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WO2025219950A1 - Small molecule cx3cr1 modulators - Google Patents

Small molecule cx3cr1 modulators

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Publication number
WO2025219950A1
WO2025219950A1 PCT/IB2025/054077 IB2025054077W WO2025219950A1 WO 2025219950 A1 WO2025219950 A1 WO 2025219950A1 IB 2025054077 W IB2025054077 W IB 2025054077W WO 2025219950 A1 WO2025219950 A1 WO 2025219950A1
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Prior art keywords
compound
formula
mmol
alkyl
pct01
Prior art date
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PCT/IB2025/054077
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French (fr)
Inventor
Karolina Nilsson
Mikael BRINK
Sara PAHLÉN
Thomas Antonsson
Martin Bauer
Henrik GRADÉN
Yantao Chen
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AstraZeneca AB
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AstraZeneca AB
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Publication of WO2025219950A1 publication Critical patent/WO2025219950A1/en
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Classifications

    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines

Definitions

  • the chemokine superfamily comprises four groups exhibiting characteristic structural motifs; the C-X-C, C-C and C-X 3 -C and XC families.
  • the C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH- 15 proximal pair of cysteine residues.
  • the C-X3-C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2). 20
  • the C-C chemokines include potent chemoattractants of monocytes, lymphocytes and neutrophils.
  • the C-X3-C chemokine also known as fractalkine, FKN, or CX3CL1 is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells.
  • Fractalkine neutralisation improves cardiac function in mouse myocardial infarction (MI) models by enhanced systolic function, ventricular remodeling and decreased infarct size (Xuan et 5 al 2011, Cardiovascular Research 92, 385) and also LVEF and survival rate 2 weeks post treatment after an induced MI in mouse (Gu et al 2015, Exp Physiol 100, 805). Additionally, fractalkine cause cardio-depressive actions with impaired contractility observed in mouse cardiomyocytes (Taube et al 2013, PLOS ONE 8(7). Human serum soluble FKN (sFKN) levels are associated with NYHA heart failure functional score where in patients 10 with HF have an increased level of soluble fractalkine (Husberg et al. J. of Mol.
  • sFKN concentration has a prognostic value in patients with acute myocardial infarction treated with primary percutaneous coronary intervention (Xu Bing et al Cytokine 2019113 (365-370). Elevated sFKN plasma levels predictor of mortality in subjects with advanced systolic HF (Richter et al 2012, Thrombosis & Haemostasis 108, 1220).
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X 3 -C family.
  • These receptors represent good targets for drug development since agents that 20 modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
  • WO2005/070903 discloses certain triazine derivatives for use in the treatment of chemokine mediated diseases and disorders.
  • WO2006/107258 discloses certain 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine 25 derivatives as antagonists of the CX3CR1 receptor.
  • WO2006/107257 and WO2009/120140 disclose certain 5,7-disubstituted [l,3]thiazolo[4,5- d]pyrimidin-2(3H)one derivatives as antagonists of the CX3CR1 receptor.
  • WO2013039057 discloses certain pyrrolidine-3-ylacetic acid derivatives having an inhibitory pathway in the fractalkine-CX3CR1 pathway.
  • Linkage of CX 3 CR1 activity to diseases has thus been implicated in cardiovascular diseases (CVD) including heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, 5 stable coronary artery disease and atherosclerosis related conditions.
  • CVD cardiovascular diseases
  • CVD cardiovascular diseases
  • alkoxy refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, 10 propoxy, tert-butoxy and the like.
  • alkyl or alkane is a straight chained or branched non-aromatic hydrocarbon which is completely saturated.
  • alkyl groups examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.
  • alkoxyalkyl refers to an alkyl group attached to an alkoxy group, where in the 15 group is attached to the rest of the molecule via a carbon on the alkyl group, i.e. a group having a structure of -R-O-R’ wherein R and R’ are the same or different alkyl groups.
  • aryl refers to an aromatic hydrocarbon.
  • aryl includes monocyclic aryls, with a single ring, such as phenyl, as well as polycyclic aryls, including “bicyclic aryls” having two or more cyclic rings, in which two or more atoms are common to two adjoining rings 20 wherein at least one of the rings is aromatic, for example, the other cyclic ring is cycloalkyl, cycloalkenyl, cycloalkynyl and/or aryl.
  • polycyclic aryl rings include naphthalene and tetrahydronaphthalene.
  • cycloalkyl refers to a partially or completely saturated monocyclic, bicyclic, polycyclic or bridged hydrocarbon ring system. 25
  • halo means fluoro, chloro, bromo, and iodo. In an embodiment, halo is fluoro or chloro. In another embodiment, halo is fluoro. In yet another embodiment, halo is chloro.
  • haloalkoxy means an alkoxy in which one or more hydrogens has been substituted with a halo. 4 201388-PCT01-NP
  • haloalkyl means an alkyl group in which one or more hydrogens has been substituted with a halo.
  • heteroaryl refers to substituted or unsubstituted aromatic ring structures whose ring structures include, e.g., at least one heteroatom selected from nitrogen, 5 oxygen, and sulphur.
  • Heteroaryl groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atom.
  • Heteroaryl groups can include monocyclic heteroaryls as well as polycyclic heteroaryls such as bicyclic heteroaryls, having two or more cyclic rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic and at least one of the rings includes at least one heteroatom selected from nitrogen, oxygen, and 10 sulphur.
  • the heteroatom in the heteroaryl is sulfur, and the sulfur can be oxidized with 1 or 2 oxygens.
  • the term heteroaryl would encompass dihydro- isothiazole-dioxide, in which the sulfur has been oxidized with two oxygen.
  • the sulphur heteroatom is not oxidized.
  • monocyclic heteroaryls include, but are not limited to, pyrrole, pyridine, 15 pyrazine, pyridazine, pyrimidine, furan, triazole, thiophene, imidazole, isoxazole, oxazole, oxadiazole, thiazole and pyrazole.
  • bicyclic heteroaryls include, but are not limited to purine, indole, indazole, quinoline, quinazoline, benzofuran, benzoxazole, benzodioxole, benzodioxin, pyrrolopyridine, indazole, 2H-indazole, isoquinoline, tetrahydroisoquinoline, dihydroquinazoline, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydrobenzo[d]oxazole, 3,4- 20 dihydroquinazoline, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-1,4-benzodioxin and 2,3-dihydro-1-benzofuran.
  • Additional polycyclic heteroaryls include, but are not limited to, carbazole and dibenzazepine.
  • the term “monocyclic N-heteroaryl” refers to a monocyclic heteroaryl whose ring structures include at least one nitrogen. Examples of monocyclic N-heteroaryls include, but are 25 not limited to imidazole, pyrrole, triazole, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.
  • heterocycle refers to a partially or completely saturated hydrocarbon ring system wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen and sulphur. Heterocyclic groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atoms. Heterocycles 30 include monocyclic heterocycles as well as polycyclic heterocycles such as bicyclic heterocycles.
  • Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, piperidine, piperazine, oxetane, and isoxazolidine.
  • S-heterocycle “S-heterocyclic” or “S-heterocyclyl” refers to partially or completely saturated heterocyclic ring system wherein at least one of the ring atoms is a sulphur. 5 Examples of such compounds include, but are not limited to, thiophene andtetrahydrothiophene.
  • the term “hydroxy” refers to an -OH group.
  • hydroxyalkyl means an alkyl group in which one or more hydrogens has been substituted with a hydroxy.
  • Cx-y as used in terms such as “Cx-y alkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group.
  • suitable C 1-3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl.
  • C1-4 alkyl groups include, but are not limited to, methyl, ethyl, n- 15 propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl.
  • a group will have two instances of C x-y in which case the prefix indicates the numerical range of carbons in each part of the group, e.g., C1-3 alkoxy- C1-4 alkyl, refers to an alkoxyalkyl group wherein the alkyl group has 1 to 3 carbons and the alkoxy group has 1-4 carbons.
  • the disclosure is directed to a compound of Formula I, wherein Z is carbon, i.e., C. In some embodiments, Z is oxygen, i.e., O. In some embodiments, Z is -NH-. 8 201388-PCT01-NP In some embodiments, when Z is C or O, and the compound has the specific stereochemistry as in the following formulas: OH OH R 1 R 1 5 )p . , p mixture of the two previous 5 compounds. In some embodiments, when Z is N, and the compound has the specific stereochemistry as in the following formulas: . In some embodiments, the compounds are a racemic mixture of the two previous compounds.
  • the compounds are a racemic mixture of the two previous compounds.
  • e compoun s are a racem c m x ure o e two previous compounds.
  • L is –S-(CR 3 R 4 ) k –.
  • k is 0.
  • k is 1.
  • k is 2.
  • each R 3 is independently as defined herein, and each R 4 is independently as defined herein, as well as each R 3 and R 4 being independently as defined herein.
  • the compounds of the present disclosure when L is –S-(CR 3 R 4 )k– and k is 1, then the compounds of the present disclosure have the formula: 15
  • the compounds of the present disclosure when L is –S-(CR 3 R 4 )k–, k is 1, and Z is N, then the compounds of the present disclosure have the formula: 10 201388-PCT01-NP , . n some em o men s, s -( )k an s or .
  • each R 3 is independently as defined herein, and each R 4 is independently as defined herein, 10 as well as each R 3 and R 4 being independently as defined herein.
  • R 3 and R 4 are H.
  • one or more R 3 and R 4 are halogen, e.g., F.
  • one or both of R 3 and R 4 are methyl.
  • each R 3 is 15 independently as defined herein, and each R 4 is independently as defined herein, as well as each R 3 and R 4 being independently as defined herein.
  • R 3 and R 4 are H.
  • one or more R 3 and R 4 are halogen, e.g., F.
  • when n is 2 or 3, 11 201388-PCT01-NP at least one R 3 and R 4 are H.
  • at least one R 3 and R 4 are halogen, e.g., F.
  • one or both of R 3 and R 4 are methyl.
  • the L can comprise a carbonyl group.
  • L is –S-(CR 3 R 4 )-C(O) –.
  • both R 3 and R 4 are H.
  • one or both of R 3 and R 4 are halogen, e.g., F.
  • one or both of R 3 and R 4 are methyl.
  • j is 1 or m is 1.
  • j is 2. In some embodiments, m is 0.
  • R 3 , R 4 , R 3a , and R 4a are independently as defined herein. In some 10 embodiments, each of R 3 , R 4 , R 3a , and R 4a are H. In some embodiments, one or more R 3 , R 4 , R 3a , and R 4a are halogen, e.g., F. In some embodiments, R 3 , R 4 , R 3a , and R 4a are methyl. In some embodiments, L comprises an ester linkage.
  • L is – (CR 3 R 4 ) n -O–, or –O-(CR 3 R 4 ) j -, wherein n or j is as described herein.
  • n is 1.
  • n is 2.
  • n is 3.
  • j is 1 or 2. 15
  • each R 3 and R 4 are H.
  • one or more R 3 and R 4 are independently halogen, e.g., F.
  • R 3 and R 4 are methyl.
  • R 3 and R 4 are not H.
  • each R 3, R 3a , R 4 , and R 4a are, independently, selected from H, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl.
  • one or more R 3 and R 4 are 20 independently methyl.
  • one or more R 3 and R 4 are independently H.
  • one or more R 3a and R 4a are independently methyl.
  • one or more R 3a and R 4a are independently H.
  • R 1 is C 1-3 alkyl or C 1-3 haloalkyl.
  • R 1 is propyl.
  • R 1 is methyl or ethyl. In some embodiments, R 1 is fluoromethyl, 25 fluoroethyl, or difluorethyl. In some embodiments, R 1 is trifluoro methyl or ethyl. In some embodiments, R 1 is fluoro or chloro propyl, e.g., fluoro propyl, chloropropyl, difluorpropyl, dichloropropyl or trifluorpropyl. In some embodiments R 1 is methyl or ethyl optionally substituted with one hydroxy, e.g., hydroxymethyl or hydroxyethyl.
  • R 1 is C3-6 cycloalkyl, e.g., the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl.
  • R 1 is C3-6 branched alkyl or C3-6 branched haloalkyl.
  • R 1 is isopropyl.
  • R 1 is isobutyl.
  • R 1 can comprise an alkyl chain linked to a cycloalkyl.
  • R 1 is a -C1-3 alkyl-C3-6 cycloalkyl, wherein the -C1-3 alkyl can be methyl, ethyl or propyl, and the C3-6 clycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • R 1 is methyl-cyclopropyl or methyl cyclohexyl.
  • R 1 is -methyl-C3-6 cycloalkyl.
  • R 1 is -methyl-cyclopropyl, - methyl-cyclobutyl, or -methyl-clyclopentyl.
  • R 11 is hydroxymethyl. In some embodiments, R 11 is H. In some embodiments, R 2 i , wherein R a is C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 carbocycle, 5-6 membered heteroa y , 1-3 alkyl-phenyl, C1-3 alkyl-C3-6 carbocycle, or S- heterocycyl. In some embodiments, R a is C1-3 alkyl or C1-3 haloalkyl, e.g., methyl or trifluormethyl.
  • R 2 is , wherein R a is C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 carbocycle, 5-6 membered heteroaryl, C1-3 alkyl-phenyl, C1-3 alkyl-C3-6 carbocycle, or S- heterocycyl.
  • R a is C1-3 alkyl or C1-3 haloalkyl.
  • R a is methyl or C 1-3 haloalkyl, e.g., trifluormethyl.
  • R a is C 1-3 alkylphenyl, C 1- 3 carbocycle or S-heterocyclyl.
  • the C 1-3 alkylphenyl is methylphenyl.
  • C1-3 carbocyclyl is cyclopropyl.
  • the S-heterocycyl is thiophene. 13 201388-PCT01-NP
  • each R b is, independently, H, C 1-3 alkyl, C1-3 haloalkyl, or C1-3 a me embodiments, both R b are C1-3 alkyl, e.g., methyl or ethyl. In some emb odiments, both R are H. In some embodiments, one R b is H and one R b is methyl or ethyl.
  • both R b are C 1-3 haloalkyl, e.g., fluoromethyl or 5 trifluoromethyl.
  • one R b is H, and one R b is C1-3 alkyl-N-(CH2)2.
  • R2 i wherein B is a 4-6 member heterocycle comprising at least one N, wherein e is bound to the S via a ring N, optionally substituted by a C 1-3 alkyl.
  • B is a 4-6 member heterocycle.
  • B is a 4-6 member heterocycle substituted by a C 1-3 alkyl, e.g., substituted with a 10 methyl.
  • B is tetrahydro oxazine, piperaziny .
  • T he compounds of any one of claims 1 to 44, wherein R2 i ,wherein Rc is C 1-3 alkyl. In some embodiments, Rc is methyl. In some embodiments, R2 i . wherein R a is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered h eteroary , C1-3 a kyl- phenyl, C 1-3 alkyl-C 3-6 carbocycle, or S-heterocycyl. In some embodiments, R a is C 1-3 alkyl or C 1- 15 3 haloalkyl.
  • R a is methyl or C 1-3 haloalkyl, e.g., trifluormethyl.
  • R a is C1-3 alkylphenyl, C1-3 carbocycle or S-heterocyclyl.
  • the C1-3 alkylphenyl is methylphenyl.
  • C1-3 carbocyclyl is cyclopropyl.
  • the S-hetercycyl is tetrahydrothiophene. 14 201388-PCT01-NP
  • X is a bond, i.e., the substituent L is bonded directly to R 5 . In some embodiments, when X is a bond, then p is 1.
  • p when X is a bond, then p is 2, i.e., L is bonded to two R 5 groups. In some embodiments, when X is a bond, then p is not 0.
  • A is a 4-6 member cycloalkyl, 4-6 member 5 heterocycle, phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl. In some embodiments, A is phenyl, e.g., an unsubstituted phenyl wherein p is 0.
  • A is a substituted phenyl, e.g., a phenyl wherein p is 1 or 2, wherein R 5 is halogen, oxo, C 1-4 alkoxy or C1-3 alkyl.
  • A is a substituted phenyl, e.g., a difluorophenyl; dichlorophenyl; fluorochlorophenyl; phenyl substituted with fluor and methoxy, or phenyl 10 substituted with chloro and methoxy.
  • A is a 4-6 membered heterocyclyl.
  • the 4-6 membered heterocyclyl is dithiolyl, thianyl, thiolanyl, oxetanyl, azetidinyl, thetanyl, tetrahydrofuranyl, dioxanyl, pyrrolinyl, piperidinyl.
  • the 4-6 membered heterocyclyl has one heteroatom.
  • the heterocycyl comprises 2 heteroatoms. 15
  • the heteroatom in the cyclic ring is para to the bond to the L group.
  • the heteroatom in the cyclic ring is meta to the bond to the L group.
  • the heterocyclyl comprise an N hetero atom.
  • the heterocyclyl comprises an O heteroatom.
  • the 20 heterocyclyl comprises an S heteroatom.
  • the heterocyclyl comprises 2 heteroatoms selected from N, O or S.
  • A is a substituted A is a 4-6 membered heterocyclyl, e.g., a heterocyclyl wherein p is 1 or 2, wherein R 5 is halogen, oxo, C1-4 alkoxy or C 1-3 alkyl.
  • A is a substituted a 4-6 membered heterocyclyl, e.g., a difluoro heterocyclyl; dichloro heterocyclyl; fluorochloro heterocyclyl; heterocyclyl substituted 25 with fluoro and methoxy, or heterocyclyl substituted with chloro and methoxy.
  • A is a 4-6 member cycloalkyl.
  • the 4-6 member cycloalklyl can be a cyclobutyl, cyclopentyl, or cyclohexyl.
  • A is a monocyclic heteroaryl, wherein the monocyclic heteroaryl is pyridinyl, pyrimidinyl, purinyl, furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazinyl, oxazinyl, or pyranyl.
  • 15 201388-PCT01-NP A is a bicyclic heteroaryl, wherein the bicyclic heteroaryl comprises benzofuranyl, benzothiophenyl, chromanyl, chromenyl, purinyl, indolyl, quinazolinyl, pteridinyl, or pyrrolizinyl.
  • A is a substituted A is a 4-6 member cycloalkyl, monocyclic heteroaryl, or bicyclic heteroaryl, e.g., a 4-6 member cycloalkyl, monocyclic heteroaryl, or bicyclic 5 heteroaryl wherein p is 1 or 2, wherein R5 is halogen, oxo, C1-4 alkoxy or C1-3 alkyl.
  • the A substituent is unsubstituted, i.e., p is 0.
  • any of the A substituents disclosed herein can be substituted with one or more of the R5 groups described herein.
  • R5 is independently selected from halo, hydroxy, and oxo.
  • R5 is halo, oxo or hydroxy and p is 10 1.
  • R5 is halo, oxo or hydroxy and p is 2.
  • R5 is F and p is 1 or 2.
  • each of the R5 substituents can be independently selected from those disclosed herein.
  • one R5 is F and one R5 is Cl.
  • one R5 is F and one R5 is methoxy.
  • R5 is oxo and p is 1 or 2.
  • R5 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C1- 4 alkoxy, C1-4 haloalkoxy, -C1-4alkoxy-C1-3alkyl, -C1-3hydroxyalkyl, -CN, -(CH2)qR8, - C(O)R8, -C(O)OR9, and -OC(O)R9.
  • R5 is independently selected from - (CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, -NR6C(O)R7, -NO2, -NR6R7, -S(O)2R6, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl.
  • X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H.
  • X is A wherein A is phenyl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is – S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H.
  • 25 X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H.
  • X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H.
  • X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H.
  • X is A wherein 16 201388-PCT01-NP A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H.
  • X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H.
  • X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, 5 R3a is methyl, and R4a is H.
  • X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1, R3a is methyl and R4a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1, R3a is methyl and R4a is H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is methyl; and R4a is H.
  • X is A wherein A is aryl and is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. In some embodiments, X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H.
  • X is A wherein A is a 4-6 member N-heteroaryl and 15 L is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. O O S HN In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl and R2 O S N . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl and R2 wherein Ra is methyl.
  • L is –S(CR3aR4a)k–
  • X is A wherein A is aryl, R1 is C1-3 alkyl, O O S 20 R11 is H, and R2 is .
  • L is –S(CR3aR4a)k–
  • X is A wherein A O O S is aryl, R1 is C3-6 branched alkyl, R11 is H, and R2 i .
  • L is – O O S S(CR3aR4a)k–
  • X is A wherein A is aryl, R1 is C3-6 cycloalkyl, R11 is H, and R2 .
  • L is –S(CR3aR4a)k–
  • X is A wherein A is aryl, R1 is propyl, R11 O O S R a HN is H, and R2 is .
  • L is –S(CR3aR4a)k–
  • X is A wherein A is O O S l, R1 is isopropyl, R11 is H, and R2 i a HN ary R .
  • L is –S(CR3aR4a)k– O O herein A is aryl, R1 is cyclopropyl, R11 is H, and R2 i a S HN , X is A w R .
  • L is –S(CR3aR4a)k–, X is A wherein A is aryl, R1 is bu s H, and R2 is O O a S HN R11 , X S HN is A wherein A is aryl, R1 is is isopropyl, R11 is H, and R2 i wherein Ra is methyl.
  • L is –S(CR3aR4a)k–
  • X is A wherein R1 is cyclopropyl, R11 is H, O O S and R2 is wherein Ra is methyl.
  • L is –S(CR3aR4a)k–
  • X is A O O S N wherein A is aryl, R1 is butyl, R11 is H, and R2 is wherein Ra is methy .
  • L is –S(CR3aR4a)k–
  • X is A wherein A is aryl, R1 is iso-butyl, R11 O O S is H, and R2 is .
  • L is –S(CR3aR4a)k–
  • X is A wherein A is O O S 15 aryl, R1 is cyclo-butyl, R11 is H, and R2 is .
  • L is – S(CR3aR4a)k– wherein k is 1, X is A wherein A is aryl, R1 is propyl, R11 is H, and R2 is 18 201388-PCT01-NP O O a S R HN .
  • L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is aryl, O O S R a HN R1 is isopropyl, R11 is H, and R2 is .
  • L is –S(CR3aR4a)k– O O S R a HN wherein k is 1, X is A wherein A is aryl, R1 is cyclopropyl, R11 is H, and R2 .
  • L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is s butyl, O O a S HN 5 R11 is H, and R2 is .
  • L is –S(CR3aR4a)k– wherein k is 1, X is O O a S HN A wherein A is aryl, R1 is iso-butyl, R11 is H, and R .
  • L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is yclo-butyl, R11 is H, and R2 is O O S HN .
  • the present disclosure provides a compound of Formula (I), as 10 defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein L is –S-(CR3R4)-C(O) –.
  • X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)- C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein 15 A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H.
  • X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H.
  • X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S- (CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -NO2 and L is –S-(CR3R4)-C(O) – wherein 19 201388-PCT01-NP R3a and R4a are independently alkyl or H.
  • X is A wherein A is phenyl and wherein at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H.
  • X is A wherein A is a 4-6 member heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or 5 H.
  • X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)- C(O) – wherein and R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H.
  • X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein k is 1 and R3a and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl.
  • X is A wherein A is phenyl and wherein at least one R5 is 15 alkoxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl.
  • X is A wherein A is phenyl and wherein at least one R5 is -NO2 and 20 L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S- (CR3R4)-C(O) – wherein R3a and R4a are both alkyl.
  • X is A wherein A is a 4-6 member heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)-C(O) 25 – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl.
  • X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein R3a30 and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)- 20 201388-PCT01-NP C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is 5 phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -NO2 and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is phenyl and wherein 10 at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is a 4-6 member heteroaryl and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – 15 wherein R3a and R4a are both H. In some embodiments, X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H.
  • the present disclosure provides a compound of Formula (I), as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein L is –S-(CR3R4)n-O– 20
  • X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H.
  • X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl.
  • X is A wherein A is aryl and L is –S- (CR3R4)n-O– wherein R3 and R3a are H. In some embodiments, X is A wherein A is phenyl and L –S-(CR3R4)n-O– wherein R3 is 25 alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl. In some embodiments, X is A wherein A is phenyl and L is – S-(CR3R4)n-O– wherein R3 and R3a are H.
  • X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and 30 L –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl. In some embodiments, X is A wherein A 21 201388-PCT01-NP is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 and R3a are H.
  • X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is H and 5 R3a is alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 and R3a are H.
  • X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is phenyl and L is 10 –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl.
  • X is A wherein A is aryl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is H and 15 R3a is methyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H.
  • X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is halo and L 20 is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl.
  • X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is 25 H and R3a is methyl. In some embodiments, the present disclosure provides a compound of Formula (I), as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein X is A and A is aryl and G1, G2, and G3 are all N.
  • X is A and A is phenyl and G1, G2, and G3 are all N. 22 201388-PCT01-NP O O embodiments, X is A and A is aryl, R2 is a S HN In some R and G1, G2, and G3 are all HN N. In some embodiments, X is A and A is phenyl, R2 i Ra a nd G1, G2, and G3 are all O S R a HN N. In some embodiments, X is A and A is aryl, R2 i , R11 is alkyl, and G1, G2, and O O S HN G3 are all N.
  • X is A and A is phenyl, R2 i Ra , R11 is alkyl, and 5 G1, G2, and G3 are all N.
  • X is A and A is aryl wherein at least one R5 is halo, R2 is O O a S HN a nd G1, G2, and G3 are all N.
  • X is A and A is phenyl wherein O O S HN at least one R5 is halo, R2 i and G1, G2, and G3 are all N.
  • X O O S HN is A and A is aryl wherein at least one R5 is halo, R2 i , R11 is alkyl, and G1, G2, 10 and G3 are all N.
  • X is A and A wherein at least one R5 is halo, O O S s alkyl, and G1, G2, and G3 are all N.
  • X is A and A is aryl wherein at least one R5 is alkoxy, R2 is , and G3 are all N.
  • X is A and A is phenyl wherein O O S R a HN at least one R5 is alkoxy, R2 is and G1, G2, and G3 are all N.
  • O O S 15 X is A and A is aryl wherein at least one R5 is alkoxy, R2 , R11 is alkyl, and G1, 23 201388-PCT01-NP G2, and G3 are all N.
  • X is A and A is phenyl wherein at least one R5 is O O xy, R2 i a S HN alko R R11 is alkyl, and G1, G2, and G3 are all N.
  • X is A and A is aryl, R2 i and R11 is alkyl.
  • X is A and A is phenyl
  • R2 is Ra em H and R11 is alkyl.
  • NH O S a N 5 X is A and A is aryl
  • R2 is wherein Ra is methyl and R11 is alkyl.
  • X is A and A is phenyl
  • R2 is wherein Ra is methyl and R11 is alkyl.
  • O O S HN In some embodiments, X is A and A is ary is alkyl. In some O S HN embodiments, X is A and A is pheny is alkyl.
  • O O S X is A and A is aryl wherein Rb is H and R11 is alkyl.
  • O O S 10 X is A and A is phenyl, wherein Rb is H and R11 is alkyl.
  • X is A and A is aryl wherein Rb is methyl and R11 is alkyl.
  • 24 201388-PCT01-NP O O S HN N In some embodiments, X is A and A is pheny wherein Rb is methyl and R11 O S HN N is alkyl.
  • X is A and A is ary wherein Rb is ethyl and O O S HN R11 is alkyl.
  • X is A and A is pheny wherein Rb is ethyl and R11 is alkyl. 5
  • the present disclosure provides a compound as found in Table 1, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound as found in Table 2 or a pharmaceutically acceptable salt thereof.
  • Table 2 24 28 201388-PCT01-NP 35 77
  • the present disclosure provides a compound as found in Table 3, or pharmaceutically acceptable salts thereof.
  • Table 3 1 24 201388-PCT01-NP 69 70 F F 27 201388-PCT01-NP 139 148
  • the present disclosure provides a compound as found in Table 4, or pharmaceutically acceptable salts thereof.
  • Cardiovascular disease includes, but is not limited to, conditions 5 associated with cardiac dysfunction and/or microvascular dysfunction and/or macrovascular pathology, such as atherosclerosis, arteriosclerosis, coronary artery disease including stable and high risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or by 53 201388-PCT01-NP biomarkers of microvascular and cardiac dysfunction), ischemic heart disease, myocardial infarction, restenosis following revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD) including erectile dysfunction due to vascular disease, stroke, cardiomyopathy, including non-ischemic dilated cardiomyopathy, transient 5 ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia, renovascular disease, and renal arterial disease.
  • atherosclerosis arteriosclerosis
  • coronary artery disease including stable and high risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of non-ischemic dilated cardiomyopathy.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of cardiovascular disease in a patient having co-morbidities such as renal dysfunction.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of cardiovascular disease 15 associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy.
  • chronic inflammatory diseases e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of cardiovascular disease 20 associated with autoimmune conditions, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of heart failure, including 25 heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of inflammatory bowel disease. 54 201388-PCT01-NP
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of lupus nephritis.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of patients with remaining 5 risk for a cardiovascular event despite standard of care (SoC) treatment, such as, but not limited to, lipid lowering statins, anti-platelets, ACE inhibitors, mineralocorticoid receptor antagonists, and beta blockers.
  • SoC standard of care
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of chronic kidney disease. 10
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of type II diabetes mellitus and complications of type II diabetes mellitus in a mammal, particularly a human. This includes and is not restricted to, diabetic micro and macrovascular pathology, neuropathy and nephropathy.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically 15 acceptable salt thereof may be useful in the prevention or treatment of renal inflammatory and vascular diseases and complications associated with renal disease in a mammal, particularly a human.
  • Renal inflammatory and vascular disease includes, but is not limited to chronic kidney disease, drug and toxin induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephritis, reflux nephropathy, focal segmental glomerulosclerosis, Henoch- 20 Schönleins purpura, and diabetic nephropathy.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in the prevention or treatment of autoimmune diseases, such as, but not limited to, dermatomyositis, polymyositis, and systemic lupus erythematosus (SLE).
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof may be useful in the prevention or treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and ASH (alcoholic steatohepatitis).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • Treatment with the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may lower the cardiovascular and/or cerebrovascular 55 201388-PCT01-NP and/or renal and/or peripheral arterial disease morbidity and mortality associated with cardiac dysfunction and/or atherosclerosis, and/or renal dysfunction and/or microvascular dysfunction and/or macrovascular pathology due to their anti-inflammatory properties and influence on vasoactive mechanisms.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may serve to prevent or reduce the risk of developing cardiac dysfunction and/or renal dysfunction and/or microvascular dysfunction and/or macrovascular pathology, as well as for halting or slowing the progression and/or promoting the regression of atherosclerotic cardiovascular disease once it has become clinically evident, comprising the administration of a 10 prophylactically or therapeutically effective amount, as appropriate, of a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic cardiovascular disease.
  • Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically 15 acceptable salt thereof may be useful in preventing or reducing the incidence or severity of acute events related to atherosclerotic plaque rupture or erosion, including, but not limited to, myocardial infarction, unstable angina and stroke.
  • Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in preventing or reducing the incidence or severity of acute 20 events by improving microvascular function, macrovascular pathology and/or cardiac function.
  • Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be useful in preventing or reducing the progression of abdominal aortic aneurysms (AAA) and incidence of rupture.
  • AAA abdominal aortic aneurysms
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof, may be useful in the prevention or treatment of respiratory inflammatory disease and complications associated with respiratory inflammatory disease in a mammal, particularly a human.
  • Respiratory inflammatory disease includes, but is not limited to asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis.
  • Some embodiments disclosed herein provide a method of treating or preventing one or more of the diseases or conditions discussed herein, wherein the method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically 5 acceptable salt thereof.
  • Some embodiments disclosed herein provide a method of treating or preventing non- ischemic dilated cardiomyopathy, wherein the method comprises administering to a person in need thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease in a patient having co-morbidities such as renal dysfunction, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount 20 of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • chronic inflammatory diseases e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy
  • Some embodiments disclosed herein provide a method of treating or preventing heart failure wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a 25 pharmaceutically acceptable salt thereof.
  • the heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.
  • Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, wherein the method comprises administering to a person in need of 57 201388-PCT01-NP thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, wherein the method comprises administering to a person in need of thereof, a 5 therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Some embodiments disclosed herein provide a method of treating or preventing respiratory inflammatory disease and complications associated with respiratory inflammatory disease, wherein the method comprises administering to a person in need of thereof, a therapeutically 10 effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and/or rhinitis.
  • the terms “preventing”, “prevention”, and “prevent” are readily understood by an 15 ordinarily skilled physician and, with respect to treatment of a particular condition, can include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition.
  • treating can include (1) diminishing the extent or cause of the condition being treated, and/or (2) alleviating or ameliorating one or more symptoms associated with that condition.
  • Treatment of cardiovascular disease can include stabilizing (i.e., not worsening), delaying, or slowing the spread or 25 progression of the cardiovascular disease; prolonging survival as compared to expected survival if not receiving treatment; and/or otherwise ameliorating or palliating the severity of the cardiovascular disease, in whole or in part.
  • the compounds disclosed herein may have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more 58 201388-PCT01-NP easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salts thereof are believed to be useful in the prevention or treatment of cardiovascular conditions, including but not limited to coronary artery disease, acute coronary syndrome, cardiomyopathy, non-ischemic dilated cardiomyopathy, heart 10 failure, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction in a mammal, particularly a human.
  • compositions 20 There is provided a method of treatment of a condition where modulation of CX 3 CR1 is required, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage 59 201388-PCT01-NP form.
  • the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E.
  • a pharmaceutical formulation comprising a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
  • the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation.
  • a further embodiment encompasses pharmaceutically acceptable salts of the compound for formula (I), or a compound disclosed herein.
  • a compound of formula (I), or a compound disclosed herein may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent.
  • a salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly where the salt is intended for administration to an animal, e.g.
  • a human or is a reagent for use in 25 making a compound or salt intended for administration to an animal
  • the salt is pharmaceutically acceptable.
  • pharmaceutically acceptable is used to characterize a moiety (e.g. a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment.
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any 60 201388-PCT01-NP deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base addition salts.
  • suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley- VCH, 2002. 10
  • certain compounds of formula (I), or a compound disclosed herein may exist in solvated form, e.g. hydrates, including solvates of a pharmaceutically acceptable salt of a compound of formula (I).
  • certain compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof may exist as a mixture of tautomers.
  • “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom, e.g., amide-imidic acid tautomerism.
  • the disclosure herein includes all tautomers of compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • certain compounds of formula (I), or a compound disclosed 20 herein, or a pharmaceutically acceptable salt thereof may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures.
  • Certain compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the 25 presence of a ring bond or double bond.
  • linkages e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds
  • Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis.
  • 61 201388-PCT01-NP EXAMPLES The following examples are non-limiting examples.
  • SYNTHETIC METHODS General conditions 5 (i) operations were carried out at room temperature (rt), i.e.
  • BIOTAGE SNAP BIOTAGE Sfär Silica HC D cartridges (20 ⁇ m, 10–100 g), INTERCHIM PURIFLASH cartridges (25 ⁇ m, 4–120 g), INTERCHIM PURIFLASH cartridges (50 ⁇ m, 25–330 g), GRACE GRACERESOLVE Silica Flash Cartridges (4–120 g) or Agela Flash Colum Silica-CS cartridges (80–330g), or on reversed phase silica using Agela Technologies C-18, spherical cartridges (20–35 ⁇ m, 100A, 80–330g), manually or 10 automated using a GRACE REVELERIS X2 Flash system or similar system; (ix) preparative TLC was performed on glass-backed silica plates (20 ⁇ 20 cm) covered with a 1 mm thick silica gel (particle size of 10–40 ⁇ m), in a glass chamber, using the
  • the NMR spectra contains residual impurities and/or residual solvent(s), this is not reported unless it partially coincides with peaks of Intermediates and/or Structures of Formula (I), in which case said peaks of Intermediates and/or Structures of Formula (I) are reported as multiplets partially overlapping with said solvent or impurity, and the Integral is omitted.
  • the structures of the end-products of the 25 Formula (I) might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported.
  • the structures of the intermediates and/or end- products of Formula (I) might appear as rotamers in a more equal relationship, in such instances the peaks of such rotamers are either reported as multiplets, if the signals of said rotamers are partially overlapping, or as individual peaks, if the signals of said rotamers are well separated.
  • Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported;
  • high resolution electrospray mass spectral data were obtained using a Waters XEVO 5 qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported
  • intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry; 10 (xviii) unless stated otherwise compounds containing an asymmetric carbon and/or sulfur atom were not resolved;
  • (xix) in general Examples are named using ACD/Name IUPAC name module 2020.2.0
  • the numbers are incremented automatically to indicate that stereocenters may vary independently to each other.
  • the same number is used after the label '&' and 'or' to indicate that said stereocenters forms a group.
  • a third stereocenter present in the same chemical structure, that varies independently to the former stereocenters, is designated with a unique new number following the label '&' and 'or'.
  • 67 201388-PCT01-NP In general, for structures of Examples and Intermediates where all stereocenters are designated as '&', the structure is named with a “rac-” prefix.
  • Examples and Intermediate compounds where all stereocenters are designated as 'or', the structure is named with a “rel-” prefix.
  • Examples and Intermediate compounds are named using the descriptors (RS) 5 and (SR) are used to denote general '&' centers for chemical structures with multiple chiral centers where only some are designated as '&'.
  • the descriptors (R*) and (S*) are used to denote the general 'or' centers for chemical structures with multiple chiral centers where only some are designated as 'or'.
  • Example 128 the second eluting isomer from the chiral separation of N-(4-((1-(2,3-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)pyrimidin-2-yl)methanesulfonamide is named “N-(4- ⁇ [(1R*)-1-(2,3-15 Difluorophenyl)ethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ pyrimidin-2- yl)methanesulfonamide” it could be N-(4- ⁇ [(1R)-1-(2,3-Difluorophenyl)ethyl]sulfanyl ⁇ -6- ⁇ [(2R)- 1-hydroxy-4-methylpentan-2-yl]amino ⁇ pyrimidin-2-yl)methane
  • Example 128 i.e., the second eluting isomer
  • F Said Example or Intermediate with a stereocenter labled with (R*) or (S*) can also in certain instances be represented by a structure as below; 68 201388-PCT01-NP OH HN F
  • a numbered example disclosed herein is prepared by chiral separation of diastereomers, such as Example 128 as described above, both diastereomers, the first eluting isomer and the second eluting isomer, are disclosed herein.
  • stereocenters are drawn with stereobonds representing their internal relationship.
  • Said stereocenters are labeled with an ‘&1’ flag representing a mixture of cis-configuration or a mixture of trans-configuration, or an ‘or1’ flag representing a single cis- 10 isomer or a single trans-isomer with unknown absolute stereochemistry.
  • the structure of said Example or Intermediate further contain one or more stereocenters that are racemic and not fixed in relation to the former stereocenters, said stereocenter(s) are drawn with a straight bond at said stereocenters.
  • the label “Isomer 1” corresponds to the first eluted isomer
  • “Isomer 2” 15 corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration.
  • “Isomer 3” and “Isomer 4” refer to the third eluted isomer and the fourth eluted isomer, respectively.
  • the reaction 73 201388-PCT01-NP may be carried out at temperatures ranging typically from 20oC to 140oC for a prolonged time (typically 0.5-72 h) using standard equipment or a single node microwave reactor.
  • Formula (III) is typically used in an equimolar amount to formula (II) but can also be used in a slight excess (typically 1.1-2.2 eq).
  • the reaction may also be conducted under an inert atmosphere 5 (e.g. an N2 atmosphere).
  • Method a2 The compounds of formula (I) in which R1, R2, R5, R11, G1, G2, G3, L, X and p are defined as in formula (I), Z is -NH- or -O- may be prepared from a compound of formula (IV) LG 2 G 1 G 2 5 )p 10 in which R 2 , R 5 , G 1 , G 2 , G 3 , L, X and ormula (I) and LG 2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro) using the methods a2a (when Z is - NH-) to a2b (when Z is -O-) below.
  • a suitable leaving group such as halide or triflate (OTf) (preferentially chloro)
  • Method a2a Reacting the compound of formula (IV) with a compound of formula (V) R 1 OH 15 in which R 1 and R 11 are defined as in form ula (I).
  • the reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH, nBuOH or mixtures thereof in the presence of a suitable base such as DIPEA, TEA or K 2 CO 3 (typically 2-5 eq).
  • the reaction may be carried out at temperatures ranging typically from 20 o C to 120 o C for a prolonged reaction time (2-120 h) using standard equipment or a single node microwave reactor.
  • Formula (V) is 20 normally used in a slight excess (typically 1.2-5 eq) to formula (IV).
