), 3.54-3.48 (m, 2H), 2.89-2.83 (m, IH), 2.57-2.54 (m, IH), 2.50 (s, 3H), 2.14 (s, 3H), 2.49-2.08 (m, 6H), 1.50-1.49 (m, 2H), 1.12 (d, J = Hz, 3H).
[00391] Example 121:
Figure imgf000242_0002
[00392] Step 1 [0322] : The procedure is similar to Step 2[0274] in example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.101 g of 2,6-dimethyl morpholine [0321] gave 0.07 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(2,6- dimethylmorpholino)pyrimidin-4-amine [0322], Compound 190. MS(M+1)+=421, 1H NMR (400 MHz, DMSO-d6) δ 7.07 (d, J = 8.0 Hz, IH), 6.01 (s, IH), 5.57 (s, IH), 4.08 (bs, 2H), 3.87 (bs, IH), 3.57 - 3.58 (m, 2H), 2.48 (s, 3H), 2.12 (s, 3H), 2.12 - 1.85 (m, 6H), 1.60-1.49 (m, 2H), 1.15 (d, J = 6.2 Hz, 6H). (angular Proton (2H) missing) [00393] Example 122:
Figure imgf000243_0001
0242 0324
[00394] Step 1 [0324] : The procedure is similar to Step 2[0274] in example 99. 0.15 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.127 g of 2-(morpholin-2-yl)propan-2-ol [0323] gave 0.050 g of 2-(4-(6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholin-2- yl)propan-2-ol [0324], Compound 227. MS(M+1)+=451, 1H NMR (400 MHz, DMSO-d6) δ 7.08 (d, J = 7.9 Hz, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 4.56 (s, 1H), 4.21 (bs, 1H), 4.11 - 3.82 (m, 3H), 3.49-340 (m, 1H), 3.16 (dd, J = 10.8, 2.4 Hz, 1H), 2.84 (t, J = 11.7 Hz, 1H), 2.70- 2.60 (m, 1H), 2.58 (s, 3H), 2.15 (s, 3H), 2.07 - 1.82 (m, 6H), 1.54-1.47 (m 2H), 1.16 (s, 3H), 1.10 (s, 3H).
[00395] Example 123:
Figure imgf000243_0002
0242 0326
[00396] Step 1[0326] : The procedure is similar to Step 2[0274] in example 99. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0242] and 0.196 g of 2-(methoxymethyl)morpholine [0325] gave 0.050 g of N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-(2-
(methoxymethyl)morpholino)pyrimidin-4-amine [0326], Compound 194. MS(M+l)+=437, 1H NMR (400 MHz, DMSO-d6) δ 7.10 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 5.57 (s, 1H), 3.80- 4.12 (m, 4H), 3.65-3.55 (m, 1H), 3.55-3.49 (m, 1H), 3.45-3.35 (m, 2H), 3.29 (s, 3H), 2.95 - 2.82 (m, 1H), 2.72 - 2.61 (m, 1H), 2.48 (s, 3H), 2.14 (s, 3H), 2.10-2.0 (m, 3H), 1.95-2.0 (m, 3H), 1.54-1.45 (m, 2H). [00397] Example 124:
Figure imgf000244_0001
0242 0328
[00398] Step 1[0328]: The procedure is similar to step 1[0301] in example 111. 0.25 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 0.16 g of (l-methyl-lH-l,2,3-triazol-5-yl)methanol [0327] gave 0.15 g of N- (4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l-methyl-lH-l,2,3-triazol-5- yl)methoxy)pyrimidin-4-amine [0328], Compound 189 as an white solid,
LCMS(MH+)=419, 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.53 (bs, 1H), 6.08 (s, 1H), 5.71 (bs, 1H), 5.47 (s, 2H), 4.11 (s, 3H), 3.43 (bs, 1H), 2.56 (s, 3H), 2.18 (s, 3H), 2.11 - 1.86 (m, 6H), 1.50-1.45 (m, 2H).
[00399] Example 126:
Figure imgf000244_0002
[00400] Step 1[0332]: To a suspension of sodium hydride (1.76 g, 44.039 mmol) in dry dichloromethane was added methyl pyrazole [0097] (3.61 g, 44.039 mmol) portion wise under N2 atm. The reaction mixture was stirred at rt for 30 min, then cooled to -78 °C, was added a solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine [0240] (10 g, 44.039 mmol) in dichloromethane drop wise. After addition the reaction mixture was stirred at -78 °C. After 1 h, the reaction mixture was quenched with water at -78 °C, slowly brought to rt and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to afford a yellow solid, which
was purified using ethyl acetate in hexane as solvent in column (60-120 silica gel) to afford 3 g of 4,6-dichloro-2-(3-methyl-lH-pyrazol-l-yl)pyrimidine[0332] as white solid. MS(M+1)+ = 230.0.
[00401] Step 2[0333] : 5 g of 4,6-dichloro-2-(methylsulfonyl) pyrimidine[0332] and 4.1 g of 4,4-difluorocyclohexylamine hydrochloride [0002] gave 3 g 6-chloro-N-(4,4- difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0333] as off-white solid (Using DIPEA, ACN 60 °C, 16h). MS(M+1) =328.2.
[00402] Example 127:
[00403] Step 3[0335]: The procedure is similar to step 4 [0244] in example 87. 0.3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] gave 0.11 g of l-(6-((4,4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)-3-methylazetidin-3-ol [0335], Compound 140 as white solid.
MS(M+l)+=379.2, 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.25 (d, J = 2.5 Hz, 1H), 5.63 (s, 1H), 5.17 (s, 1H), 3.99 (bs, 1H), 3.82 (q, J = 8.36 Hz, 4H), 2.24 (s, 3H), 2.12 - 1.85 (m, 6H), 1.62 - 1.49 (m, 2H), 1.43 (s, 3H).
[00404] Example
Figure imgf000245_0002
[00405] Step 3[0336]: The procedure is similar to step 3[0313] in Example 116 ( at 160 °C). 0.2 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0333] gave 0.058 g of N4-(4,4-difluorocyclohexyl)-N6-(3,3-dimethylcyclobutyl)-2- (3-methyl-lH-pyrazol-l-yl)pyrimidine-4,6-diamine [0336], Compound 156 as off-white sold. MS(M+1)+=391.4. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.7 Hz, 1H), 7.14 (d, J = 6.6 Hz, 1H), 6.91 (d, J = 7.7 Hz, 1H), 6.24 (d, J = 2.4 Hz, 1H), 5.17 (s, 1H), 3.90 (bs, 2H), 2.23 (s, 3H), 2.18 - 2.12 (m, 2H), 2.12 - 1.85 (m, 6H), 1.74 (d, J = 8.84 Hz, 2H), 1.62 - 1.48 (m, 2H), 1.24 (s, 3H), 1.08 (s, 3H). [00406] Example 129
Figure imgf000246_0001
0333 0337
[00407] Step 3[0337] : The procedure is similar to step 3[0313] in Example 116 ( at 160 °C). 0.2 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0333] gave 0.140 g of N4-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)- N6-neopentylpyrimidine-4,6-diamine [0337], Compound 146 as off-white solid. MS(M+1)+ =379.2. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.6 Hz, 1H), 6.90 - 6.71 (m, 2H), 6.24 (d, J = 2.5 Hz, 1H), 5.37 (s, 1H), 3.80 (bs, 1H), 3.06 (bs, 2H), 2.24 (s, 3H), 2.15 - 1.85 (m, 6H), 1.62 - 1.48 (m, 2H), 0.92 (s, 9H).
[00408] Example 130:
Figure imgf000246_0002
υ «° 0345 0344
[00409] Step 1[0340]: A stirred solution of maleic anhydride [0338] (10 g, 101.981 mmol) and benzyl amine [0339] (11.15 g, 101.981 mmol) in acetic acid (100 mL) was heated at 120 °C for 18 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to obtain l-benzyl-lH-pyrrole-2,5-dione [0340] as off-white solid (10 g, 52%).
[00410] Step 2[0342]: To a stirred suspension of l-benzyl- lH-pyrrole-2,5-dione
[0340] (13.377 g, 71.461 mmol) and potassium carbonate (9.876 g, 71.461 mmol) in acetonitrile (200 mL) was added a solution of bromonitromethane [0341] (10 g, 71.461 mmol) in acetonitrile (50 mL) under nitrogen atmosphere. Then the reaction mixture was stirred at rt for 18 h. The reaction mixture was filtered and washed with acetonitrile. The combined filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to obtain 3- benzyl-6-nitro-3-azabicyclo[3.1.0]hexane-2,4-dione [0342] as white solid (6.5 g, 37%).
[00411] Step 3[0343]: To a stirred solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane- 2,4-dione [0342] (8 g, 32.891 mmol) in tetrahydrofuran (100 mL) was added borane dimethyl sulfide complex (13.13 g, 162.455 mmol) at 0 °C under nitrogen. The reaction mixture was allowed slowly to warm to rt and then heated at 65 °C. The reaction mixture was cooled to 0°C, quenched with methanol (50 mL) and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane [0343] as a colorless gum (5 g, 71%).
[00412] Step 4[0344]: To a stirred solution of 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane [0343] (0.5 g, 2.291 mmol) in methanol (20 mL) was added Raney- nickel (0.03 g, 0.229 mmol) followed by hydrazine hydrate (1.147 g, 22.909 mmol). Then the mixture was heated at 60 °C for 8 h. The catalyst was filtered and washed with methanol (20 mL). The combined organic layer was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 2% methanol in chloroform as eluent to obtain 3- benzyl-3-azabicyclo[3.1.0]hexan-6-amine [0344] as colorless liquid (0.2 g, 46%).
MS(M+1)+=189.1.
[00413] Step 5[0345]. 0.5 g of 3-benzyl-3-azabicyclo[3.1.0]hexan-6-amine [0344] gave 0.5 g of tert-Butyl(3-benzyl-3-azabicyclo[3.1.0]hexan-6-yl)carbamate [0345], using triethylamine, boc-anhydride in tetrahydrofuran. MS(M+1)+=289.1.
[00414] Step 6[0346] : To a degassed solution of tert-Butyl (3-benzyl-3- azabicyclo[3.1.0]hexan-6-yl) carbamate [0345] (0.2 g, 0.694 mmol) in methanol (10 mL) was added palladium on carbon (0.04 g, 10% WAV) in a tiny clave hydrogen reactor. The mixture was hydrogenated under 50 psi hydrogen gas pressure for 18 h. The reaction mixture was filtered through a bed of celite and washed with methanol (20 mL). The combined filtrate was concentrated under reduced pressure to afford tert-butyl (3-azabicyclo[3.1.0]hexan-6-yl) carbamate [0346] as brownish liquid (0.1 g, 72%). It was taken as such for next step without further purification. [00415] Example 131:
Figure imgf000248_0001
[00416] Step 1[0347] The procedure is similar to Step 3[0313] in example 116 (at 180 °C). 0.2 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0333] and 0.1 g of tert-butyl (3-azabicyclo[3.1.0]hexan-6-yl) carbamate [0346] gave 0.2 g of tert-Butyl (3-(6-((4,4-difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)-3-azabicyclo [3.1.0]hexan-6-yl)carbamate [0347]. MS(M+l)+=490.2.
[00417] Step 2[0348] : A stirred solution of tert-Butyl (3-(6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)-3- azabicyclo[3.1.0]hexan-6-yl)carbamate [0347] (0.2 g, 0.409 mmol) in dichloromethane (5 mL) was cooled to 0 °C. Trifluoro acetic acid (0.235 g, 2.042 mmol) was added and the mixture was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure to afford crude which was purified by column chromatography using 2% methanol in chloroform as eluent to afford 3-(6-((4,4-difluorocyclohexyl)amino)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0] hexan-6-amine [0348], Compound 155 as white solid (60 mg, 37%). MS(M+l)+=390, 1H NMR (400 MHz, Acetone-d6) δ 8.48 (d, J = 2.6 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 4.03 (bs, 3H), 3.67 (d, J = 11.3 Hz, 2H), 3.40 (t, J = 2.4 Hz, 1H), 2.66 (s, 2H), 2.31 (s, 3H), 2.12 (s, 3H), 2.12 - 1.88 (m, 6H), 1.65 - 1.55 (m, 2H).
[00418] Example 133:
Figure imgf000249_0001
[00419] Step 1[0351] : To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0333] (4.1 g, 12.509 mmol) and tert-butyl 3- hydroxyazetidine-l-carboxylate [0021] (4.3 g, 25.018 mmol) in dioxane (40 mL) was added cesium carbonate (6.11 g, 18.763 mmol). The reaction mixture was heated at 100 °C in a sealed tube for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL). The organic layer was washed with water (20 mL), followed by brine (20 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by column chromatography using 45% ethyl acetate in pet ether as solvent to afford 2.1 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0351] as a yellow solid.
MS(M+1)+ = 465.0.
[00420] Step 2[0352] : To a cooled solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0351] (2.1 g, 4.52 mmol) in dioxane (10 mL) was added hydrogen chloride gas in dioxane (10 mL). The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to afford 2.1 g of 6-(azetidin-3-yloxy)-N-(4,4- difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0352] as a yellow color gum.
[00421] Step 3[0354] : To a cooled solution of 6-(azetidin-3-yloxy)-N-(4,4- difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0352] (0.25 g, 0.686 mmol) in dichloro methane (3 mL) was added triethylamine (0.1 mL, 0.754 mmol), followed by iso-butyryl chloride [0353] (73 g, 0.686 mmol). The reaction mixture was stirred at rt for 1 h and diluted with dichloro methane (20 mL). The organic layer was washed with 10% sodium bicarbonate solution (10 mL), followed by water (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate to afford 0.2 g of crude product which was purified by preparative HPLC to afford 0.06 g of l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- 1-yl)- 2-methylpropan-l-one [0354], Compound 210 as a white solid. MS(M+l)+=435.5, 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 2.4 H z, IH), 7.34 (d, J = 7.6 Hz, IH), 6.30 (d, J = 2.5 Hz, IH), 5.74 (s, IH), 5.40 - 5.35 (m, IH), 4.58 - 3.57 (m, 5H), 2.27 (s, 3H), 2.05 - 1.85 (m, 7H), 1.60 - 1.50 (m, 2H), 1.01 (d, J = 6.9 Hz, 6H).
[00422] Example 134
Figure imgf000250_0001
[00423] Step 1[77]: The procedure is similar to step 3[0354] in example 133. 0.8 g of 6- (azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0352] and 0.2 g of methyl chloroformate [0026] gave 0.32 g of 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0355], Compound 205 as a white solid. MS(M+l)+=423.4. IH NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.40 Hz, IH), 7.31 (d, J = 7.60 Hz, IH), 6.29 (d, J = 2.80 Hz, IH), 5.72 (s, IH), 5.41-5.38 (m, IH), 4.37-4.33 (m, 2H), 3.94-3.91 (m, 3H), 3.60 (s, 3H), 2.33 (s, 3H), 2.32-2.09 (m, 6H), 2.05-2.04 (m, 2H).
[00424 Example 135:
Figure imgf000250_0002
[00425] Step 1[0357]: The procedure is similar to step 3[0354] in example 133. 0.8 g of 6-(azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4- amine [0352] and 0.26 g of pivaloyl chloride [0356] gave 0.4 g of l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- 1-yl)- 2,2-dimethylpropan-l-one [0357], Compound 211 as a white solid. MS(M+l)+=449.4. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.6 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.29 (d, J = 2.6 Hz, 1H), 5.73 (s, 1H), 5.39 (tt, J = 6.6, 4.1 Hz, 1H), 4.52 (s, 2H), 4.07 (d, J = 7.9 Hz, 2H), 3.93 (s, 1H), 2.27 (s, 3H), 2.09 - 1.89 (m, 6H), 1.62 (d, J = 11.4 Hz, 2H), 1.14 (s, 9H).
[00426] Example 136
Figure imgf000251_0001
0333 0358
[00427] Step 1[45]: The procedure is similar to step 4 [0244] in example 87. 0.4 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.178 g of 3-Oxetanamine [0243] gave 0.07 g of N4-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)-N6-(oxetan-3-yl)pyrimidine-4,6-diamine [0358], Compound 141 as yellow solid. MS(M+l)+=364.8. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.66 (d, J = 5.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.25 (d, J = 2.5 Hz, 1H), 5.22 (bs, 1H), 4.79 (t, J = 6.5 Hz, 3H), 4.48 (t, J = 5.64 Hz, 2H), 3.87 (bs, 1H), 2.24 (s, 3H), 2.15 - 1.85 (m, 6H), 1.54 - 1.45 (m, 2H).
[00428] Example 137:
Figure imgf000251_0002
[00429] Step 1[0360]: The procedure is similar to step 4 [0244] in example 87. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.22 g of N,N-dimethylazetidin-3-amine dihydrochloride [0359] gave 0.08 g of N-(4,4- difluorocyclohexyl)-6-(3-(dimethylamino)azetidin- l-yl)-2-(3-methyl- IH-pyrazol- 1- yl)pyrimidin-4-amine [0360], Compound 143 as a yellow solid. MS(M+1)+=392.1, 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 2.6 Hz, 1H), 5.17 (s, 1H), 3.99 (t, J = 7.8 Hz, 2H), 3.74 (dd, J = 8.7, 5.2 Hz, 2H), 3.20 - 3.12 (m, 1H), 2.24 (s, 3H), 2.12 (s, 6H), 2.05 - 1.88 (m, 6H), 1.78 (bs, 1H) 1.60 - 1.48 (m, 2H).
[00430] Example 138:
Figure imgf000252_0001
0333 0361
[00431] Step 1[0361]: To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0333] (0.3 g, 0.915 mmol) in acetonitrile (6 niL) was added 3,3-difluorocyclobutanamine hydrochloride [0111] (0.26 g, 1.83 mmol) and N,N- diisopropyl ethylamine (0.236 g, 1.83 mmol). The reaction mixture was heated at 180 °C under microwave for 5 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 40% ethyl acetate in pet ether to afford 0.130 g of N4-(3,3-difluorocyclobutyl)-N6-(4,4-difluorocyclohexyl)-2- (3-methyl-lH-pyrazol-l-yl)pyrimidine-4,6-diamine [0361], Compound 147 as a white solid. MS(M+l)+=399.2. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.42 (d, J = 6.1 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H), 6.24 (d, J = 2.5 Hz, 1H), 5.24 (s, 1H), 4.08 (bs, 1H), 3.89 (bs, 1H), 3.10 - 2.90 (m, 2H), 2.64 - 2.53 (m, 2H), 2.23 (s, 3H), 2.15 - 1.84 (m, 6H), 1.60 - 1.49 (m, 2H).
[00432] Example 139:
Figure imgf000252_0002
[00433] Step 2[0362] : 0.3 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- 1H- pyrazol-l-yl)pyrimidin-4-amine [0333] and 0.3 g of tert-butyl 3-hydroxyazetidine-l- carboxylate [0021] gave 0.05 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0362], Compound 151 as a yellow solid. (Using CS2C03, Dioxane, 100 °C, 18h) MS(M+l)+=465.0, 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, IH), 7.63 (bs, IH), 6.32 (d, J = 2.5 Hz, IH), 5.70 (s, IH), 5.33 (s, IH), 4.28 (bs, 2H), 3.83 (d, J = 7.6 Hz, 2H), 2.26 (s, 3H), 2.15 - 1.85 (m, 7H), 1.60 - 1.49 (m, 2H), 1.39 (s, 9H).
[00434] Example 140:
Figure imgf000253_0001
[00435] Step 1[0364]: The procedure is similar to step 1[0361] in example 138. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.156 g of 1- (aminomethyl)-N,N-dimethylcyclobutane-l-amine[0363] gave 0.08 g of N4-(4,4-difluorocyclohexyl)-N6-((l-(dimethylamino)cyclobutyl)methyl)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidine-4,6-diamine [0364], Compound 157 as a white solid.
MS(M+1)+=420.1, 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 6.93 (bs, IH), 6.27 (s, IH), 5.41 (s, IH), 3.81-3.4 (m, 3H), 2.33-2.16 (m, 8H), 2.15-1.98 (m, 5H), 1.97-1.85 (m, 4H), 1.84-1.60 (m, 5H), 1.60-1.49 (m, 2H).
[00436] Example 141:
Figure imgf000253_0002
0365 0366 0367 0368
[00437] Step 1[0366]: To a solution of dl-a-amino-e-caprolactam [0365] (3 g, 23.405 mmol) in dichloro methane (30 mL) was added triethylamine (2.36 g, 23.405 mmol) and followed by slow addition of boc-anhydride (5.1 g, 23.405 mmol) at 0°C under N2 atm. The resultant reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure to afford 4.2 g of tert-butyl (2-oxoazepan-3-yl)carbamate [0366] as a white solid. MS(M+1)+ = 229. [00438] Step 2[0367]: To a solution of tert-butyl (2-oxoazepan-3-yl)carbamate [0366] in N,N-dimethylformamide (8 mL) was added sodium hydride (0.197 g, 4.81 mmol), the resultant reaction mixture was stirred at rt for 30 min. Then was added iodoethane and stirred at rt for 3 h. The reaction mixture was quenched with ice-cold water (20 mL). The white solid formed was filtered, washed with water and dried under vacuum to afford 0.7 g of tert-butyl (l-ethyl-2-oxoazepan-3-yl)carbamate [0367] as a white solid. MS(M+1)+ = 257.
[00439] Step 3 [0368]: To a cooled solution of tert-butyl (l-ethyl-2-oxoazepan-3- yl)carbamate [0367] (0.7 g, 2.73 mmol) in dioxane (10 mL) was added HC1 in dioxane (20 mL) at 0 °C. The resultant reaction mixture was slowly warmed to rt and stirred for 8 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was triturated with diethyl ether to afford 0.51 g of 3-amino-l-ethylazepan-2-one [0368] as a yellow solid. MS(M+1)+=157.
[00440] Step 4[0369]: To a suspension of 3-amino-l-ethylazepan-2-one [0368] in tetrahydrofuran (10 mL) was added borane dimethyl sulfide complex (1.44 g, 17.922 mmol) drop wise under N2 atm. The resultant reaction mixture was heated at 70 °C for 16 h. The reaction mixture was basified with 10% sodium bicarbonate solution (10 mL) to adjust the pH (8-9). Then the aqueous layer was extracted with ethyl acetate (2x50 mL). The combined extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford l-ethylazepan-3-amine [0369] as a yellow liquid (0.54 g). MS(M+1)+=143.
[00441] Example 142:
Figure imgf000254_0001
[00442] Step 1[0370]: The procedure is similar to step 1[0361] in example 138. 0.2 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine [0333] and 0.17 g of l-ethylazepan-3-amine [0369] gave 0.02 g of N4-(4,4-difluorocyclohexyl)-N6- (l-ethylazepan-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidine-4,6-diamine [0370],
Compound 158 as a yellow solid. MS(M+l)+=434.4. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, IH), 6.91 (bs, IH), 6.54 (bs, IH), 6.27 (bs, IH), 5.34 (bs, IH), 3.87 (bs, 2H), 2.25 (s, 3H), 2.05 (bs, 4H), 1.91 (s, 7H), 1.73 - 1.49 (m, 9H), 1.10 - 0.98 (bs, 3H).
[00443] Example 143:
Figure imgf000255_0001
0373 0374
[00444] Step 1[0371] : To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-amine [0333] (0.5 g, 1.52 mmol) in tetrahydrofuran (50 mL) was added boc-anhydride (998 g , 4.57 mmol) followed by 4-N,N-dimethylamino pyridine (35 g, 0.289 mmol). The reaction mixture was heated at 85 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford 0.8 g crude product which was purified by column chromatography using 15% ethyl acetate in pet ether as solvent to afford 0.6 g of tert-butyl (6-chloro-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)(4,4- difluorocyclohexyl)carbamate [0371] as a white solid. MS(M+l)+=428.3
[00445] Step 2[0372] : To a solution of tetrahydro-4h-pyran-4-One [0288] (0.46 g, 4.67 mmol) in tetrahydrofuran (10 mL) was added lithium bis(trimethylsilyl) amide (1 M solution in tetrahydrofuran ) (4.6 mL, 4.67 mmol) at 0 °C. After 30 min, tert-butyl (6-chloro-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)(4,4-difluorocyclohexyl)carbamate [0371] (0.5 g, 1.168 mmol) was added to the reaction mixture at 0 °C, drop wise in tetrahydrofuran (5 mL). After addition the reaction was stirred at rt for 18 h, quenched with water (5 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulfate and concentrated to afford crude product which was purified by preparative HPLC to afford 0.1 g of tert-butyl (4,4- difluorocyclohexyl)(2-(3-methyl-lH-pyrazol-l-yl)-6-(4-oxotetrahydro-2H-pyran-3- yl)pyrimidin-4-yl)carbamate [0372] as a yellow solid. MS(M+l)+=492.2.
[00446] Step 3[0373] : To a solution of tert-butyl (4,4-difluorocyclohexyl)(2-(3-methyl- lH-pyrazol-l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0372] (0.5 g, 0.101 mmol) in methanol (1 mL) was added sodium borohydride (0.038 g, 0.101 mmol). The reaction mixture was stirred at rt for 10 min, concentrated under reduced pressure, added with 10% sodium bicarbonate (5 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by preparative HPLC to afford 0.02 g of tert-butyl (4,4-difluorocyclohexyl)(6-(4-hydroxytetrahydro-2H-pyran-3- yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0373] as a white solid.
MS(M+l)+=494.2
[00447] Step 4[0374] : To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(4- hydroxytetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0373] (0.05 g, 0.101 mmol) in dioxane (2 mL) was added hydrogen chloride gas in dioxane (2 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (1 mL) and neutralized with 10% sodium bicarbonate (5 mL) solution. The aqueous layer was extracted with ethyl acetate (2=x=20 mL). The combined organic layer was washed with water (5 mL), followed by brine (5 mL) and dried over anhydrous sodium sulfate to afford 0.035 g of 3-(6-((4,4- difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)tetrahydro-2H- pyran-4-ol [0374], Compound 232 as a white solid. MS(M+l)+= 394.5, 395.5. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 6.31 (d, J = 2.5 Hz, 1H), 6.21 (bs, 1H), 5.29 (bs, 1H), 4.26 (bs, 1H), 4.15 (bs, 1H), 3.88 - 3.85 (m, 1H), 3.78 - 3.71 (m, 2H), 3.64 - 3.61 (m, 1H), 2.90 - 2.75 (m, 1H), 2.26 (s, 3H), 2.06 - 1.85 (s, 6H), 1.85 - 1.73 (m, 1H), 1.65 - 1.49 (m, 3H).
00448] Example 144:
Figure imgf000257_0001
[00449] Step 1[0375] : To an ice-cold solution of tert-butyl (4,4-difluorocyclohexyl)(2-(3- methyl- IH-pyrazol- l-yl)-6-(4-oxotetrahydro-2H-pyran-3-yl)pyrimidin-4-yl)carbamate [0372] (0.08 g, 0.162 mmol) in dichloromethane (1 mL) was added diethylamino sulfur trifluoride (0.043 mL, 0.325 mmol) drop wise. The reaction mixture was slowly warmed to rt, stirred for 1 h, quenched with 10% sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 0.05 g of tert- butyl (4,4-difluorocyclohexyl)(6-(4,4-difluorotetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)carbamate [0375] as a yellow solid. MS(M+1)+=514.5
[00450] Step 2[0376] : To a cooled solution of tert-butyl (4,4-difluorocyclohexyl)(6-(4,4- difluorotetrahydro-2H-pyran-3-yl)-2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)carbamate [0375] (0.04 g, 0.077 mmol) in dioxane (2 mL) was added hydrogen chloride gas in dioxane (2 mL). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was dissolved in water (1 mL) and neutralized with 10% sodium bicarbonate solution (10 mL). The aqueous layer was extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford 0.03 g of N-(4,4-difluorocyclohexyl)-6-(4,4- difluorotetrahydro-2H-pyran-3-yl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine [0376] as a white solid., Compound 242 MS(M+1)+ = 414.5, 415. 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.76 (s, 1H), 6.41 (s, 1H), 6.36 - 6.26 (m, 1H), 4.17 (s, 2H), 3.99 (s, 2H), 3.64 (s, 1H), 2.55 (s, 1H), 2.26 (s, 2H), 2.18 (s, 1H), 2.05 (s, 2H), 1.96 (s, 2H), 1.56 (s, 2H). [00451] Example 145:
Figure imgf000258_0001
[00452] Step 1[0377] : To a suspension of 4,6-dichloro-2-(methylthio)pyrimidine [0029] (10 g, 51.26 mmol) in N,N-dimethylformamide (50 mL) was added 3,5-dimethyl pyrazole [0017] (4.9 g, 51.26 mmol), followed by cesium carbonate (25.05 g, 76.89 mmol) and the reaction mixture was heated at 80 °C . After 16 h, the reaction mixture was filtered and washed with chloroform. The filtrate was concentrated under reduced pressure and the residue was triturated with water. The solid formed was filtered, washed with water and dried under vacuum to afford 10 g of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio)pyrimidine [0377] as an off-white solid. MS(M+l)+=255.2.
[00453] Step 2[0378]: To a solution of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio) pyrimidine [0377] (10 g, 39.255 mmol) in dichloro methane (250 mL) was added 3-chloroperbenzoic acid (20.3 g, 117.36 mmol) in portion-wise at 0 °C. The reaction mixture was slowly warmed to rt. After 6 h, the reaction mixture was diluted with
dichloromethane, washed with saturated sodium thiosulfate solution and followed by 10% sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 9 g of 4-chloro-6-(3,5-dimethyl- lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidine [0378] as an off-white solid.
MS(M+l)+=287.0.
[00454] Step 3[0379] : To the solution of 4-chloro-6-(3,5-dimethyl- lH-pyrazol- l-yl)-2- (methylsulfonyl)pyrimidine [0378] (2 g, 6.97 mmol) and N-Boc-2,5-Diaza- Bicyclo[2.2.1]Heptane [0254] (1.38 g, 6.97 mmol) in Ν,Ν-dimethylformamide was added cesium carbonate (3.4 g, 10.46 mmol) in closed vial and the reaction mixture was heated at 60 °C. After 1 h, the reaction mixture was added water and stirred for 10 min. The solid formed was filtered off and the filtrate was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a white solid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent to afford 1.8 g of t-butyl (lR,4R)-5-(6-(3,5-dimethyl- lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate [0379] as white solid. MS(M+1)+ = 449.3.
[00455] Example 146:
Figure imgf000259_0001
[00456] Step 1[0380]: To the solution of t-butyl (lR,4R)-5-(6-(3,5-dimethyl-lH-pyrazol- l-yl)-2-(methylsulfonyl) pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate
[0379] (0.4 g, 0.891 mmol) and 4,4-difluorocyclohexylamine hydrochloride [0002] (0.153 g, 0.891 mmol) in dimethylsulfoxide was added cesium carbonate (0.581 g, 1.783 mmol) in closed vial and the reaction mixture was heated at 100 °C. After 1 h, the reaction mixture was quenched with water and stirred for 10 min. The solid formed was filtered, washed with water and hexane to afford a white solid which was purified in the Reveleris flash system using ethyl acetate in hexane as eluent to afford 0.08 g of tert-butyl (lR,4R)-5-(2-((4,4- difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)-2,5- diazabicyclo [2.2. l]heptane-2-carboxy late [0380] as white solid. MS(M+l)+=504.5.
[00457] Step 2[0381]: To a cooled solution of hydrogen chloride gas in in dioxane (1.87 g, 51.39 mmol) was added tert-butyl (+)-5-(2-((4,4-difluorocyclohexyl)amino)-6-(3,5- dimethyl- lH-pyrazol- 1-yl) pyrimidin-4-yl)-2,5-diazabicyclo[2.2. l]heptane-2-carboxylate [0380], (0.07 g, 0.139 mmol) and the reaction mixture was slowly warmed to rt. After 30 min, the reaction mixture was concentrated under reduced pressure to afford a yellow gum which was triturated with diethyl ether and decanted. The residue was dried under vacuum to afford 0.05 g of 4-((lR,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(4,4-difluorocyclohexyl)- 6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-2-amine [0381], Compound 104 as a yellow solid. MS(M+l)+=404.4. 1H NMR (400 MHz, DMSO-d6) δ 9.57 (bs, 1H), 9.06 (bs, 1H), 6.12 (s, 1H), 4.95 (bs, 1H), 4.49 (s, 1H), 3.87 (m, 1H), 3.32 (m, 4H), 3.24 (m, 2H), 2.61 (s, 3H), 2.19 (s, 3H), 2.08 (m, 3H), 1.93 (m, 4H), 1.59 (m, 2H). [00458] Example 147:
Figure imgf000260_0001
[00459] Step 1[0382]: To a solution of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio)pyrimidine [0377] (1 g, 3.92 mmol) and morpholine-2-carboxamide [0269] (0.76 g, 5.88 mmol) in DMSO (8 mL) was added cesium carbonate (2.55 g, 7.85 mmol) then the reaction mixture was heated at 80 °C in a closed vial for 16 h. After the completion of the reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x70 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an brownish gum and which was purified by column of silica gel (60-120 mesh) using 85% ethyl acetate in hexane as eluent to afford 0.6 g of 4-(6-(3,5- dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidin-4-yl)morpholine-2-carboxamide
[0382] as an off-white solid. MS(M+1)+ =349.
[00460] Step 2[0383] : The procedure is similar to Step2[0378] in example 145. 0.6 g of 4- (6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidin-4-yl)morpholine-2-carboxamide [0382] gave 0.4 g of 4-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4- yl)morpholine-2-carboxamide [0383] as an white solid, MS(M+1)+ =381.
[00461] Step 3[0384]: To a solution of 4-(6-(3,5-dimethyl- lH-pyrazol-l-yl)-2- (methylsulfonyl) pyrimidin-4-yl)morpholine-2-carboxamide [0383] (0.2 g, 0.525 mmol) and 4,4-difluoro cyclohexylamine hydrochloride [0002] (0.18 g, 1.05 mmol) in ethanol (8 mL) was added Ν,Ν-diisopropyl ethylamine (0.27 g, 2.10 mmol). The reaction mixture was heated at 90 °C in a closed vial (20 mL) for 5 days. The reaction mixture was concentrated to afford as an brownish gum, which was purified by column
using 2% methanol in chloroform as eluent to afford 35 g of 4-(2-((4,4- difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholine-2- carboxamide [0384], Compound 114 as an off-white solid. MS(M+l)+=436, 1H-NMR (400 MHz, DMSO-d6): δ 7.38 (m, 1H), 7.16 (bs, 1H), 6.78 (d, J = 7.56 Hz, 1H), 6.30 (s, 1H), 6.05 (s, 1H), 4.90 (bs, 1H), 4.26 (bs, 1H), 3.85 (dd, J = 7.00, 27.24 Hz, 2H), 3.63 (s, 1H), 3.50- 3.44 (m, 2H), 2.59 (s, 3H), 2.16 (s, 3H), 2.15-1.80 (m, 6H), 1.61-1.55 (m, 2H). [00462] Example 148:
Figure imgf000261_0001
[00463] Step 1 [0385]: To a solution of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylsulfonyl) pyrimidine [0378] (3 g, 10.46 mmol) and piperazine-2-carboxamide
[0257] (1.48 g, 11.50 mmoll.) in N,N-dimethylformamide (15 mL) was added cesium carbonate (5.11 g, 15.69 mmol) and the reaction mixture was heated at 80 °C for 1 h. The reaction mixture was quenched with ice-cold water, the obtained solid was filtered, washed with hexane, dried under high vacuum to afford unidentified off-white solid. The aqueous layer was extracted with chloroform (3x100 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 1.5 g as an brownish gum, which was purified by column of silica gel (60-120 mesh) using 21% methanol in chloroform as eluent to afford 4-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4- yl)piperazine-2-carboxamide [0385] as an off-white gum. MS(M+1)+ =380.
[00464] Step 2[0386]: To a solution of 4-(6-(3,5-dimethyl- lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidin-4-yl)piperazine-2-carboxamide [0385] (0.5 g, 1.31 mmol) and 4,4-difluorocyclohexylamine hydrochloride [0002] (0.45 g, 2.63 mmol) in dimethylsulfoxide (10 mL) was added cesium carbonate (1.28 g, 3.95 mmol) and the reaction mixture was heated at 100 °C in a closed vial (20 mL) for 16 h. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.041 g of 4-(2-((4,4- difluorocyclohexyl) amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperazine-2- carboxamide [0386], Compound 106 as an brownish gum. MS(M+l)+=435, 1H-NMR (400
MHz, DMSO-d6): δ 7.33 (bs, 1H), 7.17 (bs, 1H), 6.78 (bs, H), 6.37 (s, 1H), 6.06 (s, 1H), 4.23 (bs, 1H), 3.96 (bs, 1H), 3.84 (bs, 1H), 3.19-3.17 (m, 1H), 2.96-2.92 (m, 4H), 2.68-2.61 (m, 5H), 2.18 (s, 3H), 2.09-2.06 (m, 2H), 1.91-1.85 (m, 3H), 1.59-1.56 (m, 3H). [00465] Example 149:
Figure imgf000262_0001
[00466] Step 1[0387]: The procedure is similar to Stepl [0377] in example 145. 0.5 g of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidine [0377] and 0.194 g of 2-oxa-6-azaspiro[3.3]heptane [0259] gave 0.5 g of 6-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio)pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane [0387] as an white solid.
MS(M+1)+ =318.
[00467] Step 2[0388]: The procedure is similar to Step 2[0378] in example 145. 0.5 g of 6-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidin-4-yl)-2-oxa-6- azaspiro[3.3]heptane [0387] gave 0.52 g of 6-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylsulfonyl)pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3] heptane [0388] as an brownish gum, MS(M+1)+ =350.
[00468] Step 3[0389]: The procedure is similar to Stepl [0382] in example 147 (at 100 °C). 0.45 g of 6-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4-yl)-2- oxa-6-azaspiro [3.3] heptane [0388] gave 0.055 g of N-(4,4-difluorocyclohexyl)-4-(3,5- dimethyl-lH-pyrazol-l-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-amine [0389], Compound 108 as an white solid. MS(M+l)+=405, 1H-NMR (400 MHz, DMSO-d6): δ 6.94 (bs, 1H), 6.06 (s, 1H), 5.96 (s, 1H), 4.70 (s, 4H), 4.16 (s, 4H), 3.83 (bs, 1H), 2.59 (s, 3H), 2.16 (s, 3H), 2.10-1.82 (m, 6H), 1.56-1.53 (m, 2H).
[00469] Example 150:
Figure imgf000262_0002
[00470] Step 1[0390] : To a solution of 4-chloro-6-(3,5-dimethyl- lH-pyrazol- l-yl)-2- (methylthio)pyrimidine [0377] (4 g, 15.702 mmol) in Ν,Ν-dimethyl formamide (40 mL) was added 2-amino propanamide (1.38 g, 15.702 mmol), followed by cesium carbonate (7.67 g, 23.553 mmol) and the reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with ice. The solid formed was filtered to afford crude product which was purified by column chromatography using 50% ethyl acetate in hexane as solvent to afford 2.5 g of 2-((6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylthio)pyrimidin-4- yl)amino)propanamide [0390] as a yellow solid. MS(M+l)+=307.3
[00471] Step 2[0391]: The procedure is similar to step 2[0378] in example 145. 2.7 g of 2- ((6-(3,5-dimethyl- lH-pyrazol- l-yl)-2-(methylthio)pyrimidin-4-yl)amino)propanamide [0390] gave 0.62 g of 2-((6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4- yl)amino)propanamide [0391] as a yellow solid. MS(M+1)+ = 339.2
[00472] Step 3[100]: The procedure is similar to Stepl [0382] in example 147 (at 100 °C). 0.37 g of 2-((6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4- yl)amino)propanamide [0391] gave 0.05 g of 2-((2-((4,4-difluorocyclohexyl)amino)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)amino)propanamide [0392], Compound 107 as an off-white solid. MS(M+1)+ = 394.3. 1H NMR (400 MHz, DMSO-d6) δ 7.45 - 6.81 (m, 3H), 6.63 (d, J = 7.5 Hz, 1H), 6.24 (s, 1H), 6.03 (s, 1H), 4.34 (bs, 1H), 3.83 (bs, 1H), 2.59 (s, 3H), 2.16 (s, 3H), 2.12 - 1.75 (m, 6H), 1.65 - 1.45 (m, 2H), 1.28 (d, J = 7.1 Hz, 3H).
[00473] Example 151:
Figure imgf000263_0001
o
0395
[00474] Step 1[0393]: To a solution of 4-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio)pyrimidine [0377] (10 g, 39.255 mmol) in N,N-dimethylformamide (80 mL) was added 1-acetylpiperazine (5.03 g, 39.255 mmol) and cesium carbonate (19.18 g, 58.88 mmol). The reaction mixture was heated at 60 °C in a closed vial in a thermal block for 8 h. The reaction mixture was quenched with ice. The solid formed was filtered to afford 10.3 g of l-(4-(6-(3,5-dimethyl- IH-pyrazol- l-yl)-2-(methylthio)pyrimidin-4-yl)piperazin- l-yl)ethan- 1- one [0393] as a yellow solid. MS(M+1) + = 347.4.
[00475] Step 2[0394]: To a stirred solution of l-(4-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2- (methylthio)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one [0393] (5 g, 14.431 mmol) in dichloromethane (50 mL), 3-chloroperbenzoic acid (6.22 g, 36.079 mmol) was added portion- wise at 0 °C. The reaction mixture was stirred at rt for 3 h, diluted with
dichloromethane (50 mL), washed with saturated solution of sodium thio sulfate (25 mL), followed by 10% sodium bicarbonate solution (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate to afford 4.5 g of l-(4-(6-(3,5- dimethyl- IH-pyrazol- l-yl)-2-(methylsulfonyl)pyrimidin-4-yl)piperazin- l-yl)ethan- 1-one [0394] as a yellow solid. MS(M+1) +=379.0.
[00476] Step 3[0395]: 1 The procedure is similar to step 1[0382] in example 147 (at 100 °C). 0.5 g of l-(4-(6-(3,5-dimethyl-lH-pyrazol-l-yl)-2-(methylsulfonyl)pyrimidin-4- yl)piperazin-l-yl)ethan- 1-one [0394] gave 0.070 g of l-(4-(2-((4,4- difluorocyclohexyl)amino)-6-(3,5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4-yl)piperazin- 1- yl)ethan- 1-one [0395], Compound 101 as a white solid. MS(M+l)+= 434.4. 1H NMR (400 MHz, DMSO-d6) δ 6.84 (d, J = 6.84 Hz, 1H), 6.38 (s, 1H), 6.07 (s, 1H), 3.86 (s, 1H), 3.63 (s, 2H), 3.54 - 3.47 (m, 6H), 2.61 (s, 3H), 2.18 (s, 3H), 2.04 (s, 5H), 1.99 - 1.85 (m, 4H), 1.58 - 1.55 (m, 2H).
[00477] Example 152:
Figure imgf000265_0001
0399 0400
[00478] Step 1[0396]: To a suspension of sodium hydride (2.46 g, 61.65 mmol) in dichloromethane was added ethyl lh-pyrazole-3-carboxylate [0005] (8.81 g, 61.65 mmol) at 0 °C and the reaction mixture was stirred at rt. After 1 h, 4,6-dichloro-2- (methylsulfonyl)pyrimidine [0240] (14 g, 61.65 mmol) in dichloromethane was added to the reaction mixture at -78 °C. The reaction mixture was stirred at same temperature for 2 h, quenched with water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 16.5 g of ethyl l-(4,6-dichloropyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0396] as an off-white solid. MS(M+1)+ =288.2.
[00479] Step 2[0397] : 16 g of l-(4,6-dichloropyrimidin-2-yl)- lH-pyrazole-3-carboxylate [0396] gave 21 g of ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0397] as an off-white solid (Using DIPEA, ACN, rt, 16 h)
[00480] Step 3[0398]: To an ice cooled solution of ethyl l-(4-chloro-6-((4,4- difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0397] in
tetrahydrofuran (20 mL) was added lithium borohydride. The reaction mixture was slowly brought to rt (1 h). After completion, the reaction mixture was quenched with water and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.7 g of methyl (l-(4-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0398] as an off-white solid. MS(M+1)+ =344. [00481] Step 4[0399]: To an ice cooled solution of methyl (l-(4-chloro-6- ((4,4difluorocyclohexyl)amino) pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0398] in dichloromethane (15 mL) was added diethylamino sulphur trifluoride. The reaction mixture was slowly warmed to rt and stirred for 30 min. After completion, the reaction mixture was quenched with saturated bicarbonate solution and extracted dichloromethane (2x75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an light brownish gum and which was purified by column chromatography using 40% ethyl acetate in hexane as to afford 0.450 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0399] as an off-white gum. MS(M+1)+ =346.
[00482] Step 5[0400] : To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0399] in acetonitrile (10 mL) was added 2-oxa-6-azaspiro(3,3)heptane [0259] and cesium carbonate. The reaction mixture was irradiated at 100 °C in MW for 1 h. After the completion, the reaction mixture was filtered to remove cesium carbonate. The filtrate was concentrated to afford brownish gum and which was purified by column chromatography using 75% ethyl acetate in hexane to afford N-(4,4- difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyrimidin-4-amine [0246], Compound 338 as an off-white solid 0.21 g, MS(M+1)+ =409. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 5.49 (d, JF =48.5 Hz, 2H), 5.22 (s, 1H), 4.73 (s, 4H), 4.15 (s, 4H), 2.08 - 1.88 (m, 6H), 1.54-1.52 (m, 2H).
[00483] Example 153:
Figure imgf000266_0001
[00484] Step 1[0401]: To a stirred solution of (l-(4-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0398] (3.4 g, 9.89 mmol) and imidazole (1.753 g, 14.836 mmol) in dichloro methane (50 mL) was added tert- butyl dimethylsilyl chloride (1.8 g, 11.868 mmol) in portions at 0 °C. The reaction mixture was slowly brought to rt for 4 h, concentrated under reduced pressure to afford crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to afford 2-(3-(((tert-butyldimethylsilyl) oxy) methyl) -lH-pyrazol-l-yl)-6-chloro-N-(4,4- difluorocyclohexyl) pyrimidin-4-amine [0401] as yellowish solid (3.6 g, 67%).
MS(M+1)+=459.1.
[00485] Step 2[0403] : To a degassed solution of 2-(3-(((tert- butyldimethylsilyl)oxy)methyl)-lH-pyrazol-l-yl)-6-chloro-N-(4,4- difluorocyclohexyl)pyrimidin-4-amine [0401] (3.5 g, 7.614 mmol) and tributyl(vinyl)tin
[0402] (3.747 g, 11.462 mmol) in 1,2-dichloroethane (50 mL) was added
bis(triphenylphosphine)palladium(II) dichloride (0.268 g, 0.682 mmol). The reaction mixture was heated to 80 °C for 16 h, quenched with water (50 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to afford 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-lH-pyrazol-l-yl)-N-(4,4- difluorocyclohexyl)-6-vinylpyrimidin-4-amine [0403] as off-white solid (2.56 g).
MS(M+1)+=450.61
[00486] Step 3 [0404] : To a stirred solution of 2-(3-(((tert-butyldimethylsilyl)oxy)methyl)- lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-vinylpyrimidin-4-amine [0403] (2.56 g, 5.694 mmol) and ethyl diazoacetate (0.975 g, 8.540 mmol) in toluene (30 mL) was heated at 100 °C for 16 h. The reaction mixture was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 15% ethyl acetate in hexane as eluent to afford ethyl 2-(2-(3-(((tert-butyldimethylsilyl)oxy)methyl)-lH-pyrazol-l-yl)-6- ((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)cyclopropane-l-carboxylate [0404] as an off- white solid (0.5 g, 16%). MS(M+l)+=536.7
[00487] Step 4 [0405] : To a stirred solution of ethyl 2-(2-(3-(((tert- butyldimethylsilyl)oxy)methyl)- lH-pyrazol- l-yl)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-4-yl)cyclopropane-l-carboxylate [0404] (0.5 g, 0.933 mmol) in a mixture of tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.196 g, 4.666 mmol) and the reaction mixture was stirred at rt for 18 h. The reaction mixture was acidified (pH~4-5) with aqueous hydrochloric acid (IN, 5 mL) and concentrated to dryness to afford 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)cyclopropane-l-carboxylic acid [0405] as a white solid (0.36 g). MS(M+l)+=340.4
[00488] Step 5 [0406] : To a stirred solution of 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)cyclopropane- 1-carboxylic acid [0405] (0.366 g, 0.933 mmol) in tetrahydrofuran (4 mL) in a pressure tube was added triethyl amine (0.33 mL, 2.326 mmol) followed by N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (0.267 g, 1.396 mmol) and 1 -hydro xybenzotriazole hydrate (0.154 g, 1.116 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min. Then a solution of dimethyl amine in tetrahydrofuran (4.65 mL, 2M) was added. The mixture was stirred with slow warming to rt for 24 h. The reaction mixture was quenched with water (20 mL) and the product was extracted with chloroform (3x50 mL). The combined organic layer was washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 2% methanol in chloroform as eluent to afford 2-(6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)-N,N-dimethylcyclopropane- 1- carboxamide [0406] as off-white solid (0.15 g). MS(M+1)+=421.46.
[00489] Step 6 [0407]: The procedure is similar to step 3 [0012] in example 2. 0.15 g 2-(6- ((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)- N,N-dimethylcyclopropane-l-carboxamide [0406] gave 0.02 g of 2-(6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)-N,N- dimethylcyclopropane-l-carboxamide [0407], Compound 308 as an off-white solid.
MS(M+l)+=423.45, 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.71 (s, 1H), 6.63 (d, J = 3.1 Hz, 1H), 6.38 (s, 1H), 5.50 (s, 1H), 5.45 (d, JF = 48 Hz, 1H), 4.16 (s, 1H), 3.09 (s, 3H), 2.86 (s, 3H),2.42 (bs, 1H), 2.29 (s, 1H), 2.19 - 1.82 (m, 6H), 1.71 - 1.44 (m, 3H), 1.36 (s, 1H).
[00490] Example 154:
Figure imgf000269_0001
Figure imgf000269_0002
041 1 0412 0413
[00491] Step 1[0408]: The procedure is similar to step 2 [0241] in example 87. 5 g of 4,6- dichloro-2-(methylsulfonyl)pyrimidine [0240] and 3.3 g of ethyl 4-methyl-lH-pyrazole-3- carboxylate [0148] gave 4.1 g of ethyl l-(4,6-dichloropyrimidin-2-yl)-4-methyl-lH-pyrazole- 3-carboxylate [0408] as off-white solid. MS(M+l)+=302.2.
[00492] Step 2[0409]: The procedure is similar to Step 1[0106] in example 34 (acetonitrile as solvent). 2.1 g of ethyl l-(4,6-dichloropyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carboxylate [0408] gave 1.65 g of ethyl l-(4-chloro-6-morpholinopyrimidin-2-yl)-4-methyl- lH-pyrazole-3-carboxylate [0409].MS(M+l)+=352.2.
[00493] Step 3 [0410]: The procedure is similar to Step 4[0244] in example 87. 1.5 g of ethyl l-(4-chloro-6-morpholinopyrimidin-2-yl)-4-methyl- lH-pyrazole-3-carboxylate [0409] and 4,4-difluorocyclohexan-l -amine [0002] gave 1.6 g (crude) l-(4-((4,4- difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carboxylic acid [0410] as brown solid. MS(M+l)+=422.2. This was taken as such to next step.
[00494] Step 4[0411]: The procedure is similar to Step 4[0007] in example 1. 1.6 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carboxylic acid [0410] gave 1.35 g of Ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6- morpholinopyrimidin-2-yl)-4-methyl- lH-pyrazole-3-carboxylate [0411], MS(M+l)+=451.1.
[00495] Step 4[0412]: The procedure is similar to Step 2[0019] in example 4. 1.35 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate [0411] gave 0.985 g of 4(l-(4-((4,4-difluorocyclohexyl)amino)-6- morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazol-3-yl)methanol [0412], MS(M+1)+=409.1. [00496] Step 5[0413]: The procedure is similar to Step 3 [0012] in example 2. 0.46 g of 4(l-(4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazol- 3-yl)methanol [0412] gave 0.985 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-4- methyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine [0413], Compound 281.
MS(M+1)+=411.2, MR= 146.4-154.0 °C, 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.16 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.44 (d, JF = 48 Hz, 2H), 4.01 (bs, 1H), 3.72 - 3.65 (m, 4H), 3.51 (bs, 4H), 2.11 (s, 3H), 2.12 - 1.88 (m, 6H), 1.62 - 1.54 (m, 2H).
[00497] Example 155:
Figure imgf000270_0001
[00498] Step 1[0414]: 0.51 g of 4(l-(4-((4,4-difluorocyclohexyl)amino)-6- morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazol-3-yl)methanol [0412] gave 0.38 g of l-(4- ((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carbaldehyde [0414], using manganese dioxide in dichloromethane. MS(M+l)+=407.
[00499] Step 2[0415]: The procedure is similar to Step 3 [0012] in example 2. 0.37 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-4-methyl-lH-pyrazole-3- carbaldehyde [0414] gave 0.08 g of N-(4,4-difluorocyclohexyl)-2-(3-(difluoromethyl)-4- methyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine [0415], Compound 282.
MS(M+l)+=429, 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.59 (s, 1H), 7.08 (t, JF = 53.34 Hz, 1H), 5.96 (d, J = 8.12 Hz, 1H), 4.11 (bs, 1H), 3.74 (s, 4H), 3.52 (s, 4H), 2.16 (s, 3H), 2.12 - 1.88 (m, 6H), 1.36 (bs, 2H).
[00500] Exam le 156:
Figure imgf000270_0002
[00501] Step 3[Step-l]: To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0399] (0.4 g, 1.156 mmol)
in dimethylsulfoxide (8 mL) was added thiomorpholine 1,1 -dioxide [0416] (0.18 g, 1.18 mmol) and followed by triethylamine (0.24 g, 1.735 mmol) under N2 atm. The resultant reaction mixture was irradiated in MW at 120 °C for 2 h. The reaction mixture was quenched with ice cold water (30 mL), and extracted with ethyl acetate (2x80 mL). The combined organic extract was washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford as a yellow liquid and which was purified by column chromatography using 76% ethyl acetate in hexane as an eluent to afford 4-(6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)thiomorpholine [0417], Compound 283 as an off-white solid (0.1 g). MS(M+l)+=445, 1H
NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 3.0 Hz, 1H), 5.74 (s, 1H), 5.42 (d, JF =48 Hz, 2H), 4.06 (m, 4H), 3.93 (bs, 1H), 3.17 (m, 4H), 2.10 - 1.89 (m, 6H), 1.56 (m, 2H).
[00502] Example 157:
Figure imgf000271_0001
[00503] Step 1[0418]: To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0418] (0.3 g, 0.86 mmol) in acetonitrile (12 mL) was added 2,6-dimethyl morpholine [0321] (0.19 g, 1.73 mmol) and followed by Ν,Ν-diisopropyl ethylamine (0.33 g, 2.60 mmol) under N2 atm. The resultant reaction mixture was heated at 90 °C for 4 h. The reaction mixture was quenched with ice cold water (30 mL) and extracted with ethyl acetate (2x80 mL). The combined organic extract was washed with brine (3x50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown solid, which was purified by column
chromatography using 35% ethyl acetate in hexane as an eluent to afford N-(4,4- difluorocyclohexyl)-6-(2,6-dimethylmorpholino)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-amine [0418], Compound 294 as an off-white solid (0.085 g). MS(M+l)+=425, 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 2.6 Hz, 1H), 8.31 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.59 (s, 1H), 5.56 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 4.10 - 3.81 (m, 2H), 3.66 (d, J = 13.0 Hz, 2H), 3.29 - 3.14 (m, 2H), 2.10 - 1.89 (m, 6H), 1.65 - 1.54 (m, 2H), 1.15 (d, J = 6.3 Hz, 6H).
[00504] Example 158:
Figure imgf000272_0001
[00505] Step 1[0419]: 2 g of ethyl l-(4-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0397] and 1.80 g of morpholine [0067] gave 1.85 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6- morpholinopyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0419] (Using acetonitrile, MW, 100 °C, lh) MS(M+l)+=437 and it was taken as such for next step without further purification.
[00506] Step 2[0420]: The procedure is similar to Step 2[0019] in example 4. 1.85 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0419] gave 1.56 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6- morpholinopyrimidin-2-yl)- lH-pyrazol-3-yl)methanol [0420] . MS(M+l)+=395.
[00507] Step 3[0421]: The procedure is similar to Step 3[0012] in example 2. 0.5 g of (1- (4-((4,4-difluorocyclohexyl)amino)-6-morpholinopyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0420] gave 0.1 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)-6- morpholinopyrimidin-4-amine [0421], Compound 280. MS(M+l)+=397, 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 2.6 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 6.60 (t, J = 1.8 Hz, 1H), 5.59 (s, 1H), 5.42 (d, JF =48 Hz, 2H), 3.93 (bs, 1H), 3.69 (t, J = 4.7 Hz, 4H), 3.52 (m, 4H), 2.13 - 1.85 (m, 6H), 1.55 (m, 2H).
[00508] Example 159:
Figure imgf000272_0002
[00509] Step 1[0423]: The procedure is similar to Step 1[270] in example 98. 1 g of ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0397] and 0.4 g of thiomorpholine [0422] gave 0.98 g of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-thiomorpholino pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0423]. MS(M+l)+=453 and it was taken as such for next step without further purification.
[00510] Step 2[0424]: The procedure is similar to Step 2[0019] in example 4. 0.97 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-thiomorpholinopyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0423] gave 0.78 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6- thiomorpholinopyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0424]. MS(M+1)+=411.
[00511] Step 3[0425]: The procedure is similar to Step 3 [0012] in example 2. 0.45 g of (1- (4-((4,4-difluorocyclohexyl)amino)-6-thiomorpholinopyrimidin-2-yl)-lH-pyrazol-3- yl)methanol [0424] gave 0.112 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)- 1H- pyrazol-l-yl)-6-thiomorpholinopyrimidin-4-amine [0425], Compound 284.
MS(M+1)+=413, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.59 (s, 1H), 5.58 (s, 1H), 5.40 (d, JF = 48.4 Hz, 2H), 4.01 (bs, 1H), 3.90 (s, 4H), 2.74 - 2.56 (m, 4H), 2.15 - 1.85 (m, 6H), 1.62 - 1.44 (m, 2H).
[00512] Example 160:
Figure imgf000274_0001
0432 0433
[00513] Step 1[0426]: To a solution of 4,6-dichloro-2-(methylthio)pyrimidine [0239] (150 g, 768.94 mmol) in acetonitrile (1500 mL) was added 4,4-difluorocyclohexylamine hydrochloride [0002] (158.35 g, 922.733 mmol) and cesium carbonate (526 g, 1614 mmol). The reaction mixture was heated at 75 °C for 16 h. The reaction mixture was filtered to remove cesium carbonate. The filtrate was concentrated under reduced pressure to afford 210 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0426] as a pale yellow solid. MS(M+1)+ = 294.0/295.0.
[00514] Step 2[0427] : To a stirred solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2- (methylthio)pyrimidin-4-amine [0426] (100 g, 340.40 mmol ) in acetonitrile (1500 mL), was added l-boc-3-(hydroxy)azetidine (117.9 g, 680.81 mmol) and cesium carbonate (166.37 g, 510.60 mmol). The reaction mixture was heated to 85 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (250 mL). The filtrate was concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 7% ethyl acetate in pet ether as solvent to afford 100 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0427] as an off-white solid. MS(M+l)+= 431.6, 432.4.
[00515] Step 3[0428] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0427] (1.2 g, 2.78 mmol) in tetrahydrofuran (20 mL) was added m-chloroperbenzoic acid (1.44 g, 8.316 mmol) at 0 °C. The reaction mixture was stirred at rt for 30 min. The reaction mixture was quenched with aqueous sodium thiosulfate (15 mL) and extracted with ethyl acetate (25 mL). The organic layer was washed with saturated sodium bicarbonate (2x25 mL), water (25 mL) and brine solution (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 1.2 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0428] as a white solid. MS(M+1)+ = 463.9.
[00516] Step 4[0429] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0428] (2 g, 4.32 mmol) in acetonitrile (15 mL) was added ethyl lh-pyrazole-3-carboxylate (1.23 g, 8.648 mmol) and followed by cesium carbonate (2.81 g, 8.64 mmol) under N2 atm. The resultant reaction mixture was heated at 85 °C for 16 h. The reaction mixture was filtered to remove cesium carbonate. The obtained filtrate was concentrated under reduced pressure to afford crude product, which was triturated with pet ether to afford 1.8 g of ethyl l-(4-((l- (tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazole-3-carboxylate [0429] as an off-white solid. MS(M+1)+ = 523.
[00517] Step 5[0430]: To a stirred solution of ethyl l-(4-((l-(tert-butoxycarbonyl)azetidin- 3-yl)oxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0429] (80 g, 153.095 mmol) in tetrahydrofuran (800 mL), was added lithium aluminium hydride ((2 M solution in tetrahydrofuran) 114 mL, 229.64 mmol) at -20 °C. The reaction mixture was stirred at same temperature for 30 min and quenched with saturated sodium sulfate. The solid was filtered off and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 65% ethyl acetate in pet ether as solvent to afford 31 g of tert- butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0430] as an off-white solid. MS(M+l)+= 481.2.
[00518] Step 6[0431] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0430] (10 g, 20.811 mmol) in dichloromethane (100 mL), was added diethylaminosulfurdiethylamino sulfur trifluoride (4.39 mL, 33.297 mmol) at -20 °C. The reaction mixture was stirred at same temperature for 15 min. The reaction mixture was quenched with saturated sodium bicarbonate solution (15 mL), and then extracted with dichloromethane (2x100 mL). The organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 10.5 g crude product, which was purified by column chromatography using 42% ethyl acetate in pet ether as solvent to afford 3.8 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0431] as an off-white solid. MS(M+1)+ = 483.3.
[00519] Step 7 [0432] : To a stirred solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0431] (14 g, 29.015 mmol) in dicholoromethane (140 mL), was added trifluoro acetic acid (41 g, 362.69 mmol) at 0 °C. The reaction mixture was stirred at rt for 6 h. The reaction mixture was concentrated under reduced pressure, to the residue water (15 mL) was added and neutralized with saturated sodium bicarbonate solution (25 mL), extracted with ethyl acetate(2x250 mL), the combined organic extracts were washed with brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 14.2 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2-methylpropan- 1-one [0432] as an off-white solid. MS(M+1)+ = 382.8.
[00520] Step 8[0433]: To a stirred solution of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2-methylpropan- 1-one [0432] (14.2 g, 37.135 mmol) in dicholoromethane (150 mL), was added triethylamine (10.35 mL, 74.27 mmol) and iso-butyryl chloride [0353] (7.9 g, 74.27 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 15 min and partitioned between
dicholoromethane (500 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 28% ethyl acetate in pet ether as solvent to afford 11.4 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2-methylpropan- 1-one [0433], Compound 290 as a white solid. MS(M+1)+ = 453.2. 1H NMR (400 MHz, DMSO- d6) δ 8.54 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 5.80 (s, 1H), 5.49-5.37 (d, JF = 48.0 Hz, 2H), 5.44-5.41 (m, 1H), 4.46 (bs, 3H), 3.95 (bs, 3H), 2.15 - 1.90 (m, 6H), 1.67 - 1.55 (m, 2H), 0.98 (d, J = 6.8 Hz, 6H).
[00521 Example 161:
Figure imgf000277_0001
[00522] Step 1[0434] : To a solution of tert-butyl3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0431] (0.25 g, 0.51 mmol) in dichloro methane was added trifluoroacetic acid (0.59 g, 1.03 mmol) at 0 °C and the reaction mixture was stirred at rt. After 16 h, triethylamine (~ 1.5 mL, until reaction mixture become basic) was added to the reaction mixture at 0 °C, followed by acetyl chloride [0035] (0.082 g, 1.036 mmol) and reaction mixture was stirred at rt. After 10 min, the reaction mixture was quenched with water, extracted with chloroform, washed with water and brine solution. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford colorless oil, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column, to afford 0.11 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)azetidin-l-yl)ethan- 1-one [0434], Compound 289 as white solid. MS(M+1)+ = 425.2. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (bs, 1H), 7.66 (bs, 1H), 6.67 (s, 1H), 5.75 (bs, 1H), 5.45 (d, JF = 48 Hz, 3H), 4.56 (bs, 1H), 4.28 (bs, 1H), 4.13 (dd, J = 9.9, 4.0 Hz, 2H), 3.83 (dd, J = 10.8, 4.0 Hz, 1H), 2.15 - 1.88 (m, 6H), 1.80 (s, 3H), 1.65 - 1.52 (m, 2H). [00523] Example 162:
Figure imgf000278_0001
0431 0436
[00524] Step 1[0436]: The procedure is similar to step 1[0434] in example 161. 0.25 g of tert-butyl3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0431] and 0.096 g of propionyl chloride [0435] gave 0.12 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)propan-l-one [0436], Compound 288 as white solid. MS(M+1)+ = 439.7. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J = 2.4 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 5.80 (s, 1H), 5.48 (d, JF = 48 Hz, 2H), 5.42 - 5.38 (m, 1H), 4.55 (bs, 2H), 4.10 (bs, 3H), 2.18 - 1.82 (m, 8H), 1.72 - 1.56 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H).
[00525] Example 163
Figure imgf000278_0002
0431 0438
[00526] Step 1[0438]: The procedure is similar to step 1[0434] in example 161. 0.25 g of tert-butyl3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0431] gave 0.13 g of ethyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate[0438], Compound 287 as white solid. MS(M+1) + = 455.2, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 7.2 Hz, 1H), 6.61 (s, 1H), 5.80 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 5.43 - 5.38 (m, 1H), 4.42 - 4.30 (m, 2H), 4.03 (q, J = 7.1 Hz, 2H), 3.91 (dd, J = 10.3, 4.2 Hz, 3H), 2.15 - 1.90 (m, 6H), 1.72 - 1.55 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). [00527] Example 164:
Figure imgf000279_0001
0439
[00528] Step 1 [0439]: The procedure is similar to step 1[0434] in example 161. 0.25 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0431] and 0.097 g of methyl chloroformate [0026] gave 0.13 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0439], Compound 291.
MS(M+1)+=441, 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.7 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.61 (d, J = 2.6 Hz, 1H), 5.79 (s, 1H), 5.43 (d, JF = 48 Hz, 2H), 5.46 - 5.38 (m, 1H), 4.36 (dd, J = 9.8, 6.6 Hz, 2H), 3.94 (dd, J = 10.0, 4.3 Hz, 3H), 3.60 (s, 3H), 2.15-1.90 (m, 6H), 1.70-1.55 (m, 2H).
[00529 Example 165:
Figure imgf000279_0002
0431 0440
[00530] Step 1 [0440]: The procedure is similar to step 1[0434] in example 161. 0.25 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0431] and 0.124 g of Pivaloyl Chloride
[0356] gave 0.13 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0440],
Compound 293. MS(M+l)+=467, 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.67 - 6.54 (m, 1H), 5.80 (s, 1H), 5.43 (d, JF = 48 Hz, 2H) 5.46 - 5.38 (m, 1H), 4.53 (bs, 2H), 4.10 (bs, 2H), 3.90 (bs, 1H), 2.13 - 1.88 (m, 6H), 1.68 - 1.55 (m, 2H), 1.15 (s, 9H). [00531] Example 166:
Figure imgf000280_0001
0430 0441 0442
Figure imgf000280_0002
[00532] Step 1[0441 and 0442]: The procedure is similar to step 4[0025] in example 5. 1 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0430] gave a mixture of (l-(4-(azetidin-3- yloxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0441] and l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0442] and taken as such for next step without isolation.
[00533] Step 2[0443 and 0442] (0442) : The procedure is similar to Step 5[0027] in example 5. A mixture of (l-(4-(azetidin-3-yloxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0441], l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0442] and 1.05 g of methyl chloroformate [0026] gave 0.2 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0443]. MS(M+l)+=439. and 0.175 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0442], Compound 319. MS(M+l)+=477, 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 5.77 (s, 1H), 5.52 (tt, J = 6.7, 4.3 Hz, 1H), 4.86 (m, 2H),4.59-4.50 (m, 1H), 4.52 (d, J = 5.8 Hz, 2H), 4.43 (m, 1H), 4.12 (m, 1H), 2.21 - 1.83 (m, 6H), 1.63 (d, J = 11.4 Hz, 2H).
[00534] Step 3[0444]: To a solution of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(hydroxymethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- l-carboxylate [0443] (0.3 g, 0.684 mmol) in dichloro methane (7 mL) was added manganese dioxide (0.29 g, 3.42 mmol) and the resultant reaction mixture was stirred at rt for 20h. The reaction mixture was filtered and the filtrate was concentrated to afford methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0444] as an off-white solid (0.24 g). MS(M+l)+=437.
[00535] Step 4[0445]: The procedure is similar to Step 3 [0012] in example 2. 0.18 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4- yl)oxy)azetidine- l-carboxylate [0444] gave 0.09 g of methyl 3-((6-((4,4-difluorocyclohexyl) amino)-2-(3-(difluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- l-carboxylate [0445], Compound 295. MS(M+l)+=459, 1H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.8 Hz, 1H), 7.00 (t, JF = 54.8 Hz, 1H) 6.72 (d, J = 2.7 Hz, 1H), 5.81 (s, 1H), 5.39 (tt, J = 6.7, 4.2 Hz, 1H), 4.35 (ddd, J = 9.7, 6.6, 1.2 Hz, 2H), 4.13 - 3.80 (m, 3H), 3.59 (s, 3H), 2.10-1.80 (m, 6H), 1.73 - 1.50 (m, 2H).
[00536] Example 167:
Figure imgf000281_0001
Figure imgf000281_0002
[00537] Step 1[0466]: The procedure is similar to Step 3 [0444] in example 166. 1 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- IH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine- l-carboxylate [0430] gave 0.78 g of tert-butyl 3-((6-((4,4- difluoro cyclohexyl)amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine- 1- carboxylate [0466]. MS(M+l)+=479. [00538] Step 2[0447]: The procedure is similar to Step 2[049] in example 10. 0.78 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-formyl- lH-pyrazol- l-yl)pyrimidin-4- yl)oxy) azetidine-l-carboxylate [0466] gave 0.3 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(l-hydroxyethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0447]. MS(M+l)+=495.
[00539] Step 3[0448] : To an ice cooled solution of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(l-hydroxyethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0447] (0.3 g, 0.606 mmol) in methanol (7 mL) was purged dry hydrogen chloride gas for 10 min. The reaction mixture was concentrated to afford 1-(1- (4-(azetidin-3-yloxy)-6-((4,4-difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazol-3- yl)ethan-l-ol hydrochloride salt [0448] as a yellow solid (0.33 g). MS(M+l)+=396.
[00540] Example 168:
Figure imgf000282_0001
[00541] Step 1 [0449]: The procedure is similar to Step 8[0433] in example 160. 0.18 g of l-(l-(4-(azetidin-3-yloxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3- yl)ethan-l-ol Hydrochloride salt [0448] and 0.047 g of methyl chloro formate [0026] gave 0.075 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(l-hydroxyethyl)-lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0449], Compound 307. MS(M+l)+=453, 1H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 2.6 Hz, 1H), 6.48 (d, J = 2.7 Hz, 1H), 5.60 (s, 1H), 5.40 (m, 1H), 3.32 (s, 1H), 5.14 (m, 1H), 4.53 - 4.33 (m, 2H), 4.11 (dd, J = 10.1, 4.3 Hz, 2H), 3.72 (s, 3H), 3.58 (s, 1H), 2.28 (s, 1H), 2.24 - 2.03 (m, 5H), 2.00-1.80 (m, 2H), 1.75-1.50 (m, 3H). [00542] Example 169:
Figure imgf000283_0001
[00543] Step 4[0450]: The procedure is similar to Step 8[0433] in example 160. 0.33 g of l-(l-(4-(azetidin-3-yloxy)-6-((4,4-difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazol-3- yl)ethan-l-ol Hydrochloride salt [0448] and 0.11 g of pivaloyl chloride [0356] gave 0.17 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(l-hydroxyethyl)-lH-pyrazol-l-yl)pyrimidin- 4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0450], Compound 315. MS(M+l)+=479, 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.64 (m, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.71- 5.68 (m, 1H), 5.36 (s, 1H), 5.27 - 5.18 (m, 1H), 4.93 - 4.66 (m, 2H), 4.29 (m, 2H), 3.83 (m, 1H),2.26 -1.80(m, 6H), 1.55 (m, 2H), 1.39 (d, J = 6.5 Hz, 3H), 1.12 (s, 9H).
[00544] Example 170:
Figure imgf000283_0002
[00545] Step 1[0451 and 0442]: The procedure is similar to Step 2[0443 and 0442] in example 166. A mixture of (l-(4-(azetidin-3-yloxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol [0441], l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0442] and 1.05 g of Pivaloyl Chloride
[0356] gave 0.5 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH- pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2,2-dimethylpropan- 1-one [0451] . MS(M+l)+=465 and 0.177 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2,2,2-trifluoroethan- 1- one [0442]. MS(M+l)+=477.
[00546] Step 2[0452] The procedure is similar to Step 3[0444] in example 166. 0.5 g of 1- (3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0451] gave 0.3 g of l-(4-((4,4- difluorocyclohexyl)amino)-6-((l-pivaloylazetidin-3-yl)oxy)pyrimidin-2-yl)-lH-pyrazole-3- carbaldehyde [0452]. MS(M+l)+=463.2.
[00547] Step 3[0453]: The procedure is similar to Step 3[0012] in example 2. 0.2 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-((l-pivaloylazetidin-3-yl)oxy)pyrimidin-2-yl)-lH- pyrazole-3-carbaldehyde [0452] gave 0.13 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(difluoromethyl) - IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2,2-dimethylpropan- 1-one [0453], Compound 298. MS(M+l)+=485.2, MR= 186.7-189.6 °C, 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.50 (d, J = 74.8 Hz, 1H), 7.03 (t, JF = 54 Hz, 1H), 6.74 (s, 1H), 5.83 (s, 1H), 5.42 - 5.36 (m, 1H), 4.53 (bs, 2H), 4.10 (bs, 2H), 3.94 (bs, 1H), 2.19 - 1.77 (m, 6H), 1.60 - 1.52 (m, 2H), 1.11 (s, 9H).
[00548] Example 171:
Figure imgf000284_0001
[00549] Step 1[0454] The procedure is similar to Step 3[0444] in example 166. 0.2 g of 1- (3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0442] gave 0.2 g of l-(4-((4,4- difluorocyclohexyl)amino)-6-((l-(2,2,2-trifluoroacetyl)azetidin-3-yl)oxy)pyrimidin-2-yl)-lH- pyrazole-3-carbaldehyde [0454]. MS(M+l)+=475.2.
[00550] Step 2[0455]: The procedure is similar to Step 3[0012] in example 2. 0.2 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-((l-(2,2,2-trifluoroacetyl)azetidin-3-yl)oxy)pyrimidin- 2-yl)-lH-pyrazole-3-carbaldehyde [0454] gave 0.1 g of l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2,2-trifluoroethan-l-one [0455], Compound 299. MS(M+l)+=497.2, MR= 164.7-170.8 °C, 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 2.8 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.03 (t, JF = 54 Hz, 1H), 6.74 (d, J = 2.8 Hz, 1H), 5.86 (s, 1H), 5.60 - 5.30 (m, 1H), 4.86 (bs, 1H), 4.56 (bs, 1H), 4.45 (bs, 1H), 4.13 (bs, 1H), 3.95 (bs, 1H), 2.18 - 1.82 (m, 6H), 1.64 (t, J = 10.8 Hz, 2H).
[00551] Example 172:
Figure imgf000285_0001
0457 0458
[00552] Step 1[0456]: The procedure is similar to step 2 [0274] in Example 99 (at 120 °C). 5 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0428] gave 3 g of Ethyl l-(4-((l-(tert- butoxycarbonyl)azetidin-3-yl)oxy)-6-((4,4-difluorocyclohexyl) amino) pyrimidin-2-yl)-4- methyl-lH-pyrazole-3-carboxylate [0456] as off-white solid. MS(M+l)+=537.2.
[00553] Step 2[0457] : The procedure is similar to step 2[0019] in Example 4. 6 g of Ethyl l-(4-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)-6-((4,4-difluorocyclohexyl) amino) pyrimidin-2-yl)-4-methyl-lH-pyrazole-3-carboxylate [0456] gave 5 g of tert-Butyl 3-((6- ((4,4-difluorocyclo hexyl)amino)-2-(3-(hydroxymethyl)-4-methyl- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0457] as off-white solid. MS(M+l)+=495.2.
[00554] Step 3 [0458]: The procedure is similar to step 1[0292] in Example 107. 5 g of tert-Butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0457] gave 3.5 g of (l-(4-(azetidin- 3-yloxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-4-methyl-lH-pyrazol-3- yl)methanol HCI [0458] as an brown solid. MS(M+l)+=395.2. [00555] Example 173:
Figure imgf000286_0001
[00556] Step 1[0459]: The procedure is similar to step 8[0433] in Example 160. 1 g of (1- (4-(azetidin-3-yloxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-4-methyl-lH- pyrazol-3-yl)methanol.HCl [0458] gave 0.6 g of Methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0459] as an off-white solid. MS(M+l)+=453.2
[00557] Step 2[0460]: The procedure is similar to step 3[0012] in Example 2. 0.6 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0459] gave 0.3 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0460], Compound 310 as white solid. MS(M+1)+ =455.2, 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 5.76 (s, 1H), 5.45 (d, JF = 48 Hz, 3H), 4.36 (ddd, J = 9.6, 6.6, 1.1 Hz, 2H), 3.93 (ddd, J = 9.6, 4.3, 1.1 Hz, 3H), 3.60 (s, 3H), 2.14 (s, 3H), 2.11 - 1.88 (m, 6H), 1.70 - 1.54 (m, 2H).
[00558] Example 174:
Figure imgf000286_0002
[00559] Step 1[0461]: The procedure is similar to step 3[0444] in Example 166. 0.3 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0459] gave 0.2 g of Methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-formyl-4-methyl- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0461] as off-white solid. MS(M+1)+=451.2.
[00560] Step 2[0462]: The procedure is similar to step 3[0012] in Example 2. 0.2 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-formyl-4-methyl- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0459] gave 0.075 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0462], Compound 318 as an white solid. MS(M+l)+=473.2, 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.70 (t, JF = 54 Hz, 1H), 5.79 (s, 1H), 5.40 (dd, J = 7.4, 3.7 Hz, 1H), 4.37 (dd, J = 9.9, 6.8 Hz, 2H), 3.93 (dd, J = 9.7, 4.4 Hz, 3H), 3.60 (s, 3H), 2.19 (s, 3H), 2.14 - 1.83 (m, 6H), 1.64 (t, J = 10.9 Hz, 2H).
[00561] Example 175:
Figure imgf000287_0001
[00562] Step 1[0463]: The procedure is similar to step 8[0433] in Example 160. 1.1 g of (l-(4-(azetidin-3-yloxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-4-methyl-lH- pyrazol-3-yl)methanol.HCl [0459] gave 0.6 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2- (3-(hydroxymethyl)-4-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2,2- dimethylpropan-l-one [0463] as off-white solid. MS(M+l)+=479.2.
[00563] Step 2[0464]: The procedure is similar to step 3[0012] in Example 2. 0.3 g of 1- (3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy )azetidin-l-yl)-2,2-dimethylpropan-l-one [0463] gave 0.125 g of l-(3- ((6-((4,4-difluoro cyclohexyl)amino)-2-(3-(fluoromethyl)-4-methyl- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0464], Compound 309 as white solid. MS(M+1)+=481.2, 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 5.48 (s, 1H), 5.46 (bs, 3H), 4.53 (s, 2H), 4.08 (d, J = 10.0 Hz, 2H), 2.14 (d, J = 1.2 Hz, 3H), 1.94 (td, J = 12.8, 12.0, 7.1 Hz, 7H), 1.63 (d, J = 11.2 Hz, 2H), 1.14 (d, J = 1.9 Hz, 9H).
[00564] Example 176:
Figure imgf000287_0002
[00565] Step 1[0465]: The procedure is similar to step 3[0444] in Example 166. 0.25 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-4-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy )azetidin-l-yl)-2,2-dimethylpropan-l-one [0463] gave 0.2 g l-(4-((4,4- Difluorocyclo hexyl)amino)-6-((l-pivaloylazetidin-3-yl)oxy)pyrimidin-2-yl)-4-methyl-lH- pyrazole-3-carbaldehyde [0465] as off-white solid. MS(M+l)+=477.2. [00566] Step 2[0466]: The procedure is similar to step 3 [0012] in Example 2. 0.25 g of 1- (4-((4,4-difluorocyclohexyl)amino)-6-((l-pivaloylazetidin-3-yl)oxy)pyrimidin-2-yl)-4- methyl-lH-pyra zole-3-carbaldehyde [0465] gave 0.07 g of l-(3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0466], Compound 317 as white solid. MS(M+1)+ =499.2, 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 6.9 (t, JF = 54 Hz, 1H), 5.80 (s, 1H), 5.43 - 5.36 (m, 1H), 4.54 (bs, 2H), 4.09 (bs, 2H), 3.94 (bs, 1H), 2.27 - 2.15 (m, 3H), 2.13 - 1.88 (m, 6H), 1.64 (t, J = 11.1 Hz, 2H), 1.15 (d, J = 1.5 Hz, 9H).
[00567] Example 177:
Step-6
[00568] Step 1[0468]: The procedure is similar to Step 1[270] in example 98. 2.5 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0426] and 2.39 g of 1- Boc-3-Hydroxypyrrolidine [0467] gave 1.25 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4-yl)oxy)pyrrolidine-l-carboxylate
[0468]. MS(M+l)+=445.
[00569] Step 2[0469]: The procedure is similar to Step 2[0378] in example 145. 1.25 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4- yl)oxy)pyrrolidine-l-carboxylate [0468] gave 1.3 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4-yl)oxy)pyrrolidine-l-carboxylate [0469]. MS(M+l)+=477.
[00570] Step 3[0470]: The procedure is similar to Step 2[0274] in example 99 (at 120 °C). 1.3 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4- yl)oxy)pyrrolidine-l-carboxylate [0469] and 0.708 g of Ethyl lh-Pyrazole-3-Carboxylate [0005] gave 1.3 g of ethyl l-(4-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazole-3-carboxylate [0470] .
MS(M+l)+=537.
[00571] Step 4[0471]: The procedure is similar to Step 2[0019] in example 4. 1.3 g of ethyl l-(4-((l-(tert-butoxycarbonyl)pyrrolidin-3-yl)oxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0470] gave 1 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)pyrrolidine- 1-carboxy late [0471] . MS(M+l)+=495.
[00572] Step 5[0472] : The procedure is similar to step 3 [0012] in Example 2. 0.7 g of tert- butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy) pyrrolidine- 1-carboxy late [0471] gave 0.25 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl) amino)-2-(3-(fluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4- yl)oxy)pyrrolidine-l-carboxylate [0472]. MS(M+l)+=497.
[00573] Step 6[0474]: The procedure is similar to Step 1[0434] in example 161. 0.25 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)pyrrolidine- 1-carboxy late [0472] and 0.095 g of methyl chloroformate [0026] gave 0.12 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)pyrrolidine- 1-carboxy late [0474], Compound 297.
MS(M+l)+=455, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.7 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 6.61 (dd, J = 2.8, 1.2 Hz, 1H), 5.76 (s, 1H), 5.56 (m, 1H), 5.43 (d, JF = 48 Hz, 2H), 3.93 (bs, 1H), 3.69 (dd, J = 12.2, 4.8 Hz, 1H), 3.62 (s, 3H), 3.53 - 3.38 (m, 3H), 2.23 (m, 1H), 2.11 - 1.93 (m, 7H), 1.62 (m, 2H).
[00574] Example 178:
Figure imgf000290_0001
[00575] Step 1[0475]: The procedure is similar to Step 3[0444] in example 166. 0.6 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- IH-pyrazol- 1- yl)pyrimidin-4-yl)oxy) pyrrolidine- 1-carboxylate [0471] gave 0.25 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)pyrrolidine- 1- carboxylate [0475]. MS(M+l)+=493.
[00576] Step 2[0476] : The procedure is similar to step 3 [0012] in Example 2. 0.4 g of tert- butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4- yl)oxy)pyrrolidine- 1-carboxylate [0475] gave 0.24 g of tert-butyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)pyrrolidine- 1-carboxylate [0476]. MS(M+1)+=515.
[00577] Step 3 and 4[0477 and 0478]: The procedure is similar to Step 1[0434] in example 161. 0.4 g of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (difluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)pyrrolidine- 1-carboxylate [0476] and 0.068g of methyl chloroformate [0026] gave 0.1 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)pyrrolidine- 1-carboxylate [0478], Compound 305. MS(M+l)+=473, 1H NMR (400 MHz, DMSO-d6-80 °C) δ 8.63 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.03 (t, JF =54.4 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 5.80 (s, 1H), 5.57 (m, 1H), 3.94 (bs, 1H), 3.69 (dd, J = 12.2, 4.8 Hz, 1H), 3.6 (s, 3H), 3.55-3.39 (m, 3H), 2.30-2.15 (m, 1H), 2.11 - 1.93 (m, 7H),
1.62 (m, 2H).
[00578] Example 179:
Figure imgf000291_0001
0486
[00579] Step 1[0480]: The procedure is similar to Step 1[270] in example 98. 3 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0426] and 2.8 g of 1 2- Hydroxymethyl-azetidine-l-Carboxylic acid tert-butyl ester [0479] gave 1.4 g of tert-butyl 2- (((6-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4-yl)oxy)methyl)azetidine-l- carboxylate [0480]. MS(M+l)+=445.
[00580] Step 2[0481]: The procedure is similar to Step 2[0378] in example 145. 1.4 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4- yl)oxy)methyl)azetidine-l -carboxylate [0480] gave 1.3 g of tert-butyl 2-(((6-((4,4- difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4-yl)oxy)methyl)azetidine-l- carboxylate [0481]. MS(M+l)+=477.
[00581] Step 3[0482]: The procedure is similar to Step 2[0274] in example 99 (at 120 °C). 1.3 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4- yl)oxy)methyl)azetidine-l -carboxylate [0481] and 0.585 g of Ethyl lh-Pyrazole-3- Carboxylate gave 1.4 g of ethyl l-(4-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-6- ((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazole-3-carboxylate [0482] .
MS(M+l)+=537. [00582] Step 4[0483]: The procedure is similar to Step 2[0019] in example 4. 1.4 g of ethyl l-(4-((l-(tert-butoxycarbonyl)azetidin-2-yl)methoxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0482] gave 1.25 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- IH-pyrazol- 1- yl)pyrimidin-4-yl)oxy)methyl)azetidine- 1-carboxylate [0483], MS(M+l)+=495.
[00583] Step 5[0484]: The procedure is similar to step 3 [0012] in Example 2. 0.65 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- IH-pyrazol- 1- yl)pyrimidin-4-yl)oxy) methyl) azetidine- 1-carboxylate [0483] gave 0.24 g of tert-butyl 2- (((6-((4,4-difluorocyclohexyl) amino)-2-(3-(fluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- 1-carboxylate [0484]. MS(M+l)+=497.
[00584] Step 6 and 7[0485 and 0486]: The procedure is similar to Step 1[0434] in example 161. 0.24 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl) amino)-2-(3- (fluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)methyl)azetidine- 1-carboxylate [0484] and 0.054 g of methyl chloroformate [0026] gave 0.1 g of methyl 2-(((6-((4,4- difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- 1-carboxylate [0486], Compound 306. MS(M+l)+=455, 1H NMR (400 MHz, DMSO-d6-80 °C) δ 8.55 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 6.60 (m, 1H), 5.80 (s, 1H), 5.38 (d, JF =48 Hz, 2H), 4.45-4.26 (m, 3H), 3.90 (bs, 1H), 3.87-3.80 (m, 2H), 3.55 (s, 3H), 2.40-2.30 (m, 1H), 2.20-2.10 (m, 1H), 2.11 - 1.93 (m, 6H), 1.62 (m, 2H).
[00585] Example 180:
Figure imgf000292_0001
[00586] Step 1[0487]: The procedure is similar to Step 3[0444] in example 166. 0.5 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- IH-pyrazol- 1- yl)pyrimidin-4-yl)oxy) methyl) azetidine- 1-carboxylate [0483] gave 0.4 g of tert-butyl 2-(((6- ((4,4-difluorocyclohexyl) amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- l-carboxylate [0487]. MS(M+l)+=493.
[00587] Step 2[0488] : The procedure is similar to step 3 [0012] in Example 2. 0.4 g of tert- butyl 2-(((6-((4,4-difluorocyclohexyl) amino)-2-(3-formyl- IH-pyrazol- l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- l-carboxylate [0487] gave 0.21 g of tert-butyl 2-(((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- l-carboxylate [0488]. MS(M+1)+=515.
[00588] Step 3 and 4[0489 and 0490]: The procedure is similar to Step 1[0434] in example 161. 0.2 g of tert-butyl 2-(((6-((4,4-difluorocyclohexyl)amino)-2-(3- (difluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)oxy)methyl)azetidine- l-carboxylate [0488] and 0.073 g of methyl chloroformate [0026] gave 0.09 g of methyl 2-(((6-((4,4- difluorocyclohexyl)amino)-2-(3-(difluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4- yl)oxy)methyl)azetidine- l-carboxylate [0490], Compound 314. MS(M+l)+=473, 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, IH), 7.66 (bs, IH), 7.13 (t, JF =54.4 Hz, IH), 6.79 (d, J = 2.9 Hz, IH), 5.81 (bs, IH), 4.50 (m, 3H), 4.01 (bs, IH), 3.83 (bs, 2H), 3.54 (s, 3H), 2.29 (m, IH), 2.20-1.80 (m, 7H), 1.65-1.45 (m, 2H),
[00589] Example 181:
Figure imgf000293_0001
[00590] Step 1[0492]: The procedure is similar to Step 1[270] in example 98. 13 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0426] and 4 g of 3- (benzyloxy)cyclobutan-l-ol [0491] gave 4 g of 6-(3-(benzyloxy)cyclobutoxy)-N-(4,4- difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0492] MS(M+l)+=436.
[00591] Step 2[0493]: The procedure is similar to Step 2[0378] in example 145. 3 g of 6- (3-(benzyloxy) cyclobutoxy)-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine [0492] gave 3 g of 6-(3-(benzyloxy)cyclobutoxy)-N-(4,4-difluorocyclohexyl)-2- (methylsulfonyl)pyrimidin-4-amine [0493] MS(M+l)+=468.
[00592] Step 3[0494]: The procedure is similar to Step 2[0274] in example 99 (at 120 °C). 3 g of 6-(3-(benzyloxy) cyclobutoxy)-N-(4,4-difluorocyclohexyl)-2- (methylsulfonyl)pyrimidin-4-amine [0493] and 1.37 g of ethyl lh-Pyrazole-3-carboxylate gave 3 g of ethyl l-(4-(3-(benzyloxy)cyclobutoxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0494],
MS(M+l)+=528.
[00593] Step 4[0495]: To a solution of ethyl l-(4-(3-(benzyloxy)cyclobutoxy)-6-((4,4- difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0494] (3 g, 5.686 mmol) in methanol was added palladium on carbon (10%) (0.6 g) under N2 atm. The resultant reaction mixture was hydrogenated at 3 kg/Cm3 hydrogen pressure for 24 h. The reaction mixture was filtered through celite bed and washed with methanol. The filtrate was concentrated under reduced pressure to afford as a colorless gum and which was purified by column chromatography using 50% ethyl acetate in hexane as a eluent to afford ethyl l-(4- ((4,4-difluorocyclohexyl)amino)-6-(3-hydroxycyclobutoxy)pyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0495] as an white solid (2.0 g). MS(M+l)+=438.
[00594] Step 5 [0496]: The procedure is similar to Step 3 [0444] in example 166] (Using Dess-Martin periodinane).1.5 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(3- hydroxycyclobutoxy)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0495] gave 1.56 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(3-oxo cyclobutoxy)pyrimidin-2-yl)-lH-pyrazole-3- carboxylate [0496] MS(M+l)+=436.
[00595] Example 182:
Figure imgf000294_0001
[00596] Step 1[0497]: The procedure is similar to step 3 [0012] in Example 2. 0.6 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(3-oxocyclobutoxy)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0496] gave 0.33 g of ethyl l-(4-(3,3-difluorocyclobutoxy)-6-((4,4- difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0497].
MS(M+l)+=458.
[00597] Step 2[0498]: The procedure is similar to Step 2[0019] in example 4. 0.33 g of ethyl l-(4-(3,3-difluorocyclobutoxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0497] gave 0.26 g of (l-(4-(3,3-difluorocyclobutoxy)-6-((4,4- difluoro cyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazol-3-yl)methanol [0498] .
MS(M+1)+=416.
[00598] Step 3 [0499]: The procedure is similar to step 3 [0012] in Example 2. 0.26 g of (l-(4-(3,3-difluorocyclobutoxy)-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH- pyrazol-3-yl)methanol [0498] gave 0.11 g of 6-(3,3-difluorocyclobutoxy)-N-(4,4- difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0499],
Compound 347. MS(M+1)+=418, 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.7 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 5.78 (s, 1H), 5.43 (d, JF =48.5 Hz, 2H), 5.18 (dd, J = 7.9, 4.9 Hz, 1H), 3.95 (bs, 1H), 3.18 (ddt, J = 15.4, 11.8, 7.8 Hz, 2H), 2.75 (qd, J = 14.2, 4.9 Hz, 2H), 2.10 - 1.89 (m, 6H), 1.71-1.55 (m, 2H).
[00599] Example 183:
Figure imgf000295_0001
[00600] Step 1[0500]: The procedure is similar to Step 2[0019] in example 4. 0.3 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(3-hydroxycyclobutoxy)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0495] gave 0.25 g of 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3- (hydroxymethyl)- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)cyclobutan- l-ol [0500] .
MS(M+l)+=396.
[00601] Step 2[0501]: The procedure is similar to step 3 [0012] in Example 2. 0.25 g of 3- ((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4- yl)oxy) eye lobutan- l-ol [0500] gave 0.1 g of N-(4,4-difluorocyclohexyl)-6-(3- fluorocyclobutoxy)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine [0501], Compound 346. MS(M+l)+=400, 1H-NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 7.60 (bs, 1H), 6.65 (d, J = 1.44 Hz, 1H), 5.69 (bs, 1H), 5.47 (d, JF =48.5 Hz, 2H), 5.45-5.37 (m, 1H), 5.30-5.25 (m, 1H), 4.15 (bs, 1H), 2.68-2.67 (m, 2H), 2.56-2.55 (m, 2H), 2.12-1.89 (m, 6H), 1.65-1.50 (m, 2H).
[00602] Example 184:
Figure imgf000296_0001
0431 0503
[00603] Step 1[0503]: The procedure is similar to step 1[0434] in Example 161. 0.25 g of tert-butyl3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0431] and 0.127 g of isopropyl chloroformate [0502] gave 0.11 g of isopropyl3-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(fluoromethyl)- lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate[0503], Compound 296 as white solid.(46 % yield). MS(M+1)+ = 469.2. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (bs, 1H), 7.63 (bs, 1H), 6.64 (s, 1H), 5.72 (bs, 1H), 5.45 (d, JF = 48 Hz, 3H), 4.85 - 4.75 (m, 1H), 4.33 (bs, 2H), 3.88 (bs, 3H), 2.15 - 1.85 (m, 6H), 1.70 - 1.44 (m, 2H), 1.20 (d, J = 6.3 Hz, 6H).
[00604] EXAMPLE 186
Figure imgf000296_0002
[00605] Step 1[0507] : The procedure is similar to Stepl [270] in example 98 (at 80 °C in
MW for 1 h) 0.4 g of N-(4,4-difluoro cyclohexyl)-2-(methylsulfonyl)-6-(oxetan-3- yloxy)pyrimidin-4-amine[0506] and 0.23 g of ethyl lh- Pyrazole-3-carboxylate [005] gave
0.35 g of ethyl l-(4-((4,4-difluorocyclohexyl)arnino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-lH- pyrazole-3-carboxylate [0507], MS(M+1)+ =332.
[00606] Step 2[0508] : To an ice cooled solution of ethyl l-(4-((4,4- difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate [0507] (0.35 g, 0.826 mmol) in tetrahydrofuran (10 mL) was added 2M solution of lithium aluminium hydride in tetrahydrofuran (0.062 g, 1.65 mmol), after completion of addition the reaction mixture was slowly warmed to rt and stirred for lOmin. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2x30 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford (l-(4-((4,4-difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-lH- pyrazol-3-yl)methanol [0508] as an off-white gum 0.350 g , MS(M+1)+ =325.
[00607] Step 3[0509]: The procedure is similar to step 3 [0012] in Example 2. 0.35 g of
(l-(4-((4,4-difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-lH-pyrazol-3- yl)methanol [0508] gave 0.1 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH- pyrazol-l-yl)-6-(oxetan-3-yloxy)pyrimidin-4-amine [0509], Compound 285
MS(M+1)+ =384, 1H-NMR (400 MHz, DMSO-d6): δ 8.50 (d, J = 2.40 Hz, 1H), 7.41 (d, J =
7.60 Hz, 1H), 6.60 (t, J = 1.20 Hz, 1H), 5.78 (s, 1H), 5.64 (t, J = 6.00 Hz, 1H), 5.41 (d, JF
=48.5 Hz, 2H), 4.90 (m, 2H), 4.60 (m, 2H), 4.01 (m, 1H), 2.10-1.98 (m, 6H), 1.95-1.61 (m,
2H).
[00608] Example 187:
Figure imgf000297_0001
[00609] Step 1[0510]: The procedure is similar to Step 2 [0274] in example 99 (at 100 °C). 0.5 g of N-(4,4-difluoro cyclohexyl)-2-(methylsulfonyl)-6-(oxetan-3-yloxy)pyrimidin-4- amine [0506] and 0.318 g of ethyl 4-methylpyrazole-3-carboxylate [0148] gave 0.5 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate [0510] as an off-white solid. MS(M+l)+=438.
[00610] Step 2[0511] : The procedure is similar to Step 2 [0019] in example 4. 0.5 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate [0510] gave 0.4 g of (l-(4-((4,4-difluorocyclohexyl)amino)-6- (oxetan-3-yloxy)pyrimidin-2-yl)-4-methyl-lH-pyrazol-3-yl)methanol [0511] as a brown solid. MS(M+l)+=396.
[00611] Step 3[0512]: The procedure is similar to Step 3 [0012] in example 2. 0.4 g of (1- (4-((4,4-difluorocyclohexyl)amino)-6-(oxetan-3-yloxy)pyrimidin-2-yl)-4-methyl-lH-pyrazol- 3-yl)methanol [0511] gave 0.12 g of N-(4,4-difluorocyclohexyl)-2-(3-(fluoromethyl)-4- methyl-lH-pyrazol-l-yl)-6-(oxetan-3-yloxy)pyrimidin-4-amine [0512], Compound 304 as a white solid. MS(M+l)+=398, 1H NMR (400 MHz, DMSO-d6) δ 8.35 (bs, 1H), 7.61 (bs, 1H), 5.61 (bs, 2H), 5.42 (d, JF =48.5 Hz, 2H), 4.95-4.88 (m, 2H), 4.58 (dd, J = 7.5, 5.3 Hz, 2H), 4.14 (bs, 1H), 2.13 (bs, 3H), 2.09 - 1.85 (m, 6H), 1.59-1.52 (m, 2H).
[00612] Example 188:
Figure imgf000298_0001
[00613] Step 1[0513]: To a solution of tert-butyl 3-((6-((4,4-difluorocyclohexyl)amino)-2- (methylthio)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0427] (5 g, 11.613 mmol) in tetrahydrofuran was added 4-N,N-dimethylamino pyridine (0.42 g, 3.484 mmol) and boc- anhydride (12.6 g, 58.069 mmol) at 0 °C and the reaction mixture was stirred at rt. After 16 h, the reaction mixture was concentrated under reduced pressure to afford a brown oil, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 0.120 g column to afford tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0513] as pale yellow oil. (5.8 g, 95% yield). MS(M+1)+=531.1.
[00614] Step 2[0514]: The procedure is similar to step 2 [0378] in example 145. 5.8 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2- (methylthio)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0513] gave 6 g of tert-butyl3-((6- ((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4- yl)oxy)azetidine-lcarboxylate [0514] as off-white solid.(98 % yield). MS(M+l)+=563.9. [00615] Step 3[0515] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(methylthio)py [0514], (6 g, 10.66 mmol) in dimethyl sulfoxide was added l,4-diazabicyclo[2.2.2]octane (1.31 g, 11.730 mmol) followed by sodium cyanide (0.58 g, 11.730 mmol) at 10 °C. Then reaction mixture was stirred at rt. After 10 min, the reaction mixture was quenched with ice and stirred for 15 min. The solid formed was filtered, washed with water and dried under vacuum to afford tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2- cyanopyrimidin-4-yl)oxy)azetidine-l-carboxylate [0515] as off-white solid. ( 5 g, 92 % yield). MS(M+1)+ = 509.6.
[00616] Step 4[0516] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-cyanopyrimidin-4-yl)oxy)azetidine-l-carboxylate [0515] (5 g, 9.81 mmol) in Ν,Ν-dimethylformamide was added triethylamine (1.98 g, 19.62 mmol) and ammonium sulfide in water (20%) (1.33 g, 19.625 mmol) and the reaction mixture was stirred at rt. After 5 min, the reaction mixture was quenched with ice and then extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert- butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-carbamothioylpyrimidin- 4-yl)oxy) azetidine-l-carboxylate [0516], as orange solid. ( 4.5 g, 85 % yield). MS(M+1)+ = 544.6.
[00617] Step 5[0518]: To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-carbamothioylpyrimidin-4-yl)oxy)azetidine-l-carboxylate
[0516] (5 g, 9.197 mmol) and ethyl bromopyruvate [0517] (3.58 g, 18.394 mmol) in tetrahydrofuran was stirred at rt. After 4 h, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford a brown gum, which
was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 24 g column, to afford ethyl 2-(4-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-6- ((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)thiazole-4-carboxylate [0518] as a yellow solid. (2.2 g, 40% yield). MS(M+l)+=640.2.
[00618] Step 6[0519] : To a stirred solution of ethyl 2-(4-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-6-((l-(tert-butoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2- yl)thiazole-4-carboxylate [0518] (2.2 g, 3.439 mmol) in tetrahydrofuran was added Lithium aluminum hydride (0.300 g, 7.909 mmol) at -78 °C and stirred at same temperature. After 3 h, the reaction mixture was slowly warmed to -10 °C. After 1 h, the reaction mixture was quenched with saturated ammonium chloride solution drop wise at -10 °C and stirred at rt for 10 min. The reaction mixture was filtered through celite bed, washed with tetrahydrofuran and the filtrate was concentrated to afford tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-(hydroxymethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0519] a yellow solid. (1.5 g, crude). MS(M+l)+=598.0.
[00619] Step 7[0520]: The procedure is similar to step 3 [0012] in example 2. 1.5 g of tert- butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (hydroxymethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0519], 1.2 g gave tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclo hexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0520] as orange solid ( 0.6 g , 50 % yield). MS(M+1)+=600.1.
[0062 Example 189:
Figure imgf000300_0001
[00621] Step 1[0521]: The procedure is similar to step 8 [0036] in Example 6 (using TFA). 0.27 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate[0520] and 0.08 g of methyl chloroformate [0026] gave 0.130 g of methyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-(fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0521], Compound 313 as a yellow solid (65 % yield). MS(M+l)+=458.2. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 3.3 Hz, 1H), 7.62 (bs, 1H), 5.90 (bs, 1H), 5.50 (d, JF = 48 Hz, 2H), 5.38 (bs, 1H), 4.35 (bs, 3H), 3.94 (bs, 2H), 3.58 (s, 3H), 2.15 - 1.88 (m, 6H), 1.65 - 1.50 (m, 2H).
[00622] Example 190
Figure imgf000300_0002
[00623] Step 1[0522]: The procedure is similar to step 8 [0036] in Example 6 (using TFA). 0.25 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0520] and 0.1 g of pivaloyl chloride [0356] gave 0.15 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0522], Compound 316 as an off-white solid. MS(M+l)+=484.2. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 5.90 (s, 1H), 5.55 (d, JF = 48 Hz, 2H), 5.43 - 5.35 (m, 1H), 4.53 (bs, 2H), 4.08 (bs, 2H), 3.93 (bs, 1H), 2.15 - 1.90 (m, 6H), 1.70 - 1.58 (m, 2H), 1.14 (s, 9H).
[00624] Example 191
Figure imgf000301_0001
[00625] Step 1[0523] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-(hydroxymethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0519] (2.5 g, 4.182 mmol) in dichloromethane (30 mL) was added manganese dioxide (3.63 g, 41.828 mmol) under N2 atm. The resultant reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered through celite bed, and washed with
tetrahydrofuran, filtrate was concentrated under reduced pressure to afford crude product, which was triturated with ethyl acetate to afford 1.5 g of tert-butyl 3-((6-((tert- butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4-formylthiazol-2-yl)pyrimidin-4- yl)oxy)azetidine- 1-carboxylate [0523] as a yellow solid. MS(M+l)+=596.2.
[00626] Step 2[0524] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-formylthiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0523] (0.7 g, 1.175 mmol) in dichloromethane (50 mL) was added
diethylaminosulfurdiethylamino sulfur trifluoride (0.37 g, 2.35 mmol) at -20 °C. The reaction mixture was allowed to rt for 16 h. The reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL) at 0 °C and extracted with dichloro methane (50 mL), washed with water (20 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 40% ethyl acetate in pet ether as solvent to afford 0.35 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-(difluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0524] as a white solid. MS(M+1)+=618.1.
[00627] Step 4[0525]: The procedure is similar to step 8 [0036] in Example 6 (using HC1 gas). 0.17 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (difluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0524] and 0.06 g of pivaloyl chloride gave 0.075 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (difluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0525], Compound 329 as a white solid. MS(M+l)+=502.2. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.41 (d, J = 7.2 Hz, 1H), 7.09 (t, JF = 54.8 Hz, 1H), 5.92 (s, 1H), 5.42 - 5.35 (m, 1H), 4.52 (bs, 2H), 4.09 (bs, 2H), 3.91 (bs, 1H), 2.22 - 1.88 (m, 6H), 1.72 - 1.56 (m, 2H), 1.15 (s, 9H).
[00628 Example 192
Figure imgf000302_0001
[00629] Step 1[0526]: The procedure is similar to step 8 [0036] in Example 6 (using HC1 gas). 0.17 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (difluoromethyl)thiazol-2- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0524] and 0.13 g of methyl chloroformate [0026] gave 0.060 g of methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(4-(difluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0526], Compound 330 as an off-white solid. MS(M+l)+=476.0. 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.75 (bs, 1H), 7.17 (t, JF = 55 Hz, 1H), 5.93 (bs, 1H), 5.37 (s, 1H), 4.10 (bs, 1H), 4.36 (s, 2H), 3.94 (s, 2H), 3.58 (s, 3H), 2.15 - 1.85 (m, 6H), 1.62 - 1.48 (m, 2H). [0063 Example 193
Figure imgf000303_0001
[00631] Step 1[0527]: The procedure is similar to step 8 [0036] in Example 6 (using TFA). 0.2 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0520] and 0.07 g of iso-butyryl chloride [0353] gave 0.11 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin- l-yl)-2-methylpropan- 1-one [0527], Compound 342 as a yellow solid. MS(M+1)+ = 470.2. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 3.2 Hz, 1H), 7.64 (bs, 1H), 5.91 (bs, 1H), 5.55 (d, JF = 48 Hz, 2H), 5.40 (bs, 1H), 4.58 (t, J = 9.36 Hz, 1H), 4.01 (bs, 2H), 4.28 (dd, J = 10.8, 6.8 Hz, 1H), 4.18 (dd, J = 9.8, 4.1 Hz, 1H), 3.84 (dd, J = 10.7, 4.2 Hz, 1H), 2.15 - 1.90 (m, 6H), 1.65 - 1.53 (m, 2H), 0.99 (t, J = 6.9 Hz, 6H).
[00632 Example 194
Figure imgf000303_0002
[00633] Step 1[0528]: The procedure is similar to step 8 [0036] in Example 6 (using TFA). 0.25 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0520] and 0.07 g of propionyl chloride [0435] gave 0.15 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (fluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)propan- 1-one [0528],
Compound 341 as a yellow solid. MS(M+l)+=456.2. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.35 (d, JF = 7.6 Hz, 1H), 5.91 (s, 1H), 5.55 (d, JF = 48 Hz, 2H), 5.45 - 5.35 (m, 1H), 4.44 (bs, 2H), 3.92(bs, 3H), 2.11 - 1.90 (m, 8H), 1.72 - 1.55 (m, 2H), 1.00 (t, J = 7.3 Hz, 3H). [00634] Example 195
Figure imgf000304_0001
[00635] Step 1[0529] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-formylthiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l^ carboxylate [0523] (0.9 g, 1.510 mmol) in tetrahydrofuran (5 mL) was added methyl magnesium bromide (0.9 g, 7.55 mmol) drop-wise at -15 °C ( ice + acetone ) under inert atm. Resultant reaction mixture was allowed to stir at same -15 °C to rt for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and product was extracted with dichloro methane (3x30ml). The combined organic layer were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 70% ethyl acetate in pet ether as solvent to afford 0.320 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl)amino)-2-(4-(l-hydroxyethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate [0529] as an off-white solid. MS(M+1)+ = 612.4.
[00636] Step 2[0530]: The procedure is similar to step 8 [0036] in Example 6 (using HC1 gas). 0.17 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4-(l- hydroxyethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0529] and 0.05 g of Methyl chloroformate gave 0.055 g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (1 -hydro xyethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l -carboxylate [0530], Compound
344 as a yellow solid. MS(M+1)+ = 470.2. 1H NMR (400 MHz, DMSO-d6) δ 7.68 (bs, 1H), 7.56 (s, 1H), 5.88 (bs, 1H), 5.39 (d, J = 4.44 Hz, 1H), 5.35 (s, 1H), 4.87 (t, J = 6.1 Hz, 1H), 4.34 (bs, 2H), 4.01 (bs, 1H), 3.94 (s, 2H), 3.58 (s, 3H), 2.12 - 1.88 (m, 6H), 1.62 - 1.50 (m, 2H), 1.42 (d, J = 6.5 Hz, 3H). [00637 Example 196
Figure imgf000305_0001
[00638] Step 1[0531]: The procedure is similar to step 8 [0036] in Example 6 (using TFA). 0.17 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4- (1 -hydro xyethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0529] and 0.07 g of pivaloyl chloride gave 0.025 g of [0531], Compound 337 as an off-white solid.
MS(M+1)+ = 496.2. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (bs, 1H), 7.56 (s, 1H), 5.89 (s, 1H), 5.38 (d, J = 4.76 Hz, 1H), 5.35 (b, 1H), 4.87 (t, J = 5.36 Hz, 1H), 4.82 (bs, 1H), 4.42 - 4.25 (m, 2H), 3.83 (bs, 2H), 2.12 - 1.87 (m, 6H), 1.65 - 1.50 (m, 2H), 1.48 - 1.32 (m, 4H), 1.12 (s, 8H).
[00639] Example 197
Figure imgf000305_0002
[00640] Step 1 [0532] : To a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2- (methylthio)pyrimidin-4-amine [0426] (1.4 g, 4.76 mmol) and morpholine [67] (0.83 mL, 9.53 mmol) in acetonitrile (20 mL) was heated at 85 °C in a sealed tube for 16h. After completion of the reaction, the reaction mixture was filtered to remove cesium carbonate and the filtrate was concentrated and the resulting residue which was purified by column chromatography using 30% ethyl acetate in hexane as eluent to afford N-(4,4- difluorocyclohexyl)-2-(methylthio)-6-morpholinopyrimidin-4-amine [0532] as an off-white solid (1.5 g 93%yield). MS(M+l)+=345.2.
[00641] Step 2 [0533] : To a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- morpholino pyrimidin-4-amine [0532] (lg, 2.90 mmol) in tetrahydrofuran (15 niL) was added 4-N,N-dimethylamino pyridine (O. lg, 0.87 mmolO), triethyl amine (1.2ml, 8.71 mmol) and boc-anhydride (3.16g, 14.51 mmol). The reaction mixture was heated at 80 °C for 16h, After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4-difluorocyclohexyl)(2-(methylthio)- 6-morpholino pyrimidin-4-yl)carbamate [0533] as a yellow gum (1.1 g 85%).
MS(M+l)+=445.2
[00642] Step 3 [0534]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (methylthio)-6-morpholinopyrimidin-4-yl)carbamate [0533] (1. lg, 2.47 mmol) in dichloromethane (20 mL) was added 3-chloroperbenzoic acid ( m-chloroperbenzoic acid) (1.28g, 7.42 mmol), then the reaction mixture was stirred at rt for 30 min. After the completion, the reaction mixture was quenched with saturated bicarbonate solution and extracted with dichloromethane (2x75mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4-difluorocyclohexyl)(2- (methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate [0534] as an off-white gum (0.9 g 76% yield). MS(M+1)+ =477.3
[00643] Step 4 [0535] : To a solution of tert-butyl (4,4-difluorocyclohexyl)(2- (methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate [0534] in dimethylsulfoxide (10 mL) was added l,4-diazabicyclo[2.2.2]octane (0.23g, 2.077 mmoll.) followed by sodium cyanide (0.102 g, 2.077 mmol). The reaction mixture was stirred at rt. After the completion, the reaction mixture was quenched with water, the obtained solid was filtered and dried under high vacuum to afford tert-butyl (2-cyano-6-morpholinopyrimidin-4-yl)(4,4-difluoro cyclohexyl)carbamate [0535] as an light brown solid (0.4 g 50% yield). MS(M+l)+=324.3.
[00644] Step 5 [0536]: To a solution of tert-butyl (2-cyano-6-morpholinopyrimidin-4- yl)(4,4-difluoro cyclohexyl)carbamate [0535] (0.4g, mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (0.26 mL, 1.88 mmol) and ammonium sulfide in water (20%) (0.64 g, 1.88 mmol) and the reaction mixture was stirred at rt for 10 min. After the completion, the reaction mixture was quenched with water, the obtained solid was filtered and dried under high vacuum to afford tert-butyl (2-carbamothioyl-6-morpholinopyrimidin-4- yl) (4,4-difluoro cyclohexyl) carbamate [0536] as a light brown solid (0.4 g, 93%).
MS(M+1)+ =458.2
[00 45] Example 198
Figure imgf000307_0001
[00646] Step 1 [0537]: To a solution of tert-butyl (2-carbamothioyl-6- morpholinopyrimidin-4-yl)(4,4-di fluorocyclohexyl)carbamate [0536] (0.4g, 0.87 mmol) in ethanol (10 mL) was added bromoacetone [0090] (0.155 g, 1.13 mmol). The reaction mixture was stirred at rt. After completion of the reaction, the reaction mixture was concentrated and the resulting residue was quenched with saturated bicarbonate solution and extracted with ethyl acetate (2x50 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford brownish gum and which was purified by column chromatography using 42% ethyl acetate in hexane as eluent to afford tert-butyl (4,4- difluorocyclohexyl)(2-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate
[0537] as an off-white solid (0.3 g 69% yield). MS(M+l)+=496.2.
[00647] Step 2 [0538]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-methyl thiazol-2-yl)-6-morpholino pyrimidin-4-yl)carbamate [0537] (0.3g, 0.605 mmol) in dichloro methane was added trifluoro acetic acid (0.187ml, 2.42 mmol), then the reaction mixture was stirred at rt. After the completion of the reaction, the reaction mixture was concentrated and the resulting residue was basified with saturated bicarbonate solution and extracted with ethyl acetate (2x70 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated and which was purified by column chromatography to afford N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-4-amine [0538], Compound 320 as an off-white solid (0.105 g). MS(M+l)+=396.3. 1H NMR (400 MHz, DMSO-d6) δ 7.34 (d, J = 1.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 5.66 (s, 1H), 3.89 (bs, 1H), 3.69 (dd, J = 5.8, 3.8 Hz, 4H), 3.58-3.48 (m, 4H), 2.42 (s, 3H), 2.11 - 1.90 (m, 6H), 1.59-1.52 (m, 2H). [00648] Example
Figure imgf000308_0001
[00649] Step 1 [0540] : To a solution of tert-butyl (2-carbamothioyl-6- morpholinopyrimidin-4-yl)(4,4-difluoro cyclohexyl) carbamate [0536] (0.5g, 1.09 mmol) in tetrahydrofuran (10 mL) was added 3-bromo-l,l,l-trifluoroacetone [0539] (0.313 g, 1.63 mmol), then the reaction mixture was stirred at rt. After the completion of the reaction, the reaction mixture was concentrated to afford N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol- 2-yl)-6-morpholinopyrimidin-4-amine [0540] as an off-white gum (0.6 g) and it was taken as such for next step. MS(M+l)+=568.2.