  • Method a2b Reacting the compound of formula (IV) with a compound of formula (VI) 74 201388-PCT01-NP R 1 OH HO wherein R 1 and R 11 are defined as in for reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH. The rection is preferentially carried out in an inert atmosphere (e.g. an N2-atmosphere) at ambient 5 temperature for a prolonged reaction time (typically 2-16 h).
  • an inert atmosphere e.g. an N2-atmosphere
  • Method a3 The compounds of formula (I) in which R 1 , R 2 , R 5 , R 11 , G 1 , G 2 , G 3 , Z, L, X and p are defined as in formula (I) may be prepared from a compound of formula (VII) R 1 OH 5 )p 10 wherein R 1 , R 5 , R 11 , G 1 , G 2 , G 3 , Z, L , an p are e ne as in formula (I) and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) using the methods a3a to a3b below.
  • OMs mesylate
  • OTf triflate
  • Method a3a Reacting the compound of formula (VII) with one of the compounds (one at 15 a time) of formula (VIII) to (XII) 75 201388-PCT01-NP O NH O O b O O S R R a NH 2 R a S S NH 2 N NH b 2 R in which R a, R b , R c and ay be catalyzed with a suitable palladium reagent, e.g.
  • Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5– 5 3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using standard equipment or a single node micro wave reactor.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h).
  • the reaction may also be performed without a metal catalyst in an inert 10 organic solvent such as DMF or DMSO in the presence of a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq) at elevated temperatures (e.g.90 o C) for a prolonged reaction time.
  • a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq)
  • Formulas (VIII) to (XII) is typically used in a slight excess to formula (VII) (e.g.1.1-8 eq).
  • Method a3b Reacting the compound of formula (VII) with a compound of formula (XIII) O O S (CH2)-BF3 K 15 a in which R is defined as in formula (I).
  • the reaction may be catalyzed with a suitable palladium reagent, e.g.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically on).
  • the reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3.
  • a suitable base such as DIPEA, K2CO3 or NaHCO3.
  • the reaction is carried out at temperatures ranging typically from 20 o C to 100 o C for a prolonged reaction time 20 using standard equipment or a single node microwave reactor.
  • the reaction may also be performed with the presence of water.
  • Method a4b Reacting the compound of formula (XIV) with a compound of formula (XVI) 77 201388-PCT01-NP H O L2 X (R5)p ( XVI) in which R 5 , X and p are defined as in formula (I) and L 2 is -(CR 3 R 4 )j-, wherein R 3 , R 4 and j are defined as in formula (I).
  • the reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH.
  • the rection is preferentially 5 carried out in an inert atmosphere (e.g.
  • the reaction may be catalyzed with a suitable palladium reagent, e.g. Pd-118 or PdCl2(dppf)2 in the presence of a suitable base, such as Cs2CO3 or K2CO3 in an inert organic 20 solvent, such as 1,4-dioxane or THF usually in mixture with water.
  • a suitable base such as Cs2CO3 or K2CO3
  • an inert organic 20 solvent such as 1,4-dioxane or THF usually in mixture with water.
  • the reaction is conducted at temperatures ranging typically from 20 o C to 100 o C for a prolonged reaction time (typically 2-24 h).
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere).
  • R 1 OH Z O Cl X) 10 The reaction is typically carried out in an inert organic solvent such as DCM, 1,4- dioxane, THF or MeCN in the presence of a suitable base such as pyridine, DIPEA or TEA.
  • a suitable base such as pyridine, DIPEA or TEA.
  • the reaction is preferentially carried out at ambient temperature or at slightly elevated temperatures for a prolonged reaction time.
  • the reaction may also be conducted under an inert atmosphere (e.g. an N 2 atmosphere).
  • an inert atmosphere e.g. an N 2 atmosphere.
  • Certain compounds of formula (II) in which R 1 , R 2 , R 11 , G 1 , G 2 and G 3 are defined as in formula (I) and Z is -NH- or -O- may be prepared by treating a compound of formula (XX) 20 wherein R 1 , R 2 , R 11 , G 1 , G 2 and G 3 are defined as in formula (I) and Z is -NH- or -O- 79 201388-PCT01-NP R 1 OH Z with an excess TFA in the presenc eq) which is used as a scavenger for the benzylic cation formed during the reaction.
  • the reaction is typically carried out at ambient temperature for a prolonged reaction time (typically 2-24 h).
  • the compounds of formula (III) may be prepared from a compound of formula (XXI) H O L1 X (R5 )p ( XXI) using any of the methods b1 to b5 below:
  • the reaction is typically carried out without an organic 10 solvent at slightly elevated temperatures (typically 60 o C) and when PCl 3 , PCl 5 or PBr 3 is used the reaction is typically carried out in an inert organic solvent such as DCM at temperatures ranging from 0 o C to ambient temperature and for a prolonged reaction time.
  • an organic 10 solvent typically at slightly elevated temperatures (typically 60 o C)
  • PCl 3 , PCl 5 or PBr 3 the reaction is typically carried out in an inert organic solvent such as DCM at temperatures ranging from 0 o C to ambient temperature and for a prolonged reaction time.
  • Method b4 Certain compounds of formula (III) in which R 5 and p are defined as in formula (I), LG 1 is bromo, L 1 is –(CR 3 R 4 )k- in which R 3 and R 4 are independently selected from 15 H, C1-6 alkyl or C1-6 haloalkyl and k is 1, X is A wherein A is selected from phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, may be formed by reacting a compound of formula (XXI), in which R5 and p are defined as in formula (I), L 1 is –(CR 3 R 4 )k- in which R 3 and R 4 are independently selected from H, C1-6 alkyl or C1-6 haloalkyl and k is 1, X is A wherein A is selected from phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, with an excess 20 HBr in an inert solvent such as water or AcOH.
  • Method b5 Certain compounds of formula (III) in which X, R 5 and p are defined as in formula (I), L 1 is –CR 3a R 4a -CR 3 R 4 - wherein R 3a and R 4a are independently selected from H or 25 C1-6 alkyl, R 3 and R 4 both are fluoro and LG 1 is chloro or bromo may be formed by reacting a compound of formula (XXII) in which X, R 5 and p are defined as in formula (I), R 3a and R 4a are independently selected from H or C1-6 alkyl and LG 1 is chloro or bromo 81 201388-PCT01-NP O L G 1 X (R 5 )p 4 with a deoxofluorinating agent such as hyl-1,1,1-trifluoro- ⁇ 4 -sulfanamine) or de
  • Step 1 A strong base such as for example NaH is added to a one o f the compounds of formula (VIII) to (XII), defined as above, dissolved in an inert organic solvent such as THF, 2- MeTHF or 1,4-dioxane at ambient temperature.
  • an inert organic solvent such as THF, 2- MeTHF or 1,4-dioxane
  • the mixture is left for about 1 h at ambient temperature before it is added to a solution (typically in the same solvent as above) of a 20 compound of formula (XXIII), in which LG 2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro).
  • LG 2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro).
  • the mixture is heated, typically to a temperature in the range of 50 o C to 70 o C for a prolonged reaction time to generate a compound of formula (XXIV) in which 82 201388-PCT01-NP R2 and LG2 are defined as above.
  • the reaction is preferentially performed under an inert atmosphere (e.g. an N2 atmosphere).
  • Step 2a A strong base such as for example NaH is added to a compound of formula (XV) defined as above, dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane 5 typically at 0 o C.
  • an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane 5 typically at 0 o C.
  • the mixture is left for about 1 h at ambient temperature before it is added to a cold solution (e.g.0 o C, typically in the same solvent as above) of a compound of formula (XXIV) in which R 2 and LG 2 are defined as above. This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of formula (XXV).
  • the reaction may also be carried out in an inert organic solvent such as 1,4- 10 dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K 2 CO 3 or NaHCO3.
  • a suitable base such as DIPEA, K 2 CO 3 or NaHCO3.
  • the reaction is typically carried out at temperatures ranging from 20 o C to 100 o C for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • the reaction may also be performed with the presence of water.
  • Step 2b A strong base such as for example NaH is added to a compound of formula15 (XVI), defined as above, dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4- dioxane typically at 0 o C.
  • the reaction is carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc.
  • a suitable base such as for example NaOH or NaOAc.
  • the reaction is carried out in a temperature range of 20 o C to 60 o C for a prolonged reaction time.
  • the reaction may also be performed under an inert atmosphere (e.g. an N 2 atmosphere).
  • Step 3 A compound of formula (XXIX) defined as above can be obtained by reacting a compound of formula (XXVIII) defined as above with one of the compounds (one at a time) of 20 formula (VIII) to (XII) as defined above.
  • the reaction may be performed in an inert organic 84 201388-PCT01-NP solvent such as DMF or DMSO in the presence of a suitable base such as NaH, (typically 1.5–2 eq) at elevated temperatures for a prolonged reaction time.
  • a suitable base such as NaH, (typically 1.5–2 eq)
  • the reaction may be catalyzed with a suitable palladium reagent (e.g.
  • Pd 2 (dba) 3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or 5 K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using standard equipment or a single node microwave reactor.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h).
  • an inert atmosphere e.g. an N2 atmosphere
  • a prolonged reaction time typically 3-24 h.
  • an additional amount of DIPEA is added before addition of a compound of formula (V) defined as above in an organic solvent, preferentially THF, and the reaction mixture is stirred at about 0 o C for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula (XXXI) (for S-containing L).
  • the reaction is 10 preferentially performed under an inert atmosphere (e.g. an N 2 atmosphere).
  • step 1 A compound of formula (XXX) wherein , R 5 , X and p are defined as in formula (I) and L is -O-(CR 3 R 4 )j-, wherein R 3 , R 4 and j are defined as in formula (I) and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXIII) defined as above with a 15 compound of formula (XVI) defined as above. The reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH.
  • a strong base such as NaH.
  • step 2 A compound of formula (XXXI) in which R 1 , R 5 , R 11 , X and p are 20 defined as in formula (I), L is -O-(CR 3 R 4 ) j -, wherein R 3 , R 4 and j are defined as in formula (I) and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXX) with a compound of formula (V) defined as above.
  • an inert atmosphere e.g. an N 2 -atmosphere
  • the reaction is carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as for 25 example DIPEA, TEA, K2CO3 (preferentially DIPEA).
  • a suitable base such as for 25 example DIPEA, TEA, K2CO3 (preferentially DIPEA).
  • the reaction is generally carried out at temperatures ranging from 0 o C to 40 o C for a prolonged reaction time until the reaction is complete (for O-containing L).
  • a compound of formula (XXXIII) wherein R 1 and R 11 are defined as in formula (I), Z is -NH- and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXXII) in which LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) with a compound of formula (V) defined as above.
  • the reaction is 10 typically carried out in an inert organic solvent such as THF, 1,4-dioxane or IPA in the presence of a suitable base such as TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on).
  • a regioisomer e.g. formula (XXXIV)
  • Step 2 A compound of formula (XXXV) defined as above may be formed by reaction of 15 a compound of formula (XXXIII) defined as above with a compound of formula (XV) defined as above.
  • reaction is typically carried out in an inert organic solvent such as THF, 1,4- dioxane, MeOH or IPA in the presence of a suitable base such as K 2 CO 3 , Cs 2 CO 3 , TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on).
  • a suitable base such as K 2 CO 3 , Cs 2 CO 3 , TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on).
  • a compound of formula (XXXVI) defined as above may be formed by reaction of a compound of formula (XXXIV) wherein R 1 and R 11 are defined as in formula (I), Z is -NH- and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) with a compound of formula (XV) defined as above.
  • reaction is typically carried out in an inert organic solvent such as THF, 1,4-dioxane, MeOH or IPA in the presence of a suitable base such 10 as K 2 CO 3 , Cs 2 CO 3 , TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on).
  • a suitable base such as K 2 CO 3 , Cs 2 CO 3 , TEA or DIPEA
  • a compound of formula (XXXVII) defined as above may be formed by reaction of a compound of formula (XXVIII) defined as above with a compound of formula (V) defined as above.
  • the reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as for example DIPEA, TEA, K2CO3 or 5 NaHCO3.
  • a suitable base such as for example DIPEA, TEA, K2CO3 or 5 NaHCO3.
  • the reaction is generally carried out at temperatures ranging from 20 o C to reflux for a prolonged reaction time until the reaction is complete.
  • a compound of formula (XXXIX) may be prepared by reacting a compound of formula (XXXVIII) wherein R 5 , X, p and L are defined as above, with NaOtBu in MeOH at elevated temperature (e.g.100°C) for a prolonged reaction time (e.g.15 min) followed by addition of an ammonium salt such as ammonium chloride and continued heating at 80°C for a 10 prolonged reaction time until the reaction is complete.
  • Method f step 1 A compound of formula (XL) wherein R 5 , X, p and L are defined as above, may be prepared by adding AcCl to a cold solution of a compound of formula 90 201388-PCT01-NP (XXXVIII) defined as above in EtOH and allowing the temperature to reach rt during a prolonged time, typically 15 h to 24 h.
  • Method f Step 2 A compound of formula (XXXIX) may be prepared by adding a cold solution of NH3 in a solvent such as EtOH or MeOH, to a compound of formula (XL) and 5 allowing the temperature to reach rt during a prolonged time, typically on.
  • Step 3 A compound of formula (XLI) wherein R 5 , X, p and L are defined as above may be prepared by reaction of a compound of formula (XXXIX) with diphenyl iminodicarboxylate in a suitable solvent, typically MeCN, in the presence of a base such as K2CO3, at temperatures ranging from rt to 70°C for a prolonged time, e.g.2 h to 24 h, until the reaction is complete.
  • a suitable solvent typically MeCN
  • a compound of formula (XLII) wherein R 5 , X, p, L and LG 2 are defined as above may be prepared by reaction of a compound of formula (XLI) defined as above with a suitable chlorinating reagent, typically POCl3 in excess, with or without an amine base such as N,N- diethylaniline as an additive, at elevated temperatures ranging from 70°C to reflux for a prolonged reaction time, typically 1 h to 15 h, until the reaction is complete.
  • a suitable chlorinating reagent typically POCl3 in excess
  • an amine base such as N,N- diethylaniline
  • Step 5 A compound of formula (XLIII) wherein R 1 , R 11 , R 5 , X, L, Z and LG 2 are defined as above may be prepared by reaction of a compound of formula (XLII) defined as above with a compound of formula (V) defined as above.
  • the reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as DIPEA, TEA or K 2 CO 3 (typically 2-5 eq).
  • the reaction may be carried out at temperatures 20 ranging typically from 20 o C to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • Certain compounds of formula (VII) e.g.
  • a compound of formula (XLIV) wherein R 5 , X, p and L are defined as above may be prepared by reaction of a compound of formula (XXXIX) defined as above with diethylmalonate in a suitable solvent, typically EtOH, in the presence of a base such as tert- 5 BuONa, at reflux temperatures for a prolonged time until the reaction is complete.
  • Step 2 A compound of formula (XLV) wherein R 5 , X, p and L and LG 2 are defined as above may be prepared by reaction of a compound of formula (XLIV) defined as above with a suitable chlorinating reagent, typically POCl 3 in excess, with or without an amine base such as N,N-diethylaniline as an additive, at elevated temperatures typically at reflux for a prolonged 10 reaction time until the reaction is complete.
  • Step 3 A compound of formula (XLVI) wherein R 1 , R 11 , R 5 , X, L, Z and LG 2 are defined as above may be prepared by reaction of a compound of formula (XLV) defined as above with a compound of formula (V) defined as above.
  • the reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as 15 DIPEA, TEA, NaHCO3 or K2CO3 (typically 1-5 eq).
  • a suitable base such as 15 DIPEA, TEA, NaHCO3 or K2CO3 (typically 1-5 eq).
  • the reaction may be carried out at temperatures ranging typically from 20 o C to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • Step 1 Reacting a compound of formula (XXIV) defined as above with a compound of formula (V) defined as above.
  • the reaction is carried out in an inert organic solvent such as 1,4- 10 dioxane, THF, MeOH, EtOH, MeCN or mixtures thereof in the presence of a suitable base such as DIPEA, TEA, NaHCO 3 or K 2 CO 3 (typically 2-5 eq).
  • a suitable base such as DIPEA, TEA, NaHCO 3 or K 2 CO 3 (typically 2-5 eq).
  • the reaction may be carried out at temperatures ranging typically from 20 o C to 80 o C for a prolonged reaction time (2-48 h) using standard equipment or a single node microwave reactor.
  • Formula (V) is normally used in a slight excess (typically 1.2-3 eq) to formula (XXIV).
  • a suitable base such as DIPEA or TEA.
  • a compound of formula (LIII) defined as above may be formed by treatment of a compound of formula (LII) with a reducing agent such as BH3xTHF or BH3xDMS.
  • the reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane at rt for a prolonged reaction time (typically on) until the reaction is complete.
  • reaction may also be carried out in an inert organic solvent such as 1,4- dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K 2 CO 3 or 10 NaHCO3.
  • a suitable base such as DIPEA, K 2 CO 3 or 10 NaHCO3.
  • the reaction is carried out at temperatures ranging typically from 20 o C to 100 o C for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • the reaction may also be performed with the presence of water.
  • Method g step 2 Reacting the compound of formula (LV) wherein R 2 and LG 2 are defined as above with a compound of formula (V) defined as above to generate a compound of 15 formula (LVII) wherein R 1 , R 2 , R 11 and Z are defined as above.
  • the reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq).
  • a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq).
  • the reaction may be carried out at temperatures ranging typically from 20 o C to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • Formula (V) is normally used in a slight excess 20 (typically 1.2-5 eq) to formula (LV).
  • 96 201388-PCT01-NP Method h step 1 Reacting the compound of formula (XLVII) defined as above with a compound of formula (LIV) to generate a compound of formula (LVII).
  • the reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3.
  • a suitable base such as DIPEA, K2CO3 or NaHCO3.
  • the reaction is carried out at 5 temperatures ranging typically from 20 o C to 100 o C for a prolonged reaction time using standard equipment or a single node microwave reactor.
  • the reaction may also be performed with the presence of water.
  • Method i step 1 A solution of a compound of formula (XXIII) defined as above and formula (LIV) in a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is 10 pre-cooled to about 0 o C (ice/bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, preferentially THF is added slowly (typically during 30 min) to the reaction mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h).
  • a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is 10 pre-cooled to about 0 o C (ice/bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, preferentially THF is added slowly (typically during 30 min) to the reaction mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h).
  • an additional amount of DIPEA is added before addition of a compound of formula (V) in an inert organic solvent, preferentially THF, and the reaction mixture is stirred at about 15 0 o C for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula (LVI) wherein R 1 , R 11 , Z and LG 2 are defined as above.
  • the reaction is preferentially performed under an inert atmosphere (e.g. an N 2 atmosphere).
  • Method i step 2 Reacting the compound of formula (LVI) with one of the compounds (one at a time) of formula (VIII) to (XII), defined as above to give a compound of formula 20 (LVII) defined as above.
  • the reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using standard equipment or a single node micro wave reactor.
  • a suitable palladium reagent e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq)
  • an inert organic solvent such as DMF, DMSO, 1,4-diox
  • reaction may also be performed without a metal catalyst in an inert organic solvent such as DMF or DMSO in the presence of a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq) at elevated temperatures (e.g.90 o C) for a prolonged reaction time.
  • a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq) at elevated temperatures (e.g.90 o C) for a prolonged reaction time.
  • a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq)
  • Formulas 30 (VIII) to (XII) is typically used in a slight excess to formula (LVI) (e.g.1.1-8 eq).
  • 97 201388-PCT01-NP Certain compounds of formula (XX) (e.g.
  • Method k step 1 A compound of formula (LX) wherein LG 2 is a suitable leaving group 15 such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared by reacting a compound of formula (XXXII) defined as above with a compound of formula (LIV).
  • a compound of formula (LVIII) defined as above may be formed by reaction a compound of formula (LX) with a compound of formula (V) defined as above.
  • a compound of formula (LIX) defined as above may be formed by reaction a compound of formula (LVIII) with one of the compounds (one at a time) of formulas (VIII) to (XII) defined as above.
  • the reaction may be catalyzed with a suitable palladium reagent, e.g.
  • Formulas (VIII) to (XII) is typically used in a slight excess to formula (LVIII) (e.g.1.1-8 eq).
  • a compound of formula (LXI) wherein R 1 and R 11 is defined as in formula (I), Z is -NH- and LG 2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) 25 (preferentially chloro) may be prepared by reacting a compound of formula (XXXIV) defined as above with a compound of formula (LIV).
  • Step 2 A compound of formula (LXII) defined as above may be formed by reaction a 5 compound of formula (LXI) with one of the compounds (one at a time) of formulas (VIII) to (XII) defined as above.
  • the reaction may be catalyzed with a suitable palladium reagent, e.g.
  • Pd 2 (dba) 3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using 10 standard equipment or a single node micro wave reactor.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h).
  • Formulas (VIII) to (XII) is typically used in a slight excess to formula (LXI) (e.g.1.1-8 eq).
  • a compound of formula (LXIV) can be obtained by reacting a compound of formula (XXVI) with a compound of formula (LXIII).
  • the reaction is carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc.
  • a suitable base such as for example NaOH or NaOAc.
  • the reaction is carried out in a temperature 5 range of 20 o C to 60 o C for a prolonged reaction time.
  • the reaction may also be performed under an inert atmosphere (e.g. an N 2 atmosphere).
  • Step 2 A compound of formula (LXV) wherein LG 2 is chloro can be obtained from a compound of formula (LXIV).
  • the reaction is carried out with a chlorinating agent such as POCl 3 , preferentially in the presence of an additive such as Et 4 NCl, neat or in the presence of an 10 inert organic solvent such as PrCN at elevated temperatures (e.g. reflux) for a prolonged reaction time.
  • a chlorinating agent such as POCl 3
  • Et 4 NCl neat
  • an 10 inert organic solvent such as PrCN
  • the reaction is carried out in a mixture of POCl3 and N,N-diethylaniline at reflux temperature for a prolonged reaction time.
  • the reaction may be performed in an inert organic solvent such as DMF or DMSO in the presence of a suitable base such as NaH, (typically 1.5–2 eq) at elevated temperatures for a prolonged reaction time.
  • a suitable base such as NaH, (typically 1.5–2 eq)
  • the reaction may be catalyzed with a suitable palladium 20 reagent (e.g.
  • Pd 2 (dba) 3 in combination with a phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs 2 CO 3 or K 2 CO 3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using standard equipment or a single node microwave reactor.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N 2 atmosphere) for a prolonged reaction time (typically 3-24 25 h).
  • Step 4 A compound of formula (LXVII) defined as above may be obtained by reacting a compound of formula (LXVI) defined as above with a compound of formula (V) defined as above.
  • the reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH, nBuOH or mixtures thereof in the presence of a suitable base such as DIPEA, 101 201388-PCT01-NP TEA or K2CO3 (typically 2-5 eq).
  • the reaction may be carried out at temperatures ranging typically from 20 o C to 120 o C for a prolonged reaction time (2-120 h) using standard equipment or a single node microwave reactor.
  • Step 2 The compounds of formula (XV) defined as above are prepared by hydrolysis of a compound of formula (LXVIII) with a suitable base such as NaOH, KOH, K 2 CO 3 in an organic solvent such as MeOH, EtOH, THF or 1,4-dioxane.
  • a suitable base such as NaOH, KOH, K 2 CO 3
  • an organic solvent such as MeOH, EtOH, THF or 1,4-dioxane.
  • Step 2 A compound of formula (LXXI) wherein R 1 is defined as in formula (I) can be obtained by reaction of a compound of formula (LXX) with thiourea.
  • an inert organic solvent such as EtOH
  • a base such as 10 KOH or NaOH
  • the reaction 15 is typically carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc.
  • a suitable base such as for example NaOH or NaOAc.
  • the reaction is carried out in a temperature range of 20 o C to 60 o C for a prolonged reaction time.
  • the reaction may also be performed under an inert atmosphere (e.g.
  • a suitable base such as DIPEA, TEA or pyridine.
  • Step 5 A compound of formula (LXXIV) defined as above can be obtained by reaction of a compound of formula (LXXIII) with one of the compounds (one at a time) of formula (VIII) to (XII) defined as above.
  • the reaction may be catalyzed with a suitable palladium reagent, e.g.
  • Pd 2 (dba) 3 in combination with a suitable phosphine ligand, typically X-Phos or 10 XantPhos in the presence of a base, such as Cs 2 CO 3 or K 2 CO 3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20 o C to 120 o C using standard equipment or a single node micro wave reactor.
  • the reaction is preferentially conducted under an inert atmosphere (e.g. an N 2 atmosphere) for a prolonged reaction time (typically 3-24 h).
  • Suitable protecting groups for hydroxy include trialkyl silyl or diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl ethers).
  • Suitable protecting groups for carboxylic acids include (C1-C6)alkyl or benzyl esters.
  • Suitable protecting groups for amino include tert-butyloxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethoxycrbonyl and 10 trialkyl silyl groups (e.g.
  • Suitable protecting groups for thiols include acetyl and 4-methoxy benzyl groups.
  • the protecting groups may be removed and/or introduced at any convenient stage in the synthesis using conventional techniques well known in the chemical art. It will be appreciated by those skilled in the art how a compound comprising such a group can be deprotected (see 15 “Protective groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4 rd edition, T.W. Greene & P.G.M Wutz, Wiley- Interscience (2007)).
  • substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups.
  • 105 201388-PCT01-NP Persons skilled in the art will appreciate that chiral isomers of compounds herein can be resolved at any stage in the synthetic process using chiral resolving agents described in the literature and known to person skilled in the art, or using chiral chromatography methods described in the literature and known to person skilled in the art, or as described further in the 5 Examples.
  • a deoxofluorinating agent such as for example DAST (N,N-diethyl-1,1,1-trifluoro- ⁇ 4 -sulfanamine), deoxo-fluor reagent (e.g.1,1,1- trifluoro-N,N-bis(2-methoxyethy
  • Step b) (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5- 15 triazin-2-yl)methanesulfonamide
  • Methanesulfonamide (6.20 g, 65.22 mmol) was added to a mixture of (R)-2-((4-chloro-6- ((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol
  • Step a (16.65 g, 43.48 mmol), Cs2CO3 (21.25 g, 65.22 mmol), Pd2(dba)3 (0.796 g, 0.87 mmol) and X- Phos (1.658 g, 3.48 mmol) in THF (400 mL) under an atmosphere of N 2 (g).
  • the reaction mixture 108 201388-PCT01-NP was stirred at 55°C for 12 h. After cooling to rt, the mixture was partitioned between water (500 mL) and MTBE (200 mL). The layers were separated, and the organic layer was extracted three times with 0.09 M K 2 CO 3 (aq). The combined aqueous layer was acidified with 12 N HCl (aq) and extracted twice with EtOAc (1 L). The combined organic layer was washed with water, 5 dried, filtered and concentrated at reduced pressure to give the title compound (18.48 g, 96%); MS (ESI) m/z [M+H] + 442.
  • Step b) (R)-N-(1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4,6-dichloro-1,3,5-triazin- 2-amine 5 2,4,6-Trichloro-1,3,5-triazine (775 mg, 4.2 mmol) in THF (25 mL) was added over 45 min to (R)-1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-amine Intermediate 10 Step a) (926 mg, 4.0 mmol) and K2CO3 (552 mg, 4.00 mmol) in THF (25 mL) at -6°C under an atmosphere of Ar(g) and the reaction mixture was stirred at -6 o C for 1h and then at rt for 16 h.
  • Step b) (R)-2-((2-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)pentan-1-ol S-(2,3-Difluorobenzyl) ethanethioate, Intermediate 22 (200 mg, 0.99 mmol) and K 2 CO 3 10 (164 mg, 1.19 mmol) were added to (R)-2-((2,6-dichloropyrimidin-4-yl)amino)pentan-1-ol (247 mg, 0.99 mmol) in MeOH (4 mL). The mixture was stirred at rt for 48 h and concentrated. DCM and water were added, and the organic layer was concentrated.
  • N-(tert- Butyldimethylsilyl)methanesulfonamide (0.46 g, 2.20 mmol) dissolved in CHCl3 (10 mL) was added. The reaction mixture was allowed to reach rt and stirred on. The solvent was evaporated 10 to give a crude product which was used in the next step without purification.
  • N-(tert-butyldimethylsilyl)methanesulfonimidoyl chloride Intermediate 48 Step a (501 mg, 2.2 mmol) in CHCl 3 (10 mL) was treated with NH 3 (g) until saturated as indicated by gas bubbling. The reaction mixture was stirred at ambient temperature on. The mixture was 15 diluted with MTBE and filtered, concentrated and the crude product was purified by straight phase flash chromatography on silica (60% EtOAc in heptane) to give the title compound (243 mg, 53%) as a white solid.
  • a solution of (4-methoxyphenyl)methanethiol (2.19 g, 14.2 mmol) in THF (10 mL) was added dropwise over a period of 5 min to a stirred solution of 2,4,6-trichloro-1,3,5-triazine (2.62 g, 14.2 mmol) and DIPEA (6.20 mL, 35.5 mmol) in THF (80 mL) at 0°C and under an atmosphere of N 2 (g).
  • the reaction mixture was stirred at 55°C for 15 h.
  • the reaction was incomplete and further methanesulfonamide (155 mg, 1.63 mmol), Pd2(dba)3 (74 mg, 0.08 mmol) and X-Phos (78 mg, 0.16 mmol) were added and the solution was stirred at 55°C for an additional 5 h under an atmosphere of N 2 (g).
  • the mixture was diluted with TBME (100 mL) and washed with water (2 ⁇ 50 mL).
  • the aqueous layer was 10 acidified with 2 M HCl (aq).
  • the aqueous layer was extracted with EtOAc (125 mL), and the organic layer was washed with brine (50 mL).
  • reaction 5 The reaction 5 mixture was placed on an ice bath and (R)-2-amino-4-methylpentan-1-ol (0.155 mL, 1.21 mmol) was added. The reaction mixture was stirred for 5 min on the ice bath and then at rt for 1 h. The mixture was partitioned between DCM (50 mL) and 8% NaHCO 3 (aq) (50 mL). The aqueous layer was extracted with DCM (50 mL) and the combined organic layer was filtered through a phase separator and concentrated.
  • the reaction was quenched with water and the mixture was extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated.
  • the crude intermediate was dissolved in THF (2 mL) cooled to 0 o C and imidazole (144 mg, 2.12 mmol) and TBDMSCl (319 mg, 2.12mmol) were added at 0 o C. The reaction mixture was stirred at 25 o C for 2 h. The reaction was quenched with water and the mixture was 10 extracted with EtOAc (3 ⁇ 30 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated.
  • the crude product was first purified by preparative TLC (PE:EtOAc, 30:1) then by preparative SFC on a Chiralpak IC column (5 ⁇ m, 250 ⁇ 50 mm ID) using an isocratic system of 15% IPA (0.2 % ethanolamine) in CO 2 , at a flow rate of 170 mL/min as mobile phase to give the first eluting compound (R)-1-((S)- 198 201388-PCT01-NP 2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutyl 2-chloronicotinate Intermediate 174 (6.0 g, 35%) as a yellow liquid.
  • the crude product was purified by preparative HPLC, PrepMethod Z5, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound as a white solid (100 mg, 13%).
  • F amide 56 mg, 0.37 mmol
  • K2CO3 40 mg, 0.37 5 mmol
  • Example 3 10 N-(4- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxypentan-2-yl]amino ⁇ -1,3,5- triazin-2-yl)cyclopropanesulfonamide
  • the title compound was prepar from (R)-2-(4-chloro-6-(2,3- difluorobenzylthio)-1,3,5-triazin-2-ylamino)pentan-1-ol Intermediate 1 (50 mg, 0.13 mmol) and 15 cyclopropanesulfonamide (16 mg, 0.13 mmol).
  • Example 4 20 N-(4- ⁇ [(4-Fluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ - 1,3,5-triazin-2-yl)sulfuric diamide F 201388-PCT01-NP
  • the title compound was made in a similar way to Example 24 from (R)-2-((4-chloro-6-((4- fluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 31. (100 mg, 0.27 mmol).
  • Example 6 5 N-(4- ⁇ [3-(2-Fluorophenoxy)propyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ - 1,3,5-triazin-2-yl)methanesulfonamide 1-(3-Bromopropoxy)-2-fluoro added to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 10
  • Intermediate 4 64 mg, 0.20 mmol
  • DIPEA 76 ⁇ L, 0.44 mmol
  • Example 12 N-(4- ⁇ [(2E)-But-2-en-1-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -1,3,5- 15 triazin-2-yl)methanesulfonamide
  • the title compound was prepared a p for Example 6 from (E)-1-bromobut- 2-ene (29.7 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto- 20 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (9.3 mg, 12%).
  • Example 15 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [(3-methyl-2-oxo-1,3-oxazinan-4- yl)methyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide O
  • the title compound was prepared or Example 6 from 4- 20 (bromomethyl)-3-methyl-1,3-oxazinan-2-one JACS, (1983), 105 (23), 6985–6986 (45.8 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (7.6 mg, 8%).
  • Example 18a N-(4- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ - 1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide F 5
  • Example 18a may be prepar ed herein, for example according to the method described for Example 18, using Intermediate 41 and 3- methylpiperazine-1-sulfonamide. HRMS data for Example 18a is expected to be consistent with that of Example 18, e.g.
  • the HRMS may be: HRMS (ESI) m/z [M+H] + calcd for C21H32F2N7O3S2: 532.1970, found: 532.1990. 10
  • Example 18 (3S)-N-(4- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide
  • THF (4 mL) was added to a fluorobenzylthio)-1,3,5-triazin-15 2-ylamino)-4-methylpentan-1-ol
  • Intermediate 41 80 mg, 0.21 mmol
  • Cs2CO3 134 mg, 0.41 mmol
  • X-Phos 21 mg, 0.04 mmol
  • Example 22 N-(4- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxypentan-2-yl]amino ⁇ -1,3,5- triazin-2-yl)thiophene-2-sulfonamide
  • the title compound was prepa rom (R)-2-(4-chloro-6-(2,3- difluorobenzylthio)-1,3,5-triazin-2-ylamino)pentan-1-ol Intermediate 1 (50 mg, 0.13 mmol) and thiophene-2-sulfonamide (21 mg, 0.13 mmol).
  • Example 24 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin- 2-yl)sulfuric diamide 15 Pd2(dba)3 ⁇ CHCl3 (21 mg, 0.02 m mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol) and sulfuric diamide (79 mg, 0.82 mmol) in THF (8 mL) in a sealed tube.
  • the first eluting compound 10 mixture was collected and further separated by preparative chiral HPLC on a Chiralpak IC column (5 ⁇ m, 250 ⁇ 20 mm ID) using a heptane:EtOH:TEA (80:20:0.1) mobile system as eluant, at a flow rate of 20 mL/min.
  • the first eluting compound mixture was collected and further separated by preparative chiral HPLC on a Chiralpak IC column (5 ⁇ m, 250 ⁇ 20 mm ID) using a heptane:EtOH:TEA (80:20:0.1) mobile system as eluant at a flow rate of 20 mL/min.
  • Example 43 15 N-(4- ⁇ [(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl ⁇ -6- ⁇ [(1R)-1-cyclopentyl-2- hydroxyethyl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide Isomer 2 C l
  • Intermediate 70 100 mg, 0.2 20 mmol
  • Example 56 N-(4- ⁇ [(1R)-2-Hydroxy-1-phenylethyl]amino ⁇ -6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin-2- 20 yl)methanesulfonamide 201388-PCT01-NP (2R)-2-Amino-2-phenylethan-1-ol (240 mg, 1.75 mmol) and K2CO3 (242 mg, 1.75 mmol) were added to a solution of N-(4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 47 (120 mg, 0.35 mmol) in dioxane (5 mL) and the reaction mixture was stirred for 2 h at 80 o C.
  • Example 63 20 N-(4- ⁇ [(1S)-2-Hydroxy-1-(3-methyl-1,2-oxazol-5-yl)ethyl]amino ⁇ -6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide 252 201388-PCT01-NP N O (2S)-2-Amino-2-(3-methyl-1,2- 9 mg, 1.75 mmol) and K2CO3 (242 mg, 1.75 mmol) were added to a solution of N-(4-chloro-6-((1-phenylethyl)sulfanyl)-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 47 (120 mg, 0.35 mmol) in dioxane (5 mL) 5 and the reaction mixture was stirred at 80 o C for 2 h.
  • Example 70 N-(4- ⁇ [2-(2,6-Dichlorophenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide l
  • a solution of 2-bromo-1-(2,6-dic 5 mg, 0.17 mmol) in DMF (0.6 mL), followed by DIPEA (0.061 mL, 0.35 mmol) were added to (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 20 (50 mg, 0.14 mmol).
  • Example 71 N-(4- ⁇ [2-(2-Chlorophenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide l 10
  • the title compound was prepared or Example 70 from 2-bromo-1-(2- chlorophenyl)ethan-1-one (39.7 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol) to give the title compound (32 mg, 45%).
  • Example 72 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [2-oxo-2-(thiophen-2- 20 yl)ethyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide S 201388-PCT01-NP
  • the title compound was prepared and purified as described for Example 6 from 2-bromo-1- (thiophen-2-yl)ethan-1-one (45.1 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (8.7 mg, 10%).
  • Example 74 25 N-[4-( ⁇ 1-[4-(Difluoromethoxy)phenyl]-1-oxopropan-2-yl ⁇ sulfanyl)-6- ⁇ [(2R)-1-hydroxy-4- methylpentan-2-yl]amino ⁇ -1,3,5-triazin-2-yl]methanesulfonamide 259 201388-PCT01-NP F
  • the title compound was prepa Example 70 from 2-bromo-1-(4- (difluoromethoxy)phenyl)propan-1-one (47.4 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 5 (50 mg, 0.14 mmol).
  • Example 75 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [2-(4-methylphenyl)-2- oxoethyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 15
  • the title compound was prepare Example 6 from 2-bromo-1-(p- tolyl)ethan-1-one (46.9 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (20.2 mg, 10%).
  • Example 78 N-(4- ⁇ [2-(2-Bromophenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide r
  • the title compound was prepare or Example 77 from 2-bromo-1-(2- bromophenyl)ethan-1-one (39 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 15 mmol) to give the title compound (32 mg, 48%).
  • Example 80 15 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6-[(2-methyl-1-oxo-1-phenylpropan-2- yl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide
  • the title compound was prepared p 77 from 2-bromo-2-methyl-1-20 phenylpropan-1-one (32 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol).
  • Example 82 20 N-(4- ⁇ [2-(2-Fluorophenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP
  • the title compound was prepared as described for Example 77 from 2-bromo-1-(2- fluorophenyl)ethan-1-one (30 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol).
  • Example 86 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [2-(2-methylphenyl)-2- oxoethyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 10
  • the title compound was prepare or Example 70 from 2-bromo-1-(o- tolyl)ethan-1-one (36.2 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol).
  • Example 87 20 N-(4- ⁇ [1-(4-Chlorophenyl)-1-oxopropan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide Cl 201388-PCT01-NP
  • the title compound was prepared and purified as described for Example 70 from 22-bromo-1- (4-chlorophenyl)propan-1-one (42.1 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol).
  • Example 88 N-(4- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [2-oxo-2-(thiophen-3- yl)ethyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide S The title compound was prepare or Example 6 from 2-bromo-1-15 (thiophen-3-yl)ethan-1-one (45.1 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (25.3 mg, 28%).
  • Example 90 N-[4-( ⁇ 2-[4-(Dimethylamino)phenyl]-2-oxoethyl ⁇ sulfanyl)-6- ⁇ [(2R)-1-hydroxy-4-methylpentan- 2-yl]amino ⁇ -1,3,5-triazin-2-yl]methanesulfonamide 15
  • the title compound was prep xample 70 from 2-bromo-1-(4- (dimethylamino)phenyl)ethan-1-one (41.2 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol).
  • Example 91 5 N-(4- ⁇ [2-(2,5-Dimethoxyphenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide
  • the title compound was prepare or Example 6 from 2-bromo-1-(2,5-10 dimethoxyphenyl)ethan-1-one (57.0 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (8.7 mg, 9%).
  • Example 94 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [2-(4-methoxyphenyl)-2- 20 oxoethyl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP
  • the title compound was prepared and purified as described for Example 6 from 2-bromo-1-(4- methoxyphenyl)ethan-1-one (50.4 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (21.1 mg, 22%).
  • Example 99 10 N-(4- ⁇ [2-(3-Fluorophenyl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide
  • the title compound was prepar from 2-bromo-1-(3- fluorophenyl)ethan-1-one (36.9 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- 15 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol).
  • Example 100 274 201388-PCT01-NP N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [1-(4-methoxyphenyl)-1-oxopropan-2- yl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide
  • the title compound was prepa rom 2-bromo-1-(4- 5 methoxyphenyl)propan-1-one (34 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol).
  • Example 104 N-(4- ⁇ [2-(6-Chloropyridin-3-yl)-2-oxoethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide C l
  • the title compound was prepar from 2-bromo-1-(6- chloropyridin-3-yl)ethan-1-one (40 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.16 15 mmol).
  • Example 105 20 N-[4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6-( ⁇ 2-oxo-2-[4- (trifluoromethyl)phenyl]ethyl ⁇ sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide F F 201388-PCT01-NP
  • the title compound was prepared as described for Example 83 from 2-bromo-1-(4- (trifluoromethyl)phenyl)ethan-1-one (45 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.16 mmol).
  • Example 106 N-(4- ⁇ [2-(2,3-Difluorophenoxy)ethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide
  • F 1-(2-Chloroethoxy)-2,3-difluo d DIPEA (0.043 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- 15 triazin-2-yl)methanesulfonamide, Intermediate 4 (40 mg, 0.12 mmol) dissolved in DMF (1 mL).
  • the first eluting compound mixture was collected and separated by preparative chiral SFC on a Chiralpak IA column (5 um, 250 ⁇ 20 mm ID) using 18% EtOH in CO2 as mobile phase at a flow rate of 80 mL/min.
  • The10 second eluting compound was collected to give the title compound N-(4- ⁇ [(2R*)-1-(2,3- difluorophenoxy)propan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -1,3,5- triazin-2-yl)methanesulfonamide Isomer 4
  • Example 107 (21 mg, 7%).
  • the first eluting compound mixture was collected and separated by preparative chiral SFC on a Chiralpak IA column (5um, 250 ⁇ 20 mm ID) using 18% EtOH in CO2 as mobile phase at a flow rate of 80 mL/min.
  • the first eluting compound was collected to give the title compound N-(4- ⁇ [(2R*)-1-(2,3-10 difluorophenoxy)propan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -1,3,5- triazin-2-yl)methanesulfonamide Isomer 1
  • Example 108 (4 mg, 1%).
  • Example 110 N-(4- ⁇ [(2S)-1-(2,4-Difluorophenoxy) propan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4- methylpentan-2-yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 10 F A mixture of (R)-N-(4-((1-hyd )-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (133 mg, 0.41 mmol), (R)-1-(2,4- difluorophenoxy)propan-2-yl methanesulfonate Intermediate 103 (121 mg, 0.46 mmol), DIPEA 15 (0.217 mL, 1.24 mmol) and MeCN (1.3 mL) in a sealed vessel was heated to 95 o C on.
  • Example 111 25 N-(4- ⁇ [(2S)-1-(3-Fluoro-4-methoxyphenoxy)propan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4- methylpentan-2-yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 281 201388-PCT01-NP H
  • the title compound was prep the procedure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide
  • Intermediate 4 (128 mg, 0.40 mmol) and (R)-1-(3-fluoro-4- 5 methoxyphenoxy)propan-2-yl methanesulfonate
  • Intermediate 105 122 mg, 0.44 mmol
  • Example 112 N-(4- ⁇ [(2S)-1-(3,4-Difluorophenoxy)propan-2-yl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan- 2-yl]amino ⁇ -1,3,5-triazin-2-yl)methanesulfonamide
  • the title compound was prepa o the procedure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 4 (133 mg, 0.41 mmol) and (R)-1-(3,4- difluorophenoxy)propan-2-yl methanesulfonate Intermediate 107 (121 mg, 0.46 mmol) to give 20 the title compound (79 mg, 39%).
  • Example 115 20 N-[4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2 -yl]amino ⁇ -6-( ⁇ [(2R)-oxolan-2-yl]methyl ⁇ sulfanyl)- 1,3,5-triazin-2-yl]methanesulfonamide 284 201388-PCT01-NP
  • the title compound was prepared for Example 6 from (R)-2- (iodomethyl)tetrahydrofuran (46.6 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 5 mmol) to give the title compound (17.3 mg, 21%).
  • Example 118 N-(4- ⁇ [(2R)-1-Hydroxy -4-methylpentan-2-yl]amino ⁇ -6- ⁇ [(2S)-1-(3,4,5- 25 trifluorophenoxy)propan-2-yl]sulfanyl ⁇ -1,3,5-triazin-2-yl)methanesulfonamide 286 201388-PCT01-NP H F F
  • the title compound was prepa ure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (131 mg, 0.41 mmol) and (R)-1-(3,4,5- 5 trifluorophenoxy)propan-2-yl methanesulfonate Intermediate 117 (127 mg, 0.45 mmol).
  • Example 120 N-(4- ⁇ [(2-Fluorophenyl)sulfanyl]methyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ - 15 1,3,5-triazin-2-yl)methanesulfonamide
  • Intermediate 122 (76 mg, 0.20 mmol), THF (3 mL), methanesulfonamide (39 mg, 0.41 mmol), X-Phos (40 mg, 0.08 mmol), Pd2(dba)3 (20 mg, 0.022 mmol) and Cs2CO3 20 (132 mg, 0.41 mmol) was heated in a sealed vessel under an atmosphere of Ar(g) to 65°C for 12 h.
  • Example 121 5 N-(4- ⁇ 1-[(2-Fluorophenyl)sulfanyl]ethyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ - 1,3,5-triazin-2-yl)methanesulfonamide (2R)-2-((4-Chloro-6-(1-((2-fluoro iazin-2-yl)amino)-4-methylpentan-1- ol
  • Intermediate 7 150 mg, 0.39 mmol
  • X-Phos 40 mg, 0.08 mmol
  • Pd2(dba)3 40 mg, 0.04 10 mmol
  • Cs 2 CO 3 (254 mg, 0.78 mmol) were added to methanesulfonamide (74 mg, 0.78 mmol) in THF (6 mL).
  • the reaction mixture was stirred at 65°C for 12 h under an atmosphere of Ar(g), and then diluted with THF (7 mL) and filtered through Celite. The filtrate was acidified with AcOH (24 ⁇ L) and concentrated under reduced pressure. The crude residue was dissolved in DMSO (4 mL), filtered through Celite, and purified by preparative HPLC, PrepMethod D, 15 (gradient: 20–60%). The compound containing fractions were collected and concentrated. AcOH (118 ⁇ L, 2 mmol) was added to the residue and the mixture was extracted with DCM (3 ⁇ 25 mL).
  • Example 123 N-(4-[1-(2-Fluorophenyl)ethoxy]-6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -1,3,5-triazin- 2-yl)methanesulfonamide 20
  • a solution of TMAF 100 mg, 1.0 o was added to N-(4-(((R)-1-((tert- butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(2-fluorophenyl)ethoxy)-1,3,5-triazin- 290 201388-PCT01-NP 2-yl)methanesulfonamide
  • Intermediate 12 (205 mg, 0.38 mmol) in THF (2 mL).
  • Example 126 N-(4- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6-[(1S)-1-(pyridin-2-yl)ethoxy]-1,3,5- 15 triazin-2-yl)methanesulfonamide
  • Intermediate 128 (0.120 g, 0.34 mmol) in THF (6 mL) was added to K2CO3 (0.071 g, 0.51 mmol), Pd2(dba)3 (0.062 g, 0.07 mmol) and X-Phos (0.130 g, 0.27 mmol) 20 under an atmosphere of N 2 (g).
  • the solvent was evaporated, and the residue dissolved in DCM and diluted with water.
  • the pH was adjusted with 1 M HCl (aq) to pH 3.
  • the layers were separated and the aqueous layer was extracted with DCM.
  • the combined organic layer was 10 passed over a phase separator and concentrated.
  • Example 134 N-(6- ⁇ [1-(2,3-Difluorophenyl)ethyl]sulfanyl ⁇ -2- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ pyrimidin-4-yl)methanesulfonamide
  • Step a) 1-(2,3-Difluorophenyl)et y 298 201388-PCT01-NP O O F S F O MsCl (0.161 mL, 2.09 mmol) was ad -(2,3-difluorophenyl)ethan-1-ol (300 mg, 1.90 mmol) and DIPEA (0.364 mL, 2.09 mmol) in DCM (4 mL).
  • Step b) (R)-N-(2-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-4- yl)methanesulfonamide
  • H 10 (R)-N-(2-((1-Hydroxy-4-methylpenta -methoxybenzyl)thio)pyrimidin-4- yl)methanesulfonamide, Intermediate 25 (527 mg, 1.20 mmol) was added to a solution of TFA (4 ml, 51.92 mmol) and anisole (0.157 ml, 1.44 mmol).
  • the reaction mixture was stirred at rt for 2 d then at 70°C on and concentrated.10% NaHCO3 (aq) and EtOAc were added, and the two phases were separated.
  • the organic layer was extracted with 10% NaHCO 3 (aq) and the 15 combined aqueous layer was acidified to pH 3.
  • the aqueous layer was extracted with EtOAc ( ⁇ 6) and the combined organic layer was dried over MgSO4, filtered and concentrated to give the hydrochloride of the crude subtitle compound, which was used in the next step without further purification.
  • Step c) N-(6- ⁇ [1-(2,3-Difluorophenyl)ethyl]sulfanyl ⁇ -2- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- 20 yl]amino ⁇ pyrimidin-4-yl)methanesulfonamide 1-(2,3-Difluorophenyl)ethyl methanesulfonate,
  • Example 134 Step a (36.9 mg, 0.16 mmol) was added to a solution of (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin- 4-yl)methanesulfonamide HCl
  • Example 134 Step b 50 mg, 0.16 mmol
  • DIPEA 60.0 ⁇ l, 0.34 mmol
  • the reaction mixture was heated in a microwave reactor at 70°C for 30 25 min. Water and DCM were added and the two phases were separated. The aqueous layer was 299 201388-PCT01-NP extracted with DCM and the combined organic layer was washed with water ( ⁇ 2), dried and concentrated. The residue was purified preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (62 mg, 86%).
  • Example 140 N-(2- ⁇ [(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2- yl]amino ⁇ pyrimidin-4-yl)methanesulfonamide Isomer 1 303 201388-PCT01-NP F
  • Intermediate 142 300 mg, 0.68 mmol
  • Example 142 5 N-(4- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxypentan-2-yl]amino ⁇ pyrimidin- 2-yl)azetidine-1-sulfonamide
  • (R)-2-(2-chloro-6 din-4-ylamino)pentan-1-ol Intermediate 23 (30.0 mg, 0.08 mmol), Pd2(dba)3 (7.4 mg, 8.02 ⁇ mol), K2CO3 (16.6 mg, 0.12 10 mmol), azetidine-1-sulfonamide (10.9 mg, 0.08 mmol) and X-Phos (66.2 mg, 0,14 mmol) in THF (2 mL) was stirred under an atmosphere of N 2 (g) at 60°C on.
  • Example 144 15 N-(2- ⁇ [(2R)-1-Hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [(1R*)-1- phenylethyl]sulfanyl ⁇ pyrimidin-4-yl)methanesulfonamide Isomer 2
  • Intermediate 143 (345 mg, 0.81 mmol) 20 were separated by preparative chiral SFC on a Chiralpak IA column (5 ⁇ m, 250 ⁇ 30 mm ID) using 15% MeOH/DEA (100/0.5) in CO 2 as mobile phase at a flow rate of 120 mL/min to give the second eluting compound N-(2- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ -6- ⁇ [(1
  • Example 145 5 N'-(6- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -2- ⁇ [(2R)-1-hydroxypentan -2- yl]amino ⁇ pyrimidin-4-yl)-N,N-dimethylsulfuric diamide F A mixture of (R)-2-(4-chloro-6 din-2-ylamino)pentan-1-ol Intermediate 145 (59 mg, 0.16 mmol), N,N-dimethylsulfamid (20 mg, 0.16 mmol), Pd2(dba)3 10 (14 mg, 0.02 mmol), K 2 CO 3 (32 mg, 0.24 mmol) and X-Phos (66 mg, 0,14 mmol) in THF (2 mL) was stirred under an atmosphere of N 2 (g) at 60°C for 3 h.
  • Example 149 N-(2- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxy-3-methylbutan-2- yl]amino ⁇ pyrimidin-4-yl)methanesulfonamide 309 201388-PCT01-NP OH HN F
  • a mixture of N-(6-chloro-2-((2,3 din-4-yl)methanesulfonamide Intermediate 150 (80.5 mg, 0.22 mmol), (R)-2-amino-3-methylbutan-1-ol (34 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120°C for 5 d.
  • Example 150 10 N-[2-(Benzylsulfanyl)-6- ⁇ [(2R)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ pyrimidin-4- yl]methanesulfonamide
  • N-(2-(benzylthio)-6- hanesulfonamide Intermediate 153 (73 mg, 0.22 mmol), (R)-2-amino-4-methylpentan-1-ol (39 mg, 0.33 mmol) and DIPEA (85 mg, 15 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120°C for 5 d. The mixture was concentrated, and the crude product was purified by preparative HPLC to give the title compound (13.6 mg, 15%).
  • Example 152 N-(2- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2S,3S)-1,3-dihydroxybutan-2- yl]amino ⁇ pyrimidin-4-yl)methanesulfonamide OH OH F 10
  • the title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (2S,3S)-2-aminobutane-1,3-diol as described for Example 149 to give the title compound (9.4 mg, 10%).
  • Example 156 10 N-(2- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxybutan-2-yl]amino ⁇ pyrimidin- 4-yl)methanesulfonamide OH F
  • the title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (R)-2-aminobutan-1-ol as described for Example 15 149 to give the title compound (13.4 mg, 15%).
  • Example 157 N-[2-(Benzylsulfanyl)-6- ⁇ [(2R)-1-hydroxy-3-methylbutan-2-yl]amino ⁇ pyrimidin-4- 20 yl]methanesulfonamide 313 201388-PCT01-NP OH HN
  • the title compound was prepared chloropyrimidin-4- yl)methanesulfonamide Intermediate 153 and (R)-2-amino-3-methylbutan-1-ol as described for Example 150 to give the title compound (6.2 mg, 7%).
  • Example 158 N-(2- ⁇ [(4-Cyanophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxypentan-2-yl]amino ⁇ pyrimidin-4- yl)methanesulfonamide 10 N
  • a mixture of N-(6-chloro-2-((4 -yl)methanesulfonamide Intermediate 155 (78 mg, 0.22 mmol), (R)-2-aminopentan-1-ol (34 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120°C for 5 d.
  • Example 159 N-(2- ⁇ [(2-Cyanophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(2R)-1-hydroxypentan-2-yl]amino ⁇ pyrimidin-4- 20 yl)methanesulfonamide 314 201388-PCT01-NP
  • the title compound was prepared anobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 154 and (R)-2-aminopentan-1-ol as described for Example 155 to give the title compound (3.2 mg, 3%).
  • Example 160 N-[2-(Benzylsulfanyl)-6- ⁇ [(2S)-1-hydroxy-4-methylpentan-2-yl]amino ⁇ pyrimidin-4- yl]methanesulfonamide 10
  • the title compound was prepared chloropyrimidin-4- yl)methanesulfonamide Intermediate 153 and (S)-2-amino-4-methylpentan-1-ol as described for Example 150 to give the title compound (8.6 mg, 10%).
  • Example 162 10 N-(2- ⁇ [(2-Cyanophenyl)methyl]sulfanyl ⁇ -6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4- yl)methanesulfonamide
  • the title compound was prepared yanobenzyl)thio)pyrimidin-4- yl)methanesulfonamide
  • Intermediate 154 and 2-aminopentan-1-ol as described for Example 15 155 to give the title compound (6 mg, 6%).
  • Example 163 N-(2- ⁇ [(2,3-Difluorophenyl)methyl]sulfanyl ⁇ -6- ⁇ [(1S,2S)-2- 20 hydroxycyclohexyl]amino ⁇ pyrimidin-4-yl)methanesulfonamide 316 201388-PCT01-NP HO HN F
  • the title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (1S,2S)-2-aminocyclohexan-1-olas described for Example 149 to give the title compound (4.4 mg, 5%).

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Abstract

The present disclosure relates to small molecule modulators of CX3CR1, pharmaceutical compositions thereof and uses thereof for the treatment of cardiovascular disease.

Description

201388-PCT01-NP SMALL MOLECULE CX3CR1 MODULATORS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No.63/635,708, filed April 18, 2024, which is incorporated by reference herein in its entirety for all purposes. 5 BACKGROUND Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including cardiovascular and respiratory diseases such as asthma, atherosclerosis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, lupus nephritis and 10 inflammatory myopathy. These small, secreted molecules are a growing superfamily of 8-14 kDa proteins characterized by a conserved cysteine motif. At the present time, the chemokine superfamily comprises four groups exhibiting characteristic structural motifs; the C-X-C, C-C and C-X3-C and XC families. The C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH- 15 proximal pair of cysteine residues. The C-X3-C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH-proximal pair of cysteine residues. In contrast, members of the XC family lack one of the first two cysteine residues. The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2). 20 The C-C chemokines include potent chemoattractants of monocytes, lymphocytes and neutrophils. The C-X3-C chemokine (also known as fractalkine, FKN, or CX3CL1) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells. It also functions as an adhesion molecule on immune 25 active cells, such as monocytes and others for infiltration of cells from the blood to the tissue. Blocking the interaction has been proven to reduce atherosclerosis progression and plaque growth (Poupel et al., Arterioscler. Thromb. Vasc. Biol., 2013, 33, 2297-2305). In humans, CX3CR1 and fractalkine is expressed in early and late atherosclerosis (Stolla et al. PLOS one 2012 1 201388-PCT01-NP (https://doi.org/10.1371/journal.pone.0043572) and Pucci et al. BioMed Res Int 2013 (http://dx.doi.org/10.1155/2013/451349). Fractalkine neutralisation improves cardiac function in mouse myocardial infarction (MI) models by enhanced systolic function, ventricular remodeling and decreased infarct size (Xuan et 5 al 2011, Cardiovascular Research 92, 385) and also LVEF and survival rate 2 weeks post treatment after an induced MI in mouse (Gu et al 2015, Exp Physiol 100, 805). Additionally, fractalkine cause cardio-depressive actions with impaired contractility observed in mouse cardiomyocytes (Taube et al 2013, PLOS ONE 8(7). Human serum soluble FKN (sFKN) levels are associated with NYHA heart failure functional score where in patients 10 with HF have an increased level of soluble fractalkine (Husberg et al. J. of Mol. and Cellular Cardiology, 2008, 45(2), 261). sFKN concentration has a prognostic value in patients with acute myocardial infarction treated with primary percutaneous coronary intervention (Xu Bing et al Cytokine 2019113 (365-370). Elevated sFKN plasma levels predictor of mortality in subjects with advanced systolic HF (Richter et al 2012, Thrombosis & Haemostasis 108, 1220). 15 Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX3CR1 for the C-X3-C family. These receptors represent good targets for drug development since agents that 20 modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. WO2005/070903 discloses certain triazine derivatives for use in the treatment of chemokine mediated diseases and disorders. WO2006/107258 discloses certain 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine 25 derivatives as antagonists of the CX3CR1 receptor. WO2006/107257 and WO2009/120140 disclose certain 5,7-disubstituted [l,3]thiazolo[4,5- d]pyrimidin-2(3H)one derivatives as antagonists of the CX3CR1 receptor. 2 201388-PCT01-NP WO2013039057 discloses certain pyrrolidine-3-ylacetic acid derivatives having an inhibitory pathway in the fractalkine-CX3CR1 pathway. Linkage of CX3CR1 activity to diseases has thus been implicated in cardiovascular diseases (CVD) including heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, 5 stable coronary artery disease and atherosclerosis related conditions. There is a need for an orally active modulator of CX3CR1 for the treatment cardiovascular diseases (CVD) e.g., heart failure, cardiac muscle diseases and coronary artery disease related conditions. DETAILED DESCRIPTION 10 Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least 15 one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The use of the term "or" in the claims is used to mean "and/or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or." 20 As used herein, the terms "comprising" (and any variant or form of comprising, such as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. 25 The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. 3 201388-PCT01-NP As used herein, "about" can mean plus or minus 10% of the provided value. Where ranges are provided, they are inclusive of the boundary values. "About" can additionally or alternately mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value; or "about" can mean rounded to the nearest significant digit. 5 As used herein, "between" is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y. The term “alkoxy” refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, 10 propoxy, tert-butoxy and the like. The term “alkyl” or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. The term “alkoxyalkyl” refers to an alkyl group attached to an alkoxy group, where in the 15 group is attached to the rest of the molecule via a carbon on the alkyl group, i.e. a group having a structure of -R-O-R’ wherein R and R’ are the same or different alkyl groups. The term “aryl” refers to an aromatic hydrocarbon. The term aryl includes monocyclic aryls, with a single ring, such as phenyl, as well as polycyclic aryls, including “bicyclic aryls” having two or more cyclic rings, in which two or more atoms are common to two adjoining rings 20 wherein at least one of the rings is aromatic, for example, the other cyclic ring is cycloalkyl, cycloalkenyl, cycloalkynyl and/or aryl. Examples of polycyclic aryl rings include naphthalene and tetrahydronaphthalene. The term “cycloalkyl” refers to a partially or completely saturated monocyclic, bicyclic, polycyclic or bridged hydrocarbon ring system. 25 The term “halo” means fluoro, chloro, bromo, and iodo. In an embodiment, halo is fluoro or chloro. In another embodiment, halo is fluoro. In yet another embodiment, halo is chloro. The term “haloalkoxy” means an alkoxy in which one or more hydrogens has been substituted with a halo. 4 201388-PCT01-NP The term “haloalkyl” means an alkyl group in which one or more hydrogens has been substituted with a halo. The term “heteroaryl” as used herein, refers to substituted or unsubstituted aromatic ring structures whose ring structures include, e.g., at least one heteroatom selected from nitrogen, 5 oxygen, and sulphur. Heteroaryl groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atom. Heteroaryl groups can include monocyclic heteroaryls as well as polycyclic heteroaryls such as bicyclic heteroaryls, having two or more cyclic rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic and at least one of the rings includes at least one heteroatom selected from nitrogen, oxygen, and 10 sulphur. In some embodiments, the heteroatom in the heteroaryl is sulfur, and the sulfur can be oxidized with 1 or 2 oxygens. For examples, the term heteroaryl would encompass dihydro- isothiazole-dioxide, in which the sulfur has been oxidized with two oxygen. In other some embodiments, the sulphur heteroatom is not oxidized. Examples of monocyclic heteroaryls include, but are not limited to, pyrrole, pyridine, 15 pyrazine, pyridazine, pyrimidine, furan, triazole, thiophene, imidazole, isoxazole, oxazole, oxadiazole, thiazole and pyrazole. Examples of bicyclic heteroaryls, include, but are not limited to purine, indole, indazole, quinoline, quinazoline, benzofuran, benzoxazole, benzodioxole, benzodioxin, pyrrolopyridine, indazole, 2H-indazole, isoquinoline, tetrahydroisoquinoline, dihydroquinazoline, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydrobenzo[d]oxazole, 3,4- 20 dihydroquinazoline, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-1,4-benzodioxin and 2,3-dihydro-1-benzofuran. Additional polycyclic heteroaryls include, but are not limited to, carbazole and dibenzazepine. The term “monocyclic N-heteroaryl” refers to a monocyclic heteroaryl whose ring structures include at least one nitrogen. Examples of monocyclic N-heteroaryls include, but are 25 not limited to imidazole, pyrrole, triazole, pyridine, pyrazine, pyridazine, pyrimidine, and triazine. The term “heterocycle” “heterocyclic” or “heterocyclyl” refers to a partially or completely saturated hydrocarbon ring system wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen and sulphur. Heterocyclic groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atoms. Heterocycles 30 include monocyclic heterocycles as well as polycyclic heterocycles such as bicyclic heterocycles. 5 201388-PCT01-NP Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, piperidine, piperazine, oxetane, and isoxazolidine. The term “S-heterocycle” “S-heterocyclic” or “S-heterocyclyl” refers to partially or completely saturated heterocyclic ring system wherein at least one of the ring atoms is a sulphur. 5 Examples of such compounds include, but are not limited to, thiophene andtetrahydrothiophene. The term “hydroxy” refers to an -OH group. The term “hydroxyalkyl” means an alkyl group in which one or more hydrogens has been substituted with a hydroxy. The term “oxo” refers to an “=O” group, i.e., a substituent oxygen atom connected to 10 another atom by a double bond. In this specification the prefix Cx-y as used in terms such as “Cx-y alkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group. Examples of suitable C1-3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl. Examples of suitable C1-4 alkyl groups include, but are not limited to, methyl, ethyl, n- 15 propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In some cases, a group will have two instances of Cx-y in which case the prefix indicates the numerical range of carbons in each part of the group, e.g., C1-3 alkoxy- C1-4 alkyl, refers to an alkoxyalkyl group wherein the alkyl group has 1 to 3 carbons and the alkoxy group has 1-4 carbons. Compounds: 20 In some embodiments, the disclosure is directed to a compound of formula (I) 1 OH R ), and ph alts thereof, wherein L is –(CH2)j-CR3R4–, –S-(CR3R4)k–, –(CR3R4)m-CR3=CR3–, –S-(CR3R4)k-CR3=CR3–, –CR3aR4a-CR3R4–, –(CR3R4)n-S–, –(CR3R4)n-O–, –(CH2)-NR3–, –S-(CR3R4)n-O–, –S-(CR3R4)- 25 C(O) –, –O-(CR3R4) j–, 6 201388-PCT01-NP j is 1 or 2, k is 0, 1 or 2, m is 0 or 1, n is 1, 2, or 3; 5 R1 is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl, -C1-3 alkyl-C3-6 cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the R1 C1-3 alkyl or C3-6 branched alkyl is optionally substituted with -OH and the R1 monocyclic heteroaryl is optionally substituted with -CH3; R11 is H or -CH2OH; 10 or R1 and R11 together form a 4-6-membered carbocycle, R2 is O O O O NH O O O S S HN NH O O S S N N O ) , Ra is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered heteroaryl, C1-3 alkyl- 15 phenyl, C1-3 alkyl-C3-6 carbocycle, S-heterocycyl, each Rb is, independently, H, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkyl-N(CH3)2, Rc is C1-3 alkyl, and B is a 4-6 member heterocycle comprising at least one N, wherein the heterocycle is bound to the S via a ring N, optionally substituted by a C1-3 alkyl; 20 Z is -NH-, CH2 or -O- each R3, R3a, R4 and R4a are, independently, selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl; X is a bond or A; A is 4-6 member cycloalkyl, 4-6 member heterocycle, phenyl, monocyclic heteroaryl, 25 bicyclic aryl, or bicyclic heteroaryl; p is 0, 1, 2, 3, or 4; each R5 is independently selected from halo, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -C1-4alkoxy-C1-3alkyl, -C1-3hydroxyalkyl, -CN, -(CH2)qCN, -C(O)NR6R7, 7 201388-PCT01-NP -NS(O)R6R7, -(CH2)qR8, -C(O)R8, -C(O)OR9, -OC(O)R9, -NR6C(O)R7, -NO2, -NR6R7, -S(O)2R6, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, wherein the C3-6 cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 5 substituents selected from hydroxy, oxo, halo, -CH3, and -C(O)OR9, the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents, the C1-4 alkoxy can be optionally substituted with a 4-6 member heterocyclyl, each R6 and R7 are, independently, selected from H and C1-3 alkyl, each q is, independently, 1, 2, or 3, 10 each R8 is, independently, a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy, and each R9 is, independently, a C1-5 alkyl; G1, G2, and G3 are independently selected from N or CH, provided that at least two are N, wherein if L is 15 (a) –S-CR3R4– , (b) –S-CH2-R3R4– , (c) –CH2-CR3R4–, or (d) –(CH2)2-CR3R4–, and 20 R3 and R4 are, independently, H, halo, C1-3 alkyl, and C1-3 haloalkyl then (i) R1 is not a C3-6 branched alkyl or C3-6 branched haloalkyl; O O S (ii) R2 is not wherein Ra is a C1-3 alkyl or C1-3 haloalkyl; (iii) Z is not -NH-, 25 (iv) R11 is not H, and (iv) G1, G2, and G3 are not all N. In some embodiments, the disclosure is directed to a compound of Formula I, wherein Z is carbon, i.e., C. In some embodiments, Z is oxygen, i.e., O. In some embodiments, Z is -NH-. 8 201388-PCT01-NP In some embodiments, when Z is C or O, and the compound has the specific stereochemistry as in the following formulas: OH OH R1 R 1 5 )p . , p mixture of the two previous 5 compounds. In some embodiments, when Z is N, and the compound has the specific stereochemistry as in the following formulas: . In some embodiments, the compounds are a racemic mixture of the two previous compounds. 10 In some embodiments, when Z is C or O, and the compound has the specific stereochemistry as in the following formulas: OH OH )p . 201388-PCT01-NP In some embodiments, the compounds are a racemic mixture of the two previous compounds. In some embodiments, when Z is N, and the compound has the specific stereochemistry as in the following formulas: . 5 In some em o men s, e compoun s are a racem c m x ure o e two previous compounds. In some embodiments, the compounds of Formula I have L selected from –S-(CR3R4)k–, – S-(CR3R4)m-CR3=CR3–, –(CR3R4)n-S–, –S-(CR3R4)n-O–, –S-(CR3R4)-C(O)-, or –S-(CH2)-C(O)- NH. In some embodiments, L is –S-(CR3R4)k–. In some embodiments, k is 0. In some embodiments, k is 1. In some embodiments, k is 2. 10 For clarity, as used throughout the present disclosure, when k is 2, then each R3 is independently as defined herein, and each R4 is independently as defined herein, as well as each R3 and R4 being independently as defined herein. In some embodiments, when L is –S-(CR3R4)k– and k is 1, then the compounds of the present disclosure have the formula: 15 In some embodiments, when L is –S-(CR3R4)k–, k is 1, and Z is N, then the compounds of the present disclosure have the formula: 10 201388-PCT01-NP , . n some em o men s, s -( )k an s or . In some embodiments, L is –S-(CR3R4)k-CR3=CR3–. In some embodiments, k is 0. In 5 some embodiments, k is 1. In some embodiments, k is 2. In some embodiments, L is –(CR3R4)n-S, or –S-(CR3R4)n-O–. Thus, in some embodiments, n can be 1, 2 or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 3. For clarity, as used throughout the present disclosure, when n is 2 or greater, then each R3 is independently as defined herein, and each R4 is independently as defined herein, 10 as well as each R3 and R4 being independently as defined herein. In some embodiments, R3 and R4 are H. In some embodiments, one or more R3 and R4 are halogen, e.g., F. In some embodiments, when n is 2 or three, at least one R3 and R4 are H. In some embodiments, when n is 2 or three, at least one R3 and R4 are halogen, e.g., F. In some embodiments, one or both of R3 and R4 are methyl. As used throughout the present disclosure, when j, k, or n is 2 or greater, then each R3 is 15 independently as defined herein, and each R4 is independently as defined herein, as well as each R3 and R4 being independently as defined herein. In some embodiments, R3 and R4 are H. In some embodiments, one or more R3 and R4 are halogen, e.g., F. In some embodiments, when n is 2 or 3, 11 201388-PCT01-NP at least one R3 and R4 are H. In some embodiments, when n is 2 or 3, at least one R3 and R4 are halogen, e.g., F. In some embodiments, one or both of R3 and R4 are methyl. In some embodiments, the L can comprise a carbonyl group. For example, in some embodiments, L is –S-(CR3R4)-C(O) –. In some embodiments, both R3 and R4 are H. In some 5 embodiments, one or both of R3 and R4 are halogen, e.g., F. In some embodiments, one or both of R3 and R4 are methyl. In some embodiments, L is –(CH2)j-CR3R4–, –(CR3R4)m-CR3=CR3–, –CR3aR4a-CR3R4–, or –(CH2)-NR3–. In some embodiments, j is 1 or m is 1. In some embodiments, j is 2. In some embodiments, m is 0. Each R3, R4, R3a, and R4a are independently as defined herein. In some 10 embodiments, each of R3, R4, R3a, and R4a are H. In some embodiments, one or more R3, R4, R3a, and R4a are halogen, e.g., F. In some embodiments, R3, R4, R3a, and R4a are methyl. In some embodiments, L comprises an ester linkage. In some embodiments, L is – (CR3R4)n-O–, or –O-(CR3R4)j-, wherein n or j is as described herein. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, j is 1 or 2. 15 In some embodiments, when L is –(CR3R4)n-O–, or –O-(CR3R4)j-, each R3 and R4 are H. In some embodiments, one or more R3 and R4 are independently halogen, e.g., F. In some embodiments, R3 and R4 are methyl. In some embodiments, R3 and R4 are not H. For the L groups disclosed here, each R3, R3a, R4, and R4a are, independently, selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl. In some embodiments, one or more R3 and R4 are 20 independently methyl. In some embodiments, one or more R3 and R4 are independently H. In some embodiments, one or more R3a and R4a are independently methyl. In some embodiments, one or more R3a and R4a are independently H. In some embodiments, R1 is C1-3 alkyl or C1-3 haloalkyl. In some embodiments, R1 is propyl. In some embodiments, R1 is methyl or ethyl. In some embodiments, R1 is fluoromethyl, 25 fluoroethyl, or difluorethyl. In some embodiments, R1 is trifluoro methyl or ethyl. In some embodiments, R1 is fluoro or chloro propyl, e.g., fluoro propyl, chloropropyl, difluorpropyl, dichloropropyl or trifluorpropyl. In some embodiments R1 is methyl or ethyl optionally substituted with one hydroxy, e.g., hydroxymethyl or hydroxyethyl. 12 201388-PCT01-NP In some embodiments, R1 is C3-6 cycloalkyl, e.g., the C3-6 cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl. R1 is C3-6 branched alkyl or C3-6 branched haloalkyl. In some embodiments, R1 is isopropyl. In some embodiments, R1 is isobutyl. In some embodiments, R1 can comprise an alkyl chain linked to a cycloalkyl. For example, 5 in some embodiments, R1 is a -C1-3 alkyl-C3-6 cycloalkyl, wherein the -C1-3 alkyl can be methyl, ethyl or propyl, and the C3-6 clycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R1 is methyl-cyclopropyl or methyl cyclohexyl. In some embodiments, R1 is -methyl-C3-6 cycloalkyl. In some embodiments, R1 is -methyl-cyclopropyl, - methyl-cyclobutyl, or -methyl-clyclopentyl. 10 In some embodiments, R11 is hydroxymethyl. In some embodiments, R11 is H. In some embodiments, R2 i , wherein Ra is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered heteroa y , 1-3 alkyl-phenyl, C1-3 alkyl-C3-6 carbocycle, or S- heterocycyl. In some embodiments, Ra is C1-3 alkyl or C1-3 haloalkyl, e.g., methyl or trifluormethyl. 15 In some embodiments, R2 is , wherein Ra is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered heteroaryl, C1-3 alkyl-phenyl, C1-3 alkyl-C3-6 carbocycle, or S- heterocycyl. In some embodiments, Ra is C1-3 alkyl or C1-3 haloalkyl. In some embodiments, Ra is methyl or C1-3 haloalkyl, e.g., trifluormethyl. In some embodiments, Ra is C1-3 alkylphenyl, C1- 3 carbocycle or S-heterocyclyl. In some embodiments, the C1-3 alkylphenyl is methylphenyl. In 20 some embodiments, C1-3 carbocyclyl is cyclopropyl. In some embodiments, the S-heterocycyl is thiophene. 13 201388-PCT01-NP In some embodiments , wherein each Rb is, independently, H, C1-3 alkyl, C1-3 haloalkyl, or C1-3 a me embodiments, both Rb are C1-3 alkyl, e.g., methyl or ethyl. In some emb odiments, both R are H. In some embodiments, one Rb is H and one Rb is methyl or ethyl. In some embodiments, both Rb are C1-3 haloalkyl, e.g., fluoromethyl or 5 trifluoromethyl. In some embodiments, one Rb is H, and one Rb is C1-3 alkyl-N-(CH2)2. In some embodiments, R2 i , wherein B is a 4-6 member heterocycle comprising at least one N, wherein e is bound to the S via a ring N, optionally substituted by a C1-3 alkyl. In some embodiments, B is a 4-6 member heterocycle. In some embodiments, B is a 4-6 member heterocycle substituted by a C1-3 alkyl, e.g., substituted with a 10 methyl. In some embodiments, B is tetrahydro oxazine, piperaziny . The compounds of any one of claims 1 to 44, wherein R2 i ,wherein Rc is C1-3 alkyl. In some embodiments, Rc is methyl. In some embodiments, R2 i . wherein Ra is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered h eteroary , C1-3 a kyl- phenyl, C1-3 alkyl-C3-6 carbocycle, or S-heterocycyl. In some embodiments, Ra is C1-3 alkyl or C1- 15 3 haloalkyl. In some embodiments, Ra is methyl or C1-3 haloalkyl, e.g., trifluormethyl. In some embodiments, Ra is C1-3 alkylphenyl, C1-3 carbocycle or S-heterocyclyl. In some embodiments, the C1-3 alkylphenyl is methylphenyl. In some embodiments, C1-3 carbocyclyl is cyclopropyl. In some embodiments, the S-hetercycyl is tetrahydrothiophene. 14 201388-PCT01-NP In some embodiments, X is a bond, i.e., the substituent L is bonded directly to R5. In some embodiments, when X is a bond, then p is 1. In some embodiments, when X is a bond, then p is 2, i.e., L is bonded to two R5 groups. In some embodiments, when X is a bond, then p is not 0. In some embodiments, is A, wherein A is a 4-6 member cycloalkyl, 4-6 member 5 heterocycle, phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl. In some embodiments, A is phenyl, e.g., an unsubstituted phenyl wherein p is 0. In some embodiments, A is a substituted phenyl, e.g., a phenyl wherein p is 1 or 2, wherein R5 is halogen, oxo, C1-4 alkoxy or C1-3 alkyl. In some embodiments, A is a substituted phenyl, e.g., a difluorophenyl; dichlorophenyl; fluorochlorophenyl; phenyl substituted with fluor and methoxy, or phenyl 10 substituted with chloro and methoxy. In some embodiments, A is a 4-6 membered heterocyclyl. In some embodiments, the 4-6 membered heterocyclyl is dithiolyl, thianyl, thiolanyl, oxetanyl, azetidinyl, thetanyl, tetrahydrofuranyl, dioxanyl, pyrrolinyl, piperidinyl. In some embodiments, the 4-6 membered heterocyclyl has one heteroatom. In some embodiments, the heterocycyl comprises 2 heteroatoms. 15 In some embodiments when the 4 or 6 membered heterocycle comprises one heteroatom, the heteroatom in the cyclic ring is para to the bond to the L group. In some embodiments when the 4-6 membered heterocycle comprises one heteroatom, the heteroatom in the cyclic ring is meta to the bond to the L group. In some embodiments, the heterocyclyl comprise an N hetero atom. In some embodiments, the heterocyclyl comprises an O heteroatom. In some embodiments, the 20 heterocyclyl comprises an S heteroatom. In some embodiments, the heterocyclyl comprises 2 heteroatoms selected from N, O or S. In some embodiments, A is a substituted A is a 4-6 membered heterocyclyl, e.g., a heterocyclyl wherein p is 1 or 2, wherein R5 is halogen, oxo, C1-4 alkoxy or C1-3 alkyl. In some embodiments, A is a substituted a 4-6 membered heterocyclyl, e.g., a difluoro heterocyclyl; dichloro heterocyclyl; fluorochloro heterocyclyl; heterocyclyl substituted 25 with fluoro and methoxy, or heterocyclyl substituted with chloro and methoxy. In some embodiments, A is a 4-6 member cycloalkyl. For example, the 4-6 member cycloalklyl can be a cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, A is a monocyclic heteroaryl, wherein the monocyclic heteroaryl is pyridinyl, pyrimidinyl, purinyl, furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazinyl, oxazinyl, or pyranyl. In some embodiments, 15 201388-PCT01-NP A is a bicyclic heteroaryl, wherein the bicyclic heteroaryl comprises benzofuranyl, benzothiophenyl, chromanyl, chromenyl, purinyl, indolyl, quinazolinyl, pteridinyl, or pyrrolizinyl. In some embodiments, A is a substituted A is a 4-6 member cycloalkyl, monocyclic heteroaryl, or bicyclic heteroaryl, e.g., a 4-6 member cycloalkyl, monocyclic heteroaryl, or bicyclic 5 heteroaryl wherein p is 1 or 2, wherein R5 is halogen, oxo, C1-4 alkoxy or C1-3 alkyl. In some embodiments, the A substituent is unsubstituted, i.e., p is 0. In some embodiments, any of the A substituents disclosed herein can be substituted with one or more of the R5 groups described herein. For example, in some embodiments p is 1, 2 or 3 and R5 is independently selected from halo, hydroxy, and oxo. In some embodiments, R5 is halo, oxo or hydroxy and p is 10 1. In some embodiments, R5 is halo, oxo or hydroxy and p is 2. In some embodiments, R5 is F and p is 1 or 2. When p is 2 or greater, then each of the R5 substituents can be independently selected from those disclosed herein. For example, in some embodiments, one R5 is F and one R5 is Cl. In a separate embodiment, one R5 is F and one R5 is methoxy. In some embodiments, R5 is oxo and p is 1 or 2. 