[00650] Step 2 [0541]: To a solution of N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl)-6-morpholinopyrimidin-4-amine [0540] (0.6g, 1.05 mmol) in dichloromethane (10 mL) was added triethylamine (0.29 mL, 2.11 mmol) and trifluoro acetic anhydride (0.29 mL, 2.11 mmol), then the reaction mixture was stirred at rt. After the completion of the reaction, the reaction mixture was quenched with water and extracted dichloromethane (2x35 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an light brownish gum which was purified by column of silica gel (60-120 mesh), using 35% ethyl acetate in hexane as eluent to afford tert-butyl (4,4-difluorocyclohexyl)(6- morpholino-2-(4-(trifluoromethyl)thiazol-2-yl)pyrimidin-4-yl)carbamate [0541] as an off- white solid. (0.4g, 68% Yield). MS(M+l)+=550.4
[00651] Step 3 [0542]: To a solution of tert-butyl (4,4-difluorocyclohexyl)(6-morpholino- 2-(4-(trifluoromethyl)thiazol-2-yl)pyrimidin-4-yl)carbamate [0541] (0.4g, 0.72 mmol) in dichloromethane (10 mL) was added trifluoro acetic acid (1 mL, 13.02 mmol), then the reaction mixture was stirred at rt. After the completion of the reaction, the reaction mixture was concentrated and the resulting residue was quenched with 10% sodium bicarbonate solution and extracted with ethyl acetate (2x40 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated as an brownish gum and which was purified by column chromatography using 30% ethyl acetate in hexane as to afford N-(4,4- difluorocyclohexyl)-6-morpholino-2-(4-(trifluoromethyl)thiazol-2-yl)pyrimidin-4-amine [0542], Compound 332 as an off-white solid (0.175 g, 53% yield). MS(M+1)+ =450.4. 1H- NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 3.28 Hz, IH), 7.12 (d, J = 7.60 Hz, IH), 5.69 (s, IH), 5.48 (d, JF =48.5 Hz, 2H), 3.90 (s, IH), 3.70 (m, 4H), 3.52 (m, 4H), 1.95-1.56 (m, 6H), 1.24 (s, 2H),
[00652] Example 200
Figure imgf000309_0001
[00653] Step 1 [0543]: To a solution of tert-butyl (2-carbamothioyl-6- morpholinopyrimidin-4-yl)(4,4-difluoro cyclohexyl) carbamate [0536] (2.8g, 6.11 mmol) in tetrahydrofuran (30 mL) was added ethyl bromopyruvate [0517] (1.79g, 9.17 mmol), then the reaction mixture was stirred at rt for 4 h. After the completion of the reaction, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution. The organic layer was concentrated to afford as an off-white solid which was triturated with methanol. The obtained solid was filtered and dried under high vacuum to afford ethyl 2-(4-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-6- morpholino pyrimidin-2-yl)thiazole-4-carboxylate [0543] as an off-white solid. ( 2 g, 60% Yield). MS(M+l)+=554.2.
[00654] Step 2 [0544] :To a solution of ethyl 2-(4-((tert-butoxycarbonyl)(4,4- difluorocyclo hexyl)amino)-6-morpholino pyrimidin-2-yl)thiazole-4-carboxylate [0543] (1.5g, 2.70 mmol) in tetrahydrofuran (20 mL) was added lithium borohydride (0.177g, 8.12 mmol), then the reaction mixture was stirred at rt for 1 h. After the completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2x50 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4-difluorocyclohexyl)(2-(4-(hydroxymethyl) thiazol-2-yl)- 6-morpholinopyrimidin-4-yl)carbamate [0544] as an off-white solid. (1 g, 72% Yield).
MS(M+1)+=512.2.
[00655] Step 3 [0545]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-(hydroxymethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0544] (lg, 1.95 mmol) in dichloro methane (20 mL) was added Dess-Martin periodinane (1.28 g, 2.93 mmol), then the reaction mixture was stirred at rt for 30min. After the completion of the reaction, the reaction mixture was quenched with saturated bicarbonate solution and extracted dichloromethane (2x75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4-difluorocyclohexyl)(2-(4- formylthiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0545] as an off-white solid. (0.9 g, 90% Yield). MS(M+1)+=510.4.
[00656] Example 201
Figure imgf000310_0001
[00657] Step 1[0546]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-(hydroxymethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [00544] (0.4 g, 0.78 mmol) in dichloromethane (10 mL) was added diethylamino sulfur trifluoride (0.25 g, 1.56 mmol). The reaction mixture was slowly warmed to rt and stirred for 30 min. After completion of the reaction, the reaction mixture was quenched with saturated bicarbonate solution and extracted dichloromethane (2x75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.31 g of tert-butyl (4,4- difluorocyclohexyl)(2-(4-(fluoromethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0546] as an light brownish gum and which was taken as such for next step.
MS(M+1)+=514.4.
[00658] Step 2 [0547]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-(fluoromethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0546] (0.31 g, 0.60 mmol) in dichloromethane (10 mL) was added trifluoro acetic acid (1.2 g, 10.41 mmol). The reaction mixture was slowly warmed to rt and stirred 16 h. After the completion of the reaction, the reaction mixture was concentrated and the resulting residue was quenched with 10% sodium bicarbonate solution and extracted with ethyl acetate (2x40 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an brownish gum and which was purified by column chromatography using 35% ethyl acetate in hexane as to afford N-(4,4-difluorocyclohexyl)-2-(4-(fluoromethyl)thiazol-2-yl)-6- morpholinopyrimidin-4-amine [0547], Compound 336 as an off-white solid. ( 0.115 g, 46%, Yield). MS(M+1)+=414.2. 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 3.28 Hz, 1H), 7.12 (d, J = 7.60 Hz, 1H), 5.69 (s, 1H), 5.48 (d, JF =48.5 Hz, 2H), 3.90 (s, 1H), 3.70 (m, 4H), 3.52 (m, 4H), 1.95-1.56 (m, 6H), 1.24 (s, 2H),
[00659] Example 202
Figure imgf000311_0001
[00660] Step 1 [0548]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-formylthiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0545] (0.5 g, 0.98 mmol) in dichloromethane (10 mL) was added diethylamino sulfur trifluoride (0.31 g, 1.961 mmol), then the reaction mixture was slowly warmed to rt and stirred for 30 min. After the completion of the reaction, the reaction mixture was quenched with saturated bicarbonate solution and extracted dichloromethane (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4- difluorocyclohexyl)(2-(4-(difluoromethyl)thiazol-2-yl)-6-morpholinopyrimidin-4- yl)carbamate [0548] as an light brownish gum (0.45 g) and which was taken as such for next step. MS(M+l)+=532.2.
[00661] Step 2 [0549]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-(difluoromethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0548] (0.45 g, 0.84 mmol) in dichloromethane (10 mL) was added trifluoro acetic acid (1.5 g, 13.02 mmol). The reaction mixture was slowly warmed to rt and stirred for 16h. After the completion of the reaction, the reaction mixture was concentrated and neutralized with 10% sodium bicarbonate solution and extracted with ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an brownish gum and which was purified by column chromatography using 80% ethyl acetate in hexane to afford N-(4,4- difluorocyclohexyl)-2-(4-(difluoromethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-amine [0549], Compound 339 as an off-white solid. (0.22 g, 60%, Yield). MS(M+l)+=432.2. 1H- NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 7.18 (bs, 1H), 7.16 (t, JF = 54.52 Hz, 1H), 5.70 (s, 1H), 3.88 (bs, 1H), 3.70 (s, 4H), 3.53 (s, 4H), 2.08-1.93 (m, 6H), 1.57-1.52 (m, 2H).
[00662] Example 203
Figure imgf000312_0001
[00663] Step 1 [0550]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-formylthiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0545] (0.3 g, 0.58 mmol) in tetrahydrofuran (10 mL) was added 2M solution of methyl magnesium bromide in
tetrahydrofuran (0.14 g, 1.17 mmol). After completion of addition, the reaction mixture was slowly warmed to rt and stirred at rt for lh. After the completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2x50 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4-difluorocyclohexyl)(2-(4-(l-hydroxyethyl)thiazol-2-yl)-6-morpholinopyrimidin-4- yl)carbamate [0550] as an off-white gum (0.25 g) and which was taken as such for next step. MS(M+1)+ =526.2.
[00664] Step 2 [551]: To an ice cooled solution of tert-butyl (4,4-difluorocyclohexyl)(2- (4-(l -hydro xyethyl)thiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate [0550] (0.25 g, 0.47 mmol) in dichloro methane (10 mL) was added 4N hydrochloric acid in dioxane (0.93 g, 25.6 mmol5). The reaction mixture was slowly warmed to rt and stirred for 16 h. After the completion of the reaction, the reaction mixture was concentrated and neutralized with 10% sodium bicarbonate solution and extracted with ethyl acetate, the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an brownish gum and which was purified by column chromatography using ethyl acetate as eluent to afford l-(2-(4- ((4,4-difluorocyclohexyl) amino)-6-morpholinopyrimidin-2-yl)thiazol-4-yl)ethan-l-ol [0551], Compound 340 as a light yellow solid. (0.065 g, 32%, Yield). MS(M+l)+=426.4. 1H-NMR (400 MHz, DMSO-d6): δ 7.47 (d, J = 0.72 Hz, 1H), 7.09 (d, J = 7.84 Hz, 1H), 5.67 (s, 1H), 5.34 (d, J = 4.76 Hz, 1H), 4.87-4.84 (m, 1H), 3.99 (s, 1H), 3.68 (m, 4H), 3.52 (m, 4H), 2.08- 1.92 (m, 6H), 1.61-1.56 (m, 2H), 1.42 (d, J = 6.52 Hz, 3H), [00665] Example 204
Figure imgf000313_0001
[00666] Step 1 [0552]: To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl) amino)-2-carbamothioylpyrimidin-4-yl)oxy)azetidine-l-carboxylate [0516] (0.5 g, 0.919 mmol) in tetrahydrofuran (10 rnL) was added 3-bromo-l,l,l- trifluoroacetone [0539] (0.21 g, 1.10 mmol). The reaction mixture was stirred at rt for 5h. After the completion of the reaction, the reaction mixture was concentrated to afford 0.6 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(2-hydroxy-4- (trifluoromethyl)-2,3-diJiydrothiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0552] as an off-white gum. MS(M+l)+=654.2.
[00667] Step 2 [0553]: To an ice cooled solution of tert-butyl 3-((6-((tert- butoxycarbonyl)(4,4-difluorocyclohexyl) amino)-2-(2-hydroxy-4-(trifluoromethyl)-2,3- dihydrothiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- l-carboxylate [0552] in dichloromethane (10 mL) (0.6 g, 0.917 mmol) was added triethylamine (0.18 g, 1.83 mmol) and
trifluoro acetic anhydride (0.385 g, 1.83 mmol). The reaction mixture was stirred at rt for 30min. After the completion of the reaction, the reaction mixture was quenched with water and extracted dichloromethane (2x35 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an light brownish gum and which was purified by column of silica gel (60-120 mesh), using 30% ethyl acetate in hexane as eluent to afford tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(2- hydroxy-4-(trifluoro methyl)-2,3-dihydrothiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0553] as an off-white solid.( 0.5 g, 86%, Yield). MS(M+l)+=636.4.
[00668] Step 3 [0554] : To an ice cooled solution of tert-butyl 3-((6-((tert- butoxycarbonyl)(4,4-difluorocyclohexyl) amino)-2-(2-hydroxy-4-(trifluoromethyl)-2,3- dihydrothiazol-2-yl)pyrimidin-4-yl)oxy)azetidine- l-carboxylate [0553] (0.5 g, 0.786 mmol) in dichloro methane (10 mL) was added trifluoro acetic acid (1.5 g, 13.02 mmol). The reaction mixture was slowly warmed to rt and stirred for 16 h. After the completion of the reaction, the reaction mixture was concentrated to afford crude 6-(azetidin-3-yloxy)-N-(4,4- difluorocyclohexyl)-2-(4-(trifluoromethyl) thiazol-2-yl)pyrimidin-4-amine [0554] as an off- white gum (0.42 g) which was taken as such to next step. MS(M+l)+=436.4.
9] Example 205
Figure imgf000314_0001
[00670] Step 4[0555 & 0556] : To an ice cooled solution of ethyl acetate (2x40 mL), 6- (azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl) thiazol-2-yl)pyrimidin- 4-amine [0554] (0.42 g, 0.786 mmol) in dichloro methane (10 mL) was added triethylamine (0.11 g, 0.943 mmol) and pivaloyl chloride (0.11 g, 0.943 mmol). The reaction mixture was stirred at rt for 30 min. After the completion of the reaction, the reaction mixture was quenched with water and extracted with dichloro methane (2x40mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an brownish gum and which was purified by column chromatography, fraction- 1 was eluted 20% ethyl acetate in hexane as to afford l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4- (trifluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0555], Compound 322 as an light yellow solid (0.05 g), MS(M+l)+=520, 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 0.9 Hz, 1H), 7.77 (d, J = 73.7 Hz, 1H), 6.01 (s, 1H), 5.38 (bs, 1H), 4.55 (m, 2H), 4.12 (m, 2H), 3.91 (bs, 1H), 2.01-1.92 (m, 6H), 1.59-1.52 (m, 2H), 1.12 (s, 9H). Fraction-2 was eluted 35% ethyl acetate in hexane as to afford l-(3-((6-((4,4- difluorocyclohexyl) amino)-2-(4-(trifluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidin-l- yl)-2,2,2-trifluoroethan-l-one [0556], Compound 323 as an off-white solid (0.045 g).
MS(M+l)+=532. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.80 (d, J = 8.09 Hz, 1H), 5.99 (s, 1H), 5.49 (t, J = 6.3 Hz, 1H), 4.85 (bs, 1H), 4.61 - 4.38 (m, 2H), 4.15 (dd, J = 11.4, 4.1 Hz, 1H), 3.63 (s, 1H), 2.13 - 1.90 (m, 6H), 1.58-1.52 (m, 2H). [00671] Example 206
Figure imgf000315_0001
[00672] Step 1 [0557]: The procedure is similar to step 5 [0027] in example 5. 0.300 g of 6-(azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(4-(trifluoromethyl)thiazol-2- yl)pyrimidin-4-amine [0554] gave 0.042g of methyl 3-((6-((4,4-difluorocyclohexyl)amino)-2- (4-(trifluoromethyl)thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate [0557],
Compound 324 as an off-white solid. MS(M+1)+ =494, 1H-NMR (400 MHz, DMSO-d6): δ 8.65 (s, 1H), 7.87 (bs, 1H), 5.97 (bs, 1H), 5.38 (s, 1H), 4.01 (bs, 1H), 4.36 (bs, 2H), 3.96 (bs, 2H), 3.58 (s, 3H), 2.06-1.59 (m, 6H), 1.56-1.24 (m, 2H).
[00673] Example 207
Figure imgf000315_0002
[00674] Step 1[0558] : To a solution of tert-butyl 3-((6-((tert-butoxycarbonyl)(4,4- difluorocyclohexyl) amino)-2-carbamothioylpyrimidin-4-yl)oxy)azetidine-l-carboxylate [0516] (1 g, 1.83 mmol) in tetrahydrofuran (20 mL) was added Bromoacetone (0.377 g, 2.75mmol) then the reaction mixture was stirred at rt for 16 h. After the completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl
acetate (2x50 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford as an light brownish gum and which was purified by column chromatography using 38% ethyl acetate in hexane as eluent to afford tert-butyl 3-((6-((tert- butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0558] as an off-white solid. (0.55 g), MS(M+l)+=582.
[00675] Step 2[0559] : To an ice cooled solution of tert-butyl 3-((6-((tert- butoxycarbonyl)(4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate [0558] (0.55 g, 0.94 mmol) in dichloro methane (20 mL) was added trifluoro acetic acid (1.08 g, 9.45 mmol), then the reaction mixture was stirred at rt. After the completion of the reaction, the reaction mixture was concentrated and the resulting residue was quenched with 10% sodium bicarbonate solution and extracted with ethyl acetate (2x40 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 6-(azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl)pyrimidin-4-amine [0559] as an off-white gum 0.35 g. MS(M+l)+=382.
[00676] Example 208
Figure imgf000316_0001
[00677] Step 3[0560] : To an ice cooled solution of 6-(azetidin-3-yloxy)-N-(4,4-difluoro cyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine [0559] (0.3 g, 0.78 mmol) in dichloromethane (10 mL) was added triethylamine (0.119 g, 1.17 mmol) and methyl chloro formate (0.096g, 1.02 mmol). The reaction mixture was stirred at rt for 30 min. After completion of the reaction, the reaction mixture was quenched with water and extracted with dichloromethane (2x30 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford 0.350 g as a brownish gum which was purified by column chromatography using 65% ethyl acetate in hexane as eluent to afford methyl 3-((6-((4,4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate [0560], Compound 311 as an light brown solid. (0.055 g, 16% Yield),
MS(M+l)+=440, 1H NMR (400 MHz, DMSO-d6) δ 7.60 (bs, 1H), 7.44 (s, 1H), 5.87 (bs, 1H), 5.36 (bs, 1H), 4.77 (bs, 1H), 4.30 (bs, 2H), 3.88 (bs, 2H), 2.44 (s, 3H), 2.11 - 1.92 (m, 6H), 1.59-152 (m, 2H), 1.12 (s, 9H).
[00678] Example 209
Figure imgf000316_0002
[00679] Step 1[0561]: The procedure is similar to step 5 [0027] in example 5. 0.350 g of 6-(azetidin-3-yloxy)-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4- amine[0559] gave 0.260 g of l-(3-((6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl)oxy)azetidin-l-yl)-2,2-dimethylpropan-l-one [0561], Compound 303 as an off-white solid. MS(M+l)+=440. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (bs, 1H), 7.44 (d, J = 1.1 Hz, 1H), 5.86 (bs, 1H), 5.35 (bs, 1H), 4.38-4.32 (m, 2H), 3.99-3.95 (m, 2H), 3.58 (s, 3H), 3.33 (bs, 1H), 2.44 (s, 3H), 2.22-1.85(m, 6H), 1.59-1.52 (m, 2H).
[00680] Example 210
Figure imgf000317_0001
[00681] Step 1 [0563]: The procedure is similar to step 1 [0361] in example 138. 0.4 g of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine [0242] and 3-amino-2-piperidone [0562] (0.26 g, 2.34 mmol) gave 0.16 g of 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)amino)piperidin- 2-one [0563] as a white solid. MS(M+1)+=419.
[00682] Step 3 [0564]: To a solution of 3-((6-((4,4-difluorocyclohexyl)amino)-2-(3,5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)amino)piperidin-2-one [0563] (0.1 g, 0.23 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.01 g, 0.26 mmol). The resultant reaction mixture was stirred at rt for 30 min, added iodomethane (0.037 g, 0.26 mmol) and stirred at rt for 1 h. The reaction mixture was quenched in ice and extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with water (10 mL), followed by brine (10 mL) and dried over anhydrous sodium sulfate to afford crude product which was purified by preparative HPLC to afford 0.035 g of 3-((6-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)amino)- 1- methylpiperidin-2-one [0564], Compound 133 as a white solid. MS(M+1) + = 434.2, 1H NMR (400 MHz, DMSO-d6): δ 6.97 (d, J = 8.00 Hz, 1H), 6.87 (d, J = 7.80 Hz, 1H), 5.97 (s, 1H), 5.39 (s, 1H), 4.32 (s, 1H), 3.78 (s, 1H), 3.25-3.32 (m, 2H), 2.81 (s, 1H), 2.46 (s, 3H), 2.13 (s, 3H), 2.04-2.06 (m, 3H), 1.82-1.87 (m, 7H), 1.52 (m, 2H). [00683] Example 211
Figure imgf000318_0001
[00684] Step 1[0566A]: To a stirred solution of 2,4,6-trichloropyridine [0565] (20 g, 109.627 mmol) in acetonitrile (250 mL) was added ethyl lh-pyrazole-3-carboxylate [0005] (15.6 g, 109.627 mmol) and cesium carbonate (71.43 g, 219 mmol). The reaction mixture was heated at 75 °C for 16 h. The reaction mixture water (75 mL) was added, extracted with ethyl acetate (2x250 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 4% ethyl acetate in pet ether as solvent to afford 9 g of ethyl l-(4,6-dichloropyridin-2-yl)-lH-pyrazole-3-carboxylate [0566A] as a white solid. MS(M+l)+=286.0.
[00685] Step 2[0567A] : To a stirred solution of ethyl l-(4,6-dichloropyridin-2-yl)- 1H- pyrazole-3-carboxylate [0566A] (2 g, 6.99 mmol) in dioxane (20 mL) were added 4,4- difluorocyclohexylamine hydrochloride (1.19 g, 6.990 mmol) cesium carbonate (3.41 g, 10.48 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.606 g, 1.04 mmol). Then the reaction mixture was purged with N2 for 5 min before adding palladium (II) acetate (0.158 g, 0.699 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure to afford 3.3 g of ethyl l-(6-chloro-4-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)- lH-pyrazole-3-carboxylate. This was purified by column chromatography using 11% ethyl acetate in pet ether as solvent to afford 0.450 g of ethyl l-(4-chloro-6-((4,4- difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazole-3-carboxylate [0567 A] as an off-white solid. MS(M+l)+=385.2. [00686] Step 3[0568] : The procedure is similar to step 2[0011] in example 2. 0.450 g of ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazole-3-carboxylate [0567 A] gave 0.350 g of (l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-lH- pyrazol-3-yl)methanol [0568] as an off-white solid. MS(M+1)+=343.1.
[00687] Step 4[0569]: The procedure is similar to step 3 [0012] in example 2. 0.350 g of (l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazol-3-yl)methanol [0568] gave 0.19 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3-(fluoromethyl)-lH-pyrazol- l-yl)pyridin-2-amine[0569] as an off-white solid. MS(M+1)+=345.1.
[00688] Example 212
Figure imgf000319_0001
[00689] Step 1[0570] : To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyridin-2-amine [0569] (0.120 g, 0.348 mmol) in toluene (3 mL), was added morpholine [0067] (36 g, 0.417 mmol), sodium-tert-butoxide (0.066 g, 0.692 mmol) and BINAP [rac-2,2'-bis(diphenylphosphino)-l,l'-binaphthyl] (0.033 g, 0.055 mmol). The reaction mixture was purged with N2 for 10 min before adding
bis(dibenzylideneacetone)palladium (0.016 g, 0.0278 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was filtered through celite, and then the filtrate was concentrated under reduced pressure to afford 0.067 g N-(4,4- difluorocyclohexyl)-6-(3-(fluoromethyl)-lH-pyrazol-l-yl)-4-morpholinopyridin-2-amine [0570], Compound 292 as a pale brown solid. MS(M+l)+= 395.5. 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 2.5 Hz, 1H), 6.65 (d, J = 1.8 Hz, 1H), 6.64 (s, 1H), 6.46 (d, J = 7.6 Hz, 1H), 5.80 (d, J = 1.9 Hz, 1H), 5.47-5.35(d, JF = 48.4 Hz, 2H), , 3.96 (bs, 1H), 3.71 (t, J = 4.8 Hz, 4H), 3.20 (t, J = 4.9 Hz, 4H), 2.03 - 1.93 (m, 6H), 1.54 - 1.51 (m, 2H). [00690] Example 213
Figure imgf000320_0001
[00691] Step 1[0571] : To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyridin-2-amine [0569] (0.20 g, 0.058 mmol) in toluene (1 mL), was added 3-methylazetidin-3-ol hydrochloride [0334] (0.06 g, 0.069 mmol) and potassium tert-butoxide (0.020 g, 0174 mmol). The reaction mixture was purged N2 for 10 min and finally added 2-(2'-di-tert-butylphosphine)biphenyl palladium(II) acetate (0.06 g, 0.0174 mmol). The reaction mixture was irradiated in microwave at 120 °C for 2 h. The reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure to afford 0.027 g of l-(2-((4,4-difluorocyclohexyl)amino)-6-(3-(fluoromethyl)-lH- pyrazol-l-yl)pyridin-4-yl)-3-methylazetidin-3-ol [0571], Compound 326 as an off-white solid. MS(M+l)+=396.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 6.60 (s, 1H), 6.42 (d, J = 7.56 Hz, 1H), 6.18 (s, 1H), 5.55 (d, JF = 64.25 Hz, 2H), 5.36 (d, J = 2.32 Hz, 2H), 3.95 (bs, 1H), 3.80 (d, J = 7.60 Hz, 2H), 3.70 (d, J = 7.68 Hz, 2H), 2.12-1.88 (m, 6H), 1.6-1.48 (m, 2H), 1.44 (s, 3H).
[00692] Example 214
Figure imgf000320_0002
[00693] Step 1[0572]: The procedure is similar to step 2[0274] in example 99 ( at 100 °C). 0.2 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyridin-2- amine [0569] gave 0.053 g of N-(4,4-difluorocyclohexyl)-6-(3-(fluoromethyl)-lH-pyrazol-l- yl)-4-(oxetan-3-yloxy)pyridin-2-amine [00572], Compound 302 as an off-white solid.
MS(M+l)+=383.2. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.63 (s, 1H), 6.47 (d, J = 1.9 Hz, 1H), 5.70 (d, J = 1.9 Hz, 1H), 5.48-5.36 (d, JF = 48.4 Hz, 2H), 5.3 l(t, J = 5.2 Hz, 1H), 4.89 (t, J = 6.7 Hz, 2H), 4.56 (dd, J = 7.5, 4.8 Hz, 2H), 3.98 (bs, 1H), 2.07 - 1.94 (m, 6H), 1.52-1.53 (m, 2H). [00694] Example 215
Figure imgf000321_0001
[00695] Step 1[0573]: To a stirred solution of 2,4,6-trichloropyridine [0565] (15 g, 82.22 mmol) in acetonitrile (150 rriL), was added ethyl 4-methylpyrazole-3-carboxylate [0148] (13.94 g, 90.442 mmol) and cesium carbonate (40.18 g, 123.3 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was filtered to remove cesium carbonate, filtrate was concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 8% ethyl acetate in pet ether as solvent to afford of ethyl 1- (4,6-dichloropyridin-2-yl)-4-methyl-lH-pyrazole-3-carboxylate [0573] as a white solid. MS(M+1)+=301.1.
[00696] Step 2[0574]: To a stirred solution of ethyl l-(4,6-dichloropyridin-2-yl)-4-methyl- lH-pyrazole-3-carboxylate [0573] (1.5 g, 4.99 mmol) in tetrahydrofuran (15 rriL), was added lithium borohydride (0.326 g, 14.992 mmol) at 0 °C. The reaction mixture was stirred at rt for 5 h. The reaction mixture was quenched with ice, extracted with ethyl acetate (2x100 rriL), the combined organic layer was dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 8% ethyl acetate in pet ether as solvent to afford 1.12 g of (l-(4,6- dichloropyridin-2-yl)-4-methyl-lH-pyrazol-3-yl)methanol [0574] as an off-white solid.
MS(M+1)+=259.1.
[00697] Step 3[0575]: To a stirred solution of (l-(4,6-dichloropyridin-2-yl)-4-methyl-lH- pyrazol-3-yl)methanol [0574] (1.12 g, 4.33 mmol) in dichloro methane (10 mL) was added diethylamino sulfur trifluoride (1.11 g, 6.94 mmol) at -20 °C. The reaction mixture was stirred at rt for 15 min. The reaction mixture was quenched with saturated sodium bicarbonate solution(10 mL), extracted with dichloro methane (2x50 mL) the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a crude product, which was purified by column chromatography using 4% ethyl acetate in pet ether as solvent to afford 0.660 g of 2,4-dichloro-6-(3-(fluoromethyl)-4-methyl- lH-pyrazol-l-yl)pyridine [0575] as a white solid. MS(M+1)+=261.0.
[00698] Step 4[0576] : To a stirred solution of 2,4-dichloro-6-(3-(fluoromethyl)-4-methyl- lH-pyrazol-l-yl)pyridine [0575] (0.650 g, 2.499 mmol) in acetonitrile (10 mL), was added 4,4-difluorocyclohexylamine hydrochloride [0002] (0.470 g, 2.749 mmol), cesium carbonate (1.62 g, 4.99 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.216 g, 0.374 mmol). The reaction mixture was purged with N2 for 10 min, and added by palladium (II) acetate (0.056 g, 0.249 mmol). The reaction mixture was irradiated in microwave at 100 °C for 2 h. The reaction mixture was filtered, filtrate was concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 12% ethyl acetate in pet ether as solvent to afford 0.220 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3- (fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-2-amine [0576] as a white solid.
MS(M+1)+ = 359.1.
[00699] Step 5 [0577] : To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3- (fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-2-amine [0576] (0.200 g, 0.55 mmol) in acetonitrile (5 mL), was added 3-hydroxyoxetane [0506] (0.049 g, 0.668 mmol), and cesium carbonate (0.363 g, 1.11 mmol). The reaction mixture was irradiated in microwave at 150 °C for 2 h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 31% ethyl acetate in pet ether as solvent to afford 0.032 g of N-(4,4- difluorocyclohexyl)-6-(3-(fluoromethyl)-4-methyl- lH-pyrazol-l-yl)-4-(oxetan-3- yloxy)pyridin-2-amine [0577], Compound 345 as an off-white solid. MS(M+1)+ = 397.2. 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 6.80 (d, J = 7.4 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 5.68 (s, 1H), 5.45 (d, JF = 48.5 Hz, 2H), 5.33 - 5.30 (m, 1H), 4.89 (t, J = 6.7 Hz, 2H), 4.56 (t, J = 7.4 Hz, 2H), 3.99 (bs, 1H), 2.13 (s, 3H), 2.12 - 1.90 (m, 6H), 1.58 - 1.45 (m, 2H).
[00700] Example 216
Figure imgf000323_0001
[00701] Step 1[0578A and 0578B] : To a stirred solution of 2,4,6-trichloropyridine [0565] (25 g, 137.033 mmol) in acetonitrile (400 mL) was added 3,5-dimethylpyrazole [0017] (15.8 g, 164.44 mmol) and cesium carbonate (89 g, 274 mmol). The reaction mixture was heated at 75 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (200 mL) and stirred for 10 min. The solid formed was filtered, washed with water and dried under vacuum to afford crude product, which was purified by column chromatography using 1.5% ethyl acetate in pet ether as solvent to afford 11 g of 2,4- dichloro-6-(3,5-dimethyl- IH-pyrazol- l-yl)pyridine 2,4-dichloro-6-(3,5-dimethyl- lH-pyrazol- l-yl)pyridine [0578A] as a white solid and 8 g of 2,6-dichloro-4-(3,5-dimethyl-lH-pyrazol-l- yl)pyridine [0578B] as a white solid. MS(M+1)+=242.1.
[00702] Step 2[0579A and 0579B] : To a stirred solution of 2,4-dichloro-6-(3,5-dimethyl- lH-pyrazol-l-yl)pyridine 2,4-dichloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridine [0578A] (1 g, 4.13 mmol) in dioxane (10 mL), were added 4,4-difluorocyclohexylamine hydrochloride [0002] (0.850 g, 4.956 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.286 g, 0.495 mmol) and cesium carbonate (2.69 g, 8.26 mmol). The reaction mixture was degassed for 10 min, and then added palladium (II) acetate (0.074 g, 0.33 mmol). The reaction mixture was irradiated in microwave at 100 °C for 3 h. The reaction mixture was passed through celite, washed with chloroform (20 mL) and then the filtrate was concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 5% ethyl acetate in pet ether as solvent to afford 0.950 g of 4-chloro-N-(4,4-difluorocyclohexyl)- 6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] and 0.6 g of 2-chloro-N-(4,4- difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-4-amine [0579B] as a yellow solid. MS(M+1)+=341.2 [00703] Step 3 [0580] : To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6- (3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.3 g, 0.88 mmol) in dioxane (10 mL), were added 3-oxetanamine [0243] (0.128 g, 1.76 mmol), 4,5-bis(diphenylphosphino)- 9,9-dimethylxanthene(0.061 g, 0.105 mmol) and cesium carbonate(0.537 g, 1.76 mmol). The reaction mixture was degassed for 10 min, then added
tris(dibenzylideneacetone)dipalladium(0) (0.080 g, 0.088 mmol). The reaction mixture was heated at 95 °C for 16 h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure to afford crude product, which was purified by preparative HPLC to afford 0.060 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH- pyrazol-l-yl)-N4-(oxetan-3-yl)pyridine-2,4-diamine [0580], Compound 228 as an off-white solid. MS(M+1)+ =378.2. 1H-NMR (400 MHz, DMSO-d6): δ 6.96 (d, J = 4 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 6.26 (s, 1H), 5.97 (s, 1H) 5.32 (d, J = 1.52 Hz, 1H), 4.83-4.79 (t, J = 6.4 Hz, 2H), 4.54-4.46 (m, 1H), 4.43-4.40 (t, J = 5.92 Hz, 2H), 3.82 (s, 1H), 2.53 (s, 3H), 2.15 (s, 3H), 2.10-1.81 (m, 6H), 1.53 - 1.47 (m, 2H).
[00704] Ex mple 217
Figure imgf000324_0001
[00705] Step 1[0581 and 0582]: To a suspension of sodium hydride (0.036 g, 0.908 mmol) in N, N-dimethylformamide (0.5 mL), was added N2-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)-N4-(oxetan-3-yl)pyridine-2,4-diamine [0580] (0.170 g, 0.45 mmol) drop wise at 0 °C. The reaction mixture was stirred at rt for 15 min. After 15 min iodomethane (0.076 g, 0.054 mmol) was added to the reaction mixture. The reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with ice cold water, extracted with ethyl acetate (2x10 mL), the combined organic extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 25% ethyl acetate in pet ether as solvent to afford 0.080 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl- lH-pyrazol- l-yl)-N4-methyl-N4- (oxetan-3-yl)pyridine-2,4-diamine [0581], Compound 238 as an off-white solid
MS(M+l)+=392.4. 1H NMR (400 MHz, DMSO-d6) δ 6.35 - 6.33 (m, 2H), 6.00 (s, 1H), 5.48 (d, J = 2.0 Hz, 1H), 4.93 - 4.72 (m, 3H), 4.70 - 4.51 (m, 2H), 3.85 (s, 1H), 2.91 (s, 3H),2.53 (s, 3H), 2.17 (s, 3H), 2.07 - 1.86 (m, 6H), 1.54 - 1.46 (m, 2H) and 0.008 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N2,N4- dimethyl-N4-(oxetan-3-yl)pyridine-2,4-diamine [0582], Compound 240 as pale yellow gummy liquid. MS(M+l)+=406.4. 1H NMR (400 MHz, DMSO-d6) δ 6.39 (d, J = 1.8 Hz, 1H), 6.02 (s, 1H), 5.53 (d, J = 2.0 Hz, 1H), 4.98 - 4.93 (m, 1H), 4.80 (t, J = 6.8 Hz, 2H), 4.66 (t, J = 6.6 Hz, 2H), 4.59 - 4.53 (m, 1H), 3.51 (s, 1H), 3.00 (s, 3H), 2.81 (s, 3H), 2.56 (s, 3H), 2.17 (s, 3H), 2.12 - 1.93 (m, 5H), 1.76 - 1.67 (m, 2H).
[00706] Example 218
Figure imgf000325_0001
[00707] Step l[0584]:To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.200 g, 0.586 mmol) in 50% aqueous sodium hydroxide solution (2 niL), was added (l-methyl-lh-l,2,4-triazol-3-yl)methanol [0583] (0.079 g, 0.704 mmol) and tetra butyl ammonium hydrogen sulfate (0.200 g, 0.586 mmol). The reaction mixture was heated at 110 °C for 16 h. The reaction mixture was extracted with ethyl acetate (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 51% ethyl acetate in pet ether as solvent to afford 0.018 g of N-(4,4- difluorocyclohexyl)-6-(3,5-dimethyl-lh-pyrazol-l-yl)-4-((l-methyl-lH-l,2,4-triazol-3- yl)methoxy)pyridin-2-amine [0584], Compound 275 as an off-white solid.
MS(M+1)+=418.2. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.03 (s, 1H), 5.99 (d, J = 2.0 Hz, 1H), 5.08 (s, 2H), 3.87 (s, 4H), 2.57 (s, 3H), 2.16 (s, 3H), 2.08 - 1.84 (m, 6H), 1.56 - 1.48 (m, 2H).
[00708] Examp
Figure imgf000325_0002
[00709] Step 1[0588]: To a solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.3 g, 0.880 mmol) in acetonitrile (10 mL) were added (5- methyl [l,3,4]-oxadiazol-2-yl) methanol (0.2 g, 1.760 mmol) and Cesium carbonate (0.86 g, 2.640 mmol) under N2 atm. The resultant reaction mixture was irradiated at 150 °C. After 2 h, the reaction mixture was filtered and washed with chloroform, the obtained filtrate was concentrated under reduced pressure to afford a yellow liquid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column, to afford 0.035 g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol- l-yl)-4-((5-methyl-l,3,4-oxadiazol-2-yl)methoxy)pyridin-2-amine [0588], Compound 261 as off-white solid. MS(M+1)+=419.0, 1H NMR (400 MHz, DMSO-d6) δ 6.81 (d, J = 7.5 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.04 (s, 1H), 5.97 (d, J = 2.0 Hz, 1H), 5.39 (s, 2H), 3.87 (bs, 1H), 2.58 (s, 3H), 2.54 (s, 3H), 2.17 (s, 3H), 2.15-1.85 (m, 6H), 1.58-1.45 (m, 2H).
[00710] Exam le 220
Figure imgf000326_0001
[00711] Step 1[0588]: The procedure is similar to step 3[0580] in example 216. 0.25 g of chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] and 0.25 g of (l-methyl-lH-l,2,3-triazol-5-yl)methanamine [0587] gave 0.03 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-((l-methyl-lH-l,2,3- triazol-5-yl)methyl)pyridine-2,4-diamine [0588], Compound 250 as yellow solid.
MS(M+1)+=417.0, 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 6.80 (t, J = 5.7 Hz, 1H), 6.39 (d, J = 1.7 Hz, 1H), 6.26 (d, J = 7.5 Hz, 1H), 5.97 (s, 1H), 5.52 (d, J = 1.7 Hz, 1H), 4.39 (d, J = 5.7 Hz, 2H), 4.01 (s, 3H), 3.81 (bs, 1H), 2.54 (s, 3H), 2.15 (s, 3H), 2.10 - 1.98 (m, 2H), 2.00-1.78 (m, 4H), 1.52-1.40 (m, 2H).
[00712] Example 221
Figure imgf000326_0002
[00713] Step 1[0589]: The procedure is similar to step 3[0580] in example 216. 0.3 g of chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl- IH-pyrazol- l-yl)pyridin-2-amine [579A] and 0.197 g of (2-methyl-2H-l,2,3-triazol-4-yl)methanamine [0306] gave 0.042 g of N2-(4,4- difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-((2-methyl-2H-l,2,3-triazol-4- yl)methyl)pyridine-2,4-diamine [0589], Compound 248 as yellow solid. MS(M+1)+=417.0, 1H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 6.76 (t, J = 5.9 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 5.53 (d, J = 1.8 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H), 4.11 (s, 3H), 3.80 (bs, 1H), 2.14 (s, 3H), 2.09 - 1.78 (m, 6H), 1.56 - 1.40 (m, 2H).
[00714] Example 222
Figure imgf000327_0001
[00715] Step 1[0590]: The procedure is similar to step 1[0270] in example 98. 5 g of 2,4,6-trichloropyridine [0565] and 2.2 g of 3-methylpyrazole [0091] gave 2.2 g of 2,4- dichloro-6-(3-methyl-lH-pyrazol-l-yl)pyridine [0590] as white solid. MS(M+l)+=229.2.
[00716] Step 2[0591]: The procedure is similar to step 3[0580] in example 216. 1 g of 2,4- dichloro-6-(3-methyl-lH-pyrazol-l-yl)pyridine [0590] and 0.82 g of 4,4- difluorocyclohexylamine hydrochloride [0002] gave 0.6 g of 4-chloro-N-(4,4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine [0591] as off-white solid. MS(M+l)+=327.2.
[00717] Step 3[0592]: The procedure is similar to step 1[0251] in example 90. 0.28 g of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine
[0591] gave 0.115 g of 6-cyclopropyl-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH- pyrazol-l-yl)pyrimidin-4-amine [0592], Compound 182 as white solid MS(M+l)+=333.2. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.4 Hz, 1H), 6.62 (d, J = 1.12 Hz, 1H), 6.60 (s, 1H), 6.27 (d, J = 2.4 Hz, 1H), 6.09 (d, J = 1.3 Hz, 1H), 3.95 (bs, 1H), 2.26 (s, 3H), 2.12 - 1.90 (m, 6H), 1.92 - 1.85 (m, 1H), 1.62 - 1.55 (m, 2H), 1.03 - 0.92 (m, 2H), 0.76 - 0.67 (m, 2H). [00718] Example 223
Figure imgf000328_0001
[00719] Step 1[0593] : To a cooled (-10 °C) solution of 2,4,6-trichloropyridine [0565] (2 g, 10.96 mmol) in tetrahydrofuran (10 mL) was added sodium thiomethoxide (0.762 g, 10.96 mmol) portion wise under N2 atm. The resultant reaction mixture was stirred at -10 °C. After 3 h, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2x100 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford as a colorless liquid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column to afford 0.9 g of 2,6-dichloro-4-(methylthio)pyridine [0593] as a white solid. MS(M+1)+=195.0.
[00720] Step 2[0594]: This procedure is similar to step 1[0270] in example 98. 0.25 g of 2,6-dichloro-4-(methylthio)pyridine [0594] and 0.1 g of 3-methylpyrazole [0091] gave 0.1 g of 2-chloro-6-(3-methyl-lH-pyrazol-l-yl)-4-(methylthio)pyridine [0594] as white solid. MS(M+l)+=240.0.
[00721] Step 3[0595]: This procedure is similar to step 2[0378] in example 145. 0.5 g of 2-chloro-6-(3-methyl-lH-pyrazol-l-yl)-4-(methylthio)pyridine [0594] gave 0.52 g of 2- chloro-6-(3-methyl-lH-pyrazol-l-yl)-4-(methylsulfonyl)pyridine [0595] as a white solid. MS(M+l)+=272.0.
[00722] Step 4[0596] : The procedure is similar to step 3[0580] in example 216. 0.2 g of 2- chloro-6-(3-methyl-lH-pyrazol-l-yl)-4-(methylsulfonyl)pyridine [0595] gave 0.063 g of N- (4,4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)-4-(methylsulfonyl)pyridin-2-amine [0596], Compound 153 as a white solid. MS(M+1)+=371.2, 1H NMR (400 MHz, DMSO- d6) δ 8.50 (d, J = 2.6 Hz, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.23 (s, 1H), 6.82 (s, 1H), 6.38 (d, J = 2.6 Hz, 1H), 4.09 (m, 1H), 3.27 (s, 3H), 2.29 (s, 3H), 2.13 - 1.96 (m, 6H), 1.61 - 1.52 (m, 2H). [00723] Example 22
Figure imgf000329_0001
[00724] Step 1[0597]: This procedure is similar to Step 3[0580] in example 216. 1 g of 2,4-dichloro-6-(3-methyl-lH-pyrazol-l-yl)pyridine [0590] and 0.822 g of 4,4- difluorocyclohexylamine hydrochloride [0002] gave 0.6 g of 4-chloro-N-(4,4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine [0597], Compound 179 as an off-white solid. MS(M+l)+=327.0, 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.88 (d, J = 1.5 Hz, 1H), 6.39 (d, J =1.6 Hz, 1H), 6.33 (d, J =1.6 Hz, 1H) 3.99 (s, 1H), 2.26 (s, 3H), 2.13 - 1.90 (m, 6H), 1.57 - 1.45 (m, 2H).
[00725] Example 225
Figure imgf000329_0002
[00726] Step 1[0598]: To a solution of 2,4,6-trichloropyridine [0565] and neopentylamine [0109] in a mixture of tetrahydrofuran and water (20 mL, 1: 1) was heated at 70 °C. After 18 h, the reaction mixture was concentrated under reduced pressure to afford as brown gum, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column to afford 2,6-dichloro-N-neopentylpyridin-4-amine [0598] as an off- white solid (1.5 g). MS(M+1)+=334.1.
[00727] Step 2[0599]: This procedure is similar to Step 3[0580] in example 216. 0.5 g of 2,6-dichloro-N-neopentylpyridin-4-amine [0598] gave 0.1 g of 2-chloro-6-(3,5-dimethyl-lH- pyrazol-l-yl)-N-neopentylpyridin-4-amine [0599] as an off-white solid. MS(M+1)+=332.1.
[00728] Step 3[0600] : This procedure is similar to Step 3 [0006] in example 1. 0.1 g of 2- chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N-neopentylpyridin-4-amine [0599], Compound 234 gave 0.015 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4- neopentylpyridine-2,4-diamine [0600] as brown solid. MS(M+l)+=392.2, 1H NMR (400 MHz, Chloroform-d) δ 6.29 (s, 1H), 5.98 (d, J = 7.3 Hz, 1H), 5.44 (s, 1H), 3.67 (s, 1H), 2.99 (s, 2H), 2.60 (s, 3H), 2.30 - 2.20 (m, 6H), 2.08 (bs, 4H), 1.91 (bs, 2H), 1.03 (s, 9H). [00729] Example 226
Figure imgf000330_0001
[00730] Step 1[0601]: To a solution of 2,4,6-trichloropyridine [0565] (0.35 g, 1.918 mmol) in tetrahydrofuran (12 mL) was added L-valinamide hydrochloride [0314] (0.3 g, 1.918 mmol) and cesium carbonate (1.37 g, 4.2 mmol), after addition the reaction mixture was stirred at 60 °C for 28 h. The reaction mixture was diluted with water, product was extracted with ethyl acetate (2x100 mL), combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using 25% ethyl acetate in pet ether as solvent to afford 0.11 g of 2-((2,6-dichloropyridin-4-yl)amino)-3- methylbutanamide [0601] as a brown solid. MS(M+l)+=262.4
[00731] Step 2[602]: The procedure is similar to step 4[0244] in example 87 (10 h, 100 °C). 0.19 g of [0601] and 0.15 g of 4,4-difluorocyclohexylamine hydrochloride [0002] gave 0.09 g of 2-((2-chloro-6-((4,4-difluorocyclohexyl)amino)pyridin-4-yl)amino)-3- methylbutanamide [0602] as a brown solid. MS(M+l)+=362.7.
[00732] Step 3[0603]: The procedure is similar to step 3[0580] in example 216 (10 h, 110 °C). 0.15 g of [0602] and 0.08 g of 3,5-dimethyl pyrazole [0017] gave 0.018 g of 2-((2-((4,4- difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-4-yl)amino)-3- methylbutanamide [0603], Compound 239 as an off- white solid. MS(M+1)+=421.2, 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 2H), 7.86 (s, 1H), 7.59 (s, 1H), 7.14 (d, J = 7.5 Hz, 1H), 6.91 (s, 1H), 6.41 (s, 1H), 6.08 (s, 1H), 3.88 (bs, 1H), 3.53 (d, J = 5.2 Hz, 1H), 2.60 (s, 3H), 2.17 (s, 3H), 2.10 - 1.88 (m, 6H), 1.62 - 1.53 (m, 2H), 0.95 (dd, J = 10.4, 6.9 Hz, 6H).
[00733] Example 227
Figure imgf000330_0002
[00734] Step 1[0605]: The procedure is similar to step 4[0244] in example 87 (10 h, 110 °C). 0.31 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin- 2-amine [0579A] and 0.16 g of c-(5-Methyl-[l,3,4]oxadiazol-2-Yl)-methylamine [0604] gave 0.068 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-((5-methyl- l,3,4-oxadiazol-2-yl)methyl)pyridine-2,4-diamine [0605], Compound 252 as an off- white solid. MS(M+1)+=417.9, 1H NMR (400 MHz, DMSO-d6) δ 6.97 (s, 1H), 6.36 - 6.32 (m, 2H), 5.97 (s, 1H), 5.55 (s, 1H), 4.48 (d, J = 6.2 Hz, 2H), 3.80 (bs, 1H), 2.53 (s, 3H), 2.47 (s, 3H), 2.14 (s, 3H), 2.10 - 1.88 (m, 6H), 1.62 - 1.48 (m, 2H).
[00735] Example 228
Figure imgf000331_0001
[00736] Step 1 [0606]: The procedure is similar to step 4[0244] in example 87 (20 h, 110 °C). 0.32 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin- 2-amine [0579A] and 0.12 g of l-thiazol-2-yl-ethylamine [0245] gave 0.058 g of N2-(4,4- difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-(l-(thiazol-2-yl)ethyl)pyridine- 2,4-diamine [0606], Compound 255 as an off- white solid. MS(M+l)+=433.2, 1H NMR (400 MHz, DMSO-d6) δ 7.74 (d, J = 3.3 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7.04 (d, J = 6.6 Hz, 1H), 6.42 (d, J = 1.7 Hz, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 5.44 (d, J = 1.8 Hz, 1H), 4.80 (p, J = 6.7 Hz, 1H), 3.77 (bs, 1H), 2.52 (s, 3H), 2.15 (s, 3H), 2.10 - 1.88 (m, 6H), 1.53 (d, J = 6.8 Hz, 3H), 1.45 (bs, 2H).
[00737] Example 229
Figure imgf000331_0002
[00738] Step 1[0607]: The procedure is similar to step 4[0244] in example 87 (at 100 °C for 20 h). 0.25 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-2-amine [0579A] and 0.08 g of oxazol-2-yl-methylamine [0316] gave 0.042 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-(oxazol-2- ylmethyl)pyridine-2,4-diamine [0607], Compound 259 as an off-white solid.
MS(M+l)+=403.2, 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.17 (s, 1H), 6.94 (t, J = 6.3 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 6.30 (d, J = 7.7 Hz, 1H), 5.97 (s, 1H), 5.54 (d, J = 1.8 Hz, 1H), 4.39 (d, J = 6.3 Hz, 2H), 3.80 (bs, 1H), 2.53 (s, 3H), 2.15 (s, 3H), 2.10 - 1.88 (m, 6H), 1.65 - 1.48 (m, 2H).
[00739] Example 230
Figure imgf000332_0001
[00740] Step 1[0177]: To a stirred solution of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.48 g, 1.40 mmol) in dioxane was added 1-acetylpiperazine [0272] (0.27 g, 2.11 mmol), cesium carbonate (1.4 g, 1.97 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.326 g, 0.563 mmol) and the reaction mixture was purged with nitrogen for 5 min. Then tris(dibenzylideneacetone)dipalladium (0.386 g, 0.422 mmol) was added to the reaction mixture and the reaction mixture was heated at 90 °C in sealed tube. After 16 h, the reaction mixture was passed through celite bed, washed with chloroform and the filtrate was concentrated under reduced pressure to afford as a brown oil, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 25 g column, to afford l-(4-(2-((4,4-difluorocyclohexyl)amino)-6- (3,5-dimethyl- IH-pyrazol- l-yl)pyridin-4-yl)piperazin- l-yl)ethan- 1-one [0608], Compound
134 as yellow solid (0.18 g). MS(M+l)+=433.3, 1H NMR (400 MHz, DMSO-d6) δ 6.54 (d, J = 1.9 Hz, 1H), 6.39 (d, J = 7.8 Hz, 1H), 6.00 (s, 1H), 5.78 (s, 1H), 3.87 (bs, 1H), 3.56 (s, 4H), 3.27 (d, J = 4 Hz, 2H), 3.21 (d, J = 4.28 Hz, 2H), 2.54 (s, 3H), 2.16 (s, 3H), 2.04 (s, 5H), 1.98 - 1.80 (m, 4H), 1.62 - 1.48 (m, 2H). [00741] Example 231
Figure imgf000333_0001
[00742] Step 1[0609]: The procedure is similar to step 4[0244] in example 87. 0.3 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] gave 0.03g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-(lH- pyrazol-l-yl)pyridin-2-amine [0609], Compound 127 as a white solid. MS(M+l)+=373.7, 1H-NMR (400 MHz, DMSO-d6): δ 8.52 (d, J = 2.60 Hz, IH), 7.79 (d, J = 1.60 Hz, IH), 7.35 (d, J = 1.64 Hz, IH), 7.03 (d, J = 7.52 Hz, IH), 6.80 (d, J = 1.68 Hz, IH), 6.57 - 6.56 (m, IH), 6.08 (s, IH), 3.93 - 3.91 (m, IH), 2.61 (s, 3H), 2.19 (s, 3H), 2.09 - 2.07 (m, 2H), 2.00-1.90 (m, 4H), 1.54 - 1.60 (m, 2H).
[00743] Example 232
Figure imgf000333_0002
[00744] Step 1[0610]: The procedure is similar to step 4[0244] in example 87. 0.3 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] gave 0.04 g of racemate 3-((2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH- pyrazol-l-yl)pyridin-4- yl)amino)-l-methylpyrrolidin-2-one [0610], Compound 135 as a brown solid. MS(M+l)+= 419.2. 1H NMR (400 MHz, DMSO-d6) δ 6.43 (d, J = 7.1 Hz, IH), 6.37 (s, IH), 6.20 (d, J = 7.6 Hz, IH), 5.97 (s, IH), 5.58 (s, IH), 4.10 - 4.05 (m, IH), 3.82 (bs, IH), 3.31 (m, 2H) 2.77 (s, 3H), 2.53 (s, 3H), 2.42 (m, IH), 2.15 (s, 3H), 2.06 (m, 2H), 1.92 (m, 4H), 1.76 (m, IH), 1.51 - 1.41 (m, 2H).
[00745] Step 2[0611 and 0612]: Enantiomers were separated by chiral prep HPLC to afford 0.029 g of (+)-3-((2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-4-yl)amino)-l-methylpyrrolidin-2-one [0611], Compound 138 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.42 (d, J = 7.4 Hz, IH), 6.36 (d, J = 1.7 Hz, IH), 6.19 (d, J = 7.7 Hz, IH), 5.96 (s, IH), 5.58 (d, J = 1.8 Hz, IH), 4.07 (q, J = 8.5 Hz, IH), 3.81 (bs, IH), 3.33 (s, 1H), 3.30 (d, J = 1.4 Hz, 1H), 2.76 (s, 3H), 2.53 (s, 3H), 2.43 (m, 1H), 2.14 (s, 3H), 2.05 - 1.91 (m, 2H), 1.88 - 1.80 (m, 4H), 1.78 - 1.71 (m, 1H), 1.50 (m, 2H). and 0.023 g of (-)-3-((2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-4- yl)amino)-l-methylpyrrolidin-2-one [0612], Compound 139 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 6.42 (d, J = 7.3 Hz, 1H), 6.36 (d, J = 1.6 Hz, 1H), 6.19 (d, J = 7.8 Hz, 1H), 5.96 (s, 1H), 5.58 (d, J = 1.8 Hz, 1H), 4.07 (q, J = 8.5 Hz, 1H), 3.79 (bs, 1H), 2.76 (s, 3H), 2.53 (s, 3H), 2.48 - 2.38 (m, 2H), 2.14 (s, 3H), 2.12 - 1.88 (m, 6H), 1.85 - 1.73 (m, 1H), 1.58 - 1.48 (m, 2H), 0.88 - 0.75 (m, 1H).
[00746] Example 233
Figure imgf000334_0001
[00747] Step 1[0613]: The procedure is similar to step 1[0301] in example 111. 0.3 g of4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] gave 0.050 g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4- ((l-methyl-lH-l,2,3-triazol-5-yl)methoxy)pyridin-2-amine [0613], Compound 268 as a white solid. MS(M+1)+=418.2. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.03 (s, 1H), 5.96 (d, J = 1.6 Hz, 1H), 5.31 (s, 2H), 4.04 (s, 3H), 3.87 (bs, 1H), 2.57 (s, 3H), 2.16 (s, 3H), 2.09 - 1.85 (m, 6H), 1.62 - 1.45 (m, 2H).
[00748] Example 234
Figure imgf000334_0002
[00749] Step 1[0614]: To a suspension of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.15 g, 0.44 mmol) and (1-methyl-lH- l,2,4-triazol-5-yl)methanol [0304] (0.14 g, 1.17 mmol) in 50% aq. sodium hydroxide solution (2 mL) was added tetrabutyl ammonium hydrogen Sulfate (0.14 g, 0.44 mmol), then the reaction mixture was heated at 100 °C in a closed vial for 16 h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (2x40 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford crude and which was purified by column of silica gel (60-120 mesh), using 25% ethyl acetate in hexane as eluent gave 0.03 g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-((l- methyl-lH-l,2,4-triazol-5-yl)methoxy)pyridin-2-amine [0614], Compound 271 as a white solid. MS(M+1)+=419.6, 1H-NMR (400 MHz, DMSO-d6): δ 7.95 (s, 1H), 6.77 (d, J = 7.60 Hz, 1H), 6.62 (d, J = 1.96 Hz, 1H), 6.03 (s, 1H), 5.97 (d, J = 1.96 Hz, 1H), 5.31 (s, 1H), 3.89 (s, 1H), 3.85-3.84 (m, 1H), 2.57 (s, 3H), 2.15 (s, 3H), 2.07-1.92 (m, 6H), 1.52-1.47 (m, 2H).
[00750] Exam le 235
Figure imgf000335_0001
[00751] Step 1[0615]: The procedure is similar to step 1[0614] in example 234. 0.3 g of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0242] gave 0.065 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-((l- methyl-lH-l,2,4-triazol-3-yl)methoxy)pyrimidin-4-amine [0615] as a white solid (0.065 g). MS(M+1)+=419.6, 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.53 (bs, 1H), 6.06 (s, 1H), 5.75 (bs, 1H), 5.31 (s, 2H), 4.01 (bs, 1H), 3.86 (s, 3H), 2.54 (s, 3H), 2.17 (s, 3H), 2.12 - 1.85 (m, 6H), 1.62 - 1.50 (m, 2H).
[00752] Exam le 236
Figure imgf000335_0002
[00753] Step 1[0617]: To a suspension of 4-chloro-N-(4,4-difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0579A] (0.2 g, 0.58 mmol) and 4-fluorobenzyl alcohol [0616] (0.14 g, 1.17 mmol) in 50% aq. sodium hydroxide solution (2 mL) was added tetrabutyl ammonium hydrogen Sulfate (0.11 g, 0.35 mmol), then the reaction mixture was heated at 100 °C in a closed vial for 16 h. After the completion of the reaction, the reaction mixture was extracted with ethyl acetate (2x40 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford crude and which was purified by column of silica gel (60-120 mesh), using 25% ethyl acetate in hexane as eluent to afford N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-((4-fluorobenzyl)
oxy)pyridin-2-amine [0617], Compound 263 as an off-white gum (0.075 g).
MS(M+1)+=431, 1H NMR (400 MHz, DMSO-d6) δ 7.50 (t, 2H), 7.24 (t, J = 8.6 Hz, 2H), 6.69 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 6.03 (s, 1H), 5.95 (s, 1H), 5.11 (s, 2H), 3.86 (bs, 1H), 2.58 (s, 3H), 2.16 (s, 3H), 2.01-1.90 (m, 6H), 1.59-1.52 (m, 2H).
[00754] Example 237
Figure imgf000336_0001
[00755] Step 1[0618]: The procedure is similar to step 1[0614] in example 234. 0.2 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] and 0.133 g of (2-methyl-2H-l,2,3-triazol-4-yl)methanol [0300] gave 0.07 g of N- (4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-((2-methyl-2H-l,2,3-triazol-4- yl)methoxy)pyridin-2-amine [0618], Compound 251 as an off-white solid. MS(M+1)+ =418, 1H-NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 6.70 (d, J = 7.60 Hz, 1H), 6.59 (d, J = 2.00 Hz, 1H), 6.02 (s, 1H), 5.96 (s, 1H), 5.16 (s, 2H), 4.16 (s, 3H), 3.85 (bs, 1H), 2.57 (s, 3H), 2.15 (s, 3H), 2.07-1.87 (m, 6H), 1.52-1.50 (m, 2H).
[00756] Ex mple 238
Figure imgf000336_0002
[00757] Step 1[0619]: The procedure is similar to step 1[0614] in example 234. 0.2 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] and 0.265 g of (l-methyl-lH-l,2,3-triazol-4-yl)methanol [0302] gave 0.1 g of N- (4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-((l-methyl-lH-l,2,3-triazol-4- yl)methoxy)pyridin-2-amine [0619], Compound 244 as an off-white solid. MS(M+1)+ =418, 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 6.71 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 2.0 Hz, 1H), 6.06 - 5.98 (m, 2H), 5.16 (s, 2H), 4.06 (s, 3H), 3.87 (bs, 1H), 2.58 (s, 3H), 2.16 (s, 3H), 2.11 - 1.89 (m, 6H), 1.59-1.52 (m, 2H).
[00758] Example 239
Figure imgf000337_0001
[00759] Step 1[0621] : The procedure is similar to step 4[0244] in example 87. 0.2 g of 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] gave 0.035 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4- (4-methoxybenzyl)pyridine-2,4-diamine [0621], Compound 264 as off-white solid.
MS(M+l)+=442.2. 1H NMR (400 MHz, DMSO-d6) δ 7.34 - 7.13 (m, 2H), 7.02 - 6.85 (m, 2H), 6.80 (t, J = 6.1 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 6.16 (d, J = 7.7 Hz, 1H), 5.95 (s, 1H), 5.45 (d, J = 1.9 Hz, 1H), 4.18 (d, J = 5.9 Hz, 2H), 3.76 (bs, 1H), 3.72 (s, 3H), 2.51 (s, 3H), 2.13 (s, 3H), 2.09 - 1.75 (m, 6H), 1.46 (q, J = 12.0, 10.4 Hz, 2H).
[00760] Example 240
Figure imgf000337_0002
[00761] Step 1[0623]: To a suspension of sodium hydride in tetrahydrofuran (2 mL) in a micro wave vial was added a solution of 4-methoxybenzyl alcohol [0622] (0.15 g, 1.1 mmol) in tetrahydrofuran at 0 °C under nitrogen. The solution was stirred at 0 °C for half an hour. 4- chloro-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine
[0579A] (025 g, 0.73 mmol) was added and the reaction mixture was heated at 150 °C. The reaction mixture was quenched with ice, then extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product and which was purified by column chromatography using 25% ethyl acetate in pet ether as solvent to afford N-(4,4-Difluorocyclohexyl)-6-(3,5- dimethyl-lH-pyrazol-l-yl)-4-((4-methoxybenzyl)oxy) pyridin-2-amine [0623] as an off- white solid (0.05 g). MS(M+l)+=443.2.
[00762] Step 2[0624] : A solution of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl- 1H- pyrazol-l-yl)-4-((4-methoxybenzyl)oxy)pyridin-2-amine [0623] (0.05 g, 0.11 mmol) in methanol (3 mL) was degassed with nitrogen for 5 min. Palladium on carbon (10%) (0.02 g) was added and the mixture was hydrogenated with hydrogen (63 psi) at rt for 2 h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 40% ethyl acetate in pet ether as solvent to afford of 2-((4,4-difluorocyclohexyl)amino)-6-(3,5- dimethyl-lH-pyrazol-l-yl)pyridin-4-ol [0624], Compound 276 as an white solid (0.012 g). MS(M+1)+=323.1, 1H NMR (400 MHz, Chloroform-d) δ 6.76 (d, J = 1.8 Hz, 1H), 6.00 (s, 1H), 5.74 (d, J = 1.8 Hz, 1H), 4.49 (s, 1H), 3.72 (s, 1H), 2.55 (s, 3H), 2.29 (s, 3H), 2.11 (td, J = 13.7, 11.4, 5.5 Hz, 5H), 1.87 (d, J = 27.4 Hz, 2H), 1.65 - 1.53 (m, 2H).
[00763] Example 241
Figure imgf000338_0001
[00764] Step 1[0626]: To a stirred solution of ethyl lh-pyrazole-3-carboxylate [0005] (1 g, 6.99 mmol) in tetrahydrofuran (15 mL), methyl magnesium bromide (2.5 g, 2097 mmol) was added at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated solution of sodium bisulfate (15 mL), then the reaction mixture was filtered and separated the organic layer, then the aqueous was basified with saturated solution of sodium bicarbonate (20 mL), and then extracted with ethyl acetate (2x200 mL). The combined organic layer was washed with brine solution (25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 0.650 g of 2-(lh-pyrazol-3- yl)propan-2-ol [0626] as colorless gum. MS(M+1) +=127.2. [00765] Step 2[0627]: This procedure is similar to Step 1[0270] in example 98. 0.5 g of 2,6-dichloro-4-methyl pyridine [0625] and 0.77 g of 2-(lH-pyrazol-3-yl)propan-2-ol [0626] gave 0.6 g of 2-(l-(6-chloro-4-methylpyridin-2-yl)-lH-pyrazol-3-yl)propan-2-ol [0627] as a yellow liquid. MS(M+1)+ =252.0.
[00766] Step 3[0628]: This procedure is similar to Step 1[0570] in example 212. 0.35 g of 2-(l-(6-chloro-4-methylpyridin-2-yl)-lH-pyrazol-3-yl)propan-2-ol [0627] and 0.47 g of 4,4- difluorocyclohexylamine hydrochloride [0628] gave 0.06 g of 2-(l-(6-((4,4- difluorocyclohexyl)amino)-4-methylpyridin-2-yl)- lH-pyrazol-3-yl)propan-2-ol [0628], Compound 265 as white solid. MS(M+1)+=351.0, 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.5 Hz, 1H), 6.80 (s, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.45 (d, J = 2.6 Hz, 1H), 6.18 (s, 1H), 5.02 (s, 1H), 3.97 (bs, 1H), 2.22 (s, 3H), 2.13 - 1.87 (m, 6H), 1.68-1.50 (m 2H), 1.47 (s, 6H).
[00767] Example 242
Figure imgf000339_0001
[00768] Step 1[0630]: This procedure is similar to Step 1[0270] in example 98. 0.5 g of 2,6-dichloro-4-(trifluoromethyl)pyridine [0629] and 0.24 g of 3,5-dimethyl pyrazole [0630] gave 0.48 g (crude) of 4-(tert-butyl)-2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridine [0630] as a yellow liquid. MS(M+l)+=276.2. This was taken as such to next step.
[00769] Step 2[0631] NSSy5088: This procedure is similar to Step 3[0580] in example 216. 0.48 g (crude) of 4-(tert-butyl)-2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridine
[0630] and 0.35 g of 4,4-difluorocyclohexylamine hydrochloride [0002] gave 0.28 g of N- (4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-(trifluoromethyl)pyridin-2- amine [0631], Compound 170 as a white solid. MS(M+l)+=375.2, 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 7.5 Hz, 1H), 7.07 (s, 1H), 6.62 (s, 1H), 6.11 (s, 1H), 3.93 (bs, 1H), 2.63 (s, 3H), 2.19 (s, 3H), 2.11 - 1.86 (m, 6H), 1.50-1.58 (m, 2H). [00770] Example 243
Figure imgf000340_0001
[00771] Step 1[0633]: This procedure is similar to Step 1[0270] in example 98. 1 g of 2,6- dichloro-4-methyl pyridine [0625] and 0.65 g of 3,5-dimethyl pyrazole [0017] gave 0.6 g of 2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridine [0633] as white solid.
MS(M+l)+=222.0.
[00772] Step 2[0634]. This procedure is similar to Step 3[0580] in example 216. 0.2 g of 2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridine [0633] and 0.46 g of 4,4- difluorocyclohexylamine hydrochloride [0002] gave 0.05 g of N-(4,4-difluorocyclohexyl)-6- (3,5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridin-2-amine [0634], Compound 159 as a white solid. MS(M+l)+= 321.2, 1H NMR (400 MHz, DMSO-d6) δ 6.74 (s, 1H), 6.63 (d, J = 7.5 Hz, 1H), 6.16 (s, 1H), 6.01 (s, 1H), 3.86 (bs, 1H), 2.56 (s, 3H), 2.17 (s, 3H), 2.15 (s, 3H), 2.15- 2.00 (m, 2H), 1.99 - 1.86 (m, 4H), 1.58-1.45 (m, 2H).
[00773] Example 245
Figure imgf000340_0002
[00774] Step 1[0637]: The procedure is similar to Step 1[0570] in example 212. 0.2 g of 2-chloro-4-methyl-6-(3-methyl-lH-pyrazol-l-yl)pyridine [0635] and 0.3 g of 4- (trifluoromethyl) cyclohexanamine [0113] gave 0.04 g of 4-methyl-6-(3-methyl-lH-pyrazol- l-yl)-N-(4-(trifluoromethyl) eye lohexyl)pyridin-2- amine [0637], Compound 180 as an off- white solid. MS(M+l)+=339.2, 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.5 Hz, 1H), 6.76 (s, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.26 (d, J = 2.5 Hz, 1H), 6.14 (s, 1H), 3.76-3.64 (m, 1H), 2.28 (s, 3H), 2.24 (s, 3H), 2.10 (d, J = 10.8 Hz, 2H), 1.94 (d, J = 12 Hz, 2H), 1.45 (qd, J = 12.9, 3.3 Hz, 2H), 1.23 (qd, J = 12.9, 3.4 Hz, 2H). [00775] Example 246
Figure imgf000341_0001
[00776] Step 1[0639]: This procedure is similar to Step 1[0270] in example 98. 1 g of 2,6- dichloropyridine [0638] and 0.77 g of 3,5-dimethyl pyrazole [0017] gave 0.5 g of 2-chloro-6- (3,5-dimethyl-lH-pyrazol-l-yl)pyridine [0639] as a white solid. MS(M+l)+=208.2.
[00777] Step 2[0640]: This procedure is similar to Step 3[0580] in example 216. 0.2 g of 2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridine [0639] and 0.19 g of 4,4- difluorocyclohexylamine hydrochloride [0002] gave 0.06 g of N-(4,4-difluorocyclohexyl)-6- (3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0640], Compound 154 as a white solid. MS(M+l)+=307.2, 1H-NMR (400 MHz, DMSO-d6): δ 7.46 (t, J = 7.96 Hz, 1H), 7.27 (bs, 1H), 6.77 (d, J = 7.52 Hz, 1H), 6.35 (d, J = 8.16 Hz, 1H), 6.04 (s, 1H), 3.89-3.88 (m, 1H), 2.59 (s, 3H), 2.17 (s, 3H), 2.04-1.99 (m, 2H), 1.91-1.90 (m, 4H), 1.58-1.52 (m, 2H).
[00778] Step 3[0641]: To a solution of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH- pyrazol-l-yl)pyridin-2-amine [0640] (0.15 g, 0.48 mmol) in tetrahydrofuran (10 mL) was added Lithium bis(trimethylsilyl) amide (0.16 g, 0.97 mmol) drop wise at 0 °C. Then the reaction mixture was stirred at rt for 30 min, then iodomethane (0.13 g, 0.97 mmol) was added to the reaction mixture at 0 °C and stirred at rt. After 16 h, the reaction mixture was quenched with ice and extracted with ethyl acetate (2x25 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure to afford a yellow liquid which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column, to afford of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl- IH-pyrazol- l-yl)-N-methylpyridin-2- amine [0641], Compound 166 as a white solid (0.14 g). MS(M+1)+=321.2, 1H NMR (400 MHz, DMSO-d6) δ 7.62 (t, J = 8.1 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.06 (s, 1H), 4.52 (bs, 1H), 2.86 (s, 3H), 2.62 (s, 3H), 2.18 (s, 3H), 2.13 - 1.88 (m, 4H), 1.86 - 1.63 (m, 4H). [00779] Example 2
Figure imgf000342_0001
[00780] Step 1[0643]: To a stirred suspension of 2,6-dichloroisonicotinonitrile [0642] (2 g, 11.560 mmol), 3,5-dimethyl pyrazole [0017] (1.222 g, 12.717 mmol) and cesium carbonate (5.650 g, 17.341 mmol) in acetonitrile was heated at 75°C for 20 h. The reaction mixture was filtered, washed with ethyl acetate. The combined filtrate was concentrated under reduced pressure to afford crude which was purified by column chromatography using 5% ethyl acetate in hexane as eluent to afford 1 g of 2-chloro-6-(3,5-dimethyl-lH-pyrazol-l- yl)isonicotinonitrile [0643] as a white solid. MS(M+1)+=233.1
[00781] Step 2[0644]: This procedure is similar to Step 3[0580] in example 216. 0.3 g of 2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)isonicotinonitrile [0643] and 0.26 g of 4,4- difluorocyclo hexylamine hydrochloride [0002] gave 0.12 g of 2-((4,4- difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)isonicotinonitrile [0644],
Compound 174 as off-white solid. MS(M+1)+ = 322.3, 1H-NMR (400 MHz, CDC13): δ 7.39 (d, J = 1.20 Hz, 1H), 6.39 (d, J = 0.80 Hz, 1H), 6.01 (d, J = Hz, 1H), 4.62 (d, J = 7.60 Hz, 1H), 3.86 (d, J = 7.20 Hz, 2H), 2.64 (s, 3H), 2.29 (s, 3H), 1.97-1.90 (m, 4H), 1.89-1.84 (m, 2H), 1.83-1.65 (m, 1H).
[00782] Step 3[0645] NSSy5101. To a solution of 2-((4,4-difluorocyclohexyl)amino)-6- (3,5-dimethyl-lH-pyrazol-l-yl)isonicotinonitrile [0644] (0.1 g, 0.30 mmol) in
tetrahydofuran:water (1: 1) was added potassium hydroxide (0.084 g, 1.50 mmol) and the reaction mixture was heated at 60 °C. After 8 h, the reaction mixture was concentrated under reduced pressure and the residue was diluted with water and extracted with chloroform. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford brown oil. The crude
was purified in the Reveleris flash system instrument using methanol in chloroform as solvent in 12 g column to afford 0.021 g 2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol-l-yl)isonicotinamide [0645], Compound 175 as orange solid. MS(M+l)+=350.2,
1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H), 7.48 (s, 1H), 7.24 (d, J = 1.2 Hz, 1H), 6.99 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 1.2 Hz, 1H), 6.06 (s, 1H), 3.90 (d, J = 9.2 Hz, 1H), 2.59 (s, 3H), 2.18 (s, 3H), 2.12 - 1.74 (m, 6H), 1.74 - 1.30 (m, 2H). [00783] Example 2
Figure imgf000343_0001
[00784] Step 1[0646] : This procedure is similar to Step 2[0019] in example 4. 0.1 g of 2- ((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)isonicotinonitrile [0644] gave 0.026 g of 4-(aminomethyl)-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-2-amine [0646], Compound 195 as brown solid. MS(M+l)+=336.2, 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 3H), 7.05 (s, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 3.94 (q, J = 5.9 Hz, 3H), 2.60 (s, 3H), 2.18 (s, 3H), 2.10 - 1.86 (m, 6H), 1.63 - 1.47 (m, 2H).
[00785] Example 249
Figure imgf000343_0002
[00786] Step 1[0647]: To a suspension of 2-((4,4-difluorocyclohexyl)amino)-6-(3,5- dimethyl-lH-pyrazol-l-yl)isonicotinonitrile [0647] (0.5 g, 1.51 mmol) in cone, hydrochloric acid (10 mL) was heated at 100 °C for 24 h. The reaction mixture was diluted with water and extracted with chloroform (3x50 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 2% methanol in chloroform as eluent to obtain 2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)isonicotinic acid [0647] (0.25 g, 47%) as off-white solid. MS(M+1)+=351.2.
[00787] Step 2[0648] : To a stirred solution of 2-((4,4-difluorocyclohexyl)amino)-6-(3,5- dimethyl-lH-pyrazol-l-yl)isonicotinic acid [0647] (0.25 g, 0.714 mmol) in ethanol (10 mL) was added cone, sulfuric acid and the mixture was heated at 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure to remove ethanol. The residue was basified with aq. sodium bicarbonate solution. The product was extracted with chloroform (3x25 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 2-((4,4-difluorocyclohexyl)amino)-6- (3,5-dimethyl-lH-pyrazol-l-yl)isonicotinate [0648] (0.15 g, 55%) as an off-white solid. MS(M+l)+=378.4.
[00788] Step 3[0649]: This procedure is similar to Step 1[0529] in example 195.. 0.2 g of ethyl 2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)isonicotinate
[0648] gave 0.06 g of 2-(2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-4-yl)propan-2-ol [0649], Compound 206 as an off-white solid. MS(M+l)+=365.2, 1H NMR (400 MHz, Chloroform-d) δ 7.12 (d, J = 1.3 Hz, IH), 6.44 (d, J = 1.3 Hz, IH), 5.98 (s, IH), 3.89 (s, IH), 2.61 (s, 3H), 2.31 (s, 3H), 2.24 - 2.05 (m, 4H), 2.03 - 1.75 (m, 4H), 1.64 - 1.45 (m, 8H).
[00789] Example 250
Figure imgf000344_0001
[00790] Step 1 [0650]: The procedure is similar to step 2[0019] in example 4 [at -78 °C]. 0.1 g of ethyl 2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l- yl)isonicotinate [0648] gave 0.055 g of (2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol-l-yl)pyridin-4-yl)methanol [0650], Compound 185 as an off-white solid.
MS(M+l)+=337.4, 1H NMR (400 MHz, DMSO-d6) δ 6.85 (s, IH), 6.73 (d, J = 7.6 Hz, IH), 6.36 (s, IH), 6.03 (s, IH), 5.29 (s, IH), 4.42 (s, 2H), 3.89 (d, J = 9.1 Hz, IH), 2.58 (s, 3H), 2.17 (s, 3H), 2.13 - 1.86 (m, 6H), 1.54 (q, J = 11.6, 10.9 Hz, 2H).
[00791] Step 2[0651]: This procedure is similar to Step 3[0444] in example 166. 0.25 g of (2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-4-yl)methanol [0650] gave 0.1 g of 2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l- yl)isonicotinaldehyde [0651] as an off-white solid. MS(M+l)+=335.2.
[00792] Step 3[0652]: This procedure is similar to Step 3 [0012] in example 2. 0.1 g of 2- ((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)isonicotinaldehyde [0651] gave 0.04 g of N-(4,4-difluorocyclohexyl)-4-(difluoromethyl)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-2-amine [0652], Compound 213 as an off-white solid. MS(M+1)+=357.1, 1H NMR (400 MHz, Chloroform-d) δ 7.25 (s, IH), 6.41 (s, IH), 6.36 (s, IH), 6.01 (s, IH), 4.53 (s, IH), 3.90 (s, IH), 2.65 (s, 3H), 2.31 (s, 3H), 2.23 - 2.11 (m, 4H), 2.00 - 1.81 (m, 2H), 1.75 - 1.55 (m, 2H). [00793] Example 251
Figure imgf000345_0001
[00794] Step 1[0653]: This procedure is similar to Step 3[0012] in example 2. 0.25 g of (2-((4,4-difluoro cyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)pyridin-4-yl)methanol [0650] gave 0.01 g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-4- (fluoromethyl)pyridin-2-amine [0653], Compound 229 as brown solid. MS(M+1)+=339.1, 1H NMR (400 MHz, Chloroform-d) δ 6.87 (s, IH), 6.45 (s, IH), 6.09 (s, IH), 5.48 (s, IH), 5.36 (s, IH), 3.81 (s, 2H), 2.62 (s, 3H), 2.38 (s, 3H), 2.23 (bs, 2H), 2.11 (bs, 2H), 1.94 (s, 2H), 1.79 (bs, 2H).
[00795] Example 252
Figure imgf000345_0002
[00796] Step 1[0654] : This procedure is similar to Step 2[0049] in example 10. 0.1 g of 2- ((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)isonicotinaldehyde [0651] gave 0.05 g of l-(2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl-lH-pyrazol-l- yl)pyridin-4-yl)ethan-l-ol [0654], Compound 207 as off-white solid. MS(M+1)+=351.1, 1H NMR (400 MHz, Chloroform-d) δ 7.04 (s, IH), 6.32 (s, IH), 5.98 (s, IH), 4.83 (q, J = 6.5 Hz, IH), 4.45 (s, IH), 3.87 (s, IH), 2.61 (s, 3H), 2.30 (s, 3H), 2.24 - 2.04 (m, 4H), 2.03 - 1.79 (m, 2H), 1.8 - 1.55 (m, 2H), 1.50 (d, J = 6.5 Hz, 3H).
Figure imgf000346_0001
[00798] Step 1[0655]: The procedure is similar to step 1[0270] in example 98 [at 50 °C for 6 h]. 6 g of 2,6-dichloroisonicotinonitrile [0642] and 4.9 g of ethyl lH-pyrazole-3- carboxylate [0005] gave 7.2 g of ethyl l-(6-chloro-4-cyanopyridin-2-yl)-lH-pyrazole-3- carboxylate [0655] as an off-white solid. MS(M+l)+=277.0.
[00799] Step 2[0656]: The procedure is similar to step 3[0580] in example 216 (at 90 °C for 16 h). 2.5 g of ethyl l-(6-chloro-4-cyanopyridin-2-yl)-lH-pyrazole-3-carboxylate [0655] and 1.5 g of 4,4-difluorocyclohexan-l -amine [0002] gave 1.74 g of ethyl l-(4-cyano-6-((4,4- difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazole-3-carboxylate [0656] as a yellow solid. MS(M+l)+=376.4/377.3
[00800] Step 3[0657]: The procedure is similar to step 2[0019] in example 4. 1 g of ethyl l-(4-cyano-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazole-3-carboxylate
[0656] gave 0.55 g of (l-(4-(aminomethyl)-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)- lH-pyrazol-3-yl)methanol [0657] as a brownish solid. MS(M+l)+=338.2
[00801] Step 4[0658]: To a solution of (l-(4-(aminomethyl)-6-((4,4- difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazol-3-yl)methanol [0657] (0.55 g, 1.63 mmol), in dichloromethane (15 mL) was added acetyl chloride (0.29 g, 4.07 mmol) in drop wise and followed by triethylamine (0.65 g, 6.52 mmol) at 0 °C. After addition the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product and which was dissolved in methanol:water(l: l) followed by addition of potassium carbonate (0.5 g, 1.18 mmol) and stirred at rt for 15 min. The reaction mixture was concentrated under reduced pressure to afford crude product and which was purified by column chromatography using 5% methanol in chloroform as solvent to afford of N-((2- ((4,4-difluorocyclohexyl)arnino)-6-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide [0658] as a brown solid (0.38 g). MS(M+l)+=380.2
[00802] Step 5[0659] : The procedure is similar to step 3 [0012] in example 2. 0.38 g of N- ((2-((4,4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide [0658] gave 0.038 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide [0659], Compound 312 as a white solid. MS(M+l)+=382.3, 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 2.5 Hz, 1H), 8.42 (t, J = 6.1 Hz, 1H), 6.91 (s, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 6.28 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 4.16 (d, J = 6.1 Hz, 2H), 4.01 (bs, 1H), 2.26 - 1.92 (m, 6H), 1.89 (s, 3H), 1.62 -1.54 (m, 2H).
Example 254
Figure imgf000347_0001
[00804] Step 1[0660]: The procedure is similar to step 3[0444] in example 166. 0.35 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide [0658] gave 0.29 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- formyl-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide [0660] as a brown solid.
MS(M+l)+=378.39
[00805] Step 2 [0661]: The procedure is similar to step 3[0012] in example 2. 0.29 g of N- ((2-((4,4-difluorocyclohexyl)amino)-6-(3-formyl-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide [0660] gave 0.058 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (difluoromethyl)-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide [0661], Compound 301 as an yellowish solid. MS(M+l)+=400.2, 1H-NMR (400 MHz, DMSO-d6): δ 8.64 (d, J = 2.44 Hz, 1H), 8.42 (t, J = 6.00 Hz, 1H), 7.11 (t, JF = 54 Hz, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.77 (d, J = 2.48 Hz, 1H), 6.33 (s, 1H), 4.18 (d, J = 6.00 Hz, 2H), 4.03 (bs, 1H), 2.06-1.98 (m, 6H), 1.90 (s, 3H), 1.59-1.56 (m, 2H). [00806] Example 255
Figure imgf000348_0001
[00807] Step 1[0662]: The procedure is similar to step 4[0658] in example 253. 0.5 g of (l-(4-(aminomethyl)-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazol-3- yl)methanol [0657] gave 0.3 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (hydroxymethyl)-lH-pyrazol-l-yl)pyridin-4-yl)methyl)isobutyramide [0662] as a brown solid. MS(M+1) +=408.2.
[00808] Step 2[0663] : The procedure is similar to step 3 [0012] in example 2. 0.3 g of N- ((2-((4,4-difluorocyclohexyl)arnino)-6-(3-(hydroxymethyl)-lH-pyrazol-l-yl)pyridin-4- yl) methyl) isobutyramide [0662] gave 0.1 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (fluoromethyl)-lH-pyrazol-l-yl)pyridin-4-yl)methyl)isobutyramide [0663], Compound 348 as an off-white solid. MS(M+1)+=410.2, 1H NMR (400 MHz, DMSO-d6): δ 8.56 (d, J = 2.20 Hz, 1H), 8.32 (t, J = 5.84 Hz, 1H), 6.91 (d, J = 8.04 Hz, 2H), 6.64 (s, 1H), 6.26 (s, 1H), 5.49 (s, 1H), 5.37 (s, 1H), 4.18 (d, J = 5.84 Hz, 2H), 4.02-4.01 (m, 1H), 2.45-2.43 (m, 2H), 2.07- 1.97 (m, 6H), 1.56-1.54 (m, 2H), 1.06 (d, J = 6.84 Hz, 6H).
[00809] Example 256
Figure imgf000348_0002
[00810] Step 1[0664]: The procedure is similar to step 1[0270] in example 98 [at rt for 16 h]. 10 g of 2,6-dichloroisonicotinonitrile [0642] gave 5 g of ethyl l-(6-chloro-4- cyanopyridin-2-yl)-4-methyl-lH-pyrazole-3-carboxylate [0664] as a brownish solid.
MS(M+1)+=291.0
[00811] Step 2[0665]: The procedure is similar to step 3[0580] in example 216 [at 80 °C for 12 h]. 5 g of ethyl l-(6-chloro-4-cyanopyridin-2-yl)-4-methyl-lH-pyrazole-3- [0664] gave
1.3 g of ethyl l-(4-cyano-6-((4,4-difluorocyclohexyl)arnino)pyridin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate [0665] as an off-white solid. MS(M+l)+=389.4
[00812] Step 3[0666]: The procedure is similar to step 2[0019] in example 4. 1 g of ethyl l-(4-cyano-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazole-3- carboxylate [0665] gave 0.61 g of (l-(4-(aminomethyl)-6-((4,4- difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl- lH-pyrazol-3-yl)methanol [0666] as a brownish solid. MS(M+1)+ = 351.3.
[00813] Step 4[0667]: The procedure is similar to step 4[0658] in example 253. 0.7 g of (l-(4-(aminomethyl)-6-((4,4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazol- 3-yl)methanol [0666] gave 0.4 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (hydroxymethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide [0667] as an off- white solid. MS(M+l)+=393.4.
[00814] Step 5[0668].The procedure is similar to step 3 [0012] in example 2. 0.15 g of N- ((2-((4,4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-4-methyl-lH-pyrazol-l- yl)pyridin-4-yl)methyl)acetamide [0667] gave 0.12 g of N-((2-((4,4- difluorocyclohexyl)amino)-6-(3-(fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide. This was purified by column chromatography using 1% methanol in chloroform as solvent to afford 0.028 g of N-((2-((4,4-difluorocyclohexyl)amino)-6-(3- (fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide [0668], Compound 349 as an off-white solid. MS(M+1)+ =396.2, 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (t, J = 5.88 Hz, 1H), 8.36 (s, 1H), 6.88 (s, 1H), 6.86 (s, 1H), 6.26 (s, 1H), 5.45 (d, JF = 48 Hz, 2H), 4.16 (d, J = 5.96 Hz, 2H), 4.02 (bs, 1H), 2.18 (s, 3H), 2.09-2.06 (m, 6H), 1.90 (s, 3H), 1.50- 1.28 (m, 2H). [00815] Example 257
Figure imgf000350_0001
[00816] Step 1[0669]: To a stirred solution of 2,6-dichloroisonicotinonitrile [0642] (15.0 g, 86.70 mmol) was taken in concentrated hydro chloric acid ( 120 mL) and heated to 110 °C for 3 h. The reaction mixture was cooled to rt and diluted slowly with ice cold water (300 mL). White solid thus precipitated was filtered, washed with ice cold water (100 mL) and dried under reduced pressure to afford 2,6-dichloroisonicotinic acid [0669] as a white solid (14.18 g, 90%). MS(M+1)+=190.1.
[00817] Step 2 [0670]: To a stirred solution of 2,6-dichloroisonicotinic acid [0669] (14.18 g, 73.85 mmol) in ethanol (125 mL) was added concentrated sulfuric acid (0.2 mL, 3.7 mmol). The resultant reaction mixture was heated at 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with ice-water (50 mL) and neutralized with solid sodium bicarbonate. White solid was slowly precipitated out which was filtered, washed with water (200 mL) and dried under reduced pressure to afford ethyl 2,6-dichloroisonicotinate [0670] as a white solid (11.2 g, 68%). MS(M+1)+=221.0.
[00818] Step 3 [0671] : The procedure is similar to step 2[0011] in example 2. 14.1 g of ethyl 2,6-dichloroisonicotinate [0670] gave 11.1 g of (2,6-dichloropyridin-4-yl)methanol [0671]. MS(M+1)+=179.0.
[00819] Step 4 [0672]: To a stirred solution of 2,6-dichloropyridin-4-yl)methanol [0671] ( 8.6 g, 48.31 mmol) in a mixture of dichloromethane (150 mL) and tetrahydrofuran (20 mL) was added manganese dioxide (21.01 g, 241.55 mmol) under inert atmosphere . The reaction mixture was stirred at rt for 20 h. The reaction mixture was filtered over celite and filtrate was concentrated under reduced pressure to afford crude product which was purified by column chromatography using 15% ethyl acetate in pet ether as eluent to afford 2,6- dichloroisonicotinaldehyde [0672] as a white solid (4.9 g). MS(M+1)+=177.0.
[00820] Step 5 [0674]: To a stirred solution of oxazole [0673] (2.69mL, 42.0 mmol) in tetrahydrofuran (30 mL), was added n-butyl lithium (2.5M in hexane, 16.79 mL, 42.0 mmol ) slowly under inert atmosphere at -78 °C and stirred at -78 °C for 30mins. After 30 min to the reaction mixture was added a solution of 2,6-dichloroisonicotinaldehyde [0672] (4.1 g, 24.158 mmol) in tetrahydrofuran (20 mL) at -78 °C and stirring was continued for 40 min. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) at - 78 °C. The reaction mixture was extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 60% ethyl acetate in pet ether as eluent to afford (2,6-dichloropyridin-4-yl)(oxazol-2-yl)methanol [0674] as a white solid (5.7 g). MS(M+l)+= 245.
[00821] Step 6 [0675]: To a stirred solution of (2,6-dichloropyridin-4-yl)(oxazol-2- yl)methanol [0674] ( 5.7g, 23.25 mmol) in dichloromethane (60 mL) was added imidazole (2.37g ,34.87mmol) under inert atmosphere at 0°C and stirred for lh. Then tert- butyldimethylsilyl chloride (4.18 g, 27.91 mmol) was added to the reaction mixture at 0 °C and reaction mixture was slowly warmed to rt for 16 h.The reaction mixture was quenched with water (10 mL) and product was extracted with ethyl acetate (2x75 mL). The combined organic layer was washed with brine solution (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford 2-(((tert- butyldimethylsilyl)oxy)(2,6-dichloropyridin-4-yl)methyl)oxazole[0675] as colorless liquid (6 g). MS(M+l)+= 360.2.
[00822] Step 7 [0676]: To a stirred solution of 3,5-dimethyl-lH-pyrazole [0017] (0.64g, 6.67 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (0.26g , 6.67mmol) under inert atmosphere at 0 °C and stirred at same 0 °C for 30 mins .Then to the resultant reaction mixture was added a solution of (2-(((tert-butyldimethylsilyl)oxy)(2,6-dichloropyridin-4- yl)methyl)oxazole) [0675] (2.0 g, 5.56 mmol) in tetrahydrofuran (10 mL) at 0 °C. The reaction mixture was heated at 60 °C for 16h. The reaction mixture was quenched with ice cold water (20 mL). The product was extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with brine solution (20mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 35% ethyl acetate in pet ether as eluent to afford 2-(((tert- butyldimethylsilyl)oxy)(2-chloro-6-(3,5-dimethyl- lH-pyrazol-l-yl)pyridin-4- yl)methyl)oxazole [0676] as an off-white solid (0.57 g). MS(M+l)+= 420.2.
[00823] Step 8 [0677]: The procedure is similar to step 3[0580] in example 216. 0.5 g of 2-(((tert-butyldimethylsilyl)oxy)(2-chloro-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-4- yl)methyl)oxazole [0676] and 4,4-difluorocyclohexylamine hydrochloride [0002] (0.245 g, 1.432 mmol) gave 0.28 g of 4-(((tert-butyldimethylsilyl)oxy)(oxazol-2-yl)methyl)-N-(4,4- difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0677] as an yellow solid. MS(M+1)+=518.6.
[00824] Step 9 [0678]: To a stirred solution of (((tert-butyldimethylsilyl)oxy)(oxazol-2- yl)methyl)-N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine [0677] (0.3g, 0.58 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1M solution in THF, 1.16 mL, 1.15mmol) drop wise at 0 °C under inert atmosphere and the resultant reaction mixture was allowed to stir at rt for 1 h. The reaction mixture was quenched with ice cold water (5 mL) and product was extracted with ethyl acetate (2x20 mL). The combined organic layer was washed with brine solution (10 mL ), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by column chromatography using ethyl acetate in pet ether as eluent to afford (2-((4,4-difluorocyclohexyl)amino)-6-(3,5-dimethyl- lH-pyrazol- l-yl)pyridin-4- yl)(oxazol-2-yl)methanol [0678], Compound 343 as an yellow solid (0.19 g).
MS(M+l)+=404.2, 1H-NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 0.96 Hz, 1H), 7.99 (t, J = 0.92 Hz, 1H), 6.92 (d, J = 0.48 Hz, 1H), 6.81 (d, J = 7.52 Hz, 1H), 6.44 (s, 1H), 6.03 (m, 2H), 5.52 (d, J = 4.76 Hz, 1H), 3.89-3.88 (m, 1H), 2.57 (s, 3H), 2.16 (s, 3H), 2.08-1.99 (m, 2H), 1.96-1.93 (m, 4H), 1.57-1.49 (m, 2H),
[00825] Example 258
Figure imgf000353_0001
Figure imgf000353_0002
[00826] Step 1[0679]: To a solution of 2,4,6-trichloropyridine [0565] (15 g, 82.22 mmol) in ethanol was added methylamine 30 % solution in ethanol (15.32 g, 493.32 mmol) at 0 °C and the reaction mixture was stirred at rt in sealed tube. After 2 days, the reaction mixture was concentrated under reduced pressure and triturated with water, the solid formed was filtered and dried under vacuum to afford an off-white solid, which was triturated with dichloromethane and stirred for 10 min. The solid was filtered, washed with dichloromethane and dried under vacuum to afford 2,6-dichloro-N-methylpyridin-4-amine [0679] as a white solid. (7 g, 48 % yield). MS(M+1)+=178.1.
[00827] Step 2[0680] : To a solution of 2,6-dichloro-N-methylpyridin-4-amine [0679] (8 g, 45.189 mmol) in concentrated sulfuric acid (184 g, 1876.06 mmol) was added nitric acid (2.84 g, 45.189 mmol) slowly drop wise at 0 °C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was cooled to 0 °C and quenched with ice and stirred for 10 min. The solid formed was filtered, washed with water and dried under vacuum to afford 2,6-dichloro-N-methyl-3-nitropyridin-4-amine[0680] as a pale yellow solid. (9.5 g, 95 % yield). MS(M+1)+=223.1.
[00828] Step 3[0681]: To a suspension of sodium hydride (1.80 g, 45.0388 mmol) in tetrahydrofuran was added 4,4-difluorocyclohexylamine hydrochloride [0002] (3.86 g, 22.519 mmol) at 0 °C and the reaction mixture was stirred at rt for 30 min. Then 2,6- dichloro-N-methyl-3-nitropyridin-4-amine [0680] (5 g, 22.519 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was stirred at rt. After 72 h, the reaction mixture was quenched with ice and stirred for 10 min. The solid formed was filtered and dried under vacuum to afford a yellow solid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane followed by methanol in chloroform as solvent in 24 g column to afford 6-chloro-N2-(4,4-difluorocyclohexyl)-N4-methyl-3-nitropyridine-2,4- diamine [0681] as an yellow solid, 2.5 g. MS(M+1)+=321.2.
[00829] Step 4[0682]: To a suspension of sodium hydride (0.467 g, 11.69 mmol) in tetrahydrofuran was added ethyl lh-pyrazole-3-carboxylate [0005] (1.33 g, 9.35 mmol) at 0 °C and the reaction mixture was stirred at rt for 30 min. Then 6-chloro-N2-(4,4- difluorocyclohexyl)-N4-methyl-3-nitropyridine-2,4-diamine [0681] (2.5 g, 7.79 mmol) was added to the reaction mixture at 0 °C and the reaction mixture was heated at 65 °C. After 120 h, the reaction mixture was quenched with ice and stirred at rt. The solid formed was filtered washed with water and dried under vacuum to afford a yellow solid, which
was purified in the Reveleris flash system instrument using methanol in chloroform as solvent in 80 g column to afford ethyll-(6-((4,4-difluorocyclohexyl)amino)-4-(methylamino)- 5-nitropyridin-2-yl)-lH-pyrazole-3-carboxylate [0682] as an yellow solid. (1.3 g, 40 % yield). MS(M+l)+=425.2.
[00830] Step 5[0683]: To a suspension of ethyll-(6-((4,4-difluorocyclohexyl)amino)-4- (methylamino)-5-nitropyridin-2-yl)-lH-pyrazole-3-carboxylate [0682] (1.3 g, 3.06 mmol) in dichloromethane and methanol was added Raney nickel (0.7 g, 5.35 mmol) and the reaction mixture was stirred at rt under hydrogen atmosphere. After 72 h, the reaction mixture was filtered through celite bed, washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford ethyl l-(5-amino-6-((4,4-difluorocyclohexyl)amino)-4- (methylamino)pyridin-2-yl)-lH-pyrazole-3-carboxylate [0683] as a purple solid (1.1 g). MS(M+l)+=395.6.
[00831] Step 6 [0684]: To a solution of ethyl l-(5-amino-6-((4,4- difluorocyclohexyl)amino)-4-(methylamino)pyridin-2-yl)-lH-pyrazole-3-carboxylate [0683] (1.0 g) in formic acid (20 vol) was stirred at rt. After 120 h, the reaction mixture was concentrated under reduced pressure and the residue was neutralized with sodium bicarbonate solution, extracted with ethyl acetate, washed with water and brine solution. The combined organic layer was concentrated under reduced pressure to afford a purple solid, which was purified in the Reveleris flash system instrument using ethyl acetate in hexane as solvent in 12 g column to afford ethyl l-(4-((4,4-difluorocyclohexyl)amino)- 1-methyl- 1H- imidazo[4,5-c]pyridin-6-yl)-lH-pyrazole-3-carboxylate [0684] as a purple solid ( 0.75 g). MS(M+l)+=405.2.
[00832] Step 7[0685]: The procedure is similar to step 2[0019] in example 4. 0.75 g of ethyl l-(4-((4,4-difluorocyclohexyl)amino)-l-methyl-lH-imidazo[4,5-c]pyridin-6-yl)-lH- pyrazole-3-carboxylate [0684] gave 0.65 g of (l-(4-((4,4-difluorocyclohexyl)amino)-l- methyl-lH-imidazo[4,5-c]pyridin-6-yl)-lH-pyrazol-3-yl)methanol [0685] as a purple solid.MS(M+l)+=363.1.
[00833] Step 8[0686]: The procedure is similar to step 3 [0012] in example 2. 0.65 g of (1- (4-((4,4-difluorocyclohexyl)amino)- 1-methyl- lH-imidazo[4,5-c]pyridin-6-yl)- lH-pyrazol-3- yl)methanol [0685] gave 0.165 g of N-(4,4-difluorocyclohexyl)-6-(3-(fluoromethyl)-lH- pyrazol-l-yl)- 1-methyl- lH-imidazo[4,5-c]pyridin-4-amine [0686], Compound 286 as a white solid. (30 % yield). MS(M+l)+=365.2, 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.22 (s, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.63 (t, J = 2 Hz, 1H), 5.40 (d, JF = 48.4 Hz, 2H), 4.32 (bs, 1H), 3.80 (s, 3H), 2.17 - 1.93 (m, 6H), 1.84 - 1.62 (m, 2H).
4] Example 259
Figure imgf000355_0001
[00835] Step 1[0687]: The procedure is similar to step 4[0682] in example 258. 4 g of 6- chloro-N2-(4,4-difluorocyclohexyl)-N4-methyl-3-nitropyridine-2,4-diamine [0681] gave 1 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-di methyl- lH-pyrazol- l-yl)-N4-methyl-3- nitropyridine-2,4-diamine [0687] as an yellow solid(crude). MS(M+1)+=381.3.
[00836] Step 2[0688]: The procedure is similar to step 5[0683] in example 258. 0.5 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-methyl-3-nitropyridine- 2,4-diamine [0687] gave 0.4 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l- yl)-N4methylpyridine-2,3,4-triamine [0688] as an yellow solid. MS(M+1)+=351.3.
[00837] Step 3[0689]: The procedure is similar to step 6[0684] in example 258. 0.22 g of N2-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l-yl)-N4-methylpyridine-2,3,4- triamine [0688] gave 0.052 g of N-(4,4-difluorocyclohexyl)-6-(3,5-dimethyl-lH-pyrazol-l- yl)- 1-methyl- lH-imidazo[4,5-c]pyridin-4-amine [0689], Compound 266 as an off-white. MS(M+1)+=361.6. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, lH), 7.11 (s, 1H), 6.94 (bs, 1H), 6.04 (s, 1H), 4.17 (bs,lH), 2.60 (s, 3H), 2.48 (s, 3H), 2.20 (s, 3H), 2.15 - 1.90 (m, 6H), 1.75 - 1.63 (m, 2H).
[00838] Example 260
Figure imgf000356_0001
[00839] Step 1[0692]: To a suspension of ethyl l-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride [0690] (15 g, 50.37 mmol) in ethanol was added urea [0691] (15.12 g, 251.8 mmol) and sodium methoxide (35.3 g, 654.8 mmol) and the reaction mixture was refluxed at 90 °C under nitrogen atmosphere for 16h. After the completion of the reaction, the reaction mixture was cooled to 0 °C and the pH of the suspension was adjusted to 6.0 by addition of aqueous hydrochloric acid (I N solution). The mixture was stirred at rt for 15 min and the solid formed was filtered, washed with hexanes and dried under vacuum to afford 7-benzyl- 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4(lH,3H)-dione [0692] as an off-white solid (8 g). MS(M+l)+ =258.
[00840] Step 2[0693]: A suspension of 7-benzyl-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine-2,4(lH,3H)-dione [0692] (8 g, 31.09 mmol) in phosphorus oxychloride (253 g, 1650 mmol) was heated at 110 °C under nitrogen atmosphere for 48 h. After the completion of the reaction, the reaction mixture was concentrated to remove phosphorus oxychloride and the resultant residue was purified by column of silica gel (60-120 mesh), using 20% ethyl acetate in hexane as eluent to afford 7-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidine [0693] as an light brown liquid (4.5 g). MS(M+l)+=294.
[00841] Step 3[0694] : To a solution of 7-benzyl-2,4-dichloro-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidine [0693] (0.58 g, 1.97 mmol) and 4,4- difluorocyclohexylamine hydrochloride [0002] (0.33 g, 1.97 mmol) in ethanol (10 mL) was added Ν,Ν-diisopropyl ethylamine (0.38 g, 2.95 mmol) and the reaction mixture was heated at 90 °C in a closed vial (20 mL) for 16 h. After the completion of the reaction, the reaction mixture was concentrated to dryness and the residue was purified by column of silica gel (60- 120 mesh), using 40% ethyl acetate in hexane as eluent to afford 7-benzyl-2-chloro-N-(4,4- difluorocyclohexyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine [0694] as an yellow gummy solid (0.421 g). MS(M+l)+ =393.
[00842] Step 4[0695]: The procedure is similar to step 3 [0580] in example 216 [at 90 °C for 16 h]. 0.42 g of 7-benzyl-2-chloro-N-(4,4-difluorocyclohexyl)-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-amine [0694] gave 0.31 g of 7-benzyl-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4-amine [0695], Compound 119 as an off-white solid. MS(M+1)+ =453, 1H- NMR (400 MHz, DMSO-d6): δ 7.35-7.28 (m, 4H), 7.30-7.24 (m, 1H), 6.73 (d, J = 7.84 Hz, 1H), 6.00 (s, 1H), 4.12 (m, 1H), 3.66 (s, 2H), 2.66-2.51 (m, 2H), (2.49 (s, 3H), 2.47-2.44 (m, 2H), 2.12 (s, 3H), 2.12-1.70 (m, 6H), 1.67-1.64 (m, 2H), 2H are merging with solvent.
[00843] Step 5[0696]: To a solution of 7-benzyl-N-(4,4-difluorocyclohexyl)-2-(3,5- dimethyl-lH-pyrazol-l-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine [0695] (0.12 g, 0.265 mmol) in dichloromethane (10 mL) at 0 °C was added 1-chloroethyl chloroformate (0.075 g, 0.53 mmol), then the reaction mixture was heated at 45 °C for 8 h. After the completion of the reaction, the reaction mixture was concentrated to dryness and the resulting residue was dissolved in methanol (10 mL) and refluxed for lh and concentrated to dryness to afford an off-white gum and which was triturated with dichloromethane, the obtained solid was filtered and washed with hexane, dried under high vacuum to afford N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,6,7,8-tetrahydropyrido [3,4- d]pyrimidin-4-amine hydrochloride salt [0696] as an off-white solid (0.061 g).
MS(M+l)+=363, 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 2H), 7.46 (d, J = 7.3 Hz, 1H), 6.15 (s, 1H), 4.13 (d, J = 4.5 Hz, 3H), 3.42 (d, J = 6.0 Hz, 2H), 2.70 (d, J = 5.9 Hz, 2H), 2.57 (s, 3H), 2.20 (s, 3H), 2.10 (d, J = 8.6 Hz, 2H), 1.95 (d, J = 14.2 Hz, 3H), 1.73 (m, 2H).
[00844] Exam le 261
Figure imgf000357_0001
[00845] Step 1[0697] : To a solution of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl- 1H- pyrazol-l-yl)-5,6,7,8-tetrahydropyrido [3,4-d]pyrimidin-4-amine hydrochloride salt [0696] in acetonitrile (5 mL) was added bromo acetonitrile and followed by cesium carbonate, then the reaction mixture was stirred at 80 °C for 16 h. the reaction mixture was filtered and the filtrate was concentrated to afford as a brownish gum, which was purified by column of silica gel (60-120 mesh), using ethyl acetate as eluent to afford 2-(4-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl)acetonitrile [0697], Compound 122 as an Light brown solid (0.016 g). MS(M+l)+=402, 1H-NMR (400 MHz, DMSO-d6): δ 6.81 (d, J = 7.92 Hz, 1H), 6.03 (s, 1H), 4.13 (s, 1H), 4.13 (s, 2H), 3.49 (s, 2H), 2.80 (t, J = 5.48 Hz, 2H), 2.54 (S, 3H), 2.49-2.49 (m, 2H), 2.15 (s, 3H), 2.08-1.91 (m, 6H), 1.68-1.65 (m, 2H),
[00846] Exam le 262
Figure imgf000358_0001
[00847] Step 1[0698]: The procedure is similar to step 1[0697] in example 261. 0.07 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,6,7,8-tetrahydropyrido [3,4- d]pyrimidin-4-amine hydrochloride salt [0696] gave 0.035 g of 2-(4-((4,4- difluorocyclohexyl)amino)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl)acetamide [0698], Compound 121 as an white solid. MS(M+l)+=420, 1H NMR (400 MHz, DMSO-d6) δ 7.30 (s, 1H) 7.14 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.03 (s, 1H), 4.14 (bs, 1H), 3.48 (s, 2H), 3.08 (s, 2H), 2.77 (t, J = 5.7 Hz, 2H), 2.54 (s, 3H), 2.16 (s, 3H), 2.15 - 1.85 (m, 8H), 1.69-1.75 (m, 2H).
[00848] Exam le 263
Figure imgf000358_0002
[00849] Step 1[0699]: The procedure is similar to step 1[0697] in example 261 [at 80 °C for 16 h]. 0.07 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,6,7,8- tetrahydropyrido [3,4-d]pyrimidin-4-amine hydrochloride salt [0696] gave 0.022 g of N- (4,4-difluoro cyclohexyl)-2-(3,5-dimethyl- lH-pyrazol-l-yl)-7-isopropyl-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4-amine [0699], Compound 123 as an brownish gum. MS(M+l)+=405, 1H NMR (400 MHz, DMSO-d6) δ 6.72 (d, J = 7.9 Hz, 1H), 6.03 (s, 1H), 4.12 (d, J = 6.8 Hz, 1H), 3.45 (s, 2H), 2.87 (p, J = 6.5 Hz, 1H), 2.73 (t, J = 5.7 Hz, 2H), 2.54 (s, 3H), 2.41 (t, J = 5.7 Hz, 2H), 2.16 (s, 3H), 2.00 (m, 6H), 1.68 (m, 2H), 1.06 (d, J = 6.5 Hz, 6H).
[00850] Exam le 264
Figure imgf000359_0001
[00851] Step 1[0700]: The procedure is similar to step 1[0697] in example 261 [at 70 °C for 16 h]. 0.06 g of N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-5,6,7,8- tetrahydropyrido [3,4-d]pyrimidin-4-amine hydrochloride salt [0696] gave 0.026 g of 2-(4- ((4,4-difluorocyclohexyl)amino)-2-(3,5-dimethyl- lH-pyrazol-l-yl)-5,8-dihydropyrido[3,4- d]pyrimidin-7(6H)-yl)ethan-l-ol [0700], Compound 118 as an light yellow solid.
MS(M+l)+=407, 1H NMR (400 MHz, DMSO-d6) δ 6.74 (d, J = 7.9 Hz, 1H), 6.03 (s, 1H), 4.51 (t, J = 5.4 Hz, 1H), 4.13 (s, 1H), 3.59 (q, J = 5.8 Hz, 2H), 3.44 (s, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.50 (s, 3H), 2.43 (s, 2H), 2.15 (s, 3H), 2.15-1.85 (m, 6H), 1.74 - 1.60 (m, 2H).
[00852] Example 264
Figure imgf000359_0002
[00853] Step 1:
Figure imgf000359_0003
(1 eq) [00854] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 4,6-dichloro-2-(methylsulfonyl)pyrimidine (20.0 g, 88.080 mmol, 1.0 eq) in tetrahydrofuran at -10°C and 3-methyl-lH-pyrazole (7.23 g, 88.080 mmol, 1.0 equiv.) was added dropwise over a period of five minutes via syringe. The reaction mixture was stirred for 16 hours at 25 °C and completion of reaction was determined by TLC. The reaction mixture was portioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 *100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford 4,6-dichloro-2-(3-methyl-lH-pyrazol-l-yl)pyrimidine (10.0 g, 43.859 mmol, 50% yield) as a white solid pure form. MS (MH+): m/z=229.1.
[00855] St 2:
Figure imgf000360_0001
[00856] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 2,4-dichloro-6-methylpyrimidine (11.0 g, 48.24 mmol, 1.0 equiv.), 4,4-difluorocyclohexan-l- amine hydrochloride (9.89 g, 57.89 mmol, 1.2 equiv.), and Cs2C03 (39.19 g, 120.61 mmol, 2.5 equiv.) in acetonitrile (200 mL). The reaction mixture was stirred for five hours at 80 °C and the completion of reaction was determined by TLC. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted ethyl acetate (2x100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-amine (11.0 g, 33.62 mmol, 71%) as an off-white solid. MS (MH+): m/z=328.1. [00857] Step 3:
Figure imgf000361_0001
[00858] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine 5 (14.0 g, 42.79 mmol, 1.0 eq), morpholine (14.91 mL, 171.19 mmol, 4.0 eq), and triethylamine (23.89 mL, 171.19 mmol, 4.0 eq) in acetonitrile (200 mL). The reaction mixture was stirred for 16 hours at 80 °C and completion of reaction was determined by TLC. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ethyl acetate (300 mL).
[00859] The organic layer was separated and the aqueous layer was extracted ethyl acetate (2x100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford N-(4,4- difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)-6-morpholinopyrimidin-4-amine
(Compound 359) (12.8 g, 33.84 mmol, 79% yield) as an off-white solid. MS (MH+):
m/z=379.2. Analytical Data:1H NMR (400 MHz, DMSO-D6): δ 8.41 (d, J = 2 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 5.53 (s, 1H), 3.9 (bs, 1H), 3.67 (t, J = 4.4 Hz, 4H), 3.49 (S, 4H), 2.23 (s, 3 H), 2.23- 1.97 (m, 3H), 1.92- 1.90 (m, 3H), 1.55- 1.53 (m, 2H).
[00860] Example 265
Figure imgf000361_0002
[00861] Step 1:
Figure imgf000362_0001
[00862] A 5000-mL four-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir blade (5 cm) attached with glass rod (neck 1), stopper (neck 2), and addition funnel with stopper (neck 3) and a nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 4), was charged with a suspension of sodium hydride (35.2 g, 880 mmol, 1 equiv.) in dichloromethane (1000 mL) was added 3,5-dimethylpyrazole (84.6g, 880 mmol, 1 equiv.) at 0 °C and the reaction mixture was stirred at room temperature. After 30 min, 4,6-dichloro-2- (methylsulfonyl)pyrimidine (200 g, 880 mmol, 1 equiv.) (dissolved in dichloromethane (1000 mL)) was added dropwise through dropping funnel to the reaction mixture at -78 °C. The reaction mixture was stirred at same temperature and the completion of reaction was determined by TLC and UPLC. After 2 h, the reaction mixture was quenched with water at - 78 °C and diluted with dichloromethane. After 5 min, dichloromethane was decanted and washed with brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using ethyl acetate and pet-ether as solvent to afford 4,6-dichloro-2-(3, 5- dimethyl-lh-pyrazol-l-yl) pyrimidine (138 g, 567.71 mmol, 65 %) as an off-white solid. MS (MH+): m/z = 244.2.
[00863] Step 2:
Figure imgf000362_0002
[00864] A 2000-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (5 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 4,6-dichloro-2-(3,5-dimethyl-lh-pyrazol-l-yl) pyrimidine (136 g, 559.4 mmol, 1 equiv.) in acetonitrile (1500 mL) followed by 4,4-difluorocyclohexylamine hydrochloride (105.6 g, 615.4 mmol, 1.1 equiv.) and Ν,Ν-diisopropyl ethylamine (194.88 mL, 1118.8 mmol, 2 equiv). The reaction mixture was heated at 80 °C for 16 h. The completion of reaction was determined by TLC and UPLC. The reaction mixture was concentrated and the residue was triturated with water (500 mL). The resulting solid was filtered, washed with pet-ether, dried under vacuum to afford 6-chloro-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lh-pyrazol-l-yl)pyrimidin-4-amine (191 g, 556 mmol, >95%) as an off-white solid. MS (MH+): m/z = 342.0.
[00865] Step 3:
Figure imgf000363_0001
360
[00866] A 250 mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (2 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lh-pyrazol-l- yl)pyrimidin-4-amine (20 g, 58.51 mmol, 1 equiv.) in methanol followed by sodium methoxide (21% in methanol, 5.37 g, 99.47 mmol, 1.7 equiv.). The reaction was heated to 60 °C, and completion of reaction was determined by TLC and UPLC. After 5 h, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate, washed with water, and washed with brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product which was purified by column chromatography using ethyl acetate in pet-ether as solvent system to afford N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- methoxypyrimidin-4-amine (Compound 360) [16 g (11 g ( 99 % pure)+ 5 g (92 % pure), 47.41 mmol, -80 %) as a white solid. MS (MH+): m/z =338.1. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 7.45 (bs, 1H), 6.06 (s, 1H), 5.72 (s, 1H), 4.01 (bs, 1H), 3.85 (s, 3H), 2.55 (s, 3H), 2.17 (s, 3H), 2.11- 1.82 (m, 6H), 1.60-1.55 (m, 2H).
[00867] Example 266
Figure imgf000364_0001
[00868] Step 1:
Figure imgf000364_0002
[00869] A three-necked round bottomed flask equipped with a teflon-coated stir bar was charged with diethyl ether (250 mL) and n-BuLi (241.98 mL, 604.96 mmol, 2.5M in hexane) was transferred at -78 °C. A solution of 4-methylthiazole (50.0 g, 504.13 mmol) in diethyl ether (200 mL) was added over a period of 30 min. The reaction mixture was turned into pale yellow suspension. After 1.5 hours, DMF (58.54 mL, 756.20 mmol) was added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into cold aq. HC1 (400 mL, 4N) under stirring and separated the two layers. The organic layer was washed with cold aq. HC1 (2 x 80 mL, 4N)). The combined aq. layers were slowly basified with K2CO3 (pH 7) and extracted with diethyl ether (3 x 150 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness at room temperature under vacuum to afford 4-methylthiazole-2- carbaldehyde (60.0 g, crude) as a pale yellow liquid. This crude material was used in the next step without further purification.
[00870] Step 2:
Figure imgf000364_0003
59% (2 steps)
[00871] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carbaldehyde (60.0 g, crude) in pyridine (38.04 ml, 472.40 mmol). Hydro xylamine hydrochloride (32.82 g, 472.40 mmol) was added in portions over a period of 15 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into ice cold water and stirred for 20 min, the obtained solid was filtered and dried under vacuum to afford 4-methylthiazole-2- carbaldehyde oxime (40.0 g, 281.69 mmol, 59% for two steps) as an off white solid. MS (MH+): m/z=143.0.