15 In some embodiments, R5 is independently selected from C1-3 alkyl, C1-3 haloalkyl, C1- 4 alkoxy, C1-4 haloalkoxy, -C1-4alkoxy-C1-3alkyl, -C1-3hydroxyalkyl, -CN, -(CH2)qR8, - C(O)R8, -C(O)OR9, and -OC(O)R9. In some embodiments, R5 is independently selected from - (CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, -NR6C(O)R7, -NO2, -NR6R7, -S(O)2R6, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl. 20 In some embodiments, X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H. In some embodiments, X is A wherein A is phenyl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is – S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H. In some embodiments, 25 X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is H, alkyl or C2-4 alkene and R4a is H. In some embodiments, X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H. In some embodiments, X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H. In some embodiments, X is A wherein 16 201388-PCT01-NP A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is alkyl and R4a is H. In some embodiments, X is A wherein A is aryl and L is –S(CR3aR4a)k– wherein k is 1, 5 R3a is methyl, and R4a is H. In some embodiments, X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1, R3a is methyl and R4a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1, R3a is methyl and R4a is H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S(CR3aR4a)k– wherein k is 1, R3a is methyl; and R4a is H. 10 In some embodiments, X is A wherein A is aryl and is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. In some embodiments, X is A wherein A is phenyl and L is – S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and 15 L is –S(CR3aR4a)k– wherein k is 1 and both R3a and R4a are H. O O S HN In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl and R2 O S N . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl and R2 wherein Ra is methyl. In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl, R1 is C1-3 alkyl, O O S 20 R11 is H, and R2 is . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A O O S is aryl, R1 is C3-6 branched alkyl, R11 is H, and R2 i . In some embodiments, L is – O O S S(CR3aR4a)k–, X is A wherein A is aryl, R1 is C3-6 cycloalkyl, R11 is H, and R2 . 17 201388-PCT01-NP In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl, R1 is propyl, R11 O O S Ra HN is H, and R2 is . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is O O S l, R1 is isopropyl, R11 is H, and R2 i a HN ary R . In some embodiments, L is –S(CR3aR4a)k– O O herein A is aryl, R1 is cyclopropyl, R11 is H, and R2 i a S HN , X is A w R . In some 5 embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl, R1 is bu s H, and R2 is O O a S HN R11 , X S HN is A wherein A is aryl, R1 is isopropyl, R11 is H, and R2 i wherein Ra is methyl. In 10 some embodiments, L is –S(CR3aR4a)k–, X is A wherein R1 is cyclopropyl, R11 is H, O O S and R2 is wherein Ra is methyl. In some embodiments, L is –S(CR3aR4a)k–, X is A O O S N wherein A is aryl, R1 is butyl, R11 is H, and R2 is wherein Ra is methy . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is aryl, R1 is iso-butyl, R11 O O S is H, and R2 is . In some embodiments, L is –S(CR3aR4a)k–, X is A wherein A is O O S 15 aryl, R1 is cyclo-butyl, R11 is H, and R2 is . In some embodiments, L is – S(CR3aR4a)k– wherein k is 1, X is A wherein A is aryl, R1 is propyl, R11 is H, and R2 is 18 201388-PCT01-NP O O a S R HN . In some embodiments, L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is aryl, O O S Ra HN R1 is isopropyl, R11 is H, and R2 is . In some embodiments, L is –S(CR3aR4a)k– O O S Ra HN wherein k is 1, X is A wherein A is aryl, R1 is cyclopropyl, R11 is H, and R2 . In some embodiments, L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is s butyl, O O a S HN 5 R11 is H, and R2 is . In some embodiments, L is –S(CR3aR4a)k– wherein k is 1, X is O O a S HN A wherein A is aryl, R1 is iso-butyl, R11 is H, and R . In some embodiments, L is –S(CR3aR4a)k– wherein k is 1, X is A wherein A is yclo-butyl, R11 is H, and R2 is O O S HN . In some embodiments, the present disclosure provides a compound of Formula (I), as 10 defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein L is –S-(CR3R4)-C(O) –. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)- C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein 15 A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some20 embodiments, X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S- (CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -NO2 and L is –S-(CR3R4)-C(O) – wherein 19 201388-PCT01-NP R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is a 4-6 member heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are independently alkyl or 5 H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)- C(O) – wherein and R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H. In some embodiments, X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein and R3a and R4a are independently alkyl or H. 10 In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein k is 1 and R3a and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is 15 alkoxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -NO2 and 20 L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S- (CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a 4-6 member heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)-C(O) 25 – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both alkyl. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)-C(O) – wherein R3a30 and R4a are alkyl or H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)- 20 201388-PCT01-NP C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is 5 phenyl and wherein at least one R5 is haloalkyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is hydroxy and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is -NO2 and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is phenyl and wherein 10 at least one R5 is -S(O2)R6 wherein R6 is methyl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is a 4-6 member heteroaryl and L is – S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is a 4-6 member N-heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, X is A wherein A is a 4-6 member S-heteroaryl and L is –S-(CR3R4)-C(O) – 15 wherein R3a and R4a are both H. In some embodiments, X is A wherein A is a bicyclic heteroaryl and L is –S-(CR3R4)-C(O) – wherein R3a and R4a are both H. In some embodiments, the present disclosure provides a compound of Formula (I), as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein L is –S-(CR3R4)n-O– 20 In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl. In some embodiments, X is A wherein A is aryl and L is –S- (CR3R4)n-O– wherein R3 and R3a are H. In some embodiments, X is A wherein A is phenyl and L –S-(CR3R4)n-O– wherein R3 is 25 alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl. In some embodiments, X is A wherein A is phenyl and L is – S-(CR3R4)n-O– wherein R3 and R3a are H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and 30 L –S-(CR3R4)n-O– wherein R3 is H and R3a is alkyl. In some embodiments, X is A wherein A 21 201388-PCT01-NP is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 and R3a are H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is alkyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is H and 5 R3a is alkyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 and R3a are H. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is phenyl and L is 10 –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is phenyl and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is H and 15 R3a is methyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is alkoxy and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is halo and L 20 is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is aryl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is H and R3a is methyl. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is methyl and R3a is H. In some embodiments, X is A wherein A is phenyl and wherein at least one R5 is halo and L is –S-(CR3R4)n-O– wherein R3 is 25 H and R3a is methyl. In some embodiments, the present disclosure provides a compound of Formula (I), as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein X is A and A is aryl and G1, G2, and G3 are all N. In some embodiments, X is A and A is phenyl and G1, G2, and G3 are all N. 22 201388-PCT01-NP O O embodiments, X is A and A is aryl, R2 is a S HN In some R and G1, G2, and G3 are all HN N. In some embodiments, X is A and A is phenyl, R2 i Ra and G1, G2, and G3 are all O S Ra HN N. In some embodiments, X is A and A is aryl, R2 i , R11 is alkyl, and G1, G2, and O O S HN G3 are all N. In some embodiments, X is A and A is phenyl, R2 i Ra , R11 is alkyl, and 5 G1, G2, and G3 are all N. In some embodiments, X is A and A is aryl wherein at least one R5 is halo, R2 is O O a S HN and G1, G2, and G3 are all N. In some embodiments, X is A and A is phenyl wherein O O S HN at least one R5 is halo, R2 i and G1, G2, and G3 are all N. In some embodiments, X O O S HN is A and A is aryl wherein at least one R5 is halo, R2 i , R11 is alkyl, and G1, G2, 10 and G3 are all N. In some embodiments, X is A and A wherein at least one R5 is halo, O O S s alkyl, and G1, G2, and G3 are all N. iments, X is A and A is aryl wherein at least one R5 is alkoxy, R2 is , and G3 are all N. In some embodiments, X is A and A is phenyl wherein O O S Ra HN at least one R5 is alkoxy, R2 is and G1, G2, and G3 are all N. In some embodiments, O O S 15 X is A and A is aryl wherein at least one R5 is alkoxy, R2 , R11 is alkyl, and G1, 23 201388-PCT01-NP G2, and G3 are all N. In some embodiments, X is A and A is phenyl wherein at least one R5 is O O xy, R2 i a S HN alko R R11 is alkyl, and G1, G2, and G3 are all N. NH O S Ra N In some embodiments, X is A and A is aryl, R2 i and R11 is alkyl. In some NH O S N bodiments, X is A and A is phenyl, R2 is Ra em H and R11 is alkyl. In some embodiments, NH O S a N 5 X is A and A is aryl, R2 is wherein Ra is methyl and R11 is alkyl. In some NH O S N embodiments, X is A and A is phenyl, R2 is wherein Ra is methyl and R11 is alkyl. O O S HN In some embodiments, X is A and A is ary is alkyl. In some O S HN embodiments, X is A and A is pheny is alkyl. In some embodiments, O O S X is A and A is aryl wherein Rb is H and R11 is alkyl. In some embodiments, O O S 10 X is A and A is phenyl, wherein Rb is H and R11 is alkyl. In some O O S embodiments, X is A and A is aryl wherein Rb is methyl and R11 is alkyl. 24 201388-PCT01-NP O O S HN N In some embodiments, X is A and A is pheny wherein Rb is methyl and R11 O S HN N is alkyl. In some embodiments, X is A and A is ary wherein Rb is ethyl and O O S HN R11 is alkyl. In some embodiments, X is A and A is pheny wherein Rb is ethyl and R11 is alkyl. 5 In some embodiments, the present disclosure provides a compound as found in Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound as found in Table 2 or a pharmaceutically acceptable salt thereof. Table 2 24 28 201388-PCT01-NP 35 77 In some embodiments, the present disclosure provides a compound as found in Table 3, or pharmaceutically acceptable salts thereof. Table 3 1 24 201388-PCT01-NP 69 70 F F 27 201388-PCT01-NP 139 148 In some embodiments, the present disclosure provides a compound as found in Table 4, or pharmaceutically acceptable salts thereof. Table 4 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- tri zin2 l)111trifl r m th n lf n mid - - }- - n- - 28 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(2E)-3-phenylprop-2-en-1- yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide - - - - ]- }- - }- 29 201388-PCT01-NP (S)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonimidoamide 30 201388-PCT01-NP N-(4-{[(2R)-1-Cyclopropyl-3-hydroxypropan-2-yl]amino}-6-{[(1R)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide - - 31 201388-PCT01-NP N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopentyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) - }- 32 201388-PCT01-NP N-(4-{[(1S)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopentyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 33 201388-PCT01-NP (R)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1S)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonimidoamide 2- 2- - 34 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-hydroxyphenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide n- - n- 35 201388-PCT01-NP N-(4-{[(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(methylsulfonyl)amino]-1,3,5- triazin-2-yl)sulfanyl]acetyl}phenyl)acetamide - - n- 36 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy -4-methylpentan-2-yl]amino}-6-{[(2S)-1-(3,4,5- trifluorophenoxy)propan-2-yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide }- }- - 37 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(5-methylpyrazin-2- yl)methyl]sulfanyl}pyrimidin-2-yl)methanesulfonamide - 38 201388-PCT01-NP N-(6-{[(1R)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-2-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}pyrimidin-4-yl)methanesulfonamide 4- - - 39 201388-PCT01-NP N-(2-{[(4-Cyanophenyl)methyl]sulfanyl}-6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4- yl)methanesulfonamide - - 40 201388-PCT01-NP (3S)-N-(4-{[(2S,3R)-1,2-Dihydroxy-5-methylhexan-3-yl]oxy}-6-[(1-phenylethyl)sulfanyl]- 1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide - - - - - }- - n- - - - - - ]- 41 201388-PCT01-NP N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-[(1-hydroxy-4-methylpentan-2-yl)amino]- 1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide }- - }- 42 201388-PCT01-NP (S)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonimidoamide 43 201388-PCT01-NP N-(4-{[(1R)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclobutyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide - - 44 201388-PCT01-NP N-(4-{[1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide }- 45 201388-PCT01-NP N-(4-{[(1R)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopropyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 2- 46 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-nitrophenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 2- - 47 201388-PCT01-NP N-[4-({2-[4-(Dimethylamino)phenyl]-2-oxoethyl}sulfanyl)-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide n- - n- - - - 48 201388-PCT01-NP N-(4-{[(2S)-2-(2,3-Difluorophenoxy)propyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan- 2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide n- }- }- 49 201388-PCT01-NP N-(4-{[(1S)-1-(2,3-Difluorophenyl)ethyl]oxy}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide - 50 201388-PCT01-NP N-(2-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide (Isomer 1) - 4- 51 201388-PCT01-NP N-(2-{[(2-Cyanophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide - - 52 201388-PCT01-NP N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)-N'-[3-(dimethylamino)propyl]sulfuric diamide - - - - The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease in a mammal, particularly a human. Cardiovascular disease includes, but is not limited to, conditions 5 associated with cardiac dysfunction and/or microvascular dysfunction and/or macrovascular pathology, such as atherosclerosis, arteriosclerosis, coronary artery disease including stable and high risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or by 53 201388-PCT01-NP biomarkers of microvascular and cardiac dysfunction), ischemic heart disease, myocardial infarction, restenosis following revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD) including erectile dysfunction due to vascular disease, stroke, cardiomyopathy, including non-ischemic dilated cardiomyopathy, transient 5 ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia, renovascular disease, and renal arterial disease. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of non-ischemic dilated cardiomyopathy. 10 The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease in a patient having co-morbidities such as renal dysfunction. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease 15 associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease 20 associated with autoimmune conditions, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of heart failure, including 25 heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of inflammatory bowel disease. 54 201388-PCT01-NP The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of lupus nephritis. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of patients with remaining 5 risk for a cardiovascular event despite standard of care (SoC) treatment, such as, but not limited to, lipid lowering statins, anti-platelets, ACE inhibitors, mineralocorticoid receptor antagonists, and beta blockers. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of chronic kidney disease. 10 The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of type II diabetes mellitus and complications of type II diabetes mellitus in a mammal, particularly a human. This includes and is not restricted to, diabetic micro and macrovascular pathology, neuropathy and nephropathy. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically 15 acceptable salt thereof, may be useful in the prevention or treatment of renal inflammatory and vascular diseases and complications associated with renal disease in a mammal, particularly a human. Renal inflammatory and vascular disease includes, but is not limited to chronic kidney disease, drug and toxin induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephritis, reflux nephropathy, focal segmental glomerulosclerosis, Henoch- 20 Schönleins purpura, and diabetic nephropathy. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of autoimmune diseases, such as, but not limited to, dermatomyositis, polymyositis, and systemic lupus erythematosus (SLE). The compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof, may be useful in the prevention or treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and ASH (alcoholic steatohepatitis). Treatment with the compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may lower the cardiovascular and/or cerebrovascular 55 201388-PCT01-NP and/or renal and/or peripheral arterial disease morbidity and mortality associated with cardiac dysfunction and/or atherosclerosis, and/or renal dysfunction and/or microvascular dysfunction and/or macrovascular pathology due to their anti-inflammatory properties and influence on vasoactive mechanisms. 5 The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may serve to prevent or reduce the risk of developing cardiac dysfunction and/or renal dysfunction and/or microvascular dysfunction and/or macrovascular pathology, as well as for halting or slowing the progression and/or promoting the regression of atherosclerotic cardiovascular disease once it has become clinically evident, comprising the administration of a 10 prophylactically or therapeutically effective amount, as appropriate, of a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic cardiovascular disease. Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically 15 acceptable salt thereof, may be useful in preventing or reducing the incidence or severity of acute events related to atherosclerotic plaque rupture or erosion, including, but not limited to, myocardial infarction, unstable angina and stroke. Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in preventing or reducing the incidence or severity of acute 20 events by improving microvascular function, macrovascular pathology and/or cardiac function. Compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in preventing or reducing the progression of abdominal aortic aneurysms (AAA) and incidence of rupture. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof, may be useful in the prevention or treatment of respiratory inflammatory disease and complications associated with respiratory inflammatory disease in a mammal, particularly a human. Respiratory inflammatory disease includes, but is not limited to asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis. 56 201388-PCT01-NP Some embodiments disclosed herein provide a method of treating or preventing one or more of the diseases or conditions discussed herein, wherein the method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically 5 acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing non- ischemic dilated cardiomyopathy, wherein the method comprises administering to a person in need thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 10 Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease in a patient having co-morbidities such as renal dysfunction, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 15 Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies/multisystem diseases such as psoriatic arthropathy, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount 20 of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing heart failure wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a 25 pharmaceutically acceptable salt thereof. In further embodiments the heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, wherein the method comprises administering to a person in need of 57 201388-PCT01-NP thereof, a therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, wherein the method comprises administering to a person in need of thereof, a 5 therapeutically effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing respiratory inflammatory disease and complications associated with respiratory inflammatory disease, wherein the method comprises administering to a person in need of thereof, a therapeutically 10 effective amount of a compound of formula (I), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In further embodiments, the respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and/or rhinitis. The terms “preventing”, “prevention”, and “prevent” are readily understood by an 15 ordinarily skilled physician and, with respect to treatment of a particular condition, can include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition. 20 The terms "treating”, “treatment”, and “treat” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include (1) diminishing the extent or cause of the condition being treated, and/or (2) alleviating or ameliorating one or more symptoms associated with that condition. Treatment of cardiovascular disease, for example, can include stabilizing (i.e., not worsening), delaying, or slowing the spread or 25 progression of the cardiovascular disease; prolonging survival as compared to expected survival if not receiving treatment; and/or otherwise ameliorating or palliating the severity of the cardiovascular disease, in whole or in part. The compounds disclosed herein may have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more 58 201388-PCT01-NP easily absorbed, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance), than compounds known in the prior art. These and other embodiments are described in greater detail herein below, where further aspects will be apparent to one skilled in the art from reading this specification. 5 Pharmacological Properties: The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salts thereof are believed to be useful in the prevention or treatment of cardiovascular conditions, including but not limited to coronary artery disease, acute coronary syndrome, cardiomyopathy, non-ischemic dilated cardiomyopathy, heart 10 failure, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction in a mammal, particularly a human. When a compound or salt described herein is administered as therapy for treating a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, 15 completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse. The compounds described herein are thus indicated both in the therapeutic and/or prophylactic treatment of these conditions. Pharmaceutical Compositions: 20 There is provided a method of treatment of a condition where modulation of CX3CR1 is required, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition. The compound for formula (I), or a compound disclosed herein, or a pharmaceutically 25 acceptable salt thereof, will normally be administered via the oral, topical, parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage 59 201388-PCT01-NP form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2nd 5 Ed.2002. The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various 10 other factors known to physicians and others skilled in the art. According to a further aspect there is thus provided a pharmaceutical formulation comprising a compound of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. 15 The compound for formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total formulation. A further embodiment encompasses pharmaceutically acceptable salts of the compound for formula (I), or a compound disclosed herein. 20 A compound of formula (I), or a compound disclosed herein, may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. In some instances, a salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly where the salt is intended for administration to an animal, e.g. a human, or is a reagent for use in 25 making a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable. The term “pharmaceutically acceptable” is used to characterize a moiety (e.g. a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any 60 201388-PCT01-NP deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications. Where the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts. Where the compound is sufficiently 5 acidic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base addition salts. For reviews on suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, P.H. Stahl, P.G. Vermuth, IUPAC, Wiley- VCH, 2002. 10 It is also to be understood that certain compounds of formula (I), or a compound disclosed herein, may exist in solvated form, e.g. hydrates, including solvates of a pharmaceutically acceptable salt of a compound of formula (I). It is also to be understood that certain compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may exist as a mixture of tautomers. 15 “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom, e.g., amide-imidic acid tautomerism. The disclosure herein includes all tautomers of compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In particular embodiments, certain compounds of formula (I), or a compound disclosed 20 herein, or a pharmaceutically acceptable salt thereof, may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Certain compounds of formula (I), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may also contain linkages (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the 25 presence of a ring bond or double bond. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis. 61 201388-PCT01-NP EXAMPLES The following examples are non-limiting examples. SYNTHETIC METHODS: General conditions 5 (i) operations were carried out at room temperature (rt), i.e. in the range 17 to 28oC and where needed under an atmosphere of an inert gas such as N2 or Argon; optionally reactions were carried out using a MBRAUN UNILab Plus ECO or a MBRAUN UNILab SP Eco glovebox workstation or a KitAlysis™ Benchtop Inertion Box from Sigma-Aldrich, in which case it is indicated; 10 (ii) where reactions refer to being degassed or purged, this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g)); (iii) where reactions refer to the use of a microwave reactor, one of the following 15 microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator or CEM Explorer; (iv) in general, the course of reactions was followed by thin layer chromatography (TLC) and/or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS). 20 (v) when necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4, or by using an ISOLUTE® Phase Separator, and workup procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4 or Na2SO4 is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer. 25 (vi) It is understood that washing solutions used in the work-up procedures or reagent used for acidifying such as e.g. Brine, NaHCO3, NH4Cl , HCl, NaH2PO4 are presumed to be aqueous solutions unless otherwise stated 62 201388-PCT01-NP (vii), evaporations were carried out either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (viii) unless otherwise stated, flash column chromatography was performed on straight phase silica, using either Merck Silica Gel (Art. 9385) or prep-packed cartridges such as 5 BIOTAGE SNAP cartridges (40-63 μm silica, 4–330 g), BIOTAGE Sfär Silica HC D cartridges (20 µm, 10–100 g), INTERCHIM PURIFLASH cartridges (25 µm, 4–120 g), INTERCHIM PURIFLASH cartridges (50 µm, 25–330 g), GRACE GRACERESOLVE Silica Flash Cartridges (4–120 g) or Agela Flash Colum Silica-CS cartridges (80–330g), or on reversed phase silica using Agela Technologies C-18, spherical cartridges (20–35µm, 100A, 80–330g), manually or 10 automated using a GRACE REVELERIS X2 Flash system or similar system; (ix) preparative TLC was performed on glass-backed silica plates (20×20 cm) covered with a 1 mm thick silica gel (particle size of 10–40 µm), in a glass chamber, using the appropriate solvent or solvent mixtures as eluant as stated in the experimental description; (x) preparative reverse phase HPLC and preparative reverse phase SFC were performed 15 using standard HPLC and SFC instruments, respectively, equipped with either a MS and/or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section and using one of the following methods: PrepMethod A; The compound was purified by preparative HPLC on a Xbridge C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH3 (0.2%, pH 10) buffer system as 20 mobile phase; PrepMethod B; The compound was purified by preparative HPLC on a Xbridge C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/TFA (0.05%) buffer system as mobile phase; PrepMethod C; The compound was purified by preparative SFC on a Phenomenex Luna® HILIC column (5 μm, 250×30 mm ID) using MeOH/NH3 (20 mM) in CO2 as mobile phase; PrepMethod D; The compound was purified by preparative HPLC on a 25 XBridge C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) as mobile phase; PrepMethod E; The compound was purified by preparative HPLC on a XBridge C18 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H2O/MeCN/NH3 (95/5/0.2) as mobile phase; PrepMethod F; The compound was purified by preparative HPLC on a Waters Sunfire C18 ODB column (5 μm, 150×19 mm ID) using a 30 gradient of MeCN in H2O/FA (0.1 M) as mobile phase; PrepMethod G; The compound was 63 201388-PCT01-NP purified by preparative HPLC on a Kromasil C8 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H2O/MeCN/FA (95/5/0.2) as mobile phase; PrepMethod H; The compound was purified by preparative SFC on a Phenomenex Luna® HILIC column (5 μm, 250×30 mm ID) using MeOH/DEA (100/0.5) in CO2 as mobile phase; PrepMethod I; The compound was 5 purified by preparative HPLC on a Kromasil C8 column (10 µm, 250×20 mm ID) using a gradient of MeCN in H2O/MeCN/FA (95/5/0.2) as mobile phase; PrepMethod J; The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O/FA (0.1 M) as mobile phase; PrepMethod K; The compound was purified by preparative SFC on a Kromasil DIOL, (5 µM, 50 x 30 mm ID) using 10 MeOH/DEA (100/0.5 mM) in CO2 as mobile phase; PrepMethod L; The compound was purified by preparative HPLC on a XBridge Shield C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/FA (0.1%) buffer system as mobile phase; PrepMethod M; The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/TFA (0.05%) buffer system as mobile phase; PrepMethod N; The 15 compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (8 mM) buffer system as mobile phase; PrepMethod O; The compound was purified by preparative HPLC on a Waters XSelect CSH OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O as mobile phase; PrepMethod P; The compound was purified by preparative HPLC on a XBridge C18 column (5 20 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/FA (0.1%) buffer system as mobile phase; PrepMethod Q; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/FA (0.1%) buffer system as mobile phase; PrepMethod R; The compound was purified by preparative HPLC on a XBridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (10 25 mM) buffer system as mobile phase; PrepMethod S; The compound was purified by preparative HPLC on a Waters XSelect C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O/FA (0.3%) as mobile phase; PrepMethod T; The compound was purified by preparative HPLC on a Waters XSelect CSH OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O as mobile phase; PrepMethod U; The compound was purified by preparative 30 HPLC on a XBridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (8 mM) buffer system as mobile phase; PrepMethod V; The compound was 64 201388-PCT01-NP purified by preparative HPLC on a XBridge Shield C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH3 (0.05%) buffer system as mobile phase; PrepMethod X; The compound was purified by preparative HPLC on a Xbridge C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/NH3 (0.1%) buffer system as mobile phase; 5 PrepMethod Y; The compound was purified by preparative HPLC on a XBridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O/FA (0.05%) buffer system as mobile phase; PrepMethod Z; The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP column (5 μm, 250×30) using MeOH/NH3 (100/20mM) in CO2 as mobile phase; PrepMethod Z1; The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP 10 column (5 μm, 250×30) using MeOH in CO2 as mobile phase; PrepMethod Z2; The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP column (5 μm, 250×30) using MeOH/DEA (100/0.5) in CO2 as mobile phase; PrepMethod Z3; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 100×30 mm ID) using a gradient of MeCN in a H2O/NH4HCO3 (0.5%) buffer system as mobile phase; PrepMethod Z4; The 15 compound was purified by preparative HPLC on a Kromasil C8 column (10 µm, 250×20 mm ID) using a gradient of MeCN in H2O/MeCN/AcOH (95/5/0.2) as mobile phase; PrepMethod Z5; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 100×19 mm ID) using a gradient of MeCN in a H2O/FA (0.1%) buffer system as mobile phase; PrepMethod Z6; The compound was purified by preparative HPLC on a Xbridge C18 ODB 20 column (5 μm, 150×30 mm ID) using a gradient of MeCN in a H2O/NH3 (0.2%, pH 10) buffer system as mobile phase; In some instances, the compound may be dissolved in a solvent e.g. DMSO and filtered through a syringe filter prior to purification on preparative HPLC. Relevant fractions were collected, combined, and freeze-dried or evaporated to give the 25 purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, the aqueous layer was extracted with DCM or EtOAc, and the organic layer was dried, either over Na2SO4 or by using a phase-separator, and then concentrated at reduced pressure and when needed dried in vacuo, to give the purified compound. 65 201388-PCT01-NP (xi) chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instruments, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section; (xii) yields, where present, are not necessarily the maximum attainable, and when 5 necessary, reactions were repeated if a larger amount of the reaction product was required; (xiii) where certain compounds were obtained as an acid-addition salt, for example a mono- hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data; 10 (xiv) in general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and/or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at 1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as 15 internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, 20 multiplet; br, broad; qn, quintet; p, pentet. It is understood, where the NMR spectra contains residual impurities and/or residual solvent(s), this is not reported unless it partially coincides with peaks of Intermediates and/or Structures of Formula (I), in which case said peaks of Intermediates and/or Structures of Formula (I) are reported as multiplets partially overlapping with said solvent or impurity, and the Integral is omitted. In some cases, the structures of the end-products of the 25 Formula (I) might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported. In some instances, the structures of the intermediates and/or end- products of Formula (I) might appear as rotamers in a more equal relationship, in such instances the peaks of such rotamers are either reported as multiplets, if the signals of said rotamers are partially overlapping, or as individual peaks, if the signals of said rotamers are well separated. 66 201388-PCT01-NP (xv) Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; (xvi) high resolution electrospray mass spectral data were obtained using a Waters XEVO 5 qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported (xvii) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry; 10 (xviii) unless stated otherwise compounds containing an asymmetric carbon and/or sulfur atom were not resolved; (xix) in general Examples are named using ACD/Name IUPAC name module 2020.2.0 from ACDLabs and Intermediate compounds are named using ChemDraw Professional version 22.2.0 from PerkinElmer. Both ACD/Name IUPAC name module 2020.2.0 and ChemDraw15 Professional version 22.2.0 generates the names of chemical structures using the Cahn-Ingold- Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules. ChemDraw and ACD/NAME are optionally using labels in the graphical representation of 20 stereocenters such as '&' and 'or' to describe the configuration of the stereochemical centers present in the structure. A n mber following the '&' and 'or' flag is assigned to each stereocenter present in the structure. The numbers are incremented automatically to indicate that stereocenters may vary independently to each other. In general, for chemical structures of Examples and Intermediates where more than one 25 stereocenter is present and said stereocenters have a fixed relative configuration, the same number is used after the label '&' and 'or' to indicate that said stereocenters forms a group. A third stereocenter present in the same chemical structure, that varies independently to the former stereocenters, is designated with a unique new number following the label '&' and 'or'. 67 201388-PCT01-NP In general, for structures of Examples and Intermediates where all stereocenters are designated as '&', the structure is named with a “rac-” prefix. For structures of Examples and Intermediates where all stereocenters are designated as 'or', the structure is named with a “rel-” prefix. In general, Examples and Intermediate compounds are named using the descriptors (RS) 5 and (SR) are used to denote general '&' centers for chemical structures with multiple chiral centers where only some are designated as '&'. The descriptors (R*) and (S*) are used to denote the general 'or' centers for chemical structures with multiple chiral centers where only some are designated as 'or'. It is to be understood that an Example or Intermediate with a stereocenter labelled (R*) or 10 (S*) has an absolute configuration at said stereocenter and while said stereocenter in the compound has been designated as (R*) or (S*), the actual stereochemistry of that particular isomer could be the opposite of the label. For example, while Example 128, the second eluting isomer from the chiral separation of N-(4-((1-(2,3-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)pyrimidin-2-yl)methanesulfonamide is named “N-(4-{[(1R*)-1-(2,3-15 Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin-2- yl)methanesulfonamide” it could be N-(4-{[(1R)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)- 1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin-2-yl)methanesulfonamide or N-(4-{[(1S)-1- (2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin- 2-yl)methanesulfonam. 20 That is, the actual structure of Example 128, (i.e., the second eluting isomer) could be: F Said Example or Intermediate with a stereocenter labled with (R*) or (S*) can also in certain instances be represented by a structure as below; 68 201388-PCT01-NP OH HN F One of skill in the art wou t when a numbered example disclosed herein is prepared by chiral separation of diastereomers, such as Example 128 as described above, both diastereomers, the first eluting isomer and the second eluting isomer, are disclosed herein. 5 In general, for structures of Examples and Intermediates where two or more stereocenters are present in a ring and fixed to each other and do not vary independently of each other, e.g. are ‘cis’ or ‘trans’ to each other, said stereocenters are drawn with stereobonds representing their internal relationship. Said stereocenters are labeled with an ‘&1’ flag representing a mixture of cis-configuration or a mixture of trans-configuration, or an ‘or1’ flag representing a single cis- 10 isomer or a single trans-isomer with unknown absolute stereochemistry. In general, should the structure of said Example or Intermediate further contain one or more stereocenters that are racemic and not fixed in relation to the former stereocenters, said stereocenter(s) are drawn with a straight bond at said stereocenters. In general, the label “Isomer 1” corresponds to the first eluted isomer, and “Isomer 2” 15 corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration. Additionally, “Isomer 3” and “Isomer 4” refer to the third eluted isomer and the fourth eluted isomer, respectively. (xx) in addition to the ones mentioned above, the following abbreviations and units have 20 been used: Abbreviations AcOH Acetic acid AlMe3 Aluminum trimethanide Aq aqueous 25 9-BBN 9-borabicyclo[3.3.1]nonane 69 201388-PCT01-NP Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate Brine saturated aqueous sodium chloride solution tBu tert-butyl 5 nBuOH n-butanol tBuOH t-butanol Calcd calculated DCM dichloromethane DIPEA N-ethyl-N-isopropyl-propan-2-amine 10 DMA N,N-dimethylacetamide DMAP N,N-dimethylpyridin-4-amine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine 15 eq equivalent ESI electrospray ionization Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol 20 FA formic acid (g) gas HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate HOAc acetic acid 25 HOBt 1-hydroxybenzotriazole;hydrate HPLC high performance liquid chromatography HRMS high resolution mass spectrometry ID inner diameter IPA 2-propyl alcohol 30 iPr isopropyl KSAc Potassium thioacetate 70 201388-PCT01-NP LDA lithium diisopropylamide MeCN acetonitrile MeOH methanol 2-MeTHF 2-methyltetrahydrofuran 5 MsCl methanesulfonyl chloride Ms2O methanesulfonic anhydride MTBE methyl tert-butyl ether m/z mass spectrometry peak(s) NaOAc sodium acetate 10 NaOtBu sodium tert-butoxide NMP N-methylpyrrolidone NMR nuclear magnetic resonance OMs mesylate on overnight 15 OTBS tert-butylsilyloxy Pd-118 Dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) PdCl2(MeCN)2 Bis(acetonitrile)dichloropalladium(II) Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd2dba3 × CHCl3 tris(dibenzylideneacetone)dipalladium(0) (1:1) 20 Pd Cl2(dppf)2 [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2•DCM [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) DCM complex Pd(OAc)2 palladium(II) acetate PE petroleum ether 25 PPTS pyridinium p-toluenesulfonate Pr propyl PrCN propanenitrile rt room temperature RuPhos dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphane 71 201388-PCT01-NP salen 6,6'-((1E,1'E)-(((1S,2S)-cyclohexane-1,2- diyl)bis(azaneylylidene))bis(methaneylylidene))bis(2,4-di-tert- butylphenol) SFC supercritical fluid chromatography 5 T3P propylphosphonic anhydride TBDMSCl tert-butyldimethylsilyl chloride TBME tert-butylmethylether TBTU 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate 10 TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TMAF tetramethylammonium fluoride TLC thin layer chromatography 15 TsCl 4-methylbenzenesulfonyl chloride X-Phos dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl-9H- xanthene-4,5-diyl)bis(diphenylphosphine) Units 20 atm atmosphere C Celsius d day(s) g gram h hour(s) 25 L litre M mole per liter mg milligram MHz megaherz min minute(s) 30 mL milliliter mm millimeter 72 201388-PCT01-NP mM millimole per liter mmol millimole(s) µL microlitre µm micrometer 5 N equivalents per liter nm nanometer ppm parts per million General Methods 10 In another aspect there is provided a process for preparing compounds of the formula (I) or a pharmaceutically acceptable salt thereof, which processes comprises methods a1 to a6 and scheme TA16 below: Method a1: The compounds of formula (I) in which R1, R2, R5, R11, G1, G2, G3, X and p are defined as in formula (I), Z is -NH- or -O- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, - 15 S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I) may be formed by reacting a compound of formula (II) in which R1, R2, R11, G1, G2 and G3 are defined as in formula (I) and Z is -NH- or -O-, with a compound of formula (III) in which L1 is - (CR3R4)k-, -(CR3R4)k-CR3=CR3-, -(CR3R4)n-O- or -(CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I) and LG1 is a suitable leaving group such as chloro, bromo, iodo, triflate 20 (OTf), mesylate (OMs) or tosylate (OTs) (preferentially bromo, chloro or OMs) R1 OH 5)p The reaction is carried out in an inert organic solvent such as DMF, DMSO, 1,4-dioxane, THF or MeCN (preferentially DMF or THF) in the presence of a suitable base (typically 1.1-10 eq) such as DIPEA, TEA, K2CO3, Cs2CO3 or NaOAc (preferentially DIPEA). The reaction 73 201388-PCT01-NP may be carried out at temperatures ranging typically from 20oC to 140oC for a prolonged time (typically 0.5-72 h) using standard equipment or a single node microwave reactor. Formula (III) is typically used in an equimolar amount to formula (II) but can also be used in a slight excess (typically 1.1-2.2 eq). Optionally, the reaction may also be conducted under an inert atmosphere 5 (e.g. an N2 atmosphere). Method a2: The compounds of formula (I) in which R1, R2, R5, R11, G1, G2, G3, L, X and p are defined as in formula (I), Z is -NH- or -O- may be prepared from a compound of formula (IV) LG2 G1 G2 5 )p 10 in which R2, R5, G1, G2, G3, L, X and ormula (I) and LG2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro) using the methods a2a (when Z is - NH-) to a2b (when Z is -O-) below. Method a2a: Reacting the compound of formula (IV) with a compound of formula (V) R1 OH 15 in which R1 and R11 are defined as in form ula (I). The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH, nBuOH or mixtures thereof in the presence of a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to 120oC for a prolonged reaction time (2-120 h) using standard equipment or a single node microwave reactor. Formula (V) is 20 normally used in a slight excess (typically 1.2-5 eq) to formula (IV). Method a2b: Reacting the compound of formula (IV) with a compound of formula (VI) 74 201388-PCT01-NP R1 OH HO wherein R1 and R11 are defined as in for reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH. The rection is preferentially carried out in an inert atmosphere (e.g. an N2-atmosphere) at ambient 5 temperature for a prolonged reaction time (typically 2-16 h). It is appreciated that the non- reacting OH group preferentially carries a protective group that can be introduced and removed using methods known to a person skilled in the art. Method a3: The compounds of formula (I) in which R1, R2, R5, R11, G1, G2, G3, Z, L, X and p are defined as in formula (I) may be prepared from a compound of formula (VII) R1 OH 5 )p 10 wherein R1, R5, R11, G1, G2, G3, Z, L , an p are e ne as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) using the methods a3a to a3b below. Method a3a: Reacting the compound of formula (VII) with one of the compounds (one at 15 a time) of formula (VIII) to (XII) 75 201388-PCT01-NP O NH O O b O O S R Ra NH2 Ra S S NH2 N NH b 2 R in which Ra, Rb, Rc and ay be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5– 5 3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node micro wave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). Alternatively, the reaction may also be performed without a metal catalyst in an inert 10 organic solvent such as DMF or DMSO in the presence of a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq) at elevated temperatures (e.g.90oC) for a prolonged reaction time. Formulas (VIII) to (XII) is typically used in a slight excess to formula (VII) (e.g.1.1-8 eq). Method a3b: Reacting the compound of formula (VII) with a compound of formula (XIII) O O S (CH2)-BF3 K 15 a in which R is defined as in formula (I). The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3, Pd(OAc)2 or PdCl2(MeCN)2 (preferentially PdCl2(MeCN)2) in combination with a suitable phosphine ligand, typically X-Phos or RuPhos (preferentially RuPhos) in the presence of a base, such as Cs2CO3, K2CO3 or NaOtBu in a mixture of an inert 20 organic solvent, such as tBuOH or THF, and water at elevated temperatures (e.g.100oC) using 76 201388-PCT01-NP standard equipment The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically on). (For more details on preparation and use of compounds of formula (XIII) see Org. Lett., 2011, 13, 1694-1697). Method a4: The compounds of formula (I) in which R1, R2, R5, R11, X and p are defined 5 as in formula (I), G1, G2 and G3 are N, Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O-, -S-(CR3R4)-C(O)- or -O-(CR3R4)j-, wherein R3, R4, j, k and n are defined as in formula (I) may be prepared from a compound of formula (XIV) R1 OH Z , wherein R1, R2, and R11 are defined as i o ua , G1, G2 and G3 are N and Z is -NH- and 10 LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) using the methods a4a to a4b (for the compound wherein L is -O-(CR3R4)j-) below. Method a4a: Reacting the compound of formula (XIV) with a compound of formula (XV) HS L1 X (R5)p (XV) 15 in which R5, X and p are defined as in formula (I) and L1 is -(CR3R4)k-, -(CR3R4)k-CR3=CR3-, - (CR3R4)n-O- or -(CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I). The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3. The reaction is carried out at temperatures ranging typically from 20oC to 100oC for a prolonged reaction time 20 using standard equipment or a single node microwave reactor. Optionally, the reaction may also be performed with the presence of water. Method a4b: Reacting the compound of formula (XIV) with a compound of formula (XVI) 77 201388-PCT01-NP HO L2 X (R5)p (XVI) in which R5, X and p are defined as in formula (I) and L2 is -(CR3R4)j-, wherein R3, R4 and j are defined as in formula (I). The reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH. The rection is preferentially 5 carried out in an inert atmosphere (e.g. an N2-atmosphere) at temperatures ranging typically from 20oC to 100oC for a prolonged reaction time (typically 2-16 h). Method a5: The compounds of formula (I) in which R1, R2, R5, R11, X and p are defined as in formula (I), G1, G2 and G3 are N, Z is -NH- and L is –(CH2)j-CR3R4-, -(CR3R4)m-CR3=CR3- , -CR3aR4a-CR3R4-, -(CR3R4)n-S-, -(CR3R4)n-O- or –(CH2)-NR3- in which R3, R4, R3a, R4a, j, m 10 and n are defined as in formula (I) may be prepared by reacting a compound of formula (XIV) wherein R1, R2, and R11 are defined as in formula (I), G1, G2 and G3 are N, Z is -NH- and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) with a compound of formula (XVII) in which R5, X and p are defined as in formula (I), B1 is a boron species, typically a boronic acid, boronate ester, 9-BBN derivative or trifluoroborate and15 L3 is –(CH2)j-CR3R4-, -(CR3R4)m-CR3=CR3-, -CR3aR4a-CR3R4-, -(CR3R4)n-S-, -(CR3R4)n-O- or – (CH2)-NR3- in which R3, R4, R3a, R4a, j, m and n are defined as in formula (I). R1 OH B1 L3 X (R5 )p ( ) (XVII) The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd-118 or PdCl2(dppf)2 in the presence of a suitable base, such as Cs2CO3 or K2CO3 in an inert organic 20 solvent, such as 1,4-dioxane or THF usually in mixture with water. The reaction is conducted at temperatures ranging typically from 20oC to 100oC for a prolonged reaction time (typically 2-24 h). The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere). (For conditions see also Accounts of Chemical Research, 2008, 40, 1461-1473 and references cited therein). 78 201388-PCT01-NP Method a6: The compounds of formula (I) in which R1, R5, R11, X and p are defined as in formula (I), R2 is RaSO2NH-(CH2)-, G1 is CH, G2 and G3 are N, Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, Ra, k and n are defined as in formula (I) may be formed by reacting a compound of formula (XVIII) wherein 5 R1, R5, R11, X and p are defined as in formula (I), G1 is CH, G2 and G3 are N, Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I) with a compound of formula (XIX) in which Ra is defined as in formula (I). R1 OH Z O Cl X) 10 The reaction is typically carried out in an inert organic solvent such as DCM, 1,4- dioxane, THF or MeCN in the presence of a suitable base such as pyridine, DIPEA or TEA. The reaction is preferentially carried out at ambient temperature or at slightly elevated temperatures for a prolonged reaction time. Optionally, the reaction may also be conducted under an inert atmosphere (e.g. an N2 atmosphere). 15 The compounds of formula (II) to (XIX) above are commercially available, known in the art or may be prepared by methods analogous to those described in the examples and in the descriptions following below or in a conventional manner known by a person skilled in the art. Certain compounds of formula (II) in which R1, R2, R11, G1, G2 and G3 are defined as in formula (I) and Z is -NH- or -O- may be prepared by treating a compound of formula (XX) 20 wherein R1, R2, R11, G1, G2 and G3 are defined as in formula (I) and Z is -NH- or -O- 79 201388-PCT01-NP R1 OH Z with an excess TFA in the presenc eq) which is used as a scavenger for the benzylic cation formed during the reaction. The reaction is typically carried out at ambient temperature for a prolonged reaction time (typically 2-24 h). 5 The compounds of formula (III) may be prepared from a compound of formula (XXI) HO L1 X (R5 )p (XXI) using any of the methods b1 to b5 below: Method b1: Certain compounds of formula (III) in which R5, X and p are defined as in formula (I), L1 is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or –(CR3R4)-C(O)-, in which 10 R3, R4, k 1 ate (OTf), mesylate (OMs) or tosylate (OTs) may be formed by reacting compound (XXI) wherein R5, X and p are defined as in formula (I) and L1 is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or – (CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I), with (Tf)2O, MsCl, Ms2O or TsCl in the presence of a suitable base such as DIPEA, TEA or pyridine. The reaction is 15 performed in an inert organic solvent such as DCM, THF or 1,4-dioxane (preferentially DCM) at ambient temperature for a prolonged reaction time (typically 1-5 h). Method b2: Certain compounds of formula (III) in which R5, X and p are defined as in formula (I), L1 is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or –(CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I), and LG1 is chloro or bromo may be formed by 20 reacting compound (XXI) wherein R5, X and p are defined as in formula (I) and L1 is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or –(CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I), with CCl4 (LG1 is chloro) or CBr4 (LG1 is bromo) in the presence of PPh3. The 80 201388-PCT01-NP reaction is typically carried out in an inert organic solvent such as DCM at ambient temperature for a prolonged reaction time. Method b3: Certain compounds of formula (III) in which R5, X and p are defined as in formula (I), L1 is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or –(CR3R4)-C(O)-, in which 5 R3, R4, k and n are defined as in formula (I), and LG1 is chloro or bromo may be formed by reacting compound (XXI) wherein R , X and p are defined as in formula (I) and L is –(CR3R4)k, -(CR3R4)k-CR3=CR3, -(CR3R4)n-O- or –(CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I), with a halogenating agent such as POCl3, PCl3 or PCl5 (LG1 is chloro) or PBr3 (LG1 is bromo). When POCl3 is used the reaction is typically carried out without an organic 10 solvent at slightly elevated temperatures (typically 60oC) and when PCl3, PCl5 or PBr3 is used the reaction is typically carried out in an inert organic solvent such as DCM at temperatures ranging from 0oC to ambient temperature and for a prolonged reaction time. Method b4: Certain compounds of formula (III) in which R5 and p are defined as in formula (I), LG1 is bromo, L1 is –(CR3R4)k- in which R3 and R4 are independently selected from 15 H, C1-6 alkyl or C1-6 haloalkyl and k is 1, X is A wherein A is selected from phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, may be formed by reacting a compound of formula (XXI), in which R5 and p are defined as in formula (I), L1 is –(CR3R4)k- in which R3 and R4 are independently selected from H, C1-6 alkyl or C1-6 haloalkyl and k is 1, X is A wherein A is selected from phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl, with an excess 20 HBr in an inert solvent such as water or AcOH. The reaction is typically performed at ambient temperature for a prolonged reaction time. Optionally, the reaction may be carried out at temperatures ranging from 25oC to 70oC. Method b5: Certain compounds of formula (III) in which X, R5 and p are defined as in formula (I), L1 is –CR3aR4a-CR3R4- wherein R3a and R4a are independently selected from H or 25 C1-6 alkyl, R3 and R4 both are fluoro and LG1 is chloro or bromo may be formed by reacting a compound of formula (XXII) in which X, R5 and p are defined as in formula (I), R3a and R4a are independently selected from H or C1-6 alkyl and LG1 is chloro or bromo 81 201388-PCT01-NP O LG 1 X (R5)p 4 with a deoxofluorinating agent such as hyl-1,1,1-trifluoro-λ4-sulfanamine) or deoxo-fluor reagent (e.g.1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ4-sulfanamine) in an inert organic solvent such as DCM at temperatures ranging from ambient temperature to reflux for a 5 prolonged reaction time (typically 12-48 h). Certain compounds of formula (IV) (e.g. formula (XXV)) in which in which X, R5 and p are defined as in formula (I), G1, G2 and G3 are N, R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH-, N -NH (Rb B SO )2N-SO2-NH-, 2 - or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in10 =CR3-, -S-(CR3R4)n-O-, -S-(CR3R4)-C(O)- or - O-(CR3R4)j-, wherein R3, R4, j, k and n are defined as in formula (I) and LG2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro) may be prepared as illustrated in Scheme TA1. Scheme TA1 LG2 LG2 LG2 Step 1 Step 2a or 2b N or 2 formu for tloas LG2 mulas (XV) 5 I) (XV R )p (VIII) (XI I) 15 (XXIII) (XXIV) Step 1: A strong base such as for example NaH is added to a one o f the compounds of formula (VIII) to (XII), defined as above, dissolved in an inert organic solvent such as THF, 2- MeTHF or 1,4-dioxane at ambient temperature. The mixture is left for about 1 h at ambient temperature before it is added to a solution (typically in the same solvent as above) of a 20 compound of formula (XXIII), in which LG2 is a suitable leaving group such as halide or triflate (OTf) (preferentially chloro). The mixture is heated, typically to a temperature in the range of 50oC to 70oC for a prolonged reaction time to generate a compound of formula (XXIV) in which 82 201388-PCT01-NP R2 and LG2 are defined as above. The reaction is preferentially performed under an inert atmosphere (e.g. an N2 atmosphere). Step 2a: A strong base such as for example NaH is added to a compound of formula (XV) defined as above, dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane 5 typically at 0oC. The mixture is left for about 1 h at ambient temperature before it is added to a cold solution (e.g.0oC, typically in the same solvent as above) of a compound of formula (XXIV) in which R2 and LG2 are defined as above. This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of formula (XXV). Alternatively, the reaction may also be carried out in an inert organic solvent such as 1,4- 10 dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3. The reaction is typically carried out at temperatures ranging from 20oC to 100oC for a prolonged reaction time using standard equipment or a single node microwave reactor. Optionally, the reaction may also be performed with the presence of water. Step 2b: A strong base such as for example NaH is added to a compound of formula15 (XVI), defined as above, dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4- dioxane typically at 0oC. The mixture is left for about 1 h at ambient temperature before it is added to a cold solution (e.g.0oC, typically in the same solvent as above) of a compound of formula (XXIV) in which R2 and LG2 are defined as above. This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of 20 formula (XXV). Certain compounds of formula (IV) (e.g. formula (XXIX)) in which X, R5 and p are defined as in formula (I), G1 is CH, G2 and G3 are N, R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH-, N -NH- (Rb B SO ) N-SO -NH- 2 or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in =CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)-, 25 wherein R3, R4, k and n are defined as in formula (I) and LG2 is a suitable leaving group such as chloro may be prepared as illustrated in Scheme TA2. Scheme TA2 83 201388-PCT01-NP OH OH LG2 Step 1 Step 2 N N N )p R5)p ula (I), L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I) can be obtained by reacting a compound of formula 5 (XXVI) with a compound of formula (III) defined as above. The reaction is carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc. Typically, the reaction is carried out in a temperature range of 20oC to 60oC for a prolonged reaction time. Optionally, the reaction may also be performed under an inert atmosphere (e.g. an N2 atmosphere). 10 Step 2: A compound of formula (XXVIII) wherein X, R5 and p are defined as in formula (I), L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)-, in which R3, R4, k and n are defined as in formula (I) and LG2 is chloro can be obtained from a compound of formula (XXVII) defined as above. The reaction is carried out with a chlorinating agent such as POCl3, preferentially in the presence of an additive such as Et4NCl, neat or in the presence of 15 an inert organic solvent such as PrCN at elevated temperatures (e.g. reflux) for a prolonged reaction time. Alternatively the reaction is carried out in a mixture of POCl3 and N,N- diethylaniline at reflux temperature for a prolonged reaction time. Step 3: A compound of formula (XXIX) defined as above can be obtained by reacting a compound of formula (XXVIII) defined as above with one of the compounds (one at a time) of 20 formula (VIII) to (XII) as defined above. The reaction may be performed in an inert organic 84 201388-PCT01-NP solvent such as DMF or DMSO in the presence of a suitable base such as NaH, (typically 1.5–2 eq) at elevated temperatures for a prolonged reaction time. Alternatively, the reaction may be catalyzed with a suitable palladium reagent (e.g. Pd2(dba)3) in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or 5 K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node microwave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). Certain compounds of formula (VII) (e.g. formula (XXXI)) in which R1, R5, R11, X and p10 are defined as in formula (I), G1, G2 and G3 are N, Z is -NH-, L is -S-(CR3R4)k-, -S-(CR3R4)k- CR3=CR3-, -S-(CR3R4)n-O-, -S-(CR3R4)-C(O)- or -O-(CR3R4)j-, wherein R3, R4, j, k and n are defined as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared by method c or d as illustrated in Scheme TA3. 15 Scheme TA3 HS L1 X (R5)p (XV) R1 1 2 R LG OH OH 5 )p ( ) 2 V) I) LG 5 step 1 )p step 2 85 201388-PCT01-NP Method c): A solution of a compound of formula (XXIII) defined as above and formula (XV) defined as above in a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is pre-cooled to about 0oC (ice/bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, preferentially THF is added slowly (typically during 30 5 min) to the reaction mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h). Optionally, an additional amount of DIPEA is added before addition of a compound of formula (V) defined as above in an organic solvent, preferentially THF, and the reaction mixture is stirred at about 0oC for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula (XXXI) (for S-containing L). The reaction is 10 preferentially performed under an inert atmosphere (e.g. an N2 atmosphere). Method d) step 1: A compound of formula (XXX) wherein , R5, X and p are defined as in formula (I) and L is -O-(CR3R4)j-, wherein R3, R4 and j are defined as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXIII) defined as above with a 15 compound of formula (XVI) defined as above. The reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a strong base such as NaH. The reaction is preferentially carried out in an inert atmosphere (e.g. an N2-atmosphere) at temperatures ranging typically from 0oC to rt for a prolonged reaction time (typically 2-16 h). Method d) step 2: A compound of formula (XXXI) in which R1, R5, R11, X and p are 20 defined as in formula (I), L is -O-(CR3R4)j-, wherein R3, R4 and j are defined as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXX) with a compound of formula (V) defined as above. The reaction is carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as for 25 example DIPEA, TEA, K2CO3 (preferentially DIPEA). The reaction is generally carried out at temperatures ranging from 0oC to 40oC for a prolonged reaction time until the reaction is complete (for O-containing L). Certain compounds of formula (VII) (e.g. formula (XXXV)) in which R1, R5, R11, X and p are defined as in formula (I), G1 and G3 are N, G2 is CH, Z is -NH-, L is -S-(CR3R4)k-, -S- 30 (CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined 86 201388-PCT01-NP as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared as illustrated in Scheme TA4. Scheme TA4 LG2 1 1 R1 R R OH OH OH N H2N (V) Z Z R11 HS L1 X (R5 XV R11 R5)p 5 Step 1: A compound of formula (XXXIII) wherein R1 and R11 are defined as in formula (I), Z is -NH- and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be formed by reaction of a compound of formula (XXXII) in which LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) with a compound of formula (V) defined as above. The reaction is 10 typically carried out in an inert organic solvent such as THF, 1,4-dioxane or IPA in the presence of a suitable base such as TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on). A regioisomer (e.g. formula (XXXIV)) is also formed in the reaction which is readily separated by standard methods. Step 2: A compound of formula (XXXV) defined as above may be formed by reaction of 15 a compound of formula (XXXIII) defined as above with a compound of formula (XV) defined as above. The reaction is typically carried out in an inert organic solvent such as THF, 1,4- dioxane, MeOH or IPA in the presence of a suitable base such as K2CO3, Cs2CO3, TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on). 20 Certain compounds of formula (VII) (e.g. formula (XXXVI)) in which R1, R5, R11, X and p are defined as in formula (I), G1 and G2 are N, G3 is CH, Z is -NH-, L is -S-(CR3R4)k-, -S- (CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined 87 201388-PCT01-NP as in formula (I) and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared as illustrated in Scheme TA5. Scheme TA5 R1 R1 OH OH Z Z 5 )p 5 Step 1: A compound of formula (XXXVI) defined as above may be formed by reaction of a compound of formula (XXXIV) wherein R1 and R11 are defined as in formula (I), Z is -NH- and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) with a compound of formula (XV) defined as above. The reaction is typically carried out in an inert organic solvent such as THF, 1,4-dioxane, MeOH or IPA in the presence of a suitable base such 10 as K2CO3, Cs2CO3, TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on). Certain compounds of formula (VII) (e.g. formula (XXXVII)) in which R1, R5, R11, X and p are defined as in formula (I), G2 and G3 are N, G1 is CH, Z is -NH-, L is -S-(CR3R4)k-, -S- (CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined 15 as in formula (I) and LG2 is a suitable leaving group such as chloro may be prepared as illustrated in Scheme TA6. Scheme TA6 R1 R1 LG2 OH 5)p 201388-PCT01-NP Step 1: A compound of formula (XXXVII) defined as above may be formed by reaction of a compound of formula (XXVIII) defined as above with a compound of formula (V) defined as above. The reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as for example DIPEA, TEA, K2CO3 or 5 NaHCO3. The reaction is generally carried out at temperatures ranging from 20oC to reflux for a prolonged reaction time until the reaction is complete. Certain compounds of formula (VII) (e.g. formula (XLIII)) in which R1, R5, R11, X and p are defined as in formula (I), G1, G2 and G3 are N, Z is -NH, L is –(CH2)j-CR3R4-, -(CR3R4)m- 10 CR3=CR3-, -CR3aR4a-CR3R4-, -(CR3R4)n-S-, -(CR3R4)n-O- or –(CH2)-NR3- in which R3, R4, R3a, R4a, j, m and n are defined as in formula (I) and LG2 is a suitable leaving group such as chloro may be prepared as illustrated in Scheme TA7. Scheme TA7 89 201388-PCT01-NP O method e1 or e2 HN Step 3 5 HN N NC L X (R )p L X (R5)p H N R5 2 )p (XXXVIII) method f method f Step 1 HN L X (R5 Step 2 )p Step 4 R5)p R5)p et od e : compound o ormu a ( ) may be prepared by addng a compound of formula (XXXVIII) wherein R5, X, p and L are defined as above to a mixture of AlMe3 and NH4Cl in an inert solvent, typically toluene, at temperatures ranging from 70°C to 90°C for 5 prolonged reaction times until the reaction is complete. Method e2: A compound of formula (XXXIX) may be prepared by reacting a compound of formula (XXXVIII) wherein R5, X, p and L are defined as above, with NaOtBu in MeOH at elevated temperature (e.g.100°C) for a prolonged reaction time (e.g.15 min) followed by addition of an ammonium salt such as ammonium chloride and continued heating at 80°C for a 10 prolonged reaction time until the reaction is complete. Method f step 1: A compound of formula (XL) wherein R5, X, p and L are defined as above, may be prepared by adding AcCl to a cold solution of a compound of formula 90 201388-PCT01-NP (XXXVIII) defined as above in EtOH and allowing the temperature to reach rt during a prolonged time, typically 15 h to 24 h. Method f Step 2: A compound of formula (XXXIX) may be prepared by adding a cold solution of NH3 in a solvent such as EtOH or MeOH, to a compound of formula (XL) and 5 allowing the temperature to reach rt during a prolonged time, typically on. Step 3: A compound of formula (XLI) wherein R5, X, p and L are defined as above may be prepared by reaction of a compound of formula (XXXIX) with diphenyl iminodicarboxylate in a suitable solvent, typically MeCN, in the presence of a base such as K2CO3, at temperatures ranging from rt to 70°C for a prolonged time, e.g.2 h to 24 h, until the reaction is complete. 10 Step 4: A compound of formula (XLII) wherein R5, X, p, L and LG2 are defined as above may be prepared by reaction of a compound of formula (XLI) defined as above with a suitable chlorinating reagent, typically POCl3 in excess, with or without an amine base such as N,N- diethylaniline as an additive, at elevated temperatures ranging from 70°C to reflux for a prolonged reaction time, typically 1 h to 15 h, until the reaction is complete. 15 Step 5: A compound of formula (XLIII) wherein R1, R11, R5, X, L, Z and LG2 are defined as above may be prepared by reaction of a compound of formula (XLII) defined as above with a compound of formula (V) defined as above. The reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures 20 ranging typically from 20oC to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor. Certain compounds of formula (VII) (e.g. formula (XLVI)) in which R1, R5, R11, X and p are defined as in formula (I), G1 is CH, G2 and G3 are N, Z is -NH, L is –(CH2)j-CR3R4-, - (CR3R4)m-CR3=CR3-, -CR3aR4a-CR3R4-, -(CR3R4)n-S-, -(CR3R4)n-O- or –(CH2)-NR3- in which 25 R3, R4, R3a, R4a, j, m and n are defined as in formula (I) and LG2 is a suitable leaving group such as chloro may be prepared as illustrated in Scheme TA8. Scheme TA8 91 201388-PCT01-NP O LG2 HN S Step 2 (R5 tep 1 N L X N )p 5)p R5)p Step 1: A compound of formula (XLIV) wherein R5, X, p and L are defined as above may be prepared by reaction of a compound of formula (XXXIX) defined as above with diethylmalonate in a suitable solvent, typically EtOH, in the presence of a base such as tert- 5 BuONa, at reflux temperatures for a prolonged time until the reaction is complete. Step 2: A compound of formula (XLV) wherein R5, X, p and L and LG2 are defined as above may be prepared by reaction of a compound of formula (XLIV) defined as above with a suitable chlorinating reagent, typically POCl3 in excess, with or without an amine base such as N,N-diethylaniline as an additive, at elevated temperatures typically at reflux for a prolonged 10 reaction time until the reaction is complete. Step 3: A compound of formula (XLVI) wherein R1, R11, R5, X, L, Z and LG2 are defined as above may be prepared by reaction of a compound of formula (XLV) defined as above with a compound of formula (V) defined as above. The reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as 15 DIPEA, TEA, NaHCO3 or K2CO3 (typically 1-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor. 92 201388-PCT01-NP Certain compounds of formula (XIV) (e.g. formula (XLVII)) in which R1 and R11 are defined as in formula (I), G1, G2 and G3 are N, Z is -NH-, R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH- , (Rb B N SO )2N-SO2-NH-, 2 -NH- or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in ch as halide, mesylate (OMs) or triflate (OTf) 5 (preferentially chloro) may be prepared as illustrated in Scheme TA9. Scheme TA9 R1 R1 LG2 OH OH Z 2 Step 1: Reacting a compound of formula (XXIV) defined as above with a compound of formula (V) defined as above. The reaction is carried out in an inert organic solvent such as 1,4- 10 dioxane, THF, MeOH, EtOH, MeCN or mixtures thereof in the presence of a suitable base such as DIPEA, TEA, NaHCO3 or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to 80oC for a prolonged reaction time (2-48 h) using standard equipment or a single node microwave reactor. Formula (V) is normally used in a slight excess (typically 1.2-3 eq) to formula (XXIV). 15 Certain compounds of formula (XVIII) (e.g. formula (LIII)) in which R1, R5, R11, X and p are defined as in formula (I), G1 is CH, G2 and G3 are N, Z is -NH-, L is -S-(CR3R4)k-, -S- (CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined e TA10. Scheme TA10 93 201388-PCT01-NP R1 R1 R 1 OH Cl Z OH H2 N OH (V) 11 Z N 11 N R HS L1 X (R5)p (XV) R 11 R5)p (R5)p d Z is -NH- may be prepared by reaction of a compound of formula (XLVIII) with a compound of formula (V) defined as above. The reaction is typically carried out in an inert organic solvent 5 such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as DIPEA or TEA (typically 1-5 eq). The reaction is typically carried out at reflux temperatures for a prolonged reaction time (e.g. on) until the reaction is complete. Step 2: A compound of formula (L) wherein R1, R5, R11, X and p are defined as in formula (I), Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S- 10 (CR3R4)-C(O)- wherein reaction of a compound of formula (XLIX) with a compound of formula (XV) defined as above. The reaction is typically carried out in an inert organic solvent such as THF in the presence of a suitable base such as DIPEA or TEA. The reaction is typically performed using a single node microwave reactor at elevated temperatures (e.g.150oC) for a prolonged reaction time until the 15 reaction is complete (e.g.1-5 h). Step 3: A compound of formula (LI) wherein R1, R5, R11, X and p are defined as in formula (I), Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S- (CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I), may be prepared by ester hydrolysis of the compound of formula (L) as defined above using standard conditions such as 94 201388-PCT01-NP by a base (e.g. NaOH or KOH) in a mixture of THF or 1,4-dioxane, water and MeOH at rt for a prolonged reaction time until the reaction is complete. Step 4: A compound of formula (LII) wherein R1, R5, R11, X and p are defined as in formula (I), Z is -NH- and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S- 5 (CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I), may be prepared by reaction of a compound of formula (LI) defined as above with ammonia or an ammonium salt (e.g. NH4Cl). The reaction may be performed using suitable coupling reagents such as TBTU, HATU, HOBt/EDC or T3P, in the presence of a base, typically an organic base, such as DIPEA or TEA, using a solvent such as DMF or MeCN, or mixtures thereof, and at rt until the reaction 10 is complete. Step 5: A compound of formula (LIII) defined as above may be formed by treatment of a compound of formula (LII) with a reducing agent such as BH3xTHF or BH3xDMS. The reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane at rt for a prolonged reaction time (typically on) until the reaction is complete. 15 Certain compounds of formula (XX) (e.g. formula (LVII)) in which R1 and R11 are defined as in formula (I), G1, G2 and G3 are N, Z is -NH-, R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH- b B N SO 2 -NH- , (R )2N-SO2-NH-, or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in hod g to i in Scheme TA11. Scheme TA11 95 201388-PCT01-NP SH LG2 LG2 MeO LG2 (LIV) N N SH OMe formula (LIV) dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane typically at 0oC. The mixture is left for about 1 h at ambient temperature before it is added to a 5 cold solution (e.g.0oC, typically in the same solvent as above) of a compound of formula (XXIV) in which R2 and LG2 are defined as above. This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of formula (LV). Alternatively, the reaction may also be carried out in an inert organic solvent such as 1,4- dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or 10 NaHCO3. The reaction is carried out at temperatures ranging typically from 20oC to 100oC for a prolonged reaction time using standard equipment or a single node microwave reactor. Optionally, the reaction may also be performed with the presence of water. Method g step 2: Reacting the compound of formula (LV) wherein R2 and LG2 are defined as above with a compound of formula (V) defined as above to generate a compound of 15 formula (LVII) wherein R1, R2, R11 and Z are defined as above. The reaction is typically carried out in an inert organic solvent such as MeCN, THF or 1,4-dioxane in the presence of a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to reflux for a prolonged reaction time using standard equipment or a single node microwave reactor. Formula (V) is normally used in a slight excess 20 (typically 1.2-5 eq) to formula (LV). 96 201388-PCT01-NP Method h step 1: Reacting the compound of formula (XLVII) defined as above with a compound of formula (LIV) to generate a compound of formula (LVII). The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeCN or MeOH in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3. The reaction is carried out at 5 temperatures ranging typically from 20oC to 100oC for a prolonged reaction time using standard equipment or a single node microwave reactor. Optionally, the reaction may also be performed with the presence of water. Method i step 1: A solution of a compound of formula (XXIII) defined as above and formula (LIV) in a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is 10 pre-cooled to about 0oC (ice/bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, preferentially THF is added slowly (typically during 30 min) to the reaction mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h). Optionally, an additional amount of DIPEA is added before addition of a compound of formula (V) in an inert organic solvent, preferentially THF, and the reaction mixture is stirred at about 15 0oC for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula (LVI) wherein R1, R11, Z and LG2 are defined as above. The reaction is preferentially performed under an inert atmosphere (e.g. an N2 atmosphere). Method i step 2: Reacting the compound of formula (LVI) with one of the compounds (one at a time) of formula (VIII) to (XII), defined as above to give a compound of formula 20 (LVII) defined as above. The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node micro wave reactor. The reaction is preferentially conducted 25 under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). Alternatively the reaction may also be performed without a metal catalyst in an inert organic solvent such as DMF or DMSO in the presence of a base such as K2CO3 or Na2CO3 (typically 1.5–2 eq) at elevated temperatures (e.g.90oC) for a prolonged reaction time. Formulas 30 (VIII) to (XII) is typically used in a slight excess to formula (LVI) (e.g.1.1-8 eq). 