[00872] Step 3:
Figure imgf000365_0001
[00873] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with a solution of 4-methylthiazole-2-carbaldehyde oxime (35.0 g, 246.44 mmol) and pyridine (87.33 mL, 1084.35 mmol) in 1, 4-dioxane (140 mL). Trifluoro acetic anhydride (51.38 mL, 369.66 mmol) was added slowly at -10 °C and allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water (250 mL) and extracted with diethyl ether (3 x 350 mL). The combined organic layers were washed with water (2 x 250 mL), brine (100 mL) dried over sodium sulphate and concentrated under reduced pressure to afford 4- methylthiazole-2-carbonitrile (35.0 g, crude) as light brown liquid. This crude material was used in the next step without further purification. Analytical Data: 1H-NMR (400 MHz,
DMSO-d6): δ 7.90 (s, 1 H), 2.51 (s, 3 H).
[00874] Step 4:
Figure imgf000365_0002
[00875] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carbonitrile (35.0 g, crude) in methanol (280 mL) and sodium methoxide (16.77 g, 310.45 mmol) was added. After stirring at room temperature for 3 h, ammonium chloride (30.19 g, 564.66 mmol) was added and stirred for another 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was triturated with diethyl ether (150 mL). The formed solid was filtered and dried under vacuum to afford 4-methylthiazole-2-carboximidamide hydrochloride (35.0 g, crude) as an off-white solid. This crude material was used in the next step without further purification. MS (MH+): m/z=142.0.
[00876] Step 5:
Figure imgf000366_0001
[00877] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carboximidamide hydrochloride (35.0 g, crude) in ethanol (350 mL) and diethyl malonate (150.81 mL, 988.64 mmol). Sodium ethoxide (320 mL, 988.64 mmol, 21% in EtOH) was added dropwise at room temperature and heated to 85 °C. After 3 hours, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added and acidified with 1.5 N HCl (pH 2-3). The obtained solid was filtered and dried under vacuum to afford 2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol (29.0 g, crude) as pale yellow solid. This crude material was used in the next step without further purification. MS (MH+): m/z=210.0.
[00878] Step 6:
Figure imgf000366_0002
[00879] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with a suspension of 2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol (29.0 g, crude) and POCl3 (290 mL). N,N-diethylaniline (37.84 mL, 235.85 mmol) was added at room temperature and heated reflux at 100 °C for 2 h. The progress of the reaction was monitored by TLC. Excess POCI3 was removed by distillation. The residue was diluted with 500 mL cold water, neutralized with saturated sodium bicarbonate solution, extracted with diethyl ether (2 x 500 mL). The combined organic layers were washed with water (3 x 200 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with n-pentane (100 mL). The obtained solid was filtered and dried under vacuum to afford 2-(4, 6-dichloropyrimidin-2-yl)-4-methylthiazole 7 (19.5 g, 79.59 mmol, 32% for four steps) as a pale yellow solid. MS (MH+): m/z=245.9. [00880] Step 7:
Figure imgf000367_0001
[00881] A two necked round bottomed flask equipped with a teflon-coated stir bar was charged with a suspension of 2-(4,6-dichloropyrimidin-2-yl)-4-methylthiazole (19.0 g, 77.56 mmol) and 4, 4-difluorocyclohexan- 1 -amine hydrochloride (13.30 g, 77.56 mmol) in acetonitrile (190 mL). Cesium carbonate (37.89 g, 116.34 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with ethyl acetate (500 mL). The filtrate was washed with water (2 x 100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (60-120 silica gel) eluted with 15% EtOAc in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-chloro-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl)pyrimidin-4-amine (22.5 g, 65.25 mmol, 84%) as off-white foam solid. MS (MH+):
m/z=344.9.
[00882] Step 8:
Figure imgf000367_0002
361
[00883] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine (27.0 g, 78.47mmol) in methanol (450 mL). Sodium methoxide (21.19 g, 392.36 mmol) was added and heated to 80 °C for 16 h. The progress of the reaction was monitored by TLC. Excess methanol was removed under reduced pressure and the residue was diluted with 10% aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (60-120 silica gel) eluting with 35-40% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-4-amine (Compound 361) (23.4 g, 68.82 mmol, 87%) as an off-white solid. MS (MH+): m/z=341.0. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 7.41 (s, 1 H), 7.40 (s, 1 H), 5.81 (s, 1 H), 3.87 (s, 3 H), 2.43 (s, 3 H), 2.08-1.89 (m, 6 H), 1.61-1.52 (m, 2 H).
[00884] Example 267
Figure imgf000368_0001
[00886] A 250-mL sealed tube, equipped with a teflon-coated stir bar (2 cm), was charged with a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4- amine (4.9 g, 14.24 mmol, 1.0 eq ) and tributyl(l-ethoxy vinyl) stannane (5.65 g, 15.66 mmol, 1.1 eq) in N,N-dimethylformamide (60 mL). The reaction mixture was degassed using argon gas for 5-10 min, followed by addition of bis(triphenylphosphine)palladium(II) dichloride (0.2 g, 0.28 mmol, 0.02 eq). The reaction mixture was sealed and heated at 80 °C for 16 h (completion of reaction was determined by LCMS) and cooled to room temperature. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated to afford a crude product as a light brown sticky solid. The crude material was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford N-(4,4- difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-ami (4.1 g, 10.78 mmol, 75%) as an off-white solid. MS (MH+): m/z=381.0.
[00887] Ste 2:
Figure imgf000369_0001
[00888] A round-bottomed flask equipped with a teflon-coated stir bar was charged with N-(4,4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine (9.0 g, 23.67 mmol, 1.0 eq) in acetone (120 mL) followed by addition of 2N hydrochloric acid aqueous solution (20 mL). The reaction mixture was stirred at room temperature for 3 hours and completion of reaction was determined by LCMS. The reaction mixture was concentrated to remove acetone, diluted with ice cold water (100 mL), basified with saturated sodium by carbonate solution, and extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford a crude product as a light brown sticky solid. The crude material was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford l-(6-((4,4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-one (6.1 g, 17.32 mmol, 73%) as an off-white solid. MS (MH+): m/z=353.0.
[00889] Ste
Figure imgf000369_0002
(Racemic compound)
[00890] A round-bottomed flask equipped with a teflon-coated stir bar was charged with l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-one (5.6 g, 15.90 mmol, 1.0 eq) in methanol (80 mL) at -10 °C followed by sodium borohydride (0.302 g, 7.95 mmol, 0.5 eq). The reaction mixture was stirred at same temperature for 1 hour and completion of reaction was determined by LCMS. The reaction mixture was quenched with water and concentrated under reduced pressure to remove methanol. The residue was diluted with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl)ethan-l-ol 4 (5.5 g, 15.53 mmol, 97%) as an off-white solid of racemic mixture. MS (MH+): m/z=355.0.
[00891] Step 4:
Figure imgf000370_0001
(Racemic Compound)
[00892] The racemic compound l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol- 2-yl)pyrimidin-4-yl)ethan-l-ol Compound 362 (5.5 g) was purified by chiral HPLC
(Column: Chiralpak-IC (250*20*5.0μ); Mobile phase- A:N-Hexane (0.1%DEA), Mobile phase-B: IPA:DCM(90: 10) isocratic : 50:50 (A:B); Flow rate: 15.0ml/min; 120/inj; Run time: 15 min) to afford (S)-l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl)ethan-l-ol Compound 363 (2.1 g, 5.93 mmol, 38%) as an off-white solid from first eluting fractions (Peak-1, RT= 4.24 min.). MS (MH+): m/z=355.0.1H NMR (400 MHz, DMSO-d6): δ 7.59-7.57 (d, / = 6.0 Hz, 1H), 7.37(s, 1H), 6.64 (s, 1H), 5.37-5.36 (d, / = 4.4 Hz, 1H), 4.52-4.50 (t, / = 11.2 Hz, 5.6 Hz, 1H), 4.05 (bs, 1H), 2.43 (s, 3H), 2.10-1.96 (m, 6H), 1.62-1.59 (m, 2H), 1.35-1.33 (d, / = 6.4 Hz, 3H). Other enantiomer: (R)-l-(6-((4,4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-ol Compound 364 (2.05 g, 5.78 mmol, 37%) as an off-white solid from second eluting fractions (Peak-2, RT= 6.45 min.). MS (MH+): m/z=355.0. 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.59 (d, / = 5.6 Hz, 1H), 7.37(s, 1H), 6.64 (s, 1H), 5.38 (bs, 1H ), 4.52-4.51 (d, / = 6.8 Hz, 1H), 4.10 (bs, 1H), 2.43 (s, 3H), 2.10-1.91 (m, 6H), 1.65-1.57 (m, 2H), 1.35-1.34 (d, / = 6.8 Hz, 3H). [00893] Example 268
Figure imgf000371_0001
[00894] Step 1:
Figure imgf000371_0002
[00895] A 1000-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (3 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 4,6-dichloro-2-(methylthio)pyrimidine (150 g, 768.94 mmol, 1.0 equiv.) in acetonitrile (1500 mL) followed by 4,4-difluorocyclohexylamine hydrochloride (158.35 g, 922.733 mmol) and cesium carbonate (526 g, 1614 mmol, 2.1 equiv.). The reaction mixture was heated at 75 °C for 16 h. The reaction mixture was filtered to remove cesium carbonate, then the filtrate was concentrated under reduced pressure to afford 210 g (93% yield) of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine as a pale yellow solid. MS (MH+): m/z = 294.0.
[00896] Step 2:
Figure imgf000371_0003
[00897] A solution of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4- amine (60 g, 204.24 mmol, 1.0 equiv.) and morpholine (35.6 mL, 408.48 mmol, 2.0 equiv.) in acetonitrile (600 mL) was heated at 85 °C in a sealed tube for 16h. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was quenched with ice cold water. The obtained solid was filtered and washed with water (500 mL), hexane (250 mL), dried under high vacuum to afford N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- morpholinopyrimidin-4-amine as an off-white solid (62 g, 88% yield). MS (MH+): m/z
=345.2.
[00898] Step 3:
Figure imgf000372_0001
[00899] A 100-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (3 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6-morpholino pyrimidin-4- amine (lg, 2.90 mmol) in tetrahydrofuran (15 mL) followed by 4-N,N- dimethylaminopyridine (O. lg, 0.87 mmol, 0.3 equiv.), triethylamine (1.2 mL, 8.71 mmol, 3.0 equiv.) and Boc anhydride (3.16 g, 14.51 mmol, 5.0 equiv.) then the reaction mixture was heated at 80 °C for 16h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2x75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4- difluorocyclohexyl)(2-(methylthio)-6-morpholino pyrimidin-4-yl)carbamate as a yellow gum
(1.1 g, 85%). MS (MH+): m/z
[00900] Step 4:
Figure imgf000372_0002
[00901] A 100-mL single neck round bottom flask, connected with reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil, a teflon-coated stir bar (1 cm), was charged with a solution of tert-butyl (4,4-difluorocyclohexyl)(2-(methylthio)-6- morpholinopyrimidin-4-yl)carbamate (50 g, 112.47 mmol) in dichloro methane (600 mL) followed by 3-chloroperbenzoic acid (m-chloroperbenzoic acid) (58.2 g, 337.42 mmol, 3.0 equiv.) at 0°C. The reaction mixture was slowly warmed to rt and stirred for 30 min. After the completion of the reaction, the reaction mixture was quenched with saturated bicarbonate solution and extracted with dichloro methane (2x250mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4- difluorocyclohexyl)(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate as an off- white gum (52 g, 97% yield). MS (MH+): m/z =477.3.
[00902] Ste 5:
Figure imgf000373_0001
[00903] A 100-mL single neck round bottom flask, connected with reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil, a teflon-coated stir bar (2 cm), was charged with a solution of tert-butyl (4,4-difluorocyclohexyl)(2- (methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate (0.9 g, 1.88 mmol) in acetonitrile (10 mL) followed by 3-cyclopropyl-lH-pyrazole (0.3 g, 2.83 mmol, 1.5 equiv.) and cesium carbonate (1.23 g, 3.77 mmol, 2.0 equiv.). The reaction mixture was heated at 80 °C for 16 hours, and completion of reaction was determined by TLC and LCMS. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified through column chromatography using 60-120 silica gel with ethyl acetate-pet ether as solvent system. The isolated material was dried under vacuum to afford tert-butyl (2-(3-cyclopropyl- lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-yl)(4,4-difluorocyclohexyl)carbamate as an off- white solid (0.8 g, 84%). MS (MH+): m/z =505.
[00904] St
Figure imgf000373_0002
365 [00905] A 100-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (2 cm), one septa (necks 1), stopper (neck 3) and nitrogen gas inlet- outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution tert-butyl (2-(3- cyclopropyl- lH-pyrazol- l-yl)-6-morpholinopyrimidin-4-yl)(4,4- difluorocyclohexyl)carbamate (1.2 g, 1.98 mmol, 1 eq) in dichloro methane (40 mL) followed by trifluoro acetic acid (2.5 mL, 32.55 mmol, 16.4 eq) at 0 °C. The reaction mixture was slowly warmed to rt and stirred at same temperature for 6 hours. The completion of reaction was determined by TLC and UPLC. The reaction mixture was concentrated and the resulting residue was quenched with 10% saturated sodium bicarbonate solution, extracted with ethyl acetate (2x100 mL), and concentrated under reduced pressure to afford crude product. The crude product was purified through column chromatography using 60-120 silica gel, ethyl acetate-pet ether as solvent system. The resulting solid was dried under vacuum to afford 2- (3-cyclopropyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-morpholinopyrimidin-4- amine (Compound 365) (0.73g, 90%). MS (MH+): m/z=405. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, = 2.4 Hz, IH), 7.08 (d, = 8.0 Hz, IH), 6.14 (d, 7 = 2.80 Hz, IH), 5.53 (s, IH), 3.88 (s, IH), 3.69-3.67 (m, 4H), 3.50 (m, 4H), 1.99-1.90 (m, 7H), 1.56-1.54 (m, 2H), 0.93-0.89 (m, 2H), 0.72-0.71 (m, 2H).
[00906] Example 269
N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4- amine
[00907] Step 1:
Figure imgf000374_0001
(1 eq)
[00908] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 4,6-dichloro-2-(methylsulfonyl)pyrimidine (20.0 g, 88.080 mmol, 1.0 eq) in tetrahydrofuran at -10°C and 3-methyl-lH-pyrazole (7.23 g, 88.080 mmol, 1.0 equiv.) was added dropwise over a period of five minutes via syringe. The reaction mixture was stirred for 16 hours at 25 °C and completion of reaction was determined by TLC. The reaction mixture was portioned between water (500 mL) and ethyl acetate (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 *100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford 4,6-dichloro-2-(3-methyl-lH-pyrazol-l-yl)pyrimidine (10.0 g, 43.859 mmol, 50% yield) as a white solid pure form. MS (MH+): m/z=229.1.
[00909] Step 2:
Figure imgf000375_0001
[00910] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 2,4-dichloro-6-methylpyrimidine (11.0 g, 48.24 mmol, 1.0 equiv.), 4,4-difluorocyclohexan- 1- amine hydrochloride (9.89 g, 57.89 mmol, 1.2 equiv.), and Cs2C03 (39.19 g, 120.61 mmol, 2.5 equiv.) in acetonitrile (200 mL). The reaction mixture was stirred for five hours at 80 °C and the completion of reaction was determined by TLC. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and the aqueous layer was extracted ethyl acetate (2x100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-amine (11.0 g, 33.62 mmol, 71%) as an off-white solid. MS (MH+): m/z=328.1.
[00911] Step 3:
Figure imgf000375_0002
[00912] A round-bottomed flask equipped with a teflon-coated stir bar was charged with 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-amine (14.0 g, 42.79 mmol, 1.0 eq), morpholine (14.91 mL, 171.19 mmol, 4.0 eq), and triethylamine (23.89 mL, 171.19 mmol, 4.0 eq) in acetonitrile (200 mL). The reaction mixture was stirred for 16 hours at 80 °C and completion of reaction was determined by TLC. The reaction mixture was cooled to room temperature and partitioned between water (100 mL) and ethyl acetate (300 mL).
The organic layer was separated and the aqueous layer was extracted ethyl acetate (2x100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product which was purified by column
chromatography (ethyl acetate/hexane as solvent system) to afford N-(4,4- difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)-6-morpholinopyrimidin-4-amine (359) (12.8 g, 33.84 mmol, 79% yield) as an off-white solid. MS (MH+): m/z=379.2. Analytical Data:1H NMR (400 MHz, DMSO-D6): δ 8.41 (d, = 2 Hz, 1H), 7.07 (d, = 8.3 Hz, 1H), 6.25 (d, = 2.4 Hz, 1H), 5.53 (s, 1H), 3.9 (bs, 1H), 3.67 (t, = 4.4 Hz, 4H), 3.49 (S, 4H), 2.23 (s, 3 H), 2.23-1.97 (m, 3H), 1.92-1.90 (m, 3H), 1.55-1.53 (m, 2H).
[00913] Example 270
N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6-methoxypyrimidin-4- amine
[00914] Step 1:
Figure imgf000376_0001
[00915] A 5000-mL four-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir blade (5 cm) attached with glass rod (neck 1), stopper (neck 2), and addition funnel with stopper (neck 3) and a nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 4), was charged with a suspension of sodium hydride (35.2 g, 880 mmol, 1 equiv.) in dichloromethane (1000 mL) was added 3,5-dimethylpyrazole (84.6g, 880 mmol, 1 equiv.) at 0 °C and the reaction mixture was stirred at room temperature. After 30 min, 4,6-dichloro-2- (methylsulfonyl)pyrimidine (200 g, 880 mmol, 1 equiv.) (dissolved in dichloromethane (1000 mL)) was added dropwise through dropping funnel to the reaction mixture at -78 °C. The reaction mixture was stirred at same temperature and the completion of reaction was determined by TLC and UPLC. After 2 h, the reaction mixture was quenched with water at - 78 °C and diluted with dichloromethane. After 5 min, dichloromethane was decanted and washed with brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product, which was purified by column chromatography using ethyl acetate and pet-ether as solvent to afford 4,6-dichloro-2-(3, 5- dimethyl-lh-pyrazol-l-yl) pyrimidine (138 g, 567.71 mmol, 65 %) as an off-white solid. MS (MH+): m/z = 244.2.
[00916] Ste 2:
Figure imgf000377_0001
[00917] A 2000-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (5 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 4,6-dichloro-2-(3,5-dimethyl-lh-pyrazol-l-yl) pyrimidine (136 g, 559.4 mmol, 1 equiv.) in acetonitrile (1500 mL) followed by 4,4-difluorocyclohexylamine hydrochloride (105.6 g, 615.4 mmol, 1.1 equiv.) and Ν,Ν-diisopropyl ethylamine (194.88 mL, 1118.8 mmol, 2 equiv). The reaction mixture was heated at 80 °C for 16 h. The completion of reaction was determined by TLC and UPLC. The reaction mixture was concentrated and the residue was triturated with water (500 mL). The resulting solid was filtered, washed with pet-ether, dried under vacuum to afford 6-chloro-N-(4,4- difluorocyclohexyl)-2-(3,5-dimethyl-lh-pyrazol-l-yl)pyrimidin-4-amine (191 g, 556 mmol, >95%) as an off-white solid. MS (MH+): m/z = 342.0.
[00918] Step 3:
Figure imgf000377_0002
360
[00919] A 250 mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (2 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lh-pyrazol-l- yl)pyrimidin-4-amine (20 g, 58.51 mmol, 1 equiv.) in methanol followed by sodium methoxide (21% in methanol, 5.37 g, 99.47 mmol, 1.7 equiv.). The reaction was heated to 60 °C, and completion of reaction was determined by TLC and UPLC. After 5 h, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate, washed with water, and washed with brine solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude product which was purified by column chromatography using ethyl acetate in pet-ether as solvent system to afford N-(4,4-difluorocyclohexyl)-2-(3,5-dimethyl-lH-pyrazol-l-yl)-6- methoxypyrimidin-4-amine (360) [16 g (11 g ( 99 % pure)+ 5 g (92 % pure), 47.41 mmol, -80 %) as a white solid. MS (MH+): m/z =338.1. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 7.45 (bs, 1H), 6.06 (s, 1H), 5.72 (s, 1H), 4.01 (bs, 1H), 3.85 (s, 3H), 2.55 (s, 3H), 2.17 (s, 3H), 2.11- 1.82 (m, 6H), 1.60-1.55 (m, 2H).
[00920] Example 271
N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine
[00921] Step 1:
Figure imgf000378_0001
[00922] A three-necked round bottomed flask equipped with a teflon-coated stir bar was charged with diethyl ether (250 mL) and n-BuLi (241.98 mL, 604.96 mmol, 2.5M in hexane) was transferred at -78 °C. A solution of 4-methylthiazole (50.0 g, 504.13 mmol) in diethyl ether (200 mL) was added over a period of 30 min. The reaction mixture was turned into pale yellow suspension. After 1.5 hours, DMF (58.54 mL, 756.20 mmol) was added and stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into cold aq. HC1 (400 mL, 4N) under stirring and separated the two layers. The organic layer was washed with cold aq. HC1 (2 x 80 mL, 4N)). The combined aq. layers were slowly basified with K2CO3 (pH 7) and extracted with diethyl ether (3 x 150 mL). The combined organic layers were dried over sodium sulfate and evaporated to dryness at room temperature under vacuum to afford 4-methylthiazole-2- carbaldehyde (60.0 g, crude) as a pale yellow liquid. This crude material was used in the next step without further purification. [00923] Step 2:
Figure imgf000379_0001
59% (2 steps)
[00924] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carbaldehyde (60.0 g, crude) in pyridine (38.04 ml, 472.40 mmol). Hydro xylamine hydrochloride (32.82 g, 472.40 mmol) was added in portions over a period of 15 min. The reaction mixture was stirred at room temperature for 16 h under nitrogen atmosphere. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was poured into ice cold water and stirred for 20 min, the obtained solid was filtered and dried under vacuum to afford 4-methylthiazole-2- carbaldehyde oxime (40.0 g, 281.69 mmol, 59% for two steps) as an off white solid. MS (MH+): m/z=143.0.
[00925] Step 3:
Figure imgf000379_0002
[00926] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with a solution of 4-methylthiazole-2-carbaldehyde oxime (35.0 g, 246.44 mmol) and pyridine (87.33 mL, 1084.35 mmol) in 1, 4-dioxane (140 mL). Trifluoro acetic anhydride (51.38 mL, 369.66 mmol) was added slowly at -10 °C and allowed to stir at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water (250 mL) and extracted with diethyl ether (3 x 350 mL). The combined organic layers were washed with water (2 x 250 mL), brine (100 mL) dried over sodium sulphate and concentrated under reduced pressure to afford 4- methylthiazole-2-carbonitrile (35.0 g, crude) as light brown liquid. This crude material was used in the next step without further purification. Analytical Data: 1H-NMR (400 MHz,
DMSO-d6): δ 7.90 (s, 1 H), 2.51 (s, 3 H).
[00927] Step 4:
Figure imgf000379_0003
[00928] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carbonitrile (35.0 g, crude) in methanol (280 mL) and sodium methoxide (16.77 g, 310.45 mmol) was added. After stirring at room temperature for 3 h, ammonium chloride (30.19 g, 564.66 mmol) was added and stirred for another 16 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered and washed with methanol. The filtrate was concentrated under reduced pressure and the residue was triturated with diethyl ether (150 mL). The formed solid was filtered and dried under vacuum to afford 4-methylthiazole-2-carboximidamide hydrochloride (35.0 g, crude) as an off-white solid. This crude material was used in the next step without further purification. MS (MH+): m/z=142.0.
[00929] Step 5:
Figure imgf000380_0001
[00930] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 4-methylthiazole-2-carboximidamide hydrochloride (35.0 g, crude) in ethanol (350 mL) and diethyl malonate (150.81 mL, 988.64 mmol). Sodium ethoxide (320 mL, 988.64 mmol, 21% in EtOH) was added dropwise at room temperature and heated to 85 °C. After 3 hours, the reaction mixture was concentrated under reduced pressure. Water (20 mL) was added and acidified with 1.5 N HC1 (pH 2-3). The obtained solid was filtered and dried under vacuum to afford 2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol (29.0 g, crude) as pale yellow solid. This crude material was used in the next step without further purification. MS (MH+): m/z=210.0.
[00931] Step 6:
Figure imgf000380_0002
[00932] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with a suspension of 2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol (29.0 g, crude) and POCl3 (290 mL). N,N-diethylaniline (37.84 mL, 235.85 mmol) was added at room temperature and heated reflux at 100 °C for 2 h. The progress of the reaction was monitored by TLC. Excess POCI3 was removed by distillation. The residue was diluted with 500 mL cold water, neutralized with saturated sodium bicarbonate solution, extracted with diethyl ether (2 x 500 mL). The combined organic layers were washed with water (3 x 200 mL), brine (100 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with n-pentane (100 mL). The obtained solid was filtered and dried under vacuum to afford 2-(4, 6-dichloropyrimidin-2-yl)-4-methylthiazole 7 (19.5 g, 79.59 mmol, 32% for four steps) as a pale yellow solid. MS (MH+): m/z=245.9.
[00933] Step 7:
Figure imgf000381_0001
[00934] A two necked round bottomed flask equipped with a teflon-coated stir bar was charged with a suspension of 2-(4,6-dichloropyrimidin-2-yl)-4-methylthiazole (19.0 g, 77.56 mmol) and 4, 4-difluorocyclohexan- 1 -amine hydrochloride (13.30 g, 77.56 mmol) in acetonitrile (190 mL). Cesium carbonate (37.89 g, 116.34 mmol) was added and the reaction mixture was heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with ethyl acetate (500 mL). The filtrate was washed with water (2 x 100 mL), brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (60-120 silica gel) eluted with 15% EtOAc in hexane. Relevant fractions containing the required compound were combined and evaporated to dryness under reduced pressure to afford 6-chloro-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl)pyrimidin-4-amine (22.5 g, 65.25 mmol, 84%) as off-white foam solid. MS (MH+):
m/z=344.9.
[00935] Step 8:
Figure imgf000381_0002
361 [00936] A two-necked round bottomed flask equipped with a teflon-coated stir bar was charged with 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine (27.0 g, 78.47mmol) in methanol (450 mL). Sodium methoxide (21.19 g, 392.36 mmol) was added and heated to 80 °C for 16 h. The progress of the reaction was monitored by TLC. Excess methanol was removed under reduced pressure and the residue was diluted with 10% aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with water (2 x 100 mL), brine (100 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (60-120 silica gel) eluting with 35-40% of EtOAc in hexane. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-4-amine (361) (23.4 g, 68.82 mmol, 87%) as an off-white solid. MS (MH+): m/z=341.0. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 7.41 (s, 1 H), 7.40 (s, 1 H), 5.81 (s, 1 H), 3.87 (s, 3 H), 2.43 (s, 3 H), 2.08-1.89 (m, 6 H), 1.61-1.52 (m, 2 H).
[00937] Example 272
(S)-l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l- ol
[00938] Step 1:
Figure imgf000382_0001
[00939] A 250-mL sealed tube, equipped with a teflon-coated stir bar (2 cm), was charged with a solution of 6-chloro-N-(4,4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4- amine (4.9 g, 14.24 mmol, 1.0 eq ) and tributyl(l-ethoxy vinyl) stannane (5.65 g, 15.66 mmol, 1.1 eq) in N,N-dimethylformamide (60 mL). The reaction mixture was degassed using argon gas for 5-10 min, followed by addition of bis(triphenylphosphine)palladium(II) dichloride (0.2 g, 0.28 mmol, 0.02 eq). The reaction mixture was sealed and heated at 80 °C for 16 h (completion of reaction was determined by LCMS) and cooled to room temperature. The reaction mixture was diluted with water (300 mL) and extracted with ethyl acetate (2 x 150 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated to afford a crude product as a light brown sticky solid. The crude material was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford N-(4,4- difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine (4.1 g, 10.78 mmol, 75%) as an off-white solid. MS (MH+): m/z=381.0.
[00940] Ste 2:
Figure imgf000383_0001
[00941] A round-bottomed flask equipped with a teflon-coated stir bar was charged with N-(4,4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine (9.0 g, 23.67 mmol, 1.0 eq) in acetone (120 mL) followed by addition of 2N hydrochloric acid aqueous solution (20 mL). The reaction mixture was stirred at room temperature for 3 hours and completion of reaction was determined by LCMS. The reaction mixture was concentrated to remove acetone, diluted with ice cold water (100 mL), basified with saturated sodium by carbonate solution, and extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford a crude product as a light brown sticky solid. The crude material was purified by column chromatography (ethyl acetate/hexane as solvent system) to afford l-(6-((4,4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-one (6.1 g, 17.32 mmol, 73%) as an off-white solid. MS (MH+): m/z=353.0.
[00942] Ste 3:
Figure imgf000383_0002
(Racemic compound) [00943] A round-bottomed flask equipped with a teflon-coated stir bar was charged with l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-one (5.6 g, 15.90 mmol, 1.0 eq) in methanol (80 mL) at -10 °C followed by sodium borohydride (0.302 g, 7.95 mmol, 0.5 eq). The reaction mixture was stirred at same temperature for 1 hour and completion of reaction was determined by LCMS. The reaction mixture was quenched with water and concentrated under reduced pressure to remove methanol. The residue was diluted with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and evaporated under reduced pressure to afford l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl)ethan-l-ol 4 (5.5 g, 15.53 mmol, 97%) as an off-white solid of racemic mixture. MS (MH+): m/z=355.0.
00944] Step 4:
Figure imgf000384_0001
(Racemic Compound)
[00945] The racemic compound l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol- 2-yl)pyrimidin-4-yl)ethan-l-ol 362 (5.5 g) was purified by chiral HPLC (Column: Chiralpak- IC (250*20*5.0μ); Mobile phase- A:N-Hexane (0.1%DEA), Mobile phase-B:
IPA:DCM(90: 10) isocratic : 50:50 (A:B); Flow rate: 15.0ml/min; 120/inj; Run time: 15 min) to afford (S)- l-(6-((4,4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4- yl)ethan-l-ol 363 (2.1 g, 5.93 mmol, 38%) as an off-white solid from first eluting fractions (Peak-1, RT= 4.24 min.). MS (MH+): m/z=355.0.1H NMR (400 MHz, DMSO-d6): δ 7.59- 7.57 (d, / = 6.0 Hz, 1H), 7.37(s, 1H), 6.64 (s, 1H), 5.37-5.36 (d, / = 4.4 Hz, 1H), 4.52-4.50 (t, / = 11.2 Hz, 5.6 Hz, 1H), 4.05 (bs, 1H), 2.43 (s, 3H), 2.10-1.96 (m, 6H), 1.62-1.59 (m, 2H), 1.35-1.33 (d, / = 6.4 Hz, 3H). Other enantiomer: (R)-l-(6-((4,4-difluorocyclohexyl)amino)-2- (4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-ol 364 (2.05 g, 5.78 mmol, 37%) as an off- white solid from second eluting fractions (Peak-2, RT= 6.45 min.). MS (MH+): m/z=355.0. 1H NMR (400 MHz, DMSO-d6): δ 7.60-7.59 (d, / = 5.6 Hz, 1H), 7.37(s, 1H), 6.64 (s, 1H), 5.38 (bs, 1H ), 4.52-4.51 (d, J = 6.8 Hz, 1H), 4.10 (bs, 1H), 2.43 (s, 3H), 2.10-1.91 (m, 6H), 1.65-1.57 (m, 2H), 1.35-1.34 (d, J = 6.8 Hz, 3H).
[00946] Example 273
2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-morpholinopyrimidin-4- amine
[00947] Step 1:
Figure imgf000385_0001
[00948] A 1000-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (3 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of 4,6-dichloro-2-(methylthio)pyrimidine (150 g, 768.94 mmol, 1.0 equiv.) in acetonitrile (1500 mL) followed by 4,4-difluorocyclohexylamine hydrochloride (158.35 g, 922.733 mmol) and cesium carbonate (526 g, 1614 mmol, 2.1 equiv.). The reaction mixture was heated at 75 °C for 16 h. The reaction mixture was filtered to remove cesium carbonate, then the filtrate was concentrated under reduced pressure to afford 210 g (93% yield) of 6- chloro-N-(4,4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4-amine as a pale yellow solid. MS (MH+): m/z = 294.0.
[00949] Step 2:
Figure imgf000385_0002
[00950] A solution of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio)pyrimidin-4- amine (60 g, 204.24 mmol, 1.0 equiv.) and morpholine (35.6 mL, 408.48 mmol, 2.0 equiv.) in acetonitrile (600 mL) was heated at 85 °C in a sealed tube for 16h. After completion of the reaction, the reaction mixture was concentrated, and the resulting residue was quenched with ice cold water. The obtained solid was filtered and washed with water (500 mL), hexane (250 mL), dried under high vacuum to afford N-(4,4-difluorocyclohexyl)-2-(methylthio)-6- morpholinopyrimidin-4-amine as an off-white solid (62 g, 88% yield). MS (MH+): m/z =345.2.
[00951] Step 3:
Figure imgf000386_0001
[00952] A 100-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (3 cm), one septa (neck 1), stopper (neck 3) and reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution of N-(4,4-difluorocyclohexyl)-2-(methylthio)-6-morpholino pyrimidin-4- amine (lg, 2.90 mmol) in tetrahydrofuran (15 mL) followed by 4-N,N- dimethylaminopyridine (O. lg, 0.87 mmol, 0.3 equiv.), triethylamine (1.2 mL, 8.71 mmol, 3.0 equiv.) and Boc anhydride (3.16 g, 14.51 mmol, 5.0 equiv.) then the reaction mixture was heated at 80 °C for 16h. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (2x75 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4- difluorocyclohexyl)(2-(methylthio)-6-morpholino pyrimidin-4-yl)carbamate as a yellow gum (1.1 g, 85%). MS (MH+): m/z =445.2.
[00953] Step 4:
Figure imgf000386_0002
[00954] A 100-mL single neck round bottom flask, connected with reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil, a teflon-coated stir bar (1 cm), was charged with a solution of tert-butyl (4,4-difluorocyclohexyl)(2-(methylthio)-6- morpholinopyrimidin-4-yl)carbamate (50 g, 112.47 mmol) in dichloro methane (600 mL) followed by 3-chloroperbenzoic acid (m-chloroperbenzoic acid) (58.2 g, 337.42 mmol, 3.0 equiv.) at 0°C. The reaction mixture was slowly warmed to rt and stirred for 30 min. After the completion of the reaction, the reaction mixture was quenched with saturated bicarbonate solution and extracted with dichloro methane (2x250mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4,4- difluorocyclohexyl)(2-(methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate as an off- white gum (52 g, 97% yield). MS (MH+): m/z
[00955] Ste 5:
Figure imgf000387_0001
[00956] A 100-mL single neck round bottom flask, connected with reflux condenser equipped with nitrogen gas inlet-outlet U-tube adaptor filled with oil, a teflon-coated stir bar (2 cm), was charged with a solution of tert-butyl (4,4-difluorocyclohexyl)(2- (methylsulfonyl)-6-morpholinopyrimidin-4-yl)carbamate (0.9 g, 1.88 mmol) in acetonitrile (10 mL) followed by 3-cyclopropyl-lH-pyrazole (0.3 g, 2.83 mmol, 1.5 equiv.) and cesium carbonate (1.23 g, 3.77 mmol, 2.0 equiv.). The reaction mixture was heated at 80 °C for 16 hours, and completion of reaction was determined by TLC and LCMS. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified through column chromatography using 60-120 silica gel with ethyl acetate-pet ether as solvent system. The isolated material was dried under vacuum to afford tert-butyl (2-(3-cyclopropyl- lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-yl)(4,4-difluorocyclohexyl)carbamate as an off- white solid (0.8 g, 84%). MS (MH+): m/z =505.
[00957] Ste 6:
Figure imgf000387_0002
365
[00958] A 100-mL three-necked, flame-dried, round-bottomed flask, equipped with a teflon-coated stir bar (2 cm), one septa (necks 1), stopper (neck 3) and nitrogen gas inlet- outlet U-tube adaptor filled with oil (Neck 2), was charged with a solution tert-butyl (2-(3- cyclopropyl- lH-pyrazol- l-yl)-6-morpholinopyrimidin-4-yl)(4,4- difluorocyclohexyl)carbamate (1.2 g, 1.98 mmol, 1 eq) in dichloro methane (40 mL) followed by trifluoro acetic acid (2.5 mL, 32.55 mmol, 16.4 eq) at 0 °C. The reaction mixture was slowly warmed to rt and stirred at same temperature for 6 hours. The completion of reaction was determined by TLC and UPLC. The reaction mixture was concentrated and the resulting residue was quenched with 10% saturated sodium bicarbonate solution, extracted with ethyl acetate (2x100 mL), and concentrated under reduced pressure to afford crude product. The crude product was purified through column chromatography using 60-120 silica gel, ethyl acetate-pet ether as solvent system. The resulting solid was dried under vacuum to afford 2- (3-cyclopropyl-lH-pyrazol-l-yl)-N-(4,4-difluorocyclohexyl)-6-morpholinopyrimidin-4- amine 365 (0.73g, 90%). MS (MH+): m/z=405. Analytical Data: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.14 (d, J = 2.80 Hz, 1H), 5.53 (s, 1H), 3.88 (s, 1H), 3.69-3.67 (m, 4H), 3.50 (m, 4H), 1.99-1.90 (m, 7H), 1.56-1.54 (m, 2H), 0.93-0.89 (m, 2H), 0.72-0.71 (m, 2H).
[00959] Example 274:
Figure imgf000388_0001
Step-1
[00960] Step 1: To a stirred solution of 4, 6-Dichloro-2-(Methylsulfonyl)Pyrimidine (10 g, 44.039 mmol) in tetrahydrofuran (100 mL) was added 4, 4-difluorocyclohexylamine hydrochloride (9.06 g, 52.84 mmol) and N, N-di-isopropyl ethylamine (9.2 mL, 52.84 mmol) at 0 °C. The reaction mixture was stirred at rt for 5h. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (2x250 mL). The
combined organic layer was washed with brine solution (50 mL), the organic extracts was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a pale yellowish gum. The crude product was purified by column chromatography (60-120 mesh) using ethyl acetate in pet ether as solvent to afford 4, 6-dichloro-N-(4, 4- difluorocyclohexyl) pyrimidin-2-amine as off-white solid (4 g, 32%). MS (M, M+2)+=282.0, 284.1.
Figure imgf000389_0001
Figure imgf000390_0001
[00961] Step l[A]:To a stirred solution of 4, 6-dichloro-N-(4, 4-difluorocyclohexyl) pyrimidin-2-amine (2 g, 7.08 mmol) in acetonitrile (20 mL) was added 1-acetylpiperazine (0.90 g, 7.08 mmol) and triethylamine (0.86 g, 1.18 mL, 8.50 mmol). The reaction mixture was heated at 65 °C for 2h. The reaction mixture was concentrated and the residue was triturated with water, the solid formed was filtered off, washed with hexane, dried under high vacuum to afford l-(4-(6-chloro-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)piperazin- l-yl)ethan-l-one [A] as a white solid (2.1 g, 81%). MS (M+l)+=374.2.
[00962] Step l[B]:To a stirred solution of 4, 6-dichloro-N-(4, 4-difluorocyclohexyl) pyrimidin-2-amine (1 g, 3.54 mmol) in acetonitrile (10 mL) was added 3-fluoro pyrazole (0.36 g, 4.25 mmol) and cesium carbonate (2.30 g, 7.089 mmol). The reaction mixture was heated at 80 °C for 8h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product and which was purified by column chromatography (60-120 mesh) using 22% ethyl acetate in pet ether as solvent to afford 4, 6-dichloro-N-(4, 4- difluorocyclohexyl) pyrimidin-2-amine [B] as an off-white solid (4 g, 32%). MS (M, M+2)+=282.0, 284.1.
Step 1[C, D, E, F, G, I, J, L]: The procedure is similar to Step 1[B] in Example-838.
[00963] Step 1[H]: To a solution of 4, 6-dichloro-N-(4, 4-difluorocyclohexyl) pyrimidin-2- amine (0.8 g, 2.83 mmol) in toluene (10 mL) was added 4-methyl-2-(tributylstannyl) thiazole (1.65 g, 4.25 mmol). The reaction mixture was purged with N2 for 5 min, then added bis (triphenylphosphine) Palladium (II) dichloride (0.19 g, 0.28 mmol) and the reaction mixture was heated at 100 °C for 16h. The reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to afford crude product and which was purified by flash chromatography using ethyl acetate and pet-ether as solvent system to afford 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl)pyrimidin-2-amine [H] as a white solid (0.8 g, 80%). MS (M+l)+=345.1.
[00964] Step 1[K]: The procedure is similar to Step 1[H] in Example-838.
Example-839:
Figure imgf000391_0001
Table-2A: Step 1:
Figure imgf000391_0002
NSSy6989 XX Pd(PPh3)4, o-xylene, 180 °C, 30 min, MW 52
[00965] Step l [NSSy6909 and NSSy6957] : To a solution of l-(4-(6-chloro-2-((4, 4- difluorocyclohexyl)amino)pyrimidin-4-yl)piperazin- l-yl)ethan- l-one (0.15 g, 0.40 mmol) and 3-cyclopropyl- lH-pyrazole (0.08 g, 0.80 mmol) in acetonitrile (5 mL) was added cesium carbonate (0.26 g, 0.80 mmol) and the reaction mixture was irradiated under microwave at 130 °C for 2h. The reaction mixture was filtered and the filtrate was concentrated to afford crude product, which was purified by grace instrument using 80% ethyl acetate in pet-ether to afford l-(4-(6-(3-cyclopropyl- lH-pyrazol- l-yl)-2-((4,4- difluorocyclohexyl) amino) pyrimidin-4-yl)piperazin- l-yl)ethan- l-one as off-white solid (0.095 g, 53%). MS (M+l)+=446.2; 1H-NMR (400 MHz, OMSO-d6): δ 8.38 (s, 1H), 6.88 (s, 1H), 6.37 (d, = 7.80 Hz, 1H), 6.21 (d, = 2.44 Hz, 1H), 3.95-3.93 (m, 1H), 3.66 (m, 2H), 3.57-3.54 (m, 6H), 2.07- 1.91 (m, 10H), 1.60- 1.57 (m, 2H), 0.96-0.88 (m, 2H), 0.75-0.73 (m, 2H) and l-(4-(6-(5-cyclopropyl- lH-pyrazol- l-yl)-2-((4, 4-difluorocyclohexyl)amino) pyrimidin-4-yl)piperazin- l-yl)ethan- l-one as an off-white solid (0.0053 g, 3%). MS
(M+l)+=446.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.53 (s, 1H), 6.90-6.88 (m, 1H), 6.40 (s, 1H), 6.08 (s, 1H), 3.86-3.81 (m, 1H), 3.65-3.52 (m, 4H), 3.47 (m, 4H), 2.08-2.05 (m, 6H), 1.91- 1.83 (m, 4H), 1.62- 1.57 (m, 2H), 0.99-0.94 (m, 2H), 0.68 (m, 2H).
[00966] Step 1 [NSSy6629] : To a solution of l-(4-(6-chloro-2-((4, 4-difluorocyclo hexyl)amino)pyrimidin-4-yl)piperazin- l-yl)ethan- l-one (0.3 g, 0.802 mmol) and 3- methylpyrazole (0.098 g, 1.20 mmol) in dioxane ( 10 mL) was added cesium carbonate (0.39 g, 1.20 mmol), followed by 4, 5-Bis(diphenylphosphino)-9, 9-dimethylxanthene (0.18 g, 0.32 mmol) and the reaction mixture was purged with N2 gas for 5 min. Then tris
(dibenzylideneacetone) dipalladium (0) (0.22 g, 0.24 mmol) was added and the reaction mixture was heated at 90 °C for 24h. The reaction mixture was filtered through celite bed, washed with ethyl acetate and the filtrate was concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate and pet-ether as solvent system to afford l-(4-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH- pyrazol- l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan- l-one as an off-white solid (0.052 g, 16%). MS (M+l)+=420.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 1H), 6.91 (d, = 7.60 Hz, 1H), 6.26 (s, 1H), 4.73 (s, 4H), 4.21 (s, 4H), 3.87 (s, 1H), 2.43 (s, 3H), 2.10- 1.93 (m, 6H), 1.62- 1.59 (m, 2H). [00967] Step l[NSSy6607]: The procedure is similar to Step l[NSSy6909] in Example- 839. MS (M+l)+=474.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), δ 7.1 (s, IH), 6.91 (d, J = 7.60 Hz, IH), 6.26 (s, IH), 4.73 (s, 4H), 4.21 (s, 4H), 3.87 (s, IH), 2.43 (s, 3H), 2.10- 1.93 (m, 6H), 1.62-1.59 (m, 2H).
[00968] Step 1 [NSSy6598] : To a solution of l-(4-(6-chloro-2-((4, 4-difluoro cyclohexyl) amino) pyrimidin-4-yl) piperazin-l-yl) ethan-l-one (0.3 g, 0.8 mmol) in toluene (10 mL) was added 4-methyl-2-(tributylstannyl) thiazole (0.62 g, 1.60 mmol). The reaction mixture was purged with N2 for 5 min, then added bis (triphenylphosphine) Palladium (II) dichloride (0.22 g, 0.32 mmol) and the reaction mixture was heated at 100 °C for 16h. The reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate and pet-ether as solvent system to afford l-(4-(2-((4, 4-difluorocyclohexyl)amino)-6-(4- methylthiazol-2-yl) pyrimidin-4-yl)piperazin-l-yl)ethan-l-one as an white solid (0.08 g, 22%). MS (M+l)+=437.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), 6.91 (s, IH), 6.68 (s, IH), 3.89 (d, J = 6.00 Hz, IH), 3.70 (s, 2H), 3.61 (s, 2H), 3.54 (s, 4H), 2.43 (s, 3H), 2.10- 2.06 (m, 2H), 2.05 (s, 3H), 1.96-1.89 (m, 4H), 1.66-1.58 (m, 2H).
[00969] Step l[NSSy6989]: To a solution of l-(4-(6-chloro-2-((4, 4- difluorocyclohexyl)amino)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one (0.15 g, 0.401 mmol) in o-xylene (4 mL) was added 2-methyl-6-(tributylstannyl)pyridine (0.306 g, 0.80 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.09 g, 0.080 mmol). The reaction mixture was irradiated under MW at 180 °C for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, filtered through celite bed and the filtrate was concentrated to afford crude product and which was purified by flash chromatography using ethyl acetate and pet-ether as solvent system to afford l-(4-(2-((4, 4- difluorocyclohexyl)amino)-6-(6-methylpyridin-2-yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l- one as an off-white solid (0.09 g, 52%). MS (M+l)+=431.0; 1H-NMR (400 MHz, DMSO- 6): δ 8.10 (d, J = 6.80 Hz, IH), 7.82-7.78 (m, IH), 7.32 (d, J = 7.60 Hz, IH), 6.99 (s, IH), 6.73 (s, IH), 4.01 (m, IH), 3.69-3.60 (m, 4H), 3.56-3.55 (m, 4H), 2.50 (s, 3H), 2.50-1.94 (m, 9H), 1.64-1.61 (m, 2H). Example-840:
Figure imgf000394_0001
Figure imgf000394_0002
[00970] Step l [NSSy6886] : MS (M+l)+=424; 1H-NMR (400 MHz, DMSO-d6): δ 8.36 (s, IH), 6.98 (s, IH), 6.36-6.34 (m, IH), 6.28 (s, IH), 3.92 (s, IH), 3.67-3.52 (m, 8H), 2.12- 1.85 (m, 9H), 1.62- 1.57 (m, 2H).
[00971] Step l [NSSy6919] : MS (M, M+2)+=484, 486; 1H-NMR (400 MHz, OMSO-d6): δ 8.60 (s, IH), 7.01 (s, IH), 6.70 (s, IH), 6.38 (s, IH), 4.01 (s, IH), 3.69 (s, 2H), 3.60 (s, 2H), 3.52 (s, 4H), 2.05- 1.91 (m, 9H), 1.62- 1.57 (m, 2H).
[00972] Step l [NSSy6936] : MS (M+l)+=436.2; 1H-NMR (400 MHz, OMSO-d6): δ 8.36 (s, IH), 6.85 (d, J = 4.36 Hz, IH), 6.27 (s, IH), 6.06 (s, IH), 4.00 (s, IH), 3.90 (s, 3H), 3.65- 3.54 (m, 8H), 2.09- 1.91 (m, 9H), 1.63- 1.57 (m, 2H). Example-841:
Figure imgf000395_0001
[00973] Step l[NSSy6972]: A mixture of l-(4-(2-((4, 4-difluorocyclohexyl) amino)-6-(3- methoxy-lH-pyrazol-l-yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one (0.15 g, 3.44 mmol) in Pyridine Hydrochloride (0.199 g, 1.72 mmol) was irradiated under microwave at 150 °C for 40 min. The crude reaction mixture was purified by Prep HPLC to afford l-(4-(2-((4, 4- difluorocyclohexyl) amino)-6-(3-hydroxy-lH-pyrazol-l-yl) pyrimidin-4-yl) piperazin-l-yl) ethan-l-one as a white solid (0.038 g, 26%). MS (M+l)+=422; 1H-NMR (400 MHz, DMSO- d6): δ 10.49 (s, 1H), 8.25 (s, 1H), 6.80 (d, / = 6.4 Hz, 1H), 6.17 (s, 1H), 5.84 (d, / = 2.80 Hz, 1H), 4.01 (s, 1H), 3.54 (s, 8H), 2.08-1.91 (m, 9H), 1.62-1.57 (m, 2H).
Example-842:
Figure imgf000395_0002
Figure imgf000396_0001
[00974] Step l[NSSy6389]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=393.1; 1H-NMR (400 MHz, DMSO-d6): δ 6.79 (d, / = 7.20 Hz, 1H), 6.36 (s, 1H), 6.06 (s, 1H), 3.85 (s, 1H), 3.64 (s, 4H), 3.52 (s, 4H), 2.60 (s, 3H), 2.16 (s, 3H), 2.07-2.05 (m, 2H), 1.93-1.91 (m, 4H), 1.58-1.55 (m, 2H).
[00975] Step l[NSSy6564]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=423.2; 1H-NMR (400 MHz, DMSO-d6): δ 6.84 (s, 1H), 6.05 (s, 1H), 5.94 (s, 1H), 4.83 (t, / = 5.20 Hz, 2H), 4.72 (s, 1H), 4.15 (s, 1H), 3.81 (s, 1H), 3.69 (s, 4H), 3.52 (s, 4H), 2.61 (s, 3H), 2.17 (s, 3H), 2.06-1.91 (m, 6H), 1.57-1.54 (m, 3H).
[00976] Step l[NSSy6519]: To a solution of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3, 5- dimethyl-lH-pyrazol-l-yl) pyrimidin-2-amine (0.05 g, 0.146 mmol) in methanol (2 mL) was added sodium methoxide (0.01 g, 0.219 mmol). The reaction mixture was heated at 50 °C for 16h. The reaction mixture was concentrated and the resulting residue was dissolved in water, extracted with ethyl acetate (2x20 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford N-(4, 4-difluorocyclohexyl)-4-(3, 5-dimethyl-lH-pyrazol- l-yl)-6-methoxy pyrimidin-2-amine as an off-white solid (0.045 g, 92%). MS (M+l)+=338.1; 1H-NMR (400 MHz, DMSO-J6): δ 7.38 (s, 1H), 6.34 (s, 1H), 6.11 (s, 1H), 3.86 (s, 4H), 2.64 (s, 3H), 2.18 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.52 (m, 2H). [00977] Step l [NSSy6638] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=405.6; 1H-NMR (400 MHz, OMSO-d6): δ 6.79 (s, IH), 6.09 (s, 2H), 4.88 (s, 2H), 3.85-3.76 (m, 2H), 3.67-3.65 (m, 2H), 3.46-3.43 (m, IH), 3.20 (s, IH), 2.61 (s, 3H), 2.17 (s, 3H), 2.15-2.02 (m, 2H), 1.98- 1.80 (m, 6H), 1.65- 1.50 (m, 2H).
[00978] Step l [NSSy6639] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=405.6; 1H-NMR (400 MHz, DMSO-d6) : δ 6.30 (s, IH), 6.15 (s, IH), 6.01 (s, IH), 4.90 (s, IH), 4.65 (s, IH), 3.88 (s, IH), 3.79 (d, J = 6.80 Hz, IH), 3.70 (d, J = 7.20 Hz, IH), 3.46 (d, J = 10.00 Hz, IH), 3.30 (d, J = 10.00 Hz, IH), 2.62 (s, 3H), 0.00 (s, 3H), 2.13-2.03 (m, 2H), 2.13- 1.92 (m, 3H), 1.90- 1.78 (m, 3H), 1.70- 1.60 (m, 2H).
[00979] Step l [NSSy6644] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=419.2; 1H-NMR (400 MHz, DMSO-d6) : δ 6.78 (s, IH), 6.29 (s, IH), 6.06 (s, IH), 4.40 (s, 2H), 3.86 (s, IH), 3.02-2.99 (m, 2H), 2.60 (s, 3H), 2.16 (s, 3H), 2.08-2.06 (m, 2H), 1.93- 1.81 (m, 6H), 1.69- 1.67 (m, 2H), 1.58- 1.56 (m, 2H).
Step l[NSSy6654] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=402.5; 1H-NMR (400 MHz, DMSO-d6) : δ 7.47 (s, IH), 7.45 (s, IH), 6.16 (s, IH), 3.90 (s, IH), 2.69 (s, 6H), 2.22 (s, 6H), 2.15- 1.85 (m, 6H), 1.62- 1.55 (m, 2H).
Example-843:
Figure imgf000397_0001
[00980] Step l [NSSy6391] : The Procedure is similar to Step 1 [H] in Example-838. 0.25 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-morpholinopyrimidin-2-amine gave N-(4, 4- difluorocyclohexyl)-4-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-2-amine as an off- white solid (0.09 g, 31%). MS (M+l)+=396.1 ; 1H-NMR (400 MHz, DMSO-d6) : δ 7.39 (s, IH), 6.87 (s, IH), 6.66 (s, IH), 3.87 (s, IH), 3.66 (m, 4H), 3.58 (m, 4H), 2.32 (s, 3H), 2.06- 1.91 (m, 6H), 1.61- 1.59 (m, 2H). Example-853:
Figure imgf000398_0001
[00981] Step l[NSSy6558]: The Procedure is similar to Step 1[B] in Example-838. 0.095 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl) pyrimidin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-(4-methylthiazol-2-yl)-6-(2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-2-amine as an off-white solid (0.07 g, 72%). MS (M+l)+=408.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 1H), 6.91 (d, = 7.60 Hz, 1H), 6.26 (s, 1H), 4.73 (s, 4H), 4.21 (s, 4H), 3.87 (s, 1H), 2.43 (s, 3H), 2.10-1.93 (m, 6H), 1.62-1.59 (m, 2H).
Example-854:
Figure imgf000398_0002
[00982] Step 1 [NSSy6710] : To a stirred solution of 4-chloro-N-(4, 4-difluoro cyclo hexyl)-6-(4-methylthiazol-2-yl)pyrimidin-2-amine (0.8 g, 2.32 mmol) in dimethylsulphoxide (10 mL) was added 1, 4-diazabicyclo[2.2.2]octane ( 0.286 g, 2.55 mmol) and sodium cyanide (0.126 g, 2.55 mmol) at rt for 2h. The reaction mixture was quenched with ice cold water and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude product, which was purified by flash
chromatography using 28% ethyl acetate in pet-ether as solvent system to afford 2-((4, 4- difluorocyclohexyl)amino)-6-(4-methylthiazol-2-yl)pyrimidine-4-carbonitrile as an yellow solid (0.23 g, 29%). MS (M+l)+=336.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.20 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 3.99 (bs, 1H), 2.47 (s, 3H), 2.33 (s, 3H), 2.06-1.95 (m, 6H), 1.64-1.62 (m, 2H).
[00983] Step 2: To a solution of 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methyl thiazol- 2-yl) pyrimidine-4-carbonitrile (0.20 g, 0.59 mmol) in Cone Hydrochloric acid was heated at 100 °C for 16h. The reaction mixture was allowed to cool down, and concentrated under reduced pressure to afford 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyrimidine-4-carboxylic acid as a brown solid (0.2 g, 90%). MS (M+l)+=336.1
[00984] Step 3: To a stirred solution of 2-((4, 4-difluorocyclohexyl)amino)-6-(4- methylthiazol-2-yl)pyrimidine-4-carboxylic acid (0.2 g, 0.21 mmol) in ethanol (10 mL) was added 0.5 mL Cone sulphuric acid and the reaction mixture was heated at 75 °C for 16h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with saturated bicarbonate solution and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford ethyl 2-((4, 4- difluorocyclo hexyl) amino)-6-(4-methylthiazol-2-yl) pyrimidine-4-carboxylate as an off- white gum (0.19 g, 92%). MS (M+l)+=383.1.
[00985] Step 4: To an ice-cooled solution of ethyl 2-((4, 4-difluorocyclohexyl) amino)-6- (4-methylthiazol-2-yl)pyrimidine-4-carboxylate (0.2 g, 0.52 mmol) in tetrahydrofuran (10 mL) was added Lithium aluminium hydride (2M in THF) and stirred at 0 °C for lh. The reaction mixture was quenched with ice cooled water and extracted with ethyl acetate (3x20 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford (2-((4, 4-difluoro cyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyrimidin-4-yl) methanol as an off-white gum (0.12 g, 67%). MS (M+l)+=341.1.
[00986] Step 5[NSSy6711]: To an ice cooled solution of sodium hydride (0.014 g, 0.35 mmol) in THF (3 mL) was added a solution of (2-((4, 4-difluorocyclohexyl) amino)-6-(4- methylthiazol-2-yl)pyrimidin-4-yl)methanol (0.1 g, 0.29 mmol) in tetrahydrofuran (2 mL) and stirred at 0 °C for 15 min. Iodomethane (0.045 g, 0.32 mmol) was added to the reaction mixture at 0 °C and slowly warmed to rt and stirred at rt for 5h. The reaction mixture was quenched with ice cooled water and extracted with ethyl acetate (3x20 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford N-(4, 4- difluoro cyclohexyl)-4-(methoxymethyl)-6-(4-methylthiazol-2-yl) pyrimidin-2-amine as an off-white solid (15 mg, 14%). MS (M+l)+=355.1; 1H-NMR (400 MHz, DMSO- 6): δ 6.99 (s, 1H), 6.66 (s, 1H), 6.43 (s, 1H) 5.50 (s, 1H), 5.38 (s, 1H), 3.98 (s, 1H), 3.68 (s, 2H), 3.59 (s, 2H), 3.54-3.52 (m, 4H), 2.06-2.04 (m, 6H), 1.94 (s, 3H), 1.54-1.61 (m, 2H) Example-855:
Figure imgf000400_0001
Table-5: Step 1:
Figure imgf000400_0002
Figure imgf000401_0001
[00987] Step l[NSSy6524]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=379.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 6.88 (s, IH), 6.37 (s, IH), 6.33 (s, IH), 3.98 (s, IH), 3.66 (s, 4H), 3.57 (s, 4H), 2.26 (s, 3H), 2.15-1.85 (m, 6H), 1.60- 1.57 (m, 2H).
[00988] Step l[NSSy6522]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=391.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 6.92 (d, / = 7.20 Hz, IH), 6.32 (s, IH), 5.95 (s, IH), 4.72 (s, 4H), 4.18 (s, 4H), 3.95 (s, IH), 2.26 (s, 3H), 2.08-1.89 (m, 6H), 1.59-1.56 (m, 2H).
[00989] Step l[NSSy6585]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=405.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 6.43 (s, IH), 6.26 (s, IH), 4.20-3.40 (m, 10H), 3.06 (s, 3H), 2.28 (s, 3H), 2.15-1.85 (m, 6H), 1.68-1.55 (m, 2H).
[00990] Step l[NSSy6958]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=437.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.36 (d, / = 2.40 Hz, IH), 6.51 (d, / = 7.60 Hz, IH), 6.38 (s, IH), 6.29 (s, IH), 4.36-4.35 (m, IH), 4.24 (s, IH), 4.16-4.15 (m, IH), 3.99-3.92 (m, 2H), 3.55-3.49 (m, IH), 3.18 (dd, / = 2.80, 10.80 Hz, IH), 3.04 (s, 2H), 2.98- 2.91 (m, IH), 2.84-2.78 (m, IH), 2.28 (s, 3H), 2.10-1.89 (m, 6H), 1.68-1.64 (m, 2H), 1.19 (s, 3H), 1.14 (s, 3H).
[00991] Step l[NSSy6677]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=337.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 6.73 (d, / = 6.40 Hz, IH), 6.30 (s, IH), 6.24 (s, IH), 3.93 (s, IH), 3.05 (s, 6H), 2.26 (s, 3H), 2.15-1.85 (m, 6H), 1.65- 1.52 (m, 2H).
[00992] Step l[NSSy6679]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=378.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 6.78 (d, = 6.40 Hz, IH), 6.36-6.24 (m, 2H), 4.09-3.92 (m, IH), 3.59-3.41 (m, 4H), 3.17 (s, IH), 2.72-2.64 (m, 4H), 2.25 (s, 3H), 2.08-1.90 (m, 6H), 1.62-1.57 (m, 2H)
[00993] Step l[NSSy6688]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=323.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 2.40 Hz, IH), 6.61 (s, IH), 6.25 (d, J = 2.40 Hz, IH), 6.22-6.18 (m, 2H), 3.95 (s, IH), 2.85 (s, 3H), 2.26 (s, 3H), 1.85- 2.12 (m, 6H), 1.60-1.75 (m, 2H).
[00994] Step 1 [NSSy6698] : A solution of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3- methyl-lH-pyrazol-l-yl) pyrimidin-2-amine (0.13 g, 0.39 mmol) in aqueous ammonia was heated in a sealed tube at 100 °C for 16h. The reaction mixture was extracted with ethyl acetate (2x20 mL). The combined organic layer was dried over sodium sulfate and
concentrated to afford crude which was purified by column chromatography using ethyl acetate as eluent to afford N2-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l- yl)pyrimidine-2, 4-diamine as an white solid (91 mg, 76%). MS (M+l)+=309.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.34 (s, IH), 6.62 (d, J = 6.80 Hz, IH), 6.51 (s, 2H), 6.28 (s, IH), 6.22-6.17 (m, IH), 3.93 (s, IH), 2.24 (s, 3H), 2.15-1.85 (m, 6H), 1.52-1.48 (m, 2H).
[00995] Step l[NSSy6574]: The Procedure is similar to Step l[NSSy6519] in Example- 842. MS (M+l)+=324.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, IH), 6.95 (s, IH), 6.42- 6.25 (m, 2H), 4.00 (s, IH), 3.90 (s, 3H), 2.28 (s, 3H), 2.15-1.85 (m, 6H), 1.75-1.62 (m, 2H). Step l[NSSy6580]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=389.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 6.86 (d, J = 7.16 Hz, IH),
6.31 (s, IH), 5.92 (s, IH), 3.96 (s, 4H), 2.26 (s, 3H), 2.20-2.16 (m, 4H), 2.15-1.75 (m, 7H), 1.65-1.50 (m, 2H).
[00996] Step l[NSSy6581]: The Procedure is similar to Step 1[B] in Example-2. MS (M+l)+=433.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.35 (s, IH), 6.27 (s, 2H), 6.16 (s, IH), 3.94 (s, IH), 3.70-3.50 (m, 5H), 3.38 (s, 2H), 2.28 (s, 3H), 2.15-1.85 (m, 8H), 1.75-1.50 (m, 7H).
[00997] Step l[NSSy6584]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=403.3; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (bs, IH), 6.73(s, IH), 6.30 (s, IH), 6.09 (s, IH), 3.93 (s, IH), 3.63 (s, 2H), 3.23 (s, 2H), 2.72 (s, 2H), 2.25 (s, 3H), 2.04- 1.92 (m, 6H), 1.71-1.81(m, 2H), 1.69-1.62 (m, IH), 1.55-1.58 (m, 3H), 1.14 (s, 2H). [00998] Step l[NSSy6700]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=367.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (s, IH), 7.18-7.15 (bs, IH), 6.70 (s, IH), 6.28 (s, IH), 6.19 (s, IH), 3.90 (s, IH), 3.44 (s, 4H), 3.26 (s, 3H), 2.32 (s, 3H), 2.04-1.90 (m, 6H), 1.61-1.59 (m, 2H).
[00999] Step l[NSSy6913]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=442.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (s, IH), 7.09 (d, J = 7.20 Hz, IH), 6.42 (s, IH), 6.34 (s, IH), 5.35-5.33 (m, IH), 3.97 (s, IH), 3.25-3.20 (m, 2H), 3.15-3.12 (m, 2H), 2.33-2.29 (m, 8H), 2.08-1.91 (m, 6H), 1.71-1.66 (m, 2H).
[001000] Step l[NSSy6914]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=435.2; 1H-NMR (400 MHz, DMSO-J6): δ 8.38 (s, IH), 7.05 (d, J = 7.60 Hz, IH), 6.33 (s, IH), 5.28-5.24 (m, IH), 3.96 (s, IH), 3.75 (s, 2H), 3.35-3.33 (m, 2H), 2.27 (s, 3H), 2.11-1.89 (m, IH), 1.73-1.64 (m, 4H).
[001001] Step l[NSSy6675]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=368.0; 1H-NMR (400 MHz, DMSO-d6-80 °Q: δ 8.37 (d, J = 2.40 Hz, IH), 6.91 (s, IH), 6.34 (s, IH), 6.32 (d, J = 2.40 Hz, IH), 4.45 (t, J = 4.80 Hz, 2H), 3.97 (s, IH), 3.68 (t, J = 4.80 Hz, 2H), 3.33 (s, 3H), 2.28 (s, 3H), 2.04-1.93 (m, 6H), 1.89-1.66 (m, 2H).
[001002] Step l[NSSy6686]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=381.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.40 Hz, IH), 6.90 (d, J = 6.40 Hz, IH), 6.32 (d, J = 3.20 Hz, 2H), 4.41 (t, J = 6.00 Hz, 2H), 3.98 (s, IH), 2.67-2.64 (m, 2H), 2.27-2.25 (m, 8H), 1.85-2.85 (m, 6H), 1.74-1.66 (m, 2H).
[001003] Step 1 [NSSy6625] : The Procedure is similar to Step 1 [NSSy6519] in
Example-842. MS (M+l)+=338.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 7.36 (s, IH), 6.37 (d, J = 2.40 Hz, IH), 6.27 (m, IH), 4.34 (m, 2H), 4.01 (m, IH), 2.27 (s, 3H), 2.06- 1.93 (m, 6H), 1.62-1.60 (m, 2H), 1.23 (m, 3H).
Example-856:
Figure imgf000404_0001
[001004] Step l [NSSy6525] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=379.2; IH-NMR (400 MHz, OMSO-d6): δ 7.58 (s, IH), 6.88 (s, IH), 6.43 (s, IH), 6.27 (s, IH), 3.86 (s, IH), 3.66 (s, 4H), 3.52 (s, 4H), 2.65 (s, 3H), 2.08- 1.88 (m, 6H), 1.63-
1.54 (m, 2H).
[001005] Step l [NSSy6523] : The Procedure is similar to Step 1 [B] in Example-838. MS (M+l)+=391.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.57 (s, IH), 6.99 (bs, IH), 6.26 (s, IH), 6.03 (s, IH), 4.72 (s, 4H), 4.16 (s, 4H), 3.85 (s, IH), 2.65 (s, 3H), 2.08- 1.93 (m, 6H), 1.58-
1.55 (m, 2H). Exam le-857:
Figure imgf000405_0001
[001006] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 0.2 g of 4- chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin-2-amine gave ieri-butyl 4-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4- yl) piperazine-l-carboxylate as a white solid (0.27 g, 93%). MS (M+l)+=478.
[001007] Step 2[NSSy6924] : To a stirred solution of tert-butyl 4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl) piperazine-l- carboxylate (0.15 g, 0.402 mmol) in dichloromethane (5 mL) was added trifluoro acetic acid (0.073 mL, 0.94 mmol) at 0 °C and the mixture was stirred at rt for 2h. The reaction mixture was concentrated under reduced pressure to afford crude N-(4, 4-difluorocyclohexyl)-4-(3- methyl-lH-pyrazol-l-yl)-6-(piperazin-l-yl)pyrimidin-2-amine which was dissolved in dichloromethane (5 mL) and added triethylamine (2 mL, 14.30 mmol) and methyl chloroformate (0.18 g, 0.81 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 10 min, partitioned between dichloromethane (10 mL) and water (3 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography using 60% ethyl acetate in pet ether as eluent to afford methyl 4-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)piperazine-l-carboxylate as a white solid (0.105 g, 77%). MS (M+l)+=436.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 6.90 (s, 1H), 6.38 (s, 1H), 6.32 (s, 1H), 3.96 (s, 1H), 3.64 (s, 7H), 3.47 (s, 4H), 2.27 (s, 3H), 2.15-1.91 (m, 6H), 1.62- 1.57 (m, 2H).
Figure imgf000406_0001
[001008] Step l[NSSy6995 and NSSy6986]: The Procedure is similar to Step 1[B] in Example-838. 0.13 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin-2-amine gave N-(4, 4-difluorocyclohexyl)-4(2-((difluoromethoxy) methyl) morpholino)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin -2-amine as a white solid (0.045 g, 25%). MS (M+l)+=459.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 6.65 (t, = 76.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 6.30 (s, 1H), 4.26 (s, 1H), 4.13 (s, 1H), 3.98- 3.95 (m, 4H), 3.73-3.70 (m, 1H), 3.57 (t, J = 3.20 Hz, 1H), 3.20-3.18 (m, 1H), 2.89-2.83 (m, 1H), 2.28 (s, 3H), 2.01-1.88 (m, 6H), 1.67-1.65 (m, 2H) and (4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)morpholin-2- yl)methanol as an white solid (0.056 g, 35%). MS (M+l)+=409.2; 1H-NMR (400 MHz,
DMSO-d6): δ 8.37 (s, 1H), 6.54 (d, J = 7.60 Hz, 1H), 6.40 (s, 1H), 6.30 (s, 1H), 4.55 (m, 1H), 4.24 (s, 1H), 4.14 (s, 1H), 3.95-3.92 (m, 2H), 3.54-3.46 (m, 4H), 2.97 (m, 1H), 2.79 (t, J = 3.20 Hz, 1H), 2.33 (s, 3H), 2.10-1.91 (m, 6H), 1.67-1.64 (m, 2H).
Example-859:
Figure imgf000406_0002
Figure imgf000406_0003
[001009] Step 1 [NSSy6722] : The Procedure is similar to Step 1 [NSSy6710] in
Example-854. 0.3 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin-2-amine gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidine-4-carbonitrile as an off-white solid (0.052 g, 75%). MS (M+l)+=319; 1H-NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.14 (d, J = 6.40 Hz, 1H), 7.36 (s, 1H), 6.50 (s, 1H), 4.04-3.94 (m, 1H), 2.33 (s, 3H), 2.13-1.91 (m, 6H), 1.26-1.23 (m, 2H).
[001010] Step 2[NSSy6684] : The Procedure is similar to Step 2[NSSy6711] in
Example-854. 0.22 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidine-4-carbonitrile gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol- 1-yl) pyrimidine-4-carboxylic acid as an off-white solid (0.07 g, 30%). MS (M+l)+=338.1; 1H-NMR (400 MHz, DMSO- 6): δ 13.58 (s, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.53-7.41 (m, 1H), 6.46-6.40 (m, 2H), 4.01 (m, 1H), 2.30 (s, 3H), 2.07-1.93 (m, 6H), 1.63-1.60 (m, 2H). Example-860:
Figure imgf000407_0001
[001011] Step 2[NSSy6704]: The Procedure is similar to Step 1[H] in Example-838. 0.8 g of 4, 6-dichloro-N-(4,4-difluorocyclohexyl)pyrimidin-2-amine gave N-(4, 4- difluorocyclohexyl)-4,6-bis(4-methylthiazol-2-yl)pyrimidin-2-amine as an yellow solid (0.3 g, 26%). MS (M+l)+=408.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.85-7.83 (m, 2H), 7.77 (s, 1H), 7.57 (s, 1H), 3.95 (s, 1H), 3.26 (s, 3H), 2.32 (s, 3H) 2.03-1.90 (m, 6H), 1.73-1.68 (m, 2H).
Example-861:
Figure imgf000407_0002
[001012] Step 1: To solution of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH- pyrazol-l-yl) pyrimidine-4-carbonitrile (1.8 g, 5.65 mmol) in 3M hydrochloric acid in methanol was heated at 70 °C. The reaction mixture was concentrated and the resulting residue was quenched with 10% sodium bicarbonate solution and extracted with ethyl acetate (2x60 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude and which was purified by column chromatography using 30% ethyl acetate in pet ether as eluent to afford methyl 2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH- pyrazol- l-yl)pyrimidine-4-carboxylate as an off-white gum (1.2 g, 60%). MS (M+l)+=352.1.
[001013] Step 2: The Procedure is similar to Step 4[NSSy6711] in Example-854. 1.2 g of methyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl- lH-pyrazol- l-yl) pyrimidine-4- carboxylate gave (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl- lH-pyrazol- l-yl) pyrimidin-4-yl) methanol as an off-white gum (0.6 g, 54%). MS (M+l)+=324.
[001014] Step 3: To an ice cooled solution of (2-((4, 4-difluorocyclohexyl) amino)-6-(3- methyl- lH-pyrazol- l-yl) pyrimidin-4-yl) methanol (0.65 g, 2.01 mmol) in dichloro methane (15 mL) was added thionyl chloride (0.48 g, 4.02 mmol). The reaction mixture was slowly warmed to rt and stirred for 2h. The reaction mixture was quenched with 10% sodium bicarbonate solution and extracted with ethyl acetate (2x35 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude which was purified by column chromatography using 20% ethyl acetate in pet ether as eluent to afford 4- (chloromethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- IH-pyrazol- l-yl)pyrimidin-2-amine (0.25 g, 36) as off-white gum. MS (M+l)+=342.3.
[001015] Step 4[NSSy6800] : To an ice cooled solution of 4-(chloromethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl- lH-pyrazol- l-yl) pyrimidin-2-amine (0.1 g, 0.29 mmol) in dimethyl sulphoxide (4 mL) was added sodium cyanide. The reaction mixture was slowly warmed to rt and stirred for lh. The reaction mixture was quenched with water and extracted with ethyl acetate (2x35 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude and that was purified by grace instrument using 30% ethyl acetate in pet ether as an eluent to afford 2-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)acetonitrile as white solid (0.06 g, 65%). MS (M+l)+=333.2;
1H-NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.70 (s, 1H), 7.06 (d, = 42.40 Hz, 1H), 6.44 (d, = 2.80 Hz, 1H), 4.11 (s, 2H), 2.33 (s, 3H), 2.06- 1.92 (m, 6H), 1.63- 1.60 (m, 2H). Example-862:
Figure imgf000408_0001
[001016] Step l[NSSy6744]: To an ice cooled solution of (2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl) methanol (0.2 g, 0.61 mmol) in tetrahydrofuran (8 mL) was added sodium hydride (0.037 g, 0.92 mmol) and the reaction mixture was stirred at rt for 30 min. After 30 min, added a solution of iodomethane (0.096 g, 0.68 mmol) in tetrahydrofuran (2 mL) to the above reaction mixture at 0 °C and stirred at same temperature for 2h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x35 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude and that was purified by Prep TLC using 30% ethyl acetate in pet ether as an eluent to afford N-(4, 4-difluorocyclohexyl)-4- (methoxymethyl)-6-(3-methyl-lH-pyrazol-l-yl) pyrimidin-2-amine as an off-white solid
(0.042 g, 20%). MS (M+l)+=338.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.57 (m, IH), 7.47 (m, IH), 7.01 (s, IH), 6.41 (s, IH), 4.34 (s, 2H), 3.98 (m, IH), 3.40 (s, 3H), 2.29 (s, 3H), 2.05-1.91 (m, 6H), 1.61-1.59 (m, 2H).
Example-863:
Figure imgf000409_0001
[001017] Step 1 [NSSy6783] : To a solution of 4-(chloromethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyrimidin-2-amine (0.1 g, 0.29 mmol) in acetonitrile (8 mL) was added cesium carbonate (0.38 g, 1.17 mmol) and dimethyl amine (0.079 g, 1.75 mmol). The reaction mixture was heated at 70 °C in a closed vial for 16h. The reaction mixture was filtered and the filtrate was concentrated to afford crude which was purified by Prep HPLC to afford N-(4, 4-difluorocyclohexyl)-4-((dimethylamino) methyl)-6- (3-methyl-lH-pyrazol-l-yl) pyrimidin-2-amine as light brown solid (0.06 g, 60%). MS (M+l)+=351.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.55 (m, IH), 7.44-7.42 (m, IH), 7.08 (s, IH), 6.41 (s, IH), 4.00 (m, IH), 2.33 (s, 3H), 2.28 (s, 3H), 2.24 (m, 2H), 1.95-1.88 (m, 6H), 1.61-1.59 (m, 2H). Example-864:
Figure imgf000410_0001
[001018] Step l[NSSy6468]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=382.4; 1H-NMR (400 MHz, DMSO-d6) : δ 8.40 (s, IH), 6.47 (d, = 6.80 Hz, IH), 6.27-6.23 (m, 2H), 3.96 (s, IH), 3.68 (s, 4H), 3.59 (s, 4H), 2.15-1.85 (m, 6H), 1.65-1.55 (m, 2H).
[001019] Step l[NSSy6467]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=394.4; 1H-NMR (400 MHz, DMSO-d6) : δ 8.54 (s, IH), 7.03 (s, IH), 6.35 (s, IH), 5.85 (s, IH), 4.72 (s, 4H), 4.19 (s, 4H), 4.05 (s, IH), 2.15-1.85 (m, 6H), 1.65-1.50 (m, 2H).
Example-865:
Figure imgf000410_0002
[001020] Step 1: The procedure is similar to Step 1[A] in Example-838. 0.4 g of 4, 6- dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro-N-(4-fluorocyclohexyl) pyrimidin-2-amine as a colourless gum (0.18 g, 34%). MS (M+l)+=264.12.
[001021] Step 2: The procedure is similar to Step 1[B] in Example-838. 0.18 g of 4, 6- dichloro-N-(4-fluorocyclohexyl) pyrimidin-2-amine gave 4-chloro-6-(3, 5-dimethyl-lH- pyrazol-l-yl)-N-(4-fluorocyclohexyl) pyrimidin-2- amine as a white solid (0.15 g, 68%). MS
(M+l)+=323.8.
[001022] Step 3[NSSy6471]: The procedure is similar to Step 1[B] in Example-838. 0.15 g of 4-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-N-(4-fluorocyclohexyl) pyrimidin-2- amine gave 4-(3, 5-dimethyl-lH-pyrazol-l-yl)-N-(4-fluoro cyclohexyl)-6-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyrimidin-2-amine as a white solid (0.14 g, 78%). MS
(M+l)+=386.5; 1H-NMR (400 MHz, OMSO-d6): δ 6.87 (bs, IH), 6.06 (s, IH), 5.95 (s, IH), 4.84 (s, 4H), 4.15 (s, 4H), 3.33 (bs, IH), 2.60 (s, 3H), 2.17 (s, 3H), 2.08-1.85 (m, 3H), 1.82- 1.65 (m, 2H), 1.65- 1.42 (m, 3H), 1.42-1.28 (m, IH).
Example-866:
Figure imgf000411_0001
[001023] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.8 g of ethyl l-(6-chloro-2-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl)-lH-pyrazole-3-carboxylate gave ethyl l-(6-(4-acetylpiperazin-l-yl)-2-((4, 4-difluoro cyclohexyl) amino) pyrimidin-4- yl)-lH-pyrazole-3-carboxylate as a white solid (0.6 g, 66%). MS (M+l)+=477.5.
[001024] Step 2[NSSy6931] : To an ice cooled solution of ethyl l-(6-(4-acetylpiperazin- l-yl)-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)-lH-pyrazole-3-carboxylate (0.5 g, 1.04 mmol) in THF (20 mL) was added Lithium borohydride (0.068 g, 3.14 mmol) and stirred at rt for 5h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x50 mL), the combined organic layer was dried over sodium sulfate and
concentrated to afford crude product, which was purified by flash chromatography using 60% ethyl acetate in hexane as eluent to afford l-(4-(2-((4, 4-difluorocyclohexyl)amino)-6-(3- (hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)piperazin-l-yl)ethan-l-one as a white solid (0.033 g, 7%). MS (M+l)+=435.5; 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 6.91 (s, 1H), 6.53-6.38 (m, 2H), 5.23-5.20 (m, 1H), 4.50-4.48 (m, 2H), 3.97 (s, 1H), 3.66 (s,
2H), 3.56-3.53 (m, 6H), 2.07-2.04 (m, 6H), 1.99 (s, 3H), 1.93-1.91 (m, 2H).
[001025] Step 3[NSSy6917]: To an ice cooled solution of l-(4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4-yl)piperazin- l-yl)ethan-l-one (0.15 g, 0.34 mmol) in DCM (10 mL) was added diethylamino sulphur trifluoride (0.11 g, 0.09 mL, 0.38 mmol), then the reaction mixture was slowly warmed to rt and stirred for 30 mins. Then the reaction mixture was quenched with 10% sodium
bicarbonate solution and extracted with dichloro methane (2x50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate and pet-ether as solvent system to afford as an off-white solid (0.04 g, 27%). MS (M+l)+=437.9; 1H-NMR (400 MHz, DMSO-d6): δ 6.99 (bs, 1H), 6.66 (s, 1H), 6.43 (s, 1H) 5.50 (s, 1H), 5.38 (s, 1H), 3.98 (s, 1H), 3.68 (s, 2H), 3.59 (s, 2H), 3.54-3.52 (m,
4H), 2.06-2.04 (m, 6H), 1.94 (s, 3H), 1.54-1.61 (m, 2H).
Example-867:
Figure imgf000412_0001
[001026] Step 1: To an ice-cooled solution of l-(4-(2-((4, 4-difluorocyclohexyl) amino)- 6-(3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) piperazin-l-yl) ethan-l-one (0.18 g, 0.41 mmol) in DCM (10 mL) was added dess-Martin periodinane (0.54 g, 1.24 mmol). The reaction mixture was stirred at 0 °C and slowly warmed to rt and stirred for 2h. The reaction mixture was quenched with saturated sodium thio sulfate solution and extracted with dichloro methane (2x20 mL). The combined organic layer was washed with 10% sodium bicarbonate, water, brine and dried over sodium sulfate and concentrated to afford l-(6-(4- acetylpiperazin- l-yl)-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)- lH-pyrazole-3- carbaldehyde as an off-white solid (0.16 g, 88%). MS (M+l)+=434.2.
[001027] Step 2[NSSy6930]: The procedure is similar to Step 3[NSSy6917] in
Example-21. 0.15 g of l-(6-(4-acetylpiperazin-l-yl)-2-((4, 4-difluorocyclohexyl)
amino)pyrimidin-4-yl)-lH-pyrazole-3-carbaldehyde gave l-(4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-(difluoromethyl)- lH-pyrazol- 1-yl) pyrimidin-4-yl)piperazin- l-yl)ethan-l-one as a white solid (0.035 g, 22%). MS (M+l)+=455.9; IH-NMR (400 MHz, DMSO-d6): δ 8.80 (s, IH), 7.05 (s, IH) 7.26-6.99 (m, IH), 6.80 (s, IH), 6.44 (s, IH), 3.98 (bs, IH), 3.68 (s, 2H), 3.59 (s, 2H), 3.54-3.53 (m, 4H), 2.08-2.05 (m, 6H), 1.94-1.91 (m, 3H), 1.61-1.58 (m, 2H).
Example-868:
Figure imgf000413_0001
[001028] Step 1 [NSSy6721] : The procedure is similar to Step 1 [NSSy6710] in
Example-854. 0.3 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l- yl) pyrimidin-2-amine gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH- pyrazol-l-yl) pyrimidine-4-carbonitrile as an off-white solid (0.3 g, 86%). MS
(M+l)+=333.0; IH-NMR (400 MHz, DMSO-d6): δ 8.13 (s, IH), 7.37 (s, IH), 6.25 (s, IH), 3.84 (s, IH), 2.66 (s, 3H), 2.20 (s, 3H), 2.07-1.93 (m, 6H), 1.60-1.58 (m, 2H).
[001029] Step 2: The procedure is similar to Step 2[NSSy6711] in Example-854. 0.25 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine-4- carbonitrile gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine-4-carboxylic acid as a white solid (0.3 g, 50%). MS (M+l)+=352.0. [001030] Step 3: The procedure is similar to Step 3[NSSy6711] in Example-854. 0.2 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine-4- carboxylic acid gave ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol- 1-yl) pyrimidine-4-carboxylate as an off-white solid (0.21 g, 95%). MS (M+l)+=380.0.
[001031] Step 4: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.21 g of ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine- 4-carboxylate gave (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol as an off-white solid (0.1 g, 55%). MS (M+l)+=338.0.
[001032] Step 5[NSSy6724] : The procedure is similar to Step 5[NSSy6711] in
Example-854. 0.1 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l- yl) pyrimidin -4-yl) methanol gave N-(4, 4-difluorocyclohexyl)-4-(3, 5-dimethyl-lH-pyrazol- l-yl)-6- methoxymethyl) pyrimidin-2-amine as an off-white solid (0.05 g, 50%). MS
(M+l)+=352.0; IH-NMR (400 MHz, DMSO-d6): δ 7.47 (s, IH), 7.05 (s, IH), 6.14 (s, IH), 4.29 (s, 2H), 3.85-3.84 (m, IH), 3.38 (s, 3H), 2.66 (s, 3H), 2.19 (s, 3H), 2.09-2.07 (m, 2H), 1.95-1.83 (m, 4H), 1.62-1.54 (m, 2H).
Example-869:
Figure imgf000414_0001
Figure imgf000414_0002
[001033] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 4-(3- (benzyloxy)cyclobutoxy)-6-chloro-N-(4, 4-difluorocyclohexyl)pyrimidin-2-amine gave 4-(3- (benzyloxy)cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-6-(3-Fluoro- lH-pyrazol- 1- yl)pyrimidin-2-amine as yellowish gum (0.54 g, 98%). MS (M+l)+=474.1.
[001034] Step 2: To a stirred solution of 4-(3-(benzyloxy)cyclobutoxy)-N-(4, 4- difluorocyclohexyl)-6-(3-fluoro-lH-pyrazol-l-yl)pyrimidin-2-amine (0.45 g, 0.95 mmol) in methanol (5 mL) was added Formic acid ( 0.2 mL) and followed by palladium on carbon (10%, 0.05 g). The reaction mixture was stirred at rt for 16h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure, and residue was quenched with saturated bicarbonate solution and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-((2-((4, 4-difluorocyclohexyl) amino)-6-(3-fluoro-lH-pyrazol-l- yl) pyrimidin-4-yl) oxy) cyclobutan-l-ol as a colourless gum (0.35 g, 97%). MS
(M+l)+=384.1.
[001035] Step 3: The procedure is similar to Step l[NSSy6930] in Example-867. 0.35 g of 3-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-fluoro- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy) cyclobutan-l-ol gave of 3-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-fluoro-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy)cyclobutan-l-one as a white solid (0.1 g, 29%). MS (M+l)+=382.1.
[001036] Step 4[NSSy6464] : To a pre-cooled (-78 °C) solution of 3-((2-((4, 4- difluorocyclohexyl)amino)-6-(3-fluoro- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy) cyclobutan- 1- one (0.1 g, 0.26 mmol) in tetrahydrofuran (10 mL) was added methylmagnesium bromide (1.4 M solution in THF:Toluene)(0.09 g, 0.78 mmol) and stirred at -78 °C for 2h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2x20 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford crude product, which was purified by preparative HPLC to afford 3-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-fluoro-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)-l-methylcyclobutan-l-ol as an off-white solid (5.1 mg,
5%). MS (M+l)+=398.2; IH-NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 6.88 (s, IH), 6.24 (s, IH), 5.52 (s, IH), 4.54-4.53 (m, IH), 3.67-3.66 (m, 4H), 3.65-3.40 (m, 4H), 3.36 (s, IH), 1.98 (s, 3H), 1.87-1.81 (m, 3H), 1.64-1.55 (m, IH).
Example-870:
Figure imgf000415_0001
Figure imgf000415_0002
NSSy6590 NSSy6591 NSSy6593 IN10964-041 -P1 [001037] Step 1: The procedure is similar to Step 1[B] in Example-838. 3.0 g of 2, 4- dichloro-6-methylpyrimidine gave 2-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin- 4-amine as an off-white solid (2.5 g, 52%). MS (M+l)+=262.9.
Table-8: Step 2:
Figure imgf000416_0002
[001038] Step 2[NSSy6590] : The procedure is similar to Step 1 [NSSy6989] in
Example-839. MS (M+l)+=325.0; IH-NMR (400 MHz, DMSO-d6): δ 7.48 (d, J = 0.80 Hz, IH), 7.36 (s, IH), 7.11 (s, IH), 3.93-3.88 (m, IH), 2.44 (s, 3H), 2.34 (s, 3H), 2.17-1.86 (m, 6H), 1.67-1.49 (m, 2H).
[001039] Step 2[NSSy6591]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=362.2; IH-NMR (400 MHz, DMSO-d6): δ 8.91 (bs, IH), 7.64 (bs, IH), 7.09 (s, IH), 6.98 (s, IH), 4.04 (s, IH), 2.36 (s, 3H), 2.20-1.80 (m, 6H), 1.70- 1.5 (m, 2H).
[001040] Step 2[NSSy6593]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=322.0; IH-NMR (400 MHz, DMSO-d6): δ 7.38 (s, IH), 6.89 (s, IH), 6.13 (s, IH), 3.86 (s, IH), 2.65 (s, 3H), 2.28 (s, 3H), 2.19 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.52 (m, 2H).
[001041] Step 2[IN10964-041-P1]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=387.9; IH-NMR (400 MHz, DMSO-d6): δ 7.55 (s, IH), 6.87 (s, IH), 6.52 (s, IH), 3.85 (s, IH), 2.68 (s, 3H), 2.31 (s, 3H), 2.10-1.80 (m, 6H), 1.61-1.50 (m, 2H).
Example-871:
Figure imgf000416_0001
[001042] Step 1 [NSSy6736 and NSSy6678] : To a stirred solution of N-(4, 4- difluorocyclohexyl)-4-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-methylpyrimidin-2-amine (0.54 g, 1.68 mmol) in chloroform (8 mL) was added bromine (0.29 g, 1.84 mmol) dropwise at 0 °C and stirred at rt for 3h. The reaction mixture was diluted with chloroform, washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product and which was purified by flash column chromatography using ethyl acetate in pet- ether as solvent to afford 5-bromo-4-(4-bromo-3, 5-dimethyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-methylpyrimidin-2-amine as an off-white solid (0.14 g, 17%). MS (M+l)+=479.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.84 (s, 1H), 3.92-3.79 (m, 1H), 2.23 (s, 3H), 2.62 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 2.02-1.88 (m, 6H), 1.58-1.56 (m, 2H) and 5- bromo-N-(4, 4-difluorocyclohexyl)-4-(3, 5-dimethyl- lH-pyrazol- l-yl)-6-methylpyrimidin-2- amine as an off-white solid (0.07 g, 10%). MS (M+l)+=400.0; 1H-NMR (400 MHz, DMSO- d6): δ 7.48 (s, 1H), 6.90 (s, 1H), 3.85-3.82 (m, 1H), 2.75 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 2.10-1.62 (m, 6H), 1.58-1.53 (m, 2H).
Example-872:
Figure imgf000417_0001
[001043] Step 1: The procedure is similar to Step l[NSSy6736] in Example-26. 0.6 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-2-amine gave 5-bromo-4-chloro-N- (4, 4-difluorocyclohexyl)-6-methylpyrimidin-2-amine as an off-white solid (0.25 g, 32%). MS (M+l)+=342.0.
[001044] Step 2[NSSy6604]: The procedure is similar to Step 1[B] in Example-838. 0.25 g of 5-bromo-4-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-2-amine gave 5- bromo-N-(4, 4-difluorocyclohexyl)-4-methyl-6-(3-(trifluoromethyl)- lH-pyrazol- 1-yl) pyrimidin-2-amine as a colourless gum (0.14 g, 43%). MS (M+l)+=440.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.55-8.47 (m, 1H), 7.91 (s, 1H), 7.05 (s, 1H), 3.93 (s, 1H), 2.51 (s, 3H), 2.15-1.85 (m, 6H), 1.68-1.52 (m, 2H). Example-28:
Figure imgf000418_0001
Figure imgf000418_0002
[001045] Step 1: To a stirred solution of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(l- ethoxyvinyl) pyrimidin-2-amine (0.4 g, 1.25 mmol) in acetone (20 niL) was added aqueous hydrochloric acid (2N) (2 mL). The reaction mixture was allowed to stir at rt for 12h. The reaction mixture was concentrated to remove acetone, diluted with ice-cold water, basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x25 mL). The combined organic layer was concentrated under reduced pressure to afford crude product and which was purified by column chromatography using ethyl acetate in pet-ether as solvent to afford l-(6-chloro-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)ethan-l-one as an off- white solid (0.35 g, 97%). MS (M+l)+=290.1.
[001046] Step 2: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.35 g of l-(6-chloro-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)ethan-l-one gave l-(6- chloro-2-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)ethan-l-ol as an white solid (0.31 g, 88%). MS (M+l)+=292.1.
[001047] Step 3: The procedure is similar to Step 5[NSSy6711] in Example-854. 0.31 g of l-(6-chloro-2-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-ol gave 0.27 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(l-methoxyethyl) pyrimidin-2-amine as an off-white solid (0.27 g, 87%). MS (M+l)+=306.1.
[001048] Step 4[NSSy6697]: The procedure is similar to Step 1[H] in Example-838. 0.25 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(l-methoxyethyl) pyrimidin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-(l-methoxyethyl)-6-(4-methylthiazol-2-yl) pyrimidin-2-amine as an off-white solid (0.15 g, 50%). MS (M+l)+=369.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.51 (s, 2H), 7.24 (s, IH), 4.19-4.18 (m, IH), 3.92 (s, IH), 3.28 (s, 3H), 2.46 (s, 3H), 2.15- 1.85 (m, 6H), 1.72-1.60 (m, 2H), 1.36 (d, J = 6.40 Hz, 3H).
[001049] Step 5[NSSy6729]: Racemate of N-(4, 4-difluorocyclohexyl)-4-(l-methoxy ethyl)-6-(4-methylthiazol-2-yl) pyrimidin-2-amine was separated by chiral HPLC to afford (S)-N-(4, 4-difluorocyclohexyl)-4-(l-methoxyethyl)-6-(4-methylthiazol-2-yl) pyrimidin-2- amine as an off-white solid. MS (M+l)+=369.1; IH-NMR (400 MHz, DMSO-d6): δ 7.51 (s, 2H), 7.24 (s, IH), 4.19-4.18 (m, IH), 3.92 (s, IH), 3.28 (s, 3H), 2.46 (s, 3H), 2.15-1.85 (m, 6H), 1.72-1.60 (m, 2H), 1.36 (d, J = 6.40 Hz, 3H).
Example-874:
Figure imgf000419_0001
Figure imgf000419_0002
Figure imgf000419_0003
Figure imgf000420_0001
[001050] Step 4[NSSY6614]: 1H-NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 7.60 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 5.55 (d, / = 4.80 Hz, 1H), 4.52 (s, 1H), 4.05 (s, 1H), 2.15- 1.85 (m, 6H), 1.68-1.52 (m, 2H), 1.37-1.36 (m, 3H).
[001051] Step 4[NSSY6650]: 1H-NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 7.36 (s, 1H), 7.14 (s, 1H), 6.39 (s, 1H), 5.42 (d, / = 4.80 Hz, 1H), 3.93 (s, 1H), 2.24 (s, 3H), 2.15- 1.85 (m, 6H), 1.52-1.49 (m, 2H). Table-13: Ste 5: The rocedure is similar to Ste 5[NSS 6711] in Exam le-854.
Figure imgf000421_0002
[001052] Step 5[NSSy6612] : 1H-NMR (400 MHz, DMSO-d6): δ 7.52 (s, 1H), 7.04 (s, 1H), 6.15 (s, 1H), 4.12 (d, / = 6.00 Hz, 1H), 3.86 (s, 1H), 3.26 (s, 3H), 2.67 (s, 3H), 2.20 (s 3H), 2.15- 1.85 (m, 6H), 1.65- 1.53 (m, 2H), 1.34 (d, / = 6.40 Hz, 3H).
[001053] Step 5[NSSy6613] : 1H-NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 7.71 (s 1H), 7.07 (d, J = 19.60 Hz, 2H), 4.20 (s, 1H), 4.05 (s, 1H), 3.28 (s, 3H), 2.15- 1.90 (m, 6H), 1.65- 1.55 (m, 2H), 1.36- 1.34 (m, 3H).
[001054] Step 5[NSSy6651] : 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.04 (s 1H), 6.99 (s, 1H), 6.36 (s, 1H), 4.18 (d, J = 6.40 Hz, 1H), 3.99 (s, 1H), 3.32 (s, 3H), 2.30 (s, 3H), 2.15- 1.85 (m, 6H), 1.75- 1.63 (m, 2H), 1.39- 1.37 (m, 3H).
Example-875:
Figure imgf000421_0001
[001055] Step 1 : To a solution of N-(4, 4-difluorocyclohexyl)-4-methyl-6-(3- (trifluoromethyl)- lH-pyrazol- l-yl)pyrimidin-2-amine (0.3 g, 0.83 mmol) in pyridine (4 mL) was added selenium dioxide (0.27 g, 2.49 mmol) and the reaction mixture was heated at 55 °C for 2h, then at 85 °C for 5h, the reaction was allowed to stir at room temperature for 16h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water, filtered and dried under vacuum to afford 2-((4, 4-difluorocyclohexyl) amino)-6- (3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidine-4-carboxylic acid as a pale brown solid (0.25 g). MS (M+l)+=392.2.
[001056] Step 2: To a suspension of 2-((4, 4-difluorocyclohexyl)amino)-6-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidine-4-carboxylic acid (0.25 g, 0.638 mmol) in Toluene (7 mL) and methanol (3 mL) was added (Trimethylsilyl) diazomethane (0.11 mL, 0.76 mmol), 2.0 M in hexane) at 0 °C and the reaction mixture was stirred at room temperature for lh. The reaction mixture was quenched with water and concentrated under reduced pressure to afford crude product, which was diluted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2-((4, 4-difluorocyclohexyl) amino)-6- (3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidine-4-carboxylate as a brown gum (0.2 g). MS (M+l)+=406.4.
[001057] Step 3: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.18 g of methyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidine-4-carboxylate gave (2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)- lH-pyrazol-l-yl) pyrimidin-4-yl) methanol as an off-white solid (0.15 g, 93%). MS
(M+l)+=378.4.
[001058] Step 4[NSSy6674] : The Procedure is similar to Step 5[NSSy6711] in
Example-854. 0.18 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)-lH- pyrazol-l-yl) pyrimidin-4-yl) methanol gave N-(4, 4-difluorocyclohexyl)-4- (methoxymethyl)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-2-amine as an off-white solid (0.15 g, 43%). MS (M+l)+=392.3; 1H-NMR (400 MHz, DMSO-d6): δ 8.75 (d, J = 1.60 Hz, 1H), 7.26 (d, J = 6.80 Hz, 1H), 7.11 (d, J = Hz, 1H), 6.98 (d, J = 2.80 Hz, 1H), 4.39 (s, 2H), 4.04 (s, 1H), 3.44 (s, 3H), 2.04-1.94 (m, 6H), 1.75-1.67 (m, 2H).
Example-876:
Figure imgf000423_0001
[001059] Step 1: The procedure is similar to Step 1[B] in Example-838. 1 g of 2, 4- dichloropyrimidine gave 0.7 g of 2-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid and 0.06 g of 4-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-2-amine as an off-white solid. MS (M+l)+=248.1.
[001060] Step 2[NSSy6941]: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 2-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-cyclopropyl-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as a white solid (0.12 g, 50%). MS (M+l)+=320.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 8.02 (s, IH), 7.70 (s, IH), 6.35 (s, IH), 6.22 (s, IH), 3.92-4.14 (m, IH), 2.06-1.97 (m, 7H), 1.59-1.56 (m, 2H), 0.94-0.87 (m, 2H), 0.69-0.74 (m, 2H).
[001061] Step 2A [NSSy6945]: The procedure is similar to Step 1[B] in Example-838. 0.06 g of 4-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-2-amine gave 4-(3-cyclopropyl-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-2-amine as white solid (0.031 g, 42%). MS (M+l)+=320.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.55 (s, IH), 8.32 (s, IH), 7.41 (s, IH), 6.93 (s, IH), 6.33 (s, IH), 3.99 (s, IH), 2.15-1.85 (m, 7H), 1.68-1.55 (m, 2H), 0.97-0.94 (m, 2H), 0.77-0.75 (m, 2H). Example-877:
Figure imgf000424_0001
[001062] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.3 g of 2, 4- dichloro-6-methyl-l, 3, 5-triazine gave 4-chloro-N-(4, 4-difluorocyclohexyl)-6-methyl-l, 3, 5-triazin-2-amine as white solid (0.3 g, 60 %). MS (M+l)+=263.1.
[001063] Step 2[NSSy7043]: The procedure is similar to Step 1[B] in Example-838. 0.15 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-methyl-l, 3, 5-triazin-2-amine gave 4-(3- cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-methyl-l, 3, 5-triazin-2-amine as white solid (0.15 g, 78%). MS (M+l)+=335.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.55- 8.39 (m, 1H), 8.26 (d, J = 8.00 Hz, 1H), 6.31 (s, 1H), 4.08 (s, 1H), 2.36 (s, 3H), 2.15-1.85 (m, 6H), 1.66-1.57 (m, 2H), 0.98 (s, 2H), 0.97 (s, 2H).
Example-878:
Figure imgf000424_0002
[001064] Step 1: To a solution of 2, 4, 6-trichloro-l, 3, 5-triazine (2 g, 10.84 mmol) in DMF (5 mL) was added 3-methyl pyrazole (0.88 mL, 10.84 mmol) at -40 °C and stirred at same temperature for lh. The reaction mixture was poured into ice cold Water and extract with dichloro methane (2x20 mL). The combined organic layer washed with brine water (10 mL) and dried over sodium sulfate and concentrated under reduced pressure to afford crude and which was purified by column chromatography using 5% ethyl acetate in hexane as eluent to afford 2, 4-dichloro-6-(3-methyl-lH-pyrazol-l-yl)-l, 3, 5-triazine as an yellow solid (0.25 g, 10%). MS (M+l)+=230.1.
[001065] Step 2: To an ice cooled solution of 2, 4-dichloro-6-(3-methyl-lH-pyrazol-l- yl)-l, 3, 5-triazine in DMF was added 4, 4-Difluorocyclohexylamine hydrochloride and triethylamine and stirred at 0 °C for lh. The reaction mixture was poured into ice cooled water, the obtained solid was filtered and dried under high vacuum to afford 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)-l, 3, 5-triazin-2-amine as an white solid (0.3 g, 83%). MS (M+l)+=329.1.
[001066] Step 3[IN10984-079-Pl]: The procedure is similar to Step 2[IN10984-079-Pl] in Example-878. 0.3 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l- yl)-l, 3, 5-triazin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-(3-methyl-lH-pyrazol-l-yl)-6- morpholino-1, 3, 5-triazin-2-amine as an off-white solid (0.13 g, 37%). MS (M+l)+=380.2; 1H-NMR (400 MHz, MeOD): δ 8.48 (d, J = 15.60 Hz, 1H), 6.31 (s, 1H), 4.01 (s, 1H), 3.88 (s, 4H), 3.72 (s, 4H), 2.34 (s, 3H), 2.06-1.93 (m, 7H), 1.69-1.67 (m, 2H).
Example-879:
Figure imgf000425_0001
[001067] Step 1: The procedure is similar to Step l[IN10984-079-Pl] in Example-878. 1 g of 2, 4, 6-trichloro-l, 3, 5-triazine gave 2, 4-dichloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl)- 1, 3, 5-triazine (0.2 g, 15%). MS (M+l)+=243.9.
[001068] Step 2: The procedure is similar to Step 2[IN10984-079-Pl] in Example-878. 0.2 g of 2, 4-dichloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-l, 3, 5-triazine gave 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-l, 3, 5-triazin-2-amine. (0.2 g, 71%). MS (M+l)+=343.
[001069] Step 3[IN10881-098-Pl]: The procedure is similar to Step 2[IN10984-079-Pl] in Example-878. 0.2 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol- l-yl)-l, 3, 5-triazin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-(3, 5-dimethyl-lH-pyrazol- l-yl)-6-morpholino-l, 3, 5-triazin-2-amine (0.1 g, 43%). MS (M+l)+=343.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.88 (d, J = 8.00 Hz, 1H), 6.09 (d, J = 8.00 Hz, 1H), 3.97 (s, 1H), 3.80- 3.63 (m, 8H), 2.56 (s, 3H), 2.15 (d, J = 10.80 Hz, 3H), 2.10-1.80 (m, 6H), 1.62-1.50 (m, 2H). Example-880:
Figure imgf000426_0001
[001070] Step 1: The procedure is similar to Step 1[B] in Example-838. 1 g of 4, 6- dichloropyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as a yellow solid (1.5 g, 90%). MS (M+l)+=248.0.
[001071] Step 2[NSSy6061]: The procedure is similar to Step 1[B] in Example-838. 0.4 g of 6-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave methyl 3-((6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as white solid (0.06 g, 10%). MS (M+l)+=343.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.14 (s, IH), 7.28 (s, IH), 5.80 (s, IH), 5.27 (s, IH), 4.27 (s, 2H), 3.85(s, IH), 3.84 (s, 2H), 3.56 (s, 3H), 2.02-1.89 (m, 6H), 1.54-1.46 (m, 2H).
Example-881:
Figure imgf000426_0002
Figure imgf000426_0003
NSSy6994
I
Figure imgf000426_0004
1 Table-14: Step 1:
Figure imgf000427_0001
[001072] Step l[NSSy6128]: The procedure is similar to Step l[NSy6909] in Example- 839. MS (M, M+2)+=386.0, 388.0; IH-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 7.20 Hz, IH), 6.43 (d, J = 14.00 Hz, IH), 6.26 (d, J = 21.60 Hz, IH), 4.03-3.88 (m, IH), 2.55 (s, 3H), 2.27 (s, 3H), 2.05-1.92 (m, 6H), 1.59-1.48 (m, 2H).
[001073] Step l[NSSy6935]: The procedure is similar to Step l[NSy6909] in Example- 839. MS (M+l)+=334.2; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.55 (s, IH), 6.19 (s, 2H), 4.13 (s, IH), 2.26 (s, 3H), 2.01-1.94 (m, 7H), 1.61-1.53 (m, 2H), 0.95-0.91 (m, 2H), 0.74-0.72 (m, 2H).
[001074] Step l[NSSy7028]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=370.0; IH-NMR (400 MHz, DMSO-d6): δ 8.65 (s, IH), 7.94 (d, J = 7.60 Hz, IH), 7.64 (s, IH), 7.49-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.02 (d, J = 2.40 Hz, IH), 6.25 (s, IH), 4.19 (s, IH), 2.31 (s, 3H), 2.08-1.99 (m, 6H), 1.60-1.58 (m, 2H).
[001075] Step l[NSSy7012]: The procedure is similar to Step l[NSy6909] in Example- 839. MS (M+l)+=348.0; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.54 (s, IH), 6.25 (d, J = 2.80 Hz, IH), 6.19 (s, IH), 4.14 (s, IH), 2.33 (s, 3H), 2.06-1.95 (m, 6H), 1.58-1.55 (m, 2H), 1.43 (s, 3H), 0.95-0.94 (m, 2H), 0.77-0.75 (m, 2H).
[001076] Step l[NSSy6994]: The procedure is similar to Step l[NSy6909] in Example- 839. MS (M+l)+=324.0; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.53 (s, IH), 6.20 (d, J = 28.84 Hz, IH), 6.01 (d, J = 2.72 Hz, IH), 4.01 (s, IH), 3.95 (s, 3H), 2.47 (s, 3H), 2.06- 1.96 (m, 6H), 1.57-1.55 (m, 2H).
[001077] Step 1[IN11216-001-Pl]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=369.2; IH-NMR (400 MHz, DMSO-d6): δ 8.18 (s, IH), 7.46 (d, J = 6.00 Hz, IH), 6.17 (s, IH), 4.13 (s, IH), 2.67-2.62 (m, 4H), 2.37-2.33 (m, 2H), 2.23 (s, 3H), 2.12- 1.88 (m, 6H), 1.62-1.50 (m, 2H).
[001078] Step 1 [INI 1177-029-P1] : The procedure is similar to Step 1 [B] in Example- 838. MS (M+l)+=350.0; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (bs, IH), 7.54 (bs, IH), 6.40 (d, J = 2.4 Hz, IH), 6.20 (bs, IH), 4.11 (bs, IH), 2.33 (s, 3H), 2.08-1.95 (m, 6H), 1.58- 1.55 (m, 2H), 1.29 (s, 9H).
[001079] Step 1 [INI 1216-072-P1] : The procedure is similar to Step 1 [B] in Example- 838. MS (M+l)+=406.2; IH-NMR (400 MHz, DMSO-d6): δ 8.09 (s, IH), 7.70 (d, J = 8.00 Hz, IH), 6.36 (d, J = 1.60 Hz, IH), 6.28 (s, IH), 4.04 (s, IH), 2.60 (s, 3H), 2.30 (s, 6H), 2.12- 1.90 (m, 6H), 1.61-1.55 (m, 2H).
[001080] Step 1[IN11218-034-P1]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=372.1; IH-NMR (400 MHz, CDC13): δ 8.42 (d, J = 2.40 Hz, IH), 6.45 (d, J = 2.40 Hz, IH), 6.08 (s, IH), 5.21-5.10 (m, IH), 3.80 (s, IH), 2.42 (s, 3H), 2.28-1.98 (m, 6H), 1.71-1.61 (m, 2H).
[001081] Step 1[IN11250-031-Pl]: The procedure is similar to Step l[NSSy6989] in Example-839. MS (M+l)+=320.2; IH-NMR (400 MHz, DMSO-d6): δ 8.52 (s, IH), 7.64 (s, IH), 6.79-6.76 (m, 2H), 6.23 (s, IH), 5.91 (s, IH), 5.86 (s, IH), 5.42 (d, J = 12.00 Hz, IH), 4.04-4.02 (m, IH), 2.26 (s, 3H), 1.99-2.06 (m, 6H), 1.56-1.58 (m, 2H).
Figure imgf000429_0001
[001082] Step 1 [NSSy7027] : The procedure is similar to Step 1 [NSSy6972] in
Example-841. 0.1 g of N-(4, 4-difluorocyclohexyl)-2-(3-methoxy-lH-pyrazol-l-yl)-6- methylpyrimidin-4-amine gave l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2- yl)-lH-pyrazol-3-ol as brown solid (0.021 g, 54%). MS (M+l)+=310.0; 1H-NMR (400 MHz, DMSO-d6): δ 10.43 (d, = 10.8 Hz, IH), 8.31 (s, IH), 7.45 (d, = 7.6 Hz, IH), 6.14 (s, IH), 5.81 (s, IH), 4.13 (s, IH), 2.21 (s, 3H), 2.08-1.95 (m, 6H), 1.57-1.55 (m, 2H).
[001083] Step 2[NSSy7059]: To an ice cooled solution of l-(4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-ol (0.03 g, 0.097 mmol) in dichloromethane (5 mL) was added Potassium hydroxide in 20% in water (0.032 g, 0.58 mmol) and (bromodifluoromethyl)trimethylsilane (0.039 g, 0.19 mmol), slowly warmed to room temperature. After lh, the reaction mixture was quenched with water and extracted with dichloromethane (2x10 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford crude product, which was purified by Prep HPLC using 15% ethyl acetate in hexane as eluent to afford N-(4, 4-difluorocyclohexyl)-2- (3(difluoromethoxy)-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine as an off-white solid (8 mg, 23%). MS (M+l)+=360.0; IH-NMR (400 MHz, DMSO-d6): δ 8.57 (s, IH), 7.66 (s, IH), 7.43 (t, J = 72.8 Hz, IH), 6.31 (d, J = 2.4 Hz, IH), 6.23 (s, IH), 4.12 (s, IH), 2.26 (s, 3H), 2.07-1.97 (m, 6H), 1.57-1.55 (m, 2H).
Example-883:
Figure imgf000429_0002
[001084] Step 1 [INI 1079-040-P1] : The procedure is similar to Step 1 [B] in Example- 838. 0.2 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-2-(3-ethoxy-lH-pyrazol-l-yl)-6-methylpyrimidin-4-amine as a white solid (0.07 g, 27%). MS (M+l)+=338.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 7.49 (s, IH), 6.16 (s, IH), 5.99 (d, = 3.20 Hz, IH), 4.22 (q, = 6.80 Hz, 2H), 4.10 (s, IH), 2.24 (s, 3H), 2.12-1.88 (m, 6H), 1.62-1.50 (m, 2H), 1.33 (t, = 6.80 Hz, 3H).
Example-884:
Figure imgf000430_0001
[001085] Step 1 [INI 1251-011-Pl, IN11251-020-P1 and INI 1251-011-P2]: To a solution of ethyl l-(4-((4, 4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH- pyrazole-3-carboxylate (0.2 g, 0.54 mmol) in THF (10 mL) at -10 °C was added
Titanium(IV) isopropylate (0.15 g, 0.54 mmol) and ethyl magnesium bromide (0.21 g, 1.64 mmol). The reaction mixture was slowly warmed to rt and stirred at rt for 2h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate and
concentrated to afford crude and which was purified by Prep HPLC to afford l-(l-(4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)- lH-pyrazol-3-yl)cyclopropan- l-ol as an off-white solid (0.04 g). MS (M+l)+=350.2; IH-NMR (400 MHz, DMSO-d6): δ 8.46 (s, IH), 7.54 (s, IH), 6.46 (d, J = 2.8 Hz, IH), 6.19 (s, IH), 6.06 (s, IH), 4.20 (m, IH), 2.25 (s, 3H), 2.09-1.95 (m, 7H), 1.57-1.55 (m, 2H), 1.01 (d, J = 1.6 Hz, 3H) and isopropyl l-(4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3-carboxylate as an off- white solid (0.045 g). MS (M+l)+=380.2; IH-NMR (400 MHz, DMSO-d6): δ 8.67 (s, IH), 7.73 (s, IH), 6.92 (d, J = 2.80 Hz, IH), 6.30 (s, IH), 5.14-5.17 (m, IH), 4.18 (s, IH), 2.33 (s, 3H), 2.12-1.90 (m, 6H), 1.60-1.50 (m, 2H), 1.35 (s, 6H) and l-(l-(4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)propan-l-ol as an off- white solid (0.03 g). MS (M+l)+=352.2; IH-NMR (400 MHz, DMSO-d6): δ 8.47 (s, IH), 7.56 (s, IH), 7.49 (s, IH), 6.00 (s, IH), 5.14 (d, J = 4.80 Hz, IH), 5.13 (s, IH), 4.51 (q, J = 6.40 Hz, 2H), 4.14 (s, IH), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.74-1.67 (m, 2H), 1.60-1.50 (m, 2H), 0.86 (t, J = 7.20 Hz, 3H). Example-885:
Figure imgf000431_0001
[001086] Step 1 [INI 1079-066-P1] : The procedure is similar to Step 1 [B] in Example- 838. 0.35 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave 2-(3- (benzyloxy)-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-methyl pyrimidin-4-amine as a white solid (0.2 g, 37%). MS (M+l)+=400.1; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.48 (s, 3H), 7.36-7.33 (m, 3H), 6.17 (s, 1H), 6.07 (d, J = 3.20 Hz, 1H), 5.27 (s, 2H), 4.12 (s, 1H), 2.33 (s, 3H), 2.12-1.85 (m, 6H), 1.62-1.50 (m, 2H).
[001087] Step 2[IN11079-067-P1]: The procedure is similar to Step 2[NSSy6464] in Example-869. 0.22 g of 2-(3-(benzyloxy)-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6- methylpyrimidin-4-amine gave l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2- yl)-lH-pyrazol-3-ol as a white solid (0.09 g, 53%). MS (M+l)+=308.2; IH-NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.43 (d, J = 7.60 Hz, 1H), 6.14 (s, 1H), 5.81 (d, J = 2.40 Hz, 1H), 4.11 (s, 1H), 2.21 (s, 3H), 2.15-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001088] Step 3[IN11133-094-P1]: The procedure is similar to Step 1[B] in Example- 838. 0.065 g of l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-
3- ol gave N-(4, 4-difluorocyclohexyl)-2-(3-isopropoxy-lH-pyrazol-l-yl)-6-methylpyrimidin-
4- amine as an off-white solid (0.04 g, 39%). MS (M+l)+=352.2; IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 7.49 (s, 1H), 6.15 (bs, 1H), 5.98 (d, J = 1.6 Hz, 1H), 4.88-4.83 (m, 1H), 4.15 (m, 1H), 2.24 (s, 3H), 2.05-1.96 (m, 6H), 1.57-1.55 (m, 2H), 1.31-1.30 (m, 6H). Example-886:
Figure imgf000431_0002
[001089] Step 1: To a solution of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-methyl pyrimidin-4-amine (0.5 g, 1.90 mmol) in ethanol (2 mL) was added hydrazinehydrate (10 mL) and the reaction mixture was heated at 100 °C for 16h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resultant residue was diluted with ethyl acetate and washed with water, dried over sodium sulfate and concentrated under reduced pressure to afford N-(4, 4-difluorocyclohexyl)-2-hydrazineyl-6-methylpyrimidin-4-amine as an off-white solid (0.5 g). MS (M+l)+=258.1.