97 201388-PCT01-NP Certain compounds of formula (XX) (e.g. formula (LIX)) in which R1 and R11 are defined as in formula (I), G1 and G3 are N, G2 is CH, Z is -NH-, R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH-, N SO -NH- (Rb B )2N-SO2-NH-, 2 or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in heme TA12. 5 Scheme TA12 R1 1 R1 SH R O formulas OH Z H OH MeO Z Z to R11 11 (VIII) (XII R11 LIV R ) N OMe p mula (I), Z is -NH- and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared by reacting a compound of formula (XXXIII) 10 defined as above with a compound of formula (LIV). The reaction is typically carried out in an inert organic solvent such as THF, 1,4-dioxane, MeOH or IPA in the presence of a suitable base such as K2CO3, Cs2CO3, TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on). Method k step 1: A compound of formula (LX) wherein LG2 is a suitable leaving group 15 such as halide, mesylate (OMs) or triflate (OTf) (preferentially chloro) may be prepared by reacting a compound of formula (XXXII) defined as above with a compound of formula (LIV). The reaction is typically carried out in an inert organic solvent such as THF or 1,4-dioxane in the presence of a suitable base such as DIPEA or TEA. The reaction is carried out at temperatures ranging typically from 0oC to rt for a prolonged reaction time until the reaction is complete. 98 201388-PCT01-NP Method k step 2: A compound of formula (LVIII) defined as above may be formed by reaction a compound of formula (LX) with a compound of formula (V) defined as above. The reaction is typically carried out in an inert organic solvent such as THF, 1,4-dioxane or IPA in the presence of a suitable base such as TEA or DIPEA at temperatures ranging typically from rt 5 to reflux for a prolonged reaction time (typically on) using standard equipment or a single node microwave reactor. Step 3: A compound of formula (LIX) defined as above may be formed by reaction a compound of formula (LVIII) with one of the compounds (one at a time) of formulas (VIII) to (XII) defined as above. The reaction may be catalyzed with a suitable palladium reagent, e.g. 10 Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node micro wave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 15 h). Formulas (VIII) to (XII) is typically used in a slight excess to formula (LVIII) (e.g.1.1-8 eq). Certain compounds of formula (XX) (e.g. formula (LXII)) in which R1 and R11 are defined as in formula (I), G1 and G2 are N, G3 is CH, Z is -NH-, R2 is Ra-S(=NH)(O)-NH-, Ra- B N SO -NH- SO2-NH- (Rb)2N-SO2-NH- 2 or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are 20 Scheme TA13. Scheme TA13 R SH R1 R1 1 formula OH Z OH Z OH s Z OMe Step 1: A compound of formula (LXI) wherein R1 and R11 is defined as in formula (I), Z is -NH- and LG2 is a suitable leaving group such as halide, mesylate (OMs) or triflate (OTf) 25 (preferentially chloro) may be prepared by reacting a compound of formula (XXXIV) defined as above with a compound of formula (LIV). The reaction is typically carried out in an inert 99 201388-PCT01-NP organic solvent such as THF, 1,4-dioxane, MeOH or IPA in the presence of a suitable base such as K2CO3, Cs2CO3, TEA or DIPEA at temperatures ranging typically from rt to reflux for a prolonged reaction time (typically on). Step 2: A compound of formula (LXII) defined as above may be formed by reaction a 5 compound of formula (LXI) with one of the compounds (one at a time) of formulas (VIII) to (XII) defined as above. The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using 10 standard equipment or a single node micro wave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). Formulas (VIII) to (XII) is typically used in a slight excess to formula (LXI) (e.g.1.1-8 eq). Certain compounds of formula (XX) (e.g. formula (LXVII)) in which R1 and R11 are defined as in formula (I), G1 is CH, G2 and G3are N, Z is -NH-, R2 is Ra-S(=NH)(O)-NH-, Ra- N -N 15 SO2-NH-, (Rb B SO )2N-SO2-NH-, 2 H- or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are Scheme TA14. Scheme TA14 LG3 OH MeO OH LG2 OMe OMe 201388-PCT01-NP Step 1: A compound of formula (LXIV) can be obtained by reacting a compound of formula (XXVI) with a compound of formula (LXIII). The reaction is carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc. Typically, the reaction is carried out in a temperature 5 range of 20oC to 60oC for a prolonged reaction time. Optionally, the reaction may also be performed under an inert atmosphere (e.g. an N2 atmosphere). Step 2: A compound of formula (LXV) wherein LG2 is chloro can be obtained from a compound of formula (LXIV). The reaction is carried out with a chlorinating agent such as POCl3, preferentially in the presence of an additive such as Et4NCl, neat or in the presence of an 10 inert organic solvent such as PrCN at elevated temperatures (e.g. reflux) for a prolonged reaction time. Alternatively the reaction is carried out in a mixture of POCl3 and N,N-diethylaniline at reflux temperature for a prolonged reaction time. Step 3: A compound of formula (LXVI) in which R2 is Ra-S(=NH)(O)-NH-, Ra-SO2-NH- , (Rb B N SO )2N-SO2-NH-, 2 -NH- or Rc-S(O)-NH- wherein Ra, Rb, Rc and B are defined as in 15 y reacting a compound of formula (LXV) defined as above with one of the compounds (one at a time) of formula (VIII) to (XII) as defined above. The reaction may be performed in an inert organic solvent such as DMF or DMSO in the presence of a suitable base such as NaH, (typically 1.5–2 eq) at elevated temperatures for a prolonged reaction time. Alternatively, the reaction may be catalyzed with a suitable palladium 20 reagent (e.g. Pd2(dba)3) in combination with a phosphine ligand, typically X-Phos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node microwave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 25 h). Step 4: A compound of formula (LXVII) defined as above may be obtained by reacting a compound of formula (LXVI) defined as above with a compound of formula (V) defined as above. The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH, nBuOH or mixtures thereof in the presence of a suitable base such as DIPEA, 101 201388-PCT01-NP TEA or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to 120oC for a prolonged reaction time (2-120 h) using standard equipment or a single node microwave reactor. Formula (V) is normally used in a slight excess (typically 1.2-5 eq) to formula (LXVI). 5 Certain compounds of formula (XV) defined as above may be prepared as illustrated in Scheme TA15. Scheme TA15 O 1 1 Step 1 Step 2 LG L X (R5)p S L1 X (R5 )p HS L1 X (R5 )p (III) (XV) Step 1: The compounds of formula (LXVIII) in which R5, X and p are defined as in 10 formula (I) and L1 is -(CR3R4)k-, -(CR3R4)k-CR3=CR3-, -(CR3R4)n-O- or -(CR3R4)-C(O)- wherein R3 R4 k d d fi d i f l I b d b i ompound of formula (III) defined as above with CH3COSH in the presence of a base such as for example DIPEA, TEA, K2CO3. The reaction is typically carried out in an inert organic solvent such as THF, 2-MeTHF, DMF, MeCN, or EtOH at temperatures typically ranging from ambient 15 temperature to 60oC and for a prolonged reaction time. Step 2: The compounds of formula (XV) defined as above are prepared by hydrolysis of a compound of formula (LXVIII) with a suitable base such as NaOH, KOH, K2CO3 in an organic solvent such as MeOH, EtOH, THF or 1,4-dioxane. Optionally, the reaction may also be performed with the presence of water.Certain compounds of formula (I) wherein R1, R5, X and p20 are defined as in formula (I), R11 is H, Z is CH2, L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S- (CR3R4)n-O- or -S-(CR3R4)-C(O)- wherein R3, R4, k and n are defined as in formula (I) and R2 is a a b B N SO2 -NH- R = H H R H R H Rc NH- wherein Ra, e TA16. Scheme TA 16 102 201388-PCT01-NP R1 R1 S OH LG1 L1 X 5 OH R1 HO (R )p MeCOOtBu O O H2N NH2 N (III) N (R5)p R5)p e obtained by reaction of a compound of formula (LXIX) with tert-butyl acetate using a strong base such as LDA (for the generation of the enolate of tert-butyl acetate) in an inert organic 5 solvent such as THF or 1,4-dioxane. The reaction is typically carried out at lower temperatures (e.g. -78oC) for a prolonged reaction time until the reaction is complete Step 2: A compound of formula (LXXI) wherein R1 is defined as in formula (I) can be obtained by reaction of a compound of formula (LXX) with thiourea. The reaction is typically carried out in an inert organic solvent such as EtOH in the presence of water and a base such as 10 KOH or NaOH at elevated temperatures (e.g.125oC) in a single node microwave reactor Step 3: A compound of formula (LXXII) wherein R1, R5, X and p are defined as in formula (I) and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)- C(O)- w f a compound of formula (LXXI) with a compound of formula (III) defined as above. The reaction 15 is typically carried out in an inert solvent such as MeCN, MeOH, EtOH or water or a mixture thereof in the presence of a suitable base such as for example NaOH or NaOAc. Typically, the reaction is carried out in a temperature range of 20oC to 60oC for a prolonged reaction time. Optionally, the reaction may also be performed under an inert atmosphere (e.g. an N2 atmosphere Step 4: A compound of formula (LXXIII) wherein R1, R5, X and p are defined as in20 formula (I) and L is -S-(CR3R4)k-, -S-(CR3R4)k-CR3=CR3-, -S-(CR3R4)n-O- or -S-(CR3R4)- 103 201388-PCT01-NP C(O)- wherein R3, R4, k and n are defined as in formula (I) can be obtained by reaction of a compound of formula (LXXII) with MsCl or Ms2O in the presence of a suitable base such as DIPEA, TEA or pyridine. The reaction is performed in an inert organic solvent such as DCM, THF or 1,4-dioxane (preferentially DCM) at ambient temperature for a prolonged reaction time 5 (typically 1-12 h). Step 5: A compound of formula (LXXIV) defined as above can be obtained by reaction of a compound of formula (LXXIII) with one of the compounds (one at a time) of formula (VIII) to (XII) defined as above. The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in combination with a suitable phosphine ligand, typically X-Phos or 10 XantPhos in the presence of a base, such as Cs2CO3 or K2CO3 (typically 1.5–3 eq), in an inert organic solvent, such as DMF, DMSO, 1,4-dioxane or THF, at temperatures ranging from 20oC to 120oC using standard equipment or a single node micro wave reactor. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). 15 Where necessary converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof, and where desired separating the resultant compound of formula (I) into its individual diastereoisomers or enantiomers using chiral resolving agents described in the literature and known to person skilled in the art, or using chiral chromatography methods described in the literature and known to person skilled in the art, or as described further 20 in the Examples. It is understood that the processes for preparation described above also can be performed starting from any enantiomer, or a racemic mixture, of compounds of formula (II) to formula (XXII), formula (XXIV) to formula (XXV), formula (XXVII) to formula (XXXI), formula (XXXIII) to formula (XLVII), formula (XLIX) to formula (LIII), formula (LV) to formula 25 (LIX), formula (LXI) to formula (LXII) and formula (LXVI) to formula (LXXIV), to give compounds of formula (I) or any stereoisomer of formula (I). It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive or reactive groups, that otherwise could interfere in the reaction, in the compounds. The instances where protection is necessary or desirable, suitable 30 methods for protection are known to those skilled in the art. Conventional protecting groups may 104 201388-PCT01-NP be used in accordance with standard practice (for illustration see “Protective groups in Organic Chemistry”, edited by J W F McOmie, 1Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4th edition, T.W. Greene & P.G.M Wutz, Wiley-Interscience (2007)). Thus, if reactants include groups such as amino, thiol, carboxy or hydroxy it may be desirable to protect 5 the group in some of the reactions mentioned herein. Suitable protecting groups for hydroxy include trialkyl silyl or diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl ethers). Suitable protecting groups for carboxylic acids include (C1-C6)alkyl or benzyl esters. Suitable protecting groups for amino include tert-butyloxycarbonyl, benzyloxycarbonyl, and 9-fluorenylmethoxycrbonyl and 10 trialkyl silyl groups (e.g. tert-butyldimethylsilyl and trimethylsilyl groups). Suitable protecting groups for thiols include acetyl and 4-methoxy benzyl groups. The protecting groups may be removed and/or introduced at any convenient stage in the synthesis using conventional techniques well known in the chemical art. It will be appreciated by those skilled in the art how a compound comprising such a group can be deprotected (see 15 “Protective groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4rd edition, T.W. Greene & P.G.M Wutz, Wiley- Interscience (2007)). Persons skilled in the art will appreciate that certain compounds of formula (II) to formula (XXII), formula (XXIV) to formula (XXV), formula (XXVII) to formula (XXXI), 20 formula (XXXIII) to formula (XLVII), formula (XLIX) to formula (LIII), formula (LV) to formula (LIX), formula (LXI) to formula (LXII) and formula (LXVI) to formula (LXXIV) described above may also be referred to as being “protected derivatives“ Persons skilled in the art will appreciate that in order to obtain compounds of the invention in an alternative, and on some occasions, more convenient, manner, the individual 25 process steps mentioned hereinbefore may be performed in different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This may negate, or render necessary, the need for protecting groups. 105 201388-PCT01-NP Persons skilled in the art will appreciate that chiral isomers of compounds herein can be resolved at any stage in the synthetic process using chiral resolving agents described in the literature and known to person skilled in the art, or using chiral chromatography methods described in the literature and known to person skilled in the art, or as described further in the 5 Examples. Persons skilled in the art will appreciate that a -C=O, -CHO or C-OH group can be transferred into a -CF2, -CF2H or C-F respectively using a deoxofluorinating agent such as for example DAST (N,N-diethyl-1,1,1-trifluoro-λ4-sulfanamine), deoxo-fluor reagent (e.g.1,1,1- trifluoro-N,N-bis(2-methoxyethyl)-λ4-sulfanamine), XtalFluor-E or XtalFluor-M (See J. Org. 10 Chem.2010, 75, 3401). Persons skilled in the art will appreciate that starting materials for any of the above processes can in some cases be commercially available. Persons skilled in the art will appreciate that processes could for some starting materials above be found in the general common knowledge. 15 It will also be understood that some of the compounds described in the processes above may exhibit the phenomenon of tautomerism and the processes described above includes any tautomeric form. All novel intermediates form further embodiements disclosed herein. 20 Intermediate 1 (R)-2-((4-Chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)pentan-1-ol 6 201388-PCT01-NP DIPEA (2.2 mL, 12.64 mmol) was added to 2,4,6-trichloro-1,3,5-triazine (1.554 g, 8.43 mmol) in THF (dry, 35 mL) at 0°C and under an atmosphere of N2(g). A solution of (2,3- difluorophenyl)methanethiol (1.35 g, 8.43 mmol) in dry THF (10 mL) was added dropwise over 40 min at 0oC and the reaction mixture was stirred at 0°C for 1 h. DIPEA (2.2 mL, 12.64 mmol) 5 was added, and then a solution of (R)-2-aminopentan-1-ol (0.869 g, 8.43 mmol) in dry THF (10 mL) was added over 10 min. The reaction mixture was stirred at 0°C for 1.5 h and then concentrated under reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 5–80% EtOAc in heptane) and then by straight phase flash chromatography on silica (gradient: 1–12% MeCN in DCM) to give the title compound (1.57 g, 10 50%); MS (ESI) m/z [M+H]+ 375. Intermediate 2 (2R)-2-((4-Chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol - eny e ane-1-thiol (492 mg, 3.56 mmol) was added to a solution of 2,4,6-trichloro- 15 1,3,5-triazine (657 mg, 3.56 mmol) in dry THF (20 mL) at 0°C under an atmosphere of N2(g). A solution of DIPEA (0.933 mL, 5.34 mmol) in THF (10 mL) was added over 30 min at 0°C and the reaction mixture was stirred at 0°C for 1 h. DIPEA (0.933 mL, 5.34 mmol) was added, and then a solution of (R)-2-amino-4-methylpentan-1-ol (418 mg, 3.56 mmol) in dry THF (10 mL) was added over 20 min. The reaction mixture was stirred at 0°C for 1.5 h and then concentrated 20 under reduced pressure. The crude residue was purified by preparative TLC (MeCN:water, 9:1) to give the title compound (1.00 g, 77 %); MS (ESI) m/z [M+H]+ 367. Intermediate 3 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide 107 201388-PCT01-NP -methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1- ol 5 (4-Methoxyphenyl)methanethiol (4.61 g, 29.87 mmol) was added dropwise over 30 min to a solution of 2,4,6-trichloro-1,3,5-triazine (5.51 g, 29.87 mmol) and DIPEA (9.65 g, 74.67 mmol) in THF (200 mL) at 0°C and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 30 min and then (R)-2-amino-4-methylpentan-1-ol (3.5 g, 29.87 mmol) was added over 30 min at 0°C. The reaction mixture was stirred at 15°C for 2 h, filtered and the 10 filtrate was concentrated and diluted with EtOAc (350 mL). The organic layer was washed twice with water (200 mL), dried over Na2SO4, filtered, and concentrated at reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0–30% EtOAc in PE) to give the title compound (16.65 g); MS (ESI) m/z [M+H]+ 383. Step b) (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5- 15 triazin-2-yl)methanesulfonamide Methanesulfonamide (6.20 g, 65.22 mmol) was added to a mixture of (R)-2-((4-chloro-6- ((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 3 Step a (16.65 g, 43.48 mmol), Cs2CO3 (21.25 g, 65.22 mmol), Pd2(dba)3 (0.796 g, 0.87 mmol) and X- Phos (1.658 g, 3.48 mmol) in THF (400 mL) under an atmosphere of N2(g). The reaction mixture 108 201388-PCT01-NP was stirred at 55°C for 12 h. After cooling to rt, the mixture was partitioned between water (500 mL) and MTBE (200 mL). The layers were separated, and the organic layer was extracted three times with 0.09 M K2CO3 (aq). The combined aqueous layer was acidified with 12 N HCl (aq) and extracted twice with EtOAc (1 L). The combined organic layer was washed with water, 5 dried, filtered and concentrated at reduced pressure to give the title compound (18.48 g, 96%); MS (ESI) m/z [M+H]+ 442. Intermediate 4 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide H 10 n so e ( .43 g, 50.22 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 3 (18.48 g, 41.85 mmol) in TFA (160 mL) and the reaction mixture was stirred at 20°C for 4 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The 15 organic layer was extracted twice with sat NaHCO3 until slightly basic mixture was obtained. The combined aqueous layer was acidified with 12 N HCl to pH 4 and then extracted with EtOAc. NaCl was added to the aqueous layer which was extracted three times with EtOAc. The combined organic layer was evaporated at reduced pressure to give the title compound (16.05 g); MS (ESI) m/z [M+H]+ 322. 20 Intermediate 5 2-((2-Fluorophenyl)thio)propanimidamide NH 9 201388-PCT01-NP 2-((2-Fluorophenyl)thio)propanenitrile (695 mg, 3.83 mmol) was added to NaOtBu (388 mg, 3.83 mmol) in MeOH (15 mL) and the reaction mixture was stirred at 100°C for 15 min under an atmosphere of Ar(g). NH4Cl (370 mg, 6.8 mmol) was added, and the mixture was stirred at 80°C for 15 min under an atmosphere of Ar(g), and then filtered and concentrated 5 under reduced pressure. One more batch in equal scale was prepared as described above. The combined residues were stirred with IPA (20 mL) and acetone (5 mL), filtered and the filtrate was reduced to half of its volume. Et2O (20 mL) was added, and the mixture was stirred for 1 h. The precipitate was collected by filtration and dried. The filtrate was concentrated and dissolved in MeOH (18 mL). NaOtBu (300 mg) was added, and the mixture was stirred at 100oC for 15 10 min under an atmosphere of Ar(g). NH4Cl (320 mg) was added, and the mixture was stirred at 80oC for 15 min under an atmosphere of Ar(g). The reaction mixture was filtered and concentrated and the residue was worked up as described above. All precipitates were combined to give the title compound as a hydrochloride salt (729 mg, 41%); 1H NMR (400 MHz, DMSO- d6) δ 1.03 (2H, d), 1.46–1.6 (3H, m), 3.16 (1H, s), 4.23 (1H, q), 8.95 (2H, s), 9.16 (2H, s). 15 Intermediate 6 6-(1-((2-Fluorophenyl)thio)ethyl)-1,3,5-triazine-2,4(1H,3H)-dione O HN N F Diphenyl iminodicarbonate (795 mg, 3.09 mmol) was added to a suspension of K2CO3 (426 mg, 3.09 mmol) and 2-((2-fluorophenyl)thio)propanimidamide HCl Intermediate 5 (725 20 mg, 3.09 mmol) in MeCN (15 mL) under an atmosphere of Ar(g). The reaction mixture was stirred at rt for 1 h under an atmosphere of Ar(g). K2CO3 (426 mg, 3.09 mmol) was added, and the reaction mixture was stirred at 60°C for 2 h.1 M HCl (aq, 15 mL) and EtOAc (50 mL) were added, and the aqueous phase was collected and extracted with EtOAc (2×25 mL). The combined organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated 25 under reduced pressure. The crude solid was stirred in a mixture of PE/Et2O (2:1, 30 mL) for 10 min, filtered, and the solids were collected and dried in vacuo. The solids were suspended and 110 201388-PCT01-NP stirred in Et2O (10 mL) for 30 min and then collected by filtration to give the title compound (468 mg, 57%) as a solid; MS (ESI) m/z [M+H]+ 268. Intermediate 7 (2R)-2-((4-Chloro-6-(1-((2-fluorophenyl)thio)ethyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1- 5 ol -(1-((2-fluorophenyl)thio)ethyl)-1,3,5-triazine-2,4(1H,3H)-dione, Intermediate 6 (465 mg, 1.74 mmol) and POCl3 (3 mL, 32.19 mmol) was heated to reflux for 50 min. Chlorobenzene was added to the hot mixture, and the turbid solution was decanted and10 concentrated under reduce pressure. The residue was dissolved in THF (7 mL), (R)-2-amino-4- methylpentan-1-ol (0.6 mL, 4.69 mmol) was added in two equal portions followed by the portion-wise addition of K2CO3 (450 mg, 3.26 mmol), and the mixture was stirred at rt for 3 h. The mixture was partitioned between water and EtOAc. The aqueous layer was acidified until pH 4 with 10% citric acid (aq). The layers were separated, and the aqueous layer was extracted 15 with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude residue was purified by preparative HPLC, PrepMethod E, (gradient: 50–90%). The relevant fractions were combined, concentrated under reduced pressure to a small volume and extracted with DCM (3×30 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound (150 mg, 22%); MS 20 (ESI) m/z [M+H]+ 385. Intermediate 8 (R)-N-(4-Chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide 111 201388-PCT01-NP H Dichloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol H , , richloro-1,3,5-triazine (50.0 g, 271.1 mmol) was dissolved in 2-MeTHF (500 mL) 5 under an atmosphere of N2(g) and the stirred solution was cooled to -30ºC. A solution of (R)-2- amino-4-methylpentan-1-ol (31.1 g, 265.7 mmol) in 2-MeTHF (125 mL) was added dropwise during approximately 45 min. A solution of DIPEA (47.2 mL, 271.1 mmol) in 2-MeTHF (125 mL) was added at -30ºC during 70 min. The reaction mixture was allowed to reach -5ºC during 30 min and then filtered and used directly, without purification, as described below. 10 Step b) (R)-N-(4-Chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide DMA (875 mL) and K2CO3 (75.0 g, 542.4 mmol) were added to methanesulfonamide (77.0 g, 813.5 mmol) and the mixture was stirred at 50ºC for 10 min and then the filtered reaction solution from Intermediate 8 Step a) was added during 2 min. The reaction mixture 15 was stirred at 75ºC for 48 h and then allowed to reach rt. Water (1 L) was added and pH was adjusted to approximately 3 with the addition of 6 M HCl (aq). The two phases were separated, and the aqueous layer was extracted with 2-MeTHF (2×300 mL). The combined organic layer was washed with sat NH4Cl (aq) (2×500 mL) and concentrated in vacuo. The solid was dissolved in MTBE (250 mL) and the mixture was extracted with 5% K2CO3 (aq) (3×200 mL). The pH of 20 the aqueous layer was adjusted to approximately 4 by the addition of 6 M HCl (aq) and extracted with MTBE (2×250 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to give the title compound (57.4 g, 67%); MS (ESI) m/z [M+H]+ 324. 112 201388-PCT01-NP Intermediate 9 1,2-Difluoro-3-((2-methylallyl)oxy)benzene F F O of 2,3-difluorophenol (3.15 g, 24.21 mmol), 3-bromo-2-methylprop-1-ene (1.6 5 mL, 15.87 mmol), 3-chloro-2-methylprop-1-ene (1.553 mL, 15.86 mmol) and Cs2CO3 (11.83 g, 36.32 mmol) were dissolved in dry MeCN (30 mL). The mixture was stirred at 60ºC for 20 h. TBME (200 mL) and water (30 mL) were added. The phases were separated, and the aqueous phase was extracted with TBME (40 mL). The organic layer was washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated to give the title compound (4.305 g,10 97%); 1H NMR (400 MHz, CDCl3) δ 1.84 (s, 3H), 4.51 (s, 2H), 5.01 (s, 1H), 5.10 (s, 1H), 6.63– 6.85 (m, 2H), 6.88–7.05 (m, 1H). Intermediate 10 (R)-N-(1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4,6-dichloro-1,3,5-triazin-2-amine 15 tyldimethylsilyl)oxy)-4-methylpentan-2-amine tert-Butylchlorodimethylsilane (3.00 g, 19.90 mmol) was added to a solution of (R)-2- amino-4-methylpentan-1-ol (2.25 mL, 17.61 mmol) and imidazole (2.74 g, 40.25 mmol) in DCM (40 mL) and the reaction mixture was stirred for 3 h. The mixture was diluted with DCM (40 20 mL) and washed with water (2×40 mL) and brine. The mixture was dried over Na2SO4, filtered, and concentrated to give the title compound (4.24 g, 100%).1H NMR (500 MHz, CD3CN) δ 0.05 113 201388-PCT01-NP (6H, s), 0.85–0.91 (m, overlapping with traces of TBDMSCl), 1.07 (1H, ddd), 1.17 (1H, ddd), 1.66–1.77 (1H, m), 2.75 (1H, ddt), 3.29 (1H, dd), 3.48 (1H, dd). Step b) (R)-N-(1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4,6-dichloro-1,3,5-triazin- 2-amine 5 2,4,6-Trichloro-1,3,5-triazine (775 mg, 4.2 mmol) in THF (25 mL) was added over 45 min to (R)-1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-amine Intermediate 10 Step a) (926 mg, 4.0 mmol) and K2CO3 (552 mg, 4.00 mmol) in THF (25 mL) at -6°C under an atmosphere of Ar(g) and the reaction mixture was stirred at -6oC for 1h and then at rt for 16 h. The solids were removed by filtration, washed with THF and the combined filtrates were concentrated to give the 10 title compound (1.49 g, 98%). MS (ESI) m/z [M+H]+ 379. Intermediate 11 N-((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4-chloro-6-(1-(2- fluorophenyl)ethoxy)-1,3,5-triazin-2-amine 15 A solution of (R)-N-(1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4,6-dichloro- 1,3,5-triazin-2-amine, Intermediate 10 (759 mg, 2 mmol) in THF (3 mL) was added to a stirred mixture of NaH (60% in mineral oil) (160 mg, 4 mmol) and 1-(2-fluorophenyl)ethan-1-ol (280 mg, 2.0 mmol) in THF (3 mL) and the reaction mixture was stirred at rt for 15 min. NaH (60% in mineral oil) (160 mg, 4 mmol) was added and the reaction mixture was stirred at rt for another 50 20 min. NaOtBu (60 mg) was added and the reaction mixture was stirred for 2 h. A solution of HOAc (0.5 mL) in water (10 mL) was added and the mixture was extracted with cyclohexane. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC, PrepMethod G, (gradient: 50–95%) to give the title compound (169 mg, 17%); MS (ESI) m/z [M+H]+ 483. 114 201388-PCT01-NP Intermediate 12 N-(4-(((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(2- fluorophenyl)ethoxy)-1,3,5-triazin-2-yl)methanesulfonamide 5 )-1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4-chloro-6-(1- (2-fluorophenyl)ethoxy)-1,3,5-triazin-2-amine, Intermediate 11 (169 mg, 0.35 mmol), methanesulfonamide (67 mg, 0.7 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), X-Phos (20 mg, 0.04 mmol), Cs2CO3 (228 mg, 0.7 mmol) in THF (5 mL) was stirred at 65°C for 9 h under an atmosphere of Ar(g). AcOH (50 µL) was added, and the mixture was concentrated. The residue was suspended 10 in Et2O (15 mL), filtered through a pad of silica, and concentrated to give the title compound (205 mg). MS (ESI) m/z [M+H]+ 542. Intermediate 13 2-((2-Fluorophenyl)(methyl)amino)acetonitrile F N N 15 DIPEA (5.15 mL, 29.57 mmol) was added to 2-bromoacetonitrile (2 mL, 30.01 mmol) and 2-fluoro-N-methylaniline (3.70 g, 29.57 mmol) in NMP (degassed, 7.5 mL) under an atmosphere of Ar(g). The mixture was stirred at 150°C for 1 h. The mixture was partitioned between water and EtOAc. The aqueous layer was acidified to pH 4 and the layers were separated. The aqueous layer was extracted with EtOAc (×2), and the combined organic layer was washed with brine (×3), dried 20 over Na2SO4, filtered and concentrated to give the title compound (4.60 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.19–7.01 (m, 4H), 4.14 (s, 2H), 2.95 (s, 3H). 115 201388-PCT01-NP Intermediate 14 2-((2-Fluorophenyl)(methyl)amino)acetimidamide F NH N NH2 M in toluene) (16.00 mL, 32.00 mmol) was added dropwise at 0°C under an 5 atmosphere of Ar(g) to NH4Cl (1.819 g, 34.00 mmol) in toluene (17 mL) and the mixture was stirred at 0°C for 30 min and then at rt for 30 min.2-((2-Fluorophenyl)(methyl)amino)acetonitrile, Intermediate 13 (3.28 g, 20 mmol) was added and the reaction mixture was stirred at 80°C on. After cooling to rt, the mixture was poured under ice cooling to a stirred mixture of silica (16 g) in CHCl3 (43 mL). The mixture was stirred at rt for 15 min, and the solids were removed by 10 filtration and washed with MeOH (2×60 mL). The combined filtrates were concentrated, and the residue was stirred at rt for 10 min with 1.25 M HCl in MeOH (16 mL). The mixture was concentrated, and the residue was stirred with a mixture of IPA/Et2O (4:1, 50mL) for 15 min. The precipitate was collected by filtration. The filtrate was concentrated, and this residue was stirred with IPA/ Et2O (4:1, 25mL) and 4 M HCl in dioxane (1 mL) was added. After stirring for 15 min 15 the precipitate was collected by filtration and combined with the precipitate obtained above. The solids were washed with Et2O and dried to give the title compound as a hydrochloride salt (2.402 g, 55%). MS (ESI) m/z [M+H]+ 182. Intermediate 15 6-(((2-Fluorophenyl)(methyl)amino)methyl)-1,3,5-triazine-2,4(1H,3H)-dione O O 20 A suspension of K2CO3 (3.04 g, 22 mmol), 2-((2- fluorophenyl)(methyl)amino)acetimidamide HCl, Intermediate 14 (2.4 g, 11.03 mmol) and diphenyl iminodicarbonate (2.84 g, 11.03 mmol) in MeCN (45 mL) was stirred at 60°C for 2 h under an atmosphere of Ar(g). K2CO3 (1.5 g) was added, and the mixture was stirred at 60°C for 116 201388-PCT01-NP 1 h under an atmosphere of Ar(g). 10% citric acid was added until pH 4 and the mixture was concentrated to remove MeCN and then filtered. The filtrate was saturated with NaCl and extracted repeatedly with EtOAc. The combined organic layer was extracted with 10% Na2CO3 (aq) (3×30 mL). The combined aqueous layer was washed with heptane, brought to pH 4-5 with concentrated 5 HCl, saturated with NaCl and extracted with DCM (×5). The combined organic layer was dried over Na2SO4, filtered and concentrated. EtOAc (10 mL) was added, and a precipitate was isolated by filtration after stirring for 1 h to give the title compound (299 mg, 11%). MS (ESI) m/z [M+H]+ 251. Intermediate 16 10 (R)-2-((4-Chloro-6-(((2-fluorophenyl)(methyl)amino)methyl)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol A mixture of 6-(((2-fluorophenyl)(methyl)amino)methyl)-1,3,5-triazine-2,4(1H,3H)- dione, Intermediate 15 (298 mg, 1.19 mmol) and POCl3 (2 mL, 21.46 mmol) was heated to reflux 15 for 50 min. Chlorobenzene (10 mL) was added and the mixture was concentrated. The residue was dissolved in THF (5 mL) and K2CO3 (218 mg, 1.58 mmol) was added. (R)-2-Amino-4- methylpentan-1-ol (0.413 mL, 3.22 mmol) was added in two equal portions with a 10 min interval. The mixture was stirred at rt for 18 h. THF (10 mL) was added, and the solids were removed by filtration through celite. The filtrate was concentrated, and the crude residue was purified by 20 preparative HPLC, PrepMethod D, (gradient: 40–80%). The combined relevant fractions were concentrated to half of their volume and the remaining liquid was absorbed on paper tissue (wiper 415, Tork) which was eluted with DCM (200 mL), dried over Na2SO4, filtered, and concentrated to give the title compound (62 mg, 14%). MS (ESI) m/z [M+H]+ 368. Intermediate 17 117 201388-PCT01-NP 2,4-Dichloro-6-((4-methoxybenzyl)thio)pyrimidine Cl N methanethiol (6.79 mL, 48.71 mmol) was added dropwise to 2,4,6- trichloropyrimidine (8.935 g, 48.71 mmol) and DIPEA (8.48 mL, 48.71 mmol) in THF (80 mL) at 5 0°C. The reaction mixture was stirred at 0°C for 10 min and then at rt for 1 h. The mixture was concentrated. EtOAc was added to the residue and the organic layer was washed with water and concentrated. The crude residue was purified twice by straight phase flash chromatography on silica (gradient: 0–10% EtOAc in heptane) to give the title compound (7.967 g, 54%); 1H NMR (500 MHz, CDCl3) δ 3.75 (s, 3H), 4.35 (s, 2H), 6.79–6.84 (m, 2H), 7.04 (s, 1H), 7.25–7.31 (m, 10 2H). Intermediate 18 (R)-2-((2-Chloro-6-((4-methoxybenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol (R)-2-Amino-4-methylpentan-1-ol (3.70 mL, 29.10 mmol) and DIPEA (5.07 mL, 29.10 15 mmol) were added to a solution of 2,4-dichloro-6-((4-methoxybenzyl)thio)pyrimidine, Intermediate 17 (7.967 g, 26.45 mmol) in IPA (70 mL). The reaction mixture was stirred at 50°C for 5 h and then concentrated. The residue was partitioned between EtOAc and water and the organic layer was passed through a phase separator and concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient: 10–70% EtOAc in heptane) to 20 give the title compound (2.336 g, 23%); MS (ESI) m/z [M+H]+ 382; 1H NMR (400 MHz, CD3OD) δ 0.84–1.00 (m, partly overlapping with solvent), 1.20–1.25 (m, partly overlapping with solvent), 118 201388-PCT01-NP 1.37–1.46 (m, 2H), 1.59–1.71 (m, 1H), 3.43–3.56 (m, 2H), 3.77 (s, 3H), 4.16–4.33 (m, 3H), 6.22 (s, 1H), 6.81–6.89 (m, 2H), 7.26–7.36 (m, 2H). Intermediate 19 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)pyrimidin-2- 5 yl)methanesulfonamide 1.095 g, 11.51 mmol), X-Phos (1.097 g, 2.30 mmol) and Pd2(dba)3 (0.527 g, 0.58 mmol) were added to a solution of (R)-2-((2-chloro-6-((4- methoxybenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol, Intermediate 18 (2.93 g, 7.67 10 mmol) in THF (30 mL) and the reaction mixture was stirred at rt for 10 min under an atmosphere of N2(g). K2CO3 (1.909 g, 13.81 mmol) was added, and the reaction mixture was stirred at 60°C for 20 h under an atmosphere of N2(g). X-Phos (0.585 g, 1.23 mmol) and Pd2(dba)3 (0.281 g, 0.31 mmol) were added, and the reaction mixture was stirred at 60°C for 7 h and then at rt for 2 d under an atmosphere of N2(g). The mixture was partitioned between water and MTBE and the organic 15 layer was extracted with 0.09 M K2CO3 (aq) (×3). The combined aqueous layer was acidified with 1 M HCl (aq, 70 mL) and extracted with MTBE (×2). The combined organic layer was washed with water, passed through a phase separator and concentrated to give the title compound (2.065 g, 61%); MS (ESI) m/z [M+H]+ 441. Intermediate 20 20 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-2- yl)methanesulfonamide 119 201388-PCT01-NP H , 5.12 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-((4-methoxybenzyl)thio)pyrimidin-2-yl)methanesulfonamide, Intermediate 19 (1.88 g, 4.27 mmol) in TFA (20 ml, 269.24 mmol) and the reaction mixture was heated in a microwave 5 reactor at 100°C for 13 min. The mixture was concentrated and DCM and 8 % NaHCO3 (aq) were added. The phases were separated, and the aqueous layer was acidified with 1 M HCl (aq) to about pH 4-5, washed with DCM and concentrated. The residue was suspended in IPA, filtered and the filtrate was concentrated to give the title compound as a hydrochloride salt (4.378 g); MS (ESI) m/z [M+H]+ 321. 10 Intermediate 21 N-(4-((1-(2,3-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)pyrimidin-2-yl)methanesulfonamide F DIPEA (0.113 mL, 0.647 mmol) and 1-(1-bromoethyl)-2,3-difluorobenzene (0.60 g, 0.2715 mmol) in DMF (0.15 ml) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercaptopyrimidin-2-yl)methanesulfonamide HCl, Intermediate 20 (0.818 g, 2.55 mmol) in DMF (9 mL) and the reaction mixture was stirred at rt for 2 h. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted with EtOAc and the combined organic layer was passed through a phase separator and evaporated. The crude residue 120 201388-PCT01-NP was purified by preparative SFC, PrepMethod C, (gradient: 15–20%) to give the title compound (155 mg, 13%); MS (ESI) m/z [M+H]+ 461. Intermediate 22 S-(2,3-Difluorobenzyl) ethanethioate O F F S 5 333 g, 2.42 mmol) and thioacetic acid (0.172 mL, 2.42 mmol) were added to 1- (bromomethyl)-2,3-difluorobenzene (0.5 g, 2.42 mmol) in MeCN (30 mL) and the reaction mixture was stirred at rt for 3 d. The mixture was filtered, and DCM and water were added to the filtrate. The aqueous layer was extracted with DCM and the combined organic layer was washed 10 with water, dried, and concentrated to give the title compound (497 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 3H), 4.15–4.20 (m, 2H), 7.12–7.39 (m, 3H). Intermediate 23 (R)-2-((2-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)pentan-1-ol F 15 Step a) (R)-2-((2,6-Dichloropyrimi din-4-yl)amino)pentan-1-ol H 121 201388-PCT01-NP (2,3-Difluorophenyl)methanethiol (0.873 g, 5.45 mmol) in THF (50 mL) was added dropwise over 20 min to a solution of 2,4,6-trichloropyrimidine (1 g, 5.45 mmol) and DIPEA (1.428 mL, 8.18 mmol) in THF (50 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at 0°C to rt for 30 min and then at rt for 4 h. DIPEA (1.429 mL, 8.18 mmol) 5 and (R)-2-aminopentan-1-ol (0.563 g, 5.45 mmol) were added and the reaction mixture was stirred at 65°C for 18 h. The mixture was purified by preparative HPLC, PrepMethod G, (gradient: 5–65%) to give the first eluted compound as the title compound (516 mg, 38%). Step b) (R)-2-((2-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)pentan-1-ol S-(2,3-Difluorobenzyl) ethanethioate, Intermediate 22 (200 mg, 0.99 mmol) and K2CO3 10 (164 mg, 1.19 mmol) were added to (R)-2-((2,6-dichloropyrimidin-4-yl)amino)pentan-1-ol (247 mg, 0.99 mmol) in MeOH (4 mL). The mixture was stirred at rt for 48 h and concentrated. DCM and water were added, and the organic layer was concentrated. The crude residue was purified by preparative HPLC, PrepMethod I, (gradient: 20–95%) to give the title compound (58 mg, 16%); MS (ESI) m/z [M+H]+ 374. 