[001090] Step 2[IN11054-100-P1]: To a solution of N-(4, 4-difluorocyclohexyl)-2- hydrazineyl-6-methylpyrimidin-4-amine (0.05 g, 0.19 mmol) in ethanol (2 mL) was added Ethylaceto acetate (0.056 g, 0.38 mmol) and the reaction mixture was heated at 100 °C for 24h. The reaction mixture was cooled to rt and concentrated under reduced pressure and the resultant residue was diluted with ethyl acetate and washed with water dried over sodium sulfate and concentrated under reduced pressure to afford l-(4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-5-methyl- 1 , 2-dihydro-3H-pyrazol-3- one as an off-white solid (0.05 g). MS (M+l)+=324.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.65 (bs, IH), 6.26 (s, IH), 5.32 (s, IH), 3.95 (bs, IH), 2.29 (s, 3H), 2.13 (s, 3H), 2.03-1.97 (m, 6H), 1.67-1.62 (m, 2H).
Example-887:
Figure imgf000432_0001
[001091] Step 1[IN11140-007-P1]: The procedure is similar to Step 2[IN11054-090-P1] in Example-886. 0.1 g of N-(4, 4-difluorocyclohexyl)-2-hydrazineyl-6-methylpyrimidin-4- amine gave 5-amino-l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl)-l, 2-di hydro-3H-pyrazol-3-one as a white solid (0.05 g, 41%). MS (M+l)+=325.1; 1H-NMR (400 MHz, DMSO-d6): δ 9.25 (s, IH), 7.05 (s, 2H), 6.03 (s, IH), 4.22 (s, IH), 4.02-3.90 (m, 2H), 2.23 (s, 3H), 2.15-1.90 (m, 6H), 1.40 (m, 2H).
Example-888:
[001092] Intentionally Omitted Example-889:
Figure imgf000433_0001
[001093] Step 1: To stirred solution of 2-chloro-N-(4, 4-difluorocyclohexyl)-6- methylpyrimidin-4-amine (2.6 g, 9.95 mmol) in methanol (40 mL) was added [1, - Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.813 g, 0.995 mmol) and N, N-Diisopropylethylamine (5.05 mL, 29.85 mmol) in a Steel bomb and purged with nitrogen gas for about 5 min. The Steel bomb was sealed and filled with carbon monoxide gas at 100 psi and the reaction mixture was heated to 80 °C for 16h. The reaction mixture was degassed for complete removal of CO gas and reaction mixture was
concentrated under reduced pressure to obtain crude brown liquid and which was purified by column chromatography using 75% ethyl acetate in hexane as eluent to afford methyl 4-((4, 4-difluorocyclohexyl)amino)-6-methylpyrimidine-2-carboxylate as a white solid (1.5 g, 53%). MS (M+l)+=286.2.
[001094] Step 2: The procedure is similar to Step 2[NSSy6931] in Example-21. 1 g of methyl 4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidine-2-carboxylate gave (4-((4, 4- difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl) methanol as an off-white solid (0.68 g, 75%). MS (M+l)+=258.2.
[001095] Step 3: To a stirred solution of (4-((4, 4-difluorocyclohexyl)amino)-6-methyl pyrimidin-2-yl)methanol (0.68 g, 2.64 mmol) in DCM (15 mL) was added trimethylamine (0.75 mL, 5.28 mmol) followed by methanesulfonyl chloride (0.31 mL, 3.97 mmol) at 0 °C and the reaction mixture was allowed to stir at rt for lh. The reaction mixture was diluted DCM (150 mL) and washed with saturated sodium bicarbonate solution, the organic solution was dried over sodium sulfate and concentrated under reduced pressure to afford (4-((4, 4- difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)methyl methanesulfonate as an light brown liquid (0.7 g, crude). MS (M+l)+=236.2. [001096] Step 4[IN11273-018-P1]: The procedure is similar to Step 4[NSSy6800] in Example-861. 0.5 g of (4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl) methyl methanesulfonate gave 2-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl) acetonitrile as yellow solid (0.26 g, 65%). MS (M+l)+=267.2; IH-NMR (400 MHz, DMSO- d6): δ 7.40 (d, J = 7.20 Hz, 1H), 6.25 (s, 1H), 3.97 (s, 2H), 2.20 (s, 3H), 2.06-1.91 (m, 6H), 1.58-1.55 (m, 2H).
Examp -890:
Figure imgf000434_0002
[001097] Step 1[IN11273-015-P1 and INI 1273-015-P2]: The procedure is similar to Step 5[NSSy6711] in Example-854. 0.36 g of 2-(4-((4, 4-difluorocyclohexyl) amino)-6- methylpyrimidin-2-yl) acetonitrile gave N-(4, 4-difluorocyclohexyl)-6-methyl-2-((3-methyl- lH-pyrazol-l-yl) methyl) pyrimidin-4-amine as an off-white solid (0.044 g). MS
(M+l)+=322.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.20 (d, = 6.80 Hz, 1H), 6.17 (s, 1H), 6.02 (s, 1H), 5.11 (s, 2H), 3.60-3.71 (m, 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.79-2.02 (m, 6H), 1.40-1.33 (m, 2H) and N-(4, 4-difluorocyclohexyl)-6-methyl-2-((5-methyl-lH-pyrazol-l- yl)methyl)pyrimidin-4-amine as an white solid (0.062 g). MS (M+l)+=322.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.62 (d, = 2.00 Hz, 1H), 7.22-7.21 (m, 1H), 6.18 (s, 1H), 6.00 (d, = 2.00 Hz, 1H), 5.06 (s, 2H), 3.73 (s, 1H), 2.17 (s, 3H), 2.16 (s, 3H), 2.11-1.85 (m, 6H), 1.82- 1.45 (m, 2H).
Example-891:
Figure imgf000434_0001
[001098] Step l[IN11273-006-Pl]: The procedure is similar to Step 1[IN11273-018-P1] in Example-889. 2.6 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave methyl 4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidine-2-carboxylate as a yellow solid (1.5 g, 53%). MS (M+l)+=286.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.57 (s, IH), 6.44 (s, IH), 4.12-4.01 (m, IH), 3.80 (s, 3H), 2.26 (s, 3H), 2.06-1.90 (m, 6H), 1.58-1.50 (m, 2H).
[001099] Step 2[IN11273-001-P1]: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.58 g of methyl 4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidine-2- carboxylate gave (4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl) methanol as a yellow solid (0.44 g, 84%). MS (M+l)+=258.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.22 (d, J = 7.6 Hz, IH), 6.19 (s, IH), 4.61 (t, J = 5.6 Hz, IH), 4.28 (d, J = 6.0 Hz, 2H), 2.20 (s, 3H), 2.09-1.89 (m, 6H), 1.57-1.48 (m, 2H).
Example-892:
Figure imgf000435_0001
[001100] Step 1 : The procedure is similar to Step 1 [B] in Example-838. 0.8 g of 2- chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave l-(l-(4-((4, 4- difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl) ethan-l-one as a yellow solid (0.41 g, 40%). MS (M+l)+=336.2.
[001101] Step 2: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.15 g of l-(l-(4-((4, 4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3-yl)ethan- 1-one gave l-(l-(4-((4, 4-difluorocyclohexyl)amino)-6-methylpyrimidin-2-yl)-lH-pyrazol-3- yl)ethan-l-ol as an off-white solid (0.115 g, 76%). MS (M+l)+=338.2.
[001102] Step 3[IN11243-042-P1]: The procedure is similar to Step 3[NSSy6917] in Example-21. 0.1 g of l-(l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl)-lH- pyrazol-3-yl) ethan-l-ol gave N-(4, 4-difluorocyclohexyl)-2-(3-(l-fluoroethyl)-lH-pyrazol-l- yl)-6-methylpyrimidin-4-amine as an off-white solid (0.04 g, 40%). MS (M+l)+=340.2; 1H- NMR (400 MHz, DMSO-d6): δ 8.57 (bs, IH), 6.61 (d, J = 2.0 Hz, IH), 6.25 (s, IH), 5.84- 5.67 (m, IH), 4.14 (s, IH), 2.27 (s, 3H), 2.07-1.96 (m, 6H), 1.64-1.62 (m, 3H), 1.58-1.56 (m, 2H). Example-893:
Figure imgf000436_0001
[001103] Step 1: To a solution of 4-methylthiazole-2-carboximidamide hydrogen chloride (5 g, 35.4 mmol) in ethanol (50 mL) was added ethyl 3-oxobutanoate (6.75 mL, 53.1 mmol) and sodium ethoxide (12 g, 177.0 mmol). The reaction mixture was heated at 80 °C for 16h. The reaction mixture was concentrated under reduced pressure and the resulting residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with diluted HC1, pH up to 5, then extracted into ethyl acetate (2x30 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford 6-methyl-2- (4-methylthiazol-2-yl) pyrimidin-4-ol as an off-white solid (3.2 g, 43.6%). MS (M+l)+=208.
[001104] Step 2: To a solution of 6-methyl-2-(4-methylthiazol-2-yl)pyrimidin-4-ol (3.8 g, 18.9 mmol) in Phosphorous Oxychloride (39.35 mL, 434.7 mmol) was added N, N- diethylaniline (5.15 mL, 32.13 mmol). The reaction mixture was heated at 95 °C for 2h. The reaction mixture was poured into ice cold water and extracted with ethyl acetate (2x20 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude and which was purified by column chromatography using 20% ethyl acetate in hexane as eluent to afford 2-(4-chloro-6-methylpyrimidin-2-yl)-4-methylthiazole as an off-white solid (2 g, 47%). MS (M+l)+=226.
[001105] Step 3[IN10966-057-P2]: The procedure is similar to Step l[NSSy6909] in Example-839. 0.4 g of 2-(4-chloro-6-methylpyrimidin-2-yl)-4-methylthiazole gave N-(4, 4- difluorocyclohexyl)-6-methyl-2-(4-methylthiazol-2-yl)pyrimidin-4-amine (0.17 g) MS (M+l)+=325.0; and N-(4-fluorocyclohex-3-en-l-yl)-6-methyl-2-(4-methylthiazol-2- yl)pyrimidin-4-amine as an off-white solid (0.110 g). MS (M+l)+=305.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.47 (d, J = 7.20 Hz, 1H), 7.37 (s, 1H), 6.35 (s, 1H), 5.21 (d, J = 17.20 Hz, 1H), 4.20 (s, 1H), 2.43 (s, 4H), 2.28 (s, 5H), 2.10-1.90 (m, 2H), 1.75 (s, 1H).
Figure imgf000437_0001
Figure imgf000437_0002
[001106] Step 1: The procedure is similar to Step 1[B] in Example-2. 1 g of 2-chloro- N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave l-(4-((4, 4-difluorocyclohexyl) amino)-6-methylpyrimidin-2-yl)-lH-pyrazole-3-carbonitrile as an off-white solid (1 g, 82%). MS (M+l)+=319.2.
[001107] Step 2: To a solution of l-(4-((4, 4-difluorocyclohexyl)amino)-6-methyl pyrimidin-2-yl)-lH-pyrazole-3-carbonitrile (0.3 g, 0.94 mmol) in DCM (10 mL) was added ditertiary butyl dicarbonate (0.65 mL) and N, N-dimethyl amino pyridine (0.115 g, 0.94 mmol). The reaction mixture was stirred at rt for 5h.The reaction mixture was quenched with water and extracted with DCM (2x25 mL). The combined organic layer was dried over sodium sulfate and concentrated to afford crude and which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to afford tert-buty\ (2-(3-cyano- lH-pyrazol-l-yl)-6-methylpyrimidin-4-yl)(4, 4-difluorocyclohexyl) carbamate as yellow solid (0.27 g, 70%). MS (M+l)+=419.2.
[001108] Step 3: To a solution of feri-butyl (2-(3-cyano-lH-pyrazol-l-yl)-6- methylpyrimidin-4-yl)(4, 4-difluorocyclohexyl) carbamate and Titanium isopropoxide at -78 °C was added 3M Ethylmagnesium bromide in diethyl ether. The reaction mixture was slowly warmed to rt and stirred for 17h. Borontrifluoride diethyl etherate was added slowly and stirred at rt for lh. The reaction mixture was quenched with 5 mL of 1 N dilute HCI and then basified with aqueous 10 % NaOH solution (5 mL). The reaction mixture was extracted with ethyl acetate (3x30 mL). The combined organic layers was dried over sodium sulfate and evaporated to dryness to afford crude and which was purified by column chromatography using 4% methanol in dichloromethane as eluent to afford tert-butyl (2-(3-(l- aminocyclopropyl)- lH-pyrazol- l-yl)-6-methylpyrimidin-4-yl)(4, 4- difluorocyclohexyl)carbamate as brown solid (0.16 g). MS (M+l)+=449.3.
[001109] Step 4[IN11218-026-Pl]: To a solution of tert-butyl (2-(3-(l- aminocyclopropyl)- lH-pyrazol- l-yl)-6-methylpyrimidin-4-yl)(4, 4-difluoro
cyclohexyl)carbamate (0.1 g, 0.223 mmol) in dioxane (5 mL) was added 2M HCl in ether (15 mL) and the reaction mixture was stirred at rt for 4 days. The reaction mixture was concentrated and the resulting residue was washed with diethyl ether and dried under high vacuum to afford 2-(3-(l-aminocyclopropyl)-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclo hexyl)- 6-methylpyrimidin-4-amine hydrogen chloride as a pale brown solid (0.05 g). MS
(M+l)+=349.3; 1H-NMR (400 MHz, MeOD): δ 8.76 (s, 1H), 6.67 (s, 1H), 6.45 (s, 1H), 4.35 (s, 1H), 2.57 (s, 3H), 2.15-1.85 (m, 8H), 1.65-1.55 (m, 3H), 1.57 (s, 4H).
Example-614
[001110] Intentionally Omitted:
Example-615
[001111] Intentionally Omitted:
Example-616:
Figure imgf000438_0001
[001112] Step 1: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.6 g of 4-methylthiazole-2-carboximidamide hydrochloride gave 6-isopropyl-2-(4- methylthiazol-2-yl) pyrimidin-4-ol (0.2 g, crude). MS (M+l)+=236.
[001113] Step 2: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.2 g of 6-isopropyl-2-(4-methylthiazol-2-yl) pyrimidin-4-ol gave 2-(4-chloro-6-isopropyl pyrimidin-2-yl)-4-methylthiazole (0.08 g, 37%). MS (M+l)+=254.
[001114] Step 3[IN11177-064-P1]: The procedure is similar to Step 1[B] in Example- 838. 0.07 g of 2-(4-chloro-6-isopropyl pyrimidin-2-yl)-4-methylthiazole N-(4, 4- difluorocyclohexyl)-6-isopropyl-2-(4-methylthiazol-2-yl) pyrimidin-4-amine (0.06 g, 58%). MS (M+l)+=353.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.48 (bs, 1H), 7.37 (d, J = 0.8 Hz, IH), 6.35 (s, IH), 4.07 (m, IH), 2.82-2.75 (m, IH), 2.44 (s, 3H), 2.10-1.91 (m, 8H), 1.63-1.56
(m, 2H), 1.34-1.15 (m, 6H).
[001115]
Example-617:
Figure imgf000439_0001
[001116] Step 1: 1.7 g of 4-cyclopropylthiazole-2-carbonitrile gave 4- cyclopropylthiazole-2-carboximidamide hydrochloride as a white solid (2.4 g, crude). MS (M+l)+=168.1.
[001117] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.6 g of 4-cyclopropylthiazole-2-carboximidamide hydrochloride gave 2-(4- cyclopropylthiazol-2-yl)-6-methylpyrimidin-4-ol as an off-white solid (0.45 g, 65%). MS (M+l)+=234.1.
[001118] Step 3: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.45 g of 2-(4-cyclopropylthiazol-2-yl)-6-methylpyrimidin-4-ol gave 2-(4-chloro-6- methylpyrimidin-2-yl)-4-cyclopropylthiazole as a light brown solid (0.36 g, 74%). MS (M+l)+=252.0.
[001119] Step 4[IN11147-062-P1]: The procedure is similar to Step 1[B] in Example- 838. 0.1 g of 2-(4-chloro-6-methylpyrimidin-2-yl)-4-cyclopropylthiazole gave 2-(4- cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine as an off- white solid (0.07 g, 53%). MS (M+l)+=351.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.50 (bs, IH), 7.37 (s, IH), 6.34 (s, IH), 4.04 (bs, IH), 2.33-2.15 (m, 3H), 2.06-1.89 (m, 7H), 1.62- 1.55 (m, 2H), 0.94-0.82 (m, 4H). Example-618:
Figure imgf000440_0001
Step-1 Step-2 //
Figure imgf000440_0002
[001120] Step 1: 0.6 g of 4-methyl thiophene-2-carbonitrile gave 4-methylthiophene-2- carboximid amide hydrochloride as a white solid (0.85 g). MS (M+l)+=141.1.
[001121] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.85 g of 4-methyl thiophene-2-carboximid amide hydrochloride gave 6-methyl-2-(4-methyl thiophen-2-yl) pyrimidin-4-ol as an off-white solid (0.4 g). MS (M+l)+=207.1.
[001122] Step 3: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.21 g of 6-methyl-2-(4-methyl thiophen-2-yl) pyrimidin-4-ol gave 4-chloro-6-methyl-2-(4- methylthiophen-2-yl) pyrimidine as a light brown solid (0.23 g). MS (M+l)+=225.1.
[001123] Step 4[IN11239-029-P1]: The procedure is similar to Step l[NSSy6909] in Example-839. 0.23 g of 4-chloro-6-methyl-2-(4-methylthiophen-2-yl) pyrimidine gave N-(4, 4-difluorocyclohexyl)-6-methyl-2-(4-methylthiophen-2-yl) pyrimidin-4-amine as an off- white solid (0.025 g, 7%). MS (M+l)+=324.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.24 (d, J = 6.0 Hz, 1H), 7.19 (s, 1H), 6.18 (s, 1H), 4.04 (s, 1H), 2.22 (s, 6H), 2.06-1.96 (m, 8H), 1.58-1.56 (m, 2H).
Example-619:
Figure imgf000440_0003
[001124] Step 1: The procedure is similar to Step l[IN10966-057-P2] in Exampl-48. 1 g of 4-methylthiazole-2-carboximidamide hydrochloride gave 6-(tert-butyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-ol as a yellow liquid (0.68 g, 48%). MS (M+l)+=250.2. [001125] Step 2: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.67 g of 6-(tert-butyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-ol gave 2-(4-(tert-butyl)-6- chloropyrimidin-2-yl)-4-methylthiazole as an off-white solid (0.35 g, 49%). MS
(M+l)+=268.1.
[001126] Step 3[IN11220-039-P1]: The procedure is similar to Step l[NSSy6909] in Example-839. 0.25 g of 2-(4-(tert-butyl)-6-chloropyrimidin-2-yl)-4-methylthiazole gave 6- (tert-butyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.1 g, 30%). MS (M+l)+=367.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.49- 7.48 (m, 1H), 7.36 (d, J = 1.20 Hz, 1H), 6.45 (s, 1H), 4.10-4.09 (m, 1H), 2.44 (s, 3H), 2.10- 1.99 (m, 6H), 1.97-1.59 (m, 2H), 1.25 (s, 9H).
Example-62
Figure imgf000441_0001
Figure imgf000441_0002
[001127] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 2- chloro-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine gave 2-(3-bromo-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine as an off-white solid (1 g as crude). MS (M+l)+=372.2.
[001128] Step 2[IN11250-007-Pl]: To a solution of 2-(3-bromo-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine (0.2 g, 0.53 mmol) in dioxane:water (10 mL) was added cyclopent-l-en-l-ylboronic acid (0.09 g, 0.80 mmol) and potassium phosphate (0.34 g, 1.59 mmol) and purged nitrogen for 10 min. Pd(dppf)C12 (0.043 g, 0.053 mmol) was added and the reaction mixture was heated at 120 °C for lh in MW. The reaction mixture was filtered and the filtrate was concentrated to afford crude and which was purified by Prep HPLC to afford 2-(3-(cyclopent-l-en-l-yl)-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-methylpyrimidin-4-amine as an off-white solid (0.022 g, 11%). MS (M+l)+=360.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (bs, 1H), 7.58 (bs, 1H), 6.68 (d, J = 2.8 Hz, 1H), 6.30 (t, J = 2.00 Hz, 1H), 6.22 (bs, 1H), 2.70-2.67 (m, 3H), 2.27 (s, 3H), 2.09- 1.91 (m, 9H), 1.58-1.56 (m, 3H).
[001129] Step 3[IN11250-017-P1]: The procedure is similar to Step 2[NSSy6464] in Example-869. 0.08 g of 2-(3-(cyclopent-l-en-l-yl)-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-methylpyrimidin-4-amine gave 2-(3-cyclopentyl- IH-pyrazol- l-yl)-N- (4, 4-difluorocyclohexyl)-6-methylpyrimidin-4-amine as an off-white solid (0.03 g, 37.5%). MS (M+l)+=362.2; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.54 (s, IH), 6.34 (d, J = 2.8 Hz, IH), 6.20 (bs, IH), 4.08 (bs, IH), 3.31-3.07 (m, IH), 2.26 (s, 3H), 2.09-1.96 (m, 9H), 1.73-1.58 (m, 9H).
Example-621:
[001130] Omitted Inentionally
Example-622:
Figure imgf000442_0001
[001131] Step l[IN11121-042-Pl]: The procedure is similar to Step l[NSSy6519] in Example-842. 0.3 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l- yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)- 6-ethoxypyrimidin-4-amine as an off-white solid (0.11 g, 36%). MS (M+l)+=352.1; 1H- NMR (400 MHz, DMSO-d6): δ 7.41 (s, IH), 6.05 (s, IH), 5.68 (s, IH), 4.27 (q, J = 40.00 Hz, 2H), 3.90 (s, IH), 2.54 (s, 3H), 2.16 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.48 (m, 2H), 1.29 (t, J = 7.20 Hz, 3H)
Example-623:
Figure imgf000442_0002
[001132] Step 1: The procedure is similar to Step 1[B] in Example-838. 7 g of 4, 6- dichloro-2-(methylthio) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine as a yellow solid (10.2 g, 96%). MS (M+l)+=294.2. [001133] Step 2: The procedure is similar to Step 1 [NSSy6519] in Example-842. 0.5 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-6-methoxy-2-(methylthio) pyrimidin-4-amine as yellowish gum (0.35 g, 71%). MS (M+l)+=290.0.
[001134] Step 3: To a stirred solution of N-(4, 4-difluorocyclohexyl)-6-methoxy-2- (methylthio)pyrimidin-4-amine (0.35 g, 1.20 mmol) in Dichloromethane (10 mL) was added 3-Chloroperbenzoic acid (0.62 g, 3.62 mmol) at 0 °C. The reaction mixture was stirred at room temperature. After 2h, the reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM (50 mL). The organic layer was washed with saturated sodium thiosulfate solution and brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford N-(4, 4-difluorocyclohexyl)-6-methoxy-2- (methylsulfonyl)pyrimidin-4-amine as a white solid (0.37g, 95%). MS (M+l)+=322.1.
Table-15: Step 4: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000443_0001
[001135] Step 4[NSSy7062]: MS (M+l)+=356.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.51 (s, 1H), 5.71 (s, 1H), 3.85 (s, 3H), 2.53 (s, 3H), 2.20 (s, 3H), 2.15-1.85 (m, 6H), 1.60- 1.50 (m, 2H).
[001136] Step 4[NSSy6850]: MS (M+l)+=350.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.48 (s, 1H), 6.20 (s, 1H), 5.68 (s, 1H), 3.87 (s, 1H), 2.08-2.02 (m, 3H), 1.97- 1.91 (m, 4H), 1.58 (d, / = 15.20, Hz, 2H), 0.94 (q, / = 2.00 Hz, 2H), 0.73 (q, / = 0.80 Hz, 2H). Example-624:
Figure imgf000444_0001
[001137] Step 1: To a pre (-78°C) cooled solution of 6-methyl-2-Pyridinecarbonitrile (5 g, 42.32 mmol) in Tetrahydrofuran (50 mL) was added Lithium bis(trimethylsilyl)amide (14.16 g, 84.64 mmol) and slowly warmed to rt and continued for 16h. After that 1.5 N HC1 solution (50 mL) was added to the reaction mixture and stirred for lh. Then extracted with ethyl acetate (100 mL), the aqueous layer was basified and extracted with chloroform (3x100 mL). The chloroform was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-methylpicolinimidamide as an off-white solid (3.5 g, 40%). MS
(M+l)+=136.1.
[001138] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 3.5 g of 6-methylpicolinimidamide gave 2-(6-methylpyridin-2-yl) pyrimidine-4, 6-diol as red solid (3.5 g, 67%). MS (M+l)+=204.1.
[001139] Step 3: To a suspension of 2-(6-methylpyridin-2-yl)pyrimidine-4, 6-diol (3.5 g, 17.2 mmol) in Phosphorus oxychloride (16.06 mL, 172.2 mmol) was added Phosphorus Pentachloride (3.58 g, 17.2 mmol) and heated at 105 °C. After 6h, the reaction mixture was cooled to room temperature and quenched with ice and basified using saturated sodium bicarbonate solution to pH=7. The reaction mixture was extracted with ethyl acetate and washed with brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified using ethyl acetate in pet-ether as solvent to afford 4, 6-dichloro-2-(6-methylpyridin-2-yl)pyrimidine as yellow solid (1.3 g, 32%). MS (M+l)+=242.2. Table-16: Step 4:
Figure imgf000445_0002
[001140] Step 4[W]: The procedure is similar to Step 1[B] in Example-838.
[001141] Step 4[X]: The procedure is similar to Step 1[B] in Example-838.
Table-17: Step 5: The procedure is similar to Step l[NSSy6519] in Example-842.
Figure imgf000445_0003
[001142] Step 5[NSSy6889]: 1H-NMR (400 MHz, DMSO-d6): δ 8.07 (d, J = 7.60Hz, 1H), 7.79 (t, J = 7.60 Hz, 1H), 7.32 (d, J = 7.60 Hz, 2H), 5.82 (s, 1H), 3.90 (s, 1H), 2.53 (s, 1H), 2.06-1.94 (m, 6H), 1.59-1.57 (m, 2H).
Example-625:
[001143] Intentionally Omitted
Example-626:
Figure imgf000445_0001
[001144] Step 1[IN11130-030-P1]: The procedure is similar to Step 2[NSSy6464] in Example-869. 0.14 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(6-methylpyridin-2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(6-methylpyridin-2-yl) pyrimidin-4- amine as an off-white solid (0.07 g, 56%). MS (M+l)+=305.0; 1H-NMR (400 MHz, DMSO- d6): δ 8.41 (d, / = 6.0 Hz, 1H), 8.25-8.17 (m, 1H), 7.73-7.69 (m, 1H), 7.25 (d, / = 8.0 Hz, 1H), 6.34 (d, / = 5.6 Hz, 1H), 5.15 (m, 1H), 3.89 (m, 1H), 2.70 (s, 3H), 2.31-2.09 (m, 4H), 2.13- 1.88 (m, 2H), 1.75- 1.65 (m, 2H).
Example-627:
Figure imgf000446_0001
[001145] Step 1 [INI 1130-031-P2] : The procedure is similar to Step 5[NSSy6711] in Example-854. 0.14 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(6-methylpyridin-2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(6-methylpyridin-2-yl)-6-(oxazol-5 ylmethoxy) pyrimidin-4-amine as an off-white solid (0.06 g, 36%). MS (M+l)+=402.1 ; 1H- NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 8.12 (d, / = 7.6 Hz, 1H), 7.81 (t, / = 7.6 Hz, 1H), 7.47-7.42 (m, 2H), 7.35 (d, / = 7.6 Hz, 1H), 5.86 (s, 1H), 5.49 (s, 2H), 4.01 (m, 1H), 2.55 (s, 3H), 2.08- 1.93 (m, 6H), 1.61- 1.56 (m, 2H).
Example-628:
Figure imgf000446_0002
[001146] Step 1 : The procedure is similar to Step 1 [B] in Example-838. 1.4 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-2-(methylthio)-6-morpholinopyrimidin-4-amine as an off-white solid (1.5 g, 93%). MS (M+l)+=345.2.
[001147] Step 2: To a solution of N-(4, 4-difluorocyclohexyl)-2-(methylthio)-6- morpholino pyrimidin-4-amine (1 g, 2.90 mmol) in tetrahydrofuran (15 mL) was added 4-N, N-Dimethylamino pyridine (0.1 g, 0.87 mmol), triethyl amine (1.2mL, 8.71 mmol) and Boc- anhydride (3.16 g, 14.51 mmol). The reaction mixture was heated at 80 °C for 16h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x75 mL), the combined organic layer was dried over anhydrous sodium sulfate and concentrated to afford tert-butyl (4, 4-difluorocyclohexyl)(2-(methylthio)-6-morpholino pyrimidin-4- yl)carbamate as an yellowish gum (1.1 g, 85%). MS (M+l)+=445.2.
[001148] Step 3 : The procedure is similar to Step 3 [NSSy7062] in Example-623. 1.1 g of tert-butyl (4, 4-difluorocyclohexyl) (2-(methylthio)-6-morpholinopyrimidin-4-yl) carbamate gave tert-butyl (4, 4-difluorocyclohexyl) (2-(methylsulfonyl)-6-morpholino pyrimidin-4-yl) carbamate as an off-white gum (0.9 g, 76%). MS (M+l)+=477.3.
[001149] Step 4: To a stirred solution of Tetrahydrofuran (5 mL) was added n-butyl lithium (2.5M solution in hexane)(0.62 mL, 1.57 mmol) dropwise at -78 °C, followed by dropwise addition of 2-Bromo-5-Methyl-l, 3-Thiazole (0.2 g, 1.15 mmol) in THF.
The reaction mixture was stirred at same temperature for lh. After lh tert-butyl (4, 4- difluorocyclohexyl) (2-(methylsulfonyl)-6-morpholino pyrimidin-4-yl) carbamate (0.5 g, 1.04 mmol) in THF added dropwise to the reaction mixture and stirred at same temperature for 2h. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate. The combined organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford tert-butyl(4, 4- difluorocyclohexyl)(2-(5-methylthiazol-2-yl)-6-morpholinopyrimidin-4-yl)carbamate as an off-white solid (0.15 g, 28%). MS (M+l)+=496.0.
[001150] Step 4[NSSy6067] : To an ice cooled solution of tert-butyl (4, 4- difluorocyclohexyl) (2-(5-methylthiazol-2-yl)-6-morpholinopyrimidin-4-yl) carbamate (0.15 g, 0.30 mmol) in dichloro methane was added trifluoroacetic acid (0.2 mL, 2.60 mmol). The reaction mixture was stirred at room temperature for 16h. The reaction mixture was concentrated and the resulting residue was basified with saturated sodium bicarbonate solution and extracted with ethyl acetate (2x70 mL), the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by column chromatography to afford N-(4, 4- difluorocyclohexyl)-2-(5-methylthiazol-2-yl)-6-morpholinopyrimidin-4-amine as an off- white solid (0.055 g, 55%). MS (M+l)+=396.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.60 (s, 1H), 7.01 (d, = 8.00 Hz, 1H), 5.65 (s, 1H), 3.94 (s, 1H), 3.70-3.68 (m, 4H), 3.50 (s, 4H), 2.47 (s, 3H), 2.08-1.92 (m, 6H), 1.61-1.55 (m, 2H). Example-629:
Figure imgf000448_0001
IN1 -P1 IN11216-043-P1 IN11177-068-P1 IN11216-073-P1
Figure imgf000448_0002
IN11217-088-P1 IN11216-050-P1 IN11243-041-P1 IN11243-050-P2
[001151] Step 1: To a solution of N-(4, 4-difluorocyclohexyl)-2-(methylthio)-6- morpholinopyrimidin-4-amine (1 g, 2.90 mmol) in NMP (10.0 mL) was charged Sodium Tungstate Dihydrate (0.19 g, 0.58 mmol) at room temperature. The reaction mass temperature was then raised to 70-75 °C and 30% Η202 (1 mL) was added drop wise over a period of 5.0 mins, the reaction mixture was stirred for 24h at 50 °C. The reaction was cooled to room temperature, ice cold water (50 mL) was added slowly to the reaction mixture and the mixture was stirred for lh, the resulting solid was collected by filtration and washed with water (2x50 mL), dried under vacuum at 50 °C to afford N-(4, 4-difluorocyclohexyl)-2- (methylsulfonyl)-6-morpholinopyrimidin-4-amine as an off-white solid (0.8 g, 73%). MS (M+l)+=377.1.
Figure imgf000448_0003
Figure imgf000449_0001
[001152] Step 2[IN11243-031-Pl]: The procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 8.64 (d, J = 2.80 Hz, IH), 7.25 (d, J = 7.60 Hz, IH), 6.86 (d, J = 3.20 Hz, IH), 5.64 (s, IH), 4.01-4.10 (m, IH), 3.70-3.69 (m, 4H), 3.55-3.50 (m, 4H), 2.56 (s, 3H), 2.32-1.94 (m, 6H), 1.61-1.53 (m, 2H).
[001153] Step 2[IN11216-043-P1]: The procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 8.82 (s, IH), 7.21 (d, J = 8.00 Hz, IH), 5.60 (s, IH), 4.25-4.22 (m, 2H), 4.01-3.99 (m, IH), 3.69-3.68 (m, 4H), 3.52-3.42 (m, 4H), 2.41 (s, 3H), 2.05-1.90 (m, 6H), 1.61-1.52 (m, 2H), 1.29-1.28 (m, 3H).
[001154] Step 2[IN11177-068-P1]: The procedure is similar to Step l[NSSy6909] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 8.77 (d, J = 2.00 Hz, IH), 7.29 (d, J = 7.60 Hz, IH), 7.16 (s, IH), 5.64 (s, IH), 4.01-3.90 (m, IH), 3.69-3.52 (m, 4H), 3.55-3.50 (m, 4H), 2.07-1.93 (m, 6H), 1.60-1.51 (m, 2H).
[001155] Step 2[IN11216-073-P1]: The procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 4.40 Hz, IH), 7.09 (d, J = 8.00 Hz, IH), 5.50 (s, IH), 3.94 (s, 3H), 3.89 (s, IH), 3.68-3.67 (m, 4H), 3.50-3.40 (m, 4H), 2.09-1.89 (m, 6H), 1.59-1.50 (m, 2H). [001156] Step 2[IN11217-088-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 7.02 (d, J = 8.00 Hz, IH), 5.71 (s, IH), 5.53 (s, IH), 3.79 (s, IH), 3.78 (s, 3H), 3.71-3.66 (m, 4H), 3.45-3.40 (m, 4H), 3.33 (s, 3H), 2.13-1.90 (m, 6H), 1.58-1.53 (m, 2H).
[001157] Step 2[IN11216-050-P1]: The procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 8.50 (d, J = 4.80 Hz, IH), 7.10 (d, J = 7.60 Hz, IH), 5.53 (s, IH), 4.04-4.02 (m, IH), 3.67-3.60 (m, 4H), 3.49-3.48 (m, 4H), 2.22 (s, 3H), 2.04- 1.89 (m, 6H), 1.58-1.52 (m, 2H).
[001158] Step 2[IN11243-041-P1]: Step a: The procedure is similar to Step 1[B] in Example-838. Step b: The procedure is similar to Step 2[NSSy6931] in Example-21. Step c: The procedure is similar to Step 3[NSSy6917] in Example-21. 1H-NMR (400 MHz, DMSO- d6): δ 8.54 (d, J = 2.40 Hz, IH), 7.16 (d, J = 8.00 Hz, IH), 6.58 (s, IH), 5.74 (d, J = 62.80 Hz, IH), 5.58 (s, IH), 3.91-3.90 (m, IH), 3.69-3.68 (m, 4H), 3.52-3.41 (m, 4H), 2.02 (s, 3H), 2.01-1.67 (m, 6H), 1.59-1.51 (m, 2H).
[001159] Step 2[IN11243-050-P2] : Step a: The procedure is similar to Step 1 [B] in Example-838. Step b: The procedure is similar to Step 3[NSSy6917] in Example-21. 1H- NMR (400 MHz, DMSO-d6): δ 8.61 (d, J = 2.40 Hz, IH), 7.22 (d, J = 8.40 Hz, IH), 6.68 (d, J = 2.40 Hz, IH), 5.61 (s, IH), 4.11-4.00 (m, IH), 3.70-3.69 (m, 4H), 3.53-3.52 (m, 4H), 2.05 (s, 3H), 2.03-1.91 (m, 7H), 1.57-1.54 (m, 2H).
Example-630:
Figure imgf000450_0001
[001160] Step 1: The procedure is similar to Step 4[NSSy6067] in Example-628. 1.5 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4-(4, 6-dichloropyrimidin-2-yl)-2- methylthiazole as a yellow solid (0.5 g, 30%). MS (M+l)+=248.0.
[001161] Step 2: The procedure is similar to Step 1[B] in Example-838. 0.25 g of 4-(4, 6-dichloropyrimidin-2-yl)-2-methylthiazole as yellow solid gave 6-chloro-N-cyclohexyl-2- (2-methylthiazol-4-yl) pyrimidin-4-amine as a yellow solid (0.3 g, 90%). MS (M+l)+=309.0. Table-19: Step 3:
Figure imgf000451_0002
[001162] Step 3[NSSy6134]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.16 (s, IH), 6.81 (s, IH), 5.68 (s, IH), 4.02 (s, 4H), 3.13 (s, 4H), 2.67 (s, IH), 1.89-1.86 (m, 2H), 1.73-1.70 (m, 2H), 1.60-1.57 (m, IH), 1.36-1.20 (m, 6H).
[001163] Step 3[NSSy6140]: The procedure is similar to Step 1[B] in Example-838.
IH-NMR (400 MHz, DMSO-d6): δ 8.12 (s, IH), 6.89 (s, IH), 5.19 (s, IH), 4.71 (s, 4H), 4.10
(s, 4H), 3.92 (s, IH), 2.68 (s, 3H), 2.04-1.92 (m, 6H), 1.54-1.52 (m, 2H).
[001164] Step 3[NSSy6133]: The procedure is similar to Step 1[B] in Example-838.
IH-NMR (400 MHz, DMSO-d6): δ 8.19 (s, IH), 7.26 (s, IH), 5.66 (s, IH), 5.29 (s,
IH), 4.34 (s, 2H), 3.91-3.90 (m, 2H), 3.58 (s, 3H), 1.73-1.70 (m, 2H), 1.39-1.36 (m, 2H),
1.33-1.30 (m, IH), 1.23-1.20 (m, 2H).
Ex m le-631:
Figure imgf000451_0001
NSSy6165 NSSy6132 [001165] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.15 g of 4-(4, 6-dichloropyrimidin-2-yl)-2-methylthiazole gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(2- methylthiazol-4-yl) pyrimidin-4-amine as a yellow solid (0.17 g, 81%). MS (M+l)+=345.0.
Table-20: Step 2:
Figure imgf000452_0001
[001166] Step 2[NSSy6165]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.20 (s, IH), 7.00 (s, IH), 5.71 (s, IH), 4.03 (s, 4H), 3.98 (s, IH), 3.14 (s, 4H), 2.67 (s, 3H), 2.05-1.91 (m, 6H), 1.59-1.57 (m, 2H).
[001167] Step 2[NSSy6132]: The procedure is similar to Step 1[B] in Example-838. IH-NMR (400 MHz, DMSO-d6): δ 8.24 (s, IH), 7.40 (s, IH), 5.72 (s, IH), 5.39 (s, IH), 4.34 (s, 2H), 3.92-3.91 (m, 2H), 3.58 (s, 3H), 2.68 (s, 3H), 2.04-1.93 (m, 6H), 1.56-1.54 (m, 2H).
Example-632:
Figure imgf000453_0001
[001168] Step 1: 2 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro- 2-(3-methyl-lH-pyrazol-l-yl) pyrimidine as a white solid (1.3 g, 65%). MS (M+l)+=231.0.
[001169] Step 2: The procedure is similar to Step 1[B] in Example-838. 1.3 g of 4, 6- dichloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine gave 1 g of 4-((6-chloro-2-(3-methyl-lH- pyrazol-l-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol as an off-white solid (1 g, 58%). MS (M+l)+=308.0.
[001170] Step 3: The procedure is similar to Step 3[NSSy6917] in Example-21. 1 g of 4-((6-chloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol gave 6- chloro-N-(4-fluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine as an off- white solid (0.06 g, 6%). MS (M+l)+=310.0 and 6-chloro-N-(cyclohex-3-en-l-yl)-2-(3- methyl- lH-pyrazol-l-yl)pyrimidin-4-amine as an off-white solid (0.6 g, 60%). MS (M+l)+=290.0.
Table-21: Step 4:
Figure imgf000454_0001
[001171] Step 4[NSSy5662]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.00 Hz, IH), 6.98 (d, J = 8.00 Hz, IH), 6.25 (d, J = 2.40 Hz, IH), 5.52 (s, IH), 4.67-4.53 (m, IH), 3.69-3.67 (m, 4H), 3.50 (m, 4H), 2.17 (s, 3H), 2.03-1.92 (m, 4H), 1.76-1.71 (m, 2H), 1.63-1.57 (m, 3H).
[001172] Step 4[NSSy5691]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 8.35 (s, IH), 7.03-6.96 (m, IH), 6.25 (d, J = 2.00 Hz, IH), 5.16 (s, IH), 4.85-4.72 (m, 5H), 4.13-4.04 (m, 4H), 3.92-3.81 (m, IH), 2.24 (s, 3H), 1.99-1.92 (m, 6H), 1.67-1.55 (m, 2H).
Table-22: Step 5:
Figure imgf000454_0002
[001173] Step 5[NSSy5663]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.40 Hz, IH), 6.98 (d, J = 8.00 Hz, IH), 6.25 (d, J = 2.40 Hz, IH), 5.68 (d, J = 14.40 Hz, 2H), 5.54 (s, IH), 3.96 (m, IH), 3.69-3.67 (m, 4H), 3.66 (m, 4H), 2.37-2.33 (m, IH), 2.24 (s, 3H), 2.14-1.97 (m, 2H), 1.90-1.87 (m, 2H), 1.52-1.47 (m, IH).
[001174] Step 5[NSSy5670]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 2.40 Hz, IH), 6.96 (d, J = 8.00 Hz, IH), 6.24 (d, J = 2.40 Hz, IH), 5.69-5.61 (m, 2H), 5.16 (s, IH), 4.71 (m, 4H), 4.08-4.07 (m, 4H), 3.90 (m, IH), 2.35-2.33 (m, IH), 2.32 (s, 3H), 2.23-2.13 (m, 2H), 2.07-1.96 (m, 2H), 1.50 (m, IH). Example-633:
Figure imgf000455_0001
Figure imgf000455_0002
NSSy6097 NSSy6091 NSSy6127
Table-23: Step 1: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000455_0003
K+(CH3)3CO\ 80 °C, ACN,
AD 32 337.0
3h
H
Table-25: Step 3: The procedure is similar to Step 3[NSSy7062] in Example-623.
Compound
R Condition Yield (%) MS (M+l)+ No
AE m-CPBA, DCM, 0 °C-rt, 3h 80 437.0
AF m-CPBA, DCM, 0 °C-rt, 3h 75 437.0
H
AG m-CPBA, DCM, 0 °C-rt, 3h 82 369.0
f N
H
Table-26: Step 4: The procedure is similar to Step 1 B] in Example-838.
Compound
R Condition Yield (%) MS (M+l)+ No
NSSy6097 Cs2C03, ACN, 70 °C, 16h 11 439.0
NSSy6091 Cs2C03, ACN, 75 °C, 16h 10 439.0
H
Cs2C03, DMSO, 75 °C,
NSSy6127 16 371.0
16h
H
[001175] Step 4[NSSy6097]: IH-NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 2.40 Hz, 1H), 7.14 (s, 1H), 6.34 (d, J = 2.40 Hz, 1H), 5.70 (s, 1H), 5.32 (m, 1H), 4.33 (m, 2H), 3.91- 3.90 (m, 2H), 3.58 (s, 3H), 2.26 (s, 3H), 2.09 (m, 9H), 1.69 (m, 6H).
[001176] Step 4[NSSy6091]: IH-NMR (400 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.42 (d, J = 7.60 Hz, 1H), 6.32 (d, J = 2.00 Hz, 1H), 5.85-5.79 (m, 1H), 5.35 (s, 1H), 4.10-4.08 (m, 2H), 3.97-3.93 (m, 2H), 3.56 (s, 3H), 2.13 (s, 3H), 2.05-2.03 (m, 2H), 2.00-1.95 (m, 2H), 1.85- 1.82 (m, 6H), 1.72-1.51 (m, 2H), 1.54-1.51 (m, 2H).
[001177] Step 4[NSSy6127]: IH-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.52 Hz, 1H), 8.37 (m, 1H), 6.33 (d, J = 2.52 Hz, 1H), 5.69 (s, 1H), 5.37 (s, 1H), 4.35 (m, 2H), 3.93- 3.92 (m, 2H), 3.58 (s, 3H), 2.34 (s, 3H), 2.33-2.08 (m, 6H). Example-634:
Figure imgf000457_0001
[001178] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.6 g of 6- chloro-N-(4-fluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave tert- butyl 3-((6-((4-fluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (0.3 g, 35%). MS (M+l)+=447.2.
Table-27: Step 2: The procedure is similar to Step 2[NSSy6924] in Example
Figure imgf000457_0002
[001179] Step 2[NSSy5741]: IH-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 7.63- 7.50 (m, IH), 6.31 (s, IH), 5.76-5.72 (m, IH), 5.35 (s, 2H), 4.34 (s, 2H), 3.91(s, 2H) , 3.91 (s, IH), 2.25 (s, 3H), 2.02-1.92 (m, 3H), 1.57-1.50 (m, 2H).
[001180] Step 2[NSSy5765]: IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.00 Hz, IH), 7.61 (s, IH), 6.31 (d, J = 2.40 Hz, IH), 5.69 (s, IH), 5.36 (s, IH), 4.92 (m, IH), 4.65 (m, IH), 4.26 (m, IH), 3.80 (m, IH), 2.02 (s, 3H), 1.91-2.02 (m, 3H), 1.51-1.75 (m, 5H), 0.97 (t, J = 6.80 Hz, 6H). Example-635:
Figure imgf000458_0001
NSSy5762 NSSy5786
[001181] Step 1 : The procedure is similar to Step 1 [B] in Example-838. 0.3 g of 6- chloro-N-(cyclohex-3-en- l-yl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine gave tert- butyl 3-((6-(cyclohex-3-en- l-ylamino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4- yl)oxy)azetidine- l-carboxylate as an off-white solid (0.4 g, 72%). MS (M+l)+=427.0.
Table-28: Step 2: The procedure is similar to Step 2[NSSy6924] in Example-857.
Figure imgf000458_0002
[001182] Step 2[NSSy5762] : 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (d, / = 2.40 Hz, 1H), 7.52 (s, 1H), 6.33 (d, J = 2.80 Hz, 1H), 5.69-5.67 (m, 3H), 5.39-5.37 (m, 1H), 4.61 (m, 1H), 4.26 (m, 2H), 3.83 (d, / = 10.80 Hz, 1H), 2.35 (m, 1H), 2.27 (s, 3H), 2.16 (m, 2H), 1.92- 1.89 (m, 2H), 1.51 (m, 1H), 0.99 (d, J = 6.80 Hz, 6H).
[001183] Step 2[NSSy5786] : 1H-NMR (400 MHz, OMSO-d6): δ 8.39 (d, J = 2.52 Hz, 1H), 7.50 (m, 1H), 6.32 (d, J = 2.52 Hz, 1H), 5.68-5.66 (m, 3H), 5.36 (m, 1H), 4.35-4.20 (m, 3H), 3.92-3.85 (m, 2H), 3.57 (s, 3H), 2.50 (m, 1H), 2.21 (s, 3H), 2.10 (m, 2H), 1.95 (m, 2H), 1.50 (m, 1H). Example-636:
Figure imgf000459_0001
[001184] Step 1: 14 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave ethyl l-(4, 6- dichloropyrimidin-2-yl)-lH-pyrazole-3-carboxylate as an off-white solid (16.5 g, 90%). MS (M+l)+=288.0.
[001185] Step 2: The procedure is similar to Step 1[B] in Example-838. 1.5 g of ethyl
1- (4, 6-dichloropyrimidin-2-yl)-lH-pyrazole-3-carboxylate gave ethyl l-(4-chloro-6-((4- hydroxycyclohexyl) amino) pyrimidin-2-yl)-lH-pyrazole-3-carboxylate as an off-white solid (1.9 g, 90%). MS (M+l)+=366.0.
[001186] Step 3: The procedure is similar to Step 4[NSSy6711] in Example-854. 6.7 g of ethyl l-(4-chloro-6-((4-hydroxycyclohexyl) amino) pyrimidin-2-yl)-lH-pyrazole-3- carboxylate gave 4-((6-chloro-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol as an off-white solid (4 g, 70%). MS (M+l)+=324.2.
[001187] Step 4: The procedure is similar to Step 3[NSSy6917] in Example-21. 2 g of 4-((6-chloro-2-(3-(hydroxymethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) amino) cyclo hexan-1- ol gave 6-chloro-N-(4-fluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4- amine as white gum (0.15 g, 8%). MS (M+l)+=328.0; and 6-chloro-N-(cyclohex-3-en-l-yl)-
2- (3-(fluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine as white gum (0.55 g, 30%). MS (M+l)+=308.0. [001188] Step 5[NSSy5684]: The procedure is similar to Step 1[B] in Example-838. 0.06 g of 6-chloro-N-(4-fluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl) pyrimidin- 4-amine gave N-(4-fluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)-6-morpholinopyrimidin- 4-amine as an off-white solid (0.035 g, 50%). MS (M+l)+=361.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, 2.00 Hz, IH), 6.98 (d, 8.00 Hz, IH), 6.25 (d, 2.40 Hz, IH), 5.52 (s, IH), 4.67-4.53 (m, IH), 3.69-3.67 (m, 4H), 3.50 (m, 4H), 2.17 (s, 3H), 2.03-1.92 (m, 4H), 1.76-1.71 (m, 2H), 1.63-1.57 (m, 3H).
[001189] Step 5A [NSSy5683]: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 6-chloro-N-(cyclohex-3-en-l-yl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4- amine gave N-(cyclohex-3-en- l-yl)-2-(3-methyl- IH-pyrazol- l-yl)-6-morpholinopyrimidin-4- amine as an off-white solid (0.09 g, 38%). MS (M+l)+=341.0; 1H-NMR (400 MHz, DMSO- d6): δ 8.38 (d, J = 2.40 Hz, IH), 6.98 (d, J = 8.00 Hz, IH), 6.25 (d, J = 2.40 Hz, IH), 5.68 (d, J = 14.40 Hz, 2H), 5.54 (s, IH), 3.96 (m, IH), 3.69-3.67 (m, 4H), 3.66 (m, 4H), 2.37-2.33 (m, IH), 2.24 (s, 3H), 2.14-1.97 (m, 2H), 1.90-1.87 (m, 2H), 1.52-1.47 (m, IH).
Example-637:
Figure imgf000460_0001
[001190] Step 1: The procedure is similar to Step 4[NSSy6067] in Example-628. 2 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 5-(4, 6-dichloropyrimidin-2-yl)-3-methyl- 1, 2, 4-thiadiazole as yellow solid (1.32 g, 62%). MS (M+l)+=248.9.
[001191] Step 2: The procedure is similar to Step 1[B] in Example-838. 1 g of 5-(4, 6- dichloropyrimidin-2-yl)-3-methyl-l, 2, 4-thiadiazole gave 6-chloro-N-(4, 4- difluorocyclohexyl)-2-(3-methyl-l, 2, 4-thiadiazol-5-yl) pyrimidin-4-amine as a yellow solid (1.2 g, 85%). MS (M+l)+=346.1.
Figure imgf000461_0001
[001192] Step 3[NSSy6125]: The procedure is similar to Step l[NSSy6629] in
Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.32 (d, J = 7.76 Hz, IH), 5.89 (s, IH), 4.07 (s, 4H), 3.92 (s, IH), 3.19 (s, 4H), 2.65 (s, 3H), 2.13-1.92 (m, 6H), 1.62-1.54 (m, 2H).
[001193] Step 3[NSSy6145]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 7.19 (d, J = 7.60 Hz, IH), 5.36 (s, IH), 4.73 (s, 4H), 4.16 (s, 4H), 3.86 (s, IH), 2.65 (s, 3H), 2.06-1.91 (m, 6H), 1.59-1.52 (m, 2H).
[001194] Step 3[NSSy6178]: The procedure is similar to Step l[NSSy6629] in
Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.27 (d, J = 7.92 Hz, IH), 5.80 (s, IH), 4.55(s, IH), 4.45 (t, J = 8.52 Hz, IH), 4.35 (s, IH), 4.08-4.05 (m, IH), 3.88-3.84 (m, 2H), 3.68 (d, J = 10.80 Hz, IH), 3.09-3.02 (m, IH), 2.94-2.81 (m, 2H), 2.65 (s, 3H), 2.07-1.92 (m, 6H), 1.62-1.56 (m, 2H).
[001195] Step 3[NSSy6251]: The procedure is similar to Step l[NSSy6629] in
Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.26 (d, J = 8.00 Hz, IH), 5.80 (s, IH), 4.54 (s, IH), 4.35-4.25 (m, IH), 4.44 (t, J = 8.40 Hz, IH), 4.08-4.04 (m, IH), 3.91-3.85 (m, 2H), 3.70-3.69 (m, IH), 3.09-3.02 (m, IH), 2.93-2.81 (m, 2H), 2.65 (s, 3H), 2.15-1.85 (m, 6H), 1.62-1.57 (m, 2H).
[001196] Step 3[NSSy6252]: The procedure is similar to Step l[NSSy6629] in
Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.26 (d, J = 7.60 Hz, IH), 5.80 (s, IH), 4.55(s, IH), 4.44 (t, J = 8.40 Hz, IH), 4.33 (s, IH), 4.08-4.04 (m, IH), 3.90-3.86 (m, 2H), 3.57 (d, J = 28.00 Hz, IH), 3.09-3.02 (m, IH), 2.93-2.81 (m, 2H), 2.65 (s, 3H), 2.07-1.92 (m, 6H), 1.62-1.57 (m, 2H).
[001197] Step 3[NSSy5832]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 7.22 (d, J = 8.00 Hz, IH), 5.73 (s, IH), 3.88 (s, IH), 3.70-3.68 (m, 4H), 3.52 (s, 4H), 2.64 (s, 3H), 2.08-2.01 (m, 3H), 1.95-1.92 (m, 3H), 1.60- 1.53 (m, 2H).
[001198] Step 3[NSSy6201]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 7.18 (d, J = 8.04 Hz, IH), 5.74 (s, IH), 4.59-4.56 (m, 2H), 4.50-4.47 (m, 2H), 3.90 (s, IH), 3.57 (s, 4H), 3.46-3.43 (m, IH), 2.65 (s, 3H), 2.35 (s, 4H), 2.06-1.93 (m, 6H), 1.58-1.55 (m, 2H).
[001199] Step 3[NSSy5857]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 7.48 (d, J = 7.52 Hz, IH), 5.95 (s, IH), 5.41-5.36 (m, IH), 4.37-4.33 (m, 2H), 3.96-3.93 (m, 2H), 3.60 (s, 3H), 3.09 (s, IH), 2.67 (s, 3H), 2.10-1.91 (m, 6H), 1.67-1.62 (m, 2H).
Ex m le-638:
Figure imgf000462_0001
[001200] Step 1: The procedure is similar to Step 1[B] in Example-838. 1 g of 5-(4, 6- dichloropyrimidin-2-yl)-3-methyl-l, 2, 4-thiadiazole gave 6-chloro-N-cyclohexyl-2-(3- methyl-1, 2, 4-thiadiazol-5-yl) pyrimidin-4-amine as a white solid (1.05 g, 84%). MS (M+l)+=310.1.
[001201] Step 2[NSSy6202] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. 0.3 g of 6-chloro-N-cyclohexyl-2-(3-methyl-l, 2, 4-thiadiazol-5-yl) pyrimidin-4-amine gave 4-(6-(cyclohexylamino)-2-(3-methyl-l, 2, 4-thiadiazol-5-yl) pyrimidin-4-yl) thiomorpholine 1, 1-dioxide as an off-white solid (0.048 g, 12%). MS (M+l)+=409.6; 1H-NMR (400 MHz, DMSO-d6): δ 7.14 (d, J = 8.00 Hz, 1H), 5.86 (s, 1H), 2.65 (s, 3H), 1.90-1.87 (m, 2H), 1.74-1.71 (m, 2H), 1.62-1.59 (m, 1H), 1.38-1.32 (m, 2H), 1.25-1.19 (m, 3H).
Example-639:
Figure imgf000463_0001
[001202] Step 1: The procedure is similar to Step 3[NSSy6711] in Example-854. 1 g of 4, 6-dichloropyrimidine-2-carboxylic acid gave ethyl 4, 6-dichloropyrimidine-2-carboxylate as green oil (0.9 g, 81%). MS (M+l)+=223.1.
[001203] Step 2: The procedure is similar to Step 1[B] in Example-838. 1 g of ethyl 4, 6-dichloropyrimidine-2-carboxylate gave ethyl 4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carboxylate as colourless gum (0.6 g, 42%). MS (M+l)+=320.0.
[001204] Step 3: The procedure is similar to Step 1[B] in Example-838. 0.25 g of ethyl 4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carboxylate gave ethyl 4-((4, 4- difluorocyclohexyl) amino)-6-morpholinopyrimidine-2-carboxylate as colourless gum (0.17 g, 60%). MS (M+l)+=371.1.
[001205] Step 4[NSSy5835]: The procedure is similar to Step 1[B] in Example-838. 0.17 g of ethyl 4-((4, 4-difluorocyclohexyl) amino)-6-morpholinopyrimidine-2-carboxylate gave N-(4, 4-difluorocyclohexyl)-2-(3-methyl-l, 2, 4-oxadiazol-5-yl)-6- morpholinopyrimidin-4-amine as an off-white solid (0.035 g, 20%). MS (M+l)+=381.2; 1H- NMR (400 MHz, DMSO-d6): δ 7.27-7.25 (m, 1H), 5.77 (s, 1H), 3.89 (s, 1H), 3.69-3.67 (m, 2H), 3.51-3.50 (m, 4H), 2.42-2.41 (m, 3H), 2.05-1.90 (m, 6H), 1.59-1.51 (m, 2H).
Example-640:
Figure imgf000464_0001
[001206] Step l[NSSy5830]: The procedure is similar to Step 1[B] in Example-838. 0.15 g of ethyl 4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carboxylate gave (E)-N-(6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-l, 2, 4-oxadiazol-5-yl) pyrimidin-4- yl)-N'-hydroxyacetimidamide as a white solid (0.06 g, 35%). MS (M+l)+=368.0; IH-NMR (400 MHz, DMSO-d6): δ 7.67 (s, 1H), 6.50-6.42 (m, 3H), 4.11 (s, 1H), 2.42 (s, 3H), 2.04- 1.91 (m, 6H), 1.80 (s, 3H), 1.58-1.55 (m, 2H).
Example-641:
Figure imgf000464_0002
[001207] Step l[NSSy5887]: The procedure is similar to Step 1[B] in Example-838. 0.10 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-l, 2, 4-oxadiazol-5-yl)pyrimidin-
4- amine gave methyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl-l, 2, 4-oxadiazol-
5- yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate as an off-white solid (0.06 g, 50%). MS (M+l)+=425.5; IH-NMR (400 MHz, DMSO-d6): δ 7.91 (s, 1H), 6.11 (s, 1H), 5.36 (s,
2H), 4.32 (s, 1H), 4.11-4.10 (m, 2H), 3.49 (s, 3H), 2.44 (s, 3H), 2.05-1.93 (m, 6H), 1.57-1.54 (m, 2H). Example-642:
Figure imgf000465_0001
[001208] Step 1: The procedure is similar to Step 1[A] in Example-838. 5 g of methyl 2, 6-dichloropyrimidine-4-carboxylate gave methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carboxylate as yellow solid (4.8 g, 66%). MS (M+l)+=306.1.
[001209] Step 2: The procedure is similar to Step 4[NSSy6711] in Example-854. 2 g of methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carboxylate gave (2- chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol as white solid (1.6 g, 88%). MS (M+l)+=278.2.
[001210] Step 3: The procedure is similar to Step 5[NSSy6711] in Example-854. 1.1 g (2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol gave 2-chloro-N-(4, 4-difluorocyclohexyl)-6-(methoxymethyl) pyrimidin-4-amine as a colourless gum (0.77 g, 46%). MS (M+l)+=292.1.
[001211] Step 4: The procedure is similar to Step l[NSSy6710] in Example-854. 0.38 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-(methoxymethyl) pyrimidin-4-amine gave 4-((4, 4- difluorocyclohexyl) amino)-6-(methoxymethyl) pyrimidine-2-carbonitrile as brown gum (0.3, 75%). MS (M+l)+=283.0.
[001212] Step 5: To a cooled solution of 4-((4, 4-difluorocyclohexyl)amino)-6- (methoxymethyl)pyrimidine-2-carbonitrile (0.4 g, 1.41 mmol) in N, N-dimethylformamide (5 mL) was added triethylamine (0.286 g, 2.83 mmol) and ammonium sulphide in water (20%) (0.96 g, 2.83 mmol) and stirred at room temperature. After 15 min, the reaction mixture was quenched with water and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford 4-((4, 4- difluorocyclohexyl) amino)-6-(methoxymethyl) pyrimidine-2-carbothioamide as a light brown solid (0.25 g, 55%). MS (M+l)+=317.0. [001213] Step 6[NSSy5779] : To a solution of 4-((4, 4-difluorocyclohexyl) amino)-6- (methoxymethyl) pyrimidine-2-carbothioamide (0.25 g, 0.79 mmol) in ethanol (10 mL) was added bromoacetone (0.129 g, 0.94 mmol). The reaction mixture was stirred at room temperature in a closed vial for 16h. The reaction mixture was concentrated and the resulting residue was quenched with saturated bi-carbonate solution, extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford crude product, which was purified by column chromatography (60-120 mesh silica gel), using 80% ethyl acetate in pet ether as eluent to afford N-(4, 4- difluorocyclohexyl)-6-(methoxymethyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine as an off-white solid (0.051 g, 18%). MS (M+l)+=355.0; IH-NMR (400 MHz, DMSO-d6): δ 7.63 (s, 1H), 7.39 (s, 1H), 6.52 (s, 1H), 4.34 (s, 2H), 4.10 (m, 1H), 4.10 (s, 3H), 2.32 (s, 3H), 1.97- 1.77 (m, 6H), 1.61-1.56 (m, 2H).
Example-
Figure imgf000466_0001
Table-30: Step 1:
Figure imgf000466_0002
[001214] Step l[NSSy5818]: n-Butyl lithium (1.6M, 1.1 mL) was added drop wise to a stirred solution of 4-methyl oxazole (0.12 g, 1.44 mmol) in THF (2 mL) at -78 °C. After 10 min, a solution of Zinc chloride (0.5 mol, 8.89 mL) was added dropwise. The reaction mixture was stirred for 15 min at -78 °C then the reaction mixture was warmed to room temperature. The reaction mixture was added to a microwave vial containing the 2-chloro-N- (4, 4-difluorocyclohexyl)-6-(methoxymethyl) pyrimidin-4-amine (0.22 g, 0.75 mmol) and Tetrakis (triphenylphosphine) palladium (0) (0.08 g, 0.075 mmol) under nitrogen atmosphere. The reaction mixture was irradiated under microwave at 80 °C. After 2h, the reaction mixture was filtered and the filtrate was quenched with water and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude product, which was purified by column chromatography using 70% ethyl acetate in pet ether as a eluent to afford N-(4, 4-difluorocyclohexyl)-6-(methoxymethyl)-2-(4- methyloxazol-2-yl)pyrimidin-4-amine as an light brownish gum (0.0017 g, 17%). MS (M+l)+=339.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.94 (d, J = 1.20 Hz, 1H), 7.65 (s, 1H),
6.57 (s, 1H), 4.34 (s, 2H), 4.17 (m, 1H), 3.40 (s, 3H), 2.17 (s, 3H), 2.06-1.95 (m, 6H), 1.63-
1.58 (m, 2H).
[001215] Step 1 [NSSy7001] : The procedure is similar to Step 1 [NSSy6909] in
Example-839. 0.77 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-(methoxymethyl) pyrimidin- 4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6- (methoxymethyl) pyrimidin-4-amine as a white solid (0.4 g, 42%). MS (M+l)+=364.2; 1H- NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.67 (s, 1H), 6.39 (s, 1H), 6.19 (s, 1H), 4.30 (s, 2H), 4.15 (s, 1H), 3.32 (s, 3H), 2.07-1.94 (m, 7H), 1.65-1.55 (m, 2H), 0.93-0.90 (m, 2H), 0.74-0.70 (m, 2H).
Example-644:
Figure imgf000467_0001
NSSy6881
[001216] Step 1: The procedure is similar to Step l[NSSy6930] in Example-867. 0.85 g of (2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol gave 2-chloro-6- ((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carbaldehyde as an off-white solid (0.6 g, 70%). MS (M+l)+=276.0.
[001217] Step 2: The procedure is similar to Step 4[NSSy6464] in Example-869. 0.6 g of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carbaldehyde gave l-(2-chloro- 6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-ol as a white solid (0.2 g, 31%). MS (M+l)+=292.0.
[001218] Step 3[NSSy6881]: The procedure is similar to Step 1[B] in Example-838. 0.15 g of l-(2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-ol gave 1- (2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-ol as an off-white solid (0.06 g, 32%). MS (M+l)+=364.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.67 (d, J = 17.60 Hz, 1H), 6.51 (s, 1H), 6.18 (d, J = 2.40 Hz, 1H), 5.36 (d, J = 4.00 Hz, 1H), 4.49-4.47 (m, 1H), 4.16 (d, J = 9.20 Hz, 1H), 2.06-1.97 (m, 6H), 1.59-1.57 (m, 2H), 1.35-1.24 (m, 3H), 0.94-0.92 (m, 2H), 0.82-0.80 (m, 2H).
Example-645:
Figure imgf000468_0001
[001219] Step 1: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 4 g of thiazole-2-carboximidamide gave 2-(thiazol-2-yl) pyrimidine-4, 6-diol as an off-white solid (3.6 g, 58%). MS (M+l)+=196.0.
[001220] Step 2: To a suspension of 2-(thiazol-2-yl)pyrimidine-4, 6-diol (3.5 g, 17.93 mmol) in Phosphorus oxychloride (13.19 g, 86.06 mmol) was added N, N-Diethylaniline (4.6 g, 30.48 mmol) at 0 °C and the reaction mixture was heated at 95 °C for 2.5h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL), slowly added to an ice cooled saturated sodium bi-carbonate solution and stirred for 10 min, extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(4, 6-dichloropyrimidin-2-yl) thiazole, as a brown solid (3.0 g, 72.11%). MS (M+l)+=233.0.
[001221] Step 3: The procedure is similar to Step 1[B] in Example-838. 2 g of 2-(4, 6- dichloropyrimidin-2-yl) thiazole gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(thiazol-2-yl) pyrimidin-4-amine as an off-white solid (2.2 g, 79%). MS (M+l)+=331.0.
Figure imgf000469_0002
[001222] Step 4[NSSy6167]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 2.96 Hz, 1H), 7.90 (d, J = 3.12 Hz, 1H), 7.63-7.57 (m, 1H), 5.86 (s, 1H), 5.69 (d, J = 6.52 Hz, 1H), 5.36 (s, 1H), 4.42-4.35 (m, 2H), 4.11-4.05 (m, 2H), 3.59 (s, 3H), 2.07-1.93 (m, 6H), 1.59-1.57 (m, 2H).
[001223] Step 4[NSSy6152]: The procedure is similar to Step 1[B] in Example-838. 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 1.24 Hz, 1H), 7.81 (d, J = 1.24 Hz, 1H), 7.06 (d, J = 7.80 Hz, 1H), 5.68 (s, 1H), 4.01-3.92 (m, 1H), 3.70-3.69 (m, 4H), 3.41-3.34 (m, 4H), 2.09-1.93 (m, 6H), 1.59-1.56 (m, 2H).
Example-646:
Figure imgf000469_0001
[001224] Step 1: The procedure is similar to Step 1[A] in Example-838. 1 g of 2-(4, 6- dichloropyrimidin-2-yl) thiazole gave 6-chloro-N-cyclohexyl-2-(thiazol-2-yl) pyrimidin-4- amine as an off-white solid (1 g, 83%). MS (M+l)+=295.0.
[001225] Step 2[NSSy6166]: The procedure is similar to Step 1[B] in Example-838. 1 g of 6-chloro-N-cyclohexyl-2-(thiazol-2-yl) pyrimidin-4-amine gave methyl 3-((6- (cyclohexylamino)-2-(thiazol-2-yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off- white gum (1 g, 76%). MS (M+l)+=390.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.99 (d, J = 3.08 Hz, 1H), 7.88 (d, J = 3.04 Hz, 1H), 7.42 (s, 1H), 5.81 (s, 1H), 5.35 (s, 1H), 4.35 (m, 3H), 3.94 (m, 2H), 3.54 (s, 3H), 1.74-1.71 (m, 2H), 1.59 (m, 2H), 1.37-1.34 (m, 1H), 1.31-1.20 (m, 5H). [001226] Step 3[NSSy6170]: To a solution of methyl 3-((6-(cyclohexylamino)-2- (thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate (0.03 g, 0.07 mmol) in carbon tetrachloride ( 3 mL) was added 2, 2-Azobisisobutyronltrile (AIBN) (0.001 g, 0.007 mmol) followed by N-Bromosuccinimide (0.013 g, 0.07 mmol) and the reaction mixture was heated at 70 °C. After 2h, the reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layer was dried over sodium sulfate, filtered and concentrated to afford crude product, which was purified by column chromatography using 55% ethyl acetate in pet ether as eluent to afford methyl 3-((5-bromo-6-(cyclohexylamino)-2- (thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate as an off-white solid (0.15 g, 62%). MS (M, M+2)+=468.0 and 470.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.01 (d, J = 3.20 Hz, 1H), 7.92 (d, J = 3.20 Hz, 1H), 6.75 (d, J = 8.00 Hz, 1H), 5.45-5.40 (m, 1H), 4.40-4.36 (m, 1H), 4.06-3.97 (m, 3H), 2.16 (s, 3H), 1.89-1.86 (m, 2H), 1.78-1.75 (m, 2H), 1.66-1.62 (m, 2H), 1.49-1.29 (m, 4H), 1.20-1.14 (m, 1H).
Example-647:
Figure imgf000470_0001
[001227] Step 1: The Procedure is similar to Step 1[A] in Example-838. 1.5 g of thiazole-2-carboximidamide gave 6-((4, 4-difluorocyclohexyl) methyl)-2-(4-methylthiazol-2- yl) pyrimidin-4-ol as an off-white solid (0.15 g, 5%). MS (M+l)=326.1.
[001228] Step 2: To an ice cooled solution of 6-((4, 4-difluorocyclohexyl)methyl)-2-(4- methylthiazol-2-yl)pyrimidin-4-ol (0.15 g, 0.461 mmol) in Phosphorus oxychloride (0.35 g, 2.3 mmol) was added N, N-Diethylaniline (0.11 g, 0.78 mmol) and the reaction mixture was heated at 90 °C for 2h. The reaction mixture was diluted with ethyl acetate and poured into ice cold bicarbonate solution, it was allowed to keep 5 min, extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(4-chloro-6-((4, 4- difluorocyclohexyl) methyl) pyrimidin-2-yl)-4-methylthiazole as a brown gum (0.15 g, 94%). MS (M+l)+=344.5.
[001229] Step 3[NSSy6263]: The Procedure is similar to Step 1[B] in Example-838. 0.1 g of 2-(4-chloro-6-((4, 4-difluorocyclohexyl)methyl)pyrimidin-2-yl)-4-methylthiazole gave 4-(6-((4, 4-difluorocyclohexyl)methyl)-2-(4-methylthiazol-2-yl)pyrimidin-4- yl)morpholine as an off-white solid (0.044 g, 40%). MS (M+l)+=395.2; IH-NMR (400 MHz, DMSO-d6-80 °C): δ 7.41 (s, 1H), 6.74 (s, 1H), 3.70-3.33 (m, 8H), 2.67-2.51 (m, 2H), 2.00- 1.94 (m, 4H), 1.83-1.74 (m, 4H), 1.28-1.24 (m, 3H).
Example-648:
Figure imgf000471_0001
[001230] Step 1: The procedure is similar to Step 3 [INI 1237-001-Pl] in Example-614. 1 g of 5-methylfuran-2-carbonitrile gave 5-methylfuran-2-carboximidamide as a white solid (1.5 g, crude). MS (M+l)+=125.1.
[001231] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 1 g of 5-methylfuran-2-carboximidamide gave 2-(5-methylfuran-2-yl) pyrimidine-4, 6-diol as an off-white solid (0.7 g, crude). MS (M+ 1)4= 193.0.
[001232] Step 3: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1.1 g of 2-(5-methylfuran-2-yl) pyrimidine-4, 6-diol gave 4, 6-dichloro-2-(5-methylfuran-2- yl) pyrimidine as brownish gum (1 g, 76%). MS (M+l)+=229.
[001233] Step 4: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 4, 6- dichloro-2-(5-methylfuran-2-yl) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(5- methylfuran-2-yl) pyrimidin-4-amine as an off-white solid (0.42 g, 58%). MS (M+l)+=328.
[001234] Step 5: The procedure is similar to Step 1[H] in Example-838. 0.22 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(5-methylfuran-2-yl) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(5-methylfuran-2-yl) pyrimidin-4-amine as an off- white solid (0.16 g, crude). MS (M+l)+=364.2.
[001235] Step 6: The procedure is similar to Step l[NSSy6697] in Example-873. 0.16 g of N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(5-methylfuran-2-yl) pyrimidin-4-amine gave l-(6-((4, 4-difluorocyclohexyl) amino)-2-(5-methylfuran-2-yl) pyrimidin-4-yl) ethan-1- one as an off-white solid (0.08 g, 54%). MS (M+l)+=336.2.
[001236] Step 7[IN10971-088-Pl]: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.08 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(5-methylfuran-2-yl) pyrimidin-4-yl) ethan-l-one gave l-(6-((4, 4-difluorocyclohexyl) amino)-2-(5-methylfuran-2- yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (0.05 g, 62%). MS (M+l)+=338.2; 1H- NMR (400 MHz, MeOD): δ 7.08 (d, J = 4.40 Hz, 1H), 6.46 (s, 1H), 6.18 (d, J = 2.80 Hz, 1H), 4.63 (q, J = 6.80 Hz, 1H), 4.08 (s, 1H), 2.39 (s, 3H), 2.15-1.85 (m, 6H), 1.70-1.60 (m, 2H), 1.50-1.49 (m, 3H).
Example-649:
Figure imgf000472_0001
[001237] Step 1 [IN 10971-077-P1] : The procedure is similar to Step 1 [B] in Example- 838. 0.2 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(5-methylfuran-2-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-2-(5-methylfuran-2-yl)-6-morpholinopyrimidin-4- amine as a white solid (0.14 g, 60%). MS (M+l)+=379; 1H-NMR (400 MHz, MeOD): δ 6.99 (d, J = 3.20 Hz, 1H), 6.14 (s, 1H), 5.52 (s, 1H), 3.88 (s, 1H), 3.76-3.74 (m, 4H), 3.56-3.54 (m, 4H), 2.36 (s, 3H), 2.15-1.90 (m, 6H), 1.65-1.55 (m, 2H).
Example-650:
Figure imgf000472_0002
Figure imgf000472_0003
[001238] Step 1: The procedure is similar to Step 3 [INI 1237-001-Pl] in Example-614. 1 g of furan-2-carbonitrile gave furan-2-carboximidamide as a white solid (1.5 g, crude). MS (M+l)+=l l l. l. [001239] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.8 g of furan-2-carboximidamide gave 2-(furan-2-yl) pyrimidine-4, 6-diol as an off-white solid (0.6 g, crude). MS (M+l)+=179.1.
[001240] Step 3: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.6 g of 2-(furan-2-yl) pyrimidine-4, 6-diol gave 4, 6-dichloro-2-(furan-2-yl) pyrimidine as a light brown solid (0.4 g, 55%). MS (M+l)+=216.9.
[001241] Step 4: The procedure is similar to Step 1[B] in Example-838. 0.4 g of 4, 6- dichloro-2-(furan-2-yl) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(furan-2-yl) pyrimidin-4-amine as an off-white solid (0.4 g, 54%). MS (M+l)+=314.
[001242] Step 5[IN10971-060-P1] : The procedure is similar to Step 1 [B] in Example- 838. 0.4 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(furan-2-yl) pyrimidin-4-amine gave N- (4, 4-difluorocyclohexyl)-2-(furan-2-yl)-6-morpholinopyrimidin-4-amine as a white solid (0.35 g, 75%). MS (M+l)+=365.1; 1H-NMR (400 MHz, CD30D): δ 7.60 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 3.2 Hz, 1H), 6.53 (d, J = 3.4 Hz, 1H), 5.54 (s, 1H), 3.92-3.90 (m, 1H), 3.76-3.74 (m, 4H), 3.57-3.55 (m, 4H), 2.12-1.87 (m, 6H), 1.66-1.58 (m, 2H).
Example-651:
Figure imgf000473_0001
[001243] Step 1: To an ice cooled solution of lH-pyrrole-2-carbonitrile (0.5 g, 5.42 mmol) in ethanol (5 mL) was purged with dry HCI gas for 2h. The reaction mixture was slowly warmed to rt and stirred at rt in a closed condition for 3 days. The reaction mixture was concentrated and the resulting residue was triturated with diethyl ether to afford ethyl lH-pyrrole-2-carbimidate as a grey solid (0.8 g, crude). MS (M+l)+=139.1.
[001244] Step 2: In a 100 mL sealed tube was charged with ethyl lH-pyrrole-2- carbimidate (0.7 g, 6.41 mmol) and 30 mL of ammonia in methanol at 0 °C. The sealed tube cap was fixed tightly and stirred at rt for 2 days. The reaction mixture was concentrated under vacuum to afford lH-pyrrole-2-carboximidamide as a brown solid (0.55 g, crude). MS (M+l)+=110.1. [001245] Step 3: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.7 g of lH-pyrrole-2-carboximidamide gave 2-(lH-pyrrol-2-yl) pyrimidine-4, 6-diol as an off-white solid (0.55 g, crude). MS (M+l)+=178.1.
[001246] Step 4: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.3 g of 2-(lH-pyrrol-2-yl) pyrimidine-4, 6-diol gave 4, 6-dichloro-2-(lH-pyrrol-2-yl) pyrimidine as brownish gum (0.12 g, 33%). MS (M+l)+=215.
[001247] Step 5: The procedure is similar to Step 2[IN11218-026-P1] in Example-613. 0.12 g of 4, 6-dichloro-2-(lH-pyrrol-2-yl) pyrimidine gave tert-butyl 2-(4, 6- dichloropyrimidin-2-yl)-lH-pyrrole-l-carboxylate as an off-white solid (0.2 g). MS
(M+l)+=315.
[001248] Step 6: The procedure is similar to Step 1[B] in Example-838. 0.2 g of tert- butyl 2-(4, 6-dichloropyrimidin-2-yl)-lH-pyrrole-l-carboxylate gave tert-butyl 2-(4-chloro-6- ((4, 4-difluorocyclohexyl) amino) pyrimidin-2-yl)-lH-pyrrole-l-carboxylate as an off-white solid (0.2 g). MS (M+l)+=413.4.
[001249] Step 7: The procedure is similar to Step 1[B] in Example-838. 0.2 g of tert- butyl 2-(4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-2-yl)-lH-pyrrole-l- carboxylate gave tert-butyl 2-(4-((4, 4-difluorocyclohexyl) amino)-6-morpholinopyrimidin-2- yl)-lH-pyrrole-l-carboxylate as a light yellow solid (0.11 g, Crude). MS (M+l)+=464.2.
[001250] Step 8[IN11030-023-P1]: The procedure is similar to Step 5[NSSy6067] in Example-628. 0.1 g of tert-butyl 2-(4-((4, 4-difluorocyclohexyl) amino)-6- morpholinopyrimidin-2-yl)-lH-pyrrole-l-carboxylate gave N-(4, 4-difluorocyclohexyl)-6- morpholino-2-(lH-pyrrol-2-yl) pyrimidin-4-amine as an off-white solid (0.022 g, 22%). MS (M+l)+=364.2; IH-NMR (400 MHz, DMSO-d6): δ 6.83 (s, IH), 6.70 (s, IH), 6.50 (s, IH), 6.08 (d, J = 2.40 Hz, IH), 5.43 (s, IH), 4.02 (s, IH), 3.68 (s, 4H), 3.49 (s, 4H), 2.10-1.85 (m, 6H), 1.58-1.48 (m, 2H).
Example-652:
Figure imgf000475_0001
[001251] Step 1 : The procedure is similar to Step 1 [INI 1030-023-P1] in Example-651. 2 g of 5-methyl-lH-pyrrole-2-carbonitrile gave ethyl 5-methyl-lH-pyrrole-2-carbimidate as an off-white solid (2.2 g, crude). MS (M+ 1)4= 153.2.
[001252] Step 2: The procedure is similar to Step 2[IN11030-023-P1] in Example-651. 2.2 g of ethyl 5-methyl-lH-pyrrole-2-carbimidate gave 5-methyl-lH-pyrrole-2- carboximidamide as an off-white solid (2.5 g, crude). MS (M+l)+=124.2.
[001253] Step 3: The procedure is similar to Step l[IN10966-057-P2] in Example-893. 1.2 g of 5-methyl-lH-pyrrole-2-carboximidamide gave 2-(5-methyl-lH-pyrrol-2-yl) pyrimidine-4, 6-diol as an off-white solid (1.4 g, crude). MS (M+l)+= 192.2.
[001254] Step 4: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1.4 g of 2-(5-methyl-lH-pyrrol-2-yl) pyrimidine-4, 6-diol gave 4, 6-dichloro-2-(5-methyl- lH-pyrrol-2-yl) pyrimidine as a light brown solid (0.7 g, crude). MS (M+l)+=228.1.
[001255] Step 5: The procedure is similar to Step 1[B] in Example-838. 0.3 g of 4, 6- dichloro-2-(5-methyl-lH-pyrrol-2-yl) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)- 2-(5-methyl-lH-pyrrol-2-yl) pyrimidin-4-amine as an off-white solid (0.25 g, 80%). MS (M+l)+=327.1.
[001256] Step 6[IN11196-081-Pl]: The procedure is similar to Step 1[B] in Example- 838. 0.1 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(5-methyl-lH-pyrrol-2-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-2-(5-methyl-lH-pyrrol-2-yl)-6-morpholino pyrimidin-4-amine as an off-white solid (0.025 g, 21%). MS (M+l)+=378.2; IH-NMR (400 MHz, DMSO-d6): δ 10.70 (s, IH), 6.59 (t, J = 2.40 Hz, IH), 6.54 (d, J = 7.60 Hz, IH), 5.78 (s, IH), 5.40 (s, IH), 4.01 (s, IH), 3.68 (s, 4H), 3.50 (s, 4H), 2.25 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.48 (m, 2H). Example-653:
[001257] Intentionally Omitted
Example-654:
Figure imgf000476_0001
Step l Step 2 HO N "^\ _ STEP 3 CI ^N '
Figure imgf000476_0002
[001258] Step 1: The procedure is similar to Step 3 [INI 1237-001-Pl] in Example-614.
2 g of 1, 5-dimethyl-lH-pyrrole-2-carbonitrile gave 1, 5-dimethyl-lH-pyrrole-2- carboximidamide as an off-white solid (3 g, crude). MS (M+l)+=138.2.
[001259] Step 2: The procedure is similar to Step l[IN10966-057-P2] in Example-893.
3 g of 1, 5-dimethyl-lH-pyrrole-2-carboximidamide gave 2-(l, 5-dimethyl-lH-pyrrol-2-yl) pyrimidine-4, 6-diol as an off-white solid (3 g, 84%). MS (M+l)+=206.
[001260] Step 3: The procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1 g of 2-(l, 5-dimethyl-lH-pyrrol-2-yl) pyrimidine-4, 6-diol gave 4, 6-dichloro-2-(l, 5- dimethyl-lH-pyrrol-2-yl) pyrimidine as a light brown solid (0.7 g, 59%). MS (M+l)+=241.9.
[001261] Step 4: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 4, 6- dichloro-2-(l, 5-dimethyl-lH-pyrrol-2-yl) pyrimidine gave 6-chloro-N-(4, 4-difluoro cyclohexyl)-2-(l, 5-dimethyl-lH-pyrrol-2-yl) pyrimidin-4-amine as an off-white solid (0.4 g, 56%). MS (M+l)+=341.
[001262] Step 5[IN10971-059-Pl]: The procedure is similar to Step 1[B] in Example- 838. 0.4 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(l, 5-dimethyl-lH-pyrrol-2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(l, 5-dimethyl-lH-pyrrol-2-yl)-6- morpholino pyrimidin-4-amine as an off-white solid (0.25 g, 54%). MS (M+l)+=392.1; 1H- NMR (400 MHz, MeOD): δ 6.86 (d, J = 4.00 Hz, 1H), 5.96 (d, J = 4.00 Hz, 1H), 5.57 (s, 1H), 3.88 (s, 4H), 3.78-3.71 (m, 4H), 3.65 (s, 4H), 2.28 (s, 3H), 2.13-1.95 (m, 6H), 1.70-1.64 (m, 3H).
Figure imgf000477_0001
Figure imgf000478_0001
Figure imgf000479_0001
[001263] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 2 g of 4-methylthiazole-2-carboximidamide gave 2-(4-methylthiazol-2-yl) pyrimidine-4, 6- diol as an off-white solid (2.3 g, 97%). MS (M+l)+=210.1
[001264] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893.
0.5 g of 2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol gave 2-(4, 6-dichloropyrimidin-2-yl)-4- methylthiazole as a light brown solid (0.45 g, 77%). MS (M+l)+=246.0, 248.0.
[001265] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.20 g of 2-(4,
6-dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.27 g, 96%). MS
(M+l)+=345.1.
Figure imgf000480_0001
Figure imgf000481_0001
Figure imgf000482_0001
Figure imgf000483_0001
Figure imgf000484_0001
1,4-Dioxane, 110 °C, 16h
[001266] Step 4[NSSy5774]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=451.1; IH-NMR (400 MHz, DMSO-d6): δ 7.36 (s, IH), 7.10 (s. IH), 5.73 (s, IH), 4.57-4.55 (m, IH), 4.46-4.44 (m, IH), 4.42 (s, IH), 4.07-4.04 (m, IH), 3.90 (s, 2H), 3.69 (s, IH), 3.04-3.01(m, IH), 2.90-2.77 (m, 2 H), 2.42 (s, 3H), 2.07-1.92 (m, 6H), 1.61-1.56 (m, 2H).
[001267] Step 4[NSSy5787]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=450.0; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (d, J = 0.96 Hz, IH), 6.93 (d, J = 7.88 Hz, IH), 5.66 (s, IH), 4.63-4.60 (m, 2H), 4.39-4.33 (m, 4H), 3.92 (m, IH), 2.86-2.81 (m, 2H), 2.75-2.71 (m, IH), 2.42 (s, 3H), 2.08-2.00 (m, 3H), 1.94-1.91 (m, 4H), 1.67-1.64 (m, 2H), 1.60-1.52 (m, 2H), 1.04-0.94 (m, 2H).
[001268] Step 4[NSSy5789]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=440.0; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 7.04 (s, IH), 5.66 (s, IH), 4.09-4.06 (m, 2H), 3.95-3.92 (m, 2H), 3.62-3.39 (m, 4H), 3.29 (s, 3H), 2.91 (s, IH), 2.67- 2.64 (m, IH), 2.41 (s, 3H), 2.07-1.91 (m, 6H), 1.60-1.54 (m, 2H) and isomers was separated by Chiral HPLC to afford [NSSy5796]. MS (M+l)+=440.0; IH-NMR (400 MHz, DMSO- d6): δ 7.33 (s, IH), 7.04 (s, IH), 5.66 (s, IH), 4.09-4.06 (m, 2H), 3.95-3.92 (m, 2H), 3.62- 3.39 (m, 4H), 3.29 (s, 3H), 2.91(s, IH), 2.67-2.64 (m, IH), 2.41 (s, 3H), 2.07-1.91 (m, 6H), 1.60-1.54 (m, 2H) and [NSSy5795]. MS (M+l)+=440.0; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 7.04 (s, IH), 5.66 (s, IH), 4.09-4.06 (m, 2H), 3.95-3.92 (m, 2H), 3.62-3.39 (m, 4H), 3.29 (s, 3H), 2.91(s, IH), 2.67-2.64 (m, IH), 2.41 (s, 3H), 2.07-1.91 (m, 6H), 1.60-
1.54 (m, 2H).
[001269] Step 4[NSSy6055] : The Procedure is similar to Step 1 [NSSy6909] in
Example-839. MS (M+l)+=437.0; IH-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.06 (d, = 8.04 Hz, IH), 5.67 (s, IH), 3.91 (s, IH), 3.61 (s, 2H), 3.54-3.50 (m, 4H), 2.43 (s, 3H), 2.30-1.80 (m, 9H), 1.60-1.50 (m, 2H).
[001270] Step 4[NSSy6062] : The Procedure is similar to Step 1 [NSSy6629] in
Example-839. MS (M+l)+=444.0; IH-NMR (400 MHz, DMSO-d6): δ 7.36 (s, IH), 7.15 (d, = 8.0 Hz, IH), 5.82 (s, IH), 4.07-4.01 (m, 4H), 3.89 (s, IH), 3.18-3.16 (m, 4H), 2.42 (s, 3H), 2.20-1.80 (m, 6H), 1.60-1.40 (m, 2H).
[001271] Step 4[NSSy6093]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=423.4; IH-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.09 (s, IH), 5.66 (s, IH), 4.09 (s, 2H), 3.86-3.84 (m, 3H), 3.44-3.42(m, 2H), 2.90 (s, 3H), 2.42 (s, 3H), 2.06-1.92 (m, 6H), 1.58-1.55 (m, 2H).
[001272] Step 4[NSSy6116]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=408.2; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (d, J = 0.80 Hz, IH), 6.97 (d, J = 7.60 Hz, IH), 5.40 (s, IH), 4.96-4.95 (m, IH), 4.69 (s, IH), 3.87-3.79 (m, IH), 3.79-3.65 (m, IH), 3.43-3.31 (m, IH), 3.24-3.17 (m, IH), 2.50 (s, 3H), 2.09-1.92 (m, 7H), 1.87-1.80 (m, 2H), 1.61-1.55 (m, 2H).
[001273] Step 4[NSSy6129]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=422.2; IH-NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 0.80 Hz, IH), 7.01 (d, J = 7.80 Hz, IH), 5.57 (s, IH), 4.44 (s, 2H), 3.88-3.86 (m, 2H), 3.01-2.97 (m, 2H), 2.42 (s, 3H), 2.08-1.94 (m, 3H), 1.92-1.70 (m, 8H), 1.61-1.51 (m, 2H).
[001274] Step 4[NSSy5792]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=451.0; IH-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.01 (d, J = 7.76 Hz, IH), 5.67 (s, IH), 4.59-4.56 (m, 2H), 4.50-4.47 (m, 2H), 3.90-3.88 (m, IH), 3.56 (m, 4H), 3.43 (t, J = 5.68 Hz, IH), 2.34 (s, 3H), 2.08-2.06 (m, 4H), 2.00-1.92 (m, 6H), 1.60-1.55 (m, 2H).
[001275] Step 4[NSSy6171]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=408.1; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.98 (d, J = 8.0 Hz, IH), 5.39 (s, IH), 4.95 (s, IH), 4.68 (s, IH), 3.90 (s, IH), 3.86 (d, J = 16.0 Hz, IH), 3.79 (d, J = 8.0 Hz, IH), 3.35 (bs, IH), 3.21 (s, IH), 2.08 (s, 3H), 2.06-1.91 (m, 6H), 1.86 (s, 2H) 1.57-
1.55 (m, 2H).
[001276] Step 4[NSSy6111]: The Procedure is similar to Step l[NSSy6629] in
Example-839. MS (M+l)+=427.2; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.18 (d, J = 8.0 Hz, 1H), 6.27 (s, 2H), 5.69 (s, 1H), 4.05 (s, 4H), 3.98 (s, 1H), 3.17-3.16 (m, 4H), 2.24 (s, 3H), 2.08-1.90 (m, 6H), 1.57-1.54 (m, 2H).
[001277] Step 4[NSSy5740]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=411.2; IH-NMR (400 MHz, DMSO-d6): δ 7.43 (s, 1H), 7.40 (s, 1H), 5.77 (s, 1H), 5.15 (s, 1H), 4.72 (s, 1H), 4.02 (s, 1H), 2.55-2.50 (m, 2H), 2.42 (s, 3H), 2.15-2.10 (m, 2H), 2.07-1.93 (m, 6H), 1.58-1.55 (m, 2H), 1.27 (s, 3H).
[001278] Step 4[NSSy6253]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=459.2; IH-NMR (400 MHz, DMSO-d6): δ 7.35 (s, 1H), 7.22 (d, J = 7.20 Hz, 1H),
5.89 (s, 1H), 5.38-5.34 (m, 1H), 3.23-3.12 (m, 4H), 2.45 (s, 3H), 2.37-2.31 (m, 4H), 2.15-
1.90 (m, 6H), 1.66-1.60 (m, 2H).
[001279] Step 4[NSSy5730]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=468.2; IH-NMR (400 MHz, DMSO-d6): δ 7.45 (s, 2H), 5.78 (s, 1H), 4.81 (s, 1H), 4.24 (bs, 1H), 3.59 (s, 3H), 2.81 (s, 3H), 2.54 (bs, 1H), 2.39 (s, 3H), 2.32-2.18 (m, 1H), 2.05-1.92 (m, 6H), 1.59-1.57 (m, 2H).
[001280] Step 4[NSSy6007] : The Procedure is similar to Step 1 [NSSy5828] in
Example-799. MS (M+l)+=448.0; IH-NMR (400 MHz, DMSO-d6): δ 7.91 (s, 1H), 7.51 (bs, 1H), 7.46 (s, 1H), 6.34 (s, 1H), 5.82 (s, 1H), 4.59-4.54 (m, 1H), 4.32-4.25 (m, 1H), 2.46 (s, 3H), 2.30-1.80 (m, 11H), 1.60-1.50 (m, 2H).
[001281] Step 4[NSSy6258]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=452.0; IH-NMR (400 MHz, DMSO-d6): δ 7.42 (d, J = 0.80 Hz, 2H), 5.82 (s, 1H), 5.24 (s, 1H), 3.84-3.81 (m, 1H), 3.70-3.66 (m, 1H), 3.31 (s, 1H), 3.28-3.26 (m, 2H), 2.43 (s, 3H), 2.03-1.93 (m, 11H), 1.58-1.56 (m, 4H).
[001282] Step 4[NSSy6056] : To a stirred solution of 6-chloro-N-(4, 4- difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine (0.25 g, 0.725 mmol) in methanol (5 mL) was added 10% palladium on carbon and the reaction mixture was heated at 50 °C for 6h. The reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure to afford crude
and which was purified by column chromatography using 75% ethyl acetate in pet ether as solvent to afford N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine as an off-white solid (135 mg, 28%). MS (M+l)+=311.0; IH-NMR (400 MHz, DMSO-d6): δ 8.15 (d, J = 6.00 Hz, 1H), 7.32 (s, 1H), 6.51 (d, J = 6.00 Hz, 1H), 4.02 (s, 2H), 2.45 (s, 3H), 2.12-1.93 (m, 6H), 1.71-1.65 (m, 2H).
[001283] Step 4[IN10882-020-Pl] : The Procedure is similar to Step 1 [B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.31 (s, 1H), 6.85 (d, J = 7.60 Hz, 1H), 5.34 (s, 1H), 4.71 (t, J = 5.20 Hz, IH), 3.90 (s, IH), 3.60-3.35 (m, 5H), 3.90 (s, IH), 2.41 (s, 4H), 2.15- 1.85 (m, 7H), 1.72 (m, IH), 1.62-1.50 (m, 2H).
[001284] Step 4[IN10882-014-P1]: The Procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.89 (d, J = 7.60 Hz, IH), 5.35 (s, IH),
3.88 (s, IH), 3.40 (s, 4H), 2.41 (s, 3H), 2.50-2.00 (m, 2H), 1.95-1.85 (m, 8H), 1.60-1.50 (m, 2H).
[001285] Step 4[IN11030-032-P1]: The Procedure is similar to Step l[NSSy6629] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), 7.35 (s, IH), 5.94 (s, IH), 4.50-4.35 (m, 4H), 2.50 (s, 4H), 2.18-2.09 (m, 6H), 1.65-1.52 (m, 2H).
[001286] Step 4[IN11055-015-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 2H), 5.80 (s, IH), 4.32 (q, J = 7.60 Hz, 2H), 3.80 (s, IH), 2.43 (s, 3H), 2.15-1.85 (m, 6H), 1.60-1.50 (m, 2H), 1.32 (t, J = 6.80 Hz, 3H).
[001287] Step 4[IN10864-066-Pl]: The Procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz,CD30D): δ 7.21 (s, IH), 5.65 (s, IH), 4.40-4.20 (m, 2H), 4.10 (s, IH), 3.79 (dd, J = 3.20, 11.40 Hz, IH), 3.65 (dd, J = 5.60, 11.60 Hz, IH), 3.15-3.05 (m, IH), 3.00-2.88 (m, 2H), 2.50 (s, 3H), 2.49 (s, 4H), 2.36 (s, IH), 2.15-1.85 (m, 7H), 1.68-1.55 (m, 2H).
[001288] Step 4[IN10864-060-Pl] : The Procedure is similar to Step 1 [B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.03 (d, J = 8.00 Hz, IH), 5.65 (s, IH), 4.09 (s, 2H), 3.90 (s, IH), 3.58-3.34 (m, IH), 3.31 (s, 4H), 3.05-2.95 (m, IH), 2.85-2.75 (m, 2H), 2.45 (s, 3H), 2.40-2.38 (m, 5H), 2.10-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001289] Step 4[IN10864-031-Pl] : The Procedure is similar to Step 1 [A] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.95 (d, J = 7.60 Hz, IH), 5.64 (s, IH),
3.89 (s, IH), 3.51 (s, 4H), 2.72-2.67 (m, IH), 2.41 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.50 (m, 2H), 1.00 (d, J = 6.00 Hz, 6H).
[001290] Step 4[IN10964-007-Pl] : The Procedure is similar to Step 1 [B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.07 (d, J = 7.60 Hz, IH), 5.65 (s, IH), 4.18-4.02 (m, 2H), 3.85 (d, J = 40.00 Hz, 2H), 3.62-3.40 (m, 6H), 2.41 (s, 3H), 2.12-1.85 (m, 6H), 1.60-1.50 (m, 2H), 1.08 (d, J = 6.40 Hz, 6H),
[001291] Step 4[IN11059-047-Pl]: The Procedure is similar to Step 2[IN10991-021-P1] in Example-694. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 7.51 (s, IH), 7.45 (s, IH), 7.37 (s, IH), 5.87 (s, IH), 5.46 (s, 2H), 2.43 (s, 3H), 2.12-1.85 (m, 6H), 1.62-1.50 (m, 2H). [001292] Step 4[IN11125-013-P1]: The Procedure is similar to Step 2[IN10991-021-P1] in Example-694. IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 1.6 Hz, IH), 7.05 (s, IH), 6.53 (d, J = 2.0 Hz, IH), 5.72 (s, IH), 5.60 (s, 2H), 5.29 (bs, IH), 3.57 (bs, IH), 2.56 (s, 3H), 2.17-2.04 (m, 4H), 1.98-1.84 (m, 2H), 1.70-1.62 (m, 2H).
[001293] Step 4[IN11055-049-P1] : The Procedure is similar to Step 1 [B] in Example-
838. IH-NMR (400 MHz, CD30D): δ 7.21 (s, IH), 5.41 (s, IH), 5.40 (s, IH), 4.05-3.90 (m,
IH), 2.86 (s, 3H), 2.47 (s, 3H), 2.11-1.91 (m, 7H), 1.67-1.62 (m, 2H).
[001294] Step 4[IN11055-046-P1] : The Procedure is similar to Step 1 [B] in Example-
838. IH-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.90 (d, J = 8.00 Hz, IH), 5.50 (s, IH),
3.90 (s, IH), 3.03 (s, 6H), 2.41 (s, 3H), 2.12-1.88 (m, 6H), 1.62-1.50 (m, 2H).
[001295] Step 4[IN11055-016-P1]: The Procedure is similar to Step 5[IN10963-068-Pl] in Example-694. IH-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 2H), 5.76 (s, IH), 5.27-5.25 (m,
IH), 3.80 (s, IH), 2.33 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.50 (m, 2H), 1.28 (d, J = 12.40 Hz,
6H).
[001296] Step 4[IN10864-043-Pl]: The Procedure is similar to Step 1[A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.33 (d, J = 0.8 Hz, IH), 6.97 (d, J = 7.6 Hz, IH), 5.65 (s, IH), 3.91-3.88 (m, IH), 3.71-3.69 (m, 2H), 3.52-3.38 (m, 2H), 3.38 (s, 2H), 2.41 (s, 3H), 2.12-1.91 (m, 6H), 1.61-1.53 (m, 2H), 1.18 (s, 6H).
[001297] Step 4[IN10864-034-Pl]: The Procedure is similar to Step 1[A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.31 (s, IH), 6.93-6.90 (m, IH), 5.55 (s, IH), 3.90 (m, IH), 3.76-3.62 (m, 8H), 2.41 (s, 3H), 2.06-1.88 (m, 8H), 1.58-1.55 (m, 2H).
[001298] Step 4[IN10864-033-Pl]: The Procedure is similar to Step 1[A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.96 (d, J = 8.40 Hz, IH), 5.71 (s, IH), 4.97-4.84 (m, IH), 4.00-3.70 (m, 2H), 3.55-3.36 (m, 2H), 2.42 (s, 3H), 2.15-1.73 (m, 9H), 1.82-1.50 (m, 4H).
[001299] Step 4[IN10876-013-P1]: The Procedure is similar to Step 1[A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.91 (d, J = 7.6 Hz, IH), 5.66 (s, IH), 3.96-3.92 (m, 2H), 3.70 (bs, IH), 2.41 (s, 4H), 2.06-1.94 (m, 9H), 1.72-1.69 (m, 2H), 1.60- 1.36 (m, 6H).
[001300] Step 4[IN11059-052-P1]: Step a: The Procedure is similar to Step 2[IN10991- 021-P1] in Example-694. Step b: The Procedure is similar to Step 3[IN11273-018-P1] in Example-889. IH-NMR (400 MHz, DMSO-d6): δ 7.45 (bs, IH), 7.42 (s, IH), 7.28 (t, J = 6.0 Hz, IH), 5.83 (s, IH), 4.35 (t, J = 5.6 Hz, 2H), 3.36-3.30 (m, 2H), 2.95 (s, 3H), 2.44 (s, 3H), 2.09-1.91 (m, 7H), 1.62-1.56 (m, 2H). [001301] Step 4[IN11039-009-P1]: Step a: The Procedure is similar to Step 2[IN10991- 021-P1] in Example-694. Step b: The Procedure is similar to Step 5[NSSy6067] in Example- 628. Step c: The Procedure is similar to Step 1[B] in Example-838. IH-NMR (400 MHz, MeOD): δ 7.26 (s, IH), 5.78 (s, IH), 4.41 (t, J = 6.00 Hz, 2H), 4.05 (s, IH), 3.61 (s, 3H), 3.47 (t, J = 5.60 Hz, 2H), 2.50 (s, 3H), 2.15-2.00 (m, 6H), 1.70-1.56 (m, 2H).
[001302] Step 4[IN10973-025-Pl]: The Procedure is similar to Step 1[B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.47 (s, IH), 7.42 (s, IH), 5.84 (s, IH), 5.54 (s, IH), 3.70-3.52 (m, 5H), 3.48-3.30 (m, 3H), 2.43 (s, 3H), 2.30-1.85 (m, 8H), 1.65-1.50 (m, 2H).
[001303] Step 4[IN10880-014-P1]: The Procedure is similar to Step 1[B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.99 (d, J = 8.00 Hz, IH), 5.66 (s, IH), 3.88 (s, IH), 3.53 (s, 4H), 2.41 (s, 3H), 2.38 (s, 4H), 2.22 (s, 3H), 2.10-1.85 (m, 6H), 1.60- 1.50 (m, 2H).
[001304] Step 4[IN10880-018-P1]: The Procedure is similar to Step 1[B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.05 (d, J = 8.00 Hz, IH), 6.41 (s, IH), 4.11-4.10 (m, 2H), 3.95-3.85 (m, 2H), 3.53-3.48 (m, IH), 2.91-2.85 (m, IH), 2.61-2.55 (m, IH), 2.41 (s, 3H), 2.15-1.85 (m, 6H), 1.60-1.45 (m, 4H), 0.95 (t, J = 7.20 Hz, 3H).
[001305] Step 4[IN10880-032-Pl] : The Procedure is similar to Step 1 [A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.80 (d, J = 7.6 Hz, IH), 7.33 (s, IH), 6.93 (d, J = 8.0 Hz, IH), 5.68 (s, IH), 4.24-4.21 (m, 2H), 3.91-3.81 (m, 2H), 3.01-2.95 (m, 2H), 2.42 (s, 3H), 2.09-1.91 (m, 6H), 1.80 (s, 3H), 1.60-1.55 (m, 2H), 1.36-1.29 (m, 4H).
[001306] Step 4[IN10880-033-Pl]: The Procedure is similar to Step 1[B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.05 (d, J = 7.20 Hz, IH), 6.95 (s, IH), 5.64 (s, IH), 4.20 (d, J = 12.00 Hz, IH), 4.03-3.92 (m, 3H), 3.53-3.44 (m, 2H), 3.07 (t, J = 5.20 Hz, 2H), 2.94-2.89 (m, IH), 2.62-2.56 (m, IH), 2.42 (s, 3H), 2.15-1.85 (m, 6H), 1.62- 1.52 (m, 2H), 1.40 (s, 9H).
[001307] Step 4[IN10882-040-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-839. IH-NMR (400 MHz, CD30D): δ 7.58 (s, IH), 5.70 (s, IH), 5.00-4.94 (m, IH), 4.33-4.29 (m, IH), 3.73-3.63 (m, 3H), 2.55 (s, 3H), 2.17-1.90 (m, 7H), 1.74-1.65 (m, 2H).
[001308] Step 4[IN10882-043-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-3. IH-NMR (400 MHz, CD30D): δ 7.61 (s, IH), 5.59 (s, IH), 5.02-4.89 (m, 2H), 4.22-4.18 (m, 2H), 3.98-3.92 (m, IH), 3.92-3.66 (m, IH), 3.07 (s, 3H), 2.55 (m, 3H), 2.17- 1.95 (m, 6H), 1.76-1.66 (m, 2H).
[001309] Step 4[IN10881-099-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 1.20 Hz, IH), 7.07 (d, J = 8.00 Hz, IH), 5.63 (s, IH), 4.50-4.42 (m, IH), 3.96-3.90 (m, 2H), 3.70-3.65 (m, IH), 3.55-3.46 (m, 2H), 3.29 (s, 3H), 3.08-3.07 (m, IH), 2.41 (s, 3H), 2.09-1.92 (m, 7H), 1.57-1.55 (m, 2H).
[001310] Step 4[IN10881-090-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 7.05 (d, J = 7.20 Hz, IH), 5.91 (s, IH), 3.90 (s, IH), 3.08 (s, 3H), 2.41 (s, 3H), 2.10-1.85 (m, 6H), 1.62-1.50 (m, 2H), 1.35 (s, IH), 0.86 (d, J = 6.00 Hz, 2H), 0.65 (s, 2H).
[001311] Step 4[IN10881-092-Pl]: The Procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.10 (d, J = 8.00 Hz, IH), 5.66 (s, IH), 4.30 (s, IH), 4.11-4.08 (m, IH), 3.95 (d, J = 10.00 Hz, 2H), 3.70-3.40 (m, 3H), 2.90 (t, J = 10.80 Hz, 2H), 2.80-2.60 (m, 3H), 2.41 (s, 3H), 2.06-1.91 (m, 7H), 1.60-1.49 (m, 2H), 1.05 (s, 7H).
[001312] Step 4[IN10881-021-P1]: The Procedure is similar to Step 1[A] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.30 (s, IH), 6.92 (d, J = 8.0 Hz, IH), 5.64 (s, IH), 3.88 (m, IH), 3.55 (m, 4H), 2.41 (s, 3H), 2.08-1.91 (m, 6H), 1.63-1.53 (m, 8H).
[001313] Step 4[IN11140-052-P1]: Step a: The Procedure is similar to Step 1[B] in Example-838. Step b: The Procedure is similar to Step 4[NSSy6067] in Example-628. 1H- NMR (400 MHz, DMSO-d6): δ 7.54 (bs, IH), 7.48-7.45 (m, 2H), 5.88 (m, IH), 5.43 (s, 2H), 4.10 (m, IH), 2.45 (s, 3H), 2.08-1.93 (m, 6H), 1.61-1.56 (m, 2H).
[001314] Step 4[IN11079-014-P1]: The Procedure is similar to Step 5[IN10963-068-Pl] in Example-697. 1H-NMR (400 MHz, MeOD): δ 7.41 (s, IH), 5.82 (s, IH), 5.53 (s, IH), 3.96-3.92 (m, IH), 3.88-3.75 (m, 3H), 2.43 (s, 3H), 2.30-2.20 (m, 4H), 2.15-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001315] Step 4[IN11079-007-P1]: The Procedure is similar to Step 5[IN10963-068-Pl] in Example-697. 1H-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 2H), 5.81 (s, IH), 5.20 (s, IH), 3.86 (t, J = 4.80 Hz, 2H), 3.51 (t, J = 9.20 Hz, 2H), 2.43 (s, 3H), 2.12-1.85 (m, 9H), 1.55-1.66 (m, 4H).
[001316] Step 4[IN11079-033-P1]: The Procedure is similar to Step 5[IN10963-068-Pl] in Example-697. 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (s, IH), 7.42 (s, IH), 5.85 (s, IH), 5.59 (t, J = 5.60 Hz, IH), 4.89 (t, J = 6.80 Hz, 2H), 4.58 (t, J = 6.00 Hz, 2H), 3.95 (s, IH), 2.43 (s, 3H), 2.15-1.85 (m, 6H), 1.52-1.48 (m, 2H).
[001317] Step 4[IN11054-039-P1]: The Procedure is similar to Step l[IN10965-089-Pl] in Example-705. 1H-NMR (400 MHz, CDC13): δ 7.03 (s, IH), 6.15 (s, IH), 5.19 (bs, IH), 3.66 (bs, IH), 2.55 (s, 6H), 2.18-2.00 (m, 4H), 1.99-1.86 (m, 2H), 1.70-1.65 (m, 2H). [001318] Step 4[IN11054-046-P2]: The Procedure is similar to Step 3[NSSy7062] in Example-623. IH-NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 6.80 Hz, IH), 7.49 (s, IH), 7.03 (s, IH), 4.20-4.15 (m, IH), 2.82 (s, 3H), 2.45 (s, 3H), 2.07-1.96 (m, 6H), 1.66-1.63 (m, 2H).
[001319] Step 4[IN11054-046-P1]: The Procedure is similar to Step 3[NSSy7062] in Example-623. IH-NMR (400 MHz, DMSO-d6): δ 8.71 (d, J = 9.20 Hz, IH), 7.66 (s, IH), 7.37 (s, IH), 4.00 (s, IH), 3.90 (s, 3H), 2.55 (s, 3H), 2.15-1.80 (m, 8H).
[001320] Step 4 [IN 10881-023 -P2] : The Procedure is similar to Step 1 [A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.92 (d, J = 7.6 Hz, IH), 5.64 (s, IH), 4.92 (d, J = 1.6 Hz, IH), 4.17 (m, IH), 3.98-3.95 (m, 2H), 3.48-3.46 (m, IH), 2.98-2.93 (m, IH), 2.78-2.73 (m, IH), 2.42 (s, 3H), 2.06-1.92 (m, 6H), 1.74-1.73 (m, 2H), 1.57-1.54 (m, 2H), 1.41-1.39 (m, 2H).
[001321] Step 4[IN10881-020-P1] : The Procedure is similar to Step 1 [A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.93 (d, J = 7.60 Hz, IH), 5.67 (s, IH), 4.32 (d, J = 11.60 Hz, 2H), 3.89 (s, IH), 2.84 (t, J = 12.40 Hz, 2H), 2.42 (s, 4H), 2.22 (s, 6H), 2.15-1.80 (m, 8H), 1.62-1.50 (m, 2H), 1.42-1.35 (m, 2H).
[001322] Step 4[IN10881-025-P1] : The Procedure is similar to Step 1 [A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.06 (d, J = 8.00 Hz, IH), 5.66 (s, IH), 4.87 (t, J = 5.20 Hz, IH), 4.20 (s, IH), 3.95 (d, J = 9.20 Hz, 2H), 3.55-3.40 (m, 4H), 2.91- 2.86 (m, IH), 2.70-2.60 (m, IH), 2.42 (s, 3H), 2.15-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001323] Step 4[IN10881-027-P1] : The Procedure is similar to Step 1 [A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.50 (s, IH), 7.43 (s, IH), 5.83 (s, IH), 4.19 (t, J = 5.60 Hz, 2H), 3.86-3.82 (m, IH), 3.70 (d, J = 11.20 Hz, IH), 3.50-3.40 (m, IH), 3.28-3.23 (m, IH), 3.15 (s, IH), 2.90-2.80 (m, 2H), 2.44 (s, 3H), 2.09-1.90 (m, 7H), 1.65-1.50 (m, 2H), 1.34 (s, IH).
[001324] Step 4[IN10987-056-Pl]: Step a: The Procedure is similar to Step 1[A] in Example-838. Step b: The Procedure is similar to Step 4[NSSy6711] in Example-854. 1H- NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.92 (d, J = 7.20 Hz, IH), 5.35 (s, IH), 4.70 (s, IH), 3.85 (s, IH), 3.47 (s, 2H), 3.03 (d, J = 148.40 Hz, IH), 2.75 (d, J = 60.00 Hz, IH), 2.41 (s, 4H), 2.30 (s, 3H), 2.15-1.82 (m, 7H), 1.68-1.50 (m, 3H).
[001325] Step 4[IN10987-050-Pl]: Step a: The Procedure is similar to Step 1[A] in Example-838. Step b: The Procedure is similar to Step 5[NSSy6067] in Example-628. 1H- NMR (400 MHz, DMSO-d6): δ 7.31 (s, IH), 6.86 (d, J = 7.60 Hz, IH), 5.35 (s, IH), 5.30 (s, IH), 4.70 (s, IH), 3.90 (s, IH), 3.66 (s, IH), 3.38 (s, IH), 2.90 (d, J = 8.80 Hz, 2H), 2.77 (d, J = 9.20 Hz, IH), 2.41 (s, 3H), 2.06-1.91 (m, 6H), 1.57-1.50 (m, 4H).
[001326] Step 4[IN10880-029-Pl]: The Procedure is similar to Step 3[NSSy5933] in Example-808. IH-NMR (400 MHz, DMSO-d6): δ 8.32 (s, IH), 7.52 (s, IH), 6.95 (s, IH), 4.08 (s, IH), 2.50 (s, 3H), 2.11-1.88 (m, 6H), 1.70-1.52 (m, 2H).
[001327] Step 4[IN11218-030-P1]: The Procedure is similar to Step 2[IN11250-007-P1] in Example-620. IH-NMR (400 MHz, DMSO-d6): δ 8.17 (s, 2H), 7.72 (s, IH), 7.60-7.50 (m, 3H), 7.48 (s, IH), 6.98 (s, IH), 4.15 (s, IH), 2.47 (s, 3H), 2.15-1.90 (m, 6H), 1.70-1.55 (m, 2H).
[001328] Step 4[IN11196-080-P1] : The Procedure is similar to Step 1 [H] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 8.72 (s, IH), 8.41 (d, J = 8.00 Hz, IH), 8.03 (t, J = 6.40 Hz, IH), 7.85 (s, IH), 7.55-7.52 (m, 2H), 7.46 (s, IH), 4.19 (s, IH), 2.48 (s, 3H), 2.15- 1.90 (m, 6H), 1.62-1.60 (m, 2H).
Example-656:
Figure imgf000492_0001
[001329] Step 1: To a stirred solution of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine (0.3 g, 0.87 mmol) in mixture of solvents Toluene: DMSO: Water (3.5: 1.5: 1) was added sodium hydroxide (0.14 g, 3.48 mmol). The reaction mixture was stirred at 110 °C for 24h. Added 4 eq of sodium hydroxide and stirred at 110 °C for 48h. The reaction mixture was diluted with water (50 mL), acidified with IN HC1 and extracted with ethyl acetate (2x25 mL). The combined organics were dried over sodium sulfate, filtered and evaporated to afford 6-((4, 4-difluorocyclohexyl) amino)-2-(4- methylthiazol-2-yl) pyrimidin-4-ol as an off-white solid (0.17 g, 59%). MS (M+l)+=327.2.
[001330] Step 2[IN11196-007-P1 and INI 1196-007-P2]: The procedure is similar to Step 1[A] in Example-838. 0.16 g of 6-((4, 4-difluorocyclohexyl)amino)-2-(4-methylthiazol- 2-yl)pyrimidin-4-ol gave 2-((6-((4, 4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl)oxy)acetonitrile as an off-white solid (0.03 g, 16%). MS (M+l)+=366.1; IH-NMR (400 MHz, DMSO-d6): δ 7.66 (s, IH), 7.47 (s, IH), 5.95 (s, IH), 5.25 (s, 2H), 4.01 (s, IH), 2.45 (s, 3H), 2.12-1.85 (m, 6H), 1.62-1.52 (m, 2H) and 2-(4-((4, 4- difluorocyclohexyl)amino)-2-(4-methylthiazo^ as white solid (0.04 g, 22%). MS (M+l)+=366.2; IH-NMR (400 MHz, DMSO-d6): δ 7.72 (s, 1H), 7.38 (bs, 1H), 5.57 (s, 2H), 5.25 (s, 1H), 3.51 (s, 1H), 3.41 (s, 3H), 2.08-1.93 (m, 6H), 1.61-1.53 (m, 2H).
Example-657:
Figure imgf000493_0001
[001331] Step 1: The Procedure is similar to Step 1[B] in Example-838. 25 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave methyl 3-((6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate (16 g, 50%). MS (M+l)+=440.
[001332] Step 2[NSSy6106] : To a solution of acetonitrile and hydrochloric acid (0. IN) was added methyl 3-((6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate (0.6 g, 1.36 mmol) and the reaction mixture was heated at 60 °C for 20h. The reaction mixture was concentrated to reduce the volume, then cooled at -78 °C and dried in freeze drier to afford methyl (3-chloro-2-((6-((4, 4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)oxy)propyl)carbamate as yellow solid (0.3 g, 45%). MS (M+l)+=476.2; IH-NMR (400 MHz, DMSO-d6): δ 9.72 (d, J =6.4 Hz, 0.5H), 9.33 (d, J =8.4 Hz, 0.5H), 7.96 (s, 0.5 H), 7.91 (s, 0.5H), 7.61 (s, 1H), 7.27 (t, J =51.2 Hz, 0.17H), 6.67 (s, 0.5 H), 6.37 (s, 0.5H), 5.36-5.28 (m,lH), 5.11-5.06 (m,
1H), 4.72-4.65 (m, 1H), 4.17 (s, 0.5H), 3.80 (bs, 0.5H), 3.54 (s, 5H), 2.56 (s, 3H), 2.25-1.85 (m, 6H), 1.78-1.56 (m, 2H).
Example-658:
Figure imgf000493_0002
[001333] Step 1 [NSSy5868] : To a solution of methyl 3-((6-((4, 4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin4yl)oxy) azetidine-1- carboxylate (2.3 g, 5.23 mmol) in carbon tetrachloride was added 2, 2-Azobisisobutyronltrile (AIBN) (0.08 g, 0.52 mmol) followed by N-bromosuccinimide (0.93 g, 5.23 mmol) and the reaction mixture was heated at 70 °C for lh. The reaction mixture was diluted with water, extracted with dichloro methane. The combined organic layer was washed with water and brine solution, dried over sodium sulfate. The reaction mixture was filtered and concentrated under reduced pressure to afford crude and which was purified by Reveleris flash system instrument by using 45% ethyl acetate in pet ether as eluent afford methyl 3-((5-bromo-6-((4, 4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l- carboxylate as pale yellow solid (2.6 g, 82%). MS (M, M+2)+=518, 520; 1H-NMR (400 MHz, DMSO-d6): δ 7.48 (s, 1H), 6.95 (s, 1H), 5.40-5.36 (m, 1H), 4.39-4.36 (m, 2H), 4.20- 4.17 (m, 1H), 3.99-3.96 (m, 2H), 3.58 (s, 3H), 2.46 (s, 3H), 2.10-1.91 (m, 6H), 1.67-1.62 (m, 2H).
[001334] Step 2[NSSy6045] : To a solution of methyl 3-((5-bromo-6-((4, 4- difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)oxy) azetidine-1- carboxylate (0.2 g, 0.38 mmol) in CD30D was purged with nitrogen for 2 min, then added palladium carbon and stirred under deuterium atmosphere at 5 kg pressure in tiny clave for 16h. The reaction mixture was filtered through celite bed, washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford crude which was purified by Reveleris flash system instrument using 40% ethyl acetate in pet ether as eluent to afford Deuterated methyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2- yl)pyrimidin-4-yl-5-d)oxy) azetidine-1 -carboxylate as pale yellow solid (70 mg, 36%). MS (M+l)+=441.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.62 (bs, 1H), 7.43 (s, 1H), 5.35 (s, 1H), 4.44-4.35 (m, 2H), 4.00-3.85 (m, 2H), 3.58 (s, 3H), 2.43 (s, 3H), 2.30-1.80 (m, 11H), 1.60- 1.50 (m, 2H).
Example-659:
Figure imgf000495_0001
"■ IN1105 Λ9-090-P1 IN Λ11059-095-P1 IN112 Λ51-043-P1
[001335] Step 1: To stirred solution of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl)pyrimidin-4-amine (4 g, 11.62 mmol) in ethanol (50 mL) was added [1, -Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM (0.95 g, 1.16 mmol) and N, N-Diisopropylethylamine (12.2 mL, 69.72 mmol) in a Steel bomb and purged with N2 for about 10 min. The Steel bomb was sealed and filled with carbon monoxide gas at 100 Psi and the reaction mixture was heated to 100 °C for 18h. The reaction mixture was cooled to rt, degassed the steel bomb and reaction mixture was concentrated under reduced pressure to obtain brown liquid and which was purified by column chromatography using 45% ethyl acetate in hexane as eluent to afford ethyl 6-((4, 4-difluorocyclohexyl)amino)-2- (4-methylthiazol-2-yl)pyrimidine-4-carboxylate as an yellow solid (2 g, 45%). MS
(M+l)+=383.1.
[001336] Step 2: The Procedure is similar to Step 4[NSSy6711] in Example-854. 4 g of ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-4-carboxylate gave (6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) methanol as an off-white solid (2 g, 45%). MS (M+l)+=383.1.
[001337] Step 3: To a stirred solution of (6-((4, 4-difluorocyclohexyl)amino)-2-(4- methylthiazol-2-yl)pyrimidin-4-yl)methanol (1 g, 2.94 mmol) in dichloro methane (50 mL) at 0 °C was added Phosphorus tribromide (1.4 mL, 14.70 mmol) dropwise for about 5 min and the reaction mixture was warmed to rt and stirred for about 2h. The reaction mixture was poured in ice cold water (150 mL) and extracted with DCM (3x150 mL). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution (3x75 mL) followed by brine (100 mL) and dried over sodium sulfate and evaporated to dryness to afford 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine as an off-white solid (0.69 g, 58%). MS (M+l)+=405.0.
[001338] Step 4[IN11059-096-P1]: To a stirred 6-(bromomethyl)-N-(4, 4- difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine (0.69 g, 1.72 mmol) in a Sealed tube was added Methylamine solution (2.0 M in THF) (17.2 mL, 34.4 mmol) at rt and the reaction mixture sealed and stirred at rt for about 16h. The reaction was then concentrated under reduced pressure and the product was washed with n-pentane and dried in vacuum to afford N-(4, 4-difluorocyclohexyl)-6-((methylamino) methyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.41 g, 54%). MS (M+l)+=354; 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, IH), 7.38 (s, IH), 6.56 (s, IH), 4.09 (s, IH), 3.57 (s, 2H), 2.49 (s, 3H), 2.33 (s, 4H), 2.15-1.85 (m, 6H), 1.65-1.51 (m, 2H).
Table-33: Step 5:
Figure imgf000496_0001
[001339] [INI 1059-090-P1]: The procedure is similar to Step 3[IN11273-018-P1] in Example-889. MS (M+l)+=396.1; 1H-NMR (400 MHz, DMSO-d6, 100 °C): δ 7.32 (s, 2H), 6.34 (s, IH), 4.43 (s, 2H), 4.05 (s, IH), 3.10 (s, 3H), 2.46 (s, 3H), 2.09 (s, 3H), 2.10-1.85 (m, 6H), 1.75-1.62 (m, 2H).
[001340] [IN11059-095-P1]: The procedure is similar to Step 3[IN11273-018-P1] in Example-889. MS (M+l)+=382.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 4.4 Hz, IH), 7.70-7.64 (bs, IH), 7.41 (s, IH), 6.33 (bs, IH), 4.41 (s, IH), 4.34 (s, IH), 4.11 (bs, IH), 3.01 (s, IH), 2.77 (s, 2H), 2.44 (s, 3H), 2.09-1.96 (m, 6H), 1.62-1.59 (m, 2H).
[001341] [IN11251-043-P1]: The procedure is similar to Step 3[IN11273-018-P1] in Example-889. MS (M+l)+=411.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.29 (d, J = 0.80 Hz, IH), 7.08 (s, IH), 6.86 (d, J = 6.40 Hz, IH), 6.39 (s, IH), 4.37 (s, 2H), 3.90 (s, IH), 3.66 (s, 3H), 2.86 (s, 3H), 2.41 (s, 3H), 2.09-1.90 (m, 6H), 1.63-1.56 (m, 2H). Example-660:
Figure imgf000497_0001
[001342] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(3, 3-difluorocyclobutyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.22 g, 57%). MS (M+l)+=317.
[001343] Step 2[IN11133-020-P1] : The Procedure is similar to Step 1 [B] in Example- 838. 0.14 g of 6-chloro-N-(3, 3-difluorocyclobutyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine gave N-(3, 3-difluorocyclobutyl)-2-(4-methylthiazol-2-yl)-6-((tetrahydro-2H-pyran-4- yl) oxy) pyrimidin-4-amine as an off-white solid (0.02 g, 8%). MS (M+l)+=383.1; IH-NMR (400 MHz, CD30D): δ 7.27 (d, J = 0.80 Hz, 1H), 5.73 (s, 1H), 5.44-5.40 (m, 1H), 4.30 (s, 1H), 4.00-3.90 (m, 2H), 3.70-3.60 (m, 2H), 3.12-2.98 (m, 2H), 2.65-2.52 (m, 2H), 2.50 (s, 3H), 2.10-2.00 (m, 2H), 1.80-1.68 (m, 2H).
Example-661:
Figure imgf000497_0002
[001344] Step 1: The Procedure is similar to Step 2[IN11218-026-P1] in Example-613. 0.1 g of ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-4- carboxylate gave ethyl 6-((tert-butoxycarbonyl) (4, 4-difluorocyclohexyl) amino)-2-(4- methylthiazol-2-yl) pyrimidine-4-carboxylate as an off-white solid (0.08 g, 63%). MS (M+l)+=483.
[001345] Step 2: The Procedure is similar to Step 4[NSSy6464] in Example-869. 0.08 g of ethyl 6-((tert-butoxycarbonyl) (4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-4-carboxylate gave tert-butyl (6-benzoyl-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) (4, 4-difluorocyclohexyl) carbamate as an off-white solid (0.07 g, 82%). MS (M+l)+=515.
[001346] Step 3: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.07 g of tert-butyl (6-benzoyl-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) (4, 4-difluorocyclo hexyl) carbamate gave tert-butyl (4, 4-difluorocyclohexyl) (6-(hydroxy (phenyl) methyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-yl) carbamate as an off-white solid (0.06 g, 85%). MS (M+l)+=517.
[001347] Step 4[IN10971-033-Pl]: The Procedure is similar to Step 5[NSSy6067] in Example-628. 0.06 g of tert-butyl (4, 4-difluorocyclohexyl) (6-(hydroxy (phenyl) methyl)-2- (4-methylthiazol-2-yl) pyrimidin-4-yl) carbamate gave (6-((4, 4-difluorocyclo hexyl) amino)- 2-(4-methylthiazol-2-yl) pyrimidin-4-yl) (phenyl) methanol as an off-white solid (0.035 g, 72%). MS (M+l)+=417; 1H-NMR (400 MHz, CD30D): δ 7.46 (d, J = 7.2 Hz, 2H), 7.34-7.30 (m, 2H), 7.26-7.22 (m, 2H), 6.53 (s, 1H), 5.60 (s, 1H), 4.22 (bs, 1H), 2.60 (s, 3H), 2.07-1.89 (m, 7H), 1.65-1.60 (m, 3H).
Example-662:
Figure imgf000498_0001
[001348] Step 1: The Procedure is similar to Step 1[H] in Example-838. 2.5 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off- white solid (1.9 g, 69%). MS (M+l)+=381.
[001349] Step 2[IN11030-054-P1]: The Procedure is similar to Step l[NSSy6697] in Example-873. 1.8 g of N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one as an off-white solid (1.35 g, 81%). MS (M+l)+=353.1; 1H- NMR (400 MHz, DMSO-d6): δ 8.00 (d, J = 6.00 Hz, IH), 7.47 (d, J = 1.2 Hz, IH), 6.95 (s, IH), 4.15 (bs, IH), 2.60 (s, 3H), 2.47 (s, 3H), 2.07-1.93 (m, 6H), 1.67-1.59 (m, 2H).
[001350] Step 3[IN10880-035-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 1.4 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one gave l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol- 2-yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (1.2 g, 85%). MS (M+l)+=355.2; 1H- NMR (400 MHz, DMSO-d6): δ 7.60 (s, IH), 7.38 (s, IH), 6.64 (s, IH), 5.40 (s, IH), 4.51 (d, J = 6.40 Hz, IH), 4.11 (s, IH), 2.15-1.88 (m, 6H), 1.65-1.55 (m, 2H), 1.48-1.42 (m, 3H), 2.32 (s, 3H).
[001351] Step 4: The Procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 1.1 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol gave 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a yellow solid (0.95 g). MS (M+l)+=416.9.
[001352] Step 5[IN11133-002-P1]: The Procedure is similar to Step 5[NSSy6711] in Example-854. 0.2 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave 6-(l-(lH-pyrazol-l-yl) ethyl)-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.045 g). MS (M+l)+=405.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (d, J = 2.00 Hz, IH), 7.64 (bs, IH), 7.55 (s, IH), 7.41 (s, IH), 6.35 (t, J = 2.00 Hz, IH), 5.82-5.80 (m, IH), 5.50-5.45 (m, IH), 4.10-4.00 (m, IH), 2.44 (m, 3H), 2.04-1.80 (m, 6H), 1.81 (d, J = 6.8 Hz, 3H), 1.80-1.54 (m, 2H).
Example-663:
Figure imgf000499_0001
[001353] Step 1[IN11030-083-P1]: The Procedure is similar to Step 4[NSSy6464] in Example-869. 0.3 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one gave 2-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol- 2-yl) pyrimidin-4-yl) propan-2-ol as an off-white solid (0.03 g). MS (M+l)+=369.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (bs, IH), 7.37 (s, IH), 6.76 (s, IH), 5.17 (s, IH), 4.15 (bs, IH), 2.44 (s, 3H), 2.08-1.97 (m, 6H), 1.62-1.59 (m, 2H), 1.40 (s, 6H). Example-664:
[001354] Omitted Intentionally
Example-665:
Figure imgf000500_0001
[001355] Step 1: The Procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.16 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol gave 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a yellow solid (0.09 g). MS (M+l)+=416.9.
[001356] Step 2[IN10973-053-Pl]: The Procedure is similar to Step 3[IN11273-018-P1] in Example-889. 0.08 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol- 2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-(l-(methylsulfonyl) ethyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.06 g). MS (M+l)+=417.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.86 (d, J = 5.2 Hz, IH), 7.44 (s, IH), 6.57 (s, IH), 4.46 (d, J = 6.4 Hz, IH), 4.13 (bs, IH), 3.09 (s, 3H), 2.44 (s, 3H), 2.11-1.99 (m, 6H), 1.65-1.60 (m, 5H).
Example-666:
Figure imgf000500_0002
[001357] Step 1 [INI 1104-094-P1] : The Procedure is similar to Step 1 [B] in Example- 838. 0.2 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave 2-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) propanenitrile as an off-white solid (0.09 g, 51%). MS (M+l)+=363.8; 1H- NMR (400 MHz, DMSO-d6): δ 7.87 (s, IH), 7.44 (s, IH), 6.59 (s, IH), 4.24-4.22 (m, IH), 4.13 (s, IH), 2.45 (s, 3H), 2.00 (s, 6H), 1.67-1.52 (m, 5H). Example-667:
Figure imgf000501_0001
[001358] Step l[IN10876-092-Pl]: The Procedure is similar to Step 3[NSSy6917] in Example-21. 0.1 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol gave N-(4, 4-difluorocyclohexyl)-6-(l-fluoroethyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.025 g, 24%). MS
(M+l)+=357.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.78 (s, 1H), 7.43 (s, 1H), 6.55 (s, 1H), 5.50-5.45 (m, 1H), 4.12 (s, 1H), 2.44 (s, 3H), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 5H).
Example-66
Figure imgf000501_0002
[001359] Step l[IN10973-028-Pl]: To a solution of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one and morpholine in methanol was added acetic acid. The reaction mixture was stirred at rt for 4h. Sodium cyano
borohydride was added and continued to stir at rt for 16h. The Reaction mixture was evaporated to dryness, added ice cold water and stirred for 10 minutes. The obtained solid was filtered and dried under vacuum to afford crude and which was purified by column chromatography using ethyl acetate as eluent to afford N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl)-6-(l-morpholinoethyl) pyrimidin-4-amine as an off-white solid (0.04 g, 33%). MS (M+l)+=424.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, 1H), 7.38 (s, 1H), 6.56 (s, 1H), 4.01 (s, 1H), 3.59 (t, = 4.40 Hz, 4H), 2.49 (s, 5H), 2.32-1.97 (m, 6H), 1.68-1.52 (m, 2H), 1.33-1.22 (m, 6H). Example-669
Figure imgf000502_0001
[001360] Step 2[IN10876-082-Pl]: The Procedure is similar to Step 3[NSSy6917] in Example-21. 0.4 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one gave N-(4, 4-difluorocyclohexyl)-6-(l, l-difluoroethyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.085 g, 20%). MS
(M+l)+=375.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.01 (d, = 6.80 Hz, 1H), 7.47 (s, 1H), 6.72 (s, 1H), 4.15 (s, 1H), 2.45 (s, 3H), 2.15-1.85 (m, 7H), 1.65-1.55 (m, 2H), 1.33 (s, 2H). Example-670:
Figure imgf000502_0002
[001361] Step 1 : To a solution of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl)pyrimidin-4-amine (0.2 g, 0.581 mmol) in dry DMF (1 mL) was added sodium azide (0.075 g, 1.162 mmol) and heated at 85 °C for 12h. The reaction mixture was quenched with ice cold water, the obtained solid was filtered and dried under high vacuum to afford 6-azido-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine as an off-white solid (0.2 g, 98%).
[001362] Step 2[IN11055-068-P1]: The Procedure is similar to Step 2[NSSy6464] in Example-869. 0.2 g of 6-azido-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N4-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diamine as an off-white solid (0.08 g, 43%). MS (M+l)+=326.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.30 (d, J = 0.80 Hz, 1H), 6.81 (d, J = 7.60 Hz, 1H), 6.31 (s, 2H), 5.42 (s, 1H), 3.78 (s, 1H), 2.43 (s, 3H), 2.10-1.82 (m, 6H), 1.61-1.50 (m, 2H). Example-671:
Figure imgf000503_0001
θ^Ν" F3C^^N NH
[001363] Step 1: The Procedure is similar to Step 1[H] in Example-838. 0.3 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 2-(4-chloro-6-(l-ethoxyvinyl) pyrimidin-2- yl)-4-methylthiazole as an off-white solid (0.23 g, 67%). MS (M+l)+=282.
[001364] Step 2: The Procedure is similar to Step l[NSSy6697] in Example-873. 0.23 g of 2-(4-chloro-6-(l-ethoxyvinyl) pyrimidin-2-yl)-4-methylthiazole gave l-(6-chloro-2-(4- methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one as an off-white solid (0.17 g, 82%). MS
(M+l)+=254.
[001365] Step 3: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.17 g of l-(6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one gave l-(6-chloro-2-(4- methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (0.16 g, 93%). MS (M+l)+=255.9.
Figure imgf000503_0002
[001366] Step 4[IN10880-093-Pl]: MS (M+l)+=319.1; 1H-NMR (400 MHz, DMSO- d6): δ 7.48 (s, IH), 7.36 (s, IH), 6.60 (s, IH), 5.37 (s, IH), 4.49 (s, IH), 3.91 (s, IH), 2.43 (s, 3H), 1.95-1.55 (m, 5H), 1.40-1.10 (m, 8H). [001367] Step 4[IN10880-084-Pl]: MS (M+l)+=333.1; 1H-NMR (400 MHz, DMSO- d6): δ 7.39 (s, IH), 6.72 (s, IH), 5.43 (d, J = 4.80 Hz, IH), 4.59-4.55 (m, IH), 2.96 (s, 3H), 2.44 (s, 3H), 1.84 (d, J = 28.00 Hz, 2H), 1.70-1.50 (m, 5H), 1.45-1.30 (m, 5H), 1.30-1.20 (m, 2H).
[001368] Step 4[IN10880-085-Pl]: MS (M+l)+=387.0; 1H-NMR (400 MHz, DMSO- d6): δ 7.57 (bs, IH), 7.37-7.36 (m, IH), 6.59 (s, IH), 5.40 (d, J = 4.4 Hz, IH), 4.50-4.45 (m, IH), 3.92 (bs, IH), 2.42 (s, 3H), 2.25-2.17 (m, IH), 1.99-1.97 (m, IH), 1.85-1.76 (m, 2H), 1.63-1.56 (m, 2H), 1.50-1.44 (m, IH), 1.34-1.32 (m, 3H), 1.22-1.14 (m, 2H).
Example-672:
[001369] Intentionally Omitted
Example-673:
Figure imgf000504_0001
[001370] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-2-(4-methylthiazol-2-yl)-N-(4- (trifluoromethyl) cyclohexyl) pyrimidin-4-amine as an off-white solid (0.3 g, 70%). MS (M+l)+=377.4.
[001371] Step 2[NSSy6078]: The Procedure is similar to Step 1[B] in Example-838. 0.45 g of 6-chloro-2-(4-methylthiazol-2-yl)-N-(4-(trifluoromethyl) cyclohexyl) pyrimidin-4- amine gave methyl 3-((2-(4-methylthiazol-2-yl)-6-((4-(trifluoro methyl) cyclohexyl) amino) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (0.18 g, 32%). MS (M+l)+=472.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.24 (d, J = 4.00 Hz, IH), 5.88 (s, IH), 5.39-5.36 (m, IH), 4.37-4.32 (m, 2H), 4.08 (s, IH), 4.01 (s, 2H), 3.60 (s, 3H), 2.44 (s, 3H), 2.32-2.31 (m, IH), 1.8 (d, J =8, 2H), 1.74-1.69 (m, 6H).
Figure imgf000505_0001
[001372] Step 1 : The Procedure is similar to Step 5[NSSy6711] in Example-854. 0.5 g of 2-(4, 6-dichloropyrimidin-2-yl)-4-methylthiazole gave 2-(4-chloro-6- cyclopropoxypyrimidin-2-yl)-4-methylthiazole as an off-white solid (0.32 g, 58.8%). MS (M+l)+=268.
[001373] Step 2[IN11146-033-P1]: The Procedure is similar to Step l[NSSy6629] in Example-839. 0.32 g of 2-(4-chloro-6-cyclopropoxypyrimidin-2-yl)-4-methylthiazole gave 6- cyclopropoxy-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.03 g, 6.8%). MS (M+l)+=367.0; IH-NMR (400 MHz, MeOD): δ 7.52 (s, 1H), 7.40 (s, 1H), 5.99 (s, 1H), 4.07 (s, 1H), 2.43 (s, 3H), 2.10-1.90 (m, 6H), 1.65-1.52 (m, 2H), 0.86 (s, 1H), 0.82 (d, J = 18.00 Hz, 2H), 0.75 (s, 2H).
Example-675:
Figure imgf000505_0002
Table-35: Step 1: The Procedure is similar to Step 1[B] in Example-838.
Figure imgf000506_0003
Figure imgf000506_0001
Figure imgf000506_0004
[001374] [IN10966-028-P1]: 1H-NMR (400 MHz, DMSO-d6): δ 7.35 (s, IH), 7.06 (d, J = 8.00 Hz, IH), 5.64 (s, IH), 3.98 (s, IH), 3.68 (s, 4H), 3.50 (s, 4H), 2.42 (s, 3H), 1.93-1.49 (m, 6H), 1.30-1.23 (m, 2H).
[001375] [IN10973-099-P1]: 1H-NMR (400 MHz, DMSO-d6): δ 7.31 (s, IH), 6.38 (s, IH), 5.79 (s, IH), 3.70-3.67 (m, 4H), 3.45-3.43 (m, 4H), 3.16 (s, 3H), 2.85-2.18 (m, 2H), 1.50-1.38 (m, 9H), 1.30-1.20 (m, 2H).
Example-676:
Figure imgf000506_0002
[001376] Step 1: To a stirred solution of 2-(4-methylthiazol-2-yl)pyrimidine-4, 6-diol (1 g, 4.77 mmol) in dichloro methane (18 mL) was added trifluoromethanesulfonic anhydride (1.0 mL) at -50 °C and followed by trimethylamine (1.3 mL). The reaction mixture was slowly warmed to room temperature and stirred at rt for 16h. The reaction mixture was concentrated under reduced pressure to remove excess triflic anhydride and the residue was quenched with 10% sodium bicarbonate and extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-hydroxy-2-(4-methylthiazol-2-yl)pyrimidin- 4-yl trifluoromethanesulfonate as brown solid (1.4 g, 86%). MS (M+l)+=342.2.
[001377] Step 2[NSSy6082]: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 6-hydroxy-2-(4-methylthiazol-2-yl) pyrimidin-4-yl trifluoromethane sulfonate gave 6- ((4, 4-difluorocyclohexyl) amino)-2-(4-methyl thiazol-2-yl) pyrimidin-4-ol (0.04 g, 14%). MS (M+l)+=327.2; IH-NMR (400 MHz, DMSO-d6): δ 11.42 (s, IH), 7.56 (s, IH), 7.13 (s, IH), 5.26 (s, IH), 2.44 (s, 3H), 2.32-2.31 (m, IH), 1.89-1.87 (m, 2H), 1.74-1.69 (m, 6H). Example-677:
Figure imgf000507_0001
NSSy6100 NSSy6124 NSSy6115 NSSy6149 NSSy6099
[001378] Step 1: The Procedure is similar to Step 1[B] in Example-838. 2 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-cyclohexyl-2-(4-methylthiazol-2- yl) pyrimidin-4-amine as an off-white solid (2 g, 80%). MS (M+l)+=309.5.
Table-37: Step 1:
Figure imgf000507_0002
Chiral
NSSy6115 Cs2C03, ACN, 90 °C, 16h -
NSSy6149 Cs2C03,TEA:ACN (1: 1), 75 °C, 2 days 13
NSSy6099 K+(CH3)3CO",THF, 75 °C, 3h 56
[001379] Step 2[NSSy6131]: The Procedure is similar to Step l[NSSy6629] in
Example-839. MS (M+l)+=408.2; IH-NMR (400 MHz, DMSO-d6-80 °C): δ 7.34 (s, IH), 6.94 (d, J = 8.00 Hz, IH), 5.77 (s, IH), 4.05 (s, 4H), 3.06 (s, 4H), 2.41 (s, 3H), 1.89-1.86 (m, 2H), 1.73-1.69 (m, 2H), 1.60-1.57 (m, IH), 1.35-1.13 (m, 6H).
[001380] Step 2[NSSy6100]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=404.2; IH-NMR (400 MHz, DMSO-d6): δ 7.32 (s, IH), 6.86 (d, J = 6.80 Hz, IH), 4.12-4.04 (m, 2H), 3.94-3.92 (m, IH), 3.55-3.41 (m, 3H), 3.32-3.29 (m, 4H), 2.86 (m, IH), 2.68-2.62 (m, IH), 2.41 (s, 3H), 1.34-1.19 (m, 5H) and isomers was separated by Chiral HPLC to afford [NSSy6124]. MS (M+l)+=404.2; IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.89 (d, J = 8.16 Hz, IH), 5.63 (s, IH), 4.25-4.05 (m, 2H), 3.94-3.80 (m, IH), 3.50 (s, 4H), 3.30 (s, 3H), 2.89 (t, J = 11.96 Hz, IH), 2.69-2.68 (m, IH), 2.42 (s, 3H), 1.89-1.87 (m, 2H), 1.74-1.70 (m, 2H), 1.61-1.58 (m, IH), 1.36-1.15 (m, 6H) and [NSSy6115]. MS
(M+l)+=404.2; IH-NMR (400 MHz, DMSO-d6): δ 7.30 (s, IH), 6.87 (d, J = 8.00 Hz, IH), 5.63 (s, IH), 4.05-3.93 (m, 3H), 3.51-3.41 (m, 4H), 3.30 (s, 3H), 2.90-2.87 (m, IH), 2.69- 2.51 (m, IH), 2.42 (s, 3H), 1.89-1.87 (m, 2H), 1.74-1.70 (m, 2H), 1.61 (m, IH), 1.36-1.18 (m, 6H).
[001381] Step 2[NSSy6149]: The Procedure is similar to Step 1[B] in Example-838. MS ( M+l)+=415.2; IH-NMR (400 MHz, DMSO-d6-80 °C): δ 7.31 (s, IH), 6.81 (d, J = 8.00 Hz, IH), 5.61 (s, IH), 4.57-4.54 (m, 2H), 4.85-4.45 (m, 2H), 3.53 (s, 4H), 3.48-3.41 (m, IH), 2.40 (s, 3H), 2.32 (s, 4H), 1.88-1.85 (m, 2H), 1.74- 1.69 (m, 3H), 1.60-1.57 (s,
IH), 1.34-1.13 (m, 6H).
[001382] Step 2[NSSy6099]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=404.2; IH-NMR (400 MHz, DMSO-d6): δ 7.43 (s, 2H), 5.79 (s, IH), 5.34 (s, IH), 4.33 (s, 2H), 3.91 (s, 2H), 3.58 (s, 3H), 2.43 (s, 3H), 1.89 (s, 2H), 1.73 (s, 2H), 1.60 (s, IH), 1.36-1.16 (m, 5H). Example-678:
Figure imgf000509_0001
Figure imgf000510_0001
Figure imgf000511_0001
[001383] Step 2[IN11055-069-P1]: To a stirred solution of 6-chloro-N-(4, 4- dimethylcyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine (0.2 g, 0.59 mmol) in methanol (10 mL) was added sodium methoxide (0.202 g, 2.975 mmol). The reaction mixture was heated to reflux at 80 °C for 16h. The reaction mixture was quenched with water (10 mL) and extracted with (3x30 mL) of ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure to afford crude product, which was purified by flash column chromatography using 50% ethyl acetate in pet-ether to afford N-(4, 4-dimethylcyclohexyl)-6-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.08 g, 40%). MS (M+l)+=333.1; IH-NMR (400 MHz, DMSO-d6): δ 7.45 (s, IH), 7.30 (s, IH), 5.75 (s, IH), 3.91 (s, 3H), 3.90 (s, IH), 2.46 (s, 3H), 3.90 (s, 2H), 1.45-1.20 (m, 6H), 0.92 (s, 6H).
[001384] Step 2[IN11055-066-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.40 (s, 2H), 5.73 (s, IH), 4.20 (s, IH), 3.87 (s, 3H), 2.43 (s, 3H), 2.00-1.82 (m, 2H), 1.70-1.40 (m, 6H).
[001385] Step 2[IN11104-084-P2]: IH-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), 7.23 (s, IH), 5.75 (s, IH), 4.32 (s, IH), 3.90 (s, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 2.05 (d, J = 24.00 Hz, 2H), 1.75-1.65 (m, 2H), 1.60-1.50 (m, 2H), 1.25-1.15 (m, 4H).
[001386] Step 2[IN11137-018-P1]: IH-NMR (400 MHz, DMSO-d6): δ 7.41 (s, 2H), 5.80 (s, IH), 4.05 (s, IH), 3.87 (s, 3H), 3.90 (s, IH), 2.44 (s, 4H), 2.12-2.09 (m, IH), 1.94- 1.90 (m, IH), 1.75 (s, IH), 1.44-1.41 (m, IH).
[001387] Step 2[IN11106-027-Pl]: IH-NMR (400 MHz, CD30D): δ 7.26 (d, J = 0.8 Hz, IH), 5.78 (s, IH), 3.98-3.97 (m, IH), 3.95 (s, 3H), 3.79-3.76 (m, IH), 3.54-3.48 (m, IH), 2.49 (s, 3H), 2.07-2.03 (m, IH), 1.81-1.60 (m, 4H), 1.33-1.23 (m, 2H).
[001388] Step 2[IN11067-072-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), 7.37 (s, IH), 5.79 (s, IH), 4.86-4.74 (m, IH), 3.87 (s, 3H), 2.43 (s, 3H), 2.12-1.85 (m, 2H), 1.80-1.52 (m, 6H).
[001389] Step 2IN11067-035-P1]: IH-NMR (400 MHz, CDC13): δ 7.00 (s, IH), 5.61 (s, IH), 5.28 (s, IH), 4.03 (s, 3H), 3.34 (s, IH), 2.55 (s, 3H), 2.00 (d, J = 40.00 Hz, 2H), 1.80- 1.70 (m, IH), 1.68-1.55 (m, IH), 1.45-1.20 (m, 6H).
[001390] Step 2[IN11125-028-Pl]: IH-NMR (400 MHz, MeOD): δ 7.27 (s, IH), 5.76 (s, IH), 4.50 (s, IH), 3.96 (s, 3H), 2.66-2.61 (m, IH), 2.51 (s, 3H), 2.90-1.95 (m, 5H), 1.82- 1.70 (m, IH).
[001391] Step 2[IN11107-023-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.44 (s, IH), 7.39 (d, J = 1.20 Hz, IH), 5.74 (d, J = 4.80 Hz, IH), 3.86 (s, 3H), 3.29 (s, 2H), 2.42 (s, 3H), 1.97-1.89 (m, 2H), 1.71-1.59 (m, 5H).
[001392] Step 2[IN11107-021-P1]: IH-NMR (400 MHz, DMSO-d6): δ 7.48-7.45 (m, IH), 7.42 (d, J = 0.80 Hz, IH), 5.78 (s, IH), 3.88 (s, 3H), 3.45 (s, 2H), 2.44 (s, 3H), 2.30-2.10 (m, 2H), 1.74 (t, J = 44.40 Hz, 3H). [001393] Step 2[ΙΝ11111-003-Ρ1]: IH-NMR (400 MHz, MeOD): δ 7.25 (d, J = 0.80 Hz, IH), 5.65 (s, IH), 4.50 (s, IH), 3.95 (s, 3H), 2.50 (s, 3H), 2.41 (m, 2H), 1.98-1.97 (m, 2H), 1.79 (m, 2H).
[001394] Step 2[IN11106-033-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.40 (s, IH), 7.32 (s, IH), 5.76 (d, J = 6.80 Hz, IH), 3.87 (s, 3H), 2.43 (s, 3H), 1.95-1.81 (m, 2H), 1.80- 1.62 (m, 2H), 1.50-1.30 (m, 3H), 1.10-0.95 (m, 2H), 0.40-0.20 (m, 4H).
[001395] Step 2[IN11106-004-Pl]: IH-NMR (400 MHz, MeOD): δ 7.26 (s, IH), 5.76 (s, IH), 4.10 (s, IH), 3.98 (t, J = 3.60 Hz, IH), 3.95 (s, 4H), 3.57 (t, J = 2.00 Hz, 2H), 2.50 (s, 3H), 2.00-1.96 (m, 2H), 1.58-1.53 (m, 2H).
[001396] Step 2[IN11079-072-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.41 (s, 2H), 5.79 (s, IH), 3.87 (s, 3H), 2.70 (s, 4H), 2.43 (s, 4H), 2.22-2.10 (m, 2H), 1.68-1.50 (m, 2H).
[001397] Step 2[IN11133-014-P1]: IH-NMR (400 MHz, DMSO-d6): δ 7.93 (s, IH),
7.43 (s, IH), 5.77 (s, IH), 4.10 (s, IH), 3.90 (s, 3H), 3.08-2.99 (m, 2H), 2.67-2.60 (m, 2H),
2.44 (s, 3H).
[001398] Step 2[IN11055-087-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.38 (s, 2H), 5.65 (bs, IH), 3.86 (s, 3H), 2.42 (s, 3H), 2.22-2.17 (m, 2H), 1.70-1.65 (m, IH), 1.48-1.43 (m, 4H), 1.22 (m, 2H), 1.11-1.08 (m, 2H).
Example-679:
Figure imgf000513_0001
[001399] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4, 4-difluorocyclohexyl)-N- methyl-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.38 g, 86%). MS (M+l)+=359.8.
[001400] Step 2[NSSy6105]: The Procedure is similar to Step 1[B] in Example-838. 0.38 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-N-methyl-2-(4-methylthiazol-2-yl) pyrimidin- 4-amine gave methyl 3-((6-((4, 4-difluorocyclohexyl) (methyl) amino)-2-(4-methylthiazol-2- yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (0.12 g, 27%). MS (M+l)+=454.2; IH-NMR (400 MHz, DMSO-d6): δ 7.45 (s, 2H), 6.13 (s, IH), 5.43-5.40 (m, 1H), 4.36 (t, J = 9.2 Hz, 2H), 3.92 (s, 2H), 3.58 (s, 3H), 2.95 (s, 3H), 2.45 (s, 3H), 2.20-1.85
(m, 4H), 1.85-1.66 (m, 4H).
Example-398:
Figure imgf000514_0001
[001401] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4-methylcyclohex-3-en- l-yl)-2- (4-methylthiazol-2-yl) pyrimidin-4-amin as a brownish gum (0.35 g, 89%). MS
(M+l)+=321.0.
[001402] Step 2[NSSy5854]: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 6-chloro-N-(4-methylcyclohex-3-en- l-yl)-2-(4-methylthiazol-2-yl)pyrimidin-4-amine gave methyl 3-((6-((4-methylcyclohex-3-en- l-yl)amino)-2-(4-methylthiazol-2-yl)pyrimidin- 4-yl)oxy)azetidine-l-carboxylate as an off-white solid (0.18 g, 43%). MS (M+l)+=416.4; 1H-NMR (400 MHz, DMSO-d6): δ 7.42 (s, 2H), 6.16 (s, 1H), 5.81 (s, 1H), 5.34 (s,
2H), 4.33 (s, 1H), 3.93 (s, 2H), 3.57 (s, 3H), 2.43 (s, 3H), 2.11-1.88 (m, 5H), 1.68 (s, 3H), 1.65 (s, 1H).
Example-680:
Figure imgf000514_0002
[001403] Step 1: To a stirred solution of 2-(4, 6-dichloropyrimidin-2-yl)-4- methylthiazole (0.3 g, 1.22 mmol) and 3-(isopropoxymethyl)morpholine (0.21 g, 1.34 mmol) in acetonitrile (5 mL) was added trimethylamine (0.85 mL, 6.10 mmol) and stirred at rt for 24h. The reaction mixture was diluted with ethyl acetate (100 mL), concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using 35% ethyl acetate in pet-ether to afford 4-(6-chloro-2-(4- methylthiazol-2-yl) pyrimidin-4-yl)-3-(isopropoxymethyl)morpholine as an off-white solid (0.22 g, 48%). MS (M+l)+=369.1.
[001404] Step 2[IN10965-091-P1]: The Procedure is similar to Step l[NSSy6629] in Example-839. 0.05 g of 4-(6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl)-3- (isopropoxymethyl) morpholine gave N-(4, 4-difluorocyclohexyl)-6-(3-(isopropoxymethyl) morpholino)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a white solid (0.045 g, 55%). MS (M+l)+=468.2; 1H-NMR (400 MHz, DMSO-d6) : δ 7.33 (s, 1H), 7.03 (d, / = 7.60 Hz, 1H), 5.62 (s, 1H), 4.30 (s, 1H), 4.00-3.80 (m, 4H), 3.72-3.60 (m, 2H), 3.55-3.44 (m, 2H), 3.50- 3.40 (m, 1H), 3.10-3.00 (m, 1H), 2.41 (s, 3H), 2.12-1.85 (m, 6H), 1.62-1.50 (m, 2H), 1.06 (dd, = 6.40, 13.60 Hz, 6H).
Example-681:
Figure imgf000515_0001
NSSy6126 NSSy6057
[001405] Step 1: The Procedure is similar to Step 1[B] in Example-838. 2.0 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave methyl 3-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (1.4 g, 52%). MS
(M+l)+=341.2.
Table-40: Step 2:
Figure imgf000515_0002
[001406] Step 2[NSSy6126]: The Procedure is similar to Step l[NSSy6629] in
Example-839. MS (M+l)+=430.2; 1H-NMR (400 MHz, DMSO-d6) : δ 7.31 (s, 1H), 6.86 (s, 1H), 5.61 (s, 1H), 4.12-4.04 (m, 2H), 3.93 (d, J = 9.60 Hz, 1H), 3.60-3.41 (m, 4H), 3.32-3.29 (m, 4H), 2.86 (m, 1H), 2.65 (t, / = 10.40 Hz, 1H), 2.40 (s, 3H), 1.86-1.57 (m, 5H), 1.34-1.19 (m, 5H).
Step 2[NSSy6057]: The Procedure is similar to Step 2[NSSy6464] in Example-869. MS (M+l)+=307.0; 1H-NMR (400 MHz, DMSO-d6) : δ 8.66 (d, / = 6.00 Hz, 1H), 7.55 (s, 1H), 7.05 (d, / = 5.6 Hz, 1H), 5.51-5.48 (m, 1H), 4.40 (d, / = 7.2 Hz, 2H), 4.01-4.00 (m, 2H), 3.58 (s, 3H), 2.33 (s, 3H).
Example-682:
Figure imgf000516_0001
[001407] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.2 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4-fluorocyclohexyl) -2-(4- methylthiazol-2-yl) pyrimidin-4-amine as a brownish gum (0.18 g, 67%). MS (M+l)+=327.4.
[001408] Step 2[NSSy5699]: The Procedure is similar to Step 1[B] in Example-838. 0.18 g of 6-chloro-N-(4-fluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N-(4-fluorocyclohexyl)-2-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-4-amine as an off- white solid (0.1 g, 48%). MS (M+l)+=378.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 6.99-6.92 (m, 1H), 5.64 (s, 1H), 4.74 (t, J = 37.20 Hz, 1H), 3.68-3.60 (m, 4H), 3.49-3.40 (m, 4H), 2.33 (s, 3H), 1.94-1.73 (m, 2H), 1.66-1.63 (m, 4H), 1.60-1.54 (m, 2H), 1.43-1.42 (m, 1H).
Example-683:
Figure imgf000516_0002
[001409] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.2 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(cyclohex-3-en- l-yl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.14 g, 75%). MS
(M+l)+=307.4.
[001410] Step 2[NSSy5703]: The Procedure is similar to Step 1[B] in Example-838. 0.14 g of 6-chloro-N-(cyclohex-3-en-l-yl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N-(cyclohex-3-en-l-yl)-2-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-4-amine as an off- white solid (0.09 g, 56%). MS (M+l)+=358.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.33 (s, 1H), 6.92 (d, J = 7.64 Hz, 1H), 5.66 (d, J = 4.36 Hz, 3H), 3.92-3.69 (m, 1H), 3.68-3.67 (m, 4H), 3.49-3.42 (m, 4H), 2.33 (s, 3H), 2.14-2.10 (m, 2H), 1.92-1.88 (m, 3H), 1.50-1.45 (m, 1H).
Example-684
Figure imgf000517_0001
o o
NSSy5709 NSSy5710
[001411] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 6- chloro-N-(4-fluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave ieri-butyl 3- ((6-((4-fluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) oxy) azetidine-1- carboxylate as a brownish gum (0.3 g, 71%). MS (M+l)+=464.4.
Table-41: Step 2: The Procedure is similar to Step 2[NSSy6924] in Example-857.
Figure imgf000517_0002
[001412] Step 2[NSSy5709]: MS (M+l)+=434.4; IH-NMR (400 MHz, DMSO-d6): δ 7.42-7.41 (m, 2H), 5.83 (s, IH), 5.36 (s, IH), 4.80 (d, J = 48.00 Hz, IH), 4.58-4.54 (m, IH), 4.27-4.23 (m, IH), 4.17-4.14 (m, IH), 3.84-3.80 (m, IH), 2.48 (s, 3H), 1.94-1.93 (m, 2H), 1.76-1.74 (m, 4H), 1.67-1.64 (m, 4H), 0.91-0.93 (m, 6H).
[001413] Step 2[NSSy5710]: MS (M+l)+=422.1; IH-NMR (400 MHz, DMSO-d6): δ 7.56 (s, IH), 7.43 (d, J = 0.80 Hz, IH), 5.82 (s, IH), 5.35 (s, IH), 4.79 (d, J = 44.80 Hz, IH), 4.34 (s, 2H), 3.93 (s, 2H), 3.58 (s, 3H), 2.44 (s, 3H), 2.34-1.74 (m, 6H), 1.64-1.60 (m, 3H). Example-685:
Figure imgf000518_0001
[001414] Step 1: The Procedure is similar to Step 1[B] in Example-838. 2.0 g of 2-(4, 6- dichloropyrimidin-2-yl)-4-methylthiazole gave (lS)-2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol as a brownish gum (2.0 g, 70%). MS (M+l)+=325.0.
[001415] Step 2: The Procedure is similar to Step l[NSSy6930] in Example-867. 5.0 g of (lS)-2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol gave 2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-one as a white solid (4.4 g, 88%). MS (M+l)+=323.1.
[001416] Step 2A [INI 1140-065-P1] : The Procedure is similar to Step 1 [A] in
Example-838. 0.05 g of 2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-one gave 2-((2-(4-methylthiazol-2-yl)-6-morpholinopyrimidin-4-yl) amino) cyclohexan-l-one (0.025 g, 43%). MS (M+l)+=374.0; IH-NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 1.2 Hz, 1H), 6.96 (s, 1H), 5.75 (s, 1H), 4.65 (bs, 1H), 3.75-3.65 (m, 5H), 3.60- 3.45 (m, 5H), 2.42 (s, 4H), 2.08-2.05 (m, 1H), 1.84-1.77 (m, 2H), 1.62-1.53 (m, 3H).
[001417] Step 3: The Procedure is similar to Step 3[NSSy6917] in Example-21. 4.4 g of 2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-one gave 6- chloro-N-(2, 2-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a pale yellow solid (3.0 g, 64%). MS (M+l)+=345.0.
[001418] Step 4: The Procedure is similar to Step l[NSSy6989] in Example-839. 1.0 g of 6-chloro-N-(2, 2-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N- (2, 2-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a brownish gum (0.8 g, 72%). MS (M+l)+=381.2.
[001419] Step 5[IN11140-081-Pl]: The Procedure is similar to Step l[NSSy6697] in Example-873. 0.8 g of N-(2, 2-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one as an off-white solid (0.6 g, 81%). MS (M+l)+=353.0; IH-NMR (400 MHz, DMSO-d6): δ 8.18 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 4.70-4.55 (m, 1H), 2.67 (s, 3H), 2.47 (s, 3H), 2.14 (m, 1H), 1.99-1.94 (m, 2H), 1.75 (m, 2H), 1.49 (m, 3H).
[001420] Step 6[IN11140-083-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.1 g of l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one gave l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol- 2-yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (0.08 g, 80%). MS (M+l)+=355.2; 1H- NMR (400 MHz, DMSO-d6): δ 7.75-7.73 (m, 1H), 7.38 (s, 1H), 6.79 (s, 1H), 5.40-5.38 (m, 1H), 4.54-4.51 (m, 2H), 2.44 (s, 3H), 2.15-2.09 (m, 1H), 1.91-1.89 (m, 2H), 1.75-1.69 (m, 2H), 1.36-1.34 (m, 3H).
[001421] Step 7[IN11140-089-P1]: The Procedure is similar to Step 3[NSSy6917] in Example-21. 0.05 g of l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol gave N-(2, 2-difluorocyclohexyl) -6-(l-fluoroethyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.027 g, 51%). MS
(M+l)+=357.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (s, 1H), 7.42 (s, 1H), 6.95 (s, 1H), 5.61-5.47 (m, 1H), 4.62 (s, 1H), 2.44 (s, 3H), 2.20-1.85 (m, 3H), 1.80-1.45 (m, 8H). Example-686:
Figure imgf000520_0001
[001422] Step 1: The Procedure is similar to Step 3 [INI 1273-018-P1] in Example-889. 0.1 g of l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-ol gave l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4- yl) ethyl methanesulfonate as a brown gum (0.1 g, 83%). MS (M+l)+=433.0.
[001423] Step 2[IN11140-099-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.1 g of l-(6-((2, 2-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) ethyl methanesulfonate gave N-(2, 2-difluorocyclohexyl)-6-(l- methoxyethyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a brown solid (0.035 g, 41%). MS (M+l)+=369.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.78 (d, J = 8.80 Hz, 1H), 7.40 (s, 1H), 6.67 (s, 1H), 4.60 (s, 1H), 4.19 (q, J = 6.40 Hz, 1H), 3.28 (s, 3H), 2.44 (s, 3H), 2.15 (s, 1H), 1.90 (m, 2H), 1.72 (s, 2H), 1.60-1.50 (m, 3H), 1.36-1.30 (m, 3H).
Example-687:
Figure imgf000520_0002
R= y
IN11140-096-P1 IN11140-086-P1
[001424] Step 1: The Procedure is similar to Step 3[NSSy6917] in Example-21. 0.5 g of (lS)-2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan-l-ol gave 6- chloro-N-(2-fluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a pale yellow solid (0.4 g, 80%). MS (M+l)+=225.0. Table-42: Step 2:
Figure imgf000521_0002
[001425] Step 2[IN11140-096-P1] : The procedure is similar to Step l [NSSy6519] in Example-842. 1H-NMR (400 MHz, DMSO-d6): δ 7.50 (d, J = 8.0 Hz, IH), 7.41 (s, IH), 5.83 (bs, IH), 4.50-4.37 (m, IH), 3.88 (s, 3H), 2.44 (s, 3H), 2.08- 1.94 (m, 2H), 1.72- 1.54 (m, 3H), 1.32- 1.23 (m, 4H).
[001426] Step 2[IN11140-086-Pl] : 1H-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 7.10 (d, J = 8.80 Hz, IH), 6.14 (s, IH), 4.50-4.35 (m, IH), 3.69 (s, 4H), 3.50 (s, 4H), 2.42 (s, 3H), 2.08 (s, IH), 1.92 (s, IH), 1.75- 1.45 (m, 3H), 1.35- 1.25 (m, 3H).
Example-688:
Figure imgf000521_0001
IN11140-058-P1
[001427] Step 1 [INI 1140-058-P1] : The Procedure is similar to Step 1 [B] in Example-2. 0.1 g of (lS)-2-((6-chloro-2-(4-methylthiazol-2-yl) pyrimidin-4-yl) amino) cyclohexan- l-ol gave 6-chloro-N-(2-fluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off- white solid (0.037 g, 32%). MS (M+l)+=376.1 ; 1H-NMR (400 MHz, DMSO-d6) : δ 7.33 (s, IH), 6.78 (d, / = 6.80 Hz, IH), 5.66 (s, IH), 4.68 (d, / = 4.80 Hz, IH), 3.69 (s, 4H), 3.49 (s, 4H), 2.41 (s, 3H), 2.00- 1.85 (m, 2H), 1.62- 1.56 (m, 2H), 1.35- 1.15 (m, 6H). Example-689:
Figure imgf000522_0001
[001428] Step 1[IN11140-090-P1]: The Procedure is similar to Step l[NSSy6519] in Example-6. 0.1 g of 6-chloro-N-(2-fluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine gave 6-methoxy-N-(2-methoxycyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine as an off-white solid (0.04 g, 41%). MS (M+l)+=335.2; 1H-NMR (400 MHz, DMSO- d6): δ 7.39 (s, IH), 7.31 (d, / = 8.00 Hz, IH), 5.79 (s, IH), 3.87 (s, 3H), 3.26 (s, 3H), 3.14 (s, IH), 2.43 (s, 3H), 2.05 (s, IH), 1.91 (s, IH), 1.70-1.60 (m, 2H), 1.35-1.15 (m, 5H).
Example-690:
Figure imgf000522_0002
IN11140-063-P1 IN11140-066-P1
Table-43: Step 1:
Figure imgf000522_0003
[001429] Step 1[IN11140-063-P1]: The procedure is similar to Step l[NSSy6519] in Example-842. 1H-NMR (400 MHz, DMSO-d6): δ 8.12 (d, J = 8.80 Hz, 1H), 7.50 (s, 1H), 6.68 (s, 1H), 4.59 (s, 1H), 3.53 (s, 3H), 2.45 (s, 3H), 2.15-2.05 (m, 6H), 2.00-1.70 (m, 2H).
[001430] Step l[IN11140-066-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 1.20 Hz, 1H), 7.07 (d, J = 9.20 Hz, 1H), 5.82 (s, 1H), 4.50 (s, 1H), 3.69 (t, J = 4.80 Hz, 4H), 3.49 (s, 4H), 2.45 (s, 3H), 2.11-1.40 (m, 8H).
Example-691:
Figure imgf000523_0001
[001431] Step 1: The procedure is similar to Step l[NSSy6710] in Example-854. 2.0 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(methylsulfonyl) pyrimidin-4-amine gave 4- chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carbonitrile as an off-white gum (0.9 g, 56%). MS (M+l)+=272.7.
[001432] Step 2: To a stirred solution of 4-chloro-6-((4, 4-difluorocyclohexyl) amino)pyrimidine-2-carbonitrile (0.9 g, 3.30 mmol) in N, N-dimethylformamide (15 mL) was added triethylamine (0.66 g, 6.60 mmol) and ammonium sulphide in water (20%) (2.24 g, 6.60 mmol) and the reaction mixture was stirred at room temperature. After 15 min, the reaction mixture was quenched with water and extracted with ethyl acetate (2x25 mL). The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford 4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carbothioamide as light brown solid (0.8 g, 80%). MS (M+l)+=307.0.
[001433] Step 3: To a stirred solution of 4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-2-carbothioamide (0.8 g, 2.60 mmol) in THF (30 mL) was added Ethyl bromopyruvate (0.76 g, 3.9 mmol). The reaction mixture was stirred at room temperature. After 4h, the reaction mixture was concentrated to afford crude product, which was dissolved in ethyl acetate and washed with 10% sodium bicarbonate solution, the organic layer was concentrated to afford ethyl 2-(4-chloro-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-2- yl)thiazole-4-carboxylate as an off-white solid (0.6 g, 60%). MS (M+l)+=403.0.
[001434] Step 4: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.6 g of ethyl 2-(4-chloro-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-2-yl)thiazole-4-carboxylate gave (2-(4-chloro-6-((4, 4-difluorocyclohexyl)arnino)pyrimidin-2-yl)thiazol-4-yl)methanol as an off-white gum (0.4 g, 75%). MS (M+l)+=361.0.
[001435] Step 5: The procedure is similar to Step 3[NSSy6917] in Example-21. 0.4 g of (2-(4-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-2-yl) thiazol-4-yl) methanol gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4-(fluoromethyl) thiazol-2-yl) pyrimidin-4-amine as a light yellow solid (0.2 g, 50%). MS (M+l)+=362.8.
[001436] Step 6[NSSy5715]: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4-(fluoromethyl)thiazol-2-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-2-(4-(fluoromethyl) thiazol-2-yl)-6-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyrimidin-4-amine as an off-white solid (0.06 g, 26%). MS
(M+l)+=426.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.92 (d, J = 3.20 Hz, IH), 7.09 (d, J = 8.00 Hz, IH), 5.56 (s, IH), 5.44 (s, IH), 5.32 (s, IH), 4.73 (m, 4H), 4.16 (m, 4H), 3.95 (m, IH), 2.08-1.91 (m, 6H), 1.58-1.55 (m, 2H).
Example-692:
Figure imgf000524_0001
[001437] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.25 g of 2-(4, 6-dichloropyrimidin-2-yl)-4-methylthiazole gave 2-(4-(7-azabicyclo [4.2.0] octan-7-yl)-6- chloropyrimidin-2-yl)-4-methylthiazole as a brownish gum (0.31 g, 96%). MS
(M+l)+=321.1.
[001438] Step 2[NSSy6348]: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 2-(4-(7-azabicyclo[4.2.0]octan-7-yl)-6-chloropyrimidin-2-yl)-4-methylthiazole gave 4- (6-(7-azabicyclo[4.2.0]octan-7-yl)-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)morpholine as pale yellow solid (0.088 g, 29%). MS (M+l)+=372.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.34 (s, IH), 5.50 (s, IH), 4.37-4.35 (m, IH), 3.92-3.88 (m, IH), 3.68-3.63 (m, 5H), 3.55- 3.54 (m, 4H), 2.67-2.63 (m, IH), 2.42 (s, 3H), 2.14-2.11 (m, IH), 1.88-1.87 (m, IH), 1.82- 1.61 (m, 2H), 1.61-1.34 (m, 4H).
Example-693:
Figure imgf000525_0001
Table-44: Step 1: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000525_0002
[001439] Step 2[NSSy6265]: 1H-NMR (400 MHz, DMSO-d6-80 °C): δ 7.09 (d, J = 8.12 Hz, IH), 6.01 (s, IH), 5.54 (s, IH), 3.96 (s, IH), 3.68-3.66 (m, 4H), 3.45 (s, 4H), 2.49 (s, 3H), 2.33-2.30 (m, IH), 2.15 (s, 3H), 2.00-1.90 (m, 2H), 1.82-1.67 (m, 3H), 1.49-1.45 (m, IH), 1.30-1.24 (m, IH). [001440] Step 2[NSSy6386]: 1H-NMR (400 MHz, DMSO-d6): δ 9.32 (s, IH), 6.04 (d, J = 7.60 Hz, IH), 4.48 (s, IH), 3.67-3.54 (m, 4H), 3.53-3.42 (m, 4H), 3.32 (s, 3H), 2.16 (s, 3H), 2.09-1.83 (m, 6H), 1.69-1.52 (m, 2H).
Exam le-694:
Figure imgf000526_0001
[001441] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.8 g of 4, 6- dichloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine gave 4-(6-chloro-2-(3, 5-dimethyl- lH-pyrazol-l-yl) pyrimidin-4-yl) morpholine as an off-white solid (0.8 g, 82%). MS
(M+l)+=294.0.
[001442] Step 2[IN10991-021-P1]: To a suspension of sodium hydride (0.04 g, 1.062 mmol) in N, N-Dimethylformamide (3 mL) was added 4, 4-difluorocyclohexan-l-ol (0.1 g, 0.75 mmol), stirred until effervescence ceased. 4-(6-chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) morpholine (0.2 g, 0.68 mmol) was added to the reaction mixture and heated to 110 °C for 16h. The reaction mixture was poured into ice cold Water (10 mL) and extracted with ethyl acetate (2x10 mL). The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using 15% ethyl acetate in pet-ether to afford 4-(6-((4, 4-difluorocyclohexyl) oxy)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4- yl)morpholine as a white solid (0.07 g, 17%). MS (M+l)+=394.1; 1H-NMR (400 MHz, DMSO-d6): δ 6.73 (s, IH), 6.13 (s, IH), 5.06 (s, IH), 3.66 (s, 4H), 3.59 (s, 4H), 2.61 (s, 3H), 2.19 (s, 3H), 2.10-1.95 (m, 6H), 1.90-1.80 (m, 2H).
Example-695:
Figure imgf000526_0002
[001443] Step 1: The procedure is similar to Step 1[H] in Example-838. 0.5 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- IH-pyrazol- l-yl)pyrimidin-4-amine gave (E)-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazo 1-1 -yl)-6-(2- ethoxyvinyl)pyrimidin-4-amine as a pale yellow solid (0.27 g, 49%). MS (M+l)+=378.1.
[001444] Step 2: The procedure is similar to Step l[NSSy6697] in Example-873. 0.15 g of (E)-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)-6-(2-ethoxy vinyl) pyrimidin-4-amine gave 2-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl) acetaldehyde as a brownish gum (0.14 g, 70%). MS (M+l)+=350.2.
[001445] Step 3[IN10963-077-Pl]: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.22 g of 2-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4-yl)acetaldehyde gave 2-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl) ethan-l-ol as a white solid (0.015 g, 7%). MS (M+l)+=352.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 7.60 Hz, 1H), 6.27 (s, 1H), 6.03 (s, 1H), 4.67 (t, J = 5.20 Hz, 1H), 4.01 (s, 1H), 3.75-3.65 (m, 2H), 2.70-2.60 (m, 4H), 2.16 (s, 3H), 2.10-1.85 (m, 7H), 1.60-1.50 (m, 2H).
Exampl -696:
Figure imgf000527_0001
IN10963-049-P1 IN11108-019-P1 IN11146-016-P1
Figure imgf000527_0002
Figure imgf000528_0001
Table-47: Step 2: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000528_0003
[001446] Step 2IN10963-049-P1]: 1H-NMR (400 MHz, DMSO-d6): δ 7.00 (d, J = 7.60 Hz, IH), 5.99 (s, IH), 5.54 (s, IH), 4.84-4.72 (m, IH), 3.67 (s, 4H), 3.44 (s, 4H), 2.52 (s, 3H), 2.14 (s, 3H), 1.90-1.50 (m, 8H).
[001447] Step 2[IN11108-019-P1]: 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (d, J = 6.4 Hz, IH), 6.01 (s, IH), 5.51 (s, IH), 4.11 (m, IH), 3.68-3.65 (m, 4H), 3.50-3.43 (m, 4H), 3.31- 2.96 (m, 2H), 2.67-2.59 (m, 2H), 2.55 (s, 3H), 2.14 (s, 3H).
[001448] Step 2[IN11146-016-P1]: 1H-NMR (400 MHz, DMSO-d6): δ 7.12 (s, IH), 6.00 (s, IH), 5.58 (s, IH), 4.47-4.42 (m, IH), 4.34-4.30 (m, IH), 3.91 (s, IH), 3.67 (s, 4H), 3.45 (s, 4H), 2.30 (s, 4H), 2.10-1.85 (m, 2H), 1.62-1.45 (m, 3H), 1.32-1.20 (m, 4H).
Example-697:
Figure imgf000528_0002
[001449] Step 1: The procedure is similar to Step 1[H] in Example-838. 2.0 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidin-4-amine as a brownish gum (1.2 g, 54%). MS (M+l)+=378.1.
[001450] Step 2: The procedure is similar to Step l[NSSy6697] in Example-873. 1.2 g of N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)-6-(l- ethoxyvinyl)pyrimidin-4-amine gave l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-one as a brownish gum (1.0 g, 90%). MS
(M+l)+=350.0.
[001451] Step 3: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.5 g of
1- (6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazol- l-yl)pyrimidin-4- yl)ethan-l-one gave l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazo 1-1- yl)pyrimidin-4-yl)ethan-l-ol as an off-white solid (0.45 g, 89%). MS (M+l)+=352.1.
[001452] Step 4: To a stirred solution of l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol (0.45 g, 1.28 mmol) in dichloro methane (50 mL) was added Phosphorus tribromide (0.6 mL, 6.40 mmol) slowly portion wise at 0 °C. The reaction mixture was warmed to rt and stirred for 16h. The reaction mixture was poured in ice cold water (80 mL), extracted with DCM (3x50 mL). The combined organic layers were washed with saturated NaHC03 solution (3x20 mL) followed by brine solution (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using 30% ethyl acetate in pet-ether to afford 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- 1 H- pyrazol-l-yl)pyrimidin-4-amine as an off-white solid (0.27 g, 51%). MS (M+l)+=414.0.
[001453] Step 5[IN10963-068-Pl]: Sodium metal (0.14 g, 6.05 mmol) was added to isopropanol (20 mL) at rt, the mixture was heated at 75 °C for lh. The above mixture (sodium isopropoxide) was cooled to rt, then 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-
2- (3, 5-dimethyl- lH-pyrazol-l-yl) pyrimidin-4-amine (0.25 g, 0.60 mmol) was added. The reaction mixture was stirred at rt for 6h. The reaction mixture was poured in ice cold water (40 mL), extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with brine solution (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by flash column
chromatography using 37% ethyl acetate in pet-ether to afford N-(4, 4-difluorocyclohexyl)-2- (3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l-isopropoxyethyl) pyrimidin-4-amine as a white solid (0.04 g, 17%). MS (M+l)+=394.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (s, 1H), 6.48 (s, IH), 6.04 (s, IH), 4.05 (s, IH), 3.62-3.55 (m, IH), 2.32 (s, 3H), 2.12-1.85 (m, 6H), 1.60-1.50 (m, 2H), 1.30-1.20 (m, 6H), 1.18-1.10 (m, 7H).
Example-698:
Figure imgf000530_0001
[001454] Step l[IN10987-055-Pl]: The procedure is similar to Step 1[B] in Example- 838. 0.2 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l- yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)- 6-(l-morpholinoethyl) pyrimidin-4-amine as an off-white solid (0.14 g, 68%). MS
(M+l)+=421.1; IH-NMR (400 MHz, DMSO-d6): δ 7.61 (s, IH), 6.46 (s, IH), 6.04 (s, IH), 4.03 (s, IH), 3.59 (s, 3H), 2.50 (s, 5H), 2.16 (s, 4H), 2.10-1.85 (m, 8H), 1.60-1.50 (m, 2H), 1.25 (s, 4H).
Example-699:
IN10973-004-P1 IN10973-005-P1 IN10973-007-P1 IN10973-008-P1 IN10973-006-P1
Figure imgf000530_0002
[001455] Step 1: The procedure is similar to Step 1[H] in Example-838. 1.8 g of 4, 6- dichloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine gave 4-chloro-2-(3, 5-dimethyl-lH- pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidine as an off-white solid (1.1 g, 53%). MS
(M+l)+=279.0.
[001456] Step 2: The procedure is similar to Step l[NSSy6697] in Example-873. 1.1 g of 4-chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidine gave l-(6- chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-one as an off-white solid (0.72 g, 72%). MS (M+l)+=251.0.
[001457] Step 3: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.72 g of l-(6-chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-one gave l-(6- chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (0.65 g, 92%). MS (M+l)+=253.0.
Table-48: Step 4:
Figure imgf000531_0001
[001458] Step 4[IN10973-004-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 6.60 (s, IH), 6.05 (s, IH), 5.42 (d, J = 5.20 Hz, IH), 4.50-4.52 (m, IH), 3.35 (s, 5H), 2.48 (s, 3H), 2.17 (s, 3H), 1.81 (d, J = 12.80 Hz, 2H), 1.70-1.50 (m, 5H), 1.35 (d, J = 6.80 Hz, 5H).
[001459] Step 4[IN10973-005-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 7.66 (s, IH), 6.50 (s, IH), 6.04 (s, IH), 5.40 (t, J = 4.40 Hz, IH), 4.46-4.32 (m, IH), 3.89 (s, IH), 2.43 (s, 3H), 2.16 (s, 3H), 1.90-1.59 (m, 6H), 1.38-1.26 (m, 6H).
[001460] Step 4[IN10973-008-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (d, J = 7.60 Hz, IH), 6.50 (s, IH), 6.03 (s, IH), 5.35 (s, IH), 4.45 (s, IH), 3.82 (s, IH), 2.16 (s, 3H), 1.89 (d, J = 11.20 Hz, 2H), 1.74-1.71 (m, 2H), 1.65-1.55 (m, 2H), 1.35-1.10 (m, 10H).
Example-700:
Figure imgf000532_0001
Figure imgf000532_0002
[001461] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.76 g of 4, 6- dichloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-N-(3, 3- difluorocyclobutyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-amine as an off-white solid (0.75 g, 75%). MS (M+l)+=314.0.
[001462] Step 2: To a stirred solution of 6-chloro-N-(3, 3-difluorocyclobutyl)-2-(3, 5- dimethyl-lH-pyrazol-l-yl)pyrimidin-4-amine (0.5 g, 1.59 mmol) in ethanol (10 niL) was added diisopropylethylamine (1.66 mL, 9.56 mmol) and [1, l'-Bis
(diphenylphosphino)ferrocene]dichloropalladium(II) (1: 1) DCM complex (0.065 g, 0.079 mmol). The steel bomb was sealed and filled with carbon monoxide gas up to 100 Psi pressure. Reaction mixture was heated to 100 °C for 16h. The reaction mixture was cooled to room temperature, degassed the steel bomb and reaction mixture was concentrated under reduced pressure to obtained the crude which was purified by flash column chromatography using 3% methanol in chloroform to afford ethyl 6-((3, 3-difluorocyclobutyl)amino)-2-(3, 5- dimethyl-lH-pyrazol-l-yl)pyrimidine-4-carboxylate as a brown solid (0.35 g, 55%). MS (M+l)+=352.1.
[001463] Step 3: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.25 g of ethyl 6-((3, 3-difluorocyclobutyl) amino)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine-4- carboxylate gave (6-((3, 3-difluorocyclobutyl) amino)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol as yellowish gum (0.18 g, 82%). MS (M+l)+=310.1.
[001464] Step 4: The procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.18 g of (6-((3, 3-difluorocyclobutyl) amino)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin- 4-yl) methanol gave 6-(bromomethyl)-N-(3, 3-difluorocyclobutyl)-2-(3, 5-dimethyl-lH- pyrazol-l-yl) pyrimidin-4-amine as brownish gum (0.2 g, 95%). MS (M+l)+=374.0. [001465] Step 5 [INI 1108-038-P1]: The procedure is similar to Step l[NSSy6519] in Example-842. 0.2 g of 6-(bromomethyl)-N-(3, 3-difluorocyclobutyl)-2-(3, 5-dimethyl- 1H- pyrazol-l-yl) pyrimidin-4-amine gave N-(3, 3-difluorocyclobutyl)-2-(3, 5-dimethyl- 1H- pyrazol-l-yl)-6-(methoxymethyl) pyrimidin-4-amine as a brownish gum (0.023 g, 13%). MS (M+l)+=324.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (bs, 1H), 6.41 (bs, 1H), 6.06 (s, 1H), 4.32 (s, 3H), 3.39 (s, 3H), 3.14-3.00 (m, 2H), 2.67-2.44 (m, 6H), 2.16 (s, 3H).
Example-701:
Figure imgf000533_0001
[001466] Step 1: The procedure is similar to Step 1[H] in Example-838. 0.6 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidin-4-amine as an off-white solid (0.4 g, 60%). MS (M+l)+=378.1.
[001467] Step 2: The procedure is similar to Step l[NSSy6697] in Example-873. 1.2 g of N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-1 -yl)-6- (prop-l-en-2-yl)pyrimidin-4-amine as a gummy solid (0.6 g, 54%). MS (M+l)+=350.1.
[001468] Step 3[IN10964-046-Pl]: To a stirred solution of N-(4, 4- difluorocyclohexyl)-2-(3, 5-dimethyl- IH-pyrazol- l-yl)-6-(prop- l-en-2-yl) pyrimidin-4-amine (0.1 g, 0.28 mmol) and dimethylamine in MeOH (0.0037 g, 1.145 mmol) in MeOH (25 mL) was added Titanium isopropoxide (0.16 g, 0.57 mmol). The reaction mixture was stirred at rt for 16h. The reaction mixture was diluted with MeOH, followed by NaBH4 was added. The mixture was stirred at rt for 2h. The reaction mixture was diluted with aqueous ammonia and the precipitated solids were filtered through cellite, washed with ethyl acetate, filtrate was washed with brine solution, dried over Na2S04, concentrated under reduced pressure to afford crude product. Which was purified by Preparative HPLC to afford N-(4, 4- difluorocyclohexyl)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)-6-(l-(dimethylamino) ethyl) pyrimidin-4-amine as an off-white solid (0.017 g, 15%). MS (M+l)+=379.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, IH), 6.44 (s, IH), 6.03 (s, IH), 4.05 (s, IH), 2.55 (s, 3H), 2.18 (s, 6H), 2.16 (s, 3H), 2.15-1.85 (m, 6H), 1.60-1.50 (m, 2H), 1.23 (s, 4H).
Example-702:
Figure imgf000534_0001
IN10881-040-P1
[001469] Step 1: The procedure is similar to Step 1[H] in Example-838. 0.25 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l-ethoxyvinyl) pyrimidin-4-amine as a yellow liquid (0.23 g, 83%). MS (M+l)+=378.2.
[001470] Step 2[IN10881-040-Pl]: The procedure is similar to Step l[NSSy6697] in Example-873. 0.25 g of N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6-(l- ethoxyvinyl)pyrimidin-4-amine gave l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3, 5-dimethyl- lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-one as a yellow liquid (0.06 g, 28%). MS
(M+l)+=350.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.04 (d, J = 6.8 Hz, IH), 6.85 (s, IH), 6.10 (s, IH), 4.10 (bs, IH), 2.58 (s, 3H), 2.54 (s, 3H), 2.16 (s, 3H), 2.09-1.96 (m, 6H), 1.60- 1.55 (m, 2H).
Example-703:
Figure imgf000534_0002
[001471] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 4, 6- dichloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidine gave 4-(6-chloro-2-(3, 5-dimethyl- lH-pyrazol-l-yl) pyrimidin-4-yl) morpholine-2-carbonitrile as an off-white solid (0.22 g, 84%). MS (M+l)+=319.0.
[001472] Step 2[IN10971-081-P1]: The procedure is similar to Step 1[B] in Example- 838. 0.11 g of 4-(6-chloro-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) morpholine-2- carbonitrile gave 4-(6-((4, 4-difluorocyclohexyl) amino)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-yl) morpholine-2-carbonitrile as an off-white solid (0.04 g, 27%). MS
(M+l)+=418.2; IH-NMR (400 MHz, MeOD): δ 8.00 (s, IH), 6.05 (s, IH), 5.61 (s, IH), 4.90- 4.85 (m, 2H), 4.20-3.92 (m, 3H), 3.90-3.80 (m, 2H), 3.80-3.62 (m, IH), 2.61 (s, 3H), 2.26 (s, 3H), 2.10-1.85 (m, 6H), 1.65-1.55 (m, 2H).
Example-704:
Figure imgf000535_0001
Table-49: Ste 1: The rocedure is similar to Ste 1[B] in Exam le-838.
Figure imgf000535_0002
Figure imgf000535_0003
[001473] Step 2[IN11055-044-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.30 (d, J = 8.00 Hz, IH), 6.05 (s, IH), 5.64 (s, IH), 3.82 (s, 3H), 2.54 (s, 3H), 2.16 (s, 3H), 1.90-1.50 (m, 5H), 1.40-1.10 (m, 6H).
[001474] Step 2[IN11108-018-P1]: IH-NMR (400 MHz, DMSO-d6): δ 7.94 (bs, IH), 6.07 (s, IH), 5.65 (s, IH), 3.85 (s, 3H), 3.08-2.97 (m, 2H), 2.67-2.60 (m, 5H), 2.16 (s, 3H).
[001475] Step 2[IN11055-079-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.39 (d, J = 7.20 Hz, IH), 6.05 (s, IH), 5.67 (s, IH), 4.85-4.70 (m, IH), 3.83 (s, 3H), 2.54 (s, 3H), 2.16 (s, 3H), 2.00-1.88 (m, 2H), 1.75-1.50 (m, 6H).
Example-705:
Figure imgf000536_0001
Figure imgf000536_0002
Figure imgf000537_0001
[001476] Step l[IN10965-089-Pl]: The procedure is similar to Step l[NSSy6909] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.07 (d, = 8.00 Hz, 1H), 6.00 (s, 1H), 5.52 (s, 1H), 4.20 (s, 1H), 3.98-3.90 (m, 4H), 3.61-3.48 (m, 4H), 3.10-2.95 (m, 1H), 2.14 (s, 3H), 2.05-1.92 (m, 6H), 1.63-1.45 (m, 2H), 1.06 (d, / = 6.00 Hz, 6H).
[001477] Step l[IN10984-022-Pl]: The procedure is similar to Step 1[B] in Example- 838. 1H-NMR (400 MHz, CD30D): δ 7.60 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 3.2 Hz, 1H), 6.53-6.51 (m, 1H), 5.54 (s, 1H), 3.92-3.90 (m, 1H), 3.76-3.74 (m, 4H), 3.57-3.55 (m, 4H), 2.12-1.87 (m, 6H), 1.66-1.58 (m, 2H).
[001478] Step 1[IN11067-060-P1]: To a stirred solution of 6-chloro-N-(4, 4- difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl) pyrimidin-4-amine (0.8 g, 2.34 mmol) in Ethanol (25 mL) was added Sodium thiomethoxide (0.32 g, 4.69 mmol). And the mixture was stirred for 3h at 65 °C. The reaction mixture was cooled to rt, diluted with water, extracted with ethyl acetate (3x50 mL). The combined organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a crude product which was purified by flash column chromatography using 20% ethyl acetate in pet ether as solvent to afford N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l- yl)-6-(methylthio)pyrimidin-4-amine as an off-white solid (0.6 g, 72%). MS (M+l)+=354.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 6.80 Hz, 1H), 6.22 (s, 1H), 6.05 (s, 1H), 4.10 (s, 1H), 2.53 (s, 3H), 2.48 (s, 3H), 2.16 (s, 3H), 2.12-1.83 (m, 6H), 1.61-1.48 (m, 2H).
[001479] Step 1[IN11067-061-P1]: The procedure is similar to Step 3[NSSy7062] in Example-623. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 7.20 Hz, 1H), 6.95 (s, 1H), 6.14 (s, 1H), 4.11 (s, 1H), 3.23 (s, 3H), 2.55 (s, 3H), 2.19 (s, 3H), 2.10-1.90 (m, 6H), 1.68- 1.52 (m, 2H).
[001480] Step 1[IN11067-062-P1]: The procedure is similar to Step 3[NSSy7062] in Example-623. 1H-NMR (400 MHz, DMSO-d6): δ 8.22 (d, J = 7.20 Hz, 1H), 6.90 (s, 1H), 6.10 (s, 1H), 4.10 (s, 1H), 3.90 (s, 3H), 2.51 (s, 3H), 3.90 (s, 3H), 2.12-1.85 (m, 6H), 1.65- 1.55 (m, 2H). [001481] Step l[IN10964-008-Pl]: The procedure is similar to Step 1[A] in Example- 838. 1H-NMR (400 MHz, DMSO-d6): δ 7.11 (d, J = 8.0 Hz, 1H), 6.01 (s, 1H), 5.55 (s, 1H), 4.10-3.91 (m, 4H), 3.59-3.40 (m, 5H), 2.95-2.85 (m, 1H), 2.67-2.66 (m, 2H), 2.14 (s, 3H), 2.05-1.89 (m, 7H), 1.55 (m, 3H), 1.10-1.09 (m, 6H).
[001482] Step 1[IN11030-035-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 7.37 (d, J = 7.20 Hz, 1H), 6.04 (s, 1H), 5.82 (s, 1H), 4.38 (s, 4H), 3.35 (s, 1H), 2.15 (s, 3H), 2.10-1.75 (m, 8H), 1.62-1.50 (m, 2H), 1.45-1.35 (m, 1H).
Example-706:
Figure imgf000538_0001
Figure imgf000538_0002
[001483] Step 1: The procedure is similar to Step 1[H] in Example-838. 3.0 g of 4, 6- dichloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine gave 4-chloro-6-(l-ethoxyvinyl)-2-(3- methyl-lH-pyrazol-l-yl) pyrimidine as an off-white solid (2.1 g, 60%). MS (M+l)+=265.0.
[001484] Step 2: The procedure is similar to Step l[NSSy6697] in Example-873. 2.5 g of 4-chloro-6-(l-ethoxyvinyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine gave l-(6-chloro-2- (3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-one as a yellow solid (2.2 g, 66%). MS (M+l)+=237.0.
[001485] Step 3: The procedure is similar to Step 2[NSSy6931] in Example-21. 2.2 g of l-(6-chloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-one gave l-(6-chloro-2-(3- methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) ethan-l-ol as an off-white solid (1.8 g, 56%). MS (M+l)+=239.0.
Figure imgf000539_0001
[001486] Step 4[IN10881-058-Pl]: The procedure is similar to Step 1[A] in Example- 838. MS (M+l)+=302.1; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 2.40 Hz, IH), 6.59 (s, IH), 6.29 (d, J = 2.40 Hz, IH), 5.38 (s, IH), 4.51-4.49 (m, IH), 3.81 (s, 2H), 3.55 (s, 2H), 2.26 (s, 3H), 1.75 (s, 4H), 1.50 (s, 4H), 1.36 (d, J = 6.40 Hz, 3H).
[001487] Step 4[IN10881-059-Pl]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=330.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 6.56 (d, J = 13.60 Hz, IH), 6.30 (d, J = 2.00 Hz, IH), 5.41 (s, IH), 4.52 (t, J = 5.60 Hz, IH), 3.01 (s, 2H), 2.87 (s, IH), 2.29 (s, 4H), 2.00-1.50 (m, 5H), 1.50-1.30 (m, 5H), 1.30-1.10 (m, 3H), 0.93 (d, J = 6.80 Hz, 2H).
[001488] Step 4[IN10881-060-Pl]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=330.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 6.56 (d, J = 13.60 Hz, IH), 6.30 (s, IH), 5.41 (s, IH), 4.52 (s, IH), 3.01 (s, 2H), 2.87 (s, IH), 2.29 (s, 4H), 1.95- 1.50 (m, 5H), 1.49-1.30 (m, 6H), 1.30-1.10 (m, 3H), 0.99-0.90 (m, 2H).
[001489] Step 4[IN10882-055-Pl] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=288.1; IH-NMR (400 MHz, DMSO-d6): δ 8.46 (d, J = 2.8 Hz, IH), 6.71 (s, IH), 6.29 (d, J = 2.4 Hz, IH), 5.37 (d, J = 5.2 Hz, IH), 4.58-4.49 (m, IH), 3.68 (bs, 4H), 2.26 (s, 3H), 1.72-1.56 (m, 6H), 1.37-1.32 (m, 3H).
[001490] Step 4 [IN 10881-054-P1] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=342.1; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 2.0 Hz, IH), 6.69 (d, J = 2.4 Hz, IH), 6.29 (d, J = 2.4 Hz, IH), 5.38-5.35 (m, IH), 4.53-4.50 (m, IH), 2.85 (bs, IH), 2.26 (s, 3H), 1.86-1.62 (m, 7H), 1.41-1.35 (m, 9H).
[001491] Step 4[IN10880-055-Pl]: The procedure is similar to Step 1[A] in Example- 838. MS (M+l)+=304.0; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.77 (s, IH), 6.55 (s, IH), 6.28 (d, J = 2.4 Hz, IH), 5.36 (d, J = 4.00 Hz, IH), 4.46 (d, J = 5.2 Hz, IH), 3.99 (t, J = 6.4 Hz, IH), 3.79 (d, J = 7.2 Hz, IH), 3.66-3.63 (m, IH), 3.48 (m, 2H), 2.26 (s, 3H), 1.95- 1.80 (m, 3H), 1.70-1.52 (m, IH), 1.33 (d, J = 6.0 Hz, 3H).
[001492] Step 4[IN10880-056-Pl]: The procedure is similar to Step 1[A] in Example- 838. MS (M+l)+=262.2; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 7.56 (s, IH), 6.45 (s, IH), 6.28 (d, J = 2.40 Hz, IH), 5.35 (s, IH), 4.45 (s, IH), 4.25 (s, IH), 2.26 (s, 3H), 1.33 (d, J = 6.00 Hz, 3H), 1.18 (s, 3H), 1.17 (s, 3H).
[001493] Step 4[IN10880-058-Pl]: The procedure is similar to Step 1[A] in Example- 838. MS (M+l)+=304.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.76 (bs, IH), 6.50 (s, IH), 6.28 (d, J = 2.4 Hz, IH), 5.35 (d, J = 4.4 Hz, IH), 4.47 (m, IH), 3.79-3.70 (m, 2H), 3.66-3.60 (m, IH), 3.49-3.46 (m, IH), 3.38-3.36 (m, IH), 2.26 (s, 3H), 2.02-1.94 (m, IH), 1.65-1.57 (m, IH), 1.34-1.33 (m, 3H).
[001494] Step 4[IN10880-059-Pl] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=316.1; IH-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.40 Hz, IH), 7.43 (s, IH), 6.48 (s, IH), 6.27 (d, J = 2.40 Hz, IH), 5.34-5.31 (m, IH), 4.45 (s, IH), 2.26 (s, 3H), 1.95-1.85 (m, IH), 1.60-1.10 (m, 12H), 0.90-0.80 (m, 3H).
[001495] Step 4[IN10881-061-P1]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=330.1; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, IH), 6.57 (s, IH), 6.30 (d, J = 2.40 Hz, IH), 5.42 (d, J = 4.80 Hz, IH), 4.70 (s, IH), 4.55-4.50 (m, IH), 3.50 (s, 2H), 2.27 (s, 3H), 1.75-1.55 (m, 7H), 1.48-1.30 (m, 5H), 1.35-1.10 (m, 4H).
[001496] Step 4[IN10880-062-Pl] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=370.0; IH-NMR (400 MHz, DMSO-d6): δ 8.45-8.40 (m, IH), 7.65 (bs, IH), 6.47 (s, IH), 6.30 (t, J = 2.4 Hz, IH), 5.40-5.38 (m, IH), 4.49-4.46 (m, IH), 4.01 (m, IH), 2.26 (s, 3H), 1.96 (m, IH), 1.86-1.83 (m, 2H), 1.64-1.61 (m, IH), 1.46 (m, IH), 1.35- 1.32 (m, 3H), 1.20-1.15 (m, 3H).
[001497] Step 4[IN10880-065-Pl] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=276.1; IH-NMR (400 MHz, DMSO-d6): δ 8.35 (d, J = 3.20 Hz, IH), 7.37 (s, IH), 6.54 (s, IH), 6.30 (s, IH), 5.33 (d, J = 4.40 Hz, IH), 4.45-4.43 (m, IH), 2.26 (s, 3H), 1.43 (s, 9H), 1.32 (d, J = 6.80 Hz, 3H).
[001498] Step 4[IN10880-064-Pl] : The procedure is similar to Step 1 [A] in Example- 838. MS (M+l)+=316.1; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 2.40 Hz, IH), 6.60 (s, IH), 6.30 (d, J = 2.40 Hz, IH), 5.37 (d, J = 4.80 Hz, IH), 4.52-4.49 (m, IH), 2.96 (s, 2H), 2.26 (s, 3H), 1.90-1.50 (m, 6H), 1.48-1.30 (m, 5H), 1.12-1.10 (m, IH).
Figure imgf000542_0001
Figure imgf000543_0001
Table-55: Step 3: The procedure is similar to Step l[NSSy6697] in Example-873.
Figure imgf000543_0002
[001499] Step 3[IN10876-041-P2]: IH-NMR (400 MHz, DMSO-d6): δ 8.57 (s, IH), 8.08 (d, J = 7.60 Hz, IH), 6.82 (s, IH), 6.37 (d, J = 2.40 Hz, IH), 4.21 (s, IH), 2.57 (s, 3H), 2.29 (s, 3H), 2.10-1.95 (m, 6H), 1.65-1.52 (m, 2H).
Table-56: Step 4: The procedure is similar to Step 2[NSSy6931] in Example-21.
Figure imgf000543_0003
[001500] Step 4[IN10876-051-P1]: IH-NMR (400 MHz, DMSO-d6): δ 8.47 (s, IH), 7.67 (s, IH), 6.51 (s, IH), 6.29 (d, J = 2.40 Hz, IH), 5.38 (s, IH), 4.47 (s, IH), 4.16 (s, IH), 2.26 (s, 3H), 2.15-1.90 (m, 6H), 1.62-1.50 (m, 2H), 1.02 (s, 3H).
[001501] Step 4[IN10973-069-Pl]: IH-NMR (400 MHz, CD30D): δ 8.36 (d, J = 2.40 Hz, 2H), 6.48 (s, IH), 6.31 (d, J = 2.40 Hz, IH), 4.62-4.55 (m, IH), 2.35 (s, 3H), 2.28 (s, 2H), 1.60-1.50 (m, 7H), 1.44-1.46 (m, 7H), 0.98-0.88 (m, IH). Example-708:
Figure imgf000544_0001
[001502] Step 1[IN10876-061-P1]: A solution of N-(4, 4-difluorocyclohexyl)-6-(l- ethoxyvinyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine (0.05 g, 0.13 mmol) in ethanol (2.5 mL) was added platinum oxide (0.025 g) in ethanol (2.5 mL). The reaction mixture was stirred at rt under H2 bladder for 72h. The reaction mixture was filtered through celite, washed with ethylacetae (2x10 mL), filtrate was concentrated under reduced pressure to afford crude product. Which was purified by preparative HPLC to afford N-(4, 4- difluorocyclohexyl)-6-(l-ethoxyethyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine as an off-white solid (0.04 g, 20%). MS (M+l)+=366.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.70 (s, 1H), 6.41 (s, 1H), 6.30 (d, J = 2.40 Hz, 1H), 4.23-4.17 (m, 2H), 3.49- 3.43 (m, 2H), 2.25 (s, 3H), 2.06-1.90 (m, 6H), 1.62-1.50 (m, 2H), 1.33 (d, J = 6.80 Hz, 3H), 1.16 (t, J = 6.80 Hz, 3H).
Example-709:
Figure imgf000544_0002
[001503] Step l[IN10876-069-Pl]: The procedure is similar to Step 3[NSSy6917] in Example-21. 0.2 g of l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)ethan-l-one gave N-(4, 4-difluorocyclohexyl)-6-(l,l-difluoroethyl)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-amine as an off-white solid (0.035 g, 16%). MS (M+l)+=358.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.53 (s, 1H), 8.06 (d, J = 7.20 Hz, 1H), 6.59 (s, 1H), 6.35 (s, 1H), 4.21 (s, 1H), 2.28 (s, 3H), 2.15-1.85 (m, 9H), 1.65-1.52 (m, 2H). Example-710:
Figure imgf000545_0001
[001504] Step l [IN10876-080-Pl] : The procedure is similar to Step 3[NSSy6917] in Example-21. 0.2 g of l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l- yl)pyrimidin-4-yl)ethan- l-ol gave N-(4, 4-difluorocyclohexyl)-6-(l-fluoroethyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine as a pale yellow solid (0.06 g, 29%). MS (M+l)+=340.1 ; 1H-NMR (400 MHz, OMSO-d6): δ 8.53 (s, 1H), 8.06 (d, / = 7.20 Hz, 1H), 6.59 (s, 1H), 6.35 (s, 1H), 4.21 (s, 1H), 2.28 (s, 3H), 2.15- 1.85 (m, 9H), 1.65- 1.52 (m, 2H).
Exam le-711:
Figure imgf000545_0002
[001505] Step 1 : The procedure is similar to Step 3[IN11059-090-P1] in Example-659. 0.35 g of l-(6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl- lH-pyrazol- l-yl) pyrimidin-4- yl) ethan- l-ol gave 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l- yl) pyrimidin-4-amine as an off-white solid (0.14 g, 34%). MS (M+l)+=399.9.
[001506] Step 2[IN10973-083-Pl] : The procedure is similar to Step l [NSSy6519] in Example-842. 0.35 g of 0.14 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-(l-methoxyethyl)-2- (3-methyl- lH-pyrazol- l-yl) pyrimidin-4-amine as an off-white solid (0.085 g, 69%). MS (M+l)+=352.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.68 (s, 1H), 6.39 (s, 1H), 6.30 (d, J = 2.80 Hz, 1H), 4.13 (s, 2H), 3.25 (s, 3H), 2.26 (s, 3H), 2.10- 1.90 (m, 6H), 1.65- 1.52 (m, 2H), 1.31 (d, J = 22.80 Hz, 3H). Example-712:
Figure imgf000546_0001
Figure imgf000546_0003
[001507] Step l[IN10973-060-Pl]: To a stirred solution of 6-(l-bromoethyl)-N-(4, 4- difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine (0.13 g, 0.32 mmol) in DMF (5 mL) was added methanesulfinic acid sodium salt (0.13 g, 1.302 mmol). Then heated to 80 °C for 16h. The reaction mixture was cooled to room temperature, poured in to ice cold water, extracted with ethyl acetate (3x30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using 40% ethyl acetate in pet-ether to afford N-(4,4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)-6-(l- (methylsulfonyl)ethyl)pyrimidin-4-amine as an off-white solid (0.055 g, 42%). MS
(M+l)+=400.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, 1H), 7.92 (d, / = 8.00 Hz, 1H), 6.43 (s, 1H), 6.34 (d, / = 2.40 Hz, 1H), 4.42 (d, / = 6.40 Hz, 1H), 4.18 (s, 1H), 3.11 (s, 3H), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.70-1.50 (m, 5H).
Example-713:
Figure imgf000546_0002
Figure imgf000547_0001
Cs2C03, ACN, 60 °C,
CD 53 300.0
24h
HN
Figure imgf000548_0001
Figure imgf000549_0001
[001508] Step 2[NSSy6420]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 7.02 (s IH), 6.25 (s, IH), 5.54 (s, IH), 4.54 (s, IH), 4.30 (s, IH), 4.01 (bs, IH), 3.67 (s, 4H), 3.47(s, 4H), 2.23 (s, 3H), 2.0-1.95 (m, IH), 1.41 (s, 5H).
[001509] Step 2[NSSy6445]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 7.04 (s, IH), 6.25 (s, IH), 5.54 (s, IH), 4.54 (s, IH), 4.31 (s, IH), 4.01 (bs, IH), 3.68 (s, 4H), 3.48(s, 4H), 2.24 (s, 3H), 2.00-1.95 (m, IH), 1.41 (s, 5H).
[001510] Step 2[NSSy6446]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 7.04 (s IH), 6.26 (s, IH), 5.49 (s,lH), 4.54 (s, IH), 4.31 (s, IH), 4.01 (bs, IH), 3.68 (s, 4H), 3.48(s, 4H), 2.24 (s, 3H), 2.00-1.95 (m, IH), 1.41 (s, 5H).
[001511] Step 2[NSSy6511]: IH-NMR (400 MHz, DMSO-d6): δ 8.31 (d, J = 2.40 Hz, IH), 6.69 (s, IH), 6.28 (d, J = 2.40 Hz, IH), 5.55 (s, IH), 4.52 (s, IH), 3.68-3.67 (m, 4H), 3.43-3.42 (m, 4H), 2.17 (s, 3H), 1.98 (m, 2H), 1.96 (m, 6H), 1.61-1.48 (m, 5H).
[001512] Step 2[NSSy6486]: IH-NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 6.86 (s, IH), 6.23 (s, IH), 5.48 (s, IH), 4.53 (s, IH), 3.66 (s, 4H), 3.65-3.40 (m, 4H), 3.36 (s, IH), 1.98 (s, 3H), 1.87-1.81 (m, 3H), 1.64-1.55 (m, IH).
[001513] Step 2[NSSy6526]: IH-NMR (400 MHz, DMSO-d6): δ 8.40 (s, IH), 7.12 (d, J = 7.92 Hz, 0.5H), 7.02 (d, J = 7.92 Hz, 0.5H), 6.25 (s, IH), 5.51 (s, IH), 3.67 (bs, 4H), 3.49 (bs, 4H), 3.08 (bs, 0.5 H), 2.69 (bs, 0.5H), 2.24 (s, 3H), 2.12- 2.00 (m, IH), 2.00 - 1.80 (m, 3H), 1.80- 1.60 (m, 2H), 1.60-1.49 (m, IH), 1.35-1.20 (m, IH).
[001514] Step 2[NSSy6540]: IH-NMR (400 MHz, DMSO-d6, 80 °C): δ 8.35 (s, IH), 6.52 (s, IH), 6.21 (s, IH), 5.56 (d, J = 25.20 Hz, IH), 3.94 (s, IH), 3.69 (s, 4H), 3.61 (s, 4H), 2.26 (s, 3H), 2.21 (s, 6H), 1.90-1.50 (m, 9H).
[001515] Step 2[NSSy6541]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 7.22 (s, IH), 6.94 (d, J = 8.32 Hz, IH), 6.68 (s, IH), 6.24 (s, IH), 5.50 (s, IH), 3.66 (bs, 4H), 3.50 (bs, 4H), 2.24 (s, 3H), 2.12- 2.00 (m, IH), 2.00 - 1.90 (m, 2H), 1.80- 1.70 (m, 2H), 1.51- 1.49 (m, 2H), 1.30-1.10 (m, 2H).
[001516] Step 2[NSSy6539]: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 7.22 (s, IH), 6.94 (d, J = 8.32 Hz, IH), 6.69 (s, IH), 6.24 (s, IH), 5.51(s, IH), 3.66 (bs, 4H), 3.50 (bs, 4H), 2.24 (s, 3H), 2.12-2.0 (m, IH), 2.0-1.9 (m, 2H), 1.80- 1.70 (m, 2H), 1.51-1.49 (m, 2H), 1.30-1.10 (m, 2H).
[001517] Step 2[NSSy6550]: 1H-NMR (400 MHz, DMS0-d6): δ 8.39 (s, IH), 6.93 (s, IH), 6.25 (d, J = 3.20 Hz, IH), 5.59 (s, IH), 3.68-3.66 (m, 4H), 3.47 (m, 4H), 2.73 (m, IH), 2.24 (s, 3H), 1.85-1.73 (m, 5H), 1.57-1.54 (m, 5H), 1.21 (m, IH).
[001518] Step 2[IN11140-062-Pl]: 1H-NMR (400 MHz, DMS0-d6): δ 8.44 (d, J = 2.40 Hz, IH), 7.11 (d, J = 8.40 Hz, IH), 6.26 (d, J = 2.80 Hz, IH), 5.69 (s, IH), 4.50 (s, IH), 3.72- 3.65 (m, 4H), 3.52-3.42 (m, 4H), 2.25 (s, 3H), 2.15-1.65 (m, 5H), 1.60-1.40 (m, 3H).
[001519] Step 2[IN11133-031-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.40 Hz, IH), 7.12 (d, J = 8.80 Hz, IH), 6.25 (d, J = 2.40 Hz, IH), 5.56 (s, IH), 4.47-4.33 (m, IH), 3.67 (s, 4H), 3.50 (s, 4H), 2.24 (s, 3H), 2.07 (m, IH), 1.91 (m, IH), 1.75-1.45 (m, 3H), 1.35- 1.20 (m, 4H).
[001520] Step 2[IN11107-020-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, IH), 7.60 (d, J = 5.20 Hz, IH), 6.26 (d, J = 2.40 Hz, IH), 5.48 (s, IH), 4.13 (s, IH), 3.72- 3.60 (m, 4H), 3.58-3.48 (m, 4H), 3.10-2.95 (m, 2H), 2.70-2.55 (m, 2H), 2.24 (s, 3H).
Example-714:
Figure imgf000550_0001
[001521] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.05 g of 4, 6- dichloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-N-(4, 4- dimethylcyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine as a yellow solid (0.035 g, 50%). MS (M+l)+=320.1.
[001522] Step 2[IN11055-078-P1]: The procedure is similar to Step 1[NSSY6519] in Example-842. 0.07 g of 6-chloro-N-(4, 4-dimethylcyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-dimethylcyclohexyl)-6-methoxy-2-(3-methyl-lH-pyrazol-l- yl) pyrimidin-4-amine as an off-white solid (0.040 g, 57%). MS (M+l)+=316.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, IH), 7.31 (d, J = 7.20 Hz, IH), 6.30 (d, J = 2.40 Hz, IH), 5.62 (s, IH), 3.85 (s, 3H), 2.26 (s, 3H), 1.73-1.65 (m, 2H), 1.38-1.24 (m, 7H), 0.92 (s, 6H).
Example-715:
Figure imgf000551_0001
[001523] Step 1: To a stirred solution of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine (0.45 g, 1.98 mmol) in Tetrahydrofuran (10 mL) was added 3-(tert-butyl)-lH-pyrazole (0.2 g, 1.98 mmol). The reaction mixture stirred at rt for 24h. The reaction mixture was diluted with ethyl acetate (100 mL) and water (80 mL) extracted and separated, organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2- (3-(tert-butyl)-lH-pyrazol-l-yl)-4, 6-dichloropyrimidine as an off-white solid (0.1 g, 18%). MS (M+ 1)4=271.0.
[001524] Step 2: The procedure is similar to Step 1 [B] in Example-838. 0.1 g of 2-(3- (tert-butyl)-lH-pyrazol-l-yl)-4, 6-dichloropyrimidine gave 2-(3-(tert-butyl)-lH-pyrazol-l- yl)-6-chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid (0.09 g, 66%). MS (M+l)+=371.0.
[001525] Step 3[IN11177-025-Pl]: 0.08 g of 2-(3-(tert-butyl)-lH-pyrazol-l-yl)-6- chloro-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-(tert-butyl)-lH-pyrazol-l- yl)-N-(4, 4-difluorocyclohexyl)-6-morpholinopyrimidin-4-amine as a white solid (0.07 g, 80%). MS (M+l)+=421.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.4 Hz, IH), 7.10 (d, J = 7.6 Hz, IH), 6.37 (d, J = 2.8 Hz, IH), 5.54 (s, IH), 3.69 (m, IH), 3.68-3.67 (m, 4H), 3.51 (m, 4H), 2.05-1.91 (m, 6H), 1.59-1.51 (m, 2H), 1.28 (s, 9H).
Example-716:
Figure imgf000552_0001
IN11177-049-P1 IN10984-043-P1 IN11054-012-P1 IN11054-011-P1 IN11059-069-P1 IN11053-024-P1 IN11053-022-P1
Figure imgf000552_0002
IN11053-005-P1 IN10973-041 -P1 IN11196-039-P1 IN11111 -097-P1 IN11106-091 -P1 IN11059-070-P1 IN11059-071 -P1
Figure imgf000552_0003
IN11288-005-P1 NSSy6394 NSSy6272 IN11250-032 -P1 IN11030-044-P1 IN11288-025-P1
Figure imgf000552_0004
IN11251-099-P1 IN11216-078-P1 IN11251 -092 -P1 IN11251 -091 -P1 IN11288-060-P1 IN11238-088-P1
Figure imgf000552_0005
Figure imgf000553_0001
Zn(CN)2, Pd(PPh3)4, DMF, 150 °C,
IN11288-025-P1 30 lh, MW
IN11251-099-P1 Cs2C03, ACN, 80 °C, 16h 31
IN11216-078-P1 Cs2C03, ACN, 80 °C, 16h 41
OH
IN11251-092-P1 Cs2C03, ACN, 80 °C, 16h 73
IN11251-091-P1 Cs2C03, ACN, 80 °C, 16h 16
IN11288-060-P1 Cs2C03, ACN, 80 °C, 16h 66
IN11238-088-P1 Cs2C03, ACN, 80 °C, 16h 50
[001526] Step l[NSSy6394]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=391.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.02 (s, IH), 6.25 (s, IH), 5.26 (s, IH), 4.97 (bs, IH), 4.68 (s, IH), 3.91 (s, IH), 3.79 (s, IH), 3.66 (s, IH), 3.42 (s, IH), 3.23 (s, IH), 2.50 (s, 3H), 2.05-1.86 (m, 8H), 1.56-1.53 (m, 2H).
[001527] Step l[NSSy6272]: The procedure is similar to Step 1[B] in Example-838. MS (M+l)+=363.2; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (s, IH), 7.09-7.07 (d, J = 8.00 Hz, IH), 6.25 (s IH), 5.78 (s, IH), 3.97 (bs, IH), 3.07 (s, 3H), 2.24 (s, 3H), 2.06-1.93 (m, 6H), 1.57-1.55 (m, 2H), 0.85 (s, 2H), 0.65 (s, 2H).
[001528] Step l[IN10966-095-Pl]: The procedure is similar to step 5[IN10963-068-Pl] in Example-697. MS (M+l)+=381.0; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.48 (s, IH), 6.31 (d, J = 2.40 Hz, IH), 5.67 (s, IH), 4.01 (s, IH), 4.35 (t, J = 5.20 Hz, 2H), 2.59 (t, J = 5.60 Hz, 2H), 2.25 (s, 3H), 2.20 (s, 6H), 2.10-1.88 (m, 6H), 1.60-1.50 (m, 2H).
[001529] Step l[IN10966-093-Pl]: The procedure is similar to step 5[IN10963-068-Pl] in Example-697. MS (M+l)+=368.0; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.46 (s, IH), 6.31 (s, IH), 5.69 (s, IH), 4.40 (s, 2H), 3.64 (t, J = 5.20 Hz, 2H), 3.29 (s, 3H), 2.25 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.50 (m, 2H).
[001530] Step 1 [INI 1030-095-P1] : The procedure is similar to step 1 [B] in Example- 838. MS (M+l)+=363.1; IH-NMR (400 MHz, DMSO-d6): δ 11.61 (s, IH), 8.49 (d, J = 2.40 Hz, IH), 6.65 (d, J = 7.60 Hz, IH), 6.36 (s, IH), 4.21 (s, IH), 2.72 (t, J = 7.20 Hz, 2H), 2.26 (s, 3H), 2.10-1.85 (m, 6H), 1.62-1.58 (m, 2H).
[001531] Step 1 [INI 1053-052-P1] : The procedure is similar to step 1 [H] in Example- 838. MS (M+l)+=320.0; IH-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 7.72 (s, IH), 6.64 (q, J = 6.80 Hz, IH), 6.38 (s, IH), 6.31 (d, J = 2.40 Hz, 2H), 5.57 (d, J = 10.40 Hz, IH), 4.17 (s, IH), 2.33 (s, 3H), 2.18-1.88 (m, 6H), 1.62-1.52 (m, 2H).
[001532] Step 1[IN11063-005-P1]: The procedure is similar to step 5[IN10963-068-Pl] in Example-697. MS (M+l)+=338.2; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (bs, IH), 7.44 (bs, IH), 6.30 (d, J = 2.4 Hz, IH), 5.66 (bs, IH), 4.31 (q, J = 6.80 Hz, 2H), 2.25 (s, 3H), 2.04- 1.91 (m, 6H), 1.31 (t, J = 6.80 Hz, 3H).
[001533] Step 1[IN11177-049-P1]: The procedure is similar to step l[NSSy6909] in Example-839. MS (M+l)+=406.1; IH-NMR (400 MHz, CDC13): δ 8.43 (s, IH), 7.10 (d, J = 8.00 Hz, IH), 6.28 (s, IH), 5.42 (s, IH), 4.07 (s, 2H), 3.86 (s, 3H), 3.42 (t, J = 5.20 Hz, 2H), 2.91 (s, 3H), 2.25 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001534] Step l[IN10984-043-Pl]: The procedure is similar to step l[NSSy6909] in Example-839. MS (M+l)+=379.0; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (d, J = 2.00 Hz, IH), 7.03 (d, J = 8.40 Hz, IH), 6.26 (d, J = 2.40 Hz, IH), 5.40 (s, IH), 4.00-3.95 (m, 2H), 3.69-3.35 (m, 3H), 2.86 (s, 3H), 2.21 (s, 3H), 2.10-1.80 (m, 9H), 1.60-1.50 (m, 2H).
[001535] Step 1[IN11054-012-P1]: The procedure is similar to step 2[IN10991-021-P1] in Example-694. MS (M+l)+=391.3; IH-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 8.40 (s, IH), 7.60 (bs, IH), 7.39 (s, IH), 6.34 (d, J = 2.4 Hz, IH), 5.70 (bs, IH), 5.45 (s, 2H), 2.27 (s, 4H), 2.04-1.85 (m, 6H), 1.55-1.53 (m, 2H).
[001536] Step 1[IN11054-011-Pl]: The procedure is similar to step 2[IN10991-021-P1] in Example-694. MS (M+l)+=392.2; IH-NMR (400 MHz, DMSO-d6): δ 8.53 (s, IH), 7.65 (bs, IH), 6.34 (d, J = 2.4 Hz, IH), 5.70 (bs, IH), 5.09-5.02 (m, 2H), 5.07 (d, J = 8.8 Hz, 2H), 3.90-3.50 (bs, IH).
[001537] Step 1[IN11059-069-P1]: The procedure is similar to step 3[NSSy7062] in Example-623. MS (M+l)+=356.1; IH-NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 2.40 Hz, IH), 8.22 (d, J = 7.60 Hz, IH), 6.88 (s, IH), 6.36 (d, J = 2.40 Hz, IH), 4.24 (s, IH), 2.82 (s, 3H), 2.27 (s, 3H), 2.15-1.95 (m, 6H), 1.65-1.55 (m, 2H).
[001538] Step 1[IN11053-021-P1]: The procedure is similar to step 5[IN10963-068-Pl] in Example-697. MS (M+l)+=352.2; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (s, IH), 7.42 (s, IH), 6.30 (s, IH), 5.63 (s, IH), 5.28 (s, IH), 4.05 (s, IH), 2.25 (s, 3H), 2.08-1.88 (m, 6H), 1.60-1.48 (m, 2H), 1.29 (d, J = 6.00 Hz, 6H). [001539] Step 1 [INI 1053-024-P1] : The procedure is similar to step 1 [B] in Example- 838. MS (M+l)+=391.3; IH-NMR (400 MHz, DMSO-d6): δ 8.49 (s, IH), 8.39 (s, IH), 8.29 (s, IH), 7.50 (s, IH), 6.33 (d, J = 2.80 Hz, IH), 5.70 (s, IH), 5.28 (s, 2H), 4.00 (s, IH), 2.33 (s, 3H), 2.12-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001540] Step 1[IN11053-022-P1]: The procedure is similar to step 1[B] in Example- 838. MS (M+l)+=391.3; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 8.15 (s, IH), 7.60 (s, IH), 7.26 (s, IH), 6.32 (d, J = 3.20 Hz, IH), 5.75 (s, IH), 5.49 (s, 2H), 4.10 (s, IH), 2.25 (s, 3H), 2.80-1.85 (m, 6H), 1.56-1.48 (m, 2H).
[001541] Step 1[IN11053-005-P1]: The procedure is similar to step l[NSSy6519] in Example-842. MS (M+l)+=324.2; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.42 (s, IH), 6.31 (d, J = 2.80 Hz, IH), 5.68 (s, IH), 4.01 (s, IH), 3.87 (s, 3H), 2.26 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001542] Step 1[IN10973-041-P1]: The procedure is similar to Step 1[B] in Example- 838. MS (M+l)+=306.0; IH-NMR (400 MHz, DMSO-d6): δ 8.58 (d, J = 2.80 Hz, IH), 8.41 (d, J = 7.60 Hz, IH), 6.95 (s, IH), 6.39 (d, J = 2.40 Hz, IH), 4.24 (s, IH), 3.25 (s, 3H), 2.29 (s, 3H), 2.15-1.90 (m, 6H), 1.65-1.55 (m, 2H).
[001543] Step 1 [INI 1196-039-P1] : The procedure is similar to Step 1 [B] in Example- 838. MS (M+l)+=387.3; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.06 (s, IH), 6.25 (s, IH), 5.52 (s, IH), 3.90 (s, IH), 2.24 (s, 3H), 2.15-1.88 (m, 6H), 1.62-1.45 (m, 2H).
[001544] Step 1 [INI 1111-097-P1] : The procedure is similar to Step 1 [B] in Example- 838. MS (M+l)+=393.3; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, IH), 6.96 (d, J = 8.40 Hz, IH), 6.24 (d, J = 2.80 Hz, IH), 5.43 (s, IH), 3.95 (s, IH), 3.72-3.31 (m, 8H), 2.24 (s, 3H), 2.10-1.72 (m, 8H), 1.60 (m, 2H).
[001545] Step 1[IN11106-091-P1]: The procedure is similar to step l[NSSy6909] in Example-839. MS (M+l)+=392.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 8.17 (s, IH), 7.11 (d, J = 8.0 Hz, IH), 6.26 (d, J = 2.4 Hz, IH), 5.50 (s, IH), 4.01 (s, 3H), 3.78 (s, 2H), 3.28 (s, 3H), 2.24 (s, 2H), 2.05-1.91 (m, 6H), 1.55-1.53 (m, 2H).
[001546] Step 1[IN11059-070-P1]: The procedure is similar to step 1[IN11067-060-P1] in Example-705. MS (M+l)+=340.1; IH-NMR (400 MHz, CD30D): δ 8.46 (d, J = 2.8 Hz, IH), 6.30 (d, J = 2.4 Hz, IH), 6.17 (s, IH), 4.10 (m, IH), 2.52 (s, 3H), 2.35 (s, 3H), 2.10-1.95 (m, 6H), 1.64-1.61 (m, 2H).
[001547] Step 1[IN11059-071-P1]: The procedure is similar to step 3[NSSy7062] in Example-623. MS (M+l)+=356.1; IH-NMR (400 MHz, DMSO-d6): δ 9.12 (s, IH), 8.82 (d, J = 9.60 Hz, IH), 7.49 (s, IH), 6.43 (s, IH), 4.05 (s, IH), 3.28 (s, 3H), 2.32 (s, 3H), 2.15-1.80 (m, 8H).
[001548] Step 1 [INI 1288-005-P1] : The procedure is similar to Step 1 [B] in Example- 838. MS (M+l)+=420.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, IH), 7.28 (d, J = 8.00 Hz, IH), 6.28 (d, J = 2.40 Hz, IH), 5.72 (s, IH), 4.56 (s, 4H), 3.95 (s, IH), 3.02 (s, 3H), 2.25 (s, 3H), 2.10-1.88 (m, 6H), 1.60-1.48 (m, 2H).
[001549] Step l[IN11250-032-Pl]: MS (M+l)+=353.2; 1H-NMR (400 MHz, DMSO- d6): δ 8.36 (d, J = 2.40 Hz, IH), 6.88 (d, J = 8.00 Hz, IH), 6.24 (d, J = 2.40 Hz, IH), 5.32 (s, IH), 4.77 (t, J = 5.60 Hz, IH), 3.90 (s, IH), 3.54-3.35 (m, 2H), 3.26 (s, 2H), 2.25 (s, 3H), 2.10-1.85 (m, 7H), 1.62-1.50 (m, 2H).
[001550] Step 1[IN11030-044-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 1H-NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 2.80 Hz, IH), 7.40 (s, IH), 6.29 (d, J = 2.40 Hz, IH), 5.80 (s, IH), 4.01 (s, IH), 4.42 (s, 4H), 2.33 (s, 3H), 2.10-1.85 (m, 6H), 1.62-1.50 (m, 2H).
[001551] Step 1[IN11288-025-P1]: The procedure is similar to Step 3[NSSy5933] in Example-808. 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 8.36 (d, J = 6.40 Hz, IH), 6.82 (s, IH), 6.38 (s, IH), 4.19 (s, IH), 2.27 (s, 3H), 2.10-1.85 (m, 6H), 1.65-1.52 (m, 2H).
[001552] Step l[IN11251-099-Pl]: MS (M+l)+= 394.9; 1H-NMR (400 MHz, DMSO- d6): δ 1.67-1.64 (m, 2H), 2.24-1.98 (m, 6H), 2.28 (s, 3H), 3.74-3.70 (m, 2H), 4.17 (t, J = 5.6 Hz, 2H), 4.32 (bs, IH), 4.97 (t, J = 5.2 Hz, IH), 6.28 (d, J = 2.4 Hz, IH), 6.60 (d, J = 3.2 Hz, IH), 7.14 (d, J = 3.2 Hz, IH), 7.57 (d, J = 7.8 Hz, IH), 8.53 (d, J = 2.5 Hz, IH).
[001553] Step l[IN11216-078-Pl]: MS (M+l)+= 397.2; 1H-NMR (400 MHz, DMSO- d6): δ 1.52-1.55 (m, 2 H), 1.80-1.99 (m, 6 H), 2.23 (s, 3 H), 3.55-3.57 (m, 8 H), 3.87 (bs, 1 H), 4.86 (bs, 2 H), 5.42 (s, 1 H), 6.26 (d, J = 1.6 Hz, 1 H), 6.98 (d, J = 7.6 Hz, 1 H), 8.39 (d, J = 1.6 Hz, 1 H).
[001554] Step l[IN11251-092-Pl]: MS (M+l)+= 422.2; 1H-NMR (400 MHz, DMSO- d6): δ 1.14-1.11 (m, 3H), 1.57-1.50 (m, 2H), 2.05- 1.87 (m, 6H), 2.22 (s, 3H), 3.59-3.39 (m, 6H), 3.69-3.60 (m, IH), 3.92-3.70 (m, 2H), 4.71-4.69 (m, IH), 5.50 (s, IH), 6.23 (d, J = 3 Hz, IH), 7.03 (d, J = 7.8 Hz, IH), 8.39 (d, J = 2.5 Hz, IH).
[001555] Step 1[IN11251-091-P1]: MS (M+l)+=376.7; 1H-NMR (400 MHz, DMSO- d6): δ 1.67-1.64 (m, 2H), 2.24-1.98 (m, 6H), 2.28 (s, 3H), 3.74-3.70 (m, 2H), 4.17 (t, J = 5.6 Hz, 2H), 4.32 (bs, IH), 4.97 (t, J = 5.2 Hz, IH), 6.28 (d, J = 2.4 Hz, IH), 6.60 (d, J = 3.2 Hz, IH), 7.14 (d, J = 3.2 Hz, IH), 7.57 (d, J = 7.8 Hz, IH), 8.53 (d, J = 2.5 Hz, IH). [001556] Step l[IN11288-060-Pl]: MS (M+l)+= 408.7; 1H-NMR (400 MHz, DMSO- d6): δ 1.64-1.59 (m, 2H), 2.05-1.92 (m, 6H), 2.34 (s, 3H), 3.41 (s, 3H), 3.55-3.45 (m, 1H), 3.67-3.58 (m, 3H), 3.77-3.73 (m, 1H), 4.01-3.96 (m, 2H), 4.63-4.61 (t, J = 3.6 Hz, 1H), 5.48 (s, 1H), 6.26 (d, J = 2.4 Hz, 1H), 8.43-8.42 (d, J = 2.4 Hz, 1H).