15 Intermediate 24 (R)-2-((4-Chloro-6-((4-methoxybenzyl)thio)pyrimidin-2-yl)amino)-4-methylpentan-1-ol (R)-2-Amino-4-methylpentan-1-ol (5.99 g, 51.13 mmol) was added to a solution of 2,4- dichloro-6-((4-methoxybenzyl)thio)pyrimidine, Intermediate 17 (14 g, 46.48 mmol) and DIPEA 20 (8.93 mL, 51.13 mmol) in IPA (200 mL) under an atmosphere of N2(g) and the reaction mixture was stirred at 50°C for 12 h. The mixture was concentrated, diluted with EtOAc (200 mL) and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by straight phase flash chromatography on silica 122 201388-PCT01-NP (gradient: 5–30% EtOAc in PE) to give the title compound (4.7 g, 27 %); MS (ESI) m/z [M+H]+ 382. Intermediate 25 (R)-N-(2-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)pyrimidin-4- 5 yl)methanesulfonamide .934 g, 9.82 mmol), X-Phos (0.936 g, 1.96 mmol) and Pd2(dba)3 (0.450 g, 0.49 mmol) were added to a solution of (R)-2-((4-chloro-6-((4- methoxybenzyl)thio)pyrimidin-2-yl)amino)-4-methylpentan-1-ol, Intermediate 24 (2.5 g, 6.55 10 mmol) in THF (20 mL). The mixture was stirred at rt for 10 min under an atmosphere of N2(g). K2CO3 (1.628 g, 11.78 mmol) was added, and the mixture was stirred at 60°C for 20 h under an atmosphere of N2(g). The mixture was partitioned between water and MTBE. The layers were separated, and the organic layer was extracted 0.09 M K2CO3 (aq, ×3). The combined aqueous layer was acidified with 1 M HCl (aq) and extracted with MTBE (×2). The combined organic layer 15 was washed with water, dried and concentrated to give the title compound (2.2 g, 76 %); MS (ESI) m/z [M+H]+ 441. Intermediate 26 2-((4-Methoxybenzyl)thio)pyrimidine-4,6-diol OH 23 201388-PCT01-NP 1.5 M NaOH in H2O/EtOH (1:1) (0.287 mL, 15.26 mmol) was added to a solution 2- mercaptopyrimidine-4,6-diol (2 g, 13.87 mmol) in EtOH (10 mL) and water (10 mL). 1- (Chloromethyl)-4-methoxybenzene (2.281 g, 14.57 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature over the weekend. The mixture was filtered, and the 5 solid was collected and washed with water and dried under vacuum to give the title compound (2.21 g, 60%).1H NMR (400 MHz, DMSO-d6) δ 3.71 (3H, d), 4.31 (2H, d), 5.14 (1H, s), 6.82–6.9 (2H, m), 7.3–7.37 (2H, m). Intermediate 27 4,6-dichloro-2-((4-methoxybenzyl)thio)pyrimidine Cl N 10 3 ( m ) was added to 2-((4-methoxybenzyl)thio)pyrimidine-4,6-diol Intermediate 26 (2.1 g, 7.95 mmol) and then N,N-diethylaniline (2.54 mL, 15.89 mmol) was added and the reaction mixture was heated at 100°C for 4 h. The mixture was concentrated in vacuo and the residue was poured onto ice. EtAOc was added and the phases were separated. The aqueous layer 15 was extracted with EtOAc, and the combined organic layer was washed with water, dried over MgSO4, filtered, and concentrated to yield the title compound (2.29 g, 96%) which was used in next step without further purification.1H NMR (400 MHz, CDCl3) δ 3.79 (3H, d), 4.34 (2H, s), 6.8–6.9 (2H, m), 7.03 (1H, d), 7.32–7.37 (2H, m). Intermediate 28 20 (R)-2-((6-Chloro-2-((4-methoxybenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol 124 201388-PCT01-NP hylpentan-1-ol (0.467 mL, 3.65 mmol) and DIPEA (0.694 mL, 3.98 mmol) was added to 4,6-dichloro-2-(4-methoxybenzylthio)pyrimidine Intermediate 27 (1 g, 3.32 mmol) in THF (10 mL) and the reaction mixture was heated at 120°C for 30 min in a microwave 5 reactor. The mixture was concentrated and the residue was purified by straight phase flash column chromatography on silica (heptane:EtOAc, 1:1) to yield the title compound (748 mg, 59%). MS (ESI) m/z [M+H]+ 382.1. Intermediate 29 (R)-N-(6-((1-Hydroxy-4-methylpentan-2-yl)amino)-2-mercaptopyrimidin-4- 10 yl)methanesulfonamide H Anisole (0.047 mL, 0.43 mmol) was added to a solution of (R)-N-(6-((1-hydroxy-4- methylpentan-2-yl)amino)-2-((4-methoxybenzyl)thio)pyrimidin-4-yl)methanesulfonamide Example 173 (159 mg, 0.36 mmol) in TFA (3 mL) and the reaction mixture was stirred at ambient 15 temperature for 3 h. The mixture was concentrated, and the residue was purified by straight phase flash column chromatography on silica (eluted with increasing amounts of MeOH in EtOAc) to give the title compound (50 mg, 43%). MS (ESI) m/z [M+H]+ 321.0. 125 201388-PCT01-NP Intermediate 30 1-Phenylbut-3-en-1-yl methanesulfonate O O .078 mL, 1.00 mmol) dissolved in DCM (1.5 mL) was added in portions during 15 5 min to a solution of 1-phenylbut-3-en-1-ol (0.15 mL, 1.0 mmol) and TEA (0.21 mL, 1.50 mmol) in DCM (3.5 mL) at 0oC and the mixture was stirred at 0oC for 10 min and then at rt for 1 h 15 min. DCM (10 mL) and water (2 mL)was added and the mixture was extracted and the organic layer was passed through a phase separator. The solvent was evaporated to give (194 mg, 86%) of the crude title compound (containing about 12% starting material) which was used without further 10 purification.1H NMR (400 MHz, CDCl3) δ 2.47–2.57 (2H, m), 2.54 (3H, s), 2.65–2.75 (1H, m), 4.95–5.08 (2H, m), 5.41 (1H, dd), 5.58 (1H, ddt), 7.21–7.28 (5H, m). Intermediate 31 15 (R)-2-((4-Chloro-6-((4-fluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol F (4-Fluorophenyl)methanethiol (67 g, . ved in THF (5 mL) was added to a cold (0oC) solution of 2,4,6-trichloro-1,3,5-triazine (871 mg, 4.72 mmol) in THF (15 mL) and the mixture was stirred for 1 h. DIPEA (2.47 mL, 14.1 mmol) was added followed by (R)-2- 20 amino-4-methylpentan-1-ol (554 mg, 4.72 mmol) dissolved in THF (5 mL) during 15 min at 0oC and the mixture was stirred for 20 min. The solvent was removed in vacuo and the crude product was first purified by straight phase flash chromatography on silica (gradient: 0–100% EtOAc in 126 201388-PCT01-NP heptane) followed by preparative HPLC, PrepMethod E, (gradient: 25-95%) to give the title compound (1.0 g, 57%). MS (ESI) m/z [M+H]+ 370.8. Intermediate 32 5 tert-Butyl (S)-4-(hydroxymethyl)-3-methyl-2-oxoimidazolidine-1-carboxylate HO N Boc N LiBH4 (23.9 g, 1.16 mol) was added i C to a solution of 1-(tert-butyl) 4-methyl (S)-3-methyl-2-oxoimidazolidine-1,4-dicarboxylate WO2022150707 A1 page 136 (200 g, 0.775 mol) in anhydrous THF (2 L). After complete addition, the reaction mixture was stirred at -5– 10 0oC for 1 h. The reaction was quenched with sat NH4Cl (aq, 500 mL). The organic layer was removed in vacuo and the aqueous layer was extracted with DCM (2 L). The combined organic layer was washed with brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (170 g, 95.5%). MS (ESI) m/z [M+Na]+ 253.1. 15 Intermediate 33 tert-Butyl (S)-3-methyl-4-(((methylsulfonyl)oxy)methyl)-2-oxoimidazolidine-1-carboxylate MsO N Boc N MsCl (44.39 g, 0.388 mol) was added a solution of tert-butyl (S)-4- (hydroxymethyl)-3-methyl-2-oxoimidazolidine-1-carboxylate Intermediate 32 (70 g, 0.30 mol) 20 and TEA (19.4 g, 0.39 mol) in DCM (700 mL). The reaction mixture was stirred at 25oC for 1 h. The mixture was washed with brine (500 mL), dried and concentrated. The residue was purified by normal phase chromatography on silica (PE:EtOAc, 1:1) to give the title compound (84.4 g, 91%) as a pale yellow oil. MS (ESI) m/z [M+H-Boc]+ 209.1. 25 Intermediate 34 (S)-5-(Bromomethyl)-1-methylimidazolidin-2-one Br NH 201388-PCT01-NP A mixture of compound tert-butyl (S)-3-methyl-4-(((methylsulfonyl)oxy)methyl)-2- oxoimidazolidine-1-carboxylate Intermediate 33 (70 g, 0.227 mol) and LiBr (98 g, 1.136 mol) in acetone (1 L) was refluxed for 16 h. The mixture was cooled to 25oC and filtered. The filtrate was concentrated and the residue was diluted with DCM (2 L) and H2O (500 mL). The separated 5 organic layer was washed with brine (500 mL), dried and concentrated. The residue was diluted with DCM (250 mL) and 4 M HCl in EtOAc (250 mL) was added dropwise at 0oC. The reaction mixture was stirred at 25oC for 1 h. The mixture was filtered to give a cake, which was washed with TBME (500 mL) and dried in high vacuum to give the hydrochloride of the title compound (33 g, 75%) as a pale white solid. MS (ESI) m/z [M+H]+ 192.996.1HNMR (400 MHz, DMSO- 10 d6) 3.80-3.79 (m, 1H), 3.78-3.64 (m, 2H), 3.39-3.34 (m, 1H), 3.03-3.01 (m, 1H), 2.62 (s, 3H). Intermediate 35 (R)-6-(Bromomethyl)-1-methylpiperidin-2-one Br N 15 The title compound was prepared in anal viously described methods herein and known to person skilled in the art. Intermediate 36 (S)-1-Methyl-2-oxoimidazolidine-4-carboxylic acid HO N HN 20 O NaBH4 (21 g, 0.55 mol) was added in portions at 0oC to a solution of compound (S)-1-methyl-2- oxoimidazolidine-4-carboxylic acid (80 g, 0.51 mol) in EtOH (800 mL) and then the reaction mixture was stirred at rt for 18 h. The reaction was quenched with sat NH4Cl (30 mL) and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by normal 25 phase chromatography on silica (DCM:MeOH, 10:1) to give the title compound (50 g, 76%) as yellow oil. MS (ESI) m/z [M+H]+ 131.08. Intermediate 37 128 201388-PCT01-NP (S)-(1-Methyl-2-oxoimidazolidin-4-yl)methyl 4-methylbenzenesulfonate TsO N HN TsCl (99.61 g, 522.49 mmol) was adde ution of (S)-1-methyl-2-oxoimidazolidine- 4-carboxylic acid Intermediate 36 (40 g, 261.25 mmol) in dry pyridine (170 mL). The reaction 5 mixture was stirred at rt for 16 h. The pyridine was removed in vacuo and the residue was dissolved in DCM (500 mL). The organic layer was washed with 2 M HCl (3×200 mL ). The aqueous layer was extracted with DCM (×2). The combined organic layer was washed with brine, dried over MgSO4, filtered and the filtrate was concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (PE:EtOAc, 1:2) to give the 10 title compound (40 g, 74%) as a red solid. MS (ESI) m/z [M+Na]+ 289.1. Intermediate 38 (S)-(1,3-Dimethyl-2-oxoimidazolidin-4-yl)methyl 4-methylbenzenesulfonate TsO N N 15 CH3I (215.7 g, 1.77 mol) was added to )-(1-methyl-2-oxoimidazolidin-4- yl)methyl 4-methylbenzenesulfonate Intermediate 37 (38 g, 133.65 mmol) in DMF (750 mL) and the mixture was cooled to -10oC. NaH (10.69 g, 267.29 mmol) was added. The reaction mixture was stirred at 10oC for 18 h. The reaction was quenched by addition of water (4.82 g). The mixture was concentrated in vacuo to give the title compound, which was used directly in 20 the next step. Intermediate 39 (S)-4-(Iodomethyl)-1,3-dimethylimidazolidin-2-one I N 25 NaI (100.48 g, 670.34 mmol) was added o a so u o of crude (S)-(1,3-dimethyl-2- oxoimidazolidin-4-yl)methyl 4-methylbenzenesulfonate Intermediate 38 in acetone (500 mL) at rt. The reaction mixture was stirred at 85oC for 18 h. The mixture was concentrated in vacuo. 129 201388-PCT01-NP The crude product was dissolved in DCM (1 L) and filtered and the filtrate was purified by column chromatography (PE:EtOAc, 1:1) to give the title compound as a yellow oil. MS (ESI) m/z [M+H]+ 255.0. 5 Intermediate 40 (Chloro(cyclopropyl)methyl)benzene (a) and (E)-(4-chlorobut-1-en-1-yl)benzene (b) MsCl (0.17 mL, 2 on of cyclopropyl(phenyl)methanol (300 mg, 2.02 mmol) and DIPEA (0.39 mL, 2.23 mmol) in DCM 10 (5 mL) at 0°C and the reaction mixture was stirred at 0°C for 3.5 h. The mixture was passed through a short column of silica (eluted with DCM). Evaporation of the solvent gave 81 mg of an about 2.4/1 mixture of (a) and (b) by 1H-NMR. The mixture was used without further purification in the next step. 15 Intermediate 41 (R)-2-((4-Chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol F A solution of (2,3-difluorophenyl) , mmol) in dry THF (10 mL) was added dropwise to 2,4,6-trichloro-1,3,5-triazine (1.27 g, 6.87 mmol) and DIPEA (1.79 mL, 10.3 20 mmol) in dry THF (30 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 1 h. DIPEA (1.794 mL, 10.30 mmol) followed by a solution of (R)-2-amino-4- methylpentan-1-ol (0.805 g, 6.87 mmol) in dry THF (10 mL) were added dropwise. The reaction mixture was stirred at 0°C for 1.5 h and then concentrated. The crude product was purified by 130 201388-PCT01-NP straight phase flash chromatography on silica (gradient: 5–100% EtOAc in heptane) followed by straight phase flash chromatography on silica (gradient: 1–8% MeOH in DCM) to give the title compound (1.59 g, 60%). MS (ESI) m/z [M+H]+ 389. 5 Intermediate 42 (S)-3-Methylpiperazine-1-sulfonamide O HN N S NH2 A mixture of (S)-2-methylpiperazine ( ) and sulfuric diamide (15 g, 156 mmol) in dioxane was stirred at 110°C for 3 days. The solvent was removed under reduced pressure and 10 the resulting solid was washed with PE:EtOAc (5:1) to give the title compound (25.7 g, 92%) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 0.96 (3H, d), 2.08 (1H, t), 2.15 (1H, s), 2.42 (1H, td), 2.58–2.7 (2H, m), 2.89 (1H, dt), 3.16–3.26 (2H, m), 6.65 (2H, s). Intermediate 43 15 N-(4,6-Dichloro-1,3,5-triazin-2-yl)methanesulfonamid Cl Cl NaH (2.08 g, 52.06 mmol, 60% w/w twice with heptane under an atmosphere of N2(g).2-MeTHF (40 mL) was added followed by methanesulfonamide (4.13 g, 43.38 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then added to a solution of 20 2,4,6-trichloro-1,3,5-triazine (8.0 g, 43.38 mmol) in 2-MeTHF (40 mL). The reaction mixture was heated at 70oC for 6 h and then at 50oC on. The mixture was poured over ice. The pH was adjusted to approximately 4 by the addition of 1 M HCl. EtOAc was added, and the two layers were separated. The aqueous layer was extracted with EtOAc (×3), and the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was re-solidified from 25 MTBE to give the title compound (4.61 g, 44%) as a colorless solid. MS (ESI) m/z [M+H]+ 242.9. 131 201388-PCT01-NP Intermediate 44 N-(4-Chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl N N Me DIPEA (0.75 mL, 4.32 mmol) ion of N-(4,6-dichloro-1,3,5- 5 triazin-2-yl)methanesulfonamide Intermediate 43 (1.00 g, 4.11 mmol) in DMF (6 mL) at rt and under an atmosphere of N2(g). The reaction mixture was stirred at rt for 5 min. (4- Methoxyphenyl)methanethiol (0.70 g, 4.53 mmol) was added dropwise at rt. The reaction mixture was stirred at rt for 40 h. The mixture was acidified with 20% AcOH (aq) (v/v) to pH 4- 5 and then EtOAc (150 mL) was added. The mixture was washed sequentially with brine (2×150 10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford a crude product. The crude product was purified by straight phase flash chromatography on silica (gradient: 10–50% EtOAc in PE) to give the title compound (700 mg, 47%) as a pale yellow solid. MS (ESI) m/z [M+H]+ 361. 15 Intermediate 45 (R)-N-(4-((1-Hydroxy-3-methylbutan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide OH Me K2CO3 (597 mg, 4.32 mmol) f lbutan-1-ol (446 mg, 4.32 mmol) 20 were added to N-(4-chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 44 (300 mg, 0.83 mmol) in DMF (1 mL) at rt. The reaction mixture was stirred at rt on and then at 40°C on. The solvent was removed under reduced pressure to give the title compound (300 mg, 84%) which was used without further purification. MS (ESI) m/z [M+H]+ 428.3. 132 201388-PCT01-NP Intermediate 46 (R)-N-(4-((1-Hydroxy-3-methylbutan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide OH HN 5 (R)-N-(4-((1-Hydroxy-3-methylbuta methoxybenzyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 45 (200 mg, 0.47 mmol) was added to anisole (0.061 mL, 0.56 mmol) and TFA (6 mL) at rt under an atmosphere of N2(g). The reaction mixture was stirred at rt on. The solvent was evaporated to give the title compound (130 mg, 90%) which was 10 used without further purification. MS (ESI) m/z [M+H]+ 308.2. Intermediate 47 N-(4-Chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl N N 15 NaH (1.2 g, 30 mmol, 60% w/w in riod of 5 min to a solution of N-(4,6- dichloro-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 43 (4.86 g, 20 mmol) in THF (120 mL) at 0°C and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 5 min. 1-Phenylethanethiol (2.76 g, 20 mmol) was added dropwise over 20 min at 0°C and the reaction mixture was stirred at 0°C for 2 h. The reaction was quenched with 30% AcOH (aq) (200 mL) 20 and extracted with EtOAc (3×150 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford a yellow oil which was purified by straight phase flash chromatography on silica (gradient: 0–50% EtOAc in PE) to afford the title compound as a yellow oil (4.7 g, 68%). MS (ESI) m/z [M+H]+ 345. 133 201388-PCT01-NP Intermediate 48 N-(tert-Butyldimethylsilyl)methanesulfonimidamide H N O Si S NH Step a) N-(tert-Butyldimethylsilyl)meth oyl chloride N O Si S Cl 5 A slurry of PPh3Cl2 (22 mL, 2.20 mmol mL) was cooled to 0°C. TEA (0.459 mL, 3.30 mmol) was added and the mixture was cooled to -78°C. N-(tert- Butyldimethylsilyl)methanesulfonamide (0.46 g, 2.20 mmol) dissolved in CHCl3 (10 mL) was added. The reaction mixture was allowed to reach rt and stirred on. The solvent was evaporated 10 to give a crude product which was used in the next step without purification. Step b) N-(tert-Butyldimethylsilyl)methanesulfonimidamide A solution of N-(tert-butyldimethylsilyl)methanesulfonimidoyl chloride Intermediate 48 Step a (501 mg, 2.2 mmol) in CHCl3 (10 mL) was treated with NH3(g) until saturated as indicated by gas bubbling. The reaction mixture was stirred at ambient temperature on. The mixture was 15 diluted with MTBE and filtered, concentrated and the crude product was purified by straight phase flash chromatography on silica (60% EtOAc in heptane) to give the title compound (243 mg, 53%) as a white solid.1H NMR (500 MHz, CDCl3) δ 0.12 (6H, d), 0.90 (9H, s), 3.12 (3H, s). 20 Intermediate 49 N'-(tert-Butyldimethylsilyl)-N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonimidamide 201388-PCT01-NP N-(tert-Butyldimethylsilyl)methanesulfonimidamide Intermediate 48 (0.24g, 1.15 mmol), (2R)- 2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (0.42 g, 1.15 mmol), Cs2CO3 (0.75 g, 2.30 mmol) and X-Phos (0.088 g, 0.18 mmol) were diluted with THF (11.5 mL) and degassed using N2(g). Pd2(dba)3 (0.042 g, 0.05 5 mmol) was added, and the reaction mixture was degassed again and heated to 60°C over night. Standard extractive work-up gave a crude product that was used without further purification in the next step assuming full conversion. MS (ESI) m/z [M+H]+ 539. Intermediate 50 10 N-(4-Chloro-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl N N F F NaH (2.369 g, 98.74 mmol, 60% olution of 1-(2,4- difluorophenyl)ethane-1-thiol (5.73 g, 32.91 mmol) in THF (30 mL) at 0°C and the reaction mixture was stirred at rt for 1 h. The mixture was added dropwise to a solution of N-(4,6- 15 dichloro-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 43 (8.00 g, 32.91 mmol) in THF (150 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by straight phase flash chromatography on silica (0–10% MeOH in DCM) to give the title compound (4.00 g, 32%) as a 20 white solid. MS (ESI) m/z [M+H]+ 381. Intermediate 51 (R)-2-Amino-3-cyclopentylpropan-1-ol H 25 1 M BH3 in THF (12.7 mL, 12.7 mmol) was a e ropwise to (R)-2-amino-3- cyclopentylpropanoic acid (1.0 g, 6.36 mmol) in THF (2 mL) at 0°C and the reaction mixture 135 201388-PCT01-NP was stirred at 20°C for 15 h. The reaction was quenched with a few drops of water and the mixture was concentrated to dryness to give the crude title compound as a white solid (1.2 g) which was used without further purification. MS (ESI) m/z [M+H]+ 144. 5 Intermediate 52 N-(4-(((R)-1-Cyclopentyl-3-hydroxypropan-2-yl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide F K2CO3 (218 mg, 1.58 mmol) wa -(2,4-difluorophenyl)ethyl)thio)-10 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 50 (300 mg, 0.79 mmol) and (R)-2-amino- 3-cyclopentylpropan-1-ol Intermediate 51 (196 mg, 0.95 mmol) in dioxane (10 mL) at rt and the reaction mixture was stirred at 80°C for 2 h. The mixture was concentrated to dryness. The residue was dissolved in DMF and filtered through CELITE. The filtrate was concentrated and the crude product was purified by preparative HPLC, PrepMethod N, (gradient: 20-60%) to 15 afford the title compound as a white solid (200 mg, 52%). MS (ESI) m/z [M+H]+ 488.1. Intermediate 53 N-(4-(((R)-1-Cyclobutyl-2-hydroxyethyl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide 20 F 201388-PCT01-NP K2CO3 (218 mg, 1.58 mmol) was added to N-(4-chloro-6-((1-(2,4-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 50 (300 mg, 0.79 mmol) and (R)-2-amino- 2-cyclobutylethanol (272 mg, 2.36 mmol) in dioxane (20 mL) and the reaction mixture was stirred at 80oC for 2 h. The solvent was removed under reduced pressure and the crude product 5 was purified by preparative HPLC, PrepMethod O, using decreasingly polar mixtures of water and MeCN as eluents, to afford the title compound as a white solid (200 mg, 55%). MS (ESI) m/z [M+H]+ 488.1. Intermediate 54 10 N-(4-(((R)-1-Cyclopentyl-2-hydroxyethyl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide F K2CO3 (218 mg, 1.58 mmol) wa -(2,4-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 50 (300 mg, 0.79 mmol) and (R)-2-amino- 15 2-cyclopentylethanol (305 mg, 2.36 mmol) in dioxane (15 mL) and the reaction mixture was stirred at 80oC for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod M, (gradient: 35-55%) to give the title compound as a white solid (150 mg, 40%). MS (ESI) m/z [M+H]+ 474.0. 20 Intermediate 55 N-(4-(((R)-1-Cyclopropyl-3-hydroxypropan-2-yl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide 137 201388-PCT01-NP OH F K2CO3 (181 mg, 1.31 mmol) wa clopropylpropan-1-ol (378 mg, 3.28 mmol), and N-(4-chloro-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 50 (250 mg, 0.66 mmol) in dioxane (8 mL) at rt under an 5 atmosphere of N2(g) and the reaction mixture was stirred at 80°C for 8 h. The solvent was removed under reduced pressure and the residue was diluted with DMF and filtered through CELITE. The solvent was evaporated, and the crude product was purified by preparative HPLC, PrepMethod Q (gradient: 30-70%) to afford the title compound as a white solid (200 mg, 66%). MS (ESI) m/z [M+H]+ 460.1. 10 Intermediate 56 ((2S,3S)-3-Propyloxiran-2-yl)methanol O H Ti(OiPr)4 (2.55 g, 8.99 mmol) was ad a period of 5 min to (2R,3R)-diethyl 2,3- 15 dihydroxysuccinate (2.06 g, 9.98 mmol) in DCM (150 mL) at -20°C and under an atmosphere of N2(g). The reaction mixture was stirred at -25°C for 15 min.5.5 M tert-BuOOH in decane (36.3 mL, 199.7 mmol) was added. The reaction mixture was stirred at -25°C for 30 min. (E)-Hex-2- en-1-ol (10.0 g, 99.84 mmol) in DCM (50 mL) was added and the reaction mixture was stirred at -25°C for 4 h. The mixture was warmed to 0°C and poured into a solution of Fe2SO4 (33.0 g, 20 118.7 mmol) and citric acid (11.0 g, 57.26 mmol) in water (100 mL). The mixture was stirred at 0°C for 1 h. A solution of NaOH (30%, 10 mL) was added at 0°C and the reaction mixture was stirred at rt for 15 h. The mixture was diluted with water (50 mL) and the aqueous layer was extracted with DCM (2×20mL). The combined organic layer was washed with brine (10 mL) and dried over Na2SO4, filtered and concentrated. The crude product was purified by distillation at 15 25 mmHg collecting of a fraction that distilled at 106ºC gave the title compound as a colorless oil 138 201388-PCT01-NP (6.50 g, 56%).1H NMR (400 MHz, CDCl3) δ 0.95 (3H , t), 1.36 - 1.60 (4H, m), 1.78 (1H, dd), 2.88 - 2.98 (2H, m), 3.57 - 3.67 (1H, m), 3.86 - 3.95 (1H, m). Intermediate 57 5 (2R,3R)-3-(Benzhydrylamino)hexane-1,2-diol OH OH Ti(OiPr)4 (31.3 g, 110.2 mmol) was a -propyloxiran-2-yl)methanol Intermediate 56 (6.4 g, 55.1 mmol) and (Ph)2NH (10.30 g, 56.2 mmol) in DCM (200 mL) at rt 10 and the reaction mixture was refluxed for 15 h. The mixture was cooled to rt and a solution of NaOH (10.0 g, 55.1 mmol) in brine (100 mL) was added. The mixture was stirred at rt on. The mixture was filtered through CELITE and washed with DCM (50 mL). The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by reversed phase 15 flash chromatography on a C18 column (gradient: 50–60% MeCN in water (0.1% NH4CO3)) followed by preparative HPLC, PrepMethod R (gradient: 10–70%) to give the title compound as a colorless oil (6.99 g, 36%). MS (ESI) m/z [M+H]+ 300.3. Intermediate 58 20 (2R,3R)-3-((4-Chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)hexane-1,2-diol Step a) (2R,3R)-3-Aminohexane-1 ,2-diol 139 201388-PCT01-NP OH OH Pd-C (10% Pd, 210 mg, 0.20 mmol) w 3R)-3-(benzhydrylamino)hexane-1,2-diol Intermediate 57 (2.00 g, 6.68 mmol) in EtOAc (30 mL) at rt under an atmosphere of N2(g). The reaction mixture was stirred under an atmosphere of H2 (2 atm) at rt for 24 h. The mixture was 5 filtered through CELITE and the solvent was removed under reduced pressure. The residue was washed with PE (2×5 mL) to give title compound as a yellow oil (0.65 g, 73%). MS (ESI) m/z [M+H]+ 134.4. Step b) (2R,3R)-3-((4-Chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)hexane-1,2- diol 10 A solution of (4-methoxyphenyl)methanethiol (2.19 g, 14.2 mmol) in THF (10 mL) was added dropwise over a period of 5 min to a stirred solution of 2,4,6-trichloro-1,3,5-triazine (2.62 g, 14.2 mmol) and DIPEA (6.20 mL, 35.5 mmol) in THF (80 mL) at 0°C and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 1 h. A solution of (2R,3R)-3-aminohexane-1,2- diol Intermediate 58 Step a (1.89 g, 14.2 mmol) in THF (10 mL) was added dropwise. The 15 reaction mixture was stirred at 10°C for 2 h. The mixture was concentrated and diluted with EtOAc (50 mL) and washed with brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was combined with a second batch made in the same way (4.3 mmol scale) and purified by straight phase flash chromatography on silica (0–2% MeOH in DCM) to give the title compound as a yellow gum (5.3 g, 72%). MS (ESI) m/z [M+H]+ 20 399.1. Intermediate 59 N-(4-(((2R,3R)-1,2-Dihydroxyhexan-3-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide 140 201388-PCT01-NP OH Methanesulfonamide (1.073 g, ixture of (2R,3R)-3-((4-chloro-6- ((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)hexane-1,2-diol Intermediate 58 (3.00 g, 7.52 mmol), Cs2CO3 (3.68 g, 11.28 mmol), Pd2(dba)3 (0.138 g, 0.15 mmol) and X-Phos (0.287 g, 0.60 5 mmol) in THF (30 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at 55°C for 12 h. After cooling to rt the mixture was partitioned between water (500 mL) and MTBE (200 mL). The layers were separated, and the organic layer was extracted with 0.09 M K2CO3 (aq) (×3). The combined aqueous layers were acidified with 12 N HCl (aq) which resulted in a precipitate. This was extracted into EtOAc (2×500 mL) and the combined organic 10 layer was washed with water, dried and concentrated to give a crude product which was purified by preparative SFC on a Chiralpak AD-H column (5 µm, 250×50 mm ID) using an isocratic system of 60% CO2 in IPA at a flow rate of 150 mL/min as mobile phase to give the title compound as a brown solid (2.50 g, 83%). MS (ESI) m/z [M+H]+ 458.0. 15 Intermediate 60 N-(4-(((2R,3R)-1,2-Dihydroxyhexan-3-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide OH N-(4-(((2R,3R)-1,2-Dihydroxyhexan - -y a o - - -methoxybenzyl)thio)-1,3,5-triazin-2- 20 yl)methanesulfonamide Intermediate 59 (1.50 g, 3.28 mmol) was added to a mixture of anisole (0.430 mL, 3.93 mmol) in TFA (15 mL) at 0°C and the reaction mixture was stirred at 0oC for 30 min, and then at rt for 3 h. The mixture was diluted with TBME (250 mL) and washed with sat 141 201388-PCT01-NP NaHCO3 (100 mL). The aqueous layer was acidified with 2 M HCl (aq) and washed with EtOAc (100 mL). The aqueous layer was concentrated and purified by reversed phase flash chromatography on a C18 column (gradient: 0-40% MeCN in water) to give the title compound (0.84 g, 76%) as a white solid. MS (ESI) m/z [M+H]+ 338.0. 5 Intermediate 61 N-(4-(((2R,3R)-1,2-dihydroxyhexan-3-yl)amino)-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide OH 10 DIPEA (0.435 mL, 2.49 mmol) w (4-(((2R,3R)-1,2-dihydroxyhexan-3- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 60 (280 mg, 0.83 mmol) and (1-bromoethyl)benzene (154 mg, 0.83 mmol) in DMF (8 mL) at 30°C. The reaction mixture was stirred at 30°C for 1 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod S (gradient: 18–80%) to give the 15 title compound as a white solid (310 mg, 85%). MS (ESI) m/z [M+H]+ 442.3. Intermediate 62 N-(4-(((R)-1-Cyclopropyl-2-hydroxyethyl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide 20 F 201388-PCT01-NP K2CO3 (181 mg, 1.31 mmol) was added to a mixture of (R)-2-amino-2-cyclopropylethanol (332 mg, 3.28 mmol) and N-(4-chloro-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 50 (250 mg, 0.66 mmol) in dioxane (8 mL) at 15°C under an atmosphere of N2(g) and the reaction mixture was stirred at 80°C for 5 h. The solvent was 5 removed under reduced pressure and the reaction mixture was diluted with DMF. The mixture was filtered through CELITE. The collected filtrate was concentrated to afford a crude product which was purified by preparative HPLC, PrepMethod Q to give the title compound (160 mg, 55%) as a white solid. MS (ESI) m/z [M+H]+ 446.0. 10 Intermediate 63 S-(1-(4-Chloro-2-fluorophenyl)ethyl) ethanethioate O S KSAc (12.5 g, 109.5 mmol) was added eriod of 5 min to 1-(1-bromoethyl)-4- chloro-2-fluorobenzene (13.0 g, 54.7 mmol) in acetone (150 mL) at rt and the reaction mixture 15 was stirred for 5 h. The solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (12.0 g, 94%) which was used without further purification.1H NMR (300MHz, CDCl3) δ 1.65 (3H, d), 2.30 (3H, s), 4.93-4.86 (1H, m), 7.12- 7.04 (2H, m), 7.30 (1H, d), 20 Intermediate 64 1-(4-Chloro-2-fluorophenyl)ethane-1-thiol SH 3 M NaOH (258 mL, 773.5 mmol) was a e o - -(4-chloro-2-fluorophenyl)ethyl) 25 ethanethioate Intermediate 63 (12.0 g, 51.6 mmol) in acetone (250 mL) and the reaction mixture was stirred at rt for 3 h. The solvent was removed under reduced pressure. The reaction 143 201388-PCT01-NP mixture was adjusted to pH 7 with 2 M HCl, and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 0–10% EtOAc in PE) to afford the title compound as a colorless oil (9.50 g, 97%).1H NMR (400 MHz, DMSO-d6) δ 1.61 (3H, d), 3.28 5 (1H, d), 4.38 (1H, p), 7.26–7.34 (1H, m), 7.36–7.48 (1H, m), 7.56 (1H, t). Intermediate 65 N-(4-Chloro-6-((1-(4-chloro-2-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl O N N F 10 Cl NaH (2.47 g, 61.7 mmol, 60% w/w in oil) was added to 1-(4-chloro-2-fluorophenyl)ethane-1- thiol Intermediate 64 (3.92 g, 20.6 mmol) in THF (20 mL) at 0°C. The reaction mixture was stirred at rt for 1 h. This solution was added dropwise to N-(4,6-dichloro-1,3,5-triazin-2- 15 yl)methanesulfonamide Intermediate 43 (5.00 g, 20.6 mmol) in THF (100 mL) at 0°C under an atmosphere of N2(g) and the reaction mixture was stirred at rt for 2 h. The mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 0–10% MeOH in DCM) to afford the title compound as a white solid (3.00 g, 37%). 20 MS (ESI) m/z [M+H]+ 397.0. Intermediate 66 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclobutyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 144 201388-PCT01-NP Cl K2CO3 (218 mg, 1.58 mmol) w loro-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 65 (300 mg, 0.79 mmol) and (R)-2-amino-2-cyclobutylethan-1-ol (181 mg, 1.58 mmol) in dioxane (20 mL) 5 and the reactioin mixture was stirred at 80oC for 2 h. The solvent was removed under reduced pressure to give a crude product which was purified by preparative HPLC, PrepMethod T (using decreasingly polar mixtures of water and MeCN as eluents) to afford the title compound as a white solid (200 mg, 55%). MS (ESI) m/z [M+H]+ 476.1. 10 Intermediate 67 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((2R,3R)-1,2-dihydroxyhexan-3-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide OH Cl DIPEA (0.44 mL, 2.49 mmol) w -(((2R,3R)-1,2-dihydroxyhexan-3- 15 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 60 (280 mg, 0.83 mmol) and 1-(1-bromoethyl)-4-chloro-2-fluorobenzene (197 mg, 0.83 mmol) in DMF (10 mL) at 30°C and the reaction mixture was stirred at 30°C for 1 h. The solvent was removed under reduced pressure to give a crude product which was purified by preparative HPLC, PrepMethod S, (gradient: 25-80%) to afford the title compound as a white solid (310 mg, 76%). MS (ESI) m/z 20 [M+H]+ 494.3. 145 201388-PCT01-NP Intermediate 68 (R)-2-Amino-3-cyclobutylpropan-1-ol OH 1 M BH3 in THF (13.97 mL, 13.97 mm to (R)-2-amino-3-cyclobutylpropanoic acid 5 (1.00 g, 6.98 mmol) in THF (2 mL) at 0°C and the reaction mixture was stirred at rt for 15 h. The reaction was quenched with a few drops of water and the mixture was concentrated to dryness to give the crude title compound assuming quantitative yield which was used without further purification (purity: 69% w/w). MS (ESI) m/z [M+H]+ 130.0 10 Intermediate 69 N-(4-(((R)-1-Cyclobutyl-3-hydroxypropan-2-yl)amino)-6-((1-(2,4-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide F 15 K2CO3 (218 mg, 1.58 mmol) wa -chloro-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 50 (300 mg, 0.79 mmol) and (R)-2-amino-3-cyclobutylpropan-1-ol Intermediate 68 (purity: 69% w/w, 177 mg, 0.95 mmol) in dioxane (10 mL) at rt and the reaction mixture was stirred at 80°C for 2 h. The mixture was concentrated to dryness. The residue was dissolved in DMF and filtered 20 through CELITE. The filtrate was concentrated to give a crude product, which was purified by preparative HPLC, PrepMethod U, (gradient: 20–60%) to give the title compound as a white solid (200 mg, 54%). MS (ESI) m/z [M+H]+ 474.1. Intermediate 70 146 201388-PCT01-NP N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopentyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide Cl K2CO3 (313 mg, 2.27 mmol) w chloro-6-((1-(4-chloro-2- 5 fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 65 (300 mg, 0.76 mmol) and (R)-2-amino-2-cyclopentylethan-1-ol (293 mg, 2.27 mmol) in dioxane (15 mL) and the reaction mixture was stirred at 80oC for 2 h. The solvent was removed under reduced pressure to give a crude product which was purified by preparative HPLC, PrepMethod P, (gradient: 30-50%) to give the title compound as a white solid (150 mg, 40%). MS (ESI) m/z 10 [M+H]+ 490.1. Intermediate 71 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopentyl-3-hydroxypropan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 15 Cl K2CO3 (157 mg, 1.13 mmol) wa chloro-6-((1-(4-chloro-2- fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 65 (225 mg, 0.57 mmol) and (R)-2-amino-3-cyclopentylpropan-1-ol (129 mg, 0.62 mmol) in dioxane (10 mL) at rt and the reaction mixture was stirred at 80°C for 2 h. The mixture was concentrated to dryness. 20 The residue was dissolved in DMF and filtered through CELITE. The filtrate was concentrated 147 201388-PCT01-NP to give a crude product which was purified by preparative HPLC, PrepMethod V, (gradient.25– 44%) to give the title compound as a white solid (140 mg, 49%). MS (ESI) m/z [M+H]+ 504.1. Intermediate 72 5 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclobutyl-3-hydroxypropan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Cl K2CO3 (157 mg, 1.13 mmol) wa chloro-6-((1-(4-chloro-2- fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 65 (225 mg, 0.57 10 mmol) and (R)-2-amino-3-cyclobutylpropan-1-ol Intermediate 68 (purity: 69% w/w, 117 mg, 0.62 mmol) in dioxane (2 mL) at rt and the resulting mixture was stirred at 80°C for 2 h. The mixture was concentrated to dryness. The residue was dissolved in DMF and filtered through CELITE. The filtrate was concentrated to give a crude product which was purified by preparative HPLC, PrepMethod V, (gradient: 25–42%) to give the title compound as a white solid (150 mg, 15 54%). MS (ESI) m/z [M+H]+ 490.1. Intermediate 73 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopropyl-3-hydroxypropan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 20 Cl 201388-PCT01-NP K2CO3 (139 mg, 1.01 mmol) was added to a mixture of (R)-2-amino-3-cyclopropylpropan-1-ol (290 mg, 2.52 mmol) and N-(4-chloro-6-((1-(4-chloro-2-fluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 65 (200 mg, 0.50 mmol) in dioxane (8 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at 80°C for 15 h. The solvent was 5 removed under reduced pressure. The residue was diluted with DMF and filtered through CELITE. The filtrate was evaporated to afford a crude product which was purified by preparative HPLC, PrepMethod Q, (gradient: 25-82%) to give the title compound aa a colorless solid (160 mg, 67%). MS (ESI) m/z [M+H]+ 476.1. 10 Intermediate 74 (R)-2-((4-Chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)pentan-1-ol DIPEA (3.79 ml, 21.69 mmol) wa 1,3,5-triazine (2.00 g, 10.85 mmol) in THF (40 mL) at 0°C. A solution of (4-methoxyphenyl)methanethiol (1.67 g, 10.85 mmol) in 15 THF (10 mL) was added to the stirred mixture at 0°C and the resulting suspension was stirred for 1 h. A solution of (R)-2-aminopentan-1-ol (1.12 g, 10.85 mmol) in THF (10 mL) was added to the stirred mixture at 0°C and the resulting suspension was stirred for 1.5 h at 0oC followed by 2 h at rt. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase 20 flash chromatography on silica (gradient: 0–20% EtOAc in PE) to afford the title compound as a yellow solid (2.50 g, 62%). MS (ESI) m/z [M+H]+ 369.3. Intermediate 75 (R)-N-(4-((1-Hydroxypentan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2- 25 yl)methanesulfonamide 149 201388-PCT01-NP K2CO3 (337 mg, 2.44 mmol) w (4-chloro-6-((4- methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)pentan-1-ol Intermediate 74 (600 mg, 1.63 mmol), methanesulfonamid (155 mg, 1.63 mmol), Pd2(dba)3 (74 mg, 0.08 mmol) and X-Phos (78 5 mg, 0.16 mmol) in THF (15 mL) at 15°C under an atmosphere of N2(g). The reaction mixture was stirred at 55°C for 15 h. The reaction was incomplete and further methanesulfonamide (155 mg, 1.63 mmol), Pd2(dba)3 (74 mg, 0.08 mmol) and X-Phos (78 mg, 0.16 mmol) were added and the solution was stirred at 55°C for an additional 5 h under an atmosphere of N2(g). The mixture was diluted with TBME (100 mL) and washed with water (2×50 mL). The aqueous layer was 10 acidified with 2 M HCl (aq). The aqueous layer was extracted with EtOAc (125 mL), and the organic layer was washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (460 mg, 66%) which was used without further purification. MS (ESI) m/z [M+H]+ 428.1. 15 Intermediate 76 (R)-N-(4-((1-Hydroxypentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide H Anisole (0.141 mL, 1.29 mmol) was 1-hydroxypentan-2-yl)amino)-6-((4- methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 75 (460 mg, 1.08 20 mmol) in TFA (8 mL) at 15°C and the reaction mixture was stirred at 15°C for 3 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with TBME and washed with sat NaHCO3 (2×50 mL). The aqueous layer was acidified with 2 M HCl and extracted with 150 201388-PCT01-NP EtOAc (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a pale yellow solid (260 mg, 79%) which was used without further purification. MS (ESI) m/z [M+H]+ 308.1. 5 Intermediate 77 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide OH Cl K2CO3 (139 mg, 1.01 mmol) wa -(4-chloro-2- 10 fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 65 (200 mg, 0.50 mmol), and (R)-2-amino-2-cyclopropylethanol (255 mg, 2.52 mmol) in dioxane (1 mL) at rt under an atmosphere of N2(g). The reaction mixture was stirred at 80°C for 5 h. The solvent was removed under reduced pressure. The residue was diluted with DMF and filtered through CELITE. The filtrate was concentrated to afford a crude product which was purified by 15 preparative HPLC, PrepMethod Q, (gradient: 30-75%) to give the title compound as a white solid (130 mg, 56%). MS (ESI) m/z [M+H]+ 462.0. Intermediate 78 S-(1-(4-Chloro-3-fluorophenyl)ethyl) ethanethioate O 20 KSAc (8.66 g, 75.8 mmol) was added s y period of 5 min to 4-(1-bromoethyl)-1- chloro-2-fluorobenzene (9.00 g, 37.9 mmol) in acetone (100 mL) at rt and the reaction mixture was stirred for 5 h. The solvent was removed under reduced pressure. The residue was diluted 151 201388-PCT01-NP with EtOAc and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (8.50 g, 96%) which was used without further purification.1H NMR (300 MHz, CDCl3) δ 1.65 (3H, d), 2.34 (3H, s), 4.65-4.71 (1H, m), 7.06- 7.15 (2H, m), 7.26-7.34 (1H, m). 