[001557] Step l[IN11238-088-Pl]: MS (M+l)+= 393.2; 1H-NMR (400 MHz, DMSO- d6): δ 1.48-1.62 (m, 2 H), 1.85-2.16 (m, 6 H),2.24 (s, 3 H), 3.75 (s, 2 H), 3.94 (bs, 1 H), 4.41 (s, 2 H), 4.53 (t, J = 5.2 Hz, 2 H). 5.44 (s, 1 H), 6.26 (d, J = 2.4 Hz, 1 H), 7.16 (d, J = 7.9 Hz, 1 H), 8.44 (d, J = 2.0 Hz, 1 H).
Example-717:
Figure imgf000558_0001
[001558] Step 1: The procedure is similar to Step 1[B] in Example-838. 14.0 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave N- (4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol- l-yl)-6-morpholinopyrimidin-4-amine as a yellow solid (10.0 g, 66%). MS (M+l)+=379.2.
[001559] Step 2[IN11196-041-P1]: The procedure is similar to Step 2[NSSy6464] in Example-869. 0.15 g of N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)-6- morpholinopyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3-methyl-4, 5-dihydro- lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine as an off-white solid (0.022 g, 14%). MS (M+l)+=381.1; 1H-NMR (400 MHz, DMSO-d6): δ 6.52 (s, 1H), 5.20 (s, 1H), 3.79 (t, J = 9.60 Hz, 3H), 3.69-3.60 (m, 4H), 3.50-3.45 (m, 3H), 2.80-2.60 (m, 2H), 2.10-1.80 (m, 10H), 1.60-1.45 (m, 2H). Example-718:
Figure imgf000559_0001
IN10882-072-P1
[001560] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.44 g of 4, 6- dichloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine gave (4-(6-chloro-2-(3-methyl-lH- pyrazol-l-yl) pyrimidin-4-yl) morpholin-2-yl) methanol as a white solid (0.6 g, 80%). MS (M+l)+=310.0.
[001561] Step 2[IN10882-072-Pl]: 0.1 g of (4-(6-chloro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) morpholin-2-yl) methanol gave (4-(2-(3-methyl-lH-pyrazol-l-yl)-6- (piperidin-l-yl) pyrimidin-4-yl) morpholin-2-yl) methanol as a white solid (0.06 g, 52%). MS (M+l)+=359.1; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 6.26 (s, IH), 5.77 (s, IH), 4.82 (t, J = 5.60 Hz, IH), 4.26 (dd, J = 13.20, 42.40 Hz, 2H), 3.92 (d, J = 10.00 Hz, IH), 3.62 (s, 4H), 3.55-3.44 (m, 3H), 2.88 (t, J = 11.20 Hz, IH), 2.64 (t, J = 12.00 Hz, IH), 2.25 (s, 3H), 1.63-1.53 (m, 5H).
Exam le-719:
Figure imgf000559_0002
Table-60: Ste 1: The rocedure is similar to Ste 1[A] in Exam le-838.
Figure imgf000559_0003
Figure imgf000560_0001
Figure imgf000560_0003
[001562] Step 2[IN10882-068-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.8 Hz, IH), 6.26 (d, J = 2.4 Hz, IH), 5.59 (s, IH), 4.85-4.80 (m, IH), 4.35-4.15 (m, 2H), 3.95- 3.91 (m, IH), 3.64-3.39 (m, 8H), 2.91-2.84 (m, IH), 2.67-2.60 (m, IH), 2.25 (s, 3H), 1.72 (bs, 4H), 1.48 (bs, 4H).
[001563] Step 2[IN10882-083-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.34 (d, J = 2.40 Hz, IH), 6.76 (s, IH), 6.27 (d, J = 2.40 Hz, IH), 5.57 (s, IH), 4.88-4.85 (m, IH), 4.08-3.91 (m, 3H), 3.45-3.37 (m, 3H), 2.88-2.85 (m, IH), 2.67-2.55 (m, 2H), 2.25 (s, 3H), 1.40 (s, 9H).
[001564] Step 2[IN10882-057-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.38 (s, IH), 6.89 (d, J = 7.60 Hz, IH), 6.25 (s, IH), 5.48 (s, IH), 4.81 (t, J = 2.40 Hz, IH), 4.18-3.91 (m, 4H), 3.55-3.40 (m, 4H), 2.90-2.84 (m, IH), 2.66-2.63 (m, IH), 2.33 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).
Example-720:
Figure imgf000560_0002
[001565] Step 1: The procedure is similar to Step 1[B] in Example-838. 25 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine gave tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4- yl)oxy)azetidine-l -carboxylate as a yellow gum (32 g, 91%). MS (M+l)+=465.5.
[001566] Step 2[NSSy5648] : To a stirred solution of tert-butyl 3-((6-((4, 4- difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy) azetidine- 1- carboxylate (0.3 g, 0.64 mmol) in DCM (5 mL) was added 4 (M) HCl in dioxane (2 mL) at 0 °C and the reaction mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure to afford crude product and which was purified by flash column chromatography using methanol in chloroform as solvent to afford 6-(azetidin-3- yloxy)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine as a white solid (0.18 g, 60%). MS (M+l)+=365.2; 1H-NMR (400 MHz, DMSO-d6): δ 9.31 (s, IH), 9.13 (s, IH), 8.46 (s, IH), 7.70 (s, IH), 6.35 (s, IH), 5.76 (s, IH), 5.42 (s, IH), 4.38 (s, 2H), 4.10-4.03 (m, 2H), 2.26 (s, 3H), 2.06-1.92 (m, 6H), 1.61-1.54 (m, 2H).
Example-7
Figure imgf000561_0001
[001567] Step 1 [NSSy6529] : The procedure is similar to Step 5[NSSy6711] in
Example-854. 0.2 g of 4-((2-(3-methyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-yl) amino) cyclohexan-l-ol gave N-(4-methoxycyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)-6- morpholinopyrimidin-4-amine as an off-white solid (0.035 g, 17%). MS (M+l)+=373.2; 1H- NMR (400 MHz, DMSO-d6): δ 8.38 (s, IH), 6.91 (s, IH), 6.25 (s, IH), 5.51 (s, IH), 3.68 (s, 4H), 3.47 (s, 4H), 3.24 (s, 3H), 2.24 (s, 3H), 1.99-1.79 (m, 3H), 1.61-1.53 (m, 4H), 1.23 (s, 2H). Example-722:
Figure imgf000562_0001
[001568] Step 1: The procedure is similar to Step 1[IN11273-018-P1] in Example-889. 2.0 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4- amine gave ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine-4-carboxylate as a brownish gum (1.1 g, 49%). MS (M+l)+=366.0.
[001569] Step 2: The procedure is similar to Step 4[NSSy6711] in Example-854. 1.1 g of ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidine-4- carboxylate gave (6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol as a brown solid (0.6 g, 61%). MS (M+l)+=324.1.
[001570] Step 3: The procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.9 g of (6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol carboxylate gave 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH- pyrazol-l-yl) pyrimidin-4-amine as a brown solid (0.75 g, 71%). MS (M+l)+=386.1.
[001571] Step 4: To a stirred solution of 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)- 2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine (0.2 g, 0.51 mmol) in Dioxane (10 mL) was added ammonium hydroxide (8 mL) at rt. The reaction mixture was heated at 120 °C for 16h in a sealed tube vessel. The reaction was cooled to rt, diluted with ethyl acetate and dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6- (aminomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- IH-pyrazol- l-yl)pyrimidin-4-amine as an off-white solid (0.17 g, 75%). MS (M+l)+=323.1.
[001572] Step 5[IN11053-033-P1]: The procedure is similar to step 1[A] in Example- 838. 0.015 g of 6-(aminomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4-amine gave of methyl ((6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH- pyrazol-l-yl) pyrimidin-4-yl) methyl) carbamate as a brown solid (0.04 g, 22%). MS
(M+l)+=381.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 7.72 (s, 2H), 6.30 (s, 1H), 6.26 (s, IH), 4.15 (s, IH), 4.04 (s, 2H), 3.58 (s, 3H), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.60-
1.52 (m, 2H).
Example-723:
Figure imgf000563_0001
Table-62: Step 1: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000563_0002
[001573] Step l[IN11053-046-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.48 (s, IH), 8.37 (s, IH), 8.17 (d, J = 9.20 Hz, IH), 7.80-7.70 (m, 2H), 7.52 (d, J = 9.20 Hz, IH), 6.37 (s, IH), 6.32 (d, J = 2.40 Hz, IH), 5.49 (s, 2H), 4.15 (s, IH), 2.27 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.50 (m, 2H).
[001574] Step 1[IN11053-013-P1]: IH-NMR (400 MHz, CDC13): δ 8.49 (d, J = 2.00 Hz, IH), 8.39 (d, J = 2.40 Hz, IH), 7.85-7.84 (m, IH), 6.97 (d, J = 8.80 Hz, IH), 6.24 (s, 2H), 5.46 (s, 2H), 5.10 (s, IH), 3.90 (s, IH), 2.41 (s, 3H), 2.10-1.80 (m, 6H), 1.70-1.60 (m, 2H). Example-724
Figure imgf000564_0001
[001575] Step 1[IN11053-007-P1]: The procedure is similar to Step l[NSSy6519] in Example-842. 0.2 g of 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH- pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-(methoxymethyl)-2-(3- methyl-lH-pyrazol-l-yl) pyrimidin-4-amine as a white solid (0.09 g, 51%). MS
(M+l)+=338.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (bs, 1H), 7.65 (bs, 1H), 6.41 (s, 1H), 6.30 (d, J = 2.8 Hz, 1H), 4.30 (s, 2H), 4.15 (bs, 1H), 3.93 (s, 3H), 2.25 (s, 3H), 2.07-1.97 (m, 6H), 1.59-1.56 (m, 2H).
Example-725:
Figure imgf000564_0002
Table-63: Step 1: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000564_0003
Figure imgf000565_0001
Table-64: Step 2: The procedure is similar to Step 5[NSSy6067] in Example-628.
Figure imgf000565_0002
[001576] Step 2[NSSy6993]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.80 Hz, IH), 7.07 (d, J = 8.00 Hz, IH), 5.98 (d, J = 2.80 Hz, IH), 5.51 (s, IH), 3.90 (s, 3H), 3.69-3.67 (m, 4H), 3.51 (m, 4H), 2.05-2.01 (m, 3H), 1.93-1.90 (m, 3H), 1.60-1.52 (m, 2H).
[001577] Step 2[NSSy7011]: IH-NMR (400 MHz, DMSO-d6): δ 7.12 (s, IH), 5.56 (s, IH), 3.87 (s, IH), 3.67 (s, 4H), 3.46 (s, 4H), 2.19 (s, 3H), 2.14-1.80 (m, 6H), 1.60-1.47 (m, 2H).
[001578] Step 2[NSSy7021]: IH-NMR (400 MHz, DMSO-d6): δ 8.54 (d, J = 2.00 Hz, IH), 7.20 (d, J = 8.00 Hz, IH), 6.63 (d, J = 2.40 Hz, IH), 5.58 (s, IH), 4.01 (s, IH), 3.69-3.67 (m, 4H), 3.51 (s, 4H), 2.08-1.90 (m, 6H), 1.59-1.50 (m, 2H).
[001579] Step 2[NSSy7034]: IH-NMR (400 MHz, DMSO-d6): δ 8.62 (d, J = 2.60 Hz, IH), 7.92 (d, J = 7.20 Hz, 2H), 7.46 (t, J = 7.68 Hz, 2H), 7.37 (t, J = 7.44 Hz, IH), 7.19 (d, J = 7.96 Hz, IH), 6.98 (d, J = 2.64 Hz, IH), 5.60 (s, IH), 4.01 (bs, IH), 3.72-3.70 (m, 4H), 3.56 (bs, 4H), 2.08-1.94 (m, 6H), 1.63-1.54 (m, 2H).
[001580] Step 2[NSSy6343]: 1H-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 7.17 (d, J = 8.16 Hz, IH), 6.30-6.27 (m, IH), 5.56 (s, IH), 4.01-3.92 (m, IH), 3.69-3.67 (m, 4H), 3.51- 3.41 (m, 4H), 2.08-1.91 (m, 6H), 1.56-1.53 (m, 2H).
[001581] Step 2[IN11237-056-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 7.45 (s, IH), 7.04 (d, J = 8.16 Hz, IH), 6.20 (m, IH), 5.56 (s, IH), 4.01-3.92 (m, IH), 3.69-3.67 (m, 4H), 3.51-3.41 (m, 4H), 2.08-1.91 (m, 6H), 1.56-1.53 (m, 2H).
Example-726:
Figure imgf000566_0001
[001582] Step 1 [NSSy7087] : The procedure is similar to Step 1 [NSSy6972] in
Example-841. 0.25 g of N-(4, 4-difluorocyclohexyl)-2-(3-methoxy-lH-pyrazol-l-yl)-6- morpholinopyrimidin-4-amine gave l-(4-((4, 4-difluorocyclohexyl) amino)-6- morpholinopyrimidin-2-yl)-lH-pyrazol-3-ol as an off-white solid (0.12 g, 17%). MS
(M+l)+=381.0; 1H-NMR (400 MHz, DMSO-d6): δ 10.40 (s, IH), 6.98 (d, J = 7.60 Hz, IH), 5.79 (d, J = 2.80 Hz, IH), 5.49 (s, IH), 3.97 (s, IH), 3.68-3.66 (m, 4H), 3.55-3.35 (m, 4H), 2.08-2.04 (m, 3H), 2.02 (m, 3H), 1.98-1.97 (m, 2H).
Example-727:
[001583] Intentionally Omitted
Example-728:
Figure imgf000567_0001
[001584] Step 1: The procedure is similar to Step 1[B] in Example-838. 2.0 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave 6-(3-(benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine as an off-white solid (2.5 g, 86%). MS (M+l)+=436.0.
[001585] Step 2: The procedure is similar to Step 3[NSSy7062] in Example-623. 2.5 g of 6-(3-(benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4- amine gave 6-(3-(benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(methylsulfonyl) pyrimidin-4-amine as an off-white solid (2.5 g, 93%). MS (M+l)+=468.0.
[001586] Step 3: The procedure is similar to Step 1[B] in Example-838. 3.0 g of 6-(3- (benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(methylsulfonyl) pyrimidin-4-amine gave ethyl l-(4-(3-(benzyloxy) cyclobutoxy)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin- 2-yl)-lH-pyrazole-3-carboxylate as colourless gum (3.0 g, 90%). MS (M+l)+=528.0.
[001587] Step 4: The procedure is similar to Step 2[NSSy6464] in Example-869. 3.0 g of ethyl l-(4-(3-(benzyloxy) cyclobutoxy)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-2- yl)-lH-pyrazole-3-carboxylate gave ethyl l-(4-((4, 4-difluoro cyclohexyl) amino)-6-(3- hydroxycyclobutoxy) pyrimidin-2-yl)-lH-pyrazole-3-carboxylate as a white solid (2.0 g, 80%). MS (M+l)+=436.0.
[001588] Step 5: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.3 g of ethyl l-(4-((4, 4-difluorocyclohexyl)amino)-6-(3-hydroxycyclobutoxy) pyrimidin-2-yl)- lH-pyrazole-3-carboxylate gave 3-((6-((4, 4-difluorocyclohexyl )amino)-2-(3- (hydroxymethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)oxy)cyclobutan-l-ol as colourless gum (0.25 g, 92%). MS (M+l)+=396.0.
[001589] Step 6[NSSy5618]: The procedure is similar to Step 3[NSSy6917] in
Example-21. 0.25 g of 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)cyclobutan-l-ol gave of N-(4, 4-difluorocyclohexyl)-6-(3- fluorocyclobutoxy)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine as a white solid (0.1 g, 40%). MS (M+l)+=400.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.60 (s, IH), 7.55 (s, IH), 5.80-5.69 (m, IH), 5.50-5.40 (m, IH), 5.38-5.23 (m, 3H), 4.20-3.71 (m, IH), 2.68-2.67 (m, 2H), 2.56-2.54 (m, IH), 2.34-2.33 (m, 6H), 1.95-1.60 (m, 2H).
Example-729:
[001590] Step 1: The procedure is similar to Step l[NSSy6930] in Example-867. 1.5 g of ethyl l-(4-((4, 4-difluorocyclohexyl) amino)-6-(3-hydroxycyclobutoxy) pyrimidin-2-yl)- lH-pyrazole-3-carboxylate gave ethyl l-(4-((4, 4-difluorocyclohexyl) amino)-6-(3- oxocyclobutoxy) pyrimidin-2-yl)-lH-pyrazole-3-carboxylate as a yellow solid (1.4 g, 95%). MS (M+l)+=436.0.
[001591] Step 2: The procedure is similar to Step 3[NSSy6917] in Example-21. 0.6 g of ethyl l-(4-((4, 4-difluorocyclohexyl) amino)-6-(3-oxocyclobutoxy) pyrimidin-2-yl)-lH- pyrazole-3-carboxylate gave ethyl l-(4-(3, 3-difluorocyclobutoxy)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-2-yl)-lH-pyrazole-3-carboxylate as a white solid (0.33 g, 52%). MS (M+l)+=456.0.
[001592] Step 3: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.33 g of ethyl l-(4-(3, 3-difluorocyclobutoxy)-6-((4, 4-difluorocyclohexyl)amino) pyrimidin-2-yl)- lH-pyrazole-3-carboxylate gave (l-(4-(3, 3-difluorocyclo butoxy)-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazol-3-yl) methanol as a colourless gum (0.26 g, 86%). MS (M+l)+=416.0.
[001593] Step 4[NSSy5619]: The procedure is similar to Step 3[NSSy6917] in
Example-21. 0.26 g of (l-(4-(3, 3-difluorocyclobutoxy)-6-((4, 4-difluorocyclohexyl) amino)pyrimidin-2-yl)-lH-pyrazol-3-yl)methanol gave 6-(3, 3-difluoro cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine as a white solid (0.11 g, 39%). MS (M+l)+=418.0; IH-NMR (400 MHz, DMSO-d6): δ 8.59 (s, 1H), 7.77-7.62 (m, 1H), 6.65 (d, J = 1.20 Hz, 1H), 5.76 (d, J = 12.40 Hz, 1H), 5.49 (s, 1H), 5.37 (s, 1H), 5.15 (s, 1H), 4.15-4.05 (m, 1H), 3.19-3.01 (m, 2H), 2.81-2.69 (m, 2H), 2.04-1.94 (m, 6H), 1.56-1.53 (m, 2H).
Example-730:
Figure imgf000569_0001
[001594] Step 1: The procedure is similar to Step 1[B] in Example-838. 2.5 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-6-((l-methyl-lH-l, 2, 4-triazol-3-yl) methoxy)-2-(methylthio) pyrimidin-4-amine as a white solid (1.0 g, 32%). MS (M+l)+=371.6.
[001595] Step 2: The procedure is similar to Step 2[IN11218-026-P1] in Example-613. 3.0 g of N-(4, 4-difluorocyclohexyl)-6-((l-methyl- lH-l, 2, 4-triazol-3-yl)methoxy)-2- (methylthio)pyrimidin-4-amine gave tert-butyl (4, 4-difluorocyclohexyl)(6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)-2-(methylthio)pyrimidin-4-yl) carbamate as a yellow solid (3.7 g, 97%). MS (M+l)+=471.2.
[001596] Step 3: The procedure is similar to Step 3[NSSy7062] in Example-623. 3.6 g of tert-butyl (4, 4-difluorocyclohexyl)(6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)-2- (methylthio)pyrimidin-4-yl)carbamate gave tert-butyl (4, 4-difluorocyclohexyl) (6-((l- methyl-lH-1, 2, 4-triazol-3-yl)methoxy)-2-(methylsulfonyl)pyrimidin-4-yl)carbamate as a yellow solid (3.7 g, 96%). MS (M+l)+=503.8. [001597] Step 4: The procedure is similar to Step 1[NSSY6710] in Example-854. 3.7 g of tert-butyl (4, 4-difluorocyclohexyl)(6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)-2- (methylsulfonyl)pyrimidin-4-yl)carbamate gave tert-butyl (2-cyano-6-((l-methyl-lH-l, 2, 4- triazol-3-yl)methoxy)pyrimidin-4-yl)(4, 4-difluorocyclohexyl)carbamate as a yellow solid (3.1 g, 89%). MS (M+l)+=450.7.
[001598] Step 5: The procedure is similar to Step 5[NSSy5779] in Example-642. 3.1 g of tert-butyl (2-cyano-6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)pyrimidin-4-yl)(4, 4- difluorocyclohexyl)carbamate gave tert-butyl (2-carbamothioyl-6-((l-methyl-lH-l, 2, 4- triazol-3-yl)methoxy)pyrimidin-4-yl)(4, 4-difluorocyclo hexyl ) carbamate as a yellow solid (3.2 g, 93%). MS (M+l)+=484.2.
[001599] Step 6: The procedure is similar to Step 6[NSSY5779] in Example-642. 2.0 g of tert-butyl (2-carbamothioyl-6-((l -methyl- lH-1, 2, 4-triazol-3-yl) methoxy) pyrimidin-4- yl)(4, 4-difluorocyclohexyl)carbamate gave ethyl 2-(4-((tert-butoxycarbonyl)(4, 4- difluorocyclohexyl)amino)-6-((l-methyl-lH-l, 2, 4-triazol -3-yl)methoxy)pyrimidin-2- yl)thiazole-4-carboxylate as an off-white solid (1.6 g, 67%). MS (M+l)+=579.3.
[001600] Step 7: The procedure is similar to Step 4[NSSy6711] in Example-854. 1.6 g of ethyl 2-(4-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-6-((l-methyl-lH-l, 2, 4- triazol-3-yl)methoxy)pyrimidin-2-yl)thiazole-4-carboxylate gave of tert-butyl (4, 4- difluorocyclohexyl)(2-(4-(hydroxymethyl)thiazol-2-yl)-6-(( 1-methyl- 1H- 1 , 2, 4-triazol-3- yl)methoxy)pyrimidin-4-yl)carbamate as a pale yellow solid (1.1 g, 74%). MS
(M+l)+=538.5.
[001601] Step 8: The procedure is similar to Step 3[NSSy6067] in Example-628. 0.6 g of tert-butyl (4, 4-difluorocyclohexyl)(2-(4-(hydroxymethyl)thiazol-2-yl)-6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)pyrimidin-4-yl)carbamate gave tert-butyl (4, 4- difluorocyclohexyl)(2-(4-(fluoromethyl)thiazol-2-yl)-6-((l-methyl-lH-l,2,4-triazol-3- yl)methoxy)pyrimidin-4-yl)carbamate as an off-white solid (0.26 g, 43%). MS
(M+l)+=540.7.
[001602] Step 9[NSSy5624]: The procedure is similar to Step 5[NSSy6067] in
Example-628. 0.26 g of tert-butyl (4, 4-difluorocyclohexyl)(2-(4-(fluoromethyl)thiazol-2-yl)- 6-((l-methyl-lH-l, 2, 4-triazol-3-yl)methoxy)pyrimidin-4-yl)carbamate gave N-(4, 4- difluorocyclohexyl)-2-(4-(fluoromethyl)thiazol-2-yl)-6-(( 1-methyl- lH-1, 2, 4-triazol-3- yl)methoxy)pyrimidin-4-amine as a white solid (0.19 g, 92%). MS (M+l)+=440.2; IH-NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 5.91 (s, 1H), 5.58 (s, 1H), 5.46 (s, 1H), 5.37 (s, 2H), 4.01 (s, 1H), 3.86 (s, 3H), 2.08-1.95 (m, 6H), 1.59-1.53 (m, 2H).
Figure imgf000571_0001
Figure imgf000572_0001
Figure imgf000573_0001
15 min
Figure imgf000573_0002
Figure imgf000573_0003
[001603] Step 7[NSSy5625]: IH-NMR (400 MHz, DMSO-d6): δ 7.86 (s, IH), 7.54 (s, IH), 7.46 (s, IH), 5.88 (s, IH), 5.53 (s, IH), 4.14 (s, 3H), 2.46 (s, 3H), 2.08-1.92 (m, 6H), 1.58-1.55 (m, 2H). [001604] Step 7[NSSy5651]: 1H-NMR (400 MHz, DMSO-d6): δ 7.66 (s, IH), 7.44 (d, J = 0.80 Hz, IH), 5.91 (s, IH), 5.59 (s, 2H), 4.13-3.92 (m, IH), 2.43 (s, 3H), 2.32 (s, 3H), 2.07- 1.94 (m, 6H), 1.60-1.55 (m, 2H).
[001605] Step 7[NSSy5689]: 1H-NMR (400 MHz, DMSO-d6): δ 7.89 (s, IH), 7.55 (s, IH), 7.44 (s, IH), 5.51 (s, 2H), 4.03 (s, 3H), 2.33 (s, 3H), 2.05 -1.92 (m, 6H), 1.58-1.55 (m, 2H).
[001606] Step 7[NSSy5690]: 1H-NMR (400 MHz, DMSO-d6): δ 8.64 (s, IH), 7.50 (bs, IH), 7.43 (s, IH), 5.87 (bs, IH), 5.36 (s, 2H), 4.01 (bs, IH), 3.86 (s, 3H), 2.08 (s, 3H), 2.22- 1.80 (m, 6H), 1.58-1.53 (m, 2H).
Example-732:
Figure imgf000574_0001
[001607] Step 1: The procedure is similar to Step 1[B] in Example-838. 500.0 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave tert-butyl 3-((6- ((4, 4-difluorocyclohexyl) amino)-2-(methylthio) pyrimidin-4-yl) oxy) azetidine-1- carboxylate as a white solid (510.0 g, 69%). MS (M+l)+=431.2.
[001608] Step 2: The procedure is similar to Step 2[IN11218-026-P1] in Example-613. 500.0 g of tert-butyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(methylthio)pyrimidin-4- yl)oxy) azetidine-l-carboxylate gave tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4- difluorocyclohexyl)amino)-2-(methylthio)pyrimidin -4-yl)oxy)azetidine-l-carboxylate as a white solid (518.0 g, 84%). MS (M+ 1)4=531.2.
[001609] Step 3: The procedure is similar to Step 3[NSSy7062] in Example-623. 510.0 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2-(methylthio) pyrimidin-4-yl)oxy)azetidine-l-carboxylate gave tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4- difluorocyclohexyl)amino)-2-(methylsulfonyl) pyrimidin-4-yl)oxy)azetidine- 1-carboxylate as an off-white solid (525.0 g, 97%). MS (M+l)+=563.6.
[001610] Step 4: The procedure is similar to Step l[NSSy6710] in Example-854. 515.0 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2- (methylsulfonyl)pyrimidin-4-yl)oxy)azetidine- 1-carboxylate gave tert-butyl 3-((6-((tert- butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2-cyanopyrimidin-4-yl)oxy)azetidine-l- carboxylate as an off-white solid (460.0 g, 98%). MS (M+l)+=510.2.
[001611] Step 5: The procedure is similar to Step 5[NSSy5779] in Example-642. 280.0 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2- cyanopyrimidin-4-yl)oxy)azetidine- 1-carboxylate gave tert-butyl 3-((6-((tert- butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2-carbamothioylpyrimidin-4- yl)oxy)azetidine- 1-carboxylate as a pale yellow solid (280.0 g, 93%). MS (M+l)+=544.2.
[001612] Step 6: The procedure is similar to Step 6[NSSy5779] in Example-642. 10.0 g of tert-butyl 3-((6-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2-carbamothioyl pyrimidin-4-yl)oxy)azetidine- 1-carboxylate gave ethyl 2-(4-((tert-butoxycarbonyl)(4, 4- difluorocyclohexyl)amino)-6-((l-(tert-butoxy carbonyl)azetidin-3-yl)oxy)pyrimidin-2- yl)thiazole-4-carboxylate as an off-white gummy solid (4.0 g, 36%). MS (M+l)+=639.0.
[001613] Step 7: The procedure is similar to Step 2[NSSy6924] in Example-857. 7.3 g of ethyl 2-(4-((tert-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-6-((l-(tert- butoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)thiazole-4-carboxylate gave ethyl 2-(4- (azetidin-3-yloxy)-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-2-yl)thiazole-4-carboxylate as an off-white gummy solid (4.8 g, 96%). MS (M+l)+=440.1.
[001614] Step 8: The procedure is similar to Step 2[NSSy6924] in Example-857. 4.8 g of ethyl 2-(4-(azetidin-3-yloxy)-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-2-yl)thiazole-4- carboxylate gave ethyl 2-(4-((4, 4-difluorocyclohexyl)amino)-6-((l- (methoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)thiazole-4-carboxylate as an off-white solid (2.6 g, 46%). MS (M+l)+=498.0.
[001615] Step 9[NSSy6049] : The procedure is similar to Step 4[NSSy6711] in
Example-854. 1.6 g of ethyl 2-(4-((4, 4-difluorocyclohexyl)amino)-6-((l- (methoxycarbonyl)azetidin-3-yl)oxy)pyrimidin-2-yl)thiazole-4-carboxylate gave methyl 3- ((6-((4, 4-difluorocyclohexyl)amino)-2-(4-(hydroxymethyl)thiazol-2-yl)pyrimidin-4- yl)oxy)azetidine-l-carboxylate as an off-white solid (0.94 g, 64%). MS (M+l)+=456.0; 1H- NMR (400 MHz, DMSO-d6): δ 7.58 (s, 2H), 5.87 (s, 1H), 5.41-5.36 (m, 2H), 4.63 (d, J = 5.20 Hz, 2H), 4.35 (s, 2H), 4.10 (s, 1H), 3.94 (s, 2H), 3.58 (s, 3H), 2.06-1.94 (m, 6H), 1.59- 1.56 (m, 2H).
[001616] Step 9A [NSSy6050] : To an ice-cooled solution of ethyl 2-(4-((4, 4- difluorocyclohexyl) amino)-6-((l-(methoxycarbonyl) azetidin-3-yl) oxy) pyrimidin-2-yl) thiazole-4-carboxylate (1.7 g, 3.41 mmol) in a mixture of solvent THF: Water (21:9 mL) was added Lithium hydroxide (0.16 g, 6.83 mmol) and stirred at rt for 6h. The reaction mixture was diluted with ethyl acetate, the organic layer was separated and concentrated to afford crude product and which was dissolved in water and acidified with 1.5 N HC1, the obtained solid was filtered off and washed with hexane (100 mL), dried under high vacuum to afford 2-(4-((4, 4-difluorocyclohexyl)amino)-6-((l-(methoxycarbonyl)azetidin-3-yl)oxy) pyrimidin- 2-yl)thiazole-4-carboxylic acid as an off-white solid (1.2 g, 75%). MS (M+l)+=470.0; 1H- NMR (400 MHz, DMSO-d6): δ 13.08 (bs, 1H), 8.50 (bs, 1H), 7.65 (s, 1H), 5.89 (s, 1H), 5.37 (m, 1H), 4.35 (m, 2H), 3.94 (m, 2H), 3.57 (s, 3H), 2.08-1.94 (m, 6H), 1.58-1.56 (m, 2H). Example-733:
Figure imgf000576_0001
[001617] Step 1: The procedure is similar to Step 2[NSSy6924] in Example-857. 0.5 g of tert-butyl 3-((6-((ie/t-butoxycarbonyl)(4, 4-difluorocyclohexyl)amino)-2-(4-methyl thiazol-2-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate gave 6-(azetidin-3-yloxy)-N-(4, 4- difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a pale yellow solid (0.21 g, 65%). MS (M+l)+=382.0. Table-72: Step 2: The procedure is similar to Step 1[A] in Example-838.
Figure imgf000577_0002
[001618] Step 2[NSSy5629]: MS (M+l)+=452.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.57 (s, IH), 7.44 (d, J = 0.88 Hz, IH), 5.87 (s, IH), 5.38 (s, IH), 4.57 (t, J = 6.76 Hz, IH), 4.33-4.24 (m, IH), 4.19-4.15 (m, IH), 3.85-3.81 (m, IH), 2.44 (s, 3H), 2.09-1.93 (m, 6H), 1.61-1.56 (m, 2H), 0.98 (t, J = 6.80 Hz, 6H).
[001619] Step 2[NSSy5630]: MS (M+l)+=438.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.56 (s, IH), 7.43 (s, IH), 5.89 (s, IH), 5.35 (s, IH), 4.53 (s, IH), 4.28-4.24 (m, IH), 4.12 (s, IH), 3.83 (s, IH), 2.43(s, 3H), 2.11-1.92 (m, 8H), 1.58-1.55 (m, 2H), 0.98-0.94 (m, 3H). Example-734:
Figure imgf000577_0001
[001620] Step 1: The Procedure is similar to step 1[B] in Example-838. 2.5 g of 6-(3- (benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(methylsulfonyl) pyrimidin-4-amine gave 6-(3-(benzyloxy) cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l- yl) pyrimidin-4-amine as an off-white solid (2.3 g, 92%). MS (M+l)+=470.2.
[001621] Step 2[NSSy5879] : The Procedure is similar to Step 2[NSSy6464] in
Example-869. 1 g of 6-(3-(benzyloxy)cyclobutoxy)-N-(4, 4-difluorocyclohexyl)-2-(3-methyl- lH-pyrazol-l-yl)pyrimidin-4-amine gave 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3- methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)oxy) cyclobutan-l-ol as an off-white solid (0.6 g, 80%). MS (M+l)+=380.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.49 (s, IH), 6.31 (d, J = 2.40 Hz, IH), 5.64 (s, IH), 5.19 (s, IH), 4.67 (s, IH), 3.88-3.84 (m, IH), 2.80- 2.78 (m, 2H), 2.25 (s, 3H), 2.05-1.91 (m, 9H), 1.56-1.53 (m, 2H).
[001622] Step 3[NSSy5647]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.2 g of 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl-lH-pyrazol-l- yl)pyrimidin-4-yl)oxy) cyclobutan- l-ol gave N-(4, 4-difluorocyclohexyl)-6-(3- fluorocyclobutoxy)-2-(3-methyl- lH-pyrazol- l-yl) pyrimidin-4-amine as an off-white solid (0.1 g, 50%). MS (M+l)+=382.2; 1H-NMR (400 MHz, OMSO-d6): δ 8.36 (s, 1H), 6.25 (s, 1H), 5.50-5.49 (m, 2H), 5.40-5.26 (m, 2H), 3.55 (s, 1H), 2.83-2.77 (m, 2H), 2.64-2.59 (m, 2H), 2.41 (s, 3H), 2.15- 1.88 (m, 6H), 1.72- 1.62 (m, 2H).
Example-735:
Figure imgf000578_0001
[001623] Step 1 : The Procedure is similar to Step l [NSSy6930] in Example-867. 1.2 g of 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4- yl)oxy)cyclobutan- l-ol gave 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)cyclobutan- l-one as a white solid (1 g, 52%). MS (M+l)+=378.2.
[001624] Step 2[NSSy5893] : The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.12 g of 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l- yl)pyrimidin-4-yl)oxy)cyclobutan- l-one gave 6-(3, 3-difluorocyclobutoxy)-N-(4, 4- difluorocyclohexyl)-2-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-amine as a pale yellow solid (0.056 g, 45%). MS (M+l)+=400.1 ; 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (s, 1H), 7.57- 7.54 (m, 1H), 6.32 (d, J = 2.44 Hz, 1H), 5.70 (s, 1H), 5.14 (s, 1H), 4.16-3.90 (m, 1H), 3.34- 3.18 (m, 2H), 2.77-2.68 (m, 2H), 2.33 (s, 3H), 2.26- 1.94 (m, 6H), 1.60- 1.54 (m, 2H).
[001625] Step 2A [NSSy5902] : The Procedure is similar to Step 4[NSSy6464] in Example-869. 1.0 g of 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl- lH-pyrazol- l- yl)pyrimidin-4-yl)oxy)cyclobutan- l-one gave 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3- methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)oxy)- l-methylcyclobutan- l-ol as an off-white solid (0.095 g, 10%). MS (M+l)+=394.2; 1H-NMR (400 MHz, OMSO-d6): δ 8.41 (s, 1H), 7.50 (s, 1H), 6.31 (d, / = 1.84 Hz, 1H), 5.64 (s, 1H), 5.16 (s, 1H), 4.72 (m, 1H), 4.10 (m, 1H), 2.51 2.48 (m, 2H), 2.25 (s, 3H), 2.15-1.91 (m, 8H), 1.56-1.53 (m, 2H), 1.28 (s, 3H).
Example-736:
Figure imgf000579_0001
[001626] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.5 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave methyl (3-((6-((4, 4-difluorocyclohexyl) amino)-2-(methylthio) pyrimidin-4-yl) oxy) cyclobutyl) (methyl) carbamate as a brownish gum (0.4 g, 57%). MS (M+l)+=417.1.
[001627] Step 2: The Procedure is similar to Step 3[NSSy7062] in Example-623. 0.4 g of (3-((6-((4, 4-difluorocyclohexyl)arnino)-2-(methylthio)pyrimidin-4-yl)oxy)cyclobutyl) (methyl)carbamate gave methyl (3-((6-((4, 4-difluorocyclohexyl)amino)-2- (methylsulfonyl)pyrimidin-4-yl)oxy)cyclo butyl) (methyl)carbamate as a white solid (0.41 g, 95%). MS (M+l)+=449.2.
[001628] Step 3[NSSy5672]: The Procedure is similar to Step 1[B] in Example-838. 0.1 g of methyl (3-((6-((4, 4-difluorocyclohexyl)amino)-2-(methylsulfonyl)pyrimidin-4- yl)oxy)cyclobutyl) (methyl)carbamate gave methyl (3-((6-((4, 4-difluorocyclohexyl)amino)- 2-(3-methyl-lH-pyrazol-l-yl)pyrimidin-4-yl)oxy) cyclobutyl)(methyl)carbamate as an off- white solid (0.025 g, 25%). MS (M+l)+=451.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H), 7.59-7.53 (m, 1H), 6.31 (s, 1H), 5.66 (s, 1H), 4.84 (s, 1H), 4.24-4.09 (m, 1H), 3.60 (s, 3H), 2.82 (s, 3H), 2.61-2.55 (m, 2H), 2.33-2.21 (m, 5H), 2.19-1.94 (m, 6H), 1.56-1.53 (m, 2H).
Example-737:
Figure imgf000579_0002
[001629] Step 1: The Procedure is similar to Step 1[B] in Example-838. 1 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave N-(4, 4- difluorocyclohexyl)-2-(methylthio)-6-(2-oxa-6-azaspiro [3.3] heptan-6-yl) pyrimidin-4-amine as an off-white solid (0.8 g, 66%). MS (M+l)+=357. [001630] Step 2: The Procedure is similar to Step 2[IN11218-026-P1] in Example-613. 0.8 g of N-(4, 4-difluorocyclohexyl)-2-(methylthio)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl) pyrimidin-4-amine gave tert-butyl (4, 4-difluorocyclohexyl)(2-(methylthio)-6-(2-oxa-6- azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)carbamate as an off-white solid (0.91 g, 89%). MS (M+l)+=457.
[001631] Step 3: The Procedure is similar to Step 3[NSSy7062] in Example-623. 0.9 g of tert-butyl (4, 4-difluorocyclohexyl)(2-(methylthio)-6-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyrimidin-4-yl)carbamate gave tert-butyl (4, 4-difluorocyclohexyl)(2-(methylsulfonyl)-6- (2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-4-yl)carbamate as a white solid (0.91 g, 83%). MS (M+l)+=489.
Example-738:
Figure imgf000580_0001
Table-73: Step 1:
Figure imgf000580_0002
Step 1[DI, DK and DL]: The Procedure is similar to Step 1[B] in Example-838. Step 1[DJ]: The Procedure is similar to Step 4[NSSy6067] in Example-628.
Table-74: Step 2: The Procedure is similar to Step 5[NSSy6067] in Example-628.
Figure imgf000581_0002
[001632] Step 2[NSSy5631]: MS (M+l)+=391.2; IH-NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 7.07 (d, J = 7.96 Hz, 1H), 6.25 (d, J = 2.48 Hz, 1H), 5.17 (s, 1H), 5.53 (s, 1H), 4.72 (s, 4H), 4.13 (s, 4H), 3.86 (s, 1H), 2.24 (s, 3H), 2.04-1.89 (m, 6H), 1.58-1.52 (m, 2H).
[001633] Step 2[NSSy5664]: MS (M+l)+=408.2; IH-NMR (400 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.03 (d, J = 7.60 Hz, 1H), 5.29 (s, 1H), 4.73 (m, 4H), 4.14-4.04 (m, 4H), 3.85 (m, 1H), 2.42 (s, 3H), 2.08-1.91 (m, 6H), 1.60-1.54 (m, 2H).
[001634] Step 2[NSSy5847]: MS (M+l)+=402.4; IH-NMR (400 MHz, DMSO-d6): δ 8.70 (s, 1H), 7.29 (d, J = 8.40 Hz, 1H), 7.16 (d, J = 2.80 Hz, 1H), 5.28 (s, 1H), 4.72 (m, 4H), 4.17 (m, 4H), 2.05-1.93 (m, 6H), 1.55 (m, 2H).
[001635] Step 2[NSSy5848]: MS (M+l)+=416.2; IH-NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 7.17 (d, J = 8.40 Hz, 1H), 6.46 (d, J = 2.40 Hz, 1H), 5.21 (s, 1H), 4.73 (m, 4H), 4.15 (m, 4H), 4.10 (s, 2H), 2.02-1.90 (m, 6H), 1.55-1.52 (m, 2H).
Example-739:
Figure imgf000581_0001
*Ό
[001636] Step 1: The Procedure is similar to Step 1[B] in Example-838. 15 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(methylthio) pyrimidin-4-amine gave methyl 3-((6-((4, 4-difluorocyclohexyl) amino)-2-(methylthio) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (15 g, 75%). MS (M+l)+=389.5.
[001637] Step 2: The Procedure is similar to Step 3[NSSy7062] in Example-623. 2 g of methyl 3-((6-((4, 4-difluorocyclohexyl) amino)-2-(methylthio) pyrimidin-4-yl) oxy) azetidine-l-carboxylate gave methyl 3-((6-((4, 4-difluorocyclo hexyl) amino)-2- (methylsulfonyl) pyrimidin-4-yl) oxy) azetidine-l-carboxylate as an off-white solid (2.1 g, 97%). MS (M+l)+=421.1.
[001638] Table-75: Step 3: The Procedure is similar to Step 1[B] in Example-838.
Figure imgf000582_0001
[001639] Step 3[NSSy6054]: MS (M+l)+=412.2; 1H-NMR (400 MHz, DMSO-d6): δ 6.69 (d, J = 6.96 Hz, IH), 5.21 (s, IH), 5.11 (s, IH), 4.24 (bs, 2H), 3.56 (bs, 3H), 3.38 (s, 3H), 2.68 (s, 4H), 2.20-1.70 (m, 10H), 1.60-1.40 (m, 2H).
[001640] Step 3[NSSy6101]: MS (M+l)+=489.0; 1H-NMR (400 MHz, DMSO-d6-80 °C): δ 8.48 (s, IH), 7.44 (d, J = 8.00 Hz, IH), 6.62 (s, IH), 5.79 (s,lH), 5.42-5.38 (m, IH), 4.37-4.33 (m, 2H), 3.94-3.91 (m, 3H), 3.58 (s, 3H), 2.20-1.80 (m, 6H), 1.65-1.50 (m, 2H).
[001641] Step 3[NSSy6113]: MS (M+l)+=443.2; 1H-NMR (400 MHz, DMSO-d6-80 °C): δ 8.54 (s, IH), 7.49 (d, J = 6.8 Hz, IH), 6.57 (s, IH), 5.78 (s,lH), 5.41-5.38 (m, IH), 4.37-4.33 (m, 2H), 3.94-3.90 (m, 3H), 3.59 (s, 3H), 2.20-1.80 (m, 6H), 1.65-1.45 (m, 2H).
[001642] Step 3[NSSy6162]: MS (M+l)+=427.1; 1H-NMR (400 MHz, DMSO-d6-80 °C): δ 8.45 (s, IH), 7.42 (d, J = 7.6 Hz, IH), 6.29-6.27 (m, IH), 5.76 (s,lH), 5.40-5.37 (m, IH), 4.37-4.33 (m, 2H), 3.94-3.90 (m, 3H), 3.60 (s, 3H), 2.08-1.97 (m, 6H), 1.64-1.57 (m, 2H). Example-740:
Figure imgf000583_0001
[001643] Step l[NSSy6072]: The Procedure is similar to Step 3[NSSy7062] in
Example-623: 0.3 g of methyl 3-((6-((4, 4-difluorocyclohexyl)amino)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)oxy)azetidine-l-carboxylate gave 6-((4, 4- difluorocyclohexyl)amino)-4-((l-(methoxycarbonyl)azetidin-3-yl)oxy)-2-(3-methyl-lH- pyrazol-l-yl)pyrimidine 1-oxide as an off-white solid (0.06 g, 19%). MS (M+l)+=439.2; 1H- NMR (400 MHz, DMSO-d6): δ 9.29 (d, J = 2.80 Hz, 1H), 8.13 (d, / = 8.80 Hz, 1H), 6.41 (s, 1H), 6.36 (d, J = 2.80 Hz, 1H), 5.35-5.32 (m, 1H), 4.33-4.31 (m, 1H), 3.95-3.80 (m, 2H), 3.73-3.70 (m, 1H), 3.57 (s, 1H), 2.28 (s, 3H), 2.07-1.88 (m, 7H), 1.76-1.73 (m, 2H).
Exam le-741:
Figure imgf000583_0002
[001644] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 0.33 g of tert- butyl 4-(2, 6-dichloropyrimidin-4-yl) piperidine-l-carboxylate gave tert-butyl 4-(2-chloro-6- ((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) piperidine-l-carboxylate as an off-white solid (0.25 g, 75%). MS (M+l)+=432.2 and tert-butyl 4-(6-chloro-2-((4, 4- difluorocyclohexyl)amino)pyrimidin-4-yl)piperidine-l-carboxylate as an off-white solid (0.12 g, 25%). MS (M+l) =432.2. Example-742:
Figure imgf000584_0001
[001645] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 0.25 g of tert- butyl 4-(2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) piperidine-l- carboxylate gave tert-butyl 4-(6-((4, 4-difluorocyclohexyl) amino)-2-(3-methyl-lH-pyrazol- 1-yl) pyrimidin-4-yl) piperidine-l-carboxylate as an off-white solid (0.13 g, 50%). MS (M+l)+=477.2
Table-76: Step 2: The Procedure is similar to Step 2[NSSy6924] in Example-857.
Figure imgf000584_0002
[001646] Step 2[NSSy6982]: MS (M+l)+=434.9; IH-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 7.34 (bs, IH), 6.87 (s, IH), 6.40 (d, J = 4.00 Hz, IH), 4.10 (bs, IH), 3.61- 3.60 (s, IH), 2.69-2.60 (m, IH), 2.57-2.54 (m, IH) 2.26 (s, 3H), 2.08-1.85 (m, 6H), 1.61-1.55 (m, 2H), 1.24-1.22 (m, 4H).
[001647] Step 2[NSSy6369]: MS (M+l)+=419.2; IH-NMR (400 MHz, DMSO-d6): δ 8.45 (s, IH), 7.59 (bs, IH), 6.28 (s, IH), 6.18 (bs, IH), 4.48 (d, J = 12.0 Hz, IH), 3.14 (bs, IH), 3.92 (d, J = 12.0 Hz, IH), 3.12 (s, IH), 2.69-2.60 (m, IH), 2.57-2.54 (m, IH), 2.25 (s, 3H), 2.04-1.80 (m, 11H), 0.60 (m, 4H). Example-743:
Figure imgf000585_0001
[001648] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 0.12 g of tert- butyl 4-(6-chloro-2-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) piperidine-1- carboxylate gave tert-butyl 4-(2-((4, 4-difluoro cyclohexyl) amino)-6-(3-methyl-lH-pyrazol- 1-yl) pyrimidin-4-yl) piperidine-1 -carboxylate as an off-white solid (0.062 g, 51%). MS (M+l)+=477.2.
[001649] Step 1 [NSSy6981] : The Procedure is similar to Step 2[NSSy6924] in
Example-857. 0.062 g of tert-butyl 4-(2-((4, 4-difluoro cyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyrimidin-4-yl)piperidine-l -carboxylate gave methyl 4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyrimidin-4-yl)piperidine- 1- carboxylate as an off-white solid (0.035 g, 62%). MS (M+l)+=435.2; IH-NMR (400 MHz, DMSO-d6): δ 8.46 (s, IH), 7.61-7.59 (m, IH), 6.29 (s, IH), 6.18 (s, IH), 4.10 (s, IH), 3.61 (s, IH), 2.69-2.60 (m, IH), 2.57-2.54 (m, IH), 2.26 (s, 3H), 2.08-1.85 (m, 6H), 1.61-1.55 (m, 2H), 1.24 (m, 4H).
Example-744:
Figure imgf000585_0002
[001650] Step 1 : The Procedure is similar to Step 1 [INI 1177-025-P1] in Example-715. 1.0 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro-2-(3-cyclopropyl-lH- pyrazol-l-yl) pyrimidine as an off-white solid (1.1 g, 97%). MS (M+l)+=255.0. [001651] Step 2: The Procedure is similar to Step 1 [B] in Example-838. 1.0 g of 4, 6- dichloro-2-(3-cyclopropyl-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-2-(3-cyclopropyl-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid (0.75 g, 53%). MS (M+l)+=354.0.
[001652] Step 3: The Procedure is similar to Step 2[IN11250-007-P1] in Example-620. 0.25 g of 6-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin- 4-amine gave tert-butyl 4-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl)amino)pyrimidin-4-yl)-3, 6-dihydropyridine-l(2H)-carboxylate as an off- white solid (0.25 g, 70%). MS (M+l)+=501.0.
[001653] Step 4[IN11166-038-P1]: The Procedure is similar to Step 2[NSSy6924] in Example-857. 0.25 g of tert-butyl 4-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl)-3, 6-dihydropyridine-l(2H)-carboxylate gave 1- (4-(2-(3-cyclopropyl- lH-pyrazol- l-yl)-6-((4, 4-difluorocyclohexyl)amino) pyrimidin-4-yl)-3, 6-dihydropyridin-l(2H)-yl)ethan-l-one as an off-white solid (0.09 g, 45%). MS
(M+l)+=443.3; 1H-NMR (400 MHz, DMSO-d6): δ 8.48 (s, IH), 7.69 (s, IH), 6.96 (s, IH), 6.34 (s, IH), 6.19 (s, IH), 4.22 (s, IH), 4.16 (s, 2H), 3.67-3.62 (m, 2H), 2.08 (s, 3H), 2.06 (s, 3H), 2.00-1.90 (m, 6H), 1.65-1.52 (m, 2H), 0.92 (d, / = 4.00 Hz, 2H), 0.72 (d, = 4.40 Hz, 2H).
[001654] Step 5[IN11166-042-P1]: The Procedure is similar to Step 2[NSSy6464] in Example-869. 0.09 g of l-(4-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl)-3, 6-dihydropyridin-l(2H)-yl)ethan-l-one gave l-(4-(2-(3-cyclopropyl- lH-pyrazol- l-yl)-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-4- yl)piperidin-l-yl)ethan-l-one as an off-white solid (0.03 g, 33%). MS (M+l)+=445.2; 1H- NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.58 (s, IH), 6.16 (d, J = 2.40 Hz, 2H), 4.50 (d, J = 12.80 Hz, IH), 4.12 (s, IH), 3.91 (d, J = 14.00 Hz, IH), 3.13 (t, J = 10.80 Hz, IH), 2.80- 2.60 (m, 3H), 2.10-1.80 (m, 11H), 1.60-1.35 (m, 4H), 0.95-0.88 (m, 2H), 0.75-0.65 (m, 2H).
Example-745:
Figure imgf000587_0001
[001655] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 2 g of 2, 4- Dichloro-5-Methoxypyrimidine gave 2-chloro-N-(4, 4-difluoro cyclohexyl)-5- methoxypyrimidin-4-amine as an off-white solid (2.4 g, 77%). MS (M+l)+=278.4.
Table-77: Step 2: The Procedure is similar to Step l[NSSy66629] in Example-839.
Figure imgf000587_0002
[001656] Step 2[NSSy7063]: MS (M+l)+=350.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.40 Hz, 1H), 7.74 (s, 1H), 7.22 (d, J = 8.00 Hz, 1H), 6.18 (d, J = 2.40 Hz, 1H), 4.19 (bs, 1H), 3.86 (s, 3H), 1.98-1.89 (m, 7H), 1.75-1.69 (m, 2H), 0.93-0.90 (m, 2H), 0.74- 0.71 (m, 2H). [001657] Step 2[NSSy7042]: MS (M+l)+=356.2; IH-NMR (400 MHz, DMSO-d6): δ 7.81 (s, 1H), 7.27 (d, J = 8.00 Hz, 1H), 4.06 (s, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.19 (s, 3H), 2.15-1.85 (m, 6H), 1.75-1.65 (m, 2H).
[001658] Step 2[NSSy7031]: MS (M+l)+=338.2; IH-NMR (400 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.20 (d, J = 8.00 Hz, 1H), 6.01 (s, 1H), 4.08 (d, J = 8.40 Hz, 1H), 3.88 (s, 3H), 2.45 (s, 3H), 2.15 (s, 3H), 2.08-2.05 (m, 3H), 1.98-1.89 (m, 3H), 1.72-1.69 (m, 2H).
[001659] Step 2[NSSy7055]: MS (M+l)+=324.1; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (s, 1H), 7.74 (s, 1H), 7.21 (d, J = 8.00 Hz, 1H), 6.26 (s, 1H), 4.20 (d, J = 4.40 Hz, 1H), 3.86 (s, 1H), 3.86 (s, 3H), 2.06 (t, J = 5.60 Hz, 4H), 1.90 (d, J = 14.80 Hz, 2H), 1.75-1.68 (m, 2H).
Example-746:
Figure imgf000588_0001
[001660] Step 1: The Procedure is similar to Step 4[NSSy6464] in Example-869. 5.0 g of methyl 2, 6-dichloropyrimidine-4-carboxylate gave (2, 6-dichloropyrimidin-4-yl) (phenyl) methanone as a pale yellow solid (3.1 g, 50%). MS (M+l)+=253.0.
[001661] Step 2: The Procedure is similar to Step 1 [B] in Example-838. 0.25 g of (2, 6-dichloropyrimidin-4-yl) (phenyl) methanone gave (2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) (phenyl) methanone as an off-white solid (0.22 g, 64%). MS
(M+l)+=352.0.
Table-78: Step 3: The procedure is similar to step 1[B] in Example-838.
Figure imgf000588_0002
Table-79: Ste 4: The rocedure is similar to ste 2[NSS 6931] in Exam le-21.
Figure imgf000589_0002
[001662] Step 4[IN10987-030-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.70 (s, IH), 7.40 (d, J = 7.20 Hz, 2H), 7.31 (t, J = 8.00 Hz, 2H), 7.25-7.23 (m, IH), 6.64 (s, IH), 6.07 (s, IH), 6.01 (s, IH), 5.43 (s, IH), 4.02 (s, IH), 2.40 (s, 3H), 2.14 (s, 3H), 2.10-1.85 (m, 6H), 1.57 (m, 2H).
[001663] Step 4[IN10987-039-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.45 (s, IH), 7.72 (s, IH), 7.42 (s, IH), 7.34-7.30 (m, 2H), 7.26-7.22 (m, 2H), 6.59 (s, IH), 6.28 (s, IH), 6.07 (s, IH), 5.44 (s, IH), 4.15 (s, IH), 2.23 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.50 (m, 2H). Example-747:
Figure imgf000589_0001
[001664] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893.
0.5 g 4-methylthiazole-2-carboximidamide gave ethyl 4-hydroxy-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate as a yellow solid (0.18 g, 24%). MS (M+l)+=266.1.
[001665] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893.
0.15 g ethyl 4-hydroxy-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate gave ethyl 4- chloro-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate as a brown solid (0.15 g, 93%). MS
(M+l)+=284.0.
[001666] Step 3 [INI 1238-035-P1]: The Procedure is similar to Step 1[B] in Example- 838. 0.15 g ethyl 4-chloro-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate gave ethyl 4- ((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate as a brown solid (0.08 g, 39%). MS (M+l)+=383.1; IH-NMR (400 MHz, DMSO-d6): δ 8.84 (s, IH), 8.24 (d, J = 7.60 Hz, IH), 7.57 (s, IH), 4.35-4.29 (m, 2H), 4.27 (s, IH), 2.49 (s, 3H), 2.10-1.95 (m, 6H), 1.80-1.62 (m, 2H), 1.34 (t, J = 6.80 Hz, 3H). Example-748:
Figure imgf000590_0001
[001667] Step 1[IN11238-040-P1]: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.5 g of ethyl 4-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-5-carboxylate gave (4-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-5-yl) methanol as a brown solid (0.12 g, 27%). MS (M+l)+=341.1; IH-NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.39 (s, 1H), 6.65 (d, J = 7.20 Hz, 1H), 5.29 (t, J = 5.20 Hz, 1H), 4.43 (d, J = 5.20 Hz, 2H), 4.19 (s, 1H), 2.44 (s, 3H), 2.15-1.90 (m, 6H), 1.75-1.62 (m, 2H).
[001668] Step 2: The Procedure is similar to Step 3[IN11059-090-P1] in Example-659. 0.2 g (4-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-5-yl) methanol gave 5-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine as a brown gum (0. 25 g, 95%). MS (M+l)+=403.
[001669] Step 3[IN11238-046-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.25 g 5-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave 5-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2- yl) pyrimidin-4-amine as a brown solid (0.095 g, 43%). MS (M+l)+=355.2; IH-NMR (400 MHz, DMSO-d6): δ 8.14 (s, 1H), 7.41 (s, 1H), 6.69 (d, J = 7.20 Hz, 1H), 4.38 (s, 2H), 4.22 (s, 1H), 3.30 (s, 3H), 2.44 (s, 3H), 2.12-1.90 (m, 6H), 1.75-1.65 (m, 2H).
Example-749:
Figure imgf000590_0002
[001670] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893.
1.0 g of 4-methylthiazole-2-carboximidamide gave 5-fluoro-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol as a pale yellow solid (0.17 g, 13%). MS (M+l)+=228.0.
[001671] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893.
0.17 g 5-fluoro-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol gave 2-(4, 6-dichloro-5- fluoropyrimidin-2-yl)-4-methylthiazole as a pale yellow solid (0.12 g, 61%). MS
(M+l)+=263.9.
[001672] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.12 g 2-(4, 6- dichloro-5-fluoropyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4, 4- difluorocyclohexyl)-5-fluoro-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.06 g, 36%). MS (M+l)+=363.0.
[001673] Step 4[IN11039-058-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.06 g 6-chloro-N-(4, 4-difluorocyclohexyl)-5-fluoro-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-5-fluoro-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.04 g, 67%). MS
(M+l)+=359.0; 1H-NMR (400 MHz, CD3OD): δ 7.26 (s, IH), 4.35-4.25 (m, IH), 4.03 (s, 3H), 2.50 (s, 3H), 2.10-1.85 (m, 6H), 1.78-1.65 (m, 2H).
Example-750:
Figure imgf000591_0001
[001674] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 2.0 g of methyl carbamimidothioate gave 5-fluoro-2-(methylthio) pyrimidine-4, 6-diol as a pale yellow solid (0.92 g, 36%). MS (M+l)+=177.0. [001675] Step 2: The Procedure is similar to Step 3[NSSy6908] in Example-624. 0.9 g
5- fluoro-2-(methylthio) pyrimidine-4, 6-diol gave 4, 6-dichloro-5-fluoro-2-(methylthio) pyrimidine as a pale yellow solid (0.72 g, 66%). MS (M+l)+=212.0.
[001676] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.2 g 4, 6- dichloro-5-fluoro-2-(methylthio) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-5- fluoro-2-(methylthio) pyrimidin-4-amine as a pale yellow solid (0.3 g, 95%). MS
(M+l)+=310.0.
[001677] Step 4: The Procedure is similar to Step 3[NSSy7062] in Example-623. 0.3 g
6- chloro-N-(4, 4-difluorocyclohexyl)-5-fluoro-2-(methylthio) pyrimidin-4-amine gave 6- chloro-N-(4, 4-difluorocyclohexyl)-5-fluoro-2-(methylsulfonyl) pyrimidin-4-amine as an off- white solid (0.2 g, 60%). MS (M+ 1)4=342.1.
[001678] Step 5: The Procedure is similar to Step 5[NSSy6711] in Example-854. 0.2 g 6-chloro-N-(4, 4-difluorocyclohexyl)-5-fluoro-2-(methylsulfonyl) pyrimidin-4-amine gave 6- chloro-N-(4, 4-difluorocyclohexyl)-5-fluoro-2-(3-methyl- lH-pyrazol- 1-yl) pyrimidin-4- amine as a pale yellow solid (0.1 g, 50%). MS (M+l)+=346.1.
[001679] Step 5[IN11111-100-P1]: 0.1 g 6-chloro-N-(4, 4-difluorocyclohexyl)-5- fluoro-2-(3-methyl-lH-pyrazol-l-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-5- fluoro-2-(3-methyl-lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine as an off-white solid (0.05 g, 43%). MS (M+l)+=397.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, 1H), 7.08 (d, J = 7.60 Hz, 1H), 6.26 (d, J = 2.40 Hz, 1H), 4.14 (s, 1H), 3.69-3.60 (m, 8H), 2.24 (s, 3H), 2.80-1.85 (m, 6H), 1.72-1.60 (m, 2H).
Example-751:
Figure imgf000592_0001
[001680] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 0.5 g of 4-methylthiazole-2-carboximidamide gave 6-cyclobutyl-2-(4-methylthiazol-2-yl) pyrimidin-4-ol as a brown liquid (0.5 g, 74%). MS (M+l)+=248.1.
[001681] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.5 g 6-cyclobutyl-2-(4-methylthiazol-2-yl) pyrimidin-4-ol gave 2-(4-chloro-6- cyclobutylpyrimidin-2-yl)-4-methylthiazole as an off-white solid (0.2 g, 40%). MS
(M+l)+=266.0. [001682] Step 3 [INI 1054-081-P1]: The Procedure is similar to Step 1[B] in Example- 838. 0.2 g 2-(4-chloro-6-cyclobutylpyrimidin-2-yl)-4-methylthiazole gave 6-cyclobutyl-N- (4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.04 g, 40%). MS (M+l)+=365.0; IH-NMR (400 MHz, CDC13): δ 7.00 (s, 1H), 6.14 (s, 1H), 5.09 (s, 1H), 3.79 (s, 1H), 3.61-3.52 (m, 2H), 2.30-2.25 (m, 5H), 2.20-1.85 (m, 8H), 1.70-1.60 (m, 3H).
Example-752:
Figure imgf000593_0001
[001683] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893.
0.5 g of 4-methylthiazole-2-carboximidamide gave 5-fluoro-6-methyl-2-(4-methylthiazol-2- yl) pyrimidin-4-ol as a pale yellow solid (0.4 g, 63%). MS (M+l)+=226.1.
[001684] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893.
0.2 g 5-fluoro-6-methyl-2-(4-methylthiazol-2-yl) pyrimidin-4-ol gave 2-(4-chloro-5-fluoro-6- methylpyrimidin-2-yl)-4-methylthiazole as a pale yellow solid (0.15 g, 69%). MS
(M+l)+=244.0.
[001685] Step 3 [INI 1106-077-P1]: The Procedure is similar to Step 1[B] in Example- 838. 0.1 g 2-(4-chloro-5-fluoro-6-methylpyrimidin-2-yl)-4-methylthiazole gave N-(4, 4- difluorocyclohexyl)-5-fluoro-6-methyl-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off- white solid (0.06 g, 43%). MS (M+l)+=343.1; IH-NMR (400 MHz, DMSO-d6): δ 7.59 (d, J = 7.2 Hz, 1H), 7.39 (s, 1H), 4.14-4.12 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 2.12-1.90 (m, 6H), 1.75-1.67 (m, 2H).
Example-753:
Figure imgf000594_0001
Step-1 Step-2 Step-3
Figure imgf000594_0002
[001686] Step 1: 1.7 g of 4-cyclopropylthiazole-2-carbonitrile gave 4- cyclopropylthiazole-2-carboximidamide hydrochloride as a brown gum (2.4 g, 85%). MS (M+l)+=168.1.
[001687] Step 2: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 1.8 g 4-cyclopropylthiazole-2-carboximidamide hydrochloride gave 2-(4-cyclopropylthiazol- 2-yl) pyrimidine-4, 6-diol as a pale yellow solid (1.7 g, 81%). MS (M+l)+=236.1.
[001688] Step 3: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1.7 g 2-(4-cyclopropylthiazol-2-yl) pyrimidine-4, 6-diol gave 4-cyclopropyl-2-(4, 6- dichloropyrimidin-2-yl) thiazole as a pale yellow solid (1.8 g, 91%). MS (M+l)+=274.0.
[001689] Step 4: The Procedure is similar to Step 1[B] in Example-838. 1.8 g 4- cyclopropyl-2-(4, 6-dichloropyrimidin-2-yl) thiazole gave 6-chloro-2-(4-cyclopropylthiazol- 2-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as a pale yellow solid (2.0 g, 81%). MS (M+ 1)4=371.1.
[001690] Step 5: The Procedure is similar to Step 1[IN11273-018-P1] in Example-889. 0.72 g 6-chloro-2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave ethyl 2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4- carboxylate as a pale yellow solid (0.39 g, 48%). MS (M+l)+=409.2.
[001691] Step 6[IN11147-082-P1]: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.3 g ethyl 2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carboxylate gave (2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol as a pale yellow solid (0.095 g, 35%). MS (M+l)+=367.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.60 (s, 1H), 7.36 (s, 1H), 6.61 (s, 1H), 5.44 (t, J = 6.00 Hz, IH), 4.40 (d, J = 5.60 Hz, 2H), 4.02 (s, IH), 2.80-1.90 (m, 7H), 1.70-1.55 (m, 2H), 0.95-
0.89 (m, 4H).
Example-754:
Figure imgf000595_0001
[001692] Step 1: The Procedure is similar to Step 3 [INI 1273-018-P1] in Example-889. 0.1 g (2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol gave (2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin- 4-yl) methyl methanesulfonate as a brownish gum (0.12 g, 95%). MS (M+l)+=445.1.
[001693] Step 2[IN11147-077-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.12 g (2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methyl methanesulfonate gave 2-(4-cyclopropylthiazol-2-yl)-N-(4, 4- difluorocyclohexyl)-6-(methoxymethyl) pyrimidin-4-amine as a brownish gum (0.055 g, 53%). MS (M+l)+=381.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.63 (s, IH), 7.38 (s, IH), 6.52 (s, IH), 4.35 (s, 2H), 4.10 (s, IH), 3.40 (s, 3H), 2.15-1.85 (m, 7H), 1.65-1.52 (m, 2H), 0.95-0.80 (m, 4H).
Example-755:
Figure imgf000595_0002
[001694] Step 1: The Procedure is similar to Step 1[H] in Example-838. 0.2 g 6- chloro-2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2- (4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl) pyrimidin-4- amine as an off-white solid (0.2 g, 46%). MS (M+l)+=407.2.
[001695] Step 2[IN11147-071-Pl]: The Procedure is similar to Step l[NSSy6697] in Example-873. 0.2 g 2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-6-(l- ethoxyvinyl) pyrimidin-4-amine gave l-(2-(4-cyclopropylthiazol-2-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl) ethan- l-one as a white solid (0.15 g, 80%). MS (M+l)+=379.0; IH-NMR (400 MHz, DMSO-d6): δ 8.02 (d, J = 6.80 Hz, IH), 7.45 (s, IH), 6.94 (s, IH), 4.11 (s, IH), 2.59 (s, 3H), 2.20-1.85 (m, 6H), 1.65-1.55 (m, 2H), 0.98-0.90 (m, 3H), 0.88-0.80 (m, 2H).
[001696] Step 3[IN11147-066-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.1 g l-(2-(4-cyclopropylthiazol-2-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-one gave l-(2-(4-cyclopropylthiazol-2-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl) ethan- l-ol as a white solid (0.056 g, 56%). MS (M+l)+=381.2; IH-NMR (400 MHz, DMSO-d6): δ 7.60 (s, IH), 7.36 (s, IH), 6.63 (s, IH), 5.41 (d, J = 3.6 Hz, IH), 4.53-4.50 (m, IH), 4.10 (m, IH), 2.19-1.91 (m, 7H), 1.61-1.56 (m, 2H), 1.35-1.27 (m, 3H), 0.94-0.88 (m, 2H), 0.86-0.79 (m, 2H).
Example-756:
Figure imgf000596_0001
[001697] Step 1[IN11147-054-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.15 g 6-chloro-2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-6- methoxypyrimidin-4-amine as a pale yellow solid (0.045 g, 30%). MS (M+l)+=367.1; 1H- NMR (400 MHz, DMSO-d6): δ 7.46 (s, IH), 7.39 (s, IH), 5.82 (s, IH), 3.87 (s, 3H), 2.15- 1.85 (m, 8H), 1.62-1.50 (m, 2H), 1.00-0.80 (m, 4H).
Example-757:
Figure imgf000596_0002
[001698] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 1.0 g 4-cyclopropylthiazole-2-carboximidamide gave 2-(4-cyclopropylthiazol-2-yl)-5- methoxypyrimidine-4, 6-diol as a pale yellow solid (1.2 g, 92%). MS (M+l)+=266.1.
[001699] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 0.6 g 2-(4-cyclopropylthiazol-2-yl)-5-methoxypyrimidine-4, 6-diol gave 4-cyclopropyl-2-(4, 6-dichloro-5-methoxypyrimidin-2-yl) thiazole as a pale yellow solid (0.38 g, 56%). MS (M+l)+=302.0.
[001700] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.38 g 4- cyclopropyl-2-(4, 6-dichloro-5-methoxypyrimidin-2-yl) thiazole gave 6-chloro-2-(4- cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-5-methoxypyrimidin-4-amine as an off- white solid (0.27 g, 53%). MS (M+ 1)4=401.1.
[001701] Step 4[IN11147-096-P1]: The Procedure is similar to Step 4[NSSy6056] in Example-655. 0.15 g 6-chloro-2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)-5- methoxypyrimidin-4-amine gave 2-(4-cyclopropylthiazol-2-yl)-N-(4, 4-difluorocyclohexyl)- 5-methoxypyrimidin-4-amine as a white solid (0.075 g, 55%). MS (M+l)+=367.2; IH-NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1H), 7.29 (s, 1H), 7.09 (d, J = 8.00 Hz, 1H), 4.11 (s, 1H), 3.90 (s, 3H), 2.15-1.85 (m, 7H), 1.60 (s, 2H), 0.93-0.90 (m, 2H), 0.88-0.82 (m, 2H).
Example-758:
Figure imgf000597_0001
[001702] Step 1: The Procedure is similar to Step l[NSSy6629] in Example-839. 1.0 g 2-chloro-3-methylpyrazine gave N-(4, 4-difluorocyclohexyl)-3-methylpyrazin-2-amine as an off-white solid (0.9 g, 48%). MS (M+l)+=228.0.
[001703] Step 2: The Procedure is similar to Step l[NSSy6736] in Example-26. 0.7 g N-(4, 4-difluorocyclohexyl)-3-methylpyrazin-2-amine gave 5-bromo-N-(4, 4- difluorocyclohexyl)-3-methylpyrazin-2-amine as an off-white solid (0.65 g, 67%). MS (M+l)+=307.0. [001704] Step 3: The Procedure is similar to Step 3[NSSy5933] in Example-808. 0.5 g 5-bromo-N-(4, 4-difluorocyclohexyl)-3-methylpyrazin-2-amine gave 5-((4, 4- difluorocyclohexyl) amino)-6-methylpyrazine-2-carbonitrile as an off-white solid (0.38 g, 92%). MS (M+l)+=252.0.
[001705] Step 4: The Procedure is similar to Step 5[NSSy5779] in Example-642. 0.38 g 5-((4, 4-difluorocyclohexyl) amino)-6-methylpyrazine-2-carbonitrile gave 5-((4, 4- difluorocyclohexyl) amino)-6-methylpyrazine-2-carbothioamide as an off-white solid (0.2 g, 46%). MS (M+l)+=287.0.
[001706] Step 5[IN11079-047-P1]: The Procedure is similar to Step 6[NSSy5779] in Example-642: 0.2 g 5-((4, 4-difluorocyclohexyl) amino)-6-methylpyrazine-2- carbothioamide gave N-(4, 4-difluorocyclohexyl)-3-methyl-5-(4-methylthiazol-2-yl) pyrazin- 2-amine as an off-white solid (0.08 g, 18%). MS (M+l)+=325.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 7.19 (s, 1H), 6.63 (d, J = 8.00 Hz, 1H), 4.15 (s, 1H), 2.50 (s, 3H), 2.50 (s, 3H), 2.10-1.88 (m, 6H), 1.75-1.62 (m, 2H).
Example-759:
Figure imgf000598_0001
H ep- ep- ep-
Figure imgf000598_0002
[001707] Step 1: The Procedure is similar to Step 1[B] in Example-838. 3.0 g 5- bromopyrimidine-2, 4(1H, 3H)-dione gave 5-morpholinopyrimidine-2, 4(1H, 3H)-dione as a white solid (2.7 g, 80%). MS (M+l)+=198.0.
[001708] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 2.7 g 5-morpholinopyrimidine-2, 4(1H, 3H)-dione gave 4-(2, 4-dichloropyrimidin-5-yl) morpholine as an off-white solid (1.4 g, 43%). MS (M+l)+=234.0.
[001709] Step 3: The Procedure is similar to Step 1[A] in Example-838. 0.9 g 4-(2, 4- dichloropyrimidin-5-yl) morpholine gave 2-chloro-N-(4, 4-difluorocyclohexyl)-5- morpholinopyrimidin-4-amine as an off-white solid (0.19 g, 15%). MS (M+l)+=333.0. [001710] Step 4[IN10966-011-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-839. 0.19 g 2-chloro-N-(4, 4-difluorocyclohexyl)-5-morpholinopyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-5-morpholinopyrimidin- 4-amine as an off-white solid (0.033 g, 15%). MS (M+l)+=393.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (s, IH), 6.60 (s, IH), 6.03 (s, IH), 4.10 (s, IH), 3.78 (s, 4H), 2.84 (s, 4H), 2.52 (s, 3H), 2.15 (s, 3H), 2.10-1.85 (m, 6H), 1.84-1.76 (m, 2H).
Example-760:
Figure imgf000599_0001
Step-1 Step-2 NH2 steP-3 Step-4
Figure imgf000599_0002
[001711] Step 1: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 5.0 g 4-methylpyridazine-3, 6-diol gave 3, 6-dichloro-4-methylpyridazine as an off-white solid (5.5 g, 85%). MS (M+l)+=163.0.
[001712] Step 2: The Procedure is similar to Step 1[IN11054-100-Pl] in Example-886. 3.0 g 3, 6-dichloro-4-methylpyridazine gave 3-chloro-6-hydrazineyl-4-methylpyridazine as an off-white solid (3.1 g, 80%). MS (M+l)+=159.0.
[001713] Step 3: The Procedure is similar to Step 2[IN11054-090-P1] in Example-886. 1.3 g 3-chloro-6-hydrazineyl-4-methylpyridazine gave 3-chloro-6-(3, 5-dimethyl-lH-pyrazol- l-yl)-4-methylpyridazine as an off-white solid (1.0 g, 90%). MS (M+l)+=223.0.
[001714] Step 4: The Procedure is similar to Step 1[IN11273-018-P1] in Example-889. 2.0 g 3-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine gave ethyl 6-(3, 5- dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine-3-carboxylate as a white solid (0.8 g, 34%). MS (M+l)+=260.1.
[001715] Step 5: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.5 g ethyl 6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine-3-carboxylate gave (6-(3, 5- dimethyl-lH-pyrazol-l-yl)-4-methylpyridazin-3-yl) methanol as an off-white solid (0.3 g, 75%). MS (M+l)+=219.0. [001716] Step 6: The Procedure is similar to Step 5 [INI 1059-090-P1] in Example-659. 0.5 g (6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazin-3-yl) methanol gave 3- (bromomethyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine as an off-white solid (0.25 g, 39%). MS (M+l)+=282.1.
[001717] Step 7[IN11054-078-P1]: The Procedure is similar to Step 1[B] in Example- 838. 0.25 g 3-(bromomethyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine gave N-((6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazin-3-yl) methyl)-4, 4- difluorocyclohexan-1 -amine as an off-white solid (0.04 g, 13%). MS (M+l)+=336.1; 1H- NMR (400 MHz, DMSO-d6): δ 7.89 (s, 1H), 6.19 (s, 1H), 4.03 (s, 2H), 2.75-2.65 (m, 1H), 2.60 (s, 3H), 2.46 (s, 3H), 2.22 (s, 3H), 2.10-1.75 (m, 6H), 1.52-1.42 (m, 2H).
Example-761:
Figure imgf000600_0001
[001718] Step l[IN10966-083-Pl]: The Procedure is similar to Step l[NSSy6909] in Example-839. 0.2 g 3-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazine gave N- (4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4-methylpyridazin-3-amine as an off-white solid (0.13 g, 48%). MS (M+l)+=322.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.55 (s, 1H), 6.07 (s, 2H), 4.25 (bs, 1H), 2.47 (s, 3H), 2.18 (s, 6H), 2.09-2.03 (m, 6H), 1.69- 1.67 (m, 2H).
Example-762:
[001719] Intentionally omitted
Example-763:
Figure imgf000601_0001
o
80 °C,16h
EtOH.DMA,
Step-4
IN11030-081 -P1
[001720] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.4 g 2, 4- dichloro-8-methoxyquinazoline gave of 2-chloro-N-(4, 4-difluorocyclohexyl)-8- methoxyquinazolin-4-amine as an off-white solid (0.5 g, 87%). MS (M+l)+=328.0.
[001721] Step 2: The Procedure is similar to Step 3 [INI 1079-047-P1] in Example-758. 0.5 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-8-methoxyquinazolin-4-amine gave 4-((4, 4- difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbonitrile as an off-white solid (0.35 g, 72%). MS (M+l)+=319.0.
[001722] Step 3: The Procedure is similar to Step 5[NSSy5779] in Example-642. 0.35 g of 4-((4, 4-difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbonitrile gave 4-((4, 4- difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbothioamide as an off-white solid (0.35 g, 90%). MS (M+l)+=353.1.
[001723] Step 4[IN11030-081-Pl]: The Procedure is similar to Step 6[NSSy5779] in Example-642. 0.35 g of 4-((4, 4-difluorocyclohexyl) amino)-8-methoxyquinazoline-2- carbothioamide gave N-(4, 4-difluorocyclohexyl)- 8-methoxy-2-(4-methylthiazol-2-yl) quinazolin-4-amine as an off-white solid (0.25 g, 64%). MS (M+l)+=391.0; IH-NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 6.80 Hz, 1H), 7.87 (d, J = 8.40 Hz, 1H), 7.46 (t, J = 8.40 Hz, 2H), 7.30 (d, J = 7.60 Hz, 1H), 4.35 (s, 1H), 3.95 (s, 3H), 2.48 (s, 3H), 2.20-1.85 (m, 6H), 1.85-1.70 (m, 2H).
Example-764:
Figure imgf000601_0002
[001724] Step 1: The Procedure is similar to Step 1[H] in Example-838. 0.2 g 6- chloro-N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.13 g, 59%). MS (M+l)+=411.0.
[001725] Step 2: The Procedure is similar to Step l[NSSy6697] in Example-873. 0.13 g of N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave l-(6-((4, 4-difluorocyclohexyl) amino)-5-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-4-yl) ethan-l-one as an off-white solid (0.09 g, 74%). MS (M+l)+=383.0.
[001726] Step 3[IN11104-039-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.08 g of l-(6-((4, 4-difluorocyclohexyl)amino)-5-methoxy-2-(4- methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-one gave l-(6-((4, 4-difluorocyclohexyl)amino)-5- methoxy-2-(4-methylthiazol-2-yl)pyrimidin-4-yl)ethan-l-ol as an off-white solid (0.07 g, 87%). MS (M+l)+=385.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.36 (s, IH), 7.18 (d, J = 8.00 Hz, IH), 5.10 (s, IH), 4.94-4.90 (m, IH), 3.90 (s, IH), 3.70 (s, 3H), 3.30 (s, 3H), 2.15-1.85 (m, 6H), 1.85-1.70 (m, 2H), 1.36 (s, 3H).
Example-765:
Figure imgf000602_0001
[001727] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893. 2.0 g 4-methylthiazole-2-carboximidamide gave 5-methoxy-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol as a pale yellow solid (1.8 g, 66%). MS (M+l)+=240.0.
[001728] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1.8 g of 5-methoxy-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol gave 4-methyl-2-(4, 5, 6- trichloropyrimidin-2-yl) thiazole as a pale yellow solid (0.6 g, 28%). MS (M+l)+=282.0.
[001729] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.4 g of 4- methyl-2-(4, 5, 6-trichloropyrimidin-2-yl) thiazole gave 5, 6-dichloro-N-(4, 4- difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.3 g, 55%). MS (M+l)+=378.9.
[001730] Step 4[IN11111-024-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.2 g of 5, 6-dichloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4-amine gave 5-chloro-N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.18 g, 91%). MS
(M+l)+=375.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.49 (s, 1H), 7.10 (d, J = 7.60 Hz, 1H), 4.18 (s, 1H), 4.02 (s, 3H), 2.48 (s, 3H), 2.15-1.90 (m, 6H), 1.88-1.72 (m, 2H).
Example-766:
Figure imgf000603_0001
T
IN11125-001-P1 IN11104-041-P1 IN11111-023-P1 IN11111-021-P1
[001731] Step 1: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893. 1.36 g 5-methoxy-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol gave 2-(4, 6-dichloro-5- methoxypyrimidin-2-yl)-4-methylthiazole as a pale yellow solid (0.53 g, 33%). MS
(M+l)+=275.9.
[001732] Step 2: The Procedure is similar to Step 1 [B] in Example-838. 0.53 g of 2-(4, 6-dichloro-5-methoxypyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4, 4- difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as a pale yellow solid (0.53 g, 73%). MS (M+l)+=375.0.
Table-80: Step 3:
Figure imgf000603_0002
IN11111-021- N^ o NaH, THF, 70 °C, 3h 68 438.0 Pl to
[001733] Step 3 [INI 1125-001-Pl]: The procedure is similar to step 1[B] in Example- 838. 1H-NMR (400 MHz, DMSO- 6): δ 7.32 (d, / = 1.20 Hz, 1H), 6.66 (d, J = 8.00 Hz, 1H), 4.07 (s, 1H), 3.77-3.71 (m, 4H), 3.65-3.59 (m, 7H), 2.49 (s, 3H), 2.15-1.85 (m, 6H), 1.80- 1.65 (m, 2H).
[001734] Step 3 [INI 1104-041-P1]: The procedure is similar to step 1[A] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 7.37 (s, 1H), 7.34 (s, 1H), 6.88 (d, J = 8.00 Hz, 1H), 4.37 (t, J = 5.20 Hz, 2H), 4.07 (s, 1H), 3.71 (s, 3H), 3.52 (s, 3H), 3.41 (q, J = 4.80 Hz, 2H), 2.43 (s, 3H), 2.15-1.85 (m, 6H), 1.80-1.65 (m, 2H).
[001735] Step 3 [INI 1111-023-P1]: Step a: The procedure is similar to Step 2[IN10991- 021-P1] in Example-694. Step b: The procedure is similar to Step l[NSSy6697] in Example- 873. IH-NMR (400 MHz, DMSO-d6): δ 7.37 (s, 1H), 6.88 (d, J = 8.00 Hz, 1H), 4.85 (t, J = 5.20 Hz, 1H), 4.40 (t, J = 5.20 Hz, 1H), 4.08 (s, 1H), 3.76-3.73 (m, 5H), 3.57 (s, 1H), 2.43 (s, 3H), 2.15-1.85 (m, 6H), 1.80-1.62 (m, 2H).
[001736] Step 4[IN11111-021-P1]: The procedure is similar to Step 2[IN10991-021-P1] in Example-694. IH-NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.41 (d, J = 4.40 Hz, 2H), 7.00 (d, J = 7.60 Hz, 1H), 5.52 (s, 2H), 4.08 (s, 1H), 3.66 (s, 3H), 2.45 (s, 3H), 2.15-1.85 (m, 6H), 1.75-1.65 (m, 2H).
Exam le-767:
Figure imgf000604_0001
[001737] Step 1[IN11039-064-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.8 g 6-chloro-N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2-(4-methylthiazol- 2-yl) pyrimidin-4-amine as an off-white solid (0.75 g, 95%). MS (M+l)+=371.1; IH-NMR (400 MHz, CDC13): δ 6.97 (s, 1H), 5.03 (d, J = 7.60 Hz, 1H), 4.21-4.19 (m, 1H), 1.00 (s, 3H), 3.84 (s, 3H), 2.55 (s, 3H), 2.20-1.85 (m, 6H), 1.70-1.60 (m, 2H).
[001738] Step 2: To a stirred solution of N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2- (4-methylthiazol-2-yl)pyrimidin-4-amine (0.25 g, 0.13 mmol) in HBr in acetic acid (2.5 mL) was heated at 80 °C under nitrogen atmosphere for 16h. Reaction mixture was allowed to cool down and quenched with water (5 mL), the precipitate was filtered off and solids were dissolved in ethyl acetate (50 mL) and washed with saturated bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford as a dark green solid (0.22 g, 95%). MS (M+l)+=343.0
[001739] Step 3 [INI 1125-006-P1]: The Procedure is similar to Step 1[A] in Example- 838. 0.1 g of 6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-4, 5- diol gave 4-((4, 4-difluorocyclohexyl) amino)-6-hydroxy-2-(4-methylthiazol-2-yl) pyrimidin- 5-yl methylcarbamate as a pale green solid (0.035 g, 30%). MS (M+l)+=400.0; 1H-NMR (400 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.57 (s, 1H), 7.37 (s, 1H), 6.68 (s, 1H), 3.99 (s, 1H), 2.65 (d, J = 4.40 Hz, 3H), 2.42 (s, 3H), 2.15-1.80 (m, 6H), 1.80-1.60 (m, 2H).
Example-768:
Figure imgf000605_0001
[001740] Step 1 : The Procedure is similar to Step 2[IN11125-006-P1] in Example-767. 2.0 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin- 4-amine gave 4-chloro-6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-5-ol as a pale yellow solid (2.2 g, 80%). MS (M+l)+=361.0.
[001741] Step 2: The Procedure is similar to Step 1 [B] in Example-838. 0.25 g of 4- chloro-6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidin-5-ol gave 5- (benzyloxy)-6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4-methylthiazol-2-yl) pyrimidin-4- amine as a white solid (0.2 g, 64%). MS (M+l)+=451.1.
[001742] Step 3 [INI 1125-095-P1]: The Procedure is similar to Step 4[NSSy6056] in Example-655. 0.2 g of 5-(benzyloxy)-6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- methylthiazol-2-yl) pyrimidin-4-amine gave 4-((4, 4-difluorocyclohexyl) amino)-2-(4- methylthiazol-2-yl) pyrimidin-5-ol as an off-white solid (0.025 g, 17%). MS (M+l)+=327.1; 1H-NMR (400 MHz, CD30D): δ 7.56 (s, 1H), 7.22 (s, 1H), 4.32 (m, 1H), 2.49 (s, 3H), 2.11- 1.93 (m, 6H), 1.77-1.71 (m, 2H). Example-769:
Figure imgf000606_0001
[001743] Step 1[IN11125-014-P1]: The Procedure is similar to Step 4[NSSy6056] in Example-655. 0.1 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol- 2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2- yl) pyrimidin-4-amine as a white solid (0.045 g, 80%). MS (M+l)+=341.1; IH-NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.31 (s, 1H), 7.07 (d, J = 8.00 Hz, 1H), 4.15 (s, 1H), 3.90 (s, 3H), 2.42 (s, 3H), 2.15-1.65 (m, 8H).
Example-770:
Figure imgf000606_0002
[001744] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 0.3 g of 4- chloro-6-((4, 4-difluorocyclohexyl)amino)-2-(4-methylthiazol-2-yl)pyrimidin-5-ol gave tert- butyl (2-((4-chloro-6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl)pyrimidin-5- yl)oxy)ethyl)carbamate as a pale yellow solid (0.21 g, 50%). MS (M+l)+=504.0.
[001745] Step 2: The Procedure is similar to Step 1 [NSSy6519] in Example-842. 0.21 g of tert-butyl (2-((4-chloro-6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2- yl)pyrimidin-5-yl)oxy)ethyl)carbamate gave tert-butyl (2-((4-((4, 4- difluorocyclohexyl)amino)-6-methoxy-2-(4-methylthiazol-2-yl)pyrimidin-5- yl)oxy)ethyl)carbamate as a pale yellow solid (0.18 g, 86%). MS (M+l)+=500.1. [001746] Step 3: The Procedure is similar to Step 5[NSSy6067] in Example-628. 0.18 g of tert-butyl (2-((4-((4, 4-difluorocyclohexyl)amino)-6-methoxy-2-(4-methylthiazol-2- yl)pyrimidin-5-yl)oxy)ethyl)carbamate gave 5-(2-aminoethoxy)-N-(4, 4-difluorocyclohexyl)- 6-methoxy-2-(4-methylthiazol-2-yl)pyrimidin-4-amine as a pale yellow gum (0.14 g, 96%). MS (M+l)+=400.1.
[001747] Step 4[IN11125-052-P1] : The Procedure is similar to Step 1 [B] in Example- 838. 0.08 g of 5-(2-aminoethoxy)-N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4- methylthiazol-2-yl)pyrimidin-4-amine gave methyl (2-((4-((4, 4-difluorocyclohexyl)amino)- 6-methoxy-2-(4-methylthiazol-2-yl)pyrimidin-5-yl)oxy)ethyl)carbamate as a pale yellow solid (0.055 g, 60%). MS (M+l)+=458.1; IH-NMR (400 MHz, MeOD): δ 7.23 (s, IH), 4.20 (s, IH), 3.80 (s, 5H), 3.55 (s, 3H), 3.40 (t, J = 4.80 Hz, 2H), 2.50 (s, 3H), 2.15-1.80 (m, 6H), 1.75-1.65 (m, 2H).
[001748] Step 5[IN11125-065-P1]: The Procedure is similar to Step 2[IN11125-006-P1] in Example-767. 0.1 g of methyl (2-((4-((4, 4-difluorocyclohexyl)amino)-6-methoxy-2-(4- methylthiazol-2-yl)pyrimidin-5-yl)oxy)ethyl)carbamate gave methyl (2-((4-((4, 4- difluorocyclohexyl)amino)-6-hydroxy-2-(4-methylthiazol-2-yl)pyrimidin-5- yl)oxy)ethyl)carbamate as a pale yellow solid (0.06 g, 62%). MS (M+l)+=444.0; IH-NMR (400 MHz, CD30D): δ 7.40 (s, IH), 4.13-4.03 (m, 3H), 3.65 (s, 3H), 3.41-3.39 (m, 2H), 2.50 (s, 3H), 2.16-1.88 (m, 6H), 1.79-1.71 (m, 2H).
Example-771:
Figure imgf000607_0001
[001749] Step 1: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.4 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-5-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2-(4-methylthiazol-2-yl) pyrimidin- 4-amine as an off-white solid (0.351 g, 88%). MS (M+l)+=371.0.
[001750] Step 2[IN11039-094-P1]: The Procedure is similar to Step 2[IN11125-006-P1] in Example-767. 0.25 g of N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave 6-((4, 4-difluorocyclohexyl) amino)-2-(4-methylthiazol-2-yl) pyrimidine-4, 5-diol as an off-white solid (0.22 g, 95%). MS (M+l)+=343.0; IH-NMR (400 MHz, DMSO-d6): δ 11.95 (bs, 1H), 9.05 (bs, 1H), 7.42 (s, 1H), 6.05 (d, J = 6.8 Hz, 1H), 4.06-3.95 (m, 1H), 2.42 (s, 3H), 2.12-1.86 (m, 6H), 1.73-1.64 (m, 2H).
Example-772:
Figure imgf000608_0001
[001751] Step 1[IN11039-092-P1]: The Procedure is similar to Step l[NSSy6972] in Example-615. 0.05 g of N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave 4-((4, 4-difluorocyclohexyl) amino)-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-5-ol as a pale yellow solid (0.03 g, 62%). MS (M+l)+=371.0; IH-NMR (400 MHz, DMSO-d6): δ 11.95 (bs, 1H), 7.51 (s, 1H), 6.58-6.56 (m, 1H), 4.01- 3.90 (m, 1H), 3.68 (s, 3H), 2.44 (s, 3H), 2.09-1.92 (m, 6H), 1.71-1.68 (m, 2H).
[001752] Step 2[IN11196-065-P1]: The Procedure is similar to Step l[NSSy6972] in Example-615. 0.16 g of N-(4, 4-difluorocyclohexyl)-5, 6-dimethoxy-2-(4-methylthiazol-2- yl) pyrimidin-4-amine gave 4-((4, 4-difluorocyclohexyl) amino)-6-methoxy-2-(4- methylthiazol-2-yl) pyrimidin-5-ol as an off-white solid (0.04 g, 22%). MS (M+l)+=366.2; IH-NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1H), 6.90 (d, J = 7.20 Hz, 1H), 5.64 (s, 2H), 3.96 (s, 1H), 3.71 (s, 3H), 2.30 (s, 3H), 2.15-1.85 (m, 6H), 1.75-1.65 (m, 2H).
Example-773:
Figure imgf000608_0002
Step-1 PBr3, 0 °C,
ACN
Figure imgf000608_0003
[001753] Step 1: The Procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.075 g of oxazol-5-ylmethanol gave 5-(bromomethyl) oxazole as a brown liquid (0.1 g). MS (M+l)+=163.0.
[001754] Step 2[IN11125-091-P1]: The Procedure is similar to Step [B] in Example- 838. 0.090 g of 4-((4, 4-difluorocyclohexyl) amino)-6-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-5-ol gave N-(4, 4-difluorocyclohexyl)-6-methoxy-2-(4-methylthiazol-2-yl)-5- (oxazol-5-ylmethoxy) pyrimidin-4-amine as an off-white solid (0.07 g, 63%). MS
(M+l)+=438.2; IH-NMR (400 MHz, MeOD): δ 8.20 (s, IH), 7.24 (s, IH), 7.13 (s, IH), 5.13 (s, 2H), 4.24-4.21 (m, IH), 4.06 (s, 3H), 3.90 (s, 3H), 2.20-1.90 (m, 7H), 1.65-1.55 (m, 2H). Example-77
Figure imgf000609_0001
[001755] Step 1 [INI 1106-065-P1] : The Procedure is similar to Step 1 [A] in Example- 838. 0.1 g of 4-((4, 4-difluorocyclohexyl) amino)-6-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-5-ol gave 4-((4, 4-difluorocyclohexyl) amino)-6-methoxy-2-(4-methylthiazol-2-yl) pyrimidin-5-yl methylcarbamate as an off-white solid (0.07 g, 63%). MS (M+l)+=414.0; 1H- NMR (400 MHz, DMSO-d6): δ 7.54-7.50 (m, IH), 7.41 (d, J = 0.80 Hz, IH), 6.99 (d, J = 7.20 Hz, IH), 4.10 (s, IH), 3.90 (s, IH), 2.67 (d, J = 4.40 Hz, 3H), 2.49 (s, 3H), 2.15-1.85 (m, 6H), 1.75-1.65 (m, 2H).
Example-775:
Figure imgf000609_0002
[001756] Step 1: The Procedure is similar to Step l[IN10966-057-P2] in Example-893.
0.25 g of 4-methylthiazole-2-carboximidamide gave 5-methyl-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol as an off-white solid (0.2 g, 64%). MS (M+l)+=224.1.
[001757] Step 2: The Procedure is similar to Step 2[IN10966-057-P2] in Example-893.
0.8 g of 5-methyl-2-(4-methylthiazol-2-yl) pyrimidine-4, 6-diol gave 2-(4, 6-dichloro-5- methylpyrimidin-2-yl)-4-methylthiazole as a pale yellow solid (0.8 g, 68%). MS
(M+l)+=260.0.
[001758] Step 3: The Procedure is similar to Step 1[B] in Example-838. 0.8 g of 2-(4, 6-dichloro-5-methylpyrimidin-2-yl)-4-methylthiazole gave 6-chloro-N-(4, 4- difluorocyclohexyl)-5-methyl-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.8 g, 72%). MS (M+l)+=359.1.
[001759] Step 4[IN11130-076-P1]: The Procedure is similar to Step 4[NSSy6056] in Example-655. 0.15 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-5-methyl-2-(4-methylthiazol- 2-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-5-methyl-2-(4-methylthiazol-2-yl) pyrimidin-4-amine as an off-white solid (0.11 g, 81%). MS (M+l)+=325.1; IH-NMR (400 MHz, DMSO-d6): δ 8.22 (s, IH), 8.13 (s, IH), 7.79 (s, IH), 4.30 (s, IH), 2.10-1.90 (m, 11H), 1.85-1.70 (m, 3H).
Example-776:
Figure imgf000610_0001
[001760] Step 1 : The Procedure is similar to Step 1 [INI 1177-025-P1] in Example-715. 3.8 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl) pyrimidine as a brown solid (1.2 g, 25%). MS
(M+l)+=283.0.
[001761] Step 2: The Procedure is similar to Step 1[B] in Example-838. 1.2 g of 4, 6- dichloro-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-N-(4, 4- difluorocyclohexyl)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine as a pale yellow solid (2.8 g, 70%). MS (M+l)+=382.0.
[001762] Step 3: The Procedure is similar to Step 1[H] in Example-838. 0.2 g of 6- chloro-N-(4, 4-difluorocyclohexyl)-2-(3-(trifluoromethyl)- IH-pyrazol- 1-yl) pyrimidin-4- amine gave N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(3-(trifluoromethyl)-lH- pyrazol-l-yl) pyrimidin-4-amine as a brown gum (0.2 g, 91%). MS (M+l)+=418.1.
[001763] Step 4[IN11053-059-P1]: The Procedure is similar to Step l[NSSy6697] in Example-873. 1.0 g of N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine gave l-(6-((4, 4- difluorocyclohexyl)amino)-2-(3-(trifluoromethyl)- IH-pyrazol- l-yl)pyrimidin-4-yl)ethan- 1- one as a white solid (0.65 g, 69%). MS (M+l)+=390.0; 1H-NMR (400 MHz, CDC13): δ 8.81 (d, J = 1.60 Hz, 1H), 6.96 (s, 1H), 6.86 (d, J = 3.20 Hz, 1H), 4.36 (s, 1H), 2.65 (s, 3H), 2.15- 1.90 (m, 6H), 1.75-1.60 (m, 2H).
[001764] Step 5[IN11053-062-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.36 g of l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3-(trifluoromethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)ethan-l-one gave l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol as a white solid (0.3 g, 83%). MS (M+l)+=392.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.79 (bs, 1H), 7.89 (bs, 1H), 6.97 (d, J = 2.8 Hz, 1H), 6.65 (s, 1H), 5.44 (d, J = 3.6 Hz, 1H), 4.52 (bs, 1H), 4.20 (bs, 1H), 2.07- 1.98 (m, 6H), 1.59-1.57 (m, 2H), 1.35 (d, J = 5.6 Hz, 3H).
[001765] Step 6: The Procedure is similar to Step 3[IN11059-090-P1] in Example-659. 0.3 g of l-(6-((4, 4-difluorocyclohexyl)arnino)-2-(3-(trifluoromethyl)-lH-pyrazol-l- yl)pyrimidin-4-yl)ethan-l-ol gave 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl)pyrimidin-4-amine as an off-white solid (0.2 g, 57%). MS (M+l)+=454.0.
[001766] Step 7[IN11053-076-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.14 g of 6-(l-bromoethyl)-N-(4, 4-difluorocyclohexyl)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6- (l-methoxyethyl)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine as a brown solid (0.03 g, 24%). MS (M+l)+=406.1; IH-NMR (400 MHz, MeOD): δ 8.73 (s, IH), 6.82 (d, J = 2.80 Hz, IH), 6.52 (s, IH), 4.26-4.24 (m, IH), 3.36 (s, 3H), 2.09-1.96 (m, 6H), 1.75- 1.60 (m, 3H), 1.41-1.33 (m, 4H).
Example-777:
Figure imgf000612_0001
[001767] Step 1: The Procedure is similar to Step 1[IN11273-018-P1] in Example-889. 1.0 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine gave ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(3-(trifluoromethyl)-lH- pyrazol-l-yl) pyrimidine-4-carboxylate as a brownish gum (0.7 g, 45%). MS (M+l)+=420.1.
[001768] Step 2[IN11053-060-P1]: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.6 g of ethyl 6-((4, 4-difluorocyclohexyl) amino)-2-(3-(trifluoromethyl)- lH-pyrazol-l-yl) pyrimidine-4-carboxylate gave (6-((4, 4-difluorocyclohexyl) amino)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol as a white solid (0.39 g, 72%). MS (M+l)+=378.0; IH-NMR (400 MHz, DMSO-d6): δ 8.79 (s, IH), 7.90 (s, IH), 6.97 (d, J = 2.40 Hz, IH), 6.62 (s, IH), 5.51 (s, IH), 4.40 (d, J = 4.40 Hz, 2H), 4.20 (s, IH), 2.12-1.90 (m, 6H), 1.65-1.50 (m, 2H).
[001769] Step 3: The Procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.39 g of (6-((4, 4-difluorocyclohexyl) amino)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-yl) methanol gave 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine as a white solid (0.3 g, 66%). MS (M+l)+=440.0. [001770] Step 4[IN11053-071-Pl]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.12 g of 6-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-2-(3- (trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6- (methoxymethyl)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine as a white solid (0.05 g, 35%). MS (M+l)+=392.0; IH-NMR (400 MHz, DMSO-d6): δ 8.79 (s, 1H), 7.92 (s, 1H), 6.98 (s, 1H), 6.54 (s, 1H), 4.36 (s, 2H), 4.21 (s, 1H), 3.41 (s, 3H), 2.10-1.85 (m, 6H), 1.62-1.50 (m, 2H).
Example-77
Figure imgf000613_0001
[001771] Step 1[IN11053-073-P1]: The Procedure is similar to Step 5[NSSy6711] in Example-854. 0.04 g of l-(6-((4, 4-difluorocyclohexyl)amino)-2-(3-(trifluoromethyl)-lH- pyrazol-l-yl)pyrimidin-4-yl)ethan-l-ol gave N-(4, 4-difluorocyclohexyl)-6-(l- methoxyethyl)-N-methyl-2-(3-(trifluoromethyl)- lH-pyrazol- l-yl)pyrimidin-4-amine as an off-white solid (0.04 g, 53%). MS (M+l)+=420.1; IH-NMR (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.00 (d, J = 2.40 Hz, 1H), 6.66 (s, 1H), 4.27 (q, J = 6.40 Hz, 1H), 3.29 (s, 3H), 2.99 (s, 3H), 2.25-2.05 (m, 4H), 1.85-1.70 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H).
Example-779:
Figure imgf000613_0002
Figure imgf000613_0003
80 °C,16h
EtOH.DMA,
Step-4
IN11030-081-P1 [001772] Step 1: The Procedure is similar to Step 1[B] in Example-838. 0.4 g of 2, 4- dichloro-8-methoxyquinazoline gave 2-chloro-N-(4, 4-difluorocyclohexyl)-8- methoxyquinazolin-4-amine (0.5 g, 87%). MS (M+l)+=328.1.
[001773] Step 2: The Procedure is similar to Step 3 [INI 1079-047-P1] in Example-758. 0.5 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-8-methoxyquinazolin-4-amine gave 4-((4, 4- difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbonitrile (0.35 g, 72%). MS (M+l)+=319.
[001774] Step 3: The Procedure is similar to Step 5[NSSy5779] in Example-642. 0.35 g of 4-((4, 4-difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbonitrile gave 4-((4, 4- difluorocyclohexyl) amino)-8-methoxyquinazoline-2-carbothioamide (0.35 g, 90%). MS (M+l)+=353.1.
[001775] Step 4[IN11030-081-Pl]: The Procedure is similar to Step 6[NSSy5779] in Example-642. 0.35 g of 4-((4, 4-difluorocyclohexyl) amino)-8-methoxyquinazoline-2- carbothioamide gave N-(4, 4-difluorocyclohexyl)- 8-methoxy-2-(4-methylthiazol-2-yl) quinazolin-4-amine (0.25 g, 64%). MS (M+l)+=391.0; IH-NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 6.80 Hz, IH), 7.87 (d, J = 8.40 Hz, IH), 7.46 (t, J = 8.40 Hz, 2H), 7.30 (d, J = 7.60 Hz, IH), 4.35 (s, IH), 3.95 (s, 3H), 2.48 (s, 3H), 2.20-1.85 (m, 6H), 1.85-1.70 (m, 2H). Example-78
Figure imgf000614_0001
[001776] Step 1 [INI 1079-009-P1] : The Procedure is similar to Step 1 [B] in Example- 838. 0.08 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(3-(trifluoromethyl)-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-morpholino-2-(3-(trifluoromethyl)- lH-pyrazol-l-yl) pyrimidin-4-amine as an off-white solid (0.148 g, 99 %). MS
(M+l)+=433.1; IH-NMR (400 MHz, DMSO-d6): δ 8.74 (s, IH), 7.30 (d, J = 8.00 Hz, IH), 6.93 (s, IH), 5.64 (s, IH), 3.90 (s, IH), 3.62 (s, 4H), 3.54 (s, 4H), 2.10-1.85 (m, 6H), 1.60- 1.50 (m, 2H). Example-781:
Figure imgf000615_0001
[001777] Step 1: To a solution of 4, 6-dichloro-2-(methylsulfonyl)pyrimidine (1 g, 4.42 mmol) in THF was added 3-cyclopropyl-lH-pyrazole (0.48 g, 4.42 mmol) and stirred at 25 °C for 16h. The reaction mixture was evaporated to dryness under vacuum to afford crude product, which was purified by column chromatography using ethyl acetate in pet-ether as solvent to afford 4, 6-dichloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)pyrimidine as an off-white solid ( 1.1 g, 98 %). MS (M+l)+=255.0.
[001778] Step 2: The Procedure is similar to Step 1[B] in Example-838. 0.3 g of 4, 6- dichloro-2-(3-cyclopropyl-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-2-(3-cyclopropyl-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid (0.29 g, 96 %). MS (M+l)+=355.0.
[001779] Step 3: The Procedure is similar to Step 1[H] in Example-838. 0.3 g of 6- chloro-2-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl) pyrimidin-4-amine as an off-white solid (0.26 g, 78%). MS (M+l)+=390.1.
[001780] Step 4: The Procedure is similar to Step l[NSSy6697] in Example-873. 0.25 g of 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl) pyrimidin-4-amine gave l-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan-l-one as an off-white solid (0.18 g, 77 %). MS (M+l)+=361.9.
[001781] Step 5[IN11104-099-Pl]: The Procedure is similar to Step 2[NSSy6931] in Example-21. 0.18 g of l-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl)amino)pyrimidin-4-yl)ethan- 1-one gave l-(2-(3-cyclopropyl- lH-pyrazol- l-yl)-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)ethan-l-ol as an off-white solid (0.15 g, 83 %). MS (M+l)+=364.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 7.64 (bs, 1H), 6.50 (s, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.34 (d, J = 4.4 Hz, 1H), 4.48-4.46 (m, 1H), 4.14 (m, IH), 2.06-1.95 (m, 6H), 1.58-1.56 (m, 2H), 1.35-1.30 (m, 3H), 0.94-0.84 (m, 2H), 0.74-0.69 (m, 2H).
[001782] Step 6[IN11104-100-Pl]: The Procedure is similar to Step 5[NSSy6711] in Example-854. 0.1 g of l-(2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino)pyrimidin-4-yl)ethan- l-ol gave 2-(3-cyclopropyl- lH-pyrazol- l-yl)-N-(4,4- difluorocyclohexyl)-6-(l-methoxyethyl)-N-methylpyrimidin-4-amine as a brown sticky solid (0.05 g, 46%). MS (M+l)+=392.2; IH-NMR (400 MHz, DMSO-d6): δ 8.51 (s, IH), 6.54 (bs, IH), 6.20 (d, J = 2.4 Hz, IH), 4.23-4.18 (m, IH), 3.28 (s, 3H), 3.10 (s, 3H), 2.50-1.90 (m, 5H), 1.89-1.65 (m, 4H), 1.38-1.36 (m, 3H), 0.94-0.84 (m, 2H), 0.79-0.73 (m, 2H).
Example-782:
Figure imgf000616_0001
Step 1: The Procedure is similar to Step 3[IN11059-090-Pl] in Example-659. 0.15 g of l-(2- (3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) ethan- l-ol gave 6-(l-bromoethyl)-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid (0.12 g, 80%). MS (M, M+2)+=426.1, 428.1.
[001783] Step 2[IN11196-026-P1]: The Procedure is similar to Step l[NSSy6519] in Example-842. 0.13 g of 6-(l-bromoethyl)-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-(l-methoxyethyl) pyrimidin-4-amine as an off-white Solid (0.05 g, 43%). MS (M+l)+=378.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.67 (s, IH), 6.38 (s, IH), 6.18 (d, J = 2.40 Hz, IH), 4.10 (s, IH), 2.33 (s, 3H), 2.10-1.85 (m, 8H), 1.65- 1.50 (m, 2H), 1.33 (d, J = 6.40 Hz, 3H), 0.95-0.88 (m, 2H), 0.75-0.70 (m, 2H). Exampl -783:
Figure imgf000617_0001
[001784] Step 1 [INI 1217-003-P1] : The Procedure is similar to Step 1 [B] in Example- 838. 0.15 g of 6-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6- (1, 4-oxazepan-4-yl) pyrimidin-4-amine as an off-white Solid (0.042 g, 24%). MS
(M+l)+=419.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.00 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.43 (s, 1H), 3.83-3.60 (m, 9H), 2.05-1.88 (m, 10H), 1.56- 1.52 (m, 2H), 0.95-0.84 (m, 3H), 0.71-0.67 (m, 2H).
Example-784:
Figure imgf000617_0002
[001785] Step 1: The Procedure is similar to Step 1[H] in Example-838. 1.7 g of 6- chloro-2-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave (E)-2-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl)-6-(2-ethoxyvinyl) pyrimidin-4-amine as pale yellow solid (1.1 g, 60%). MS (M+l)+=390.2.
[001786] Step 1[IN11217-069-P1]: The Procedure is similar to Step 2[NSSy6465] in Example-869. 0.65 g of (E)-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)- 6-(2-ethoxyvinyl) pyrimidin-4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-(2-ethoxyethyl) pyrimidin-4-amine as an off-white Solid (0.48 g, 74%). MS (M+l)+=392.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.65-7.57 (m, 1H), 6.24 (s, 1H), 6.18 (d, J = 2.80 Hz, 1H), 4.10 (s, 1H), 3.69 (t, J = 6.40 Hz, 2H), 3.44 (q, J = 7.20 Hz, 2H), 2.72 (s, 2H), 2.12-1.90 (m, 6H), 1.62-1.50 (m, 2H), 1.09 (t, J = 7.20 Hz, 3H),
0.97-0.90 (m, 2H), 0.76-0.70 (m, 2H).
Example-785:
Figure imgf000618_0001
[001787] Step 1: The Procedure is similar to Step 1[IN11273-018-P1] in Example-889. 0.5 g of 6-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin- 4-amine gave ethyl 2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carboxylate as a yellow Solid (0.45 g, 81 %). MS (M+l)+=392.2.
[001788] Step 2[IN11137-074-P1]: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.45 g of ethyl 2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carboxylate gave (2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl) methanol as an off-white solid (0.25 g, 62%). MS (M+l)+=350.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (s, 1H), 7.65 (s, 1H), 6.48 (s, 1H), 6.18 (d, J = 2.40 Hz, 1H), 5.41 (t, J = 5.20 Hz, 1H), 4.36 (d, J = 5.20 Hz, 2H), 4.15 (s, 1H), 2.12-1.88 (m, 7H), 1.65-1.50 (m, 2H), 0.94-0.90 (m, 2H), 0.73-0.71 (m, 2H).
[001789] Step 3 [INI 1137-079-P1]: To the solution of (2-(3-cyclopropyl-lH-pyrazol-l- yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol (0.2 g, 0.57 mmol) in THF was added 2, 2, 2-trichloro acetyl isocyanate (0.136 mL, 1.145 mmol) at -78 °C and allowed to stir at 30 °C for 16h. Then the reaction mixture was quenched with 5 mL of saturated sodium bicarbonate solution and stirred for 12h. Then extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness to afford crude product and which was purified by column chromatography using ethyl acetate in pet-ether as solvent to afford (2- (3-cyclopropyl-lH-pyrazol-l-yl)-6-(l-(4, 4-difluorocyclohexyl) ureido) pyrimidin-4-yl) methyl carbamate as an off-white solid (0.05 g, 20%). MS (M+l)+=436.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.45 (d, J = 2.4 Hz, 1H), 6.97 (s, 1H), 6.22 (d, J = 2.8 Hz, 1H), 5.10 (s, 2H), 4.62 (t, J = 11.6 Hz, 1H), 2.37-2.30 (m, 2H), 2.12-1.89 (m, 8H), 1.30 (s, 1H), 1.03-0.98 (m, 2H), 0.85-0.81 (m, 2H). Example-786:
Figure imgf000619_0001
[001790] Step 1: The Procedure is similar to Step l[NSSy6930] in Example-867. 0.27 g of (2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidine-4-carbaldehyde as an off-white Solid (0.17 g, crude). MS (M+l)+=348.2.
[001791] Step 2[IN11217-068-Pl]: The Procedure is similar to Step 1[IN11104-100-P1] in Example-781. 0.17 g of 2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl)amino)pyrimidine-4-carbaldehyde gave l-(2-(3-cyclopropyl- lH-pyrazol- l-yl)-6-((4, 4-difluorocyclohexyl)amino)pyrimidin-4-yl)-2, 2, 2-trifluoroethan-l-ol as an off- white Solid (0.12 g, 60%). MS (M+l)+=418.2; IH-NMR (400 MHz, DMSO-d6): δ 8.46 (s, IH), 7.86 (s, IH), 7.00 (d, J = 6.00 Hz, IH), 6.62 (s, IH), 6.20 (d, J = 2.00 Hz, IH), 4.93 (t, J = 6.00 Hz, IH), 4.17-4.15 (m, IH), 2.15-1.95 (m, 7H), 1.65-1.50 (m, 2H), 0.95-0.92 (m, 2H), 0.73-0.70 (m, 2H).
Example-787:
Figure imgf000619_0002
IN11239-001 -P1
[001792] Step 1[IN11239-001-P1]: The Procedure is similar to Step 3[IN11137-079-Pl] in Example-785. 0.05 g of (2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyrimidin-4-yl) methanol gave (2-(3-cyclopropyl-lH-pyrazol-l-yl)-6-((4, 4- difluorocyclohexyl) amino) pyrimidin-4-yl) methyl carbamate as white solid (0.04 g, 35%). MS (M+l)+=393.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 7.80 (s, IH), 6.80 (m, 2H), 6.27 (s, IH), 6.20 (d, J = 2.80 Hz, IH), 4.85 (s, 2H), 4.15 (s, IH), 2.10-1.90 (m, 7H), 1.62-1.50 (m, 2H), 0.94-0.90 (m, 2H), 0.73-0.70 (m, 2H).
Example-788:
Figure imgf000620_0001
[001793] Step 1 : The Procedure is similar to Step 1 [H] in Example-838. 0.1 g of 6- chloro-2-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine gave 2-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl)-6-vinylpyrimidin-4- amine as a yellow liquid (0.05 g, 51%). MS (M+l)+=346.2.
[001794] Step 2[IN11137-072-P1]: The Procedure is similar to Step 2[NSSy6464] in Example-869. 0.15 g of 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl)-6- vinylpyrimidin-4-amine gave 2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl)-6-ethylpyrimidin-4-amine as an off-white Solid (0.05 g, 33%). MS (M+l)+=348.2; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 7.55 (s, IH), 6.21 (s, IH), 6.17 (s,lH), 4.10 (m, IH), 2.60-2.55 (m, IH), 2.05-1.94 (m, 7H), 1.61-1.52 (m, 2H), 1.24- 1.17 (m, 4H), 0.95-0.90 (m, 2H), 0.73-0.69 (m, 2H).
Example-789:
Figure imgf000620_0002
I
IN11106-066-P1 IN11166-020-P1 Table-81: Step 1:
Figure imgf000621_0002
[001795] Step 1[IN11106-066-P1]: The Procedure is similar to Step 5[NSSy6711] in Example-854. IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 2H), 7.53 (s, IH), 6.27 (s, IH), 5.73 (s, IH), 5.30 (s, 2H), 2.51 (s, 3H), 2.10-1.85 (m, 8H), 1.60-1.48 (m, 2H), 0.94-0.91 (m, 2H), 0.73-0.70 (m, 2H).
[001796] Step 1 [INI 1166-020-P1] : The Procedure is similar to Step 1 [B] in Example- 838. IH-NMR (400 MHz, DMSO-d6): δ 8.48 (s, IH), 8.40 (s, IH), 7.60 (s, IH), 7.41 (s, IH), 6.24 (d, J = 2.40 Hz, IH), 5.75 (s, IH), 5.45 (s, 2H), 2.10-1.85 (m, 8H), 1.60-1.50 (m, 2H), 0.96-0.92 (m, 2H), 0.76-0.72 (m, 2H).
Example-790:
Figure imgf000621_0001
[001797] Step 1 INI 1166-036-P1: The Procedure is similar to Step 2[IN11250-007-P1] in Example-620. 0.1 g of 6-chloro-2-(3-cyclopropyl-lH-pyrazol-l-yl)-N-(4, 4- difluorocyclohexyl) pyrimidin-4-amine gave 6-cyclopropyl-2-(3-cyclopropyl-lH-pyrazol-l- yl)-N-(4, 4-difluorocyclohexyl) pyrimidin-4-amine as an off-white solid (0.035 g, 35%). MS (M+l)+=360.2; IH-NMR (400 MHz, DMSO-d6): δ 8.36 (s, IH), 7.48 (s, IH), 6.25 (s, IH), 6.14 (s, IH), 2.12-1.93 (m, 9H), 1.58-1.55 (m, 2H), 0.97-0.85 (m, 7H), 0.71-0.68 (m, 2H). Example-791:
[001798] Intentionally Omitted Example-792:
Figure imgf000622_0001
[001799] Step 1 : The Procedure is similar to Step 1 [INI 1104- 100-Pl] in Example-781. 4 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro-2-(lH-pyrazol-l-yl) pyrimidine as an off-white solid (1.9 g, 50%). MS (M+l)+=214.9.
[001800] Step 2: The Procedure is similar to Step 1[B] in Example-838. 1.05 g of 4, 6- dichloro-2-(lH-pyrazol-l-yl) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(lH- pyrazol-l-yl) pyrimidin-4-amine as off-white solid (1.25 g, 81%). MS (M+l)+=314.2.
[001801] Step 3[IN10973-038-Pl]: 0.1 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2- (lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-6-morpholino-2-(lH- pyrazol-l-yl) pyrimidin-4-amine as an off-white solid (0.1 g, 86%). MS (M+l)+=365.1; 1H- NMR (400 MHz, DMSO-d6): δ 8.53 (d, J = 2.00 Hz, 1H), 7.68 (s, 1H), 7.10 (d, J = 8.40 Hz, 1H), 6.45 (t, J = 1.60 Hz, 1H), 5.57 (s, 1H), 3.96 (s, 1H), 3.68-3.67 (m, 4H), 3.51 (s, 4H), 2.10-1.80 (m, 6H), 1.62-1.50 (m, 2H).
Example-793:
Figure imgf000622_0002
[001802] Step 1 : The Procedure is similar to Step 1 [INI 1104- 100-Pl] in Example-781. 0.5 g of 4, 6-dichloro-2-(methylsulfonyl) pyrimidine gave 4, 6-dichloro-2-(4-fluoro-lH- pyrazol-l-yl) pyrimidine as an off-white solid (0.25 g, 49%). MS (M+l)+=232.9.
[001803] Step 2: The Procedure is similar to Step 1 [B] in Example-838. 0.1 g of 4, 6- dichloro-2-(4-fluoro-lH-pyrazol-l-yl) pyrimidine gave 6-chloro-N-(4, 4-difluorocyclohexyl)- 2-(4-fluoro-lH-pyrazol-l-yl) pyrimidin-4-amine as off-white solid (0.11 g, 77%). MS (M+l)+=332.0. [001804] Step 3[IN11030-013-P1]: 0.1 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-2-(4- fluoro-lH-pyrazol-l-yl) pyrimidin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(4-fluoro- lH-pyrazol-l-yl)-6-morpholinopyrimidin-4-amine as an off-white solid (0.09 g, 78%). MS (M+l)+=383.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.59 (d, J = 4.40 Hz, 1H), 7.78 (d, J = 4.00 Hz, 1H), 7.13 (d, J = 8.00 Hz, 1H), 5.56 (s, 1H), 4.01 (s, 1H), 3.67 (t, J = 4.40 Hz, 4H), 3.50 (s, 4H), 2.04-1.93 (m, 6H), 1.55-1.52 (m, 2H).
Example-794:
Figure imgf000623_0001
[001805] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 6 g of 2, 6- dichloroisonicotinonitrile gave ethyl l-(6-chloro-4-cyanopyridin-2-yl)-lH-pyrazole-3- carboxylate (4.6 g, 48%). MS (M+l)+=277.
[001806] Step 2: The Procedure is similar to Step l[NSSy6629] in Example-839. 2.5 g of ethyl l-(6-chloro-4-cyanopyridin-2-yl)-lH-pyrazole-3-carboxylate gave ethyl l-(4-cyano- 6-((4, 4-difluorocyclohexyl) amino) pyridin-2-yl)- lH-pyrazole-3-carboxylate (1.74 g, 51%). MS (M+l)+=376.4.
[001807] Step 3: The Procedure is similar to Step 4[NSSy6711] in Example-854. 1 g of ethyl l-(4-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazole-3- carboxylate gave (l-(4-(aminomethyl)-6-((4, 4-difluorocyclohexyl)amino) pyridin-2-yl)-lH- pyrazol-3-yl)methanol (0.55 g, 61%). MS (M+l)+=338.2.
[001808] Step 4: The Procedure is similar to Step 1[A] in Example-838. 0.8 g of (l-(4- (aminomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazol-3-yl)methanol gave (l-(6-((4, 4-difluorocyclohexyl)amino)-4-(isobutyramidomethyl)pyridin-2-yl)-lH- pyrazol-3-yl)methyl isobutyrate (0.78 g, 78%). MS (M+l)+=478.2.
[001809] Step 5: The Procedure is similar to Step 1[A] in Example-838. 0.78 g of (1- (6-((4, 4-difluorocyclohexyl)amino)-4-(isobutyramidomethyl)pyridin-2-yl)-lH-pyrazol-3- yl)methyl isobutyrate gave N-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyridin-4-yl)methyl)isobutyramide (0.67 g, 87%). MS (M+l)+=408.1.
[001810] Step 6[NSSy5620]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.38 g of N-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-lH- pyrazol-l-yl)pyridin-4-yl)methyl)isobutyramide gave N-((2-((4, 4- difluorocyclohexyl)amino)-6-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyridin-4- yl)methyl)isobutyramide, (0.038 g, 18 %). MS (M+l)+=410.2; 1H-NMR (400 MHz, DMSO- d6): δ 8.56 (d, / = 2.40 Hz, IH), 8.32 (t, / = 5.96 Hz, IH), 6.91 (d, / = 7.72 Hz, 2H), 6.65- 6.64 (m, IH), 6.26 (s, IH), 5.43 (d, / = 48.2 Hz, 2H), 4.19-4.04 (m, 2H), 4.02-4.01 (m, IH), 2.41 (m, IH), 2.07-1.97 (m, 6H), 1.58-1.54 (m, 2H), 1.06 (d, / = 6.84 Hz, 6H).
Example-795:
Figure imgf000624_0001
[001811] Step 1: The Procedure is similar to Step 1[A] in Example-838. 0.31 g of (1- (4-(aminomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-lH-pyrazol-3-yl)methanol gave methyl ((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-lH-pyrazol-l- yl)pyridin-4-yl)methyl)carbamate, (0.17 g, 50%). MS (M+l)+=396.2.
[001812] Step 2[NSSy5653]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.17 g of methyl ((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyridin-4-yl)methyl)carbamate gave methyl ((2-((4, 4- difluorocyclohexyl)amino)-6-(3-(fluoromethyl)-lH-pyrazol-l-yl)pyridin-4- yl)methyl)carbamate, (0.085 g, 50%). MS (M+l)+=398.2; IH-NMR (400 MHz, DMSO-d6): δ 8.56 (d, J = 2.00 Hz, IH), 7.77-7.74 (m, IH), 6.63 (s, IH), 6.30 (s, IH), 5.49 (s, IH), 5.37 (s, IH), 4.10 (d, J = 6.00 Hz, 2H), 4.02 (s, IH), 3.56 (s, 3H), 2.06-1.95 (m, 6H), 1.55-1.53 (m, 2H). Example-796:
Figure imgf000625_0001
[001813] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 10 g of 2, 6- dichloroisonicotinonitrile gave ethyl l-(6-chloro-4-cyanopyridin-2-yl)-4-methyl-lH- pyrazole-3-carboxylate (5 g, 30%). MS (M+l)+=291.0.
[001814] Step 2: The Procedure is similar to Step l[NSSy6629] in Example-839. 5 g of ethyl l-(6-chloro-4-cyanopyridin-2-yl)-4-methyl-lH-pyrazole-3-carboxylate gave ethyl 1- (4-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazole-3- carboxylate (1.3 g, 20%). MS (M+l)+=390.2.
[001815] Step 3: The Procedure is similar to Step 4[NSSy6711] in Example-854. 1 g of ethyl l-(4-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazole-
3- carboxylate gave (l-(4-(aminomethyl)-6-((4, 4-difluorocyclohexyl)amino) pyridine-2-yl)-
4- methyl-lH-pyrazol-3-yl)methanol (0.61 g, 58%). MS (M+l)+=352.0.
[001816] Step 4: The Procedure is similar to Step 1[A] in Example-838. 0.75 g of (1- (4-(aminomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazol-3- yl)methanol gave (l-(4-(acetamidomethyl)-6-((4, 4-difluoro cyclohexyl)amino)pyridin-2-yl)- 4-methyl-lH-pyrazol-3-yl)methyl acetate (0.61 g, 30%). MS (M+l)+=436.2.
[001817] Step 5: The Procedure is similar to Step 1[A] in Example-838. 0.7 g of (l-(4- (acetamidomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)-4-methyl-lH-pyrazol-3- yl)methyl acetate gave N-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-4- methyl-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide (0.4 g, 64%). MS (M+l)+=394.2.
[001818] Step 6[NSSy5622]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.15 g of N-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-(hydroxymethyl)-4- methyl-lH-pyrazol-l-yl)pyridin-4-yl)methyl)acetamide gave N-((2-((4, 4- difluorocyclohexyl)amino)-6-(3-(fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridin-4- yl)methyl)acetamide (0.028 g, 25%). MS (M+l)+=396.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43-8.36 (m, 2H), 6.87 (d, J = 10.04 Hz, 2H), 6.26 (s, 1H), 5.49 (s, 1H), 5.37 (s, 1H), 4.16 (d, J = 5.96 Hz, 2H), 4.02-4.01 (m, 1H), 3.12 (s, 1H), 2.15 (s, 3H), 2.09-1.95 (m, 7H), 1.60 (s, 3H), 1.54-1.50 (m, 2H).
Example-797:
Figure imgf000626_0001
[001819] Step 1 : The Procedure is similar to Step 1 [B] in Example-838. 2 g of 2, 6- dichloroisonicotinonitrile gave 2-chloro-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile (2.3 g, 92%). MS (M+l)+=219.2.
[001820] Step 2: The Procedure is similar to Step l[NSSy6629] in Example-839. 2.2 g of 2-chloro-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile (1.8 g, 54%). MS (M+l)+=318.1.
[001821] Step 3: The Procedure is similar to Step 4[NSSy6711] in Example-854. 1 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 4- (aminomethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- IH-pyrazol- 1-yl) pyridin-2-amine (0.8 g, 79%). MS (M+l)+=322.
Table-82: Step 4:
Figure imgf000626_0002
[001822] Step 4[NSSy5635]: The Procedure is similar to Step 1[A] in Example-838. MS (M+l)+=380.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.44 Hz, 1H), 7.76-7.75 (m, IH), 6.29 (d, J = 2.48 Hz, IH), 6.23 (s, IH), 4.12-4.08 (m, 2H), 4.00-3.98 (m, IH), 3.57 (s, 3H), 2.33 (s, 3H), 2.26-1.95 (m, 6H), 1.56-1.53 (m, 2H).
[001823] Step 4[NSSy5637]: The Procedure is similar to Step 1[A] in Example-838. MS (M+l)+=392.0; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.32 Hz, IH), 8.32-8.29 (m, IH), 6.29 (d, J = 2.36 Hz, IH), 6.19 (s, IH), 4.16 (d, J = 6.00 Hz, 2H), 3.97-3.88 (m, IH), 2.43-2.41 (m, 2H), 2.26 (s, 3H), 2.08-1.96 (m, 6H), 1.56-1.53 (m, 2H), 1.06 (d, J = 6.84 Hz, 6H).
Example-798:
Figure imgf000627_0001
[001824] Step 1 : The Procedure is similar to Step 2[NSSy6711] in Example-854. 0.85 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinic acid (0.8 g, 88%). MS (M+l)+=337.
[001825] Step 2: The Procedure is similar to Step 3[NSSy6711] in Example-854. 0.8 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinic acid gave ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinate (0.75 g, 87%). MS (M+l)+=365.
Table-83: Step 3:
Figure imgf000627_0002
[001826] Step 3[NSSy5846]: The Procedure is similar to Step 4[NSSy6464] in
Example-869. MS (M+l)+=351.2; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, IH), 7.01 (d, J = 1.20 Hz, IH), 6.73 (d, J = 7.20 Hz, IH), 6.47 (d, J = 1.20 Hz, IH), 6.28 (d, J = 2.40 Hz, IH), 5.13 (s, IH), 4.03-3.99 (m, IH), 2.27 (s, 3H), 2.06-1.96 (m, 6H), 1.57-1.55 (m, 2H), 1.39 (d, J = 0.80 Hz, 6H). [001827] Step 3[NSSy5827]: The Procedure is similar to Step 4[NSSy6711] in
Example-854. MS (M+l)+=323.1; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, 1H), 6.89 (s, 1H), 6.75 (d, J = 7.60 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 2.40 Hz, 1H), 5.31 (t, J = 6.00 Hz, 1H), 4.43 (d, J = 6.00 Hz, 2H), 4.00-3.98 (m, 1H), 2.26 (s, 3H), 2.08-1.96 (m, 6H), 1.57-1.54 (m, 2H).
Example-799:
Figure imgf000628_0001
NSSy5828 NSSy5860 NSSy5861 NSSy5869
Figure imgf000628_0002
NSSy5996 NSSy6371 NSSy6417 NSSy6451
Table-84: Step 1:
Figure imgf000628_0003
NSSy6371 2-Bromo-5-Cyanopyridine, CS2CO3, DMF, rt, 8h 20
6-Chloro-3-Pyridazinecarbonitrile, CS2CO3, DMF,
NSSy6417 40 rt, 16h
N'Vt 6-Chloropyridazine-3-Carboxamide, CS2CO3,
NSSy6451 40
DMF, 100 °C, 16h
NH2
[001828] Step 1 [NSSy5828] : A solution of (2-((4, 4-difluorocyclohexyl)amino)-6-(3- methyl-lH-pyrazol-l-yl)pyridin-4-yl)methanol (0.15 g, 0.465 mmol), 3-bromo-6- methylpyridazine (0.16 g, 0.93 mmol) and tetrabutylammonium Hydrogen sulfate (0.15 g, 0.46 mmol) in 50% aqueous sodium hydroxide solution (8 mL) was heated at 100 °C in a closed vial for 16h. The reaction mixture was extracted with ethyl acetate (2x40 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude which was purified by column chromatography using 55% ethyl acetate in hexane as an eluent to afford (N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)-4-(((6- methylpyridazin-3-yl) oxy)methyl)pyridin-2-amine as an off-white solid (0.07 g, 36%). MS (M+l)+=415.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 2.40 Hz, 1H), 7.55 (d, J = 8.80 Hz, 1H), 7.26 (d, J = 8.80 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 7.60 Hz, 1H), 6.40 (s, 1H), 6.30 (d, J = 2.40 Hz, 1H), 5.43 (s, 2H), 3.99 (m, 1H), 2.26 (s, 3H), 2.08-1.96 (m, 6H), 1.56- 1.53 (m, 2H).
[001829] Step 1 [NSSy5860] : The Procedure is similar to Step 5[NSSy6711] in
Example-854. MS (M+l)+=337.0; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.36 Hz, 1H), 6.87 (s, 1H), 6.81 (d, J = 7.32 Hz, 1H), 6.31-6.29 (m, 2H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.12 (s, 3H), 2.26 (s, 3H), 2.07-1.96 (m, 6H), 1.56-1.54 (m, 2H).
[001830] Step l[NSSy5861]: The Procedure is similar to Step 5[NSSy6711] in
Example-854. MS (M+l)+=419.2; IH-NMR (400 MHz, DMSO-d6): δ 8.74 (s, 2H), 8.43 (d, J = 2.40 Hz, 1H), 6.96 (s, 1H), 6.90 (d, J = 7.28 Hz, 1H), 6.38 (s, 1H), 6.30 (d, J = 2.40 Hz, 1H), 5.34 (s, 2H), 4.01-3.90 (m, 1H), 2.26 (s, 3H), 2.06-1.96 (m, 6H), 1.55-1.53 (m, 2H).
[001831] Step l[NSSy5869]: The Procedure is similar to Step 5[NSSy6711] in
Example-854. MS (M, M+2)+=479, 481; IH-NMR (400 MHz, DMSO-d6): δ 8.75 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 6.98-6.94 (m, 2H), 6.41 (d, J = 18.8 Hz, 1H), 6.28 (d, J = 26.2 Hz, 1H), 5.26 (s, 2H), 4.00-3.80 (m, 1H), 2.27 (s, 3H), 2.06-1.96 (m, 6H), 1.56-1.53 (m, 2H). [001832] Step l[NSSy5996]: The Procedure is similar to Step l[NSSy5828] in
Example-799. MS (M+l)+=418.2; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (s, IH), 8.16 (s, IH), 7.77-7.72 (m, IH), 7.03-7.00 (m, IH), 6.99 (s, IH), 6.86 (d, J = 7.20 Hz, IH), 6.36 (s, IH), 6.29 (d, J = 2.00 Hz, IH), 5.28 (s, 2H), 4.00 (m, IH), 2.26 (s, 3H), 2.08-1.95 (m, 6H), 1.24-1.19 (m, 2H).
[001833] Step l[NSSy6371]: The Procedure is similar to Step 1[A] in Example-838. MS (M+l)+=425.1; IH-NMR (400 MHz, DMSO-d6): δ 8.72 (d, J = 2.40 Hz, IH), 8.42 (d, J = 2.40 Hz, IH), 8.24-8.21 (m, IH), 7.16 (d, J = 8.80 Hz, IH), 6.95 (s, IH), 6.89 (d, J = 7.20 Hz, IH), 6.35 (s, IH), 6.30 (d, J = 2.40 Hz, IH), 5.40 (s, 2H), 4.00 (s, IH), 2.26 (s, 3H), 2.05- 1.95 (m, 6H), 1.55-1.24 (m, 2H).
[001834] Step l[NSSy6417]: The Procedure is similar to Step 1[A] in Example-838. MS (M+l)+=426.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (t, J = 2.40 Hz, IH), 8.31-8.27 (m, IH), 7.66-7.62 (m, IH), 7.01 (d, J = 3.20 Hz, IH), 6.92 (s, IH), 6.41 (s, IH), 6.30 (t, J = 2.40 Hz, IH), 5.58 (s, 2H), 4.01-3.98 (m, IH), 2.27 (s, 3H), 2.06-1.99 (m, 6H), 1.56-1.50 (m, 2H).
[001835] Step l[NSSy6451]: The Procedure is similar to Step 1[B] in Example-838. MS (M+l)+=444.2; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 2.80 Hz, IH), 8.36 (s, IH), 8.14 (d, J = 12.00 Hz, IH), 7.79 (s, IH), 7.49 (d, J = 12.00 Hz, IH), 7.00 (s, IH), 6.89 (d, J = 10.00 Hz, IH), 6.41 (s, IH), 6.30 (d, J = 3.20 Hz, IH), 5.56 (s, 2H), 4.00 (m, IH), 2.26 (s, 3H), 2.05-1.95 (m, 6H), 1.57 (m, 2H).
Example-800:
Figure imgf000630_0001
[001836] Step 1: The Procedure is similar to Step l[NSSy6930] in Example-867. 1.5 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinaldehyde (1.2 g, 80%). MS (M+l)+=321.
[001837] Step 2[NSSy6019]: To a solution of 2-((4, 4-difluorocyclohexyl)amino)-6-(3- methyl-lH-pyrazol-l-yl)isonicotinaldehyde (0.21 g, 0.655 mmol) in methanol (10 mL) was added methyl 4-aminobutanoate (0.09 g, 0.78 mmol) and triethylamine (0.086 g, 0.85 mmol), the reaction mixture was stirred at rt for lh. After lh, added Sodium borohydride (0.032 g, 0.85 mmol) to the above reaction mixture and heated at 50 °C for 16h. The reaction mixture was concentrated and diluted with water and extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude and which was purified by column chromatography using 40% ethyl acetate in pet ether as eluent to afford l-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4- yl)methyl)pyrrolidin-2-one as an off-white solid (60 mg, 23%). MS (M+l)+=390.0; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.40 Hz, 1H), 6.85 (d, J = 7.20 Hz, 1H), 6.79 (s, 1H), 6.30 (d, J = 2.40 Hz, 1H), 6.18 (s, 1H), 4.14 (m, 2H), 3.98-3.38 (m, 1H), 3.28-3.27 (m, 2H), 2.46-2.34 (m, 2H), 2.32 (s, 3H), 2.30-2.00 (m, 8H), 1.50-1.61 (m, 2H).
Example-801:
Figure imgf000631_0001
[001838] Step l[NSSy5829]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.12 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave N-(4, 4-difluorocyclohexyl)-4-(fluoromethyl)-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-amine (1.2 g, 15%). MS (M+l)+=325.1; IH-NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 2.40 Hz, 1H), 6.93 (d, J = 7.20 Hz, 1H), 6.88 (s, 1H), 6.31 (d, J = 2.40 Hz, 1H), 5.46 (s, 1H), 5.34 (s, 1H), 4.01-4.00 (m, 1H), 2.25 (s, 3H), 2.07-1.96 (m, 6H), 1.56-1.53 (m, 2H).
Example-802:
Figure imgf000631_0002
[001839] Step 1[IN11217-056-P1]: The Procedure is similar to Step l[NSSy5828] in Example-799. 0.15 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)-4- ((pyridazin-3-yloxy) methyl) pyridin-2-amine as an off-white solid (0.04 g, 22%). MS (M+l)+=401.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.93-8.92 (m, 1H), 8.43 (d, / = 2.4 Hz, 1H), 7.69-7.66 (m, 1H), 7.35 (dd, / = 9.2, 1.6 Hz, 1H), 6.99 (s, 1H), 6.88 (d, / = 7.6 Hz, 1H), 6.41 (s, 1H), 6.29 (d, / = 2.0 Hz, 1H), 5.48 (s, 2H), 4.00 (m, 1H), 2.26 (s, 3H), 2.06-1.96 (m, 6H), 1.56-1.54 (m, 2H).
Example-803:
Figure imgf000632_0001
[001840] Step 1: The Procedure is similar to Step 3[IN11059-090-P1] in Example-659. 1.2 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave 4-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine as an off-white solid (0.5 g, 35 %). MS (M+l)+=385.4.
Table-85: Step 2:
Figure imgf000632_0002
[001841] [IN11083-014-P1]: The Procedure is similar to Step 2[IN10991-021-P1] in Example-694. 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, 1H), 6.85-6.82 (m, 2H), 6.29 (d, J = 2.40 Hz, IH), 6.24 (s, IH), 4.37 (s, 2H), 4.24 (t, J = 5.20 Hz, 2H), 4.00 (s,
IH), 3.25-3.20 (m, 2H), 2.26 (s, 3H), 2.10-1.90 (m, 8H), 1.60-1.48 (m, 2H).
[001842] [IN10991-091-P1]: The Procedure is similar to Step 2[IN10991-021-P1] in
Example-694. IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.4 Hz, IH), 6.88 (d, J = 7.2
Hz, IH), 6.83 (s, IH), 6.29 (d, J = 2.4 Hz, IH), 6.26 (s, IH), 4.33-4.26 (m, 4H), 4.08-4.00 (m,
IH), 3.50-3.46 (m, 2H), 2.26 (s, 3H), 2.09-1.96 (m, 6H), 1.56-1.54 (m, 2H).
[001843] [INI 1039-026-P1]: The Procedure is similar to Step 1[A] in Example-838.
IH-NMR (400 MHz, MeOD): δ 8.37 (s, IH), 6.94 (d, J = 14.80 Hz, IH), 6.33 (d, J = 11.20
Hz, IH), 6.25 (s, IH), 4.11 (s, IH), 3.95 (s, IH), 3.64 (d, J = 12.40 Hz, 2H), 2.40 (s, 3H), 2.33
(s, 3H), 2.15-1.85 (m, 6H), 1.70-1.60 (m, 2H).
Example-804:
Figure imgf000633_0001
[001844] Step l[NSSy5839]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.12 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl- lH-pyrazol- 1-yl) isonicotinaldehyde gave N-(4, 4-difluorocyclohexyl)-4-(difluoromethyl)-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-amine (0.1 g, 78%). MS (M+l)+=343.1; IH-NMR (400 MHz, DMSO-d6): δ 8.47 (d, J = 2.32 Hz, IH), 7.20 (d, J = 7.28 Hz, IH), 6.95 (t, J = 55.40 Hz, IH), 6.98 (m, IH), 6.50 (s, IH), 6.34 (d, J = 2.36 Hz, IH), 4.05 (m, IH), 2.27 (s, 3H), 2.09-1.99 (m, 6H), 1.60-1.57 (m, 2H).
Figure imgf000634_0001
Table-86: Step 1:
Figure imgf000634_0002
[001845] Step l[NSSy6395]: The Procedure is similar to Step 4[NSSy6067] in Example-628. MS (M+l)+=390.2; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, 1H), 8.29 (d, J = 0.80 Hz, 1H), 7.99-7.98 (m, 1H), 6.95 (s, 1H), 6.82 (d, J = 7.60 Hz, 1H), 6.44 (s, 1H), 6.27 (d, J = 2.40 Hz, 1H), 6.04 (d, J = 4.80 Hz, 1H), 5.54 (d, J = 4.40 Hz, 1H), 3.98 (s, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 6H), 1.56-1.54 (m, 2H). [001846] Step l[NSSy6415]: MS (M+l)+=390.2; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, 1H), 8.29 (d, J = 0.80 Hz, 1H), 7.99-7.98 (m, 1H), 6.95 (s, 1H), 6.82 (d, J = 7.60 Hz, 1H), 6.44 (s, 1H), 6.27 (d, J = 2.40 Hz, 1H), 6.04 (d, J = 4.80 Hz, 1H), 5.54 (d, J = 4.40 Hz, 1H), 3.98 (s, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 6H), 1.56-1.54 (m, 2H).
[001847] Step l[NSSy6416]: MS (M+l)+=390.2; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, 1H), 8.29 (d, J = 0.80 Hz, 1H), 7.99-7.98 (m, 1H), 6.95 (s, 1H), 6.82 (d, J = 7.60 Hz, 1H), 6.44 (s, 1H), 6.27 (d, J = 2.40 Hz, 1H), 6.04 (d, J = 4.80 Hz, 1H), 5.54 (d, J = 4.40 Hz, 1H), 3.98 (s, 1H), 2.25 (s, 3H), 2.06-1.95 (m, 6H), 1.56-1.54 (m, 2H).
[001848] Step l[NSSy6846]: The Procedure is similar to Step 4[NSSy6067] in
Example-628. MS (M+l)+=390.1; IH-NMR (400 MHz, DMSO-d6): δ 8.30 (s, 1H), 7.99 (d, J = 0.80 Hz, 1H), 7.51 (s, 1H), 6.95 (s, 1H), 6.86 (d, J = 7.20 Hz, 1H), 6.50 (s, 1H), 6.23 (s, 1H), 6.06 (d, J = 4.72 Hz, 1H), 5.54 (d, J = 4.52 Hz, 1H), 3.90 (s, 1H), 2.61 (s, 3H), 2.09-1.89 (m, 7H), 1.56-1.53 (m, 2H).
[001849] Step l[NSSy6576]: The Procedure is similar to Step 4[NSSy6067] in
Example-628. MS (M+l)+=405.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.32 Hz, 1H), 6.95 (d, J = 6.00 Hz, 2H), 6.80 (d, J = 5.12 Hz, 1H), 6.46 (s, 1H), 6.30 (d, J = 2.36 Hz, 1H), 5.91 (d, J = 5.12 Hz, 1H), 3.99 (s, 1H), 2.48 (s, 3H), 2.25 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.50 (m, 2H).
[001850] Step 1 [NSSy6469] : To a solution of 6-(bromomethyl)nicotinonitrile (0.03 g, 0.15 mmol) in tetrahydrofuran (1 mL) was added Isopropylmagnesium Bromide at -78 °C and stirred for 0.5h. A solution of 2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)isonicotinaldehyde (0.05 g, 0.15 mmol) in tetrahydrofuran was added to the reaction mixture at -56 °C and stirred for 15 min at same temperature. The reaction mixture was slowly warmed to room temperature and stirred for 15 min. The reaction mixture was quenched with saturated ammonium chloride solution at 0 °C and extracted with ethyl acetate (2*20 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude and which was purified by Prep HPLC to afford 6-(2-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-4-yl)- 2-hydroxyethyl)nicotinonitrile as an yellow solid (0.025 g, 36%). MS (M+l)+=439.1; 1H- NMR (400 MHz, DMSO-d6): δ 8.97 (s, 1H), 8.41 (s, 1H), 8.23 (m, 1H), 7.53 (d, = 8.08 Hz, 1H), 6.97 (s, 1H), 6.75 (d, = 7.32 Hz, 1H), 6.29 (d, = 14.2 Hz, 2H), 4.92 (m,
1H), 3.96 (m, 2H), 2.27 (s, 3H), 2.15-1.85 (m, 7H), 1.57-1.49 (m,3H). Example-806:
Figure imgf000636_0001
[001851] Step l[NSSy6891]: To a solution of (2-((4, 4-difluorocyclohexyl)amino)-6-(3- methyl-lH-pyrazol-l-yl)pyridin-4-yl)methanol (0.1 g, 0.31 mmol) in tetrahydrofuran was added trichloro acetyl isocyanate (0.11 g, 0.62 mmol) at -78°C and stirred at room
temperature for 16h. Added saturated sodium bicarbonate solution and stirred at room temperature for 30 min. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude and which was purified in the Reveleris flash system instrument using 4% methanol in chloroform as eluent to afford (2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-4-yl)methyl carbamate as an off-white solid (0.025 g, 23%). MS (M+l)+=366.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.40 Hz, 1H), 6.90 (s, 1H), 6.88 (s, 1H), 6.65 (s, 2H), 6.30 (d, J = 2.40 Hz, 1H), 6.27 (s, 1H), 4.92 (s, 2H), 3.99 (s, 1H), 2.27 (s, 3H), 2.08-1.96 (m, 6H), 1.56-1.36 (m, 2H). Example-807:
Figure imgf000636_0002
[001852] Step l[NSSy6812]: The Procedure is similar to Step l[NSSy6891] in
Example-806. 0.1 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave l-(4, 4-difluorocyclohexyl)- l-(4-(hydroxymethyl)-6-(3-methyl- lH-pyrazol-l-yl) pyridin-2-yl) urea (0.072 g, 65%). MS (M+l)+=366.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (d, = 2.40 Hz, 1H), 7.71 (s, 1H), 7.02 (s, 1H), 6.39 (d, = 2.40 Hz, 1H), 6.04 (s, 2H), 5.57 (t, J = 5.60 Hz, 1H), 4.61 (d, J = 6.00 Hz, 2H), 4.33 (t, J = 6.40 Hz, 1H),
2.30 (s, 3H), 1.89-1.70 (m, 8H).
Example-808:
Figure imgf000637_0001
[001853] Step 1 : The Procedure is similar to Step 5[NSSy6711] in Example-854. 1.8 g of (2, 6-dichloropyridin-4-yl) methanol gave 2, 6-dichloro-4-(methoxymethyl) pyridine (1.5 g, 75%). MS (M+l)+=193.
[001854] Step 2: The Procedure is similar to Step l[NSSy6629] in Example-839. 1.5 g of (2, 6-dichloropyridin-4-yl) methanol gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- (methoxymethyl) pyridin-2-amine (0.8 g, 35%). MS (M+l)+=291.
[001855] Step 3: To a stirred degassed solution of 6-chloro-N-(4, 4-difluorocyclohexyl)- 4-(methoxymethyl)pyridin-2-amine (0.65 g, 2.23 mmol), 1, Γ- bis(diphenylphosphino)ferrocene (0.124 g, 0.22 mmol), zinc cyanide (0.53 g, 4.47 mmol) and zinc dust (0.014 g, 0.22 mmol) in N, N-dimethylformamide (10 mL) was added
tris(dibenzylideneacetone) dipalladium(0) (0.204 g, 0.22 mmol) and the mixture was heated at 120 °C for 16h. The reaction mixture was filtered through celite bed and the filtrate was quenched with water and extracted with ethyl acetate (2x75 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford 6-((4, 4-difluorocyclohexyl) amino)-4-(methoxymethyl) picolinonitrile as a light brownish gum (0.65 g, 98%) and it was forwarded to the next step without any further purification. MS (M+l)+=281.
[001856] Step 4: The Procedure is similar to Step 5[NSSy5779] in Example-642. 0.6 g of 6-((4, 4-difluorocyclohexyl) amino)-4-(methoxymethyl) picolino nitrile gave 6-((4, 4- difluorocyclohexyl) amino)-4-(methoxymethyl) pyridine-2-carbothioamide (0.62 g, 92%). MS (M+l)+=316. [001857] Step 5[NSSy5933]: The Procedure is similar to Step 6[NSSy5779] in
Example-642. 0.6 g of 6-((4, 4-difluorocyclohexyl) amino)-4-(methoxymethyl) pyridine-2- carbothioamide gave N-(4, 4-difluorocyclohexyl)-4-(methoxymethyl)-6-(4-methylthiazol-2- yl) pyridin-2-amine (0.16 g, 24%). MS (M+l)+=354.0; IH-NMR (400 MHz, DMSO-d6): δ 7.29 (d, J = 0.96 Hz, 1H), 7.17 (s, 1H), 6.82 (d, J = 6.92 Hz, 1H), 6.52 (s, 1H), 4.36 (d, J = 16.68 Hz, 2H), 3.90-3.88 (m, 1H), 3.21 (s, 3H), 2.41 (s, 3H), 2.10-2.00 (m, 6H), 1.61-1.58 (m, 2H).
Example-809:
Figure imgf000638_0001
[001858] Step 1: The Procedure is similar to Step 1[B] in Example-838. 2 g of 2, 6- dichloroisonicotinonitrile gave 2-chloro-6-((4, 4-difluorocyclohexyl) amino)
isonicotinonitrile (2 g, 63%). MS (M+l)+=272.0.
[001859] Step 2: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.1 g of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile gave 4-(aminomethyl)-6- chloro-N-(4, 4-difluorocyclohexyl) pyridin-2-amine (0.1 g, 99%). MS (M+l)+=276.0.
[001860] Step 3: The Procedure is similar to Step 1[A] in Example-838. 1.2 g of 4- (aminomethyl)-6-chloro-N-(4, 4-difluorocyclohexyl)pyridin-2-amine gave N-((2-chloro-6- ((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl) acetamide (1 g, 72%). MS
(M+l)+=318.1.
[001861] Step 4: The Procedure is similar to Step 3[NSSy5933] in Example-808. 2 g of N-((2-chloro-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl) acetamide gave N-((2- cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl)acetamide (0.75 g, 38%). MS (M+l)+=309.1. [001862] Step 5: The Procedure is similar to Step 5[NSSy5779] in Example-642. 1 g of N-((2-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl)acetamide gave N-((2- carbamothioyl-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl)acetamide (1 g, 90%). MS (M+l)+=343.1.
[001863] Step 6[NSSy5640]: The Procedure is similar to Step 6[NSSy5779] in
Example-642. 0.2 g of N-((2-carbamothioyl-6-((4, 4-difluorocyclohexyl)amino)pyridin-4- yl)methyl)acetamide gave N-((2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)pyridin-4-yl)methyl)acetamide (0.075 g, 34%). MS (M+l)+=381.1; IH-NMR (400 MHz, DMSO-d6): δ 8.42 (t, J = 5.72 Hz, 1H), 7.29 (d, = 0.92 Hz, 1H), 7.14 (s, 1H), 6.82 (d, = 6.76 Hz, 1H), 6.42 (s, 1H), 4.17 (d, = 5.92 Hz, 2H), 3.91-3.90 (m, 1H), 2.33 (s, 3H), 2.08- 1.93 (m, 6H), 1.90 (s, 3H), 1.63-1.58 (m, 2H).
Example-810:
Figure imgf000639_0001
[001864] Step 1: The Procedure is similar to Step 6[NSSy5779] in Example-642. 0.8 g of N-((2-carbamothioyl-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)methyl) acetamide gave ethyl 2-(4-(acetamidomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)thiazole- 4-carboxylate (0.3 g, 30%). MS (M+l)+=439.2.
[001865] Step 2: The Procedure is similar to Step 4[NSSy6711] in Example-854. 0.3 g of ethyl 2-(4-(acetamidomethyl)-6-((4, 4-difluorocyclohexyl)amino)pyridin-2-yl)thiazole-4- carboxylate gave N-((2-((4, 4-difluorocyclohexyl) amino)-6-(4-(hydroxymethyl)thiazol-2- yl)pyridin-4-yl)methyl)acetamide (0.25 g, 92%). MS (M+l)+=397.1.
[001866] Step 3[NSSy5644]: The Procedure is similar to Step 3[NSSy6917] in
Example-21. 0.25 g of N-((2-((4, 4-difluorocyclohexyl) amino)-6-(4-(hydroxymethyl)thiazol- 2-yl)pyridin-4-yl)methyl)acetamide gave N-((2-((4, 4-difluorocyclohexyl)amino)-6-(4- (fluoromethyl)thiazol-2-yl)pyridin-4-yl) methyl) acetamide (0.08 g, 32%). MS
(M+l)+=399.1; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (t, J = 5.64 Hz, 1H), 7.88 (d, J = 2.20 Hz, 1H), 7.19 (s, 1H), 6.89 (d, J = 6.60 Hz, 1H), 6.46 (s, 1H), 5.54 (s, 1H), 5.42 (s, 1H), 4.19 (d, J = 5.96 Hz, 2H), 3.91 (s, 1H), 2.09-2.01 (m, 6H), 1.95 (s, 3H), 1.59-1.56 (m, 2H). Example-811:
Figure imgf000640_0001
[001867] Step 1: The Procedure is similar to Step 4[NSSy6067] in Example-628. 1 g of 2, 6-dichloroisonicotinaldehyde gave (2, 6-dichloropyridin-4-yl) (oxazol-2-yl) methanol (0.8 g, 57%). MS (M+l)+=246.
[001868] Step 2: To an ice-cooled solution of (2, 6-dichloropyridin-4-yl) (oxazol-2-yl) methanol (5.7 g, 23.25 mmol) in DCM (40 mL) was added imidazole (4.12 g, 34.88 mmol) and followed by tert-butyl dimethylsilyl chloride (4.33 g, 27.91 mmol). The reaction mixture was slowly warmed to rt and stirred at rt for 20h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x75 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude and which was purified by column chromatography using 10% ethyl acetate in hexane as eluent to afford 2-(((tert- butyldimethylsilyl)oxy)(2, 6-dichloropyridin-4-yl)methyl)oxazole as an colourless liquid (6 g, 72%). MS (M+l)+=359.
[001869] Step 3: The Procedure is similar to Step 2[IN10991-021-P1] in Example-694. 2 g of 2-(((tert-butyldimethylsilyl)oxy)(2, 6-dichloropyridin-4-yl)methyl)oxazole gave 2- (((tert-butyldimethylsilyl)oxy)(2-chloro-6-(3, 5-dimethyl- lH-pyrazol- l-yl)pyridin-4- yl)methyl)oxazole (0.57 g, 25%). MS (M+l)+=420.2. [001870] Step 4: The Procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 2-(((tert-butyldimethylsilyl)oxy)(2-chloro-6-(3, 5-dimethyl- lH-pyrazol- l-yl)pyridin-4- yl)methyl)oxazole gave of 4-(((tert-butyldimethylsilyl)oxy)(oxazol-2-yl)methyl)-N-(4,4- difluorocyclohexyl)-6-(3, 5-dimethyl- lH-pyrazol-l-yl)pyridin-2-amine (0.28 g, 45%). MS (M+ 1)4=518.2.
[001871] Step 5: To an ice cooled solution of 4-(((tert-butyldimethylsilyl) oxy) (oxazol- 2-yl) methyl)-N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl- lH-pyrazol-l-yl) pyridin-2-amine (0.3 g, 0.579 mmol) in THF (4 mL) was added Tetrabutylammoniumfluoride (1M soln. in tetrahydrofuran) (0.33 mL, 1.15 mmol). The reaction mixture was slowly warmed to rt and stirred for lh.
The reaction was quenched with ice cold water and was extracted with ethyl acetate (2x15 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude and which was purified by column chromatography using 50% ethyl acetate in hexane as eluent to afford (2-((4, 4-difluorocyclohexyl)amino)-6-(3, 5-dimethyl- lH-pyrazo 1-1- yl)pyridin-4-yl) (oxazol-2-yl)methanol as an yellow solid (0.19 g, 82%). MS (M+l)+=404.2.
[001872] Step 6: To an ice cooled solution of (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl- lH-pyrazol-l-yl) pyridin-4-yl) (oxazol-2-yl) methanol (0.11 g, 0.27 mmol) in DCM (10 mL) was added triphenyl phosphine (0.14 g, 0.54 mmol) and followed by carbon tetrabromide (0.13 g, 0.40 mmol). The reaction mixture was slowly warmed to rt and heated at 45 °C for lh. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (2x30 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude and which was purified by column chromatography using 25% ethyl acetate in hexane as eluent to afford 4-(bromo(oxazol-2-yl)methyl)-N-(4, 4- difluorocyclohexyl)-6-(3, 5-dimethyl- lH-pyrazol-l-yl)pyridin-2-amine as an yellow solid (0.06 g, 50%). MS (M+l)+=467.1.
[001873] Step 7[NSSy5645]: The Procedure is similar to Step 2[NSSy6464] in
Example-869. 0.06 g of 4-(bromo(oxazol-2-yl)methyl)-N-(4, 4-difluorocyclohexyl)-6-(3, 5- dimethyl-lH-pyrazol-l-yl)pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-6-(3, 5- dimethyl-lH-pyrazol-l-yl)-4-(oxazol-2-ylmethyl) pyridin-2-amine (0.024 g, 50%). MS (M+l)+=388.2; 1H-NMR (400 MHz, CDC13): δ 7.86 (s, 1H), 7.53-7.50 (m, 1H), 7.00 (d, J = 7.20 Hz, 1H), 6.20 (s, 1H), 5.99 (d, J = 12.80 Hz, 1H), 3.88-3.83 (m, 3H), 3.44 (s, 1H), 2.65 (s, 3H), 2.32 (s, 3H), 2.11-1.85 (m, 8H), 1.33-1.30 (m, 3H). Example-812:
Figure imgf000642_0001
[001874] Step 1: The Procedure is similar to Step 4[NSSy6067] in Example-628. 3.6 g of 2, 6-dichloroisonicotinaldehyde gave (2, 6-dichloropyridin-4-yl) (pyridin-3-yl) methanol (1.4 g, 27%). MS (M+l)+=256.0.
[001875] Step 2: The Procedure is similar to Step 2[NSSy5645] in Example-811. 1 g of
(2, 6-dichloropyridin-4-yl) (pyridin-3-yl) methanol gave 4-(((tert-butyldimethylsilyl) oxy)
(pyridin-3-yl) methyl)-2, 6-dichloropyridine (0.51 g, 45%). MS (M+l)+=370.2.
[001876] Step 3: The Procedure is similar to Step 2[IN10991-021-P1] in Example-694.
0.45 g of 4-(((tert-butyldimethylsilyl)oxy)(pyridin-3-yl)methyl)-2, 6-dichloropyridine gave
4-(((tert-butyldimethylsilyl)oxy)(pyridin-3-yl)methyl)-2-chloro-6-(3-methyl-lH-pyrazol-l- yl)pyridine (0.16 g, 32%). MS (M+l)+=416.0.
[001877] Step 4: The Procedure is similar to Step l[NSSy6629] in Example-839. 0.2 g of 4-(((tert-butyldimethylsilyl)oxy)(pyridin-3-yl)methyl)-2-chloro-6-(3-methyl- lH-pyrazol- 1- yl)pyridine gave 4-(((tert-butyldimethylsilyl)oxy)(pyridin-3-yl)methyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine (0.11 g, 45%). MS (M+l)+=514.2.
[001878] Step 5[NSSy5676]: The Procedure is similar to Step 5[NSSy5645] in
Example-811. 0.12 g of 4-(((tert-butyldimethylsilyl)oxy)(pyridin-3-yl)methyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine gave (2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)(pyridin-3-yl)methanol (0.035 g, 37%). MS (M+l)+=401.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 2.04 Hz, 1H), 8.47-8.46 (m, 1H), 8.39 (d, J = 2.40 Hz, 1H), 7.75-7.72 (m, 1H), 7.37-7.34 (m, 1H), 6.92 (d, = 5.08 Hz, 1H), 6.84 (d, = 7.28 Hz, 1H), 6.44 (s, 1H), 6.27 (d, = 2.40 Hz, 1H), 6.18 (t, = 4.16 Hz, 1H), 5.68 (d, = 4.16 Hz, 1H).
Example-813
[001879] Intentionally Omitted: Example-814:
Figure imgf000643_0001
[001880] Step 1: The procedure is similar to Step 1[B] in Example-838. 15 g of 2, 6- dichloroisonicotinonitrile gave 2-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile as white solid (13.6 g, 67%). MS (M+l)+=233.1.
[001881] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 2- chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile as an off-white solid (4 g, 36%). MS (M+l)+=332.0.
[001882] Step 3: To a solution of 2-((4, 4-difluorocyclohexyl)amino)-6-(3, 5-dimethyl- lH-pyrazol-l-yl)isonicotinonitrile ( 4.7 g, 12.07 mmol) in cone. Hydrochloric acid and acetic acid ratio of (8:2) was heated at 100 °C for 16h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with ice water and stirred for 10 min, the solid formed was filtered off and washed with water and dried under vacuum to afford 2-((4, 4-difluorocyclohexyl)amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)isonicotinic acid as a brown solid (4 g, 81%). MS (M+l)+=351.0.
[001883] Step 4: The procedure is similar to Step 3[NSSy6711] in Example-854. 4 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinic acid gave ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinate as yellow solid (3 g, 70%). MS (M+l)+=379.2.
[001884] Step 5[NSSy6355]: The procedure is similar to Step 4[NSSy6711] in
Example-854. 1.6 g of ethyl2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH- pyrazol-l-yl) isonicotinate gave (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH- pyrazol-l-yl) pyridin-4-yl) methanol as brown solid (1.3 g, 88%). MS (M+l)+=337.1; 1H- NMR (400 MHz, DMSO-d6): δ 6.85 (s, 1H), 6.73 (d, J = 7.20 Hz, 1H), 6.36 (s, 1H), 6.03 (s, IH), 5.31-5.28 (m, IH), 4.42 (d, J = 5.60 Hz, 2H), 3.89 (d, J = 5.60 Hz, IH), 2.58 (s, 3H), 2.17 (s, 3H), 2.09-2.07 (m, 2H), 1.97-1.95 (m, 4H), 1.55-1.52 (m, 2H).
[001885] Step 6[NSSy6861]: The procedure is similar to Step 5[NSSy6711] in
Example-854. 0.15 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l- yl) pyridin-4-yl) methanol gave N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l- yl)-4-(methoxymethyl) pyridin-2-amine as white solid (0.14 g, 90%). MS (M+l)+=351.2; 1H-NMR (400 MHz, DMSO-d6): δ 6.84 (s, IH), 6.79 (d, J = 7.48 Hz, IH), 6.32 (s, IH), 6.04 (s, IH), 4.35 (s, 2H), 3.90 (s, IH), 3.34 (s, 3H), 2.59 (s, 3H), 2.17 (s, 3H), 2.10-1.80 (m, 6H), 1.60-1.50 (m, 2H).
Example-815:
Figure imgf000644_0001
[001886] Step 1: The procedure is similar to Step l[NSSy6930] in Example-867. 0.5 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-4-yl) methanol gave 2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinaldehyde as a yellow solid (0.35 g, 70%). MS (M+l)+=335.0.
[001887] Step 2: 2-((4, 4-difluorocyclohexyl)amino)-6-(3, 5-dimethyl- lH-pyrazol- 1- yl)isonicotinaldehyde (0.35 g , 1.04 rnmmol) was added to a stirred mixture of propargyl bromide(0.38 g, 2.61 mmol) and activated zinc dust (0.27 g , 4.18 mmol) in Tetrahydrofuran. The reaction was stirred at room temperature. After lhr, the reaction was quenched with sodium bicarbonate solution and filtered through a celite bed and washed with ethyl acetate. The filtrate was extracted with ethyl acetate and washed with brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified through column chromatography using ethyl acetate in pet-ether as solvent system to afford l-(2-((4, 4-difluorocyclohexyl)amino)-6-(3, 5- dimethyl-lH-pyrazol-l-yl)pyridin-4-yl)but-3-yn-l-ol as an off-white solid (0.25 g, 63%). MS (M+l)+=375.0. [001888] Step 3: To a solution of l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3, 5- dimethyl-lH-pyrazol-l-yl) pyridin-4-yl) but-3-yn- l-ol (0.280 g, 0.53 mmol) in
Dichloromethane was added Imidazole (0.054 g, 0.80 mmol), Tert-butyl dimethylsilyl chloride (0.073 g, 0.47 mmol) at 0 °C and stirred at room temperature. After 5h, the reaction was quenched with ice cold water and extracted with DCM. The combined organic extracts was washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to afford 4-(l-((tert-butyldimethylsilyl)oxy)but-3-yn-l-yl)-N-(4, 4-difluoro cyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine as an off-white solid (0.32 g, 88%). MS (M+l)+=489.2.
[001889] Step 4: To a solution of 4-(l-((tert-butyldimethylsilyl)oxy)but-3-yn-l-yl)-N- (4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine in N, N- Dimethylformamide and water (4: 1) was added Copper (II) Sulfate Pentahydrate, Sodium ascorbate, triethylamine and the reaction mixture was irradiated under microwave at 100 °C for lh. The reaction mixture was filtered through celite bed, washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was diluted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford 4-(l-((tert- butyldimethylsilyl) oxy)-2-(lH-l, 2, 3-triazol-4-yl) ethyl)-N-(4, 4-difluorocyclo hexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-2-amine as a brown gum (0.25 g, 70%). MS
(M+l)+=532.3.
[001890] Step 5: The procedure is similar to Step 5[NSSy6711] in Example-854. 0.25 g of 4-(l-((tert-butyldimethylsilyl)oxy)-2-(lH-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine gave 4-(l-((tert- butyldimethylsilyl)oxy)-2-(2-methyl-2H-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)pyridin-2-amine as a brown oil (0.3 g, crude), MS (M+l)+=546.3.
[001891] Step 6[NSSy7053]: To a solution of 4-(l-((tert-butyldimethylsilyl)oxy)-2-(2- methyl-2H-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH- pyrazol-l-yl)pyridin-2-amine (0.3 g , 0.54 mmol) in tetrahydro furan was added
tetrabutylammonium fluoride (0.21 g, 0.82 mmol) at 0 °C and the reaction mixture was stirred at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered and
concentrated under reduced pressure to afford crude product, which was purified by flash chromatography using ethyl acetate in pet-ether as solvent to afford l-(2-((4, 4- difluorocyclohexyl)amino)-6-(3, 5-dimethyl- IH-pyrazol- l-yl)pyridin-4-yl)-2-(2-methyl-2H- 1, 2, 3-triazol-4-yl) ethan-l-ol as an off-white solid (0.017 g, 10%). MS (M+l)+=432.2; 1H- NMR (400 MHz, DMSO-d6): δ 7.51 (s, IH), 6.92 (s, IH), 6.75 (d, J = 7.20 Hz, IH), 6.35 (s, IH), 6.04 (s, IH), 5.54 (s, IH), 4.71-4.70 (m, IH), 4.07 (m, 3H), 3.89-3.88 (m, IH), 3.19-3.15 (m, IH), 2.96-2.85 (m, 2H), 2.59 (s, 3H), 2.18 (s, 3H), 2.09-2.07 (m, 2H), 1.97-1.85 (m, 3H), 1.61-1.50 (m, 2H).
Example-816:
Figure imgf000646_0001
[001892] Step 1: The procedure is similar to Step 2[NSSy7053] in Example-815. 1.8 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotin aldehyde gave l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) but- 3-yn-l-ol as a colourless oil (1.8 g, 90%). MS (M+l)+=361.0.
[001893] Step 2: The procedure is similar to Step 3[NSSy7053] in Example-815. 1.8 g l-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)but-3-yn-l- ol gave 4-(l-((tert-butyldimethylsilyl)oxy)but-3-yn-l-yl)-N-(4, 4-difluorocyclohexyl)-6-(3- methyl-lH-pyrazol-l-yl)pyridin-2-amine as an off-white solid (2.2 g, 90%). MS
(M+l)+=475.6.
[001894] Step 3: The procedure is similar to Step 4[NSSy7053] in Example-815. 2.2 g of 4-(l-((tert-butyldimethylsilyl)oxy)but-3-yn-l-yl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- lH-pyrazol-l-yl)pyridin-2-amine gave 4-(l-((tert-butyldimethylsilyl)oxy)-2-(lH- 1,2,3- triazol-4-yl)ethyl)-N-(4, 4-difluorocyclo hexyl)-6-(3-methyl- IH-pyrazol- l-yl)pyridin-2- amine as brown gum (2 g, crude). MS (M+l)+=475.2. [001895] Step 4: The procedure is similar to Step 5[NSSy6711] in Example-854. 2 g of 4-(l-((tert-butyldimethylsilyl)oxy)-2-(lH-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine gave mixture of 4-(l- ((tert-butyldimethylsilyl)oxy)-2-(2-methyl-2H-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine, 4-(l-((tert- butyldimethylsilyl)oxy)-2-(l-methyl-lH-l, 2, 3-triazol-5-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine and 4-(l-((tert- butyldimethylsilyl)oxy)-2-(l-methyl-lH-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine as brown oil (1.8 g crude, 6: 1:0.5 by LCMS). MS (M+l)+=532.2.
[001896] Step 5[NSSy7079, 7064, 7065]: The procedure is similar to Step 6[NSSy7053] in Example-815. 1.8 g Mixture of 4-(l-((tert-butyldimethylsilyl)oxy)-2-(2-methyl-2H-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-2- amine, 4-(l-((tert-butyldimethylsilyl)oxy)-2-(l -methyl- lH-1, 2, 3-triazol-5-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine and 4-(l-((tert- butyldimethylsilyl)oxy)-2-(l-methyl-lH-l, 2, 3-triazol-4-yl)ethyl)-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-2-amine gave l-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)-2-(2-methyl-2H-l, 2, 3-triazol-4-yl)ethan-l-ol as white solid (0.041 g, 3%). MS (M+l)+=418.0. l-(2-((4, 4- difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl)-2-(l-methyl-lH-l, 2, 3-triazol-5-yl) ethan-l-ol as an off-white solid (0.14 g, 10%). MS (M+l)+=418.0; l-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)-2-(l-methyl-lH-l, 2, 3-triazol-4-yl)ethan-l-ol as white solid (0.11 g, 10%). MS (M+l)+=418.0.
[001897] [NSSy7063]: 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.50 (s, 1H), 6.95 (s, 1H), 6.75 (d, J = 7.60 Hz, 1H), 6.33 (s, 1H), 6.29 (s, 1H), 5.54 (s, 1H), 4.75-4.70 (m, 1H), 4.06 (s, 3H), 3.97 (bs, 1H), 2.97-2.68 (m, 2H), 2.26 (s, 3H), 2.07-1.95 (m, 6H), 1.56- 1.51 (m, 2H).
[001898] [NSSy7065]: 1H-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.40 Hz, 1H), 7.49 (s, 1H), 6.99 (s, 1H), 6.79 (d, J = 7.60 Hz, 1H), 6.36 (s, 1H), 6.30 (d, J = 2.40 Hz, 1H), 5.69 (d, J = 4.40 Hz, 1H), 4.77-4.73 (m, 1H), 4.01 (s, 1H), 3.92 (s, 3H), 3.07-3.03 (m, 1H), 2.97-2.93 (m, 1H), 2.27 (s, 3H), 2.08-1.95 (m, 6H), 1.60-1.50 (m, 2H).
[001899] [NSSy7079]: 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, = 2.40 Hz, 1H), 7.77 (s, 1H), 6.95 (s, 1H), 6.75 (d, = 7.60 Hz, 1H), 6.32 (s, 1H), 6.29 (d, = 2.40 Hz, 1H), 5.51 (d, J = 4.80 Hz, 1H), 4.72-4.68 (m, 1H), 3.98 (s, 3H), 3.96 (s, 1H), 2.99-2.94 (m, 2H),
2.27 (s, 3H), 2.06-1.85 (m, 6H), 1.60-1.53 (m, 2H).
Example-81
Figure imgf000648_0001
[001900] Step 1: The procedure is similar to Step 3[NSSy6711] in Example-854. 5 g of 4, 6-dichloropicolinic acid gave ethyl 4, 6-dichloropicolinate as colourless oil, (5 g, 87%). MS (M, M+2)+=220.0, 222.0.
[001901] Step 2: The procedure is similar to Step 4[NSSy6464] in Example-869. 0.6 g of ethyl 4, 6-dichloropicolinate gave (4, 6-dichloropyridin-2-yl) (4-fluorophenyl) methanone as an off-white solid (0.97 g, 97%). MS (M, M+2)+=270.0, 272.0.
[001902] Step 3: The procedure is similar to Step 1[B] in Example-2. 0.96 g of (4, 6- dichloropyridin-2-yl) (4-fluorophenyl) methanone gave (6-chloro-4-morpholinopyridin-2-yl) (4-fluorophenyl) methanone as a yellow gum (0.6 g, 54%). MS (M+l)+=321.2.
[001903] Step 4[NSSy6470] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. (LI = (r)-(-)-l- (s)-2-(dicyclohexylphosphino) ferrocenyl ethyl di-t- butylphosphine). 0.3 g of (6-chloro-4-morpholinopyridin-2-yl) (4-fluorophenyl) methanone gave (4-fluorophenyl) (6-(3-methyl-lH-pyrazol-l-yl)-4-morpholinopyridin-2-yl) methanone as a white solid (0.28 g, 82%). MS (M+l)+=367.2; IH-NMR (400 MHz, DMSO-d6): δ 8.24 (d, = 2.0 Hz, 1H), 8.15-8.10 (m, 2H), 7.39 (t, = 17.6 Hz, 3H), 7.33 (d, = 1.6 Hz, 1H), 6.33 (d, = 2.00 Hz, 1H), 3.75-3.74 (m, 4H), 3.45-3.44 (m, 4H), 2.29 (s, 3H).
[001904] Step 5[NSSy6472] : The procedure is similar to Step 2[NSSy6931] in
Example-21. 0.06 g of (4-fluorophenyl) (6-(3-methyl-lH-pyrazol-l-yl)-4-morpholinopyridin- 2-yl) methanone gave (4-fluorophenyl) (6-(3-methyl-lH-pyrazol-l-yl)-4-morpholinopyridin- 2-yl) methanol as white solid (0.055 g, 92%). MS (M+l)+=369.1; IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 8.15-8.10 (m, 2H), 7.51 (t, / = 12.36 Hz, 2H), 7.07 (s, IH), 6.95 (s, IH), 6.30 (s, IH), 6.06-6.05 (m, IH), 5.59-5.58 (m, IH), 3.73 (bs, 4H), 2.26 (s, 3H). Example-818:
Figure imgf000649_0001
[001905] Step l[NSSy6513, 6514]: 0.12 g of (4-fluorophenyl)(6-(3-methyl-lH-pyrazol- l-yl)-4-morpholinopyridin-2-yl)methanol gave (S)-(4-fluorophenyl)(6-(3-methyl- lH-pyrazol- l-yl)-4-morpholinopyridin-2-yl)methanol as a yellow solid (0.055 g) MS (M+l)+=369.1 and (R)-(4-fluorophenyl)(6-(3-methyl- lH-pyrazol- l-yl)-4-morpholinopyridin-2-yl)methanol as a yellow solid (0.055 g), MS (M+l)+=369.1.
[001906] [NSSy6513]: 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.52-7.48 (m, 2H), 7.14-7.06 (m, 3H), 6.95 (s, IH), 6.30 (s, IH), 6.06-6.05 (m, IH), 5.59-5.58 (m, IH), 3.73 (s, 4H), 2.26 (s, 3H).
[001907] [NSSy6514]: 1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 7.52-7.48 (m, 2H), 7.14-7.06 (m, 3H), 6.95 (s, IH), 6.30 (s, IH), 6.06-6.05 (m, IH), 5.59-5.58 (m, IH), 3.73 (s, 4H), 2.25 (s, 3H).
Example-819:
Figure imgf000650_0001
[001908] Step 1: The procedure is similar to Step l[NSSy6930] in Example-867. 3 g of (2, 6-dichloropyridin-4-yl) methanol gave 2, 6-dichloroisonicotinaldehyde as an off-white solid (2.2 g, 75%). MS (M+2)+=178.0.
[001909] Step 2: To a pre-cooled (-78 °C) solution Oxazole (1.47 g, 21.30 mmol) in 2, 2, 6, 6-tetramethylpiperidinylmagnesium chloride lithium chloride complex solution (1.0 M in THF/toluene) (2.67 g, 15.62 mmol) was added a solution of 2, 6- dichloroisonicotinaldehyde (2.5 g, 14.204 mmol) in THF and stirred at same temperature. After lh, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate, filtered and concentrated to afford a crude product, which was purified by column chromatography using 30% ethyl acetate in pet ether as eluent to afford (2, 6-dichloropyridin-4-yl)(oxazol-2-yl)methanol as an off-white gum (2.5 g, 73%). MS (M+l)+=246.0.
[001910] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.6 g of (2, 6-dichloropyridin-4-yl) (oxazol-2-yl) methanol gave (2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyridin-4-yl) (oxazol-2-yl) methanol as off-white gum (0.4 g, 52%). MS (M+l)+=344.0. Table-87: Step 4: The procedure is similar to Step l[NSSy6629] in Example-839.
(Li = (r)-(-)-l- (s)-2-(dicyclohexylphosphino) ferrocenyl ethyl di-i-butylphosphine)
Figure imgf000651_0001
[001911] Step 4[NSSy6473]: IH-NMR (400 MHz, DMSO-d6): δ 8.30 (s, IH), 7.99 (s, IH), 6.92 (s, IH), 6.87 (d, J = 7.40 Hz, IH), 6.47 (s, IH), 6.05 (d, J = 4.72 Hz, IH), 5.54 (d, J = 4.56 Hz, IH), 4.03-3.89 (m, IH), 2.50 (s, 3H), 2.09 (s, 3H), 2.07-1.86 (m, 6H), 1.58-1.52 (m, 2H).
[001912] Step 4[NSSy6563]: IH-NMR (400 MHz, DMSO-d6): δ 8.29 (s, IH), 8.00 (s, IH), 7.25 (d, J = 8.80 Hz, 2H), 6.83 (d, J = 6.80 Hz, IH), 6.65 (s, IH), 6.06 (d, J = 4.80 Hz, IH), 5.56 (d, J = 4.80 Hz, IH), 3.91 (m, IH), 2.39 (s, 3H), 2.04-1.88 (m, 6H), 1.63-1.56 (m, 2H).
[001913] Step 4[NSSy6435]: IH-NMR (400 MHz, DMSO-d6): δ 8.60 (d, J = 3.60 Hz, IH), 8.30 (d, J = 0.80 Hz, IH), 7.99 (s, IH), 7.80 (d, J = 4.00 Hz, IH), 6.99 (s, IH), 6.91 (d, J = 7.60 Hz, IH), 6.49 (s, IH), 6.08 (d, J = 4.80 Hz, IH), 5.55 (d, J = 4.40 Hz, IH), 4.07-4.05 (m, IH), 2.10-1.95 (m, 6H), 1.58-1.54 (m, 2H).
Example-820:
Figure imgf000652_0001
[001914] Step 1: To a solution of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile (0.1 g, 0.368 mmol) in HCl in methanol (3M solution) (3mL) is heated at 80 °C in sealed tube for 16h. The reaction mixture was concentrated under reduced pressure to afford methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinate as an off-white solid (0.1 g, 90%). MS (M+l)+=305.2.
[001915] Step 2: The procedure is similar to Step 1[H] in Example-838. 0.7 g of methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinate gave methyl 2-((4, 4- difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinate as an off-white solid (0.52 g, 61%). MS (M+l)+=368.1.
[001916] Step 3[NSSy6730]: The procedure is similar to Step 4[NSSy6711] in
Example-854. 0.5 g of methyl 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinate gave (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4- yl) methanol as pale yellow solid (0.43 g, 93%). MS (M+l)+=340.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.27 (s, 1H), 7.19 (s, 1H), 6.75 (d, J = 6.80 Hz, 1H), 6.55 (s, 1H), 5.32 (t, J = 5.60 Hz, 1H), 4.44 (d, J = 5.60 Hz, 2H), 3.90 (s, 1H), 2.40 (s, 3H), 2.15-1.85 (m, 6H), 1.65- 1.55 (m, 2H).
[001917] Step 4: The procedure is similar to Step l[NSSy6930] in Example-867. 0.4 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) methanol gave 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinaldehyde as yellow solid (0.27 g, 70%). MS (M+l)+=338.0.
[001918] Step 5[NSSy6750]: The procedure is similar to Step 4[NSSy6067] in
Example-628. 0.25 g of 2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)isonicotinaldehyde gave (2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)pyridin-4-yl)(5-methyl-l, 3, 4-oxadiazol-2-yl)methanol as an off-white solid (0.006 g, 15%). MS (M+l)+=422.4; IH-NMR (400 MHz, DMSO-d6): δ 7.30 (s, IH), 7.25 (s, IH), 6.97 (d, J = 7.20 Hz, IH), 6.83 (d, J = 5.20 Hz, IH), 6.68 (s, IH), 5.95 (d, J = 5.20 Hz, IH), 3.91 (s, IH), 2.48 (s, 3H), 2.40 (s, 3H), 2.15-1.90 (m, 6H), 1.62-1.52 (m, 2H).
Example-821:
Figure imgf000653_0001
[001919] Step 1 [NSSy6782] : The procedure is similar to Step 4[NSSy6067] in Example-628. 2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)isonicotinaldehyde gave l-(2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)pyridin-4-yl)-2-(l, 3, 4-oxadiazol-2-yl)ethan-l-ol as an off-white (0.03 g, 20%). MS (M+l)+=422.4; IH-NMR (400 MHz, DMSO-d6): δ 9.16 (s, IH), 7.30 (d, J = 0.80 Hz, 2H), 6.83 (d, J = 6.80 Hz, IH), 6.57 (s, IH), 5.86 (s, IH), 4.97-4.93 (m, IH), 3.89 (s, IH), 3.30- 3.15 (m, 2H), 2.42 (s, 3H), 2.18-1.90 (m, 6H), 1.62-1.50 (m, 2H).
Example-822:
[001920] Intentionally Omitted
Example-823:
Figure imgf000653_0002
[001921] Step 1: The procedure is similar to Step 1[B] in Example-838. 15 g of 2, 4, 6- trichloropyridine gave ethyl l-(4, 6-dichloropyridin-2-yl)-4-methyl-lH-pyrazole-3- carboxylate as white solid (6 g, 25%). MS (M, M+2)+=300.0, 302.1.
[001922] Step 2: The procedure is similar to Step 4[NSSy6711] in Example-854. 2.25 g of ethyl l-(4, 6-dichloropyridin-2-yl)-4-methyl-lH-pyrazole-3-carboxylate gave (l-(4, 6- dichloropyridin-2-yl)-4-methyl-lH-pyrazol-3-yl) methanol as off-white solid (1.12 g, 85%). MS (M, M+2)+=258.0, 260.1.
[001923] Step 3: The procedure is similar to Step 3[NSSy6917] in Example-21. 1.12 g of (l-(4, 6-dichloropyridin-2-yl)-4-methyl-lH-pyrazol-3-yl) methanol gave 2, 4-dichloro-6- (3-(fluoromethyl)-4-methyl-lH-pyrazol-l-yl) pyridine as white solid (0.65 g, 60%). MS (M, M+2)+=260.0, 262.1.
[001924] Step 4: The procedure is similar to Step l[NSSy6629] in Example-839. 0.65 g of 2, 4-dichloro-6-(3-(fluoromethyl)-4-methyl-lH-pyrazol-l-yl)pyridine gave 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-(fluoromethyl)-4-methyl- IH-pyrazol- l-yl)pyridin-2-amine as an off-white solid (0.22 g, 24%). MS (M+l)+=359.2.
[001925] Step 5[NSSy5615]: The procedure is similar to Step l[NSSy6909] in
Example-839. 0.2 g of 4-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-(fluoromethyl)-4-methyl- lH-pyrazol-l-yl)pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-6-(3-(fluoromethyl)-4- methyl-lH-pyrazol-l-yl)-4-(oxetan-3-yloxy)pyridin-2-amine as an off-white solid (0.032 g, 14%). MS (M+l)+=397.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 6.80 (d, J = 7.52 Hz, 1H), 6.43 (d, J = 1.72 Hz, 1H), 5.68 (s, 1H), 5.48 (s, 1H), 5.35 (s, 1H), 5.33-5.30 (m, 1H), 4.89 (t, J = 6.72 Hz, 2H), 4.56 (dd, J = 4.80, 7.28 Hz, 2H), 3.98 (s, 1H), 2.13 (s, 3H), 2.08- 1.94 (m, 6H), 1.57-1.51 (m, 2H).
Example-824:
[001926] Intentionally Omitted
Exampl -825:
Figure imgf000655_0001
[001927] Step 1: The procedure is similar to Step 1[B] in Example-838. 10 g of 2, 4, 6- trichloropyridine gave 2, 4-dichloro-6-(3-methyl-lH-pyrazol-l-yl) pyridine as white solid (5.8 g, 46%). MS (M, M+2)+=228.0, 230.2 and 2, 6-dichloro-4-(3-methyl-lH-pyrazol-l- yl)pyridine as white solid (2.1 g, 20%). MS (M, M+2)+=228.0, 230.2.
[001928] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 3 g of 2, 4-dichloro-6-(3-methyl-lH-pyrazol-l-yl) pyridine gave 4-chloro-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine as colourless liquid (1.3 g, 30%). MS (M+l)+=327.2 and 2-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-amine as yellow gum (0.3 g, 10%). MS (M+l)+=327.2.
Table-89: Step 3:
Figure imgf000655_0002
Figure imgf000656_0001
Dioxane, 120 °C, MW, 3h
[001929] Step 3[NSSy5641]: The procedure is similar to Step l[NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 8.43 (s, IH), 8.33 (d, J = 2.32 Hz, IH), 6.75 (d, J = 7.28 Hz, IH), 6.55 (s, IH), 6.34 (t, J = 2.32 Hz, 2H), 5.26 (s, 2H), 3.98 (s, IH), 3.84 (s, 3H), 2.24 (s, 3H), 1.98-1.91 (m, 6H), 1.55-1.50 (m, 2H).
[001930] Step 3[NSSy5737]: The procedure is similar to Step l[NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, IH), 7.96 (s, IH), 6.79 (d, J = 7.60 Hz, IH), 6.65 (d, J = 2.00 Hz, IH), 6.29 (d, J = 2.40 Hz, IH), 5.98 (d, J = 2.00 Hz, IH), 5.35 (s, 2H), 3.96-3.91 (m, 4H), 2.26 (s, 3H), 2.08-1.95 (m, 6H), 1.55-1.52 (m, 2H).
[001931] Step 3[NSSy5643]: The procedure is similar to Step l[NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 8.33 (s, IH), 7.78 (s, IH), 6.81 (d, J = 7.60 Hz, IH), 6.58 (s, IH), 6.39 (s, IH), 6.34 (s, IH), 5.46 (s, 2H), 4.06 (s, 3H), 3.80-3.93 (m, IH), 2.24 (s, 3H), 2.08-1.92 (m, 6H), 1.57-1.52 (m, 2H).
[001932] Step 3[NSSy5681]: The procedure is similar to Step l[NSSy6909] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.35 (d, J = 2.40 Hz, IH), 6.84 (d, J = 7.60 Hz, IH), 6.59 (d, J = 1.60 Hz, IH), 6.42 (d, J = 1.60 Hz, IH), 6.34 (d, J = 2.80 Hz, IH), 5.49 (s, 2H), 3.92-3.82 (m, IH), 3.32 (s, 3H), 2.25 (s, 3H), 2.08-1.85 (m, 6H), 1.49-1.46 (m, 2H).
[001933] Step 3[NSsy6849]: The procedure is similar to Step l[NSSy6629] in Example- 839. IH-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.00 Hz, IH), 7.91 (s, IH), 6.70 (d, J = 7.60 Hz, IH), 6.50 (dd, J = 1.60, 16.60 Hz, IH), 6.28 (d, J = 2.00 Hz, IH), 5.84 (s, IH), 4.72- 4.67 (m, 2H), 4.40 (t, J = 4.80 Hz, 2H), 3.94 (s, IH), 2.37 (s, IH), 2.25 (s, 3H), 2.23 (s, 2H), 2.05-1.90 (m, 6H), 1.60-1.42 (m, 2H).
[001934] Step 3[NSsy6719]: The procedure is similar to Step l[NSSy6629] in Example- 839. IH-NMR (400 MHz, DMSO-d6): δ 8.37 (s, IH), 7.54 (s, IH), 6.67 (s, IH), 6.46 (s, IH), 6.27 (s, IH), 5.83 (s, IH), 4.70 (s, 2H), 4.47 (s, 2H), 3.95 (s, IH), 2.23 (d, J = 5.60 Hz, 6H), 1.99 (d, J = 34.40 Hz, 6H), 1.53 (s, 2H).
[001935] Step 3[NSSy5763]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.35 (d, J = 2.00 Hz, IH), 6.30 (d, J = 1.64 Ηζ,ΙΗ), 6.23 (d, J = 2.40 Hz, IH), 6.13 (d, J = 1.60 Hz, IH), 5.29 (d, J = 1.60 Hz, IH), 4.00- 3.85 (m, 3H), 3.70-3.60 (m, 2H), 3.22-3.15 (m, IH), 2.24 (s, 3H), 2.11 (s, 6H), 2.10-1.85 (m, 6H), 1.62-1.45 (m, 2H).
[001936] Step 3[NSSy6573]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.40 Hz, IH), 6.61 (d, J = 1.64 Hz, IH), 6.38 (d, J = 7.64 Hz, IH), 6.25 (d, J = 2.40 Hz, IH), 5.76 (d, J = 1.72 Hz, IH), 3.95 (s, IH), 3.72 (t, J = 4.92 Hz, 4H), 3.19 (t, J = 4.68 Hz, 4H), 2.19 (s, 3H), 2.04-1.90 (m, 6H), 1.60-1.51 (m, 2H).
[001937] Step 3[NSSy5721]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 8.36 (d, J = 2.40 Hz, IH), 6.32 (d, J = 7.60 Hz, IH), 6.24 (d, J = 2.40 Hz, IH), 6.13 (d, = 1.60 Hz, IH), 5.63 (s, IH), 5.31 (d, = 2.00 Hz, IH), 3.92 (m, IH), 3.80-3.78 (m, 2H), 3.70-3.68 (m, 2H), 2.25 (s, 3H), 2.07-1.92 (m, 6H), 1.53-1.51 (m, 2H), 1.44 (s, 3H). Example-826:
Figure imgf000658_0001
[001938] Step l[NSSy5638]: The procedure is similar to Step l[NSSy5828] in Example-799. 0.3 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-((l-methyl-lH-l, 2, 4-triazol-5- yl)methoxy)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-amine as an off-white solid (0.015 g, 10%). MS (M+l)+=404.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.34 (d, J = 2.48 Hz, 1H), 7.90 (s, 1H), 6.80 (d, J = 7.52 Hz, 1H), 6.58 (d, J = 1.52 Hz, 1H), 6.41 (d, J = 1.52 Hz, 1H), 6.34 (d, J = 2.44 Hz, 1H), 5.47 (s, 2H), 3.90 (s, 4H), 2.24 (s, 3H), 2.12-1.82 (m, 6H), 1.55- 1.45 (m, 2H).
Example-827:
Figure imgf000658_0002
[001939] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 1.4 g of 2, 4-dichloro-6-(3-methyl-lH-pyrazol-l-yl) pyridine gave 4-((4-chloro-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-yl) amino) cyclohexan-l-ol as an off-white solid (0.3 g, 15%). MS (M+l)+=307.1.
[001940] Step 2: The procedure is similar to Step 3[NSSy6917] in Example-21. 0.3 g of 4-((4-chloro-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-yl) amino) cyclohexan-l-ol gave 4- chloro-N-(cyclohex-3-en-l-yl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine as an off-white solid (0.11 g, 39%). MS (M+l)+=289.0.
[001941] Step 3[NSSy5759]: The procedure is similar to Step l[NSSy6629] in
Example-839. 0.1 g of 4-chloro-N-(cyclohex-3-en- l-yl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine gave N-(cyclohex-3-en- l-yl)-6-(3-methyl- lH-pyrazol- l-yl)-4-morpholino pyridin-2-amine as a yellow solid (0.035 g, 31%). MS (M+l)+=340.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 2.00 Hz, 1H), 6.59 (d, J = 1.60 Hz, 1H), 6.24 (t, J = 3.20 Hz, 2H), 5.78 (d, J = 1.60 Hz, 1H), 5.66 (s, 2H), 3.93 (s, 1H), 3.71 (t, J = 4.80 Hz, 4H), 3.19 (t, J = 4.80 Hz, 4H), 2.36 (d, J = 10.00 Hz, 1H), 2.25 (s, 3H), 2.14 (s, 2H), 1.96-1.93 (m, 2H), 1.49- 1.41 (m, 1H).
Example-828:
Figure imgf000659_0001
[001942] Step 1: The procedure is similar to Step 5[NSSy5779] in Example-642. 8 g gave 4, 6-dichloropicolinonitrile gave 4, 6-dichloropyridine-2-carbothioamide as yellow solid (6.2 g, 66%). MS (M+l)+=208.2.
[001943] Step 2: The procedure is similar to Step 6[NSSy5779] in Example-642. 6 g of 4, 6-dichloropyridine-2-carbothioamide gave 2-(4, 6-dichloropyridin-2-yl)-4-methylthiazole as off-white solid (6 g, 84%). MS (M, M+2)+=245.0, 247.0. [001944] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 1 g of 2-(4, 6-dichloropyridin-2-yl)-4-methylthiazole gave 4-chloro-N-(4, 4-difluorocyclohexyl)-6- (4-methylthiazol-2-yl) pyridin-2-amine as yellow solid (0.55 g, 39%). MS (M+l)+=344.1.
Table-90: Step 4:
Figure imgf000660_0001
Figure imgf000661_0001
[001945] Step 4[NSSy5824] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.26 (s, IH), 6.95 (s, IH), 6.40 (d, J = 6.80 Hz, IH), 5.96 (s, IH), 4.42 (t, J = 28.00 Hz, IH), 4.04-4.00 (m, 2H), 3.95-3.88 (m, 3H), 3.66 (dd, J = 2.80, 13.00 Hz, IH), 3.14-3.07 (m, IH), 2.87-2.75 (m, 2H), 2.40 (s, 3H), 2.00-1.90 (m, 6H), 1.62-1.57 (m, 2H).
[001946] Step 4[NSSy5838] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.27 (d, J = 0.84 Hz, IH), 6.95 (d, J = 1.92 Hz, IH), 6.41 (d, J = 7.12 Hz, IH), 5.96 (d, J = 1.92 Hz, IH), 4.41 (t, J = 8.48 Hz, IH), 4.04- 4.01 (m, 2H), 3.91-3.79 (m, 3H), 3.66 (dd, J = 2.68, 13.06 Hz, IH), 2.40 (s, 3H), 2.15-1.85 (m, 6H), 1.59-1.56 (m, 2H).
[001947] Step 4[NSSy5837] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.25 (s, IH), 6.94 (s, IH), 6.39 (d, J = 7.20 Hz, IH), 5.95 (s, IH), 4.40 (t, J = 8.80 Hz, IH), 4.03-3.99 (m, 2H), 3.95-3.75 (m, 3H), 3.67- 3.63 (m, IH), 3.12-3.06 (m, IH), 2.85-2.74 (m, 2H), 2.39 (s, 3H), 2.15-1.85 (m, 6H), 1.61- 1.56 (m, 2H).
[001948] Step 4[NSSy5819] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.24 (s, IH), 6.91 (s, IH), 6.36 (d, J = 7.2 Ηζ,ΙΗ), 5.92 (s, IH), 4.57 (t, J = 6.4 Hz, 2H), 4.76 (t, J = 6.0 Hz, 2H), 3.83-3.79 (bs, IH), 3.50-3.40 (m, IH), 3.30-3.25 (m, 4H), 2.45-2.35 (m, 7H), 2.20-1.80 (m, 6H), 1.15-1.10 (m, 2H). [001949] Step 4[NSSy5815] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.23 (s, IH), 6.90 (s, IH), 6.30 (d, J = 6.8 Hz, IH), 5.92 (s, IH), 4.60 (t, J = 6.0 Hz, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.83-3.79 (m, 3H), 2.82 (t, J = 11.6 Hz, 2H), 2.70-2.67 (m, IH), 2.39 (s, 3H), 2.20-1.80 (m, 7H), 1.70-1.50 (m, 4H), 1.15-1.00 (m, 2H).
[001950] Step 4[NSSy6288] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.25 (s, IH), 6.75 (d, J = 2.00 Hz, IH), 6.35 (d, J = 7.20 Hz, IH), 5.61 (d, J = 1.60 Hz, IH), 4.88-4.83 (m, IH), 4.79 (t, J = 7.20 Hz, 2H), 4.65 (t, J = 6.00 Hz, 2H), 3.87 (s, IH), 2.96 (s, 3H), 2.41 (s, 3H), 2.15-1.85 (m, 6H), 1.62-1.50 (m, 2H).
[001951] Step 4[NSSy5646]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.25 (s, IH), 6.92 (s, IH), 6.38 (d, J = 7.04 Hz, IH), 5.93 (s, IH), 3.88-3.82 (m, 4H), 3.21 (m, 4H), 2.40 (s, 3H), 2.07-1.90 (m, 6H), 1.59- 1.56 (m, 2H).
[001952] Step 4[NSSy5675]: The procedure is similar to Step l[NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.24 (s, IH), 6.44 (d, J = 1.64 Hz, IH), 6.35 (d, J = 7.00 Hz, IH), 5.47 (s, IH), 4.72-4.69 (m, 4H), 4.06-3.93 (m, 4H), 3.84-3.81 (m, IH), 2.33 (s, 3H), 2.06-1.88 (m, 6H), 1.59-1.54 (m, 2H).
[001953] Step 4[NSSy5807] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.25 (s, IH), 6.91 (s, IH), 6.43 (d, J = 7.04 Hz, IH), 5.94 (s, IH), 4.13-4.09 (m, IH), 3.94-3.93 (m, 2H), 3.62-3.39 (m, 4H), 3.46- 3.42 (m, 2H), 3.30 (s, 3H), 2.91-2.85 (s, IH), 2.67 (t, J = 11.48 Hz, IH), 2.40 (s, 3H), 2.08- 1.97 (m, 6H), 1.58-1.56 (m, 2H).
[001954] Step 4[NSSy5695] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 7.96 (s, IH), 7.31 (d, J = 1.00 Hz, IH), 6.96 (d, J = 2.08 Hz, IH), 6.79 (d, J = 6.96 Hz, IH), 6.17 (d, J = 2.08 Hz, IH), 5.37 (s, 2H), 3.91 (s, 3H), 3.89-3.88 (m, IH), 2.41 (s, 3H), 2.07-1.99 (m, 6H), 1.65-1.52 (m, 2H).
[001955] Step 4[NSSy5686] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 8.17 (s, IH), 7.30 (s, IH), 6.90 (d, J = 2.00 Hz, IH), 6.71 (d, J = 7.20 Hz, IH), 6.16 (d, J = 2.00 Hz, IH), 5.20 (s, 2H), 4.05 (s, 3H), 3.85 (s, IH), 2.32 (s, 3H), 2.02-1.99 (m, 6H), 1.59-1.56 (m, 2H).
[001956] Step 4[NSSy5717] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 7.85 (s, IH), 7.31 (s, IH), 6.91 (d, J = 1.60 Hz, IH), 6.73 (d, J = 7.20 Hz, IH), 6.15 (d, J = 1.60 Hz, IH), 5.21 (s, 2H), 4.17 (s, 3H), 3.91- 3.88 (m, IH), 2.33 (s, 3H), 2.08-1.91 (m, 6H), 1.62-1.57 (m, 2H).
[001957] Step 4[NSSy5680] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. IH-NMR (400 MHz, DMSO-d6): δ 8.17 (s, IH), 7.30 (s, IH), 6.91 (d, J = 1.88 Hz, IH), 6.71 (d, J = 7.08 Hz, IH), 6.17 (d, J = 1.92 Hz, IH), 5.20 (s, 2H), 4.06 (s, 3H), 3.86 (s, IH), 2.33 (s, 3H), 2.07-1.91 (m, 6H), 1.62-1.57 (m, 2H).
[001958] Step 4[NSSy5694] : The procedure is similar to Step 1 [NSSy6909] in
Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.33 (s, IH), 6.95 (d, J = 2.00 Hz, IH), 6.82 (d, J = 6.80 Hz, IH), 6.16 (d, J = 2.00 Hz, IH), 5.45 (s, 2H), 4.08-3.87 (m, IH), 2.61 (s, 3H), 2.38 (s, 3H), 2.03-2.00 (m, 6H), 1.73-1.52 (m, 2H).
Example-829:
Figure imgf000663_0001
Figure imgf000663_0002
NSSy5677 NSSy5687
Table-91: Step 1: The procedure is similar to Step l[NSSy6909] in Example-839.
Figure imgf000663_0003
Table-92: Step 2: The procedure is similar to Step l[NSSy6629] in Example-839.
Figure imgf000664_0002
[001959] Step 2[NSSy5677]: 1H-NMR (400 MHz, DMSO-d6): δ 7.24 (s, IH), 6.46 (s,
IH), 6.32 (d, J = 6.80 Hz, IH), 5.47 (s, IH), 3.97-3.93 (m, 2H), 3.84 (s, IH), 3.66-3.63 (m,
2H), 3.20-3.19 (m, IH), 2.39 (s, 3H), 2.12-1.97 (m, 12H), 1.58-1.55 (m, 2H).
[001960] Step 2[NSSy5687]: 1H-NMR (400 MHz, CDC13): δ 9.10 (s, IH), 6.92 (s, IH),
6.68 (s, IH), 6.46-6.32 (m, IH), 5.34 (s, IH), 4.24 (s, IH), 3.99-3.90 (m, 4H), 2.53 (s, 3H),
2.15-1.91 (m, 6H), 1.65-1.58 (m, 2H), 1.58 (s, 3H).
Example-830:
Figure imgf000664_0001
[001961] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 2-(4, 6- dichloropyridin-2-yl)-4-methylthiazole gave methyl 3-((2-chloro-6-(4-methylthiazol-2-yl) pyridin-4-yl) oxy) azetidine-l-carboxylate as white solid (0.2 g, 29%). MS (M+l)+=340.2.
[001962] Step 2[NSSy5980] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. 0.18 g of methyl 3-((2-chloro-6-(4-methylthiazol-2-yl)pyridin-4- yl)oxy)azetidine-l-carboxylate as white solid gave methyl 3-((2-((4-methylcyclohex-3-en-l- yl)amino)-6-(4-methylthiazol-2-yl)pyridin-4-yl)oxy)azetidine-l-carboxylate as white solid (0.019 g, 8%). MS (M+l)+=415.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.28 (d, J = 3.60 Hz, IH), 6.70 (s, IH), 6.57 (s, IH), 5.89-5.85 (d, J =12.40 Hz, IH), 5.35 (s, IH), 5.06 (s,
IH), 4.33 (s, 2H), 3.89 (s, 2H), 3.68 (s, IH), 3.57 (s, 3H), 2.39 (s, 3H), 2.09-1.94 (m,
4H), 1.81-1.55 (m, 5H). Example-831:
Figure imgf000665_0001
[001963] Step 1 : The procedure is similar to Step 1 [B] in Example-838. 1.5 g of 2-(4, 6-dichloropyridin-2-yl)-4-methylthiazole gave 4-(2-chloro-6-(4-methylthiazol-2-yl) pyridin- 4-yl) morpholine as a white solid (0.6 g, 62%). MS (M+l)+=295.9.
[001964] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 0.15 g of 4-(2-chloro-6-(4-methylthiazol-2-yl) pyridin-4-yl) morpholine gave 4-((6-(4- methylthiazol-2-yl)-4-morpholinopyridin-2-yl) amino) cyclohexan- l-ol as a white solid (0.09 g, 47%). MS (M+l)+=374.1.
[001965] Step 3[NSSy5655]: The procedure is similar to Step 3[NSSy6917] in
Example-21. 0.1 g of 4-((6-(4-methylthiazol-2-yl)-4-morpholinopyridin-2-yl) amino) cyclohexan- l-ol gave N-(cyclohex-3-en- l-yl)-6-(4-methylthiazol-2-yl)-4-morpholinopyridin- 2-amine as a yellow solid (0.03 g, 32%). MS (M+l)+=357.2; IH-NMR (400 MHz, DMSO- d6): δ 7.23 (d, J = 0.88 Hz, 1H), 6.90 (d, J = 1.92 Hz, 1H), 6.24 (d, J = 7.28 Hz, 1H), 5.92 (d, J = 1.92 Hz, 1H), 5.67-5.55 (m, 2H), 3.93-3.73 (m, 1H), 3.72-3.70 (m, 4H), 3.21-3.20 (m, 4H), 2.42 (s, 3H), 2.14-1.97 (m, 4H), 1.52-1.51 (m, 1H).
Example-832:
Figure imgf000665_0002
Table-93: Step 1:
Figure imgf000666_0002
[001966] Step 1 [NSSy5688] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. MS (M+l)+=377.2; IH-NMR (400 MHz, DMSO-d6): δ 7.24-7.23 (m, IH), 6.90 (d, J = 2.00 Hz, IH), 6.53 (s, IH), 6.30-6.23 (m, IH), 5.93-5.90 (m, IH), 4.84 (s, IH), 3.73-3.72 (m, 4H), 3.37-3.36 (m, 4H), 2.39 (s, 3H), 2.09-1.92 (m, 4H), 1.83-1.78 (m, 2H), 1.63-1.60 (m, 2H).
[001967] Step 1 [NSSy6285] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. MS (M+l)+=396.1; IH-NMR (400 MHz, DMSO-d6-80 °C): δ 7.34 (s,
IH), 7.23 (s, IH), 6.25 (s, IH), 5.16 (bs, IH), 3.72-3.32 (m, 4H), 2.68-2.67 (m, 4H), 2.42 (s,
3H), 2.20-1.97 (m, 6H), 1.96-1.85 (m, 2H).
Example-833:
Figure imgf000666_0001
[001968] Step 1: The procedure is similar to Step l[NSSy6909] in Example-839. 1.0 g of 2-(4, 6-dichloropyridin-2-yl)-4-methylthiazole gave 4-(2-chloro-6-(4-methylthiazol-2-yl) pyridin-4-yl)-l-methylpiperazin-2-one as a pale yellow solid (0.3 g, 23%). MS
(M+l)+=322.0.
[001969] Step 2[NSSy5674] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. 0.3 g of 4-(2-chloro-6-(4-methylthiazol-2-yl) pyridin-4-yl)-l-methylpiperazin- 2-one gave 4-(2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl)-l- methylpiperazin-2-one as a pale yellow solid (0.095 g, 23%). MS (M+l)+=422.2; IH-NMR (400 MHz, DMSO-d6): δ 7.26 (s, IH), 6.90 (s, IH), 6.38 (d, J = 7.20 Hz, IH), 5.88 (s, IH), 3.87-3.85 (m, 3H), 3.60-3.58 (m, 2H), 3.45-3.43 (m, 2H), 2.86 (s, 3H), 2.34 (s, 3H), 2.07-
1.91 (m, 6H), 1.61-1.56 (m, 2H).
Example-834:
Figure imgf000667_0001
[001970] Step 1: The procedure is similar to Step 5[NSSy5779] in Example-642. 5.0 g of 2, 6-dichloroisonicotinonitrile gave 2, 6-dichloropyridine-4-carbothioamide as a yellow solid (4.1 g, 66%). MS (M+l)+=207.0.
[001971] Step 2: To a stirred solution of 2, 6-dichloropyridine-4-carbothioamide (1 g, 4.82 mmol) in Acetonitrile(20 mL), was added Bromoacetone (0.99 g, 7.24 mmol) and N, N- Diisopropyl ethylamine (1.24 g, 9.65 mmol). The reaction mixture was stirred at room temperature for lh. To the above reaction mixture was added N, N-Diisopropyl ethylamine (0.93 g, 7.24 mmol) and Trifluoro acetic anhydride (2.02 g, 9.65 mmol). The reaction mixture was stirred at room temperature. The reaction mixture was extracted with ethyl acetate (100 mL), the organic layer was washed with saturated sodium bicarbonate solution (20 mL), and brine solution (20 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash column chromatography using ethyl acetate in pet ether as solvent. The product spot was isolated with 10% ethyl acetate in pet ether to afford 2-(2, 6-dichloropyridin-4-yl)-4-methylthiazole as an off-white solid (0.9 g, 76%). MS (M+l)+=245.0.
[001972] Step 3: The procedure is similar to Step 1[B] in Example-838. 0.6 g of 2-(2, 6-dichloropyridin-4-yl)-4-methylthiazole gave 4-(6-chloro-4-(4-methylthiazol-2-yl) pyridin- 2-yl) morpholine as an off-white solid (0.3 g, 41%). MS (M+l)+=296.0.
[001973] Step 4[NSSy6374] : The procedure is similar to Step 1 [NSSy5828] in
Example-799. 0.25 g of 4-(6-chloro-4-(4-methylthiazol-2-yl) pyridin-2-yl) morpholine gave 4-(6-((4, 4-difluorocyclohexyl) oxy)-4-(4-methylthiazol-2-yl) pyridin-2-yl) morpholine as a brownish gum (0.068 g, 18%). MS (M+l)+=396.1; IH-NMR (400 MHz, DMSO-d6): δ 7.45 (s, IH), 6.76 (s, IH), 6.52 (s, IH), 5.16 (s, IH), 3.72 (s, 4H), 3.49 (s, 4H), 2.44 (s, 3H), 1.98- 1.86 (m, 8H).
Example-835:
Figure imgf000668_0001
[001974] Step 1: The procedure is similar to Step 3[NSSy6711] in Example-854. 10.0 g of 4, 6-dichloropicolinic acid gave methyl 4, 6-dichloropicolinate as white solid (9 g, 85%). MS (M+l)+=208.2.
[001975] Step 2: The procedure is similar to Step 1[B] in Example-838. 5.0 g of methyl 4, 6-dichloropicolinate gave 5-(4, 6-dichloropyridin-2-yl)-3-methyl-l, 2, 4-oxadiazole as white solid (2.2 g, 40%). MS (M+l)+=231.7.
[001976] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 5-(4, 6-dichloropyridin-2-yl)-3-methyl-l, 2, 4-oxadiazole gave 4-chloro-N-(4, 4- difluorocyclohexyl)-6-(3-methyl-l, 2, 4-oxadiazol-5-yl) pyridin-2-amine as colourless gum (0.24 g, 33%). MS (M+l)+=328.9.
Table-94: Step 4:
Figure imgf000668_0002
[001977] Step 4[NSSy5959]: The procedure is similar to Step 1[B] in Example-838 (M+l)+=424.2; IH-NMR (400 MHz, DMSO-d6): δ 6.97 (d, J = 7.20 Hz, IH), 6.87 (d, J 2.00 Hz, 1H), 6.06 (d, J = 2.00 Hz, 1H), 5.12-5.09 (m, 1H), 4.36 (s, 2H), 3.93 (s, 3H), 3.59 (s, 3H), 2.42 (s, 3H), 2.08-1.96 (m, 6H), 1.60-1.53 (m, 2H).
[001978] Step 1 [NSSy5957] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. MS (M+l)+=380.9; IH-NMR (400 MHz, DMSO-d6): δ 7.03 (s, 1H), 6.57 (d, J = 8.00 Hz, 1H), 6.05 (s, 1H), 3.95 (s, 1H), 3.71 (t, J = 4.80 Hz, 4H), 3.22 (t, J = 4.40 Hz, 4H), 2.39 (s, 3H), 2.04-1.92 (m, 6H), 1.60-1.50 (m, 2H).
Example-836:
Figure imgf000669_0001
[001979] Step 1: To a stirred solution of 3, 5-dimethylbenzonitrile (5 g, 38.11 mmol) in carbontetrachloride (50 mL), was added N-Bromosuccinimide (6.78 g, 38.11 mmol) and benzoyl peroxide (0.46 g, 1.90 mmol). The reaction mixture was refluxed under 200
W tungsten lamp for 3h. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure. The residue was crystallized from diethyl ether (10 mL) and hexane (40 mL) to afford 3-(bromomethyl)-5-methylbenzonitrile as white solid (2.5 g, 31%). MS (M+l)+=211.0.
[001980] Step 2: The procedure is similar to Step 1 [B] in Example-838. 1.0 g of 3- (bromomethyl)-5-methylbenzonitrile gave 3-((4, 4-difluoropiperidin-l-yl) methyl)-5- methylbenzonitrile as a pale yellow solid (0.9 g, 75%). MS (M+l)+=251.0.
[001981] Step 3: The procedure is similar to Step 5[NSSy5779] in Example-642. 0.3 g of 3-((4, 4-difluoropiperidin-l-yl) methyl)-5-methylbenzonitrile gave 3-((4, 4- difluoropiperidin-l-yl) methyl)-5-methylbenzothioamide as a brownish gum (0.3 g, 88%). MS (M+l)+=285.0.
[001982] Step 4[NSSy6044] : The procedure is similar to Step 6[NSSy5779] in
Example-642. 0.3 g of 3-((4, 4-difluoropiperidin-l-yl) methyl)-5-methylbenzothioamide gave 2-(3-((4, 4-difluoropiperidin-l-yl) methyl)-5-methylphenyl)-4-methyl thiazole as a colourless gum (0.16 g, 47%). MS (M+l)+=323.0; IH-NMR (400 MHz, DMSO-d6): δ 7.63 (d, J =15.2 Hz, 2H), 7.26 (d, J = 35.6 Hz, 2H), 3.55 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 1.99- 1.95 (m, 4H).
Example-837:
Figure imgf000670_0001
[001983] Step 1: The procedure is similar to Step 1[B] in Example-838. 3.0 g of 4, 6- dichloro-lH-imidazo [4, 5-c] pyridine gave 4, 6-dichloro-l-(oxetan-3-yl)-lH-imidazo [4, 5-c] pyridine as light brown solid (2 g, 52%). MS (M+l)+=244.0.
[001984] Step 2: The procedure is similar to Step 1 [B] in Example-838. 1.0 g of 4, 6- dichloro-l-(oxetan-3-yl)-lH-imidazo [4, 5-c] pyridine gave 6-chloro-N-(4, 4- difluorocyclohexyl)-l-(oxetan-3-yl)-lH-imidazo [4, 5-c] pyridin-4-amine as an off-white solid (0.3 g, 21%). MS (M+l)+=342.0.
[001985] Step 3[NSSy5808]: The procedure is similar to Step l[NSSy6629] in
Example-839. 0.3 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-l-(oxetan-3-yl)-lH-imidazo[4, 5-c]pyridin-4-amine gave of N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)- l-(oxetan-3-yl)-lH-imidazo[4, 5-c]pyridin-4-amine as an off-white solid (0.015 g, 4%). MS (M+l)+=403.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.25 (s, 1H), 7.00 (d, J = 8.04 Hz, 1H), 6.04 (s, 1H), 5.74-5.67 (m, 1H), 5.06 (t, J = 7.4 Hz, 2H), 4.95 (t, J = 6.16 Hz, 2H), 4.16 (bs, 1H), 2.67 (s, 3H), 2.19 (s, 3H), 2.22-1.80 (m, 6H), 1.58-1.53 (m, 2H).
Example-838:
Figure imgf000670_0002
[001986] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 1, 3- difluoro-5-nitrobenzene gave methyl 3-(3-fluoro-5-nitrophenoxy) azetidine-l-carboxylate as an off-white solid (0.8 g, 95%). MS (M+l)+=271.0. [001987] Step 2: The procedure is similar to Step 1[B] in Example-838. 0.8 g of methyl 3-(3-fluoro-5-nitrophenoxy) azetidine-l-carboxylate gave methyl 3-(3-(3-methyl-lH-pyrazol- l-yl)-5-nitrophenoxy) azetidine-l-carboxylate as an off-white solid (0.25 g, 25%). MS (M+l)+=333.0.
[001988] Step 3: To a solution of methyl 3-(3-(3-methyl-lH-pyrazol-l-yl)-5- nitrophenoxy) azetidine-l-carboxylate (0.25 g, 0.75 mmol) in methanol (8 mL) was added raney-nickel (0.03 g, 0.22 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere using bladder. After 16h, the reaction mixture was filtered through celite, filtrate was concentrated to afford methyl 3-(3-amino-5-(3-methyl-lH- pyrazol-l-yl) phenoxy) azetidine-l-carboxylate as an off-white solid (0.21 g, 95%). MS (M+l)+=303.0.
[001989] Step 4[NSSy5934] : To a solution of methyl 3-(3-amino-5-(3-methyl- 1H- pyrazol-l-yl)phenoxy)azetidine-l-carboxylate (0.23 g, 0.76 mmol) and 4, 4- Difluorocyclohexanone (0.15 g, 1.14 mmol) in methanol (10 mL) was added molecular sieves powder and acetic acid and the reaction mixture was stirred at room temperature for 16h. Sodium cyanoborohydride was added to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature. The reaction mixture was quenched with water and concentrated to remove methanol, residue was extracted with ethyl acetate (2x50 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude product, which was purified by column chromatography using 40% ethyl acetate in hexane as eluent to afford methyl 3-(3-((4, 4-difluorocyclohexyl) amino)-5-(3-methyl-lH-pyrazol-l- yl)phenoxy) azetidine-l-carboxylate as an off-white solid (0.135 g, 42%). MS (M+l)+=421.0; 1H-NMR (400 MHz, DMSO- 6): δ 8.25 (d, = 2.40 Hz, 1H), 6.71 (d, = 1.60 Hz, 1H), 6.27 (d, J = 2.40 Hz, 1H), 5.94-5.92 (m, 1H), 5.90 (s, 1H), 5.05-5.00 (m, 1H), 4.38-4.35 (m, 2H), 3.87-3.80 (m, 2H), 3.59 (s, 3H), 3.52 (d, J = 8.00 Hz, 1H), 2.24 (s, 3H), 2.05-1.91 (m, 6H), 1.49-1.47 (m, 2H).
Example-839:
Figure imgf000672_0001
[001990] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 3, 5- dinitrobenzonitrile gave methyl 3-(3-cyano-5-nitrophenoxy) azetidine-l-carboxylate as an off-white solid (0.6 g, 77%). MS (M+l)+=278.0.
[001991] Step 2: The procedure is similar to Step 5[NSSy5779] in Example-642. 1.0 g of methyl 3-(3-cyano-5-nitrophenoxy) azetidine-l-carboxylate gave methyl 3-(3-amino-5- carbamothioylphenoxy) azetidine-l-carboxylate as a brownish gum (0.8 g, 72%). MS
(M+l)+=282.0.
[001992] Step 3: The procedure is similar to Step 6[NSSy5779] in Example-642. 1.1 g of methyl 3-(3-amino-5-carbamothioylphenoxy) azetidine-l-carboxylate gave methyl 3-(3- amino-5-(4-methylthiazol-2-yl) phenoxy) azetidine-l-carboxylate as an off-white solid (0.4 g, 32%). MS (M+l)+=320.0.
[001993] Step 4[NSSy5972] : The procedure is similar to Step 4[NSSy5934] in
Example-838. 0.4 g of methyl 3-(3-amino-5-(4-methylthiazol-2-yl) phenoxy) azetidine-l- carboxylate gave methyl 3-(3-((4, 4-difluorocyclohexyl) amino)-5-(4-methylthiazol-2-yl) phenoxy) azetidine-l-carboxylate as pale yellow solid (0.088 g, 16%). MS (M+l)+=438.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.28 (s, IH), 6.85 (s, IH), 6.46 (s, IH), 6.13 (s, IH), 5.97 (d, J = 8.40 Hz, IH), 5.05-5.04 (m, IH), 4.35 (m, 2H), 3.89 (m, 2H), 3.59 (s, 3H), 3.34-3.21 (m, IH), 2.41 (s, 3H), 2.08-1.92 (m, 6H), 1.50-1.48 (m, 2H). Example-840:
Figure imgf000673_0001
[001994] Step 1: To a solution of 3, 5-Dibromoaniline (3.5 g, 13.9 mmol), 3, 5- Dimethyl-lH-pyrazole (1.34 g, 13.9 mmol), Tripotassium phosphate (14.80 g, 69.7 mmol), Copper(I) iodide (1.32 g, 6.97 mmol), L-Proline (0.64 g, 5.57 mmol) in Dimethyl sulfoxide in sealed tube was heated at 120 °C for 36h. The reaction mixture was extracted with ethyl acetate, washed with water and brine solution. The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product, which was purified through column chromatography using ethyl acetate in pet-ether as solvent to afford
3- bromo-5-(3, 5-dimethyl-lH-pyrazol-l-yl)aniline (0.3 g, 08%). MS (M+l)+=266.0.
[001995] Step 2: The procedure is similar to Step 1 [IN10963-024-P1] in Example-840. 0.3 g of 3-bromo-5-(3, 5-dimethyl-lH-pyrazol-l-yl) aniline gave 3-(3, 5-dimethyl-lH- pyrazol-l-yl)-5-morpholinoaniline as a brown gum (0.15 g, 48%). MS (M+l)+=273.1.
[001996] Step 3[IN10963-024-Pl]: The procedure is similar to Step 4[NSSy5934] in Example-838. 0.195 g of 3-(3, 5-dimethyl-lH-pyrazol-l-yl)-5-morpholinoaniline gave N-(4,
4- difluorocyclohexyl)-3-(3, 5-dimethyl-lH-pyrazol-l-yl)-5-morpholinoaniline as a brown solid (0.07 g, 25%). MS (M+l)+=391.1; 1H-NMR (400 MHz, DMSO-d6): δ 6.16 (s, 3H), 5.98 (s, 1H), 5.63 (d, J = 8.0 Hz, 1H), 3.73-3.70 (m, 4H), 3.50 (bs, 1H), 3.08-3.05 (m, 4H), 2.25 (s, 3H), 2.14 (s, 3H), 2.07-2.03 (m, 3H), 1.94-1.90 (m, 3H), 1.48-1.45 (m, 2H).
Example-841:
Figure imgf000673_0002
[001997] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 0.25 g of 3-bromo-5-methylbenzonitrile gave 3-((4, 4-difluorocyclohexyl) amino)-5- methylbenzonitrile as an off-white solid (0.21 g, crude), MS (M+l)+=251.0. [001998] Step 2: The procedure is similar to Step 5[NSSy5779] in Example-642. 0.21 g of 3-((4, 4-difluorocyclohexyl) amino)-5-methylbenzonitrile gave 3-((4, 4- difluorocyclohexyl) amino)-5-methylbenzothioamide as brown gum (0.25 g, crude), MS (M+l)+=285.0.
[001999] Step 3[IN11063-086-P2]: The procedure is similar to Step 6[NSSy5779] in Example-642. 0.25 g of 3-((4, 4-difluorocyclohexyl) amino)-5-methylbenzothioamide gave N-(4, 4-difluorocyclohexyl)-3-methyl-5-(4-methylthiazol-2-yl) aniline as brown oil (0.06 g, 60 %). MS (M+l)+=323.1; IH-NMR (400 MHz, DMSO-d6): 57.23 (s, IH), 7.00 (s, IH), 6.89 (s, IH), 6.51 (s, IH), 5.74 (d, J = 8.4 Hz, IH), 3.51 (m, IH), 2.39 (s, 3H), 2.25 (s, 3H), 2.10-2.00 (m, 3H), 1.95-1.92 (m, 3H), 1.54-1.49 (m, 2H).
Example-842:
Figure imgf000674_0001
[002000] Step 1: The procedure is similar to Step 5[NSSy5779] in Example-642. 2 g of 3, 5-dibromobenzonitrile gave 3, 5-dibromobenzothioamide as an off-white solid (2.0 g, 88%). MS (M+l)+=293.8.
[002001] Step 2: The procedure is similar to Step 6[NSSy5779] in Example-839. 2 g of 3, 5-dibromobenzothioamide gave 2-(3, 5-dibromophenyl)-4-methylthiazole as grey solid (0.85 g, 75 %). MS (M+l)+=331.2.
[002002] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 1 g of 2-(3, 5-dibromophenyl)-4-methylthiazole gave 3-bromo-N-(4, 4-difluorocyclohexyl)-5-(4- methylthiazol-2-yl) aniline as brown gum (0.3 g, crude) MS (M+l)+=387.2.
[002003] Step 4[IN11104-059-P1] : The procedure is similar to Step 1 [H] in Example- 838. 0.3 g of 3-bromo-N-(4, 4-difluorocyclohexyl)-5-(4-methylthiazol-2-yl) aniline gave 1- (3-((4, 4-difluorocyclohexyl) amino)-5-(4-methylthiazol-2-yl) phenyl) ethan-l-one as yellow gum (0.15 g, 40%). MS (M+l)+=351.0; IH-NMR (400 MHz, DMSO-d6): 5 7.58 (s, IH), 7.41-7.39 (m, 1H), 7.33 (s, 1H), 7.21 (s, 1H), 6.17 (d, J = 8.40 Hz, 1H), 3.55 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.48 (m, 2H).
[002004] Step 5[IN11104-077-Pl]: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.1 g of l-(3-((4, 4-difluorocyclohexyl) amino)-5-(4-methylthiazol-2-yl) phenyl) ethan-l-one gave l-(3-((4, 4-difluorocyclohexyl) amino)-5-(4-methylthiazol-2-yl) phenyl) ethan-l-ol as an off-white solid (0.05 g, 50%). MS (M+l)+=353.0; IH-NMR (400 MHz, DMSO-d6): δ 7.23 (s, 1H), 7.04 (s, 1H), 7.07 (s, 1H), 6.68 (s, 1H), 5.80 (d, J = 8.40 Hz, 1H), 5.11 (d, J = 4.00 Hz, 1H), 4.58-4.52 (m, 1H), 3.59-3.49 (m, 1H), 2.40 (s, 3H), 2.13- 1.89 (m, 6H), 1.58-1.45 (m, 2H), 1.32 (d, J = 6.80 Hz, 3H).
Example-843:
Figure imgf000675_0001
[002005] Step 1: To a stirred solution of L-4-hydroxyproline methyl ester hydrochloride (2 g, 11.01 mmol) in dichloro methane (20 mL), was added triethylamine (4.45 g, 44.04 mmol) and benzyl bromide (2.26 g, 13.21 mmol) at 0 °C. The reaction mixture was heated to 45 °C for 5h. Then the reaction mixture was partitioned between DCM (50 mL) and water (25 mL), the organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to afford methyl (2S, 4R)-l-benzyl-4-hydroxypyrrolidine-2-carboxylate (1.8 g, 69%) as a brown colour liquid, MS (M+l)+=236.1.
[002006] Step 2: To a stirred solution of methyl (2S, 4R)- l-benzyl-4- hydroxypyrrolidine-2-carboxylate (1.8 g, 7.65 mmol) in dichloro methane (20 mL) at 0 °C under argon atmosphere, was added triethylamine (4.6 mL, 33.66 mmol) followed by methanesulphonyl chloride (1.33 mL, 16.83 mmol). The reaction mixture was stirred at room temperature. The reaction mixture was diluted with DCM (25 mL), washed with water (20 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford methyl (2S, 4R)-l-benzyl-4-((methylsulfonyl)oxy)pyrrolidine-2-carboxylate (1.8 g, 75%) as a brown colour liquid. MS (M+l)+=314.2.
[002007] Step 3: To a stirred solution of methyl (2S, 4R)-l-benzyl-4-((methylsulfonyl) oxy) pyrrolidine-2-carboxylate (1.8 g, 5.744 mmol) in acetonitrile (20 mL), was added Tetra- N-Butylammonium azide (4.08 g, 14.36 mmol). The reaction mixture was heated at 70 °C for lh. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL), brine solution (25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford methyl (2S, 4S)-4-azido-l-benzylpyrrolidine- 2-carboxylate (1.4 g, 93%) as brown liquid. MS (M+l)+=261.1.
[002008] Step 4: The procedure is similar to Step 4[NSSy6711] in Example-854. 3.3 g of methyl (2S, 4S)-4-azido-l-benzylpyrrolidine-2-carboxylate gave ((2S, 4S)-4-amino-l- benzylpyrrolidin-2-yl) methanol as a colourless liquid (2.5 g, 96%). MS (M+l)+=207.2.
[002009] Step 5: The procedure is similar to Step 2[IN11218-026-P1] in Example-613. 4.5 g of ((2S, 4S)-4-amino-l-benzylpyrrolidin-2-yl) methanol gave tert-butyl ((3S, 5S)-1- benzyl-5-(hydroxymethyl) pyrrolidin-3-yl) carbamate as a brown liquid, (4.5 g, 68%). MS (M+l)+=307.2.
[002010] Step 6: To a stirred solution of tert-butyl ((3S, 5S)-l-benzyl-5- (hydroxymethyl)pyrrolidin-3-yl)carbamate (2.3 g, 7.50 mmol) in tetrahydrofuran (40 mL) was added Trifluoro acetic anhydride (1.89 g, 9.00 mmol) at 0 °C under N2 atmosphere then followed by Triethylamine (4.18 mL, 30.02 mmol). The reaction mixture was heated at 100 °C in a sealed tube for lOh. 1 M sodium hydroxide solution (15 mL) was added to the reaction mixture and stirred for lh. The reaction mixture was extracted with ethyl acetate (2x50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using 35% ethyl acetate in hexane as eluent to afford tert-butyl ((3S, 5R)-l-benzyl-5-hydroxypiperidin-3- yl)carbamate as an off-white solid (1.5 g, 65%). MS (M+l)+=307.2. [002011] Step 7: To a stirred solution of tert-butyl ((3S, 5R)-l-benzyl-5- hydroxypiperidin-3-yl)carbamate (2.3 g, 7.50 mmol) in Dichloromethane(30 mL), was added trifluoromethanesulfonic anhydride (2.56 g, 9.00 mmol) and Triethylamine (1.21 g, 12.01 mmol) in Dichloromethane at -50 °C. The resulting mixture was stirred for lh, then morpholine (1.30 g, 15.01 mmol) was added to the reaction and slowly warmed to room temperature. After 16h, the reaction mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (150 mL), washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product, which was purified by flash chromatography to afford tert-butyl ((3S, 5S)-l-benzyl-5-morpholinopiperidin-3- yl)carbamate as brown solid (1.6 g, 57%). MS (M+l)+=376.3.
[002012] Step 8: The procedure is similar to Step 2[NSSy6464] in Example-869. 1.6 g of afford tert-butyl ((3S, 5S)-l-benzyl-5-morpholinopiperidin-3-yl) carbamate gave tert-butyl ((3S, 5S)-5-morpholinopiperidin-3-yl) carbamate as a brownish gum (1.0 g, 83%). MS (M+l)+=286.0.
[002013] Step 9: The procedure is similar to Step l[NSSy6629] in Example-839. 0.6 g of tert-butyl ((3S, 5S)-5-morpholinopiperidin-3-yl) carbamate gave tert-butyl ((3S, 5S)-l-(4- methylthiazol-2-yl)-5-morpholinopiperidin-3-yl) carbamate as brownish gum (0.25 g, 31%). MS (M+l)+=383.2.
[002014] Step 10: The procedure is similar to Step 4[IN11218-027-P1] in Example-613. 0.25 g of tert-butyl ((3S, 5S)-l-(4-methylthiazol-2-yl)-5-morpholinopiperidin-3-yl) carbamate gave (3S, 5S)-l-(4-methylthiazol-2-yl)-5-morpholinopiperidin-3-amine as a yellow solid (0.17 g, 94%). MS (M+l)+=283.2.
[002015] Step 1 l[NSSy6342]: To a stirred solution of (3S, 5S)-l-(4-methylthiazol-2- yl)-5-morpholinopiperidin-3-amine (0.22 g, 0.77 mmol) in dimethyl sulphoxide (3 mL) was added 4-fluoronitrobenzene (0.1 g, 0.77 mmol) and triethylamine (0.23 g, 2.33 mmol). The reaction mixture was heated at 90 °C. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (15 mL), the organic layer was washed with brine solution (15 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford crude product which was purified by flash column chromatography using ethyl acetate as eluent to afford (3S, 5S)-l-(4-methylthiazol-2-yl)-5-morpholino-N-(4-nitrophenyl)piperidin- 3-amine as a yellow solid (0.045 g, 15%). MS (M+l)+=404.1; 1H-NMR (400 MHz, DMSO- d6): δ 8.03 (d, J = 9.16 Hz, 2H), 7.37 (d, J = 7.84 Hz, 1H), 6.78 (d, J = 9.20 Hz, 2H), 6.41 (s, 1H), 4.06 (d, J = 2.80 Hz, 1H), 3.88 (d, J = 8.92 Hz, 1H), 3.64-3.58 (m, 5H), 3.05 (t, J = 12.04 Hz, 1H), 2.76 (t, J = 10.72 Hz, 1H), 2.57-2.51 (m, 4H), 2.29 (m, 1H), 2.16 (s, 3H), 2.09 (s, 6H), 1.53-1.44 (m, 1H).
Example-84
Figure imgf000678_0001
[DQ, DR, DS]
Figure imgf000678_0002
[002016] Step 1: PI: zinc dust (1.6 g, 24.83 mmol) was suspended in N, N-dimethyl acetamide (5 mL), was added chlorotrimethyl silane (0.311 g, 2.86 mmol), 1, 2- dibromoethane (0.53 g, 2.86 mmol) over 5 min, the reaction mixture was stirred for 15 min, after 15 min tert-butyl 4-iodocyclohexane-l-carboxylate (6.67 g, 21.4 mmol) in N, N- dimethyl acetamide (5 mL) was added dropwise to the reaction mixture over 30 min. The addition was completed the reaction mixture was stirred for further 30 min. After 30 min the reaction mixture was passed through celite.
P2: To a stirred solution of 4-iodo-2, 6-dichloro pyridine (4 g, 14.3 mmol) in N, N-dimethyl acetamide (5 mL), was added copper (I) iodide (0.275 g, 1.43 mmol) and 1, l'-bis
(diphenylphosphino) ferrocene palladium dichloride (0.52 g, 0.715 mmol). The reaction mixture was purged with N2 and added to the reaction mixture of PI. The reaction mixture was heated to 100 °C for 16h. The reaction mixture was quenched with water and extracted with ethyl acetate (2x100 mL). The combined organic layer was dried over sodium sulphate and concentrated to afford crude product which was purified by column chromatography using 20% ethyl acetate in pet-ether as eluent to afford tert-butyl 4-(2, 6-dichloropyridin-4-yl) piperidine-l-carboxylate as an off-white solid (2.7 g, 57%). MS (M+l)+=332.0. [002017] Step 2: The procedure is similar to Step 5[NSSy6067] in Example-628. 0.3 g of tert-butyl 4-(2, 6-dichloropyridin-4-yl) piperidine-l-carboxylate gave 2, 6-dichloro-4- (piperidin-4-yl) pyridine as a colorless gum (0.2 g, 95%). MS (M+l)+=233.1.
Table-95: Step 3:
Figure imgf000679_0001
[002018] [DQ, DR]: The procedure is similar to Step 1[A] in Example-838.
[002019] Step 3[DS]: To a stirred solution of 2, 6-dichloro-4-(piperidin-4-yl)pyridine (0.45 g, 1.94 mmol) in Methanol (10 mL) was added formaldehyde, 37% solution in water (0.31 g, 3.89 mmol) and followed by Palladium Hydroxide (50 mg, 10% wt). The reaction mixture was stirred under H2 pressure for 5h. The reaction mixture was filtered through celite, the organic layer was concentrated under reduced pressure to afford 2,6-dichloro-4-(l- methylpiperidin-4-yl) pyridine (0.45 g, 95%) as an off-white solid MS (M+l)+=245.1.
Table-96: Step 4:
Figure imgf000679_0002
[002020] [DT, DU] : The procedure is similar to Step 1 [NSSy6629] in Example-839.
[002021] [DV] : The procedure is similar to Step 1 [B] in Example-838.
Table-97: Step 5: The procedure is similar to Step l[NSSy6629] in Example-839.
Figure imgf000680_0001
[002022] Step 5[NSSy6370]: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.40 Hz, IH), 6.83 (s, IH), 6.70 (d, J = 7.60 Hz, IH), 6.27 (d, J = 2.40 Hz, IH), 6.21 (s, IH), 4.53-4.50 (m, IH), 3.98-3.89 (m, 2H), 3.15-3.09 (m, IH), 2.73-2.67 (m, IH), 2.61-2.55 (m, IH), 2.26 (s, 3H), 2.03-1.96 (m, 9H), 1.82-1.76 (m, 2H), 1.59-1.53 (m, 3H), 1.40-1.36 (m, IH).
[002023] Step 5[NSSy6885]: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 6.83 (s, IH), 6.70 (d, J = 7.20 Hz, IH), 6.28 (s, IH), 6.21 (s, IH), 4.10 (s, 2H), 4.08 (s, IH), 3.61 (s, 3H), 2.85 (s, 2H), 2.70-2.60 (m, IH), 2.26 (s, 3H), 2.08-1.95 (m, 6H), 1.80-1.77 (m, 2H), 1.51-1.43 (m, 4H).
[002024] Step 5[NSSy6888]: 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.40 Hz, IH), 6.83 (s, IH), 6.70 (d, J = 7.60 Hz, IH), 6.28 (s, IH), 6.22 (s, IH), 3.97 (s, IH), 2.85 (d, J = 11.20 Hz, 2H), 2.37-2.34 (m, IH), 2.26 (s, 3H), 2.19 (s, 3H), 2.06-1.92 (m, 8H), 1.76-1.73 (m, 2H), 1.61-1.54 (m, 4H). Example-845:
Figure imgf000681_0001
[002025] Step 1 [NSSy6897] : The procedure is similar to Step 1 [NSSy6629] in
Example-839. 0.15 g of methyl 4-(2-chloro-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) piperidine-l-carboxylate gave N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl)-4- (piperidin-4-yl) pyridin-2-amine as a brown solid (0.04 g, 23%). MS (M+l)+=376.0; 1H- NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, 1H), 6.83 (s, 1H), 6.71 (d, J = 7.60 Hz, 1H), 6.28 (d, J = 2.00 Hz, 1H), 6.21 (s, 1H), 4.01 (s, 1H), 3.06 (d, J = 12.00 Hz, 2H), 2.70- 2.60 (m, 2H), 2.26 (s, 3H), 2.10-1.96 (m, 6H), 1.89 (s, 3H), 1.71 (d, J = 12.00 Hz, 2H), 1.52- 1.48 (m, 4H).
Figure imgf000681_0002
[002026] Step 1: The procedure is similar to Step l[NSSy6469] in Example-805. 1.0 g of 2, 6-dichloro-4-iodopyridine gave l-(4-(2, 6-dichloropyridin-4-yl)-4-hydroxypiperidin-l- yl) ethan-l-one as an off-white solid (0.49 g, 47%). MS (M+l)+=289.0.
[002027] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 0.65 g of l-(4-(2, 6-dichloropyridin-4-yl)-4-hydroxypiperidin-l-yl) ethan-l-one gave l-(4-(2-chloro- 6-((4, 4-difluorocyclohexyl) amino) pyridin-4-yl)-4-hydroxypiperidin-l-yl) ethan-l-one as an off-white solid (0.35 g, 40%). MS (M+l)+=388.2.
[002028] Step 3[NSSy6436]: The procedure is similar to Step 1[H] in Example-838. 0.2 g of l-(4-(2-chloro-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)-4-hydroxy piperidin- l-yl)ethan-l-one gave l-(4-(2-((4, 4-difluorocyclohexyl)amino)-6-(4-methylthiazol-2- yl)pyridin-4-yl)-4-hydroxy piperidin-l-yl)ethan-l-one as an off-white solid (0.045 g, 33%). MS (M+l)+=451.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.30 (d, J = 14.40 Hz, 2H), 6.79 (d, J = 6.80 Hz, 1H), 6.70 (s, 1H), 5.29 (s, 1H), 4.34 (d, J = 11.20 Hz, 1H), 3.92 (d, J = 3.60 Hz, 1H), 3.72 (d, J = 11.60 Hz, 1H), 3.45-3.38 (m, 1H), 2.93-2.87 (m, 1H), 2.41 (s, 3H), 2.05 (s, 3H), 2.02-1.91 (m, 7H), 1.72-1.57 (m, 5H).
Example-847:
Figure imgf000682_0001
NSSy6489
[002029] Step 1: The procedure is similar to Step 1[A] in Example-838. 0.25 g of 2, 6- dichloropyridine-4-sulfonyl chloride gave 2, 6-dichloro-4-((4, 4-difluoropiperidin-l-yl) sulfonyl) pyridine as a yellowish gum (0.2 g, 60%). MS (M+l)+=332.1.
[002030] Step 2: The procedure is similar to Step 1 [B] in Example-838. 0.05 g of 2, 6- dichloro-4-((4, 4-difluoropiperidin-l-yl)sulfonyl)pyridine gave 4-(6-chloro-4-((4, 4- difluoropiperidin-l-yl)sulfonyl)pyridin-2-yl)morpholine as a yellowish solid (0.05 g, 87%). MS (M+l)+=382.1.
[002031] Step 3[NSSy6489]: The procedure is similar to Step l[NSSy6629] in
Example-839. 0.2 g of 4-(6-chloro-4-((4, 4-difluoropiperidin-l-yl)sulfonyl)pyridin-2- yl)morpholine gave 4-(4-((4, 4-difluoropiperidin- l-yl)sulfonyl)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-2-yl)morpholine as a white solid (0.1 g, 45%). MS (M+l)+=428.1; IH-NMR (400 MHz, DMSO-d6): δ 8.55 (d, J = 2.40 Hz, 1H), 7.21 (d, J = 0.80 Hz, 1H), 6.83 (d, J = 0.80 Hz, 1H), 6.39 (d, J = 2.40 Hz, 1H), 3.74-3.63 (m, 8H), 3.21 (t, J = 5.20 Hz, 4H), 2.29 (s, 3H), 2.14-2.07 (m, 4H).
Example-848:
Figure imgf000682_0002
[002032] Step 1: The procedure is similar to Step 1[A] in Example-838. 5 g of 2, 4, 6- trichloropyridine gave 4-(4, 6-dichloropyridin-2-yl) morpholine as yellow solid (1.5 g, 24%). MS (M+l)+=233.0 and 4-(2, 6-dichloropyridin-4-yl)morpholine as an off-white solid (2.5 g, 40%). MS (M+l)+=233.0. Example-849:
Figure imgf000683_0001
[002033] Step 1: The procedure is similar to Step 1[B] in Example-838. 1.5 g of 4-(4, 6- dichloropyridin-2-yl) morpholine gave 4-(4-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-2-yl) morpholine as yellow solid (0.4 g, 21%). MS (M+l)+=293.1 and 4-(6-chloro-4- (3,5-dimethyl-lH-pyrazol-l-yl)pyridin-2-yl)morpholine as an off-white solid (0.5 g, 27%). MS (M+l)+=293.1.
Example- 50:
Figure imgf000683_0002
[002034] Step l[IN10991-065-Pl]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.2 g of 4-(4-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-2-yl) morpholine gave N-(4, 4-difluorocyclohexyl)-2-(3, 5-dimethyl-lH-pyrazol-l-yl)-6- morpholinopyridin-4-amine as a pale yellow solid (0.13 g, 25%). MS (M+l)+=392.3; 1H- NMR (400 MHz, DMSO-d6): δ 6.48 (s, 1H), 6.41 (d, J = 7.60 Hz, 1H), 5.98 (s, 1H), 5.80 (s, 1H), 3.69 (t, J = 4.80 Hz, 4H), 3.60 (s, 1H), 3.35 (t, J = 4.40 Hz, 4H), 2.48 (s, 3H), 2.16 (s, 3H), 2.12-1.85 (m, 6H), 1.55-1.40 (m, 2H). Example-851:
Figure imgf000684_0001
[002035] Step l[IN10991-067-Pl]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 4-(6-chloro-4-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-2-yl) morpholine gave N-(4, 4-difluorocyclohexyl)-4-(3, 5-dimethyl-lH-pyrazol-l-yl)-6- morpholinopyridin-2-amine as an off-white solid (0.05 g, 8%). MS (M+l)+=392.3; IH-NMR (400 MHz, DMSO-d6): δ 6.43 (d, J = 7.20 Hz, IH), 6.04 (s, IH), 5.98 (d, J = 5.20 Hz, 2H), 3.85 (s, IH), 3.69-3.66 (m, 4H), 3.40-3.37 (m, 4H), 2.34 (s, 3H), 2.15 (s, 3H), 2.10-1.85 (m, 6H), 1.60-1.50 (m, 2H).
Example-852:
Figure imgf000684_0002
[002036] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.6 g of 4-(2, 6- dichloropyridin-4-yl) morpholine gave 4-(2-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-4-yl) morpholine as an off-white solid (0.4 g, 53%). MS (M+l)+=293.0.
[002037] Step 2[IN10991-044-Pl]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.2 g of 4-(2-chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) pyridin-4-yl) morpholine gave N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4- morpholinopyridin-2-amine as an off-white solid (0.09 g, 17%). MS (M+l)+=392.1; 1H- NMR (400 MHz, DMSO-d6): δ 6.53 (d, J = 1.20 Hz, IH), 6.36 (d, J = 7.60 Hz, IH), 5.99 (s, IH), 5.78 (d, J = 1.60 Hz, IH), 3.85 (s, IH), 3.72-3.69 (m, 4H), 3.15-3.18 (m, 4H), 2.54 (s, 3H), 2.15 (s, 3H), 2.10-1.80 (m, 6H), 1.60-1.48 (m, 2H). Example-853:
Figure imgf000685_0001
Step-1 CI N CI Step-2 Step-3
Figure imgf000685_0002
[002038] Step 1: The procedure is similar to Step 2[IN11218-026-P1] in Example-613. 4 g of 2, 6-dichloropyridin-4-amine gave tert-butyl (2, 6-dichloropyridin-4-yl) carbamate as white solid (6.4 g, 80%). MS (M+l)+=262.9.
[002039] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 2.5 g of tert-butyl (2, 6-dichloropyridin-4-yl) carbamate gave tert-butyl (2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyridin-4-yl) carbamate as yellow solid (1.4 g, 41%). MS
(M+l)+=362.9.
[002040] Step 3: The procedure is similar to Step 3[NSSy5933] in Example-808. 1.2 g of tert-butyl (2-chloro-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)carbamate gave tert- butyl (2-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)carbamate as an off-white solid (0.52 g, 42%). MS (M+l)+=353.1.
[002041] Step 4: The procedure is similar to Step 5[NSSy5779] in Example-642. 0.52 g of tert-butyl (2-cyano-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)carbamate gave tert- butyl (2-carbamothioyl-6-((4, 4-difluorocyclohexyl)amino)pyridin-4-yl)carbamate as brown liquid (0.7 g, crude). MS (M+l)+=387.2.
[002042] Step 5[IN11083-048-P1]: The procedure is similar to Step 6[NSSy5779] in Example-640. 0.7 g of tert-butyl (2-carbamothioyl-6-((4, 4-difluorocyclo hexyl) amino) pyridin-4-yl) carbamate gave tert-butyl (2-((4, 4-difluorocyclo hexyl) amino)-6-(4- methylthiazol-2-yl) pyridin-4-yl) carbamate as yellow solid (0.5 g, 66%). MS (M+l)+=425.1; 1H-NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 7.40 (d, J = 1.6 Hz, 1H), 7.26 (s, 1H), 6.79 (d, J = 1.6 Hz, 1H), 6.69 (d, J = 6.8 Hz, 1H), 3.87 (m, 1H), 2.40 (s, 3H), 2.09-1.87 (m, 6H), 1.63-1.57 (m, 2H), 1.49 (s, 9H). [002043] Step 6[IN11063-096-P1]: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.2 g of tert-butyl (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2- yl) pyridin-4-yl) carbamate gave N2-(4, 4-difluorocyclohexyl)-N4-methyl-6-(4- methylthiazol-2-yl) pyridine-2, 4-diamine as an off-white solid (0.04 g, 25%). MS
(M+l)+=339.2; IH-NMR (400 MHz, DMSO-d6): δ 7.19 (s, 1H), 6.67 (d, J = 2.00 Hz, 1H), 6.29 (q, J = 4.40 Hz, 1H), 6.18 (d, J = 6.80 Hz, 1H), 5.58 (d, J = 1.60 Hz, 1H), 3.85 (d, J = 5.60 Hz, 1H), 2.52 (d, J = 5.20 Hz, 3H), 2.38 (s, 3H), 2.10-1.84 (m, 6H), 1.62-1.52 (m, 2H). Example-854:
Figure imgf000686_0001
[002044] Step 1[IN11063-087-P1]: The procedure is similar to Step 4[IN11218-027-P1] in Example-613. 0.06 g of tert-butyl (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol- 2-yl) pyridin-4-yl) carbamate gave N2-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl) pyridine-2, 4-diamine as a pink solid (0.04 g, 60%). MS (M+l)+=325.2; IH-NMR (400 MHz, DMSO-d6): δ 7.19 (s, 1H), 6.68 (s, 1H), 6.09 (d, J = 6.80 Hz, 1H), 5.75 (s, 1H), 3.90 (s, 2H), 3.80 (s, 1H), 3.90 (s, 3H), 2.10-1.80 (m, 6H), 1.60-1.50 (m, 2H).
Example-855:
Figure imgf000686_0002
[002045] Step 1[IN11130-007-P1]: The procedure is similar to Step 5[NSSy6711] in Example-854. 0.06 g of N2-(4, 4-difluorocyclohexyl)-N4-methyl-6-(4-methylthiazol-2-yl) pyridine-2, 4-diamine gave N2-(4, 4-difluorocyclohexyl)-N4-methyl-6-(4-methylthiazol-2-yl) pyridine-2, 4-diamine as an off-white solid (0.04 g, 65%). MS (M+l)+=353.1; IH-NMR (400 MHz, DMSO-d6): δ 7.22 (d, J = 1.20 Hz, 1H), 6.76 (d, J = 2.00 Hz, 1H), 6.24 (d, J = 6.80 Hz, 1H), 5.71 (d, J = 2.00 Hz, 1H), 3.88 (s, 1H), 2.95 (s, 6H), 2.50 (s, 3H), 2.10-1.80 (m, 6H),
1.60-1.50 (m, 2H).
Example-856:
Figure imgf000687_0001
[002046] Step 1: The procedure is similar to Step 4[NSSy6067] in Example-628. 3.2 g of tert-butyl (2, 6-dichloropyridin-4-yl) carbamate gave tert-butyl (2, 6-dichloro-3-(2- hydroxyethyl) pyridin-4-yl) carbamate as yellow solid (2.8 g, 76%). MS (M+l)+=307.0.
[002047] Step 2: The procedure is similar to Step 3[IN11273-018-P1] in Example-889. 2.8 g of tert-butyl (2, 6-dichloro-3-(2-hydroxyethyl) pyridin-4-yl) carbamate gave tert-butyl 4, 6-dichloro-2, 3-dihydro-lH-pyrrolo [3, 2-c] pyridine- l-carboxy late as a brownish gum (3.5 g, 70%). MS (M+l)+=289.0.
Example-857:
Figure imgf000687_0002
[002048] Step 1: 1 g of tert-butyl 4, 6-dichloro-2, 3-dihydro-lH-pyrrolo [3, 2-c] pyridine- l-carboxy late gave tert-butyl 4-chloro-6-morpholino-2, 3-dihydro-lH-pyrrolo [3, 2- c] pyridine- l-carboxy late as an off-white solid (0.55 g, 47%). MS (M+l)+=340.1 and tert- butyl 6-chloro-4-morpholino-2,3-dihydro-lH-pyrrolo[3, 2-c]pyridine- l-carboxy late as an off- white solid (0.23 g, 25%). MS (M+l)+=340.1.
Example-858:
Figure imgf000687_0003
IN11063-092-P1 [002049] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 0.1 g of tert-butyl 4-chloro-6-morpholino-2, 3-dihydro-lH-pyrrolo [3, 2-c] pyridine- l-carboxy late gave 4-(4-(3-methyl-lH-pyrazol-l-yl)-2, 3-dihydro-lH-pyrrolo[3, 2-c]pyridin-6- yl)morpholine as an brownish gum (0.03 g, 28%). MS (M+l)+=286.1.
[002050] Step 2[IN11063-092-P1]: The procedure is similar to Step 4[IN11218-027-P1] in Example-613. 0.03 g of 4-(4-(3-methyl-lH-pyrazol-l-yl)-2, 3-dihydro-lH-pyrrolo[3, 2- c]pyridin-6-yl)morpholine gave 4-(4-(3-methyl-lH-pyrazol-l-yl)-2, 3-dihydro-lH-pyrrolo[3, 2-c]pyridin-6-yl)morpholine hydrochloride as an off-white solid (0.04 g, 90%). MS
(M+l)+=286.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.40 Hz, 1H), 6.40 (s, 1H), 6.22 (d, J = 2.40 Hz, 1H), 5.74 (s, 1H), 3.68 (t, J = 4.80 Hz, 4H), 3.51 (t, J = 8.40 Hz, 2H), 3.34 (t, J = 5.20 Hz, 4H), 3.23 (t, J = 8.80 Hz, 2H), 2.24 (s, 3H).
Example-859:
Figure imgf000688_0001
[002051] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 0.4 g of tert-butyl 6-chloro-4-morpholino-2, 3-dihydro-lH-pyrrolo [3, 2-c] pyridine- l-carboxy late gave tert-butyl 6-(3-methyl-lH-pyrazol-l-yl)-4-morpholino-2, 3-dihydro-lH-pyrrolo[3, 2- c]pyridine- l-carboxy late as an off-white solid (0.08 g, 18%). MS (M+l)+=386.1.
[002052] Step 2[IN11130-005-P1]: The procedure is similar to Step 5[NSSy6067] in Example-628. 0.08 g of tert-butyl 6-(3-methyl-lH-pyrazol-l-yl)-4-morpholino-2, 3-dihydro- lH-pyrrolo[3, 2-c]pyridine- l-carboxy late gave 4-(6-(3-methyl-lH-pyrazol-l-yl)-2, 3- dihydro-lH-pyrrolo[3,2-c]pyridin-4-yl)morpholine as pale brown solid (0.05 g, 84%). MS (M+l)+=286.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.32 (d, J = 2.40 Hz, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 6.22 (d, J = 2.40 Hz, 1H), 3.69-3.63 (m, 4H), 3.52 (t, J = 8.80 Hz, 2H), 3.36- 3.31 (m, 4H), 2.99 (t, J = 8.80 Hz, 2H), 2.24 (s, 3H). Example-860:
Figure imgf000689_0001
[002053] Step 1: The procedure is similar to Step 1[IN11251-001-P2] in Example-884. 0.5 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 4-(2-aminopropan-2-yl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- IH-pyrazol- 1-yl) pyridin-2-amine as brown oil (0.65 g, crude). MS (M+l)+=350.2.
[002054] Step 2[IN11063-030-P1] : The procedure is similar to Step 1 [A] in Example- 838. 0.65 g of 4-(2-aminopropan-2-yl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol- l-yl)pyridin-2-amine gave methyl (2-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)propan-2-yl)carbamate as pale brown gum (0.06 g, 15%). MS (M+l)+=408.1; IH-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.40 Hz, 1H), 6.99 (d, J = 1.20 Hz, 1H), 6.38 (s, 1H), 6.24 (d, J = 2.40 Hz, 1H), 3.98 (s, 1H), 3.55 (s, 3H), 2.32 (s, 3H), 2.15-1.85 (m, 7H), 1.70-1.60 (m, 3H), 1.57 (s, 6H).
Example-861:
Figure imgf000689_0002
[002055] Step l[IN10967-063-Pl]: The procedure is similar to Step 3[NSSy5934] in Example-838. 0.25 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 4-(aminomethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-amine as brown oil (0.21 g, 80%). MS (M+l)+=322.1; IH-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.4 Hz, 1H), 6.95 (s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), 6.27 (d, J = 2.4 Hz, 1H), 4.08-4.00 (m, 1H), 3.67 (s, 2H), 3.01 (bs, 1H), 2.26 (m, 3H), 2.05-1.95 (m, 6H), 2.06-1.95 (m, 2H). [002056] Step 2[IN11063-006-P1]: The procedure is similar to Step 4[NSSy5934] in Example-838. 0.3 g of 4-(aminomethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-((dimethylamino) methyl)- 6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine as white solid (0.125 g, 40%). MS
(M+l)+=350.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.40 Hz, IH), 6.91 (s, IH), 6.72 (d, J = 7.60 Hz, IH), 6.31 (s, IH), 6.28 (d, J = 2.00 Hz, IH), 4.02 (s, IH), 3.25(s, 2H), 2.25 (s, 3H), 2.16 (s, 6H), 2.10-1.90 (m, 6H), 1.62-1.48 (m, 2H).
Example-862:
Figure imgf000690_0001
[002057] Step 1: The procedure is similar to Step 1[A] in Example-838. 2 g of 2, 6- dichloro-4-iodopyridine gave 4-(6-chloro-4-iodopyridin-2-yl) morpholine as an off-white solid (0.65 g, 27%). MS (M+l)+=324.8.
[002058] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 0.35 g of 4-(6-chloro-4-iodopyridin-2-yl) morpholine gave 2-chloro-N-(4, 4-difluorocyclohexyl)-6- morpholinopyridin-4-amine as brown gummy solid (0.2 g, 55%). MS (M+l)+=332.2.
[002059] Step 3[IN10973-098-Pl]: 0.1 g of 2-chloro-N-(4, 4-difluorocyclohexyl)-6- morpholinopyridin-4-amine gave N-(4, 4-difluorocyclohexyl)-2-(3-methyl-lH-pyrazol-l-yl)- 6-morpholinopyridin-4-amine as an off-white solid (0.035 g, 30%). MS (M+l)+=378.2; 1H- NMR (400 MHz, DMSO-d6): δ 8.34 (d, = 2.40 Hz, IH), 6.55 (s, IH), 6.45 (d, = 8.40 Hz, IH), 6.22 (s, IH), 5.77 (s, IH), 3.69 (s, 4H), 3.68 (s, IH), 3.39 (s, 4H), 2.24 (s, 3H), 2.15-1.85 (m, 6H), 1.55-1.45 (m, 2H).
Example-863:
Figure imgf000691_0001
[002060] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 5 g of 4-(2, 6-dichloropyridin-4-yl) morpholine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- morpholinopyridin-2-amine as an off-white solid (2.8 g, 39%). MS (M+l)+=332.1.
[002061] Step 2: The procedure is similar to Step 1[H] in Example-838. 2 g of 6-chloro- N-(4, 4-difluorocyclohexyl)-4-morpholinopyridin-2-amine gave N-(4, 4-difluorocyclohexyl)- 6-(l-ethoxyvinyl)-4-morpholinopyridin-2-amine as brown gum (2.5 g, crude). MS
(M+l)+=368.1.
[002062] Step 3[IN11104-090-P1]: The procedure is similar to Step l[NSSy6697] in Example-873. 2.5 g of N-(4, 4-difluorocyclohexyl)-6-(l-ethoxyvinyl)-4-morpholinopyridin- 2-amine gave l-(6-((4, 4-difluorocyclohexyl) amino)-4-morpholinopyridin-2-yl) ethan-l-one as a colourless gummy solid (0.6 g, 30%). MS (M+l)+=340.1; IH-NMR (400 MHz, DMSO- d6): δ 6.77 (d, J = 1.60 Hz, 1H), 6.43 (d, J = 7.20 Hz, 1H), 6.05 (d, J = 1.20 Hz, 1H), 3.93 (s, 1H), 3.70 (t, J = 4.40 Hz, 4H), 3.17 (t, J = 4.80 Hz, 4H), 2.49 (s, 3H), 2.12-1.85 (m, 6H), 1.62-1.50 (m, 2H).
[002063] Step 4: The procedure is similar to Step 1[B] in Example-838. 0.3 g of l-(6- ((4, 4-difluorocyclohexyl) amino)-4-morpholinopyridin-2-yl) ethan-l-one gave (E)-l-(6-((4, 4-difluorocyclohexyl) amino)-4-morpholinopyridin-2-yl)-3-(dimethylamino) prop-2-en- 1-one as a colourless gummy solid (0.3 g, 86%). MS (M+l)+=395.2.
[002064] Step 5[IN11104-095-P1]: The procedure is similar to Step 6[NSSy5779] in Example-642. 0.3 g of (E)-l-(6-((4, 4-difluorocyclohexyl) amino)-4-morpholinopyridin-2- yl)-3-(dimethylamino) prop-2-en- 1-one gave N-(4, 4-difluorocyclohexyl)-6-(2- methylpyrimidin-4-yl)-4-morpholinopyridin-2-amine as a colourless gummy solid (0.12 g, 40%). MS (M+l)+=390.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.75 (d, = 4.80 Hz, 1H), 8.06 (d, 7 = 4.80 Hz, 1H), 7.35 (d, 7 = 2.00 Hz, 1H), 6.38 (d, 7 = 7.20 Hz, 1H), 6.01 (d, 7 = 1.20 Hz, 1H), 4.03 (s, 1H), 3.74 (t, 7 = 4.80 Hz, 3H), 3.22 (t, 7 = 4.40 Hz, 3H), 2.67 (s, 3H), 2.12- 1.90 (m, 6H), 1.62-1.50 (m, 2H), 1.23 (s, 1H), 0.89-0.84 (m, 1H).
Example-864:
Figure imgf000692_0001
[002065] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 2 g of methyl 2, 6-dichloroisonicotinate gave methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinate as a pale yellow solid (1.4 g, 48%). MS (M+l)+=305.1.
[002066] Step 2: The procedure is similar to Step 2[NSSy6931] in Example-21. 1.4 g of methyl 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinate gave (2-chloro-6-((4, 4- difluorocyclohexyl) amino) pyridin-4-yl) methanol as colourless gum (1.2 g, crude). MS (M+l)+=277.1.
[002067] Step 3: The procedure is similar to Step 3[NSSy7053] in Example-815. 1.2 g of (2-chloro-6-((4, 4-difluorocyclohexyl) amino) pyridin-4-yl) methanol gave 4-(((tert- butyldimethylsilyl) oxy) methyl)-6-chloro-N-(4, 4-difluorocyclohexyl) pyridin-2-amine as a colourless oil (1.07 g, 63%). MS (M+l)+=391.2.
[002068] Step 4: The procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 4-(((tert-butyldimethylsilyl) oxy) methyl)-6-chloro-N-(4, 4-difluorocyclohexyl) pyridine- amine gave 4-(((tert-butyldimethylsilyl) oxy) methyl)-6-(3-cyclopropyl-lH-pyrazol-l-yl)-N- (4, 4-difluorocyclohexyl) pyridin-2-amine as a yellow solid (0.21 g, 36%). MS
(M+l)+=463.3.
[002069] Step 5[IN11111-092-P1]: The procedure is similar to Step 5[NSSy5645] in Example-811. 0.21 g of 4-(((tert-butyldimethylsilyl) oxy) methyl)-6-(3-cyclopropyl-lH- pyrazol-l-yl)-N-(4, 4-difluorocyclohexyl) pyridin-2-amine gave 2-(3-cyclopropyl-lH- pyrazol-l-yl)-6-((4, 4-difluorocyclohexyl) amino) pyridin-4-yl) methanol as an off-white solid (0.11 g, 70%). MS (M+l)+=349.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.40 Hz, 1H), 6.86 (s, 1H), 6.74 (d, J = 7.20 Hz, 1H), 6.33 (s, 1H), 6.19 (d, J = 2.40 Hz, 1H), 5.32 (t, J = 5.60 Hz, 1H), 4.42 (d, J = 6.00 Hz, 2H), 3.97 (s, 1H), 2.15-1.85 (m, 6H), 1.65-1.45 (m, 2H), 0.97-0.85 (m, 3H), 0.75-0.65 (m, 2H).
Example-865:
Figure imgf000693_0001
[002070] Step 1: The procedure is similar to Step l[NSSy6929] in Example-839. 0.5 g of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile gave 6-((4, 4- difluorocyclohexyl) amino)-6'-methyl-[2, 2'-bipyridine]-4-carbonitrile as a pale yellow solid (0.48 g, 80%). MS (M+l)+=329.1.
[002071] Step 2: The procedure is similar to Step 1[B] in Example-838. 0.8 g of 6-((4, 4-difluorocyclohexyl) amino)-6'-methyl-[2, 2'-bipyridine]-4-carbonitrile gave 6-((4, 4- difluorocyclohexyl) amino)-6'-methyl-[2, 2'-bipyridine]-4-carboxylic acid as a pale yellow solid (0.64 g, 75%). MS (M+l)+=346.1.
[002072] Step 3[IN11111-063-P1]: To a solution of 6-((4, 4-difluorocyclohexyl) amino)-6'-methyl-[2, 2'-bipyridine]-4-carboxylic acid (0.64 g, 1.84 mmol) in THF, was added BH3DMS (2M solution in THF, 4.60 mL, 9.21 mmol), at 0 °C and the reaction mixture was stirred at room temperature for 12h. Then the reaction mixture was cooled to 0 °C, quenched with methanol and heated the reaction mixture at 60 °C for lh, the reaction mixture was cooled to 0 °C, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layer was washed with water and brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (6-((4, 4-difluorocyclohexyl)amino)-6'-methyl-[2, 2'-bipyridin]-4-yl)methanol as a yellow liquid (0.025 g, 4%). MS (M+l)+=334.1; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, J = 7.6 Hz, 1H), 7.78-7.74 (m, 1H), 7.51 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.56 (d, J = 6.8 Hz, 1H), 6.53 (s, 1H), 5.27 (t, J = 6.00 Hz, 1H), 4.45 (d, J = 8.00 Hz, 2H), 4.01 (m, 1H), 2.11-1.92 (m, 6H), 1.65-1.56 (m, 2H). Example-866:
Figure imgf000694_0001
[002073] Step 1: The procedure is similar to Step l[A]in Example-838. 2.5 g of piperidin-4-one gave methyl 4-oxopiperidine-l-carboxylate as a colourless oil (2.5 g, 98%). MS (M+l)+=158.2.
[002074] Step 2: The procedure is similar to Step 4[NSSy6067] in Example-628. 1 g of methyl 4-oxopiperidine-l-carboxylate gave methyl 4-(2, 6-dichloropyridin-4-yl)-4- hydroxypiperidine-l-carboxylate as off-white solid (0.8 g, 72%). MS (M+l)+=305.1.
[002075] Step 3: The procedure is similar to Step 1[B] in Example-838. 0.6 g of methyl 4-(2, 6-dichloropyridin-4-yl)-4-hydroxypiperidine- l-carboxylate gave methyl 4-(2-chloro-6- (3-methyl-lH-pyrazol-l-yl) pyridin-4-yl)-4-hydroxypiperidine-l-carboxylate as brownish gum (0.2 g, 29%). MS (M+l)+=351.1.
[002076] Step 4[IN11130-077-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.15 g of methyl 4-(2-chloro-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)-4- hydroxypiperidine-l-carboxylate gave methyl 2'-((4, 4-difluorocyclohexyl)amino)-6'-(3- methyl-lH-pyrazol-l-yl)-3,6-dihydro-[4, 4'-bipyridine]-l(2H)-carboxylate as an off-white solid (0.035 g, 18%). MS (M+l)+=432.3; 1H-NMR (400 MHz, DMSO-d6): δ 8.12 (d, J = 2.40 Hz, 1H), 7.68 (d, J = 8.80 Hz, 1H), 6.82 (d, J = 7.20 Hz, 1H), 6.69 (s, 1H), 6.52 (d, J = 8.80 Hz, 1H), 6.34 (d, J = 2.40 Hz, 1H), 3.75 (s, 1H), 3.70-3.60 (m, 2H), 3.54 (s, 3H), 3.15 (s, 2H), 2.25 (s, 3H), 2.12-1.85 (m, 5H), 1.60-1.40 (m, 5H).
Example-867:
Figure imgf000694_0002
[002077] Step 1 : The procedure is similar to Step 1 [B] in Example-838. 2 g of 2, 6- dichloroisonicotinonitrile gave mixture of 2-chloro-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile and 2-chloro-6-(5-methyl-lH-pyrazol-l-yl) isonicotinonitrile as a white solid (0.84 g, crude). MS (M+l)+=219.4.
[002078] Step 2[IN10967-061-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 1.4 g of mixture of 2-chloro-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile and 2-chloro-6-(5-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((4, 4- difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile as an off-white solid (0.48 g, 24%). MS (M+l)+=318.1 and 2-((4, 4-difluorocyclohexyl)amino)-6-(5- methyl-lH-pyrazol-l-yl)isonicotinonitrile as an off-white solid (0.22 g, 12%). MS
(M+l)+=318.1; 1H-NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.45 (d, J = 7.60 Hz, 1H), 7.15 (s, 1H), 6.72 (s, 1H), 6.30 (s, 1H), 3.90 (s, 1H), 2.67 (s, 3H), 2.11-1.85 (m, 6H), 1.60- 1.50 (m, 2H).
Example-868:
Figure imgf000695_0001
[002079] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 2 g of 2, 6-dichloroisonicotinonitrile gave 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile as a brown solid (1 g, 31%). MS (M+l)+=272.2.
[002080] Step 2: The procedure is similar to Step l[NSSy6909] in Example-839. 0.4 g of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile gave mixture of 2-((4, 4- difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)- lH-pyrazol-l-yl) isonicotino nitrile as pale yellow solid (0.22 g, 40%). MS (M+l)+=370.2 and 2-((4, 4-difluorocyclohexyl)amino)- 6-(3-(trifluoromethyl)-lH-pyrazol-l-yl) isonicotinic acid as pale yellow solid (0.6 g, 90%). MS (M+l)+=391.1.
[002081] Step 3: The procedure is similar to Step 3[NSSy6711] in Example-854. 0.6 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl) isonicotinic acid gave ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)-lH-pyrazol-l-yl) isonicotinate as off-white solid (0.09 g, 19%). MS (M+l)+=417.2.
[002082] Step 4[IN11133-097-P1]: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.15 g of ethyl 2-((4, 4-difluorocyclohexyl) amino)-6-(3-(trifluoromethyl)-lH- pyrazol-l-yl) isonicotinate gave (2-((4, 4-difluorocyclo hexyl) amino)-6-(3-(trifluoromethyl)- lH-pyrazol-l-yl) pyridin-4-yl) methanol as an off-white solid (0.115 g, 85%). MS
(M+l)+=377.1; IH-NMR (400 MHz, DMSO-d6): δ 8.74 (d, J = 1.60 Hz, IH), 6.99-6.97 (m, 3H), 6.49 (d, J = 0.80 Hz, IH), 5.40 (t, J = 5.60 Hz, IH), 4.47 (d, J = 6.00 Hz, 2H), 4.06 (s, IH), 2.12-1.82 (m, 6H), 1.61-1.50 (m, 2H).
Example-869:
Figure imgf000696_0001
[002083] Step 1: The procedure is similar to Step l[NSSy6989] in Example-839. 1 g of 2-chloro-6-((4, 4-difluorocyclohexyl) amino) isonicotinonitrile gave 2-((4, 4- difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinonitrile as a pale yellow solid (1 g, 81%). MS (M+l)+=335.0.
[002084] Step 2[IN11130-053-P1]: The procedure is similar to Step 4[NSSy6464] in Example-869. 0.3 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinonitrile gave l-(2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) ethan-l-one as a yellow solid (0.05 g, 16%). MS (M+l)+=350.2; IH-NMR (400 MHz, DMSO-d6): δ 7.57 (s, IH), 7.35 (s, IH), 7.17 (d, J = 10.40 Hz, IH), 7.02 (s, IH), 3.95 (s, IH), 2.58 (s, 3H), 2.42 (s, 3H), 2.15-1.90 (m, 6H), 1.65-1.55 (m, 2H).
[002085] Step 3[IN11130-051-P1]: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.35 g of l-(2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) ethan-l-one gave l-(2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2- yl) pyridin-4-yl) ethan-l-ol as a yellow solid (0.1 g, 29%). MS (M+l)+=354.0; IH-NMR (400 MHz, DMSO-d6): δ 7.26 (s, IH), 7.22 (s, IH), 6.73 (d, J = 6.80 Hz, IH), 6.57 (s, IH), 5.28 (s, IH), 4.68-4.60 (m, IH), 3.90 (s, IH), 2.41 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.55 (m, 2H), 1.33 (d, J = 6.80 Hz, 3H). Example-870:
Figure imgf000697_0001
o o
R- IN11 Λ133-069-P1 IN11 Λ133-068-P1
[002086] Step 1: The procedure is similar to Step 3 [INI 1059-090-P1] in Example-659. 0.2 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) methanol gave 4-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl) pyridin-2-amine as pale brown solid (0.2 g, 84%). MS (M, M+2)+=402.1, 404.1
[002087] Step 2[IN11133-062-P1] : The procedure is similar to Step 1 [B] in Example-2. 0.1 g of 4-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl) pyridine- amine gave N-(4, 4-difluorocyclohexyl)-4-((methylamino) methyl)-6-(4-methylthiazol-2-yl) pyridin-2-amine as white solid (0.035 g, 39%). MS (M+l)+=353.2; IH-NMR (400 MHz, CD30D): 57.30 (s, 1H), 7.18 (d, J = 1.2 Hz, 1H), 6.55 (s, 1H), 4.02 (s, 2H), 3.99 (m, 1H), 2.70 (s, 3H), 2.47 (s, 3H), 2.14-1.91 (m, 6H), 1.70-1.65 (m, 2H).
Table-98: Step 3: The procedure is similar to Step 1[A] in Example-838.
Figure imgf000697_0002
[002088] Step 3[IN11133-069-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.24 (d, J = 26.40 Hz, 1H), 7.30 (d, J = 4.40 Hz, 1H), 7.09 (d, J = 6.80 Hz, 1H), 6.88 (dd, J = 6.80, 20.40 Hz, 1H), 6.40 (d, J = 6.40 Hz, 1H), 4.42 (s, 1H), 4.37 (s, 1H), 3.90 (s, 1H), 2.89 (s, 1H), 2.69 (s, 1H), 2.41 (s, 3H), 2.10-1.88 (m, 7H), 1.65-1.50 (m, 2H). [002089] Step 3[IN11133-068-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 7.29 (d, J = 5 Hz, 1H), 7.08 (d, J = 8.40 Hz, 1H), 6.85 (dd, J = 6.40, 39.00 Hz, 1H), 6.37 (s, 1H), 4.52 (s, 1H), 4.42 (s, 1H), 3.91 (s, 1H), 2.95 (s, 2H), 2.84 (s, 1H), 2.41 (s, 3H), 2.15-1.85 (m, 7H), 1.68-1.52 (m, 2H).
Example-871:
Figure imgf000698_0001
[002090] Step 1[IN11133-061-P1]: The procedure is similar to Step 3[IN11137-079-Pl] in Example-785. 0.15 g of (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) methanol gave (2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) pyridin-4-yl) methyl carbamate as an off-white solid (0.035 g, 15%). MS (M+l)+=383.2; 1H- NMR (400 MHz, DMSO-d6): δ 7.29 (s, 1H), 7.18 (s, 1H), 6.87 (d, J = 6.80 Hz, 1H), 6.75 (s, 1H), 6.47 (s, 1H), 4.50 (s, 2H), 3.89 (s, 1H), 2.41 (s, 4H), 2.15-1.85 (m, 6H), 1.65-1.55 (m, 2H).
Example-872:
Figure imgf000698_0002
[002091] Step 1[IN11133-049-P1]: The procedure is similar to Step 3[NSSy5934] in Example-838. 0.1 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(4-methylthiazol-2-yl) isonicotinonitrile gave 4-(aminomethyl)-N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl) pyridin-2-amine as pale brown gum (0.04 g, 39%). MS (M+l)+=339.1; IH-NMR (400 MHz, CDC13): δ 7.39 (s, 1H), 6.92 (s, 1H), 6.41 (s, 1H), 4.42 (d, J = 7.20 Hz, 1H), 3.90 (s, 3.84 (s, 2H), 2.50 (s, 3H), 2.20-2.10 (m, 3H), 2.15-1.85 (m, 3H), 1.70-1.60 (m, 4H).
Table-99: Step 2: The procedure is similar to Step 1[A] in Example-838.
Figure imgf000699_0002
[002092] [IN11130-047-P1]: IH-NMR (400 MHz, DMSO-d6): δ 7.74 (t, J = 6.00 Hz, 1H), 7.28 (s, 1H), 7.15 (s, 1H), 6.82 (d, J = 6.80 Hz, 1H), 6.43 (s, 1H), 4.11 (d, J = 6.00 Hz, 2H), 3.89 (s, 1H), 3.57 (s, 3H), 2.33 (s, 3H), 2.15-1.85 (m, 6H), 1.65-1.55 (m, 2H).
[002093] [IN11133-037-P1]: IH-NMR (400 MHz, DMSO-d6): δ 8.56 (s, 1H), 8.19 (s, 1H), 7.28 (s, 1H), 7.16 (s, 1H), 3.90 (d, J = 7.20 Hz, 1H), 6.43 (s, 1H), 3.90 (d, J = 6.40 Hz, 2H), 3.91 (s, 1H), 2.41 (s, 3H), 2.15-1.85 (m, 6H), 1.55-1.52 (m, 2H).
Example-873:
Figure imgf000699_0001
[002094] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 0.2 g of 2, 6-dichloro-4-methylpyridine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- methylpyridin-2-amine as an off-white solid (0.14 g, 43%). MS (M+l)+=261.0.
[002095] Step 2[IN11137-041-P1]: The procedure is similar to Step l[NSSy6989] in Example-839. 0.14 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-4-methylpyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-4, 6'-dimethyl-[2, 2'-bipyridin]-6-amine as an off-white solid (0.03 g, 17%). MS (M+l)+=318.1; IH-NMR (400 MHz, DMSO-d6): δ 8.11-8.07 (m, 1H), 7.83-7.72 (m, 1H), 7.41 (bs, 1H), 7.30-7.21 (m, 1H), 6.47 (d, J = 7.2 Hz, 1H), 6.35 (s, 1H), 4.10-3.80 (m, 1H), 2.55-2.45 (m, 3H), 2.23 (s, 3H), 2.10-1.92 (m, 6H), 1.64-1.55 (m, 2H). Example-874:
[002096] Intentionally Omitted
Example-875:
Figure imgf000700_0001
OH OH
- IN o1103r9-069-P1 IN11039-066-P1
Table-100: Step 1: The procedure is similar to Step 2[IN10991-021-P1] in Example-694.
Figure imgf000700_0002
[002097] Step l[IN11039-069-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.37 (d, J = 2.00 Hz, 1H), 8.00 (d, J = 3.60 Hz, 1H), 7.93 (d, J = 7.20 Hz, 1H), 7.02 (s, 1H), 6.96 (q, J = 5.60 Hz, 1H), 6.42 (s, 1H), 6.25 (d, J = 2.00 Hz, 1H), 5.37 (s, 2H), 3.95 (s, 1H), 2.31 (s, 3H), 2.10- 1.85 (m, 6H), 1.63 (s, 9H).
[002098] Step l[IN11039-066-Pl]: IH-NMR (400 MHz, MeOD): δ 8.38 (d, J = 2.40 Hz, 1H), 8.01 (q, J = 3.60 Hz, 1H), 7.84 (q, J = 2.00 Hz, 1H), 7.00-6.97 (m, 2H), 6.43 (d, J = 0.80 Hz, 1H), 6.25 (d, J = 2.40 Hz, 1H), 5.36 (q, J = 4.40 Hz, 2H), 5.19-5.16 (m, 1H), 3.97 (s, 1H), 2.31 (s, 3H), 2.20-1.90 (m, 6H), 1.72-1.60 (m, 3H), 1.42 (d, J = 4.80 Hz, 4H). Example-876:
Figure imgf000701_0001
"^ IN110Λ67-004-P1 I ΛN11067-003-P1
[002099] Step 1: The procedure is similar to Step 2[NSSy5701] in Example-813. 0.13 g of 4-(bromomethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl- IH-pyrazol- l-yl)pyridin-2- amine gave tert-butyl 3-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-4-yl)methoxy)piperidine-l-carboxylate as colourless gum (0.16 g, 93%). MS (M+l)+=506.2.
[002100] Step 2[IN11039-019-P1]: The procedure is similar to Step 5[NSSy6067] in Example-628. 0.16 g of tert-butyl 3-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)methoxy)piperidine-l-carboxylate gave N-(4, 4- difluorocyclohexyl)-6-(3-methyl- IH-pyrazol- l-yl)-4-((piperidin-3-yloxy) methyl)pyridin-2- amine as an off-white solid (0.045 g, 35%). MS (M+l)+= 406.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 1.60 Hz, 1H), 6.85 (s, 1H), 6.79 (d, J = 7.60 Hz, 1H), 6.35 (s, 1H), 6.28 (d, J = 2.40 Hz, 1H), 4.45 (s, 2H), 3.98 (s, 1H), 3.26-3.21 (m, 2H), 3.07-3.04 (m, 1H), 2.75-2.65 (m, 1H), 2.42-2.32 (m, 4H), 2.25 (s, 3H), 2.10-1.90 (m, 8H), 1.62-1.48 (m, 2H).
Table-101: Step 3: The procedure is similar to Step 1[A] in Example-838.
Figure imgf000701_0002
[002101] Step 3[IN11067-004-Pl]: 1H-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, 1H), 6.86 (s, 1H), 6.80 (d, J = 7.60 Hz, 1H), 6.33 (s, 1H), 6.28 (d, J = 2.40 Hz, 1H), 4.45 (q, J = 10.80 Hz, 2H), 3.99 (s, IH), 3.58 (s, 4H), 3.48-3.41 (m, 2H), 2.26 (s, 3H), 1.98-1.85 (m, 8H), 1.69-1.37 (m, 6H).
[002102] Step 3[IN11067-003-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.41 (s, IH), 6.85 (s, IH), 6.80 (d, J = 4.00 Hz, IH), 6.33 (s, IH), 6.28 (s, IH), 4.50-4.40 (m, 2H), 4.00 (s, IH), 3.85 (d, J = 24.00 Hz, IH), 3.60 (d, J = 16.00 Hz, IH), 3.50-3.35 (m, 3H), 3.25-3.20 (m, IH), 2.26 (s, 3H), 2.15-1.85 (m, 6H), 1.70-1.50 (m, 4H), 1.50-1.30 (m, 4H).
Example-
Figure imgf000702_0001
IN11039-017-P1 IN11125-012-P1
Table-102: Step 1: The procedure is similar to Step 2[NSSy5701] in Example
Figure imgf000702_0002
[002103] Step 1[IN11039-017-P1]: IH-NMR (400 MHz, CD30D): δ 8.36 (d, J = 2.8 Hz, IH), 6.95 (s, IH), 6.36 (s, IH), 6.25 (d, J = 2.4 Hz, IH), 3.96-3.94 (m, IH), 3.56-3.53 (m, 2H), 3.49 (s, 2H), 3.33 (s, 4H), 2.64-2.61 (m, 2H), 2.32 (s, 3H), 2.28 (s, 3H), 2.09-1.91 (m, 6H), 1.69-1.61 (m, 2H).
[002104] Step 1[IN11125-012-P1]: IH-NMR (400 MHz, CDC13): δ 8.31 (d, J = 2.40 Hz, IH), 7.07 (s, IH), 6.31 (s, IH), 6.19 (d, J = 2.40 Hz, IH), 4.52 (s, 2H), 4.26 (d, J = 114.40 Hz, IH), 3.90-3.80 (m, IH), 3.65-3.58 (m, 4H), 3.41 (s, 3H), 2.36 (s, 3H), 2.20-2.10 (m, 4H), 2.00-1.82 (m, 2H), 1.70-1.60 (m, 2H). Example-878:
Figure imgf000703_0001
IN11039-006-P1 IN11125-008-P1
Table-103: Step 1: The procedure is similar to Step 2[IN10991-021-P1] in Example-694.
Figure imgf000703_0003
[002105] Step l[IN11039-006-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.42 (d, J = 2.80 Hz, 1H), 6.90 (d, J = 7.20 Hz, 1H), 6.85 (s, 1H), 6.30 (d, J = 2.00 Hz, 2H), 4.99 (s, 2H), 3.99 (s, 1H), 3.00 (s, 3H), 2.86 (s, 3H), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.62-1.50 (m, 2H).
[002106] Step l[IN11125-008-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 2.40 Hz, 1H), 8.05 (d, J = 2.00 Hz, 1H), 7.20 (d, J = 2.00 Hz, 2H), 6.29 (s, 1H), 6.20 (d, J = 2.40 Hz, 1H), 5.39 (s, 2H), 4.40 (d, J = 7.20 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 1H), 2.37 (s, 3H), 2.15- 1.99 (m, 4H), 1.93-1.85 (m, 2H), 1.67-1.62 (m, 2H).
Figure imgf000703_0002
[002107] Step 1: The procedure is similar to Step 2[NSSy5701] in Example-813. 1 g of 2, 4, 6-trichloropyridine gave 2-(((2, 6-dichloropyridin-4-yl) oxy) methyl) oxazole as an off- white solid (0.75 g, 60%). MS (M+l)+=245.0.
[002108] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 0.75 g of 2-(((2, 6-dichloropyridin-4-yl) oxy) methyl) oxazole gave 6-chloro-N-(4, 4- difluorocyclohexyl)-4-(oxazol-2-ylmethoxy) pyridin-2-amine as a pale green solid (0.26 g, 25%). MS (M+l)+=344.0.
[002109] Step 3[IN11067-023-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.26 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-4-(oxazol-2-ylmethoxy) pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)-4- (oxazol-2-ylmethoxy) pyridin-2-amine as a white solid (0.065 g, 21%). MS (M+l)+=404.0; 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (s, IH), 7.29 (s, IH), 6.75 (d, J = 7.60 Hz, IH), 6.61 (s, IH), 6.03 (s, IH), 5.97 (s, IH), 5.24 (s, 2H), 3.87 (s, IH), 2.57 (s, 3H), 2.19 (s, 3H), 1.90- 1.85 (m, 6H), 1.55-1.45 (m, 2H).
Example-880:
Figure imgf000704_0001
Figure imgf000704_0002
[002110] Step 1: The procedure is similar to Step l[NSSy6519] in Example-842. 3 g of 2, 4, 6-trichloropyridine gave 2, 6-dichloro-4-methoxypyridine as a white solid (2.1 g, 72%). MS (M+l)+=177.9. [002111] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 1.5 g of 2, 6-dichloro-4-methoxypyridine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- methoxypyridin-2-amine as a brown solid (0.5 g, 32%). MS (M+l)+=277.3.
[002112] Step 3 [INI 1054-054-P1, INI 1054-030-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.2 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-4- methoxypyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-methoxy-6-(3-methyl-lH- pyrazol-l-yl) pyridin-2-amine as an off-white solid (0.018 g, 12%). MS (M+l)+=323.; 1H- NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.40 Hz, IH), 6.67 (d, J = 7.60 Hz, IH), 6.54 (s, IH), 6.28 (s, IH), 5.88 (s, IH), 3.90 (s, IH), 3.78 (s, 3H), 2.25 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.48 (m, 2H) and N-(4, 4-difluorocyclohexyl)-4, 6-bis(3-methyl-lH-pyrazol-l- yl)pyridin-2-amine as an off-white solid (0.06 g, 22%). MS (M+l)+=373.1; IH-NMR (400 MHz, DMSO-d6): δ 8.45 (s, IH), 8.41 (s, IH), 7.33 (s, IH), 6.96 (d, J = 6.80 Hz, IH), 6.75 (s, IH), 6.38 (s, IH), 6.33 (s, IH), 4.02 (s, IH), 2.29 (d, J = 4.80 Hz, 6H), 2.10-1.90 (m, 6H), 1.65-1.55 (m, 2H).
Example-
Figure imgf000705_0001
Table-104: Step 1:
Figure imgf000705_0002
[002113] Step 1[IN11054-038-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. IH-NMR (400 MHz, DMSO-d6): δ 6.66 (d, J = 7.20 Hz, IH), 6.52 (s, IH), 6.02 (s, IH), 5.89 (s, IH), 3.86 (s, IH), 4.05 (s, 3H), 2.57 (s, 3H), 2.16 (s, 3H), 2.10-1.85 (m, 6H), 1.58-1.48 (m, 2H).
[002114] Step 1[IN11146-013-P1]: The procedure is similar to Step l[NSSy6989] in Example-839. IH-NMR (400 MHz, DMSO-d6): δ 7.29 (s, IH), 6.84 (d, J = 1.6 Hz, IH), 6.68 (d, J = 6.8 Hz, IH), 6.07 (d, J = 1.6 Hz, IH), 3.89-3.84 (m, IH), 3.79 (s, 3H), 2.41 (s, 3H), 2.09-1.88 (m, 6H), 1.62-1.57 (m, 2H).
Example-882:
Figure imgf000706_0001
[002115] Step 1: The procedure is similar to Step 4[NSSy6464] in Example-869. 0.1 g of 2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) isonicotinonitrile gave l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) ethan-1- one as a yellow solid (0.1 g, 95%). MS (M+l)+=335.0.
[002116] Step 2: The procedure is similar to Step 2[NSSy6931] in Example-21. 0.2 g of l-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-4-yl)ethan- 1-one gave l-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-4-yl)ethan- l-ol as a yellow solid (0.16 g, 80%). MS (M+l)+=337.2.
[002117] Step 3[IN11054-003-P1]: The procedure is similar to Step 5[NSSy6711] in Example-854. 0.1 g of l-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-4-yl)ethan-l-ol gave l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)ethyl dimethylcarbamate as a yellow solid (0.035 g, 29%). MS (M+l)+=408.2; IH-NMR (400 MHz, DMSO-d6): δ 8.41 (d, J = 2.40 Hz, IH), 6.86 (t, J = 3.20 Hz, 2H), 6.30-6.29 (m, 2H), 5.54 (q, J = 6.40 Hz, IH), 3.98 (s, IH), 2.95 (s, 3H), 2.82 (s, 3H), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.50 (m, 2H), 1.43 (d, J = 6.80 Hz, 3H). Example-883:
Figure imgf000707_0001
[002118] Step 1: To a solution of l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl- lH-pyrazol-l-yl) pyridin-4-yl) ethan-l-one (0.2 g, 0.59 mmol) in ethanol was added hydro xylamine hydrochloride (0.082 g, 1.18 mmol) and sodium acetate (0.097 g, 1.18 mmol). The reaction mixture was heated at 90 °C for lh. The reaction mixture was evaporated, quenched with water, extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (Z)-l-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)ethan-l-one oxime as a yellow solid (0.18 g, 89%). MS (M+l)+=350.1.
[002119] Step 2: The procedure is similar to Step 2[NSSy6464] in Example-869. 0.1 g of (Z)- 1-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridine-4- yl)ethan-l-one oxime gave 4-(l-aminoethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-2-amine as a pale brown solid (0.1 g, crude). MS (M+l)+=336.2.
[002120] Step 3[IN11054-005-P1]: The procedure is similar to Step 1[A] in Example- 838. 0.1 g of 4-(l-aminoethyl)-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine gave methyl (l-(2-((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH- pyrazol-l-yl) pyridin-4-yl) ethyl) carbamate as pale brown solid (0.025 g, 21%). MS
(M+l)+=394.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, J = 2.00 Hz, IH), 7.77 (d, J = 8.00 Hz, IH), 6.91 (s, IH), 6.79 (d, J = 7.20 Hz, IH), 6.27 (d, J = 8.00 Hz, 2H), 4.52-4.48 (m, IH), 3.97 (s, IH), 3.51 (s, 3H), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.50 (m, 2H), 1.31 (d, J = 7.60 Hz, 3H).
Example-884:
Figure imgf000707_0002
[002121] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 2, 6-dichloro-4-methylpyridine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- methylpyridin-2-amine as an off-white solid (0.35 g, 43%). MS (M+l)+=261.0.
[002122] Step 2[IN11106-062-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-4-methylpyridin-2-amine gave 6-(3-cyclopropyl- IH-pyrazol- l-yl)-N-(4, 4-difluorocyclohexyl)-4-methylpyridin-2-amine as a white solid (0.11 g, 19%). MS (M+l)+=333.1; IH-NMR (400 MHz, DMSO-d6): δ 8.36 (s, 1H), 6.77 (s, 1H), 6.62 (d, J = 7.20 Hz, 1H), 6.18 (d, J = 5.20 Hz, 2H), 3.96 (s, 1H), 2.20 (s, 3H), 2.10-1.90 (m, 7H), 1.60-1.45 (m, 2H), 0.92-0.85 (m, 2H), 0.77-0.71 (m, 2H).
Figure imgf000708_0001
[002123] Step 1: The procedure is similar to Step l[NSSy6629] in Example-839. 2 g of
2- chloro-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((3, 3- difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile as a yellow solid (0.75 g, 29%). MS (M+l)+=304.0.
[002124] Step 2: The procedure is similar to Step 1[B] in Example-838. 0.2 g of 2-((3,
3- difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinonitrile gave 2-((3, 3-difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinic acid as a white solid (0.2 g, 94%). MS (M+l)+=323.0.
[002125] Step 3: The procedure is similar to Step 3[NSSy6711] in Example-854. 0.2 g of 2-((3, 3-difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl) isonicotinic acid gave ethyl 2-((3, 3-difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH-pyrazol-l-yl)
isonicotinate as a white solid (0.17 g, 78%). MS (M+l)+=351.0.
[002126] Step 4[IN11146-039-P1]: The procedure is similar to Step 4[NSSY6711] in Example-854. 0.17 g of ethyl 2-((3, 3-difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH- pyrazol-l-yl) isonicotinate gave (2-((3, 3-difluorocyclobutyl) amino)-6-(3, 5-dimethyl-lH- pyrazol-l-yl) pyridin-4-yl) methanol as an off-white solid (0.06 g, 40%). MS (M+l)+=309.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.16 (d, J = 6.00 Hz, 1H), 6.93 (s, 1H), 6.35 (s, 1H), 6.03 (s, 1H), 5.31 (t, J = 5.60 Hz, 1H), 4.44 (d, J = 5.60 Hz, 2H), 4.17-4.13 (m, 1H), 3.05-2.90 (m, 2H), 2.55 (s, 3H), 2.55-2.50 (m, 2H), 2.16 (s, 3H).
Example-886:
Figure imgf000709_0001
[002127] Step 1 : The procedure is similar to Step 5[NSSy6711] in Example-854. 2 g of 2, 4, 6-trichloropyridine gave 2, 6-dichloro-4-((tetrahydro-2H-thiopyran-4-yl) oxy) pyridine as a white solid (1.6 g, 55%). MS (M+l)+=264.0.
[002128] Step 2: The procedure is similar to Step 3[NSSy7062] in Example-623. 0.95 g of 2, 6-dichloro-4-((tetrahydro-2H-thiopyran-4-yl) oxy) pyridine gave 4-((2, 6- dichloropyridin-4-yl) oxy) tetrahydro-2H-thiopyran 1, 1-dioxide as white solid (0.77 g, 68%). MS (M+l)+=298.0.
[002129] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.42 g of 4-((2, 6-dichloropyridin-4-yl) oxy) tetrahydro-2H-thiopyran 1, 1-dioxide gave 4-((2- chloro-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) oxy) tetrahydro-2H-thiopyran 1, 1-dioxide as an off-white solid (0.25 g, 51%). MS (M+l)+=342.1.
[002130] Step 4[IN11146-089-P1]: The procedure is similar to Step l[NSSy6629] in Example-839. 0.25 g of 4-((2-chloro-6-(3-methyl- lH-pyrazol-l-yl)pyridin-4- yl)oxy)tetrahydro-2H-thiopyran 1, 1-dioxide gave 4-((2-((4, 4-difluorocyclohexyl)amino)-6- (3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)oxy) tetrahydro-2H-thiopyran 1, 1-dioxide as a white solid (0.04 g, 12%). MS (M+l)+=441.2; 1H-NMR (400 MHz, DMSO-d6): δ 8.39 (d, J = 2.00 Hz, 1H), 6.70 (d, J = 8.00 Hz, 1H), 6.64 (s, 1H), 6.29 (d, J = 2.40 Hz, 1H), 5.92 (s, 1H), 4.70 (s, 1H), 3.94 (s, 1H), 4.12-3.15 (m, 4H), 2.33 (s, 7H), 2.10-1.90 (m, 6H), 1.60-1.48 (m, 2H). Example-887:
Figure imgf000710_0001
[002131] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.3 g of 4- chloro-N-(4, 4-difluorocyclohexyl)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-2-amine gave 2- ((4, 4-difluorocyclohexyl) amino)-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-ol as an off-white solid (0.035 g, 12%). MS (M+l)+=342.1.
Table-105: Step 2: The procedure is similar to Step 1[B] in Example-838.
Figure imgf000710_0002
[002132] Step 2[IN11177-056-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.44 (s, IH), 8.39 (d, J = 2.40 Hz, IH), 7.34 (s, IH), 6.71 (s, IH), 6.62 (d, J = 2.00 Hz, IH), 6.29 (d, J = 2.80 Hz, IH), 5.96 (d, J = 2.00 Hz, IH), 5.23 (s, 2H), 3.95 (s, IH), 2.26 (s, 3H), 2.10-1.90 (m, 6H), 1.60-1.48 (m, 2H).
[002133] Step 2[IN11177-043-Pl]: IH-NMR (400 MHz, DMSO-d6): δ 8.39 (s, IH), 8.19 (s, IH), 7.29 (s, IH), 6.76 (d, J = 7.60 Hz, IH), 6.63 (s, IH), 6.29 (s, IH), 5.96 (s, IH), 5.28 (s, 2H), 3.93 (s, IH), 2.25 (s, 3H), 2.10-1.90 (m, 6H), 1.58-1.48 (m, 2H). Example-888:
Figure imgf000711_0001
[002134] Step 1: To a solution of 2,4,6-trichloropyridine (2 g, 11.05 mmol) in methanol was added sodium thiomethoxide (1.26 g, 17.68 mmol) and stirred at room temperature for 16h. The reaction mixture was diluted with cold water, stirred for 10 min, the solid formed was filtered and dried under vacuum to afford 2, 6-dichloro-4-(methylthio)pyridine as a white solid (1.3 g, 61%). MS (M+l)+=195.8.
[002135] Step 2: The procedure is similar to Step l[NSSy6629] in Example-839. 0.8 g of 2, 6-dichloro-4-(methylthio) pyridine gave 6-chloro-N-(4, 4-difluorocyclohexyl)-4- (methylthio) pyridin-2-amine as an off-white solid (0.51 g, 42%). MS (M+l)+=292.9.
[002136] Step 3 [INI 1147-026-P1]: The procedure is similar to Step l[NSSy6989] in Example-839. 0.51 g of 6-chloro-N-(4, 4-difluorocyclohexyl)-4-(methylthio) pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol-2-yl)-4-(methylthio) pyridin-2-amine as an off-white solid (0.28 g, 39%). MS (M+l)+=356.0; 1H-NMR (400 MHz, DMSO-d6): δ 7.31 (s, 1H), 7.07 (s, 1H), 6.78 (d, J = 6.80 Hz, 1H), 6.38 (s, 1H), 3.90 (s, 1H), 2.48 (s, 3H), 2.44 (s, 3H), 2.12-1.88 (m, 6H), 1.62-1.52 (m, 2H).
[002137] Step 4[IN11147-031-Pl and IN11147-036-P1]: The procedure is similar to Step 3[NSSy7062] in Example-623. 0.1 g of N-(4, 4-difluorocyclohexyl)-6-(4-methylthiazol- 2-yl)-4-(methylthio) pyridin-2-amine gave N-(4, 4-difluorocyclohexyl)-4-(methylsulfinyl)-6- (4-methylthiazol-2-yl) pyridin-2-amine as an off-white solid (0.04 g, 40%). MS
(M+l)+=372.2; 1H-NMR (400 MHz, DMSO-d6): δ 7.37 (s, 2H), 7.30 (d, J = 6.80 Hz, 1H), 6.88 (s, 1H), 3.95 (s, 1H), 2.81 (s, 3H), 2.42 (s, 3H), 2.15-1.90 (m, 6H), 1.68-1.55 (m, 2H) and N-(4, 4-difluorocyclohexyl)-4-(methylsulfonyl)-6-(4-methylthiazol-2-yl)pyridin-2-amine as an off-white solid (0.032 g, 30%). MS (M+l)+=388.1; 1H-NMR (400 MHz, DMSO- 6): δ 7.53-7.50 (m, 2H), 7.42 (s, IH), 7.03 (s, IH), 4.02 (bs, IH), 3.28 (s, 3H), 2.44 (s, 3H), 2.10-
1.85 (m, 6H), 1.65-1.55 (m, 2H).
Example-889:
Figure imgf000712_0001
[002138] Step 1: The procedure is similar to Step 1[B] in Example-838. 0.5 g of 2, 6- dichloro-4-nitropyridine gave tert-butyl 4-((2, 6-dichloropyridin-4-yl) oxy) piperidine-l- carboxylate as a pale yellow solid (0.33 g, 37%). MS (M+l)+=347.1.
[002139] Step 2: The procedure is similar to Step 1 [B] in Example-838. 0.33 g of tert- butyl 4-((2, 6-dichloropyridin-4-yl) oxy) piperidine-l-carboxylate gave tert-butyl 4-((2- chloro-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl) oxy) piperidine-l-carboxylate as an off- white solid (0.11 g, 29%). MS (M+l)+=393.2.
[002140] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.1 g of tert-butyl 4-((2-chloro-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)oxy)piperidine -1- carboxylate gave tert-butyl 4-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol- l-yl)pyridin-4-yl)oxy)piperidine-l-carboxylate as pale yellow solid (0.06 g, 43%). MS (M+l)+=492.3.
[002141] Step 4[IN11218-025-P1]: The procedure is similar to Step 2[NSSy6924] in Example-857. 0.06 g of tert-butyl 4-((2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)oxy)piperidine-l-carboxylate gave l-(4-((2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- lH-pyrazol- l-yl)pyridin-4-yl)oxy)piperidin- 1- yl)ethan-l-one as an off-white solid (0.03 g, 57%). MS (M+l)+=434.3; IH-NMR (400 MHz, DMSO-d6): δ 8.38 (d, J = 2.4 Hz, IH), 6.63 (d, J = 7.2 Hz, IH), 6.57 (d, J = 2.0 Hz, IH), 6.28 (d, J = 2.4 Hz, IH), 5.91 (d, J = 2.0 Hz, IH), 4.70-4.63 (m, IH), 3.96-3.94 (m, IH), 3.79-3.75 (m, IH), 3.66-3.63 (m, IH), 2.28 (s, 3H), 2.05-2.00 (m, 13H), 1.65-1.54 (m, 5H). Example-890:
Figure imgf000713_0001
[002142] Step 1 : The procedure is similar to Step 4[NSSy6067] in Example-628. 2 g of 2, 6-dichloro-4-iodopyridine gave tert-butyl 4-(2, 6-dichloropyridin-4-yl)-4- hydroxypiperidine-l-carboxylate as an off-white solid (1.5 g, 30%). MS (M+l)+=347.2.
[002143] Step 2: The procedure is similar to Step 1[B] in Example-838. 1.5 g of tert- butyl 4-(2, 6-dichloropyridin-4-yl)-4-hydroxypiperidine-l-carboxylate gave tert-butyl 4-(2- chloro-6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl)-4-hydroxypiperidine-l-carboxylate as red colour solid (0.7 g, 41%). MS (M+l)+=393.2.
[002144] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.6 g of tert-butyl 4-(2-chloro-6-(3-methyl- IH-pyrazol- 1 -yl)pyridin-4-yl)-4-hydroxypiperidine- 1- carboxylate gave tert-butyl 4-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-4-yl)-4-hydroxypiperidine-l-carboxylate as an off-white solid (0.4 g, crude). MS (M-H20)+=474.3.
[002145] Step 4[IN11251-024-P1]: The procedure is similar to Step 4[NSSy6711] in Example-854. 0.35 g of tert-butyl 4-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)-4-hydroxypiperidine-l-carboxylate gave 4-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl- IH-pyrazol- l-yl)pyridin-4-yl)- l-methylpiperidin-4- ol as a white solid (0.04 g, 10%). MS (M+l)+=406.3; 1H-NMR (400 MHz, DMSO-J6): δ 8.15 (d, / = 2.40 Hz, 1H), 7.63 (d, / = 8.40 Hz, 1H), 6.81 (d, / = 7.20 Hz, 1H), 6.73 (s, 1H), 6.50 (d, / = 8.40 Hz, 1H), 6.35 (d, / = 2.40 Hz, 1H), 3.85 (s, 1H), 2.48-2.22 (m, 7H), 2.10 (s, 3H), 2.05-1.80 (m, 6H), 1.60-1.40 (m, 6H). Example-891:
Figure imgf000714_0001
[002146] Step 1: The procedure is similar to Step 4[NSSy6067] in Example-628. 2 g of 2, 6-dichloro-4-iodopyridine gave tert-butyl 3-(2, 6-dichloropyridin-4-yl)-3- hydroxypyrrolidine-l-carboxylate as pale brown solid (2 g, crude).
[002147] Step 2: The procedure is similar to Step 1[B] in Example-838. 1 g of tert-butyl 3-(2, 6-dichloropyridin-4-yl)-3-hydroxypyrrolidine-l-carboxylate gave tert-butyl 3-(2-chloro- 6-(3-methyl-lH-pyrazol-l-yl) pyridin-4-yl)-3-hydroxypyrrolidine-l-carboxylate as an off- white solid (0.7 g, 63%). MS (M+l)+=379.2.
[002148] Step 3: The procedure is similar to Step l[NSSy6629] in Example-839. 0.58 g of tert-butyl 3-(2-chloro-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)-3-hydroxypyrrolidine-l- carboxylate gave tert-butyl 3-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l- yl)pyridin-4-yl)-3-hydroxypyrrolidine-l-carboxylate as a brown solid (0.47 g, 55%). MS (M+l)+=478.3.
[002149] Step 4[IN11251-035-P1]: The procedure is similar to Step 2[NSSy6924] in Example-857.0.47 g of tert-butyl 3-(2-((4, 4-difluorocyclohexyl)amino)-6-(3-methyl-lH- pyrazol-l-yl)pyridin-4-yl)-3-hydroxypyrrolidine-l-carboxylate gave methyl 3-(2-((4, 4- difluorocyclohexyl)amino)-6-(3-methyl-lH-pyrazol-l-yl)pyridin-4-yl)-3-hydroxypyrrolidine- 1-carboxylate as an off-white solid (0.08 g, 20%). MS (M+l)+=436.3; 1H-NMR (400 MHz, DMSO-d6) : δ 8.41 (d, / = 2.80 Hz, 1H), 7.02 (d, = 1.60 Hz, 1H), 6.81 (d, = 6.80 Hz, 1H), 6.50 (s, 1H), 6.29 (d, = 2.80 Hz, 1H), 5.57 (s, 1H), 3.99 (s, 1H), 3.65-3.40 (m, 7H), 2.26 (s, 3H), 2.20-1.90 (m, 8H), 1.62-1.50 (m, 2H). Example-892:
Figure imgf000715_0001
-
[002150] Step 1: The Procedure is similar to Step 1[B] in Example-838. 1 g of 1, 3- dichloroisoquinoline gave l-chloro-3-(3-methyl-lH-pyrazol-l-yl) isoquinoline (1.15 g, 93%). MS (M+l)+=244.1.
[002151] Step 2[IN11039-023-P1]: The Procedure is similar to Step l[NSSy6629] in Example-839. 0.5 g of l-chloro-3-(3-methyl-lH-pyrazol-l-yl) isoquinoline gave N-(4,4- difluorocyclohexyl)-3-(3-methyl-lH-pyrazol-l-yl)isoquinolin-l-amine (0.4 g, 57%). MS (M+l)+=343.2; IH-NMR (400 MHz, DMSO-d6): δ 8.35 (d, J = 8.80 Hz, 1H), 8.11 (d, J = 2.00 Hz, 1H), 7.58 (d, J = 8.40 Hz, 1H), 7.46 (t, J = 7.20 Hz, 1H), 7.16 (t, J = 8.00 Hz, 1H), 6.70 (s, 1H), 6.37 (d, J = 2.00 Hz, 1H), 3.90-3.80 (m, 1H), 2.39 (s, 3H), 2.20-1.85 (m, 7H), 1.75-1.60 (m, 2H).
[002152] Step 3 [INI 1039-036-P1]: The Procedure is similar to Step 2[NSSy6464] in Example-869. 0.2 g of N-(4, 4-difluorocyclohexyl)-3-(3-methyl-lH-pyrazol-l-yl)
isoquinolin-1 -amine gave N-(4, 4-difluorocyclohexyl)-3-(3-methyl-lH-pyrazol-l-yl)-5, 6, 7, 8-tetrahydro isoquinolin-1 -amine (0.11 g, 54%). MS (M+l)+=347.1; IH-NMR (400 MHz, CDC13): δ 7.80 (d, J = 2.40 Hz, 1H), 6.17 (d, J = 2.00 Hz, 1H), 6.12 (s, 1H), 4.23 (d, J = 8.00 Hz, 1H), 3.72-3.62 (m, 1H), 2.78-2.70 (m, 4H), 2.33 (s, 3H), 2.15-2.00 (m, 4H), 1.95-1.80 (m, 2H), 1.78-1.65 (m, 4H), 1.64-1.60 (m, 2H).
Example-89
Figure imgf000715_0002
IN11337-019-P1 [002153] Step 1: A 250 mL 2-neck round-bottomed equipped with stir bar was charged with 4,6-dichloro-2-(methylsulfonyl)pyrimidine (5.0 g, 22.12 mmol, 1.0 eq.), ethyl 1H- pyrazole-3-carboxylate (3.10 g, 22.12 mmol, 1.0 eq.) and cesium carbonate (7.28 g, 22.12 mmol, 1.0 eq.) in acetonitrile (50 mL) stirred at rt for 8 h. Progress of the reaction was monitored by TLC. Reaction mass diluted with water (80 mL), extracted with ethyl acetate (2 x 40 mL) and the combined organic layer was washed with water (50 ml), brine (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by CombiFlash by using with 15% ethyl acetate in hexane as eluent. The desired fractions were evaporated under reduced pressure to afford ethyl l-(4,6- dichloropyrimidin-2-yl)-lH-pyrazole-3-carboxylate (off-white solid) (1.8 g, 6.26 mmol, 28%) MS (M+H): m/z=287.10.
[002154] Step 2: A 100 mL 2-neck round-bottomed equipped with stir bar was charged with ethyl l-(4,6-dichloropyrimidin-2-yl)-lH-pyrazole-3-carboxylate (1.80 g, 6.29 mmol, 1.0 eq.), 4,4-difluorocyclohexan-l -amine hydrochloride (1.180 g, 6.92 mmol, l.Oleq.) and cesium carbonate (4.70 g, 14.4 mmol, 2.3 eq.) in toluene (20 mL) stirred at 85 oC for 1 h. Progress of the reaction was monitored by TLC. Reaction mass cooled to rt, diluted with water (60 mL), extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude product was triturated with diethyl ether (20.0 mL) and dried to afford ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazole-3-carboxylate (1.6 g, 6.26 mmol, 66%) MS (M+H): m/z=385.6.
[002155] Step 3: A 100 mL 2-neck round-bottomed equipped with stir bar was charged with ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)- lH-pyrazole-3- carboxylate (100.0 mg, 0.25 mmol, 1.0 eq.) added THF:Methanol (9: 1 mixture) then added Sodium borohydride (98.0 mg, 2.59 mmol, 10.36 eq.) (Spectrochem) at RT, then whole reaction mixture together stirred at RT for 6 h. Progress of the reaction was monitored by TLC. Reaction mass was diluted with (water 30 mL) ethyl acetate (20 mL X 2) times extracted and separated organic layer was dried over anhydrous sodium sulfate and concentrated and dried to get the crude compound. The crude product was purified by CombiFlash using 12 g column and 8% MeOH in DCM as eluents. The desired fractions were evaporated under reduced pressure to afford ethyl l-(4-chloro-6-((4,4- difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate (40 mg, 0.116 mmol, 47%) MS (M+H): m/z=343.10. [002156] Step 4: A 100 mL sealed tube equipped with small stir bar charged with ethyl l-(4-chloro-6-((4,4-difluorocyclohexyl)amino)pyrimidin-2-yl)-lH-pyrazole-3-carboxylate (40.0 mg, 0.116 mmol, 1.0 eq.), Et3N (0.16 mL, 1.16 mmol, 10.0 eq.) and 2,2'-azanediylbis- ethan-l-ol (122.0 mg, 1.16 mmol, 10.0 eq.). Then sealed tube was capped tightly and heated at 110 °C for 7 h. The progress of the reaction was monitored by TLC. Reaction mass was diluted with water (10 mL) extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and under reduced pressure. The crude product was purified by CombiFlash using 12 g column and 10% MeOH in DCM as eluents. The desired fractions were evaporated under reduced pressure to afford 2,2'-((6-((4,4-difluorocyclohexyl)amino)-2-(3-(hydroxymethyl)- lH-pyrazol-l-yl)pyrimidin-4-yl)azanediyl)bis-(ethan-l-ol) IN11337-019-P1 (20 mg, 0.048 mmol, 42%) MS (M+H): m/z=412.7. 1H NMR (DMSO-d6, 400MHz) δ ppm: 1.52-1.57 (m, 2 H), 1.85-2.08 (m, 6 H), 3.56-3.58 (m, 8 H), 4.0 (brs, 1 H), 4.47 (d, J = 5.6 Hz, 2 H), 4.84 (t, J = 5.6 Hz, 2 H), 5.14 (t, J = 5.6 Hz, 1 H), 5.44 (s, 1 H), 6.41 (d, J = 2.4 Hz,l H), 6.97 (d, J = 7.6 Hz, 1 H), 8.43 (d, J = 3.2 Hz, 1H).
BIOLOGICAL ASSAYS
[002157] The biological activity was determined as follows. The ionic current through small-conductance Ca2+-activated K+ channels (SK channels, subtype 2) was measured using the whole-cell configuration of the patch-clamp technique in a patch-clamp set-up using HEK293 tissue culture cells expressing SK2 channels as described in Hougaard et al., British Journal of Pharmacology 151, 655 - 665, May 8, 2007, the entire teachings of which are incorporated herein by reference. In one aspect, a compound is defined to be an SK PAM if the compound increases current in this assay, for example, if the SCioo value of the compound is less than or equal to 10 μΜ as determined by this assay. The SCioo value is defined to be the concentration of compound that increases the basal current by 100%.
[002158] The SCioo values are given in Table 106 and 107.
Table 106
Figure imgf000717_0001
Figure imgf000717_0002
Figure imgf000717_0003
Figure imgf000717_0004
107 + 173 ++ 239 ++ 305 ++
108 + 174 ++ 240 + 306 +
109 + 175 ++ 241 + 307 +
110 ++ 176 + 242 + 308 +
111 + 177 + 243 + 309 ++
112 ++ 178 + 244 ++ 310 ++
113 ++ 179 ++ 245 + 311 +++
114 + 180 + 246 +++ 312 ++
115 + 181 + 247 ++ 313 ++
116 ++ 182 ++ 248 ++ 314 +
117 ++ 183 + 249 + 315 +
118 + 184 + 250 ++ 316 +++
119 + 185 ++ 251 ++ 317 +++
120 ++ 186 ++ 252 + 318 ++
121 + 187 ++ 253 ++ 319 +
122 + 188 ++ 254 + 320 ++
123 + 189 +++ 255 + 321 +
124 + 190 ++ 256 ++ 322 ++
125 + 191 ++ 257 + 323 ++
126 ++ 192 ++ 258 ++ 324 ++
127 ++ 193 + 259 + 325 +
128 + 194 ++ 260 + 326 ++
129 + 195 ++ 261 ++ 327 +
130 + 196 + 262 ++ 328 +
131 + 197 ++ 263 ++ 329 ++
132 ++ 198 + 264 ++ 330 ++
133 + 199 ++ 265 + 331 +
134 ++ 200 ++ 266 ++ 332 ++
135 + 201 ++ 267 + 333 +
136 ++ 202 + 268 ++ 334 +
137 ++ 203 ++ 269 + 335 ++
138 + 204 + 270 + 336 ++
139 + 205 ++ 271 ++ 337 +
140 + 206 + 272 + 338 ++
141 ++ 207 + 273 ++ 339 ++
142 + 208 ++ 274 + 340 +
143 ++ 209 + 275 + 341 ++
144 + 210 ++ 276 + 342 ++
145 + 211 +++ 277 ++ 343 ++
146 ++ 212 + 278 ++ 344 +
147 ++ 213 ++ 279 ++ 345 ++
148 ++ 214 + 280 + 346 +
149 ++ 215 + 281 ++ 347 ++
150 + 216 ++ 282 + 348 ++
151 ++ 217 + 283 ++ 349 ++ 152 + 218 ++ 284 ++ 350 +
153 + 219 + 285 + 351 +
154 + 220 ++ 286 +++ 352 +
155 + 221 + 287 ++ 353 +
156 ++ 222 + 288 ++ 354 +
157 ++ 223 + 289 ++ 355 +
158 ++ 224 + 290 ++ 356 +
159 ++ 225 + 291 ++ 357 +
160 + 226 ++ 292 ++ 358 +
161 + 227 ++ 293 ++ 360 ++
162 ++ 228 ++ 294 ++ 361 ++
163 + 229 ++ 295 ++ 362 ++
164 + 230 + 296 ++ 363 ++
165 + 231 ++ 297 ++ 364 ++
365 ++
+ means > 1 uM; ++ means 200 nM - 1000 nM; +++ means < 200 nM.
Table 107
Figure imgf000719_0001
Figure imgf000720_0001
Figure imgf000721_0001
+ means > 1 uM; ++ means 200 nM - 1000 nM; +++ means < 200 nM; NT means not tested.
Table 107 - Continued
Figure imgf000721_0002
Figure imgf000722_0001
Figure imgf000723_0001
+ means > 1 uM; ++ means 200 nM - 1000 nM; +++ means < 200 nM; NT means not tested.
Table 107 - Continued
NSSy # SCioo
Figure imgf000724_0001
Figure imgf000725_0001
Figure imgf000726_0001
+ means > 1 uM; ++ means 200 nM - 1000 nM; +++ means < 200 nM; NT means not tested.
Table 107 - Continued
Figure imgf000726_0002
Table 107 - Continued
Figure imgf000727_0001
IN11111-092-P1 ++
IN11140-083-P1 +
IN11147-036-P1 +++
IN11133-062-P1 NT
IN11137-074-P1 ++
IN11106-077-P1 ++
IN11166-036-P1 ++
IN11133-061-P1 +++
IN11133-069-P1 +++
IN11133-068-P1 ++
IN11140-065-P1 +
IN11104-059-P1 +
IN11130-053-P1 +++
IN11166-038-P1 +++
IN11104-100-P1 +
IN11140-066-P1 +
IN11133-049-P1 ++
IN11137-072-P1 ++
IN11106-066-P1 +
IN11140-063-P1 +
IN11106-065-P1 +
IN11147-031-P1 ++
IN11146-039-P1 +
IN11104-094-P1 ++
IN11147-026-P1 +++
IN11140-058-P1 +
IN11140-052-P1 +++
IN11121-042-P1 +
IN11166-020-P1 ++
IN11106-062-P1 +++
IN11111-063-P1 +
IN11140-062-P1 +
IN11125-065-P1 +
IN11108-038-P1 +
IN11104-084-P2 +
IN11146-033-P1 +
IN11104-095-P1 +
IN11130-047-P1 +++
IN11130-051-P1 +++
IN11146-016-P1 +
IN11133-031-P1 +
IN11137-041-P1 +
IN11125-052-P1 +
IN11133-037-P1 +++
IN11104-077-P1 +
INI 1130-031-P2 +
IN11130-030-P1 +
IN11146-013-P1 ++
IN11108-019-P1 +
IN11108-018-P1 + IN11059-090-P1 ++
IN11059-095-P1 ++
IN11107-023-P1 +
IN11107-021-P1 +
IN11133-020-P1 +
IN11125-028-P1 +
IN11137-018-P1 +
IN11106-027-P1 +
IN11106-033-P1 +
IN11140-007-P1 +
IN11104-099-P1 +
IN11079-066-P1 +
IN11059-096-P1 +
IN11111-024-P1 ++
IN11125-014-P1 ++
IN11104-041-P1 ++
IN11111-023-P1 +
IN11107-020-P1 +
IN11133-014-P1 +
IN11079-072-P1 +
IN11079-067-P1 +
IN11054-100-P1 NT
IN11130-005-P1 +
IN11039-094-P1 +
IN11125-012-P1 ++
IN11125-006-P1 +
IN11125-001-P1 +
IN11104-039-P1 +
IN11111-021-P1 ++
IN11125-013-P1 ++
IN11055-087-P1 +
IN11133-002-P1 +
IN11130-007-P1 ++
IN11063-096-P1 ++
IN11063-092-P1 +
IN11125-008-P1 +++
IN11039-092-P1 +
IN11079-040-P1 +
INI 1059-071 -PI +
IN11059-070-P1 ++
INI 1067-061 -PI +
IN11067-060-P1 +
IN11067-062-P1 +
IN11059-069-P1 ++
IN11111-003-P1 +
IN11106-004-P1 +
IN11063-087-P1 ++
IN11063-086-P2 +
IN11054-081-P1 ++
IN11055-079-P1 + IN11067-072-P1 +
IN11079-047-P1 +
IN11055-069-P1 ++
IN11055-078-P1 +
IN11054-078-P1 +
IN11083-048-P1 +++
IN11079-033-P1 ++
IN11055-066-P1 +
IN11039-069-P1 +++
IN11055-068-P1 +
IN11053-076-P1 +
IN11053-073-P1 +
IN11053-062-P1 +
IN11053-059-P1 +
IN11053-060-P1 ++
IN11055-049-P1 ++
IN11125-010-P1 ++
IN11059-052-P1 ++
IN11053-071-P1 +
IN11039-066-P1 +++
IN11054-054-P1 ++
IN11030-095-P1 +
IN11054-046-P1 +
IN11030-081-P1 ++
IN11059-047-P1 +++
IN11055-046-P1 ++
IN11055-044-P1 +
IN11039-058-P1 ++
IN11053-052-P1 ++
IN11054-030-P1 +
IN11067-035-P1 ++
IN11054-046-P2 ++
IN11030-083-P1 ++
IN11054-039-P1 ++
INI 1079-014-P1 +
IN11053-046-P1 +++
IN11054-038-P1 +
IN11030-054-P1 +
IN11039-036-P1 +
IN11079-007-P1 +
IN11079-009-P1 ++
IN11067-023-P1 +++
IN11063-030-P1 +
IN11053-033-P1 +
IN11083-014-P1 +
IN11030-044-P1 ++
IN11039-026-P1 ++
IN10966-095-P1 +
IN11053-021-P1 +
INI 1054-012-P1 ++ IN11053-024-P1 +
IN11053-022-P1 +
IN11067-004-P1 ++
IN10966-093-P1 +
IN11063-005-P1 +
IN11063-006-P1 ++
IN11030-035-P1 ++
IN11055-016-P1 +
IN11055-015-P1 +
IN10991-091-P1 ++
IN11039-023-P1 +
INI 1054-011-Pl +
IN11053-013-P1 ++
IN11053-005-P1 +
IN11067-003-P1 ++
IN11053-007-P1 +
IN10966-083-P1 +
IN11039-019-P1 +++
IN11039-017-P1 ++
IN11030-032-P1 +++
IN11039-009-P1 ++
IN10965-091-P1 +
IN11054-005-P1 +
IN11054-003-P1 ++
IN10984-079-P1 +
IN11030-023-P1 +
IN11039-006-P1 +++
IN10965-089-P1 ++
IN10963-077-P1 +
IN10971-088-P1 +
IN10991-065-P1 +
IN10991-067-P1 +
IN11030-013-P1 +
IN 10967-061 -PI +
IN10966-057-P2 ++
IN10967-063-P1 ++
IN10963-068-P1 +
IN10973-099-P1 +
IN10973-098-P1 +
IN10971-081-P1 ++
IN10971-077-P1 +
IN10987-055-P1 +
IN10987-056-P1 ++
IN10964-046-P1 +
IN10991-044-P1 ++
IN10973-069-P1 +
IN10973-083-P1 +
IN10987-050-P1 +
IN10973-060-P1 +
IN10971-060-P1 + IN10971-059-P1 +
IN10987-039-P1 +
IN10984-043-P1 +
IN10963-049-P1 ++
IN 10964-041 -PI ++
IN10973-053-P1 +
IN10966-028-P1 ++
IN10987-030-P1 +
IN10973-028-P1 +
IN10973-041-P1 +
IN10973-038-P1 +
IN10991-021-P1 +
IN10984-022-P1 ++
IN10963-024-P1 +
IN10971-033-P1 +
IN10973-025-P1 1
IN10966-011-P1 +
IN10964-008-P1 ++
IN10964-007-P1 +++
IN10876-092-P1 ++
IN10881-099-P1 +
IN10881-098-P1 +
IN10881-092-P1 +++
IN10876-082-P1 +
IN10876-080-P1 +
IN10973-008-P1 +
IN10973-004-P1 +
IN10973-005-P1 +
IN10880-093-P1 ++
IN10881-090-P1 +
IN10882-083-P1 +
IN10876-069-P1 +
IN10882-072-P1 +
IN10880-085-P1 +
IN10880-084-P1 +
IN10882-068-P1 +
IN10880-065-P1 +
IN10880-062-P1 +
IN10876-061-P1 +
IN10881-061-P1 +
IN10881-060-P1 +
IN10881-059-P1 +
IN10881-058-P1 +
IN10881-054-P1 +
IN10880-059-P1 +
IN10880-058-P1 +
IN10880-064-P1 +
IN10864-066-P1 ++
IN10882-055-P1 +
IN10882-057-P1 + IN10864-060-P1 +++
IN10880-056-P1 +
IN10876-041-P2 +
IN10880-055-P1 +
IN10882-040-P1 +
IN10882-043-P1 +
IN10876-051-P1 +
IN10881-040-P1 +
IN10880-029-P1 +
IN10864-043-P1 +++
IN10881-027-P1 ++
IN10880-033-P1 ++
IN10880-035-P1 ++
IN10881-025-P1 ++
IN10880-032-P1 ++
IN10864-034.P1 +++
IN10882-020-P1 ++
IN10881-023-P2 ++
IN10864-33.P1 ++
IN10880-018-P1 ++
IN10882-014-P1 +
IN10876-013-P1 ++
IN10881-020.P1 +++
IN10881-021.P1 ++
IN10864-031-P1 +++
IN10880-014-P1 ++
IN11147-062-P1 +
IN11218-034-P1 ++
IN11104-090-P1 +
IN11288-025-P1 +
IN11196-065-P1 +
IN11216-072-P1 +
IN11273-018-P1 +
INI 1250-031 -PI +
IN11243-031-P1 +
IN11216-043-P1 +
IN11177-068-P1 +
IN11147-071-P1 +
IN11140-099-P1 +
IN11140-090-P1 +
IN11216-073-P1 +++
IN11217-088-P1 +
IN11273-015-P2 +
IN11243-050-P2 ++
IN11273-015-P1 +
IN11217-069-P1 +
IN11217-068-P1 +
IN11273-006-P1 +
IN11251-043-P1 ++
IN11216-050-P1 ++ IN11288-005-P1 ++
IN11243-042-P1 ++
IN11243-041-P1 +++
IN11250-032-P1 ++
IN11273-001-P1 +
IN11238-035-P1 +
IN11238-046-P1 +
IN11238-040-P1 +
IN11251-035-P1 ++
IN11251-024-P1
IN11217-056-P1 ++
IN11220-039-P1 ++
IN11238-088-P1 ++
IN11288-060-P1 NT
IN11237-056-P1 +
IN11251-091-P1 NT
IN11251-092-P1 NT
IN11337-019-P1 +
IN11216-078-P1 +
IN11251-099-P1 NT
+ means > 1 uM; ++ means 200 nM - 1000 nM; +++ means < 200 nM; NT means not tested.
[002159] Male Sprague Dawley rats were administered with either Vehicle, 10, or 30 mg/Kg Compound 359 by oral administration 30 minutes prior to harmaline injection to investigate the therapeutic effect of Compound 359 on harmaline induced tremor.
Immediately following harmaline injection, animals were placed in the tremor quantification apparatus and tremor events were quantified for 60 minutes. A tremor event signal was generated when a small metal transmitter band fitted to the right forepaw of the animal moved within the electromagnetic field generated by a loop antenna within the testing apparatus. Outputs from the amplifier were digitized at a sampling rate of 1,000 Hz and the signal was processed and analyzed using LabView software (National Instruments). To minimize signal from ambulatory and grooming behavior, the signal was filtered with a 128- ms nonweigthed moving average filter, and events with amplitudes > 0.5 V and lasting > 300 ms in duration were counted as a tremor event. Data were analyzed in one-minute bins over the course of the test and presented as the sum of tremor events over the entire 60 minute test. As shown by FIG. 1, significant inhibition of tremors was observed at a dose of 30 mg/Kg Compound 359.
[002160] The extent to which compounds modulate SK2 channels in vivo is expressed as %SK2 SCioo, which is the ratio of the concentration of the drug free in the brain to the measured potency of the compound against the SK2 channel. It is calculated as follows: CFB = CMB X BFF, where CMB is the concentration of compound measured by mass spectrometry from brains harvested immediately following tremor recording (Table 3, "Measured Brain Concentration"). CFB is the amount of free compound not complexed with protein and therefore free to interact with the SK2 channel (Table 3, "Calculated Brain Free Fraction"). BFF is average free fraction of compound as measured by equilibrium dialysis in separate experiments (Table 3, "Brain Free Fraction"). Free drug in brain available to interact with SK2 channels (CFB) is arrived at by multiplying the measured total brain level (CMB) by the average free fraction (BFF).
[002161] The amount of free compound is then expressed in terms of its potency against the SK2 channel as follows: %SK2 SCioo = CFB /SK2 SCioo x 100, where SK2 SCioo (Table 3, "SK2 SCioo") is the measured value of potency of the compound against SK2 channels and %SK2 SCioo (Table 3, "%SK2 SCioo") is the free brain concentration (CFB) normalized to SK2 SCioo- Thus the %SK2 SCioo gives a measure of the degree to which each of the compounds is modulating SK2 channels regardless of differences in potency or exposure. Values are given in
Table 3
Figure imgf000735_0001
[002162] Compound 359 displayed efficacy at a dose that represented modulation of the SK2 channel, regardless of potency. See e.g., FIG. 2 showing the SK2 SCioo Compound 1 compared to chlorzoxazone (CHZ).
[002163] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific
embodiments that have been represented by way of example.
[002164] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

Claims

Listing of Claims:
1. A compound having the structural Formula I:
or a pharmaceutically acceptab
selected from
Figure imgf000736_0001
Figure imgf000736_0002
X1 is selected from C(Ra) and N;
X2 is selected from C(Rb) and N, wherein X1 and X2 are not simultaneously nitrogen; each of Ra and Rb is independently selected from hydrogen, halo, -CN, optionally substituted C1-C4 alkyl, optionally substituted -0-(Ci-C4 alkyl), -OH, -NH2, optionally substituted -NH(Ci-C4 alkyl), optionally substituted -N(Ci-C4 alkyl)2, optionally
substituted -S-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
each R1, if present, is independently selected from halo, -CN, optionally
substituted -Ci-C6 alkyl, optionally substituted -0-(Ci-C4 alkyl), optionally
substituted -NH(Ci-C4 alkyl), optionally substituted -N(Ci-C4 alkyl)2, optionally
substituted -S-(Ci-C4 alkyl), optionally substituted -S(0)-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
each R is independently selected from halo, -CN, optionally substituted C3-C6 cycloalkyl, optionally substituted -Ci-C6 alkyl, optionally substituted -0-(Ci-C4 alkyl), optionally substituted -NH(Ci-C4 alkyl), optionally substituted -S-(Ci-C4 alkyl), optionally substituted -S(0)-(Ci-C4 alkyl), and optionally substituted -S(0)2-Ci-C4 alkyl;
R3 is selected from halo, -C(=0)NH2, -OH, -CN, -(C0-C4 alkylene)- carbocyclyl, -(C0-C4 alkylene)-heteroaryl, -(C0-C4 alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, -O-carbocyclyl, -O-heterocyclyl, -O-heteroaryl, -O-aryl, -S-carbocyclyl, -S- heterocyclyl, -S-heteroaryl, -S-aryl, -S(0)-carbocyclyl, -S(0)-heterocyclyl, -S(0)-heteroaryl, -S(0)-aryl, -S(0)2-carbocyclyl, -S(0)2-heterocyclyl, -S(0)2-heteroaryl, -S(0)2-aryl, -N(R6)- carbocyclyl, -N(R6)-heterocyclyl, -N(R6)-heteroaryl, -N(R6)-aryl, -0(Ci-C4 alkyl)carbocyclyl, -0(Ci-C4 alkylene)heterocyclyl, -0(Ci-C4 alkylene)heteroaryl, -0(Ci-C4 alkylene)aryl, - S(Ci-C4 alkylene)carbocyclyl, -S(Ci-C4 alkylene)heterocyclyl, -S(Ci-C4 alkylene)heteroaryl, -S(Ci-C4 alkylene)aryl, -S(0)(Ci-C4 alkylene)carbocyclyl, -S(0)(Ci-C4
alkylene)heterocyclyl, -S(0)(Ci-C4 alkylene)heteroaryl, -S(0)(Ci-C4 alkylene)aryl, - S(0)2(Ci-C4 alkylene)carbocyclyl, -S(0)2(Ci-C4 alkylene)heterocyclyl, -S(0)2(Ci-C4 alkylene)heteroaryl, -S(0)2(Ci-C4 alkylene)aryl, -0-(d-C4 alkyl), -NH(Ci-C4 alkyl), -S-(d- C4 alkyl), -S(0)-(Ci-C4 alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, alkylene, and alkyl are optionally substituted; or
R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl;
R4a is selected from fluoro and -CF3;
R4b is selected from hydrogen and fluoro;
R5 is selected from hydrogen and optionally substituted Q-C4 alkyl;
each R6 is independently selected from hydrogen and optionally substituted Ci-C4 alkyl;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
n is 1, 2 or 3;
o is 1 or 2; and
p is 1, 2, 3 or 4,
rovided the compound of Formula I is not
Figure imgf000737_0001
, or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1, wherein the compound is of the Formula la:
Figure imgf000738_0001
3. The com ound of Claim 1 or 2, wherein the compound is of the Formula II or III:
Figure imgf000738_0002
or a pharmaceutically acceptable salt thereof.
4. The compound of any one of Claims 1 to 3, wherein:
R3 is selected from -C(=0)NH2, -(C0-C4 alkylene)-heteroaryl, -(C0-C4
alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, -O-carbocyclyl, -O-heterocyclyl, -O- heteroaryl, -O-aryl, -S-carbocyclyl, -S-heterocyclyl, -S-heteroaryl, -S-aryl, -S(O)- carbocyclyl, -S(0)-heterocyclyl, -S(0)-heteroaryl, -S(0)-aryl, -S(0)2-carbocyclyl, -S(0)2- heterocyclyl, -S(0)2-heteroaryl, -S(0)2-aryl, -N(R6)-carbocyclyl, -N(R6)-heterocyclyl, - N(R6)-heteroaryl, -N(R6)-aryl, -0(d-C4 alkylene)carbocyclyl, -0(d-C4
alkylene)heterocyclyl, -0(Ci-C4 alkylene)heteroaryl, -0(Ci-C4 alkylene)aryl, -S(Ci-C4 alkylene)carbocyclyl, -S(Ci-C4 alkylene)heterocyclyl, -S(Ci-C4 alkylene)heteroaryl, -S(Ci-C4 alkylene)aryl, -S(0)(Ci-C4 alkylene)carbocyclyl, -S(0)(Ci-C4 alkylene)heterocyclyl, - S(0)(Ci-C4 alkylene)heteroaryl, -S(0)(Ci-C4 alkylene)aryl, -S(0)2(Ci-C4
alkylene)carbocyclyl, -S(0)2(Ci-C4 alkylene)heterocyclyl, -S(0)2(Ci-C4 alkylene)heteroaryl, -S(0)2(Ci-C4 alkylene)aryl, -NH(Ci-C4 alkyl), -S-(Ci-C4 alkyl), -S(0)-(Ci-C4
alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each instance of said heterocyclyl, carbocyclyl, heteroaryl, aryl, Ci-C4 alkylene, and Ci-C4 alkyl are optionally substituted, and wherein said (Ci-C6)alkyl is substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)-0-(Ci-C4 alkyl), -NHC(=0)-(Ci-C4 alkyl), -CN, -NHC(=0)-cycloalkyl, -NHC(=0)-heterocyclyl, -OH, or -0(Ci-C4 alkyl); or
R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl.
5. The compound of any one of Claims 1 to 4, wherein:
R3 is selected from -C(=0)NH2, -(C0-C4 alkylene)-heteroaryl, -(C0-C4
alkylene)-heterocyclyl, -(C0-C4 alkylene)-aryl, -O-carbocyclyl, -O-heterocyclyl, -O- heteroaryl, -O-aryl, -S-carbocyclyl, -S-heterocyclyl, -S-heteroaryl, -S-aryl, -S(O)- carbocyclyl, -S(0)-heterocyclyl, -S(0)-heteroaryl, -S(0)-aryl, -S(0)2-carbocyclyl, -S(0)2- heterocyclyl, -S(0)2-heteroaryl, -S(0)2-aryl, -0(Ci-C4 alkylene)carbocyclyl, -0(Ci-C4 alkylene)heterocyclyl, -0(Ci-C4 alkylene)heteroaryl, -0(Ci-C4 alkylene)aryl, -S(Ci-C4 alkylene)carbocyclyl, -S(Ci-C4 alkylene)heterocyclyl, -S(Ci-C4 alkylene)heteroaryl, -S(Ci-C4 alkylene)aryl, -S(0)(Ci-C4 alkylene)carbocyclyl, -S(0)(Ci-C4 alkylene)heterocyclyl, - S(0)(Ci-C4 alkylene)heteroaryl, -S(0)(Ci-C4 alkylene)aryl, -S(0)2(Ci-C4
alkylene)carbocyclyl, -S(0)2(Ci-C4 alkylene)heterocyclyl, -S(0)2(Ci-C4 alkylene)heteroaryl, -S(0)2(Ci-C4 alkylene)aryl, -S-(Ci-C4 alkyl), -S(0)-(Ci-C4 alkyl), -S(0)2-(Ci-C4 alkyl), and -Ci-C6 alkyl, wherein each of said heterocyclyl, carbocyclyl, heteroaryl, aryl, Ci-C4 alkylene, and Ci-C4 alkyl are optionally substituted, and wherein said (Ci-C6)alkyl is substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)-0-(Ci-C4 alkyl), NHC(=0)-(Ci-C4 alkyl), -CN, -NHC(=0)-cycloalkyl, -NHC(=0)-heterocyclyl, -OH, or -0(d-C4 alkyl); or
R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered heterocyclyl or carbocyclyl.
6. The compound of any one of Claims 1 to 5, wherein each of said heterocyclyl, heteroaryl, carbocyclyl, aryl, Ci-C4 alkylene, and Ci-C4 alkyl for R are optionally substituted
7 7
with 1 to 3 groups independently selected from R , where R is halogen,
CN, -ORc, -NRdRe, -S(0)iRc, -NRcS(0)2Rc, -S(0)2NRdRe, -C(=0)ORc, -OC(=0)ORc,- OC(=0)Rc, -OC(=S)ORc, -C(=S)ORc, -0(C=S)Rc, -C(=0)NRdRe, -NRcC(=0)Rc,
-C(=S)NRdRe, -NRCC(=S)RC, -NRc(C=0)ORc, -0(C=0)NRdRe, -NRc(C=S)ORc, -0(C=S)NRd Re, -NRc(C=0)NRdRe, -NRc(C=S)NRdRe, -C(=S)RC, -C(=0)Rc, (Ci-C6)alkyl, cycloalkyl, - (CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4-heterocyclyl, aryl, -(CH2)i-4-aryl, heteroaryl or - (CH2)i-4-heteroaryl, wherein each of said (Ci-C6)alkyl, cycloalkyl, -(CH2)i-4-cycloalkyl, heterocyclyl, -(CH2)i-4-heterocyclyl, aryl, -(CH2)i-4-aryl, heteroaryl and -(CH2)i-4-heteroaryl for R are optionally substituted with halogen,
ORc, -NO2, -CN, -NRcC(=0)Rc, -NRdRe, -S(0)kRc,
-C(=0)ORc, -C(=0)NRdRe, -C(=0)Rc, (Ci-C3)alkyl, halo(Ci-C3)alkyl, (Ci-C3)alkoxy(Ci- C3)alkyl, (Ci-C3)alkoxy, and halo(Ci-C3)alkoxy; or two instances of R are taken together on the same atom to form =0;
Rc is hydrogen or (Ci-C6)alkyl optionally substituted with 1 to 3 halogen;
Rd and Re are each independently selected from hydrogen and (Ci-C6)alkyl; and k is 0, 1 or 2.
7. The compound of any one of Claims 1 to 6, wherein R is selected from:
1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5-dihydro-l,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 3 groups selected from R ;
2) -S-(Ci-C2 alkyl), -0-(Ci-C2 haloalkyl), -C(=0)NH2, -(C1-C2 alkylene)- morpholinyl, -(C1-C2 alkylene)-piperazinyl, -(XC1-C2 alky lene) azetidinyl, -0(Ci-C2 alkylene)triazolyl, -0(Ci-C2 alkylene)pyrrolidinyl, -0(Ci-C2 alkylene)oxadiazole, -0(Ci-C2 alkylene)thiomorpholinyl, -(XC1-C2 alky lene)thio morpholinyl- 1,1 -dioxide, -0(Ci-C2 alkylene)oxazolyl, -0(Ci-C2 hydroxyalkylene)oxazolyl, -0(Ci-C2 alkylene)phenyl, and - (XC1-C2 alkylene)cyclobutyl each of said morpholinyl, piperazinyl, azetidinyl, triazolyl, pyrrolidinyl, oxadiazole, thio morpholinyl, thio morpholinyl- 1,1 -dioxide, oxazolyl, phenyl, and cyclobutyl being optionally substituted with 1 to 3 groups selected from R ; and
3) (Ci-C4)alkyl substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)0(Ci-C4 alkyl), - NHC(=0)-Ci-C4 alkyl, -CN, -NHC(=0)-cyclobutyl, -NHC(=0)-oxetanyl, -OH, or -0(Ci-C4 alkyl);
R7 is halo, -C(=0)NRdRe, -C(=0)Rc, ORc, -C(=0)ORc, -NRdRe, or (Ci-C4)alkyl optionally substituted with -C(=0)ORc or ORc; or two instances of R7 are taken together on the same atom to form =0;
Rc is hydrogen or (Ci-COalkyl optionally substituted with 1 to 3 halogen;
Rd and Re are each independently selected from hydrogen and
Figure imgf000740_0001
8. The compound of any one of Claims 1 to 7, wherein R is selected from: 1) piperizinyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, morpholinyl, azetidinyl, pyrazolyl, 4,5-dihydro-l,2,4-oxadiazolyl, 1,2,4-oxadiazolyl, tetrahydropyranyl, 2,5- diazabicyclo[2.2.1]heptanyl, and 3-azabicyclo[3.1.0]hexanyl, each of which is optionally substituted with 1 to 2 groups selected from R ;
2) -S-(Ci-C2 alkyl), -0-(Ci-C2 haloalkyl), -C(=0)NH2, -(Ci-C2 alkylene)- morpholinyl, -(Ci-C2 alkylene)-piperazinyl, -0(Ci-C2 alky lene) azetidinyl, -0(Ci-C2 alkylene)triazolyl, -0(Ci-C2 alkylene)pyrrolidinyl, -0(Ci-C2 alkylene)oxadiazole, -0(Ci-C2 alkylene)thiomorpholinyl, -0(Ci-C2 alky lene)thio morpholinyl- 1,1 -dioxide, -0(Ci-C2 alkylene)oxazolyl, -0(Ci-C2 hydroxyalkylene)oxazolyl, -0(Ci-C2 alkylene)phenyl, and - 0(Ci-C2 alkylene)cyclobutyl, each of said azetidinyl, triazolyl, pyrrolidinyl, oxadiazole, phenyl, and cyclobutyl being optionally substituted with 1 to 2 groups selected from R ; and
3) (Ci-C4)alkyl substituted with -NH2, -N(Ci-C4 alkyl)2, -NHC(=0)0-Ci-C4 alkyl, - NHC(=0)-Ci-C4 alkyl, -CN, -NHC(=0)-cyclobutyl, -NHC(=0)-oxetanyl, -OH, or -0(d-C4 alkyl).
9. The compounds of any one of Claims 1 to 8, wherein R is independently selected from halo, -CN, -0(Ci-C4 alkyl), Ci-C4 alkyl, C3-C4 cycloalkyl, cyanoCi-C4 alkyl, haloCi-C4 alkyl, and hydroxyCi-C4 alkyl.
10. The compound of any one of Claims 1 to 9, wherein each R is independently selected from chloro, bromo, fluoro, -CN, -CH3, -CH2F, -CHF2, -CF3,
-CH2OH, -CH2CH3, -CH2CN, -CH(CH3)CH3, -CH(CH3)OH,
-C((CH3)2)OH, -OCH3, and cyclopropyl.
11. The compound of any one of Claims 1 to 10, wherein each of n, o, and p is 1 or 2.
12. The compound of any one of Claims 1 and 4 to 11, wherein each of Ra and Rb is independently selected from hydrogen and Ci-C4 alkyl, or wherein R3 and Ra or R3 and Rb taken together with the atoms they are attached form an optionally substituted 5-6 membered, nitrogen-containing heterocyclyl.
13. The compound of Claim 12, wherein Ra is selected from hydrogen, methyl, and ethyl; or Ra and R3 are taken together with the atoms they are attached form an optionally substituted piperidinyl or an optionally substituted lH-imidazolyl.
14. The compound of Claim 13, wherein the piperidinyl or lH-imidazolyl is optionally substituted at a ring nitrogen.
15. The compound of any one of Claims 1, 2, 3, and 9 to 12, wherein R is selected from halo, -CN, alkyl, -NH-(Ci-C6 alkyl), alkyl-NH(R7), -C(0)NH(R7), carbocyclyl,
heterocyclyl, -O-heterocyclyl, -NH-heterocyclyl, -O-alkylene-heterocyclyl, -O-alkylene- carbocyclyl, -NH-alkylene-carbocyclyl, and -NH-alkylene-heterocyclyl, or
R3 is taken together with Ra to form an optionally substituted heterocyclyl, wherein R is selected from hydrogen and C1-C4 alkyl; and
any alkyl, alkylene, carbocyclyl, or heterocyclyl portion of R is optionally substituted.
Figure imgf000742_0001
17. The compound of any one of Claims 1 to 16, wherein R5 is selected from hydrogen, methyl and ethyl.
18. The compound of any one of Claims 1 to 17, wherein R4a and R4b are simultaneously fluoro.
19. The compound of any one of Claims 1 to 18, wherein R a is -CF3; and R is hydrogen.
20. The compound of any one of Claims 1 to 19, wherein m is 0.
The compound of one of Claims 1 to 8, wherein R is selected from:
M
Figure imgf000743_0001
Figure imgf000743_0002
The compound of any one of Claims 1 to 8 and 21, wherein R is selected from:
Figure imgf000743_0003
0 , and 0
23. The compound of any one of Claims 1 to 8, 21, and 22, wherein R is
Figure imgf000744_0001
24. The compound of any one of Claims 1 to 8 and 21 to 23, wherein the compound is of the Formula IV
Figure imgf000744_0002
or a pharmaceutically acceptable salt thereof.
25. The compound of any one of Claims 1 to 8 and 21 to 23, wherein the compound is of the Formula VI or VII:
Figure imgf000744_0003
or a pharmaceutically acceptable salt thereof. ound of any one of Claims 1 to 8 and 21 to 25, wherein ring A is
Figure imgf000744_0004
27. The compound of any one of Claims 1 to 8 and 21 to 26, wherein ring A is
Figure imgf000745_0001
28. The compound of any one of Claims 1 to 8 and 21 to 27, wherein R is independently selected from C1-C4 alkyl, haloCi-C4 alkyl, and hydroxyCi-C4 alkyl.
29. The compound of any one of Claims 1 to 8 and 21 to 28, wherein R is independently selected from CH3, CHF2, CH2F, -CH(CH3)OH, and -CH2OH.
30. The compound of any one of Claims 1 to 8 and 21 to 29, wherein R5 is hydrogen or Ci-C4 alkyl.
31. The compound of any one of Claims 1 to 8 and 21 to 30, wherein R5 is hydrogen.
32. The compound of Claim 1, selected from any one of the compounds in table 1.
33. A pharmaceutical composition comprising a compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
34. A method of positively modulating a SK2 channel in a cell comprising the step of contacting the cell with a compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof.
35. A method of treating a disease or condition in a subject selected from a
neurodegenerative disease, dementia, heart disease, withdrawal symptoms associated with termination of addiction, metabolic disease, and bladder disease comprising the step of administering a compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof, or a composition of Claim 33 to the subject.
36. The method of Claim 35, wherein the disease or condition is selected from ataxia, dystonia, tremors, Parkinson's disease, ischemia, traumatic brain injury, amyotrophic lateral sclerosis, hypertension, atherosclerosis, diabetes, arrhythmia, over-active bladder, and withdrawal symptoms caused by the termination of abuse of alcohol and other drugs of abuse.
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