5 Intermediate 79 1-(4-Chloro-3-fluorophenyl)ethane-1-thiol F HS Cl 3 M NaOH (229 mL, 687 mmol) was added to S-(1-(4-chloro-3-fluorophenyl)ethyl) 10 ethanethioate Intermediate 78 (8.00 g, 34.4 mmol) in acetone (250 mL) and the reaction mixture was stirred at rt for 3 h. The organic solvent was removed under reduced pressure and the pH of the remaining water phase was adjusted to pH 7 with 2 M HCl and then extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 0–10% EtOAc in PE) to 15 afford the title compound as a colorless oil (6.0 g, 92%). Intermediate 80 (2R)-2-((4-Chloro-6-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2- cyclobutylethan-1-ol F 20 Cl 1-(4-Chloro-3-fluorophenyl)ethan e- -t o ntermed ate 79 (517 mg, 2.71 mmol) was added dropwise to a mixture of 2,4,6-trichloro-1,3,5-triazine (500 mg, 2.71 mmol) and DIPEA (701 mg, 5.42 mmol) in THF (10 mL) at 0°C under an atmosphere of N2(g) and the reaction mixture was stirred at 0oC for 1 h. (R)-2-Amino-2-cyclobutylethanol (312 mg, 2.71 mmol) was added and 152 201388-PCT01-NP the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (PE:EtOAc, 3:1) to afford the title compound as a yellow gum (300 mg, 26%). MS (ESI) m/z [M+H]+ 417.0/419.0. 5 Intermediate 81 N-(4-((1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclobutyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide F Cl Pd2(dba)3×CHCl3 (372 mg, 0.36 re of (2R)-2-((4-chloro-6-((1-(4- 10 chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2-cyclobutylethan-1-ol Intermediate 80 (300 mg, 0.72 mmol), methanesulfonamide (547 mg, 5.75 mmol), K2CO3 (298 mg, 2.16 mmol) and X-Phos (514 mg, 1.08 mmol) in THF (15 mL) under an atmosphere of N2(g) and the reaction mixture was stirred at 55°C for 3 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, 15 filtered and concentrated to afford a brown solid. The crude product was purified by preparative HPLC, PrepMethod Q, (gradient: 30–75%) to afford the title compound as a white solid (100 mg, 29 %). MS (ESI) m/z [M+H]+ 476.0. Intermediate 82 20 (2R)-2-((4-Chloro-6-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2- cyclopentylethan-1-ol 153 201388-PCT01-NP F Cl 1-(4-Chloro-3-fluorophenyl)ethan 9 (517 mg, 2.71 mmol) was added dropwise to a mixture of 2,4,6-trichloro-1,3,5-triazine (500 mg, 2.71 mmol) and DIPEA (701 mg, 5.42 mmol) in THF (15 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was 5 stirred at 0oC for 1 h. (R)-2-Amino-2-cyclopentylethanol (350 mg, 2.71 mmol) was added and the reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (PE:EtOAc, 1:1), to afford the title compound as a yellow solid (500 mg, 43%). MS (ESI) m/z [M+H]+ 431.0/433.0. 10 Intermediate 83 N-(4-((1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopentyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide F Cl Pd2(dba)3×CHCl3 (360 mg, 0.35 re of (2R)-2-((4-chloro-6-((1-(4- 15 chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2-cyclopentylethan-1-ol Intermediate 82 (300 mg, 0.70 mmol), methanesulfonamide (529 mg, 5.56 mmol), K2CO3 (288 mg, 2.09 mmol) and X-Phos (498 mg, 1.04 mmol) in THF (15 mL) under an atmosphere of N2(g) and the reaction mixture was stirred at 55°C for 3 h. The solid was filtered off and the filtrate was concentrated to give a crude product which was purified by preparative HPLC, 20 PrepMethod M, (gradient: 19–67%) to give the title compound as a white solid (100 mg, 29%). 154 201388-PCT01-NP Intermediate 84 N-(4-((1-(4-Chlorophenyl)ethyl)thio)-6-(((2R,3R)-1,2-dihydroxyhexan-3-yl)amino)-1,3,5-triazin- 2-yl)methanesulfonamide OH Cl 5 DIPEA (0.435 mL, 2.49 mmol) 4-(((2R,3R)-1,2-dihydroxyhexan-3- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 60 (280 mg, 0.83 mmol), and 1-(1-bromoethyl)-4-chlorobenzene (182 mg, 0.83 mmol) in DMF (10 mL) at 30°C and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure to give a crude product which was purified by preparative HPLC, PrepMethod S, (gradient: 25– 10 80%) to give the title compound as a white solid (330 mg, 84%). MS (ESI) m/z [M+H]+ 476.3/478.3. Intermediate 85 (2R)-2-((4-Chloro-6-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-3- 15 cyclopentylpropan-1-ol F Cl 1-(4-Chloro-3-fluorophenyl)ethane 9 (1.03 g, 5.42 mmol) was added dropwise over a period of 5 min to a mixture of 2,4,6-trichloro-1,3,5-triazine (1.00 g, 5.42 mmol) and DIPEA (1.75 g, 13.56 mmol) in THF (10 mL) at 0°C under an atmosphere of N2(g). The 20 reaction mixture was stirred at rt for 3 h. (R)-2-Amino-3-cyclopentylpropan-1-ol (903 mg, 5.42 mmol) was added dropwise to the solution at 0°C and the reaction mixture was stirred at rt for 4 155 201388-PCT01-NP h. The solvent was removed under reduced pressure to afford the crude product which was purified by straight phase flash chromatography on silica (gradient: 0–90% EtOAc in PE) to afford the title compound as a yellow oil (2.10 g, 87%). MS (ESI) m/z [M+H]+ 445.2/447.2. 5 Intermediate 86 (2R)-2-((4-Chloro-6-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2- cyclopropylethan-1-ol OH F Cl A solution of 1-(4-chloro-3-fluoro ermediate 79 (414 mg, 2.17 mmol)10 in THF (2 mL) was added dropwise over a period of 5 min to a stirred solution of 2,4,6-trichloro- 1,3,5-triazine (400 mg, 2.17 mmol) and DIPEA (0.758 mL, 4.34 mmol) in THF (20 mL) at 0°C and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 1 h. (R)-2-Amino- 2-cyclopropylethanol (219 mg, 2.17 mmol) in THF (2 mL) was added dropwise over a period of 3 min at 0°C and the reaction mixture was stirred at 0°C for 30 min and then at rt for 1 h. The 15 mixture was diluted with EtOAc (100 mL) and washed sequentially with water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc 2:1) to afford the title compound as a colorless oil (340 mg, 39%). MS (ESI) m/z [M+H]+ 403.0/405.0. 20 Intermediate 87 N-(4-((1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopropyl-2-hydroxyethyl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 156 201388-PCT01-NP OH HN F Cl K2CO3 (170 mg, 1.23 mmol) wa 2-((4-chloro-6-((1-(4-chloro-3- fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-2-cyclopropylethanol Intermediate 86 (330 mg, 0.82 mmol), methanesulfonamide (389 mg, 4.09 mmol), Pd2(dba)3 (75 mg, 0.08 mmol) and 5 X-Phos (78 mg, 0.16 mmol) in THF (10 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at 55°C for 15 h. The reaction was incomplete and further methanesulfonamide (156 mg, 1.64 mmol), Pd2(dba)3 (75 mg, 0.08 mmol), X-Phos (78 mg, 0.16 mmol) and K2CO3 (56 mg, 0.41 mmol) were added, and the reaction mixture was stirred at 55°C for an additional 5 h. The solvent was removed under reduced pressure and the residue was first 10 purified by preparative TLC (DCM:MeOH, 20:1) and then by preparative HPLC, PrepMethod X, (gradient: 21–85%) to give the title compound as a white solid (60 mg, 16%). MS (ESI) m/z [M+H]+ 462.0. Intermediate 88 15 (2R)-2-((4-Chloro-6-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-3- cyclopropylpropan-1-ol F Cl A solution of 1-(4-chloro-3-fluorop eny )et ane- -t o ntermediate 79 (414 mg, 2.17 mmol) in THF (3.00 mL) was added dropwise over a period of 5 min to a stirred solution of 2,4,6- 20 trichloro-1,3,5-triazine (400 mg, 2.17 mmol) and DIPEA (0.76 mL, 4.34 mmol) in THF (20 mL) at 0°C and under an atmosphere of N2(g) and the reaction mixture was stirred at 0°C for 1 h. (R)- 2-Amino-3-cyclopropylpropan-1-ol (250 mg, 2.17 mmol) was added dropwise and the reaction 157 201388-PCT01-NP mixture was stirred at 0°C for 20 min and then at rt for 1 h. The mixture was diluted with EtOAc (150 mL) and washed sequentially with water (75 mL) and brine (75 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 2:1) to afford the title compound as a colorless oil (405 mg, 45%). MS (ESI) 5 m/z [M+H]+ 417.0/419.0. Intermediate 89 N-(4-((1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclopropyl-3-hydroxypropan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 F Cl K2CO3 (199 mg, 1.44 mmol) wa 2-((4-chloro-6-((1-(4-chloro-3- fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-3-cyclopropylpropan-1-ol Intermediate 88 (400 mg, 0.96 mmol), methanesulfonamide (456 mg, 4.79 mmol), Pd2(dba)3 (88 mg, 0.10 mmol) 15 and X-Phos (92 mg, 0.19 mmol) in THF (10 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at 55°C for 15 h. The reaction was incomplete and further methanesulfonamide (274 mg, 2.88 mmol), Pd2(dba)3 (88 mg, 0.10 mmol) and X-Phos (92 mg, 0.19 mmol) were added, and the reaction mixture was stirred at 55°C for an additional 5 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC 20 (DCM:MeOH, 20:1) followed by preparative HPLC, PrepMethod X, (gradient: 21–85%) to give the title compound as a white solid (130 mg, 28%). MS (ESI) m/z [M+H]+ 476.0. Intermediate 90 tert-Butyl (S)-2,2-dimethyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)oxazolidine-3-carboxylate Boc N O 25 201388-PCT01-NP A mixture of (S)-3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidine-4-carboxylic acid (45 g, 184 mmol), N'-hydroxyacetimidamide (15 g, 202 mmol), EDC×HCl (43 g, 220 mmol) HOBt (30 g, 220 mmol) and TEA (186 g, 1835 mmol) in DCM (1 L) was stirred at rt on. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. 5 The organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in DMF (300 mL) and heated at reflux for 6 h. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: 0–10% EtOAc in PE) to afford the title compound as a 10 yellow oil. MS (ESI) m/z [M+H]+ 283.1. Intermediate 91 (S)-2-Amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)ethan-1-ol×HCl N H 15 4 M HCl in MeOH (500 mL, 2 mol) was wise to tert-butyl (S)-2,2-dimethyl-4-(3- methyl-1,2,4-oxadiazol-5-yl)oxazolidine-3-carboxylate Intermediate 90 (58 g, 205 mmol) at 0oC and the mixture was stirred at 0oC for 1 h. The solvent was removed under reduced pressure and the residue was dissolved in acetone (100 mL) and TBME (300 mL) was added. After standing for 2 h at rt the white precipitate was filtered off and dried to give the title compound as 20 a white solid (23.5 g, 64%). MS (ESI) m/z [M+H]+ 144.0. Intermediate 92 1-Phenylpropan-2-yl methanesulfonate O S O 25 DIPEA (1.41 mL, 8.08 mmol) and Ms . , . mmol) were added to a solution of 1- phenylpropan-2-ol (1.00 g, 7.34 mmol) in DCM (15 mL), and the reaction mixture was stirred at rt for 20 h. The mixture was passed through a short column of silica (eluent DCM) to give the 159 201388-PCT01-NP title compound (1.12 g, 71%).1H NMR (400 MHz, CDCl3) δ 1.50 (3H, d), 2.53 (3H, s), 2.88– 3.06 (2H, m), 4.86–4.98 (1H, m), 7.23–7.31 (3H, m), 7.32–7.39 (2H, m). Intermediate 93 5 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylpropan-2-yl)thio)-1,3,5-triazin- 2-yl)methanesulfonamide DIPEA (0.099 mL, 0.57 mmol) a pan-2-yl methanesulfonate Intermediate 92 (111 mg, 0.52 mmol) in DMF (0.5 mL) were added to a solution of (R)-N-(4- 10 ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (208 mg, 0.52 mmol) in DMF (2 mL) and the reaction mixture was heated to 100°C for 1.5 h. Water and MTBE were added and the two layers were separated. The aqueous layer was extracted with MTBE and the combined organic layer was washed twice with water and concentrated to give a crude product. This was combined with a second batch made in the 15 same way (0.64 mmol scale) and purified by straight phase flash chromatography on silica (DCM/MeOH as eluent) to give the title compound (176 mg, 47%). MS (ESI) m/z [M+H]+ 440.3. Intermediate 941-(2,3-Difluorophenoxy)propan-2-ol and 20 Intermediate 952-(2,3-difluorophenoxy)propan-1-ol F F O F 1-Bromopropan-2-ol (6.88 mL, 53.0 mmol) was added to a slurry of 2,3-difluorophenol (3.45 g, 26.5 mmol) and K2CO3 (7.33 g, 53.0 mmol) in DMF (50 mL) and the mixture was heated to 80oC on. Water (70 mL) was added, and the mixture was extracted with TBME (1×100 mL, then 160 201388-PCT01-NP 2×50 mL). The combined organic layer was washed with water (20 mL) and brine (20 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (gradient: of 20–50% EtOAc in PE) to afford a mixture of the title compounds (4:1) as a light brown oil (1.54 g, 31%).1H NMR (400 MHz, 5 CDCl3, major isomer) δ 1.30 (3H, d), 2.39 (1H, d), 3.88 (1H, dd), 4.02 (1H, dd), 4.18–4.31 (1H, m), 6.69–6.87 (2H, m), 6.92–7.04 (1H, m). Intermediate 961-(2,3-difluorophenoxy)propan-2-yl methanesulfonate and Intermediate 972-(2,3-difluorophenoxy)propyl methanesulfonate O F O F S O F S O F 10 MsCl (0.968 mL, 12.42 mmol) in DCM (3 mL) was added to a mixture of Intermediate 94 and Intermediate 95 (4:1, 1.67 g, 8.87 mmol) and DIPEA (4.65 mL, 26.6 mmol in DCM (6 mL) at 0oC and the reaction mixture was stirred at rt on. NaHCO3(aq) was added, and the mixture was stirred for 10 min. The organic layer was separated and concentrated to give a mixture of the title 15 compounds (about 4:1) in quantitative yield.1H NMR (500 MHz, CDCl3, major isomer) δ 1.54 (3H, d), 3.14 (3H, s), 4.07–4.18 (2H, m), 5.07–5.14 (1H, m), 6.7–6.78 (1H, m), 6.79–6.87 (1H, m), 6.96–7.05 (1H, m). Intermediate 98 N-(4-((1-(2,3-difluorophenoxy)propan-2-yl)thio)-6-(((R)-1-hydroxy-4- 20 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamideand and Intermediate 99 N-(4-((2-(2,3-difluorophenoxy)propyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 161 201388-PCT01-NP F A microwave vial was charged with (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (0.387 g, 1.20 mmol), DIPEA (0.631 mL, 3.61 mmol), MeCN (4 mL), and the mixture of 1-(2,3-difluorophenoxy)propan-2-yl 5 methanesulfonate Intermediate 96 and 2-(2,3-difluorophenoxy)propyl methanesulfonate Intermediate 97 (4:1, 0.449 g, 1.69 mmol). The vial was capped and heated in a microwave reactor at 100oC for 4.5 h. This batch was combined with two other batches made in the same way (both on 0.5 mmol scale) and EtOAc (75 mL) was added. The mixture was washed with 1 M citric acid (10 mL), water (10 mL) and brine (10 mL). The organic layer was concentrated to10 give a crude product which was purified by preparative HPLC, PrepMethod G, (gradient: 35– 75%) to give a mixture of the two title compounds (300 mg, 28%). MS (ESI) m/z [M+H]+ 492.0. Intermediate 100 (R)-1-(4-Fluorophenoxy)propan-2-yl methanesulfonate O O S O 15 DIPEA (0.57 mL, 3.28 mmol) and M . , . mmol) were added to a solution of (R)- 1-(4-fluorophenoxy)propan-2-ol (507 mg, 2.98 mmol) in DCM (5 mL) and the reaction mixture was stirred at rt for 2.5 h. Water and DCM were added and the two layers were separated. The organic layer was filtered through a short plug of silica to give the title compound as a colorless 20 oil (494 mg, 67%).1H NMR (400 MHz, CDCl3) δ 1.53 (3H, d), 3.09 (3H, s), 3.97–4.11 (2H, m), 5.02–5.13 (1H, m), 6.79–6.9 (2H, m), 6.94–7.05 (2H, m). 162 201388-PCT01-NP Intermediate 101 (S,S)-(Salen)Co(III)(OC(CF3)3)×H2O 3 O 5 The compound was prepared accor ure described by Jacobsen, E.N. et.al. in J.Am.Chem.Soc.1999, 121, 6086-87 (the enantiomer to catalyst 3c in the article by using the (S,S)-(salen)Co(II) complex (CAS Reg. No.188264-84-8)). Intermediate 102 10 (R)-1-(2,4-Difluorophenoxy)propan-2-ol OH O (S,S)-(Salen)Co(III)(OC(CF3)3)×H2O (0.077 g, 0.09 mmol) was added to a precooled (-16oC) mixture of 2-methyloxirane (1.260 mL, 18.00 mmol), 2,4-difluorophenol (0.215 mL, 2.25 mmol), molecular sieves (60 mg, 3 Å, powdered, activated by drying at 200oC 15 in an oven) and MTBE (0.2 mL) and the reaction mixture was stirred at -16oC for 24 h. PPTS (0.075 g, 0.3 mmol) and MTBE (5 mL) were added and the mixture was filtered through a plug of silica (2.2 g SiO2, eluted with 50 mL heptane:EtOAc, (40:60) followed by 10 mL EtOAc). The compound containing fractions were collected and concentrated and the crude product was dissolved in TBME (35 mL) and washed with water (2×5 mL) and brine (5 mL). The organic 20 layer was dried over Na2SO4, filtered and concentrated to give the title compound as a light brown oil (409 mg, 97%).1H NMR (400 MHz, CDCl3) δ 1.27 (3H, d), 2.32 – 2.53 (1H, m, OH), 3.82 (1H, dd), 3.97 (1H, dd), 4.13 – 4.28 (1H, m), 6.59 – 7.07 (3H, m). 163 201388-PCT01-NP Intermediate 103 (R)-1-(2,4-Difluorophenoxy)propan-2-yl methanesulfonate O F S O O F MsCl (0.095 mL, 1.21 mmol) di added to a solution of (R)-1-(2,4- 5 difluorophenoxy)propan-2-ol Intermediate 102 (202 mg, 1.07 mmol) and TEA (0.224 mL, 1.61 mmol) in DCM (4 mL) at 0oC and the reaction mixture was stirred at 0oC for 25 min and then at rt for 2 h 20 min. DCM (10 mL) and water (2 mL) were added and the layers were separated using a phase separator. The organic layer was concentrated to give the title compound as a light brown oil (249 mg, 87 %).1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.12 (3H, s), 4 – 4.14 10 (2H, m), 4.99 – 5.18 (1H, m), 6.72 – 7.01 (3H, m). Intermediate 104 (R)-1-(3-fluoro-4-methoxyphenoxy)propan-2-ol O F HO 15 Prepared in a similar way as descr 2 using 2-methyloxirane (0.63 mL, 9 mmol) and 3-fluoro-4-methoxyphenol (159 mg, 1.12 mmol) to give the title compound as a brown oil (207 mg, 92%).1H NMR (400 MHz, CDCl3) δ 1.27 (3H, d), 2.28 (1H, d), 3.73 (1H, dd), 3.85 (3H, s), 3.88 (1H, dd), 4.1 – 4.25 (1H, m), 6.61 (1H, ddd), 6.71 (1H, dd), 6.88 (1H, t). 20 Intermediate 105 (R)-1-(3-Fluoro-4-methoxyphenoxy)propan-2-yl methanesulfonate O S O F Prepared in a similar way as descr e o e e a e 3 from (R)-1-(3-fluoro-4- methoxyphenoxy)propan-2-ol Intermediate 104 (202 mg, 1.01 mmol) to give the title 25 compound as a dark oil (253 mg, 90%).1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.07 (3H, s), 164 201388-PCT01-NP 3.85 (3H, s), 3.97 (1H, dd), 4.03 (1H, dd), 5 – 5.13 (1H, m), 6.59 (1H, ddd), 6.69 (1H, dd), 6.89 (1H, t). Intermediate 106 5 (R)-1-(3,4-Difluorophenoxy)propan-2-ol OH O Prepared in a similar way as described 102 using 2-methyloxirane (0.63 mL, 9 mmol) and 3-fluoro-4-methoxyphenol (146 mg, 1.12 mmol) to give the title compound as a brown oil (196 mg, 93%).1H NMR (400 MHz, CDCl3) δ 1.28 (3H, d), 3.75 (1H, dd), 3.88 (1H, 10 dd), 4.12 – 4.26 (1H, m), 6.55 – 6.66 (1H, m), 6.68 – 6.82 (1H, m), 7.01 – 7.13 (1H, m). Intermediate 107 (R)-1-(3,4-Difluorophenoxy)propan-2-yl methanesulfonate O S O O F 15 Prepared in a similar way as descr 03 from (R)-1-(3,4- difluorophenoxy)propan-2-ol Intermediate 106 (193 mg, 1.03 mmol) to give the title compound as a brown oil (246 mg, 90%).1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.07 (3H, s), 3.99 (1H dd), 4.04 (1H, dd), 5.01 – 5.14 (1H, m), 6.56 – 6.64 (1H, m), 6.72 (1H, ddd), 7.03 – 7.13 (1H, m). 20 Intermediate 108 (R)-1-(3-Chlorophenoxy)propan-2-ol OH Cl 201388-PCT01-NP Prepared in a similar way as described for Intermediate 102 using 2-methyloxirane (0.63 mL, 9 mmol) and 3-chlorophenol (144 mg, 1.12 mmol) to give the title compound as a light-yellow oil (209 mg, 100%).1H NMR (400 MHz, CDCl3) δ 1.29 (3H, d), 2.25 (1H, d), 3.79 (1H, dd), 3.93 (1H, dd), 4.19 (1H, dtd), 6.80 (1H, ddd), 6.92 (1H, t), 6.95 (1H, ddd), 7.20 (1H, t). 5 Intermediate 109 (R)-1-(3-Chlorophenoxy)propan-2-yl methanesulfonate O S O Cl O O Prepared in a similar way as descri 03 from (R)-1-(3- 10 chlorophenoxy)propan-2-ol Intermediate 108 (205 mg, 1.10 mmol) to give the title compound as a light brown oil (273 mg, 94%).1H NMR (400 MHz, CDCl3) δ 1.53 (3H, d), 3.08 (3H, s), 3.95 – 4.21 (2H, m), 5 – 5.16 (1H, m), 6.78 (1H, ddd), 6.89 (1H, t), 6.98 (1H, ddd), 7.22 (1H, t). Intermediate 110 15 (R)-1-(4-Chloro-2-fluorophenoxy)propan-2-ol OH O Cl Prepared in a similar way as describe 102 using 2-methyloxirane (1.26 mL, 18 mmol) and 4-chloro-2-fluorophenol (330 mg, 2.25 mmol) to give the title compound as a brown oil (468 mg, 102%).1H NMR (400 MHz, CDCl3) δ 1.28 (3H, d), 2.37 (1H, d), 3.83 (1H, 20 dd), 3.98 (1H, dd), 4.16 – 4.28 (1H, m), 6.90 (1H, t), 7.04 (1H, ddd), 7.11 (1H, dd). Intermediate 111 (R)-1-(4-Chloro-2-fluorophenoxy)propan-2-yl methanesulfonate O O S 201388-PCT01-NP Prepared in a similar way as described for Intermediate 103 from (R)-1-(4-chloro-2- fluorophenoxy)propan-2-ol Intermediate 110 (140 mg, 0.68 mmol) to give the title compound as a light brown oil (123 mg, 64%).1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.11 (3H, s), 4.02–4.16 (2H, m), 5.02–5.14 (1H, m), 6.88 (1H, t), 7.06 (1H, ddd), 7.12 (1H, dd). 5 Intermediate 112 1-(2,6-Difluorophenoxy)propan-2-ol F OH O Powdered KOH (0.3 g, 5.35 mmol) wa O (10 mL) followed by a solution of 2,6- 10 difluorophenol (1.821 g, 14.0 mmol) in DMSO (10 mL) and the reaction mixture was stirred at rt for 10 min before 2-methyloxirane (1.00 g, 17.22 mmol) was added dropwise. The reaction mixture was stirred at 55°C for 19 h. Water and Et2O was added. The organic layer was washed with Na2CO3 (aq) and water, dried over MgSO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography (heptane:EtOAc, 3:1) to give the title 15 compound (412 mg, 15%).1H NMR (400 MHz, CDCl3) δ 1.24 (3H, d), 2.59 (1H, d), 3.91 (1H, dd), 4.1–4.23 (2H, m), 6.85–7.04 (3H, m). Intermediate 113 1-(2,6-Difluorophenoxy)propan-2-yl methanesulfonate O O S F O 20 DIPEA (0.407 mL, 2.34 mmol) and M . , .34 mmol) were added to a solution of 1- (2,6-difluorophenoxy)propan-2-ol Intermediate 112 (400 mg, 2.13 mmol) in DCM (5 mL) and the reaction mixture was stirred at ambient temperature for 3 h. Water was added and the two layers were separated and the organic layer was filtered through a short plug of silica (eluted 25 with DCM) to give the title compound (391 mg, 69%).1H NMR (400 MHz, CDCl3) δ 1.51 (3H, d), 3.12 (3H, s), 4.13–4.3 (2H, m), 5.02–5.14 (1H, m), 6.86–7.09 (3H, m). 167 201388-PCT01-NP Intermediate 114 1-(4-Chlorophenoxy)propan-2-yl methanesulfonate O O S O O 5 MsCl (0.177 mL, 2.27 mmol) dissolv was added to a solution of 1-(4- chlorophenoxy)propan-2-ol (0.412 g, 2.21 mmol) and TEA (0.462 mL, 3.31 mmol) in DCM (7 mL) at 0oC and the reaction mixture was stirred at 0oC for 20 min and then at rt for 2h. An additional amount of MsCl (0.017 mL, 0.22 mmol) was added and the reaction mixture was stirred at rt for 1 h. DCM (20 mL) and water (4 mL) were added, and the layers were separated 10 by a phase separator. The organic layer was concentrated to give the title compound as a light brown oil (0.543 g, 93 %) which was used without further purification.1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.07 (3H, s), 4.01 (1H, dd), 4.07 (1H, dd), 4.9 7 – 523 (1H, m), 6.79 – 6.86 (2H, m), 7.22 – 7.28 (2H, m). 15 Intermediate 115 N-(4-((1-(4-Chlorophenoxy)propan-2-yl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide Cl A microwave vial was charged . , -((1-hydroxy-4-methylpentan-2- 20 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (0.235 g, 0.73 mmol), 1-(4-chlorophenoxy)propan-2-yl methanesulfonate Intermediate 114 (0.271 g, 1.02 mmol) and DIPEA (0.383 mL, 2.19 mmol). The vial was capped and heated in a micro wave reactor to 100oC for 5 h. EtOAc (50 mL) was added, and the mixture was washed with sat NaHCO3 (8 mL), water (5 mL) and brine (5 mL). The organic layer was dried over Na2SO4, 168 201388-PCT01-NP filtered and cocnetrated. The crude product was purified by preparative HPLC, PrepMethod D (gradient: 15–55%) to give the title compound as a white solid (118 mg, 33%). MS (ESI) m/z [M+H]+ 490.3. 5 Intermediate 116 (R)-1-(3,4,5-Trifluorophenoxy)propan-2-ol O HO F F Prepared in a similar way as describe 102 using 2-methyloxiran (0.63 mL, 9 mmol) and 3,4,5-trifluorophenol (166 mg, 1.12 mmol) to give the title compound as a greenish 10 oil (222 mg, 96%). This reaction needed stirring at -16oC for 48 h followed by +5oC for 72 h.1H NMR (400 MHz, CDCl3) δ 1.28 (3H, d), 2.16 (1H, d), 3.74 (1H, dd), 3.86 (1H, dd), 4.07 – 431 (1H, m), 6.36 – 6.69 (2H, m). Intermediate 117 15 (R)-1-(3,4,5-Trifluorophenoxy)propan-2-yl methanesulfonate O S O O F F Prepared in a similar way as descri 03 from (R)-1-(3,4,5- trifluorophenoxy)propan-2-ol Intermediate 116 (224 mg, 1.09 mmol) to give the title compound as a brown solid (273 mg, 88%).1H NMR (400 MHz, CDCl3) δ 1.52 (3H, d), 3.07 (3H, s), 3.93– 20 4.06 (2H, m), 5–5.11 (1H, m), 6.48–6.56 (2H, m). Intermediate 118 (R)-1-(4-Chloro-3-fluorophenoxy)propan-2-ol OH O 201388-PCT01-NP Prepared in a similar way as described for Intermediate 102 using 2-methyloxiran (1.26 mL, 18 mmol) and 4-chloro-3-fluorophenol (331mg, 2.26 mmol) to give the title compound as a greenish oil (469 mg, 100%).1H NMR (400 MHz, CDCl3) δ 1.29 (3H, d), 2.23 (1H, d), 3.77 (1H, dd), 3.90 (1H, dd), 4.13 – 4.28 (1H, m), 6.66 (1H, ddd), 6.72 (1H, dd), 7.27 (1H, t) 5 Intermediate 119 (R)-1-(4-Chloro-3-fluorophenoxy)propan-2-yl methanesulfonate O O S O Prepared in a similar way as describ 03 from (R)-1-(4-chloro-3- 10 fluorophenoxy)propan-2-ol Intermediate 118 (121 mg, 0.59 mmol) to give the title compound as a brown solid (95 mg, 57%).1H NMR (400 MHz, CDCl3) δ 1.53 (3H, d), 3.07 (3H, s), 3.97– 4.11 (2H, m), 5.02–5.14 (1H, m), 6.64 (1H, ddd), 6.71 (1H, dd), 7.29 (1H, t). Intermediate 120 15 2-((2-Fluorophenyl)thio)acetimidamide×HCl NH S H N A mixture of 2-((2-fluorophenyl)thio)a mg, 2.03 mmol) a solution of NaOtBu (0.586 g, 6.10 mmol) in MeOH (15 mL) was heated in a sealed vessel to 100°C for 15 min. NH4Cl (200 mg, 3.74 mmol) was added and reaction mixture was heated at 80°C for 15 min. 20 Two more batches (2.03 mmol scale) were prepared as described above. The solutions from all three batches were combined and concentrated. The residue was stirred with a mixture of IPA:acetone (4:1, 30 mL) for 45 min. The solid was removed by filtration and the filtrate was concentrated to about half volume and an equal volume of Et2O was added dropwise under stirring. After 1 h the formed precipitate was collected by filtration, washed with Et2O and dried 25 to give the title compound (1.12 g, 59%). MS (ESI) m/z [M+H]+ 185.2. 170 201388-PCT01-NP Intermediate 121 6-(((2-Fluorophenyl)thio)methyl)-1,3,5-triazine-2,4(1H,3H)-dione O HN N 5 A suspension of K2CO3 (426 mg, 3.0 luorophenyl)thio)acetimidamide×HCl Intermediate 120 (682 mg, 3.09 mmol) in MeCN (15 mL) was stirred for 5 min under an atmosphere of Ar(g). Bis(phenoxycarbonyl)imine (795 mg, 3.09 mmol) was added and the reaction mixture was stirred at rt for 1 h. K2CO3 (426 mg, 3.09 mmol) was added and the reaction mixture was stirred for 2 h at 60°C. The mixture was cooled to rt the residue was 10 dissolved in 1 M HCl (15 mL ) and EtOAc (50 mL). The layers were separated, the aqueous layer was extracted with EtOAc (2×25 mL), and the combined organic layer was washed with brine and dried over Na2SO4. The organic layer was concentrated and the remaining solid was stirred for 10 min with a mixture of PE:Et2O (2:1, 30 mL), filtered, and the residue was dried. The solid was stirred for 30 min with Et2O (10 mL), and the insoluble material was isolated by 15 filtration to give the title compound (783 mg, 87%). MS (ESI) m/z [M-H]+ 252.0. Intermediate 122 (R)-2-((4-Chloro-6-(((2-fluorophenyl)thio)methyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1- ol 20 A mixture of 6-(((2-fluorophenyl)thio y - , , - zine-2,4(1H,3H)-dione Intermediate 121 (293 mg, 1.16 mmol) and POCl3 (2 mL, 21.46 mmol) was heated in a sealed vessel for 50 min to reflux. After cooling, chlorobenzene (10 mL) was added and the mixture was stirred for a few min. The turbid solution was decanted from some droplets of gum. The solution was 171 201388-PCT01-NP concentrated and the orange residue was dissolved in THF (5 mL). (R)-2-Amino-4- methylpentan-1-ol (0.40 mL, 3.13 mmol) and K2CO3 (200 mg, 1.45 mmol) were added and the reaction mixture was stirred for 1 h at rt. The mixture was diluted with THF (10 mL) and the insoluble material were removed by filtration. The filtrate was concentrated to give a crude 5 product which was purified by preparative HPLC, PrepMethod E, (gradient: 50-100%) to give the title compound as a yellow oil (76 mg, 18%). MS (ESI) m/z [M+H]+ 371.4/373.5 Intermediate 123 3-(1-((4-(((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5- 10 triazin-2-yl)oxy)ethyl)benzonitrile N A solution of (R)-N-(1-((tert-butyl hylpentan-2-yl)-4,6-dichloro-1,3,5- triazin-2-amine Intermediate 10 (0.759 g, 2 mmol) in THF (3 mL) was added to a stirred mixture of NaH (0.24 g, 6.00 mmol, 60% w/w in oil) and 3-(1-hydroxyethyl)benzonitrile (0.294 15 g, 2.00 mmol) in THF (3 mL). The reaction mixture was stirred for 1.5 h. NaH (60 mg, 1.5 mmol, 60% w/w in oil) was added and the reaction mixture was stirred overnight. The reaction was quenched by cautious addition of AcOH (240 µL) in water (10 mL). The mixture was concentrated and distributed between 10% citric acid and DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, 20 PrepMethod I, (gradient: 70–100%) to give the title compound (278 mg, 28%). MS (ESI) m/z [M+H]+ 490.7. Intermediate 124 N-(4-(((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(3- 25 cyanophenyl)ethoxy)-1,3,5-triazin-2-yl)methanesulfonamide 172 201388-PCT01-NP O N A mixture of 3-(1-((4-(((R)-1-((t 4-methylpentan-2-yl)amino)-6- chloro-1,3,5-triazin-2-yl)oxy)ethyl)benzonitrile Intermediate 123 (278 mg, 0.57 mmol), methanesulfonamide (108 mg, 1.14 mmol), Pd2(dba)3 (40 mg, 0.04 mmol), X-Phos (40 mg, 0.08 5 mmol), Cs2CO3 (371 mg, 1.14 mmol) and THF (6 mL) was heated under an atmosphere of Ar(g) at 65°C for 9 h. AcOH (50 µL) was added and the mixture was concentrated. The residue was suspended in DIPE (15 mL), filtered through a silica pad and concentrated to give the title compound (331 mg, 106%) which was used without further purification. MS (ESI) m/z [M+H]+ 549.8. 10 Intermediate 125 N-((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4-chloro-6-(1-(2,3- difluorophenyl)ethoxy)-1,3,5-triazin-2-amine F 15 Prepared in a similar way as descri 23 from (R)-N-(1-((tert- butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4,6-dichloro-1,3,5 e Intermediate 10 (0.759 g, 2.00 mmol) and 1-(2,3-difluorophenyl)ethan-1-ol (316 mg, 2.00 mmol) to give the title compound (204 mg, 20%). MS (ESI) m/z [M+H]+ 501.7/503.7. 20 Intermediate 126 N-(4-(((R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(2,3- difluorophenyl)ethoxy)-1,3,5-triazin-2-yl)methanesulfonamide 173 201388-PCT01-NP O F Prepared in a similar way as desc from N-((R)-1-((tert- butyldimethylsilyl)oxy)-4-methylpentan-2-yl)-4-chloro-6-(1-(2,3-difluorophenyl)ethoxy)-1,3,5- triazin-2-amine Intermediate 125 (202 mg, 0.40 mmol) to give the title compound (240 mg, 5 106%) which was used without further purification. MS (ESI) m/z [M+H]+ 560.8. Intermediate 127 N-(4-(1-(2,3-Difluorophenyl)ethoxy)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide 10 F Prepared in a similar way as descri m N-(4-(((R)-1-((tert- Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(2,3-difluorophenyl)ethoxy)-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 126 (240 mg, 0.43 mmol) to give the title 15 compound (72 mg, 38%). MS (ESI) m/z [M+H]+ 446.2. Intermediate 128 (R)-2-((4-Chloro-6-((S)-1-(pyridin-2-yl)ethoxy)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol 174 201388-PCT01-NP K2CO3 (0.798 g, 5.78 mmol) and (S) nol (0.149 g, 1.21 mmol) were added to a cold (ice bath) solution of 2,4,6-trichloro-1,3,5-triazine (0.161 mL, 1.16 mmol) in THF (5 mL) and the reaction mixture was stirred for 10 min on the ice bath and then at rt for 1 h. The reaction 5 mixture was placed on an ice bath and (R)-2-amino-4-methylpentan-1-ol (0.155 mL, 1.21 mmol) was added. The reaction mixture was stirred for 5 min on the ice bath and then at rt for 1 h. The mixture was partitioned between DCM (50 mL) and 8% NaHCO3 (aq) (50 mL). The aqueous layer was extracted with DCM (50 mL) and the combined organic layer was filtered through a phase separator and concentrated. The crude product was purified by straight phase flash 10 chromatography (0-100% EtOAc:MeOH:TEA (100:10:1) in heptane as eluent) to give the title compound (209 mg, 51%). MS (ESI) m/z [M+H]+ 351.9/353.8. Intermediate 129 2,4-Dichloro-6-((2,3-difluorobenzyl)thio)pyrimidine Cl F 15 A solution of (2,3-difluorophenyl) .93 mmol) in anhydrous THF (5 mL) was added dropwise over 20 min to a solution of 2,4,6-trichloropyrimidine (170 mg, 0.93 mmol) and DIPEA (0.243 mL, 1.39 mmol) in anhydrous THF (5 mL) at 0oC and under an atmosphere of N2(g). The reaction mixture was stirred at 0oC for 30 min and then at rt for 4 h. The mixture was 20 concentrated and the crude mixture (142 mg) was used directly in the next step. Intermediate 130 (R)-2-((4-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-2-yl)amino)-4-methylpentan-1-ol and 175 201388-PCT01-NP Intermediate 131 (R)-2-((2-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol F DIPEA (0.122 mL, 0.70 mmol) and (R)-2-amino-4-methylpentan-1-ol (54 mg, 0.46 mmol) were 5 added to a solution of 2,4-dichloro-6-(2,3-difluorobenzylthio)pyrimidine Intermediate 129 (142 mg, 0.46 mmol) in dry THF (1.5 mL) and the reaction mixture was heated to 65oC for 18 h. The mixture was concentrated, and the residue was purified by preparative HPLC, PrepMethod E (gradient: 45–85%) to give a mixture of the title compounds in an unknown ratio. MS (ESI) m/z [M+H]+ 388.0. 10 Intermediate 132 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)pyrimidin-2- yl)methanesulfonamide 15 DIPEA (0.402 mL, 2.31 mmol) an (0.132 mL, 0.97 mmol) in DMF (0.15 ml) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercaptopyrimidin-2-yl)methanesulfonamide Intermediate 20 (285 mg, 0.89 mmol) in DMF (10 mL) and the reaction mixture was stirred at ambient temperature for 2.5 h. Water and EtOAc were added and the two phases were separated. The aqueous phase was extracted once more with 20 EtOAc. The combined organic layer was passed through a phase separator and concentrated to 176 201388-PCT01-NP give a crude product which was purified by preparative HPLC, PrepMethod G, (gradient: 25– 65%) to give the title compound as a white solid (189 mg, 49%). MS (ESI) m/z [M+H]+ 425.2. Intermediate 133 5 2-((1-(2,3-Difluorophenyl)ethyl)thio)pyrimidine-4,6-diol OH N F F NaOAc (1.34 g, 16.29 mmol) was a imidine-4,6-diol (2.35 g, 16.29 mmol) in water (20 mL) and the mixture was stirred at rt for 30 min.1-(1-Bromoethyl)-2,3- difluorobenzene (3.00 g, 13.57 mmol) in MeCN (20 mL) was added dropwise and the reaction 10 mixture was stirred at rt for 20 h. The mixture was filtered through a pad of CELITE. The solvents were evaporated and the remaining solid was dried in vacuo, washed with PE and dried again in vacuo to afford the title compound as a white solid (3.00 g, 78%). MS (ESI) m/z [M+H]+ 284.9. 15 Intermediate 134 4,6-Dichloro-2-((1-(2,3-difluorophenyl)ethyl)thio)pyrimidine Cl N F F POCl3 (5.43 mL, 58.4 mmol) and te loride (3.88 g, 23.4 mmol) were added to a stirred suspension of 2-((1-(2,3-difluorophenyl)ethyl)thio)pyrimidine-4,6-diol 20 Intermediate 133 (1.66 g, 5.84 mmol) in propionitrile (27 mL). The reaction mixture was heated to gentle reflux for 2 h. The mixture was concentrated in vacuo, and the residue was partitioned between water (60 mL) and EtOAc (30 mL). The aqueous layer was extracted once more with EtOAc, and the combined organic layer was thoroughly washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a 25 light yellow oil (1.83 g, 98%).1H NMR (400 MHz, CDCl3) δ 1.76 (3H, d), 5.27 (1H, q), 7.11 – 7.00 (3H, m), 7.29 – 7.23 (1H, m). 177 201388-PCT01-NP Intermediate 135 (2R)-2-((6-Chloro-2-((1-(2,3-difluorophenyl)ethyl)thio)pyrimidin-4-yl)amino)-4-methylpentan- 1-ol 5 OH F (R)-2-Amino-4-methylpentan-1-ol ( ) was added to a stirred mixture of 4,6- dichloro-2-((1-(2,3-difluorophenyl)ethyl)thio)pyrimidine Intermediate 134 (1.83 g, 5.70 mmol) and NaHCO3 (0.479 g, 5.7 mmol) in MeCN (20 mL). The reaction mixture was heated to 50°C 10 for 5 h. The mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with water, 5% citric acid (aq) and brine, dried over Na2SO4, filtered and concentrated. The crude product was dissolved in DCM and cyclohexane (5 mL) was added, and the solution was concentrated to give a crude product which was purified by preparative HPLC, PrepMethod G, (gradient: 50–100%) to give the title compound (1.78 g, 15 78%). MS (ESI) m/z [M+H]+ 402.4/404.4. Intermediate 136 (E)-3-(2,3-Difluorophenyl)but-2-enenitrile F N F 20 Diethyl cyanomethylphosphonate (4. , was added to a solution of NaOtBu (2.64 g, 27.5 mmol) in absolute EtOH (33 mL) at 0°C, and the mixture was stirred for 15 min.1- (2,3-Difluorophenyl)ethanone (3.90 g, 25.0 mmol) was added and the reaction mixture was stirred at rt for 2 h.10% Citric acid (33 mL) was added and the mixture was extracted with PE (100 mL, then 2×50 mL). The combined organic layer was washed with brine, dried over 25 Na2SO4, filtered and concentrated to give the title compound (3.94 g, 88%).1H NMR showed a 178 201388-PCT01-NP mixture of E- and Z-isomer (~ 4:1) was obtained; 1H NMR (400 MHz, CDCl3) 2.28 – 2.48 (3H, m), 5.54 – 5.66 (1H, m), 7.03 – 7.25 (3H, m). Intermediate 137 5 3-(2,3-Difluorophenyl)butanenitril F N F 10% Pd/C (1.20 g, 1.13 mmol) was a ution of crude (E)-3-(2,3- difluorophenyl)but-2-enenitrile Intermediate 136 (E/Z-mixture, 4:1, 9.92 g, 55.4 mmol) in EtOAc (240 mL) under an atmosphere of Ar(g). The reaction mixture was stirred under an 10 atmosphere of H2(g) (1 atm) at rt for 14 h. The catalyst was removed by filtration through silica and CELITE. The filtrate was concentrated to give the title compound (9.62, 96%) as a colorless oil.1H NMR (400 MHz, CDCl3) 1.48 (3H, dd), 2.58 – 2.75 (2H, m), 3.45 – 3.57 (1H, m), 6.94 – 7.15 (3H, m). 15 Intermediate 138 3-(2,3-Difluorophenyl)butanimidamide×HCl F NH F NH2 2 M AlMe3 in toluene (4.8 mL, 9.6 m pwise to an ice-cold suspension of NH4Cl (0.551 g, 10.3 mmol) in toluene (6 mL) under an atmosphere of Ar(g). The reaction 20 mixture was warmed to rt and stirred for 1 h.3-(2,3-Difluorophenyl)butanenitrile Intermediate 137 (1.09 g, 6.01 mmol) was added and the reaction mixture was stirred at 80°C on. After cooling to rt, the mixture was slowly poured into an ice-cold slurry of silica (4 g) in CHCl3 (15 mL) and stirred for 15 min. The slurry was filtered, and the residue was washed with MeOH (2×40 mL). The combined filtrates were concentrated. The residue was stirred for 5 min with 25 1.25 M HCl in MeOH (4 mL) and then concentrated. The colorless residue was stirred with a mixture of IPA:acetone (4:1, 16 mL) for 45 min, the insoluble material was removed by filtration, and the filtrate was concentrated. The crude product was dissolved in IPA (5 mL).1.25 M HCl in MeOH (0.5 mL) was added under stirring followed by dropwise addition of Et2O (~ 20 179 201388-PCT01-NP mL). The mixture was stirred at rt for 30 min and then cooled to 5°C for 1 h. The colorless precipitate was collected by filtration, washed with Et2O and dried in vacuo to yield the title compound (0.79 g, 56%).1H NMR (400 MHz, D2O) 1.41 (3H, d), 2.68 – 2.9 (2H, m), 3.53 – 3.66 (1H, m), 7.12 – 7.26 (3H, m). 5 Intermediate 139 2-(2-(2,3-Difluorophenyl)propyl)pyrimidine-4,6-diol OH N Diethyl malonate (2.4 mL, 15.8 mm phenyl)butanimidamide×HCl 10 Intermediate 138 (2.47 g, 10.5 mmol) were added to a solution of NaOtBu (3.1 g, 32.3 mmol) in 99.5% EtOH (180 mL) and the reaction mixture was heated to reflux for 7 h. The mixture was concentrated, and the residue was stirred in 50 mL of water and acidified to pH 3 with concentrated HCl on an ice bath. After stirring for 1 h the semi-solid was collected by filtration, washed once with water and dried in vacuo. The solid material was then stirred with 20 mL of 15 cyclohexane for 30 min, and the colourless solid was collected by filtration and dried in vacuo to give the title compound (1.30 g, 46%). MS (ESI) m/z [M+H]+ 267.4. Intermediate 140 4,6-Dichloro-2-(2-(2,3-difluorophenyl)propyl)pyrimidine 20 Cl F 2-(2-(2,3-Difluorophenyl)propyl)p , mediate 139 (1.3 g, 4.88 mmol) was dissolved in POCl3 (0.447 ml, 4.88 mmol) and cooled on an ice bath. N,N-Diethylaniline (727 mg, 4.88 mmol) was added, the cooling bath was removed, and the darkening mixture was 25 heated to reflux for 2.5 h. After cooling to rt the mixture was added to 100 mL of stirred mixture 180 201388-PCT01-NP of ice and water. After complete hydrolysis of the excess POCl3 the mixture was extracted with EtOAc (30 mL, then 2×20 mL). The combined organic layer was washed with 1 M HCl (100 mL) and brine, dried over Na2SO4, filtered and concentrated. The crude residue was dissolved in DCM (15 mL) and filtered through a pad of silica and concentrated to give the title compound as 5 an oil (1.25 g, 84%).1H NMR (400 MHz, CDCl3) δ 1.34 (3H, d), 3.17–3.32 (2H, m), 3.83 (1H, h), 6.97–7.05 (3H, m), 7.23 (1H, s). Intermediate 141 (2R)-2-((6-Chloro-2-(2-(2,3-difluorophenyl)propyl)pyrimidin-4-yl)amino)-4-methylpentan-1-ol F 10 A mixture of 4,6-dichloro-2-(2-(2, pyrimidine Intermediate 140 (0.51 g, 1.68 mmol), (R)-2-amino-4-methylpentan-1-ol (0.289 g, 2.47 mmol) and NaHCO3 (173 mg, 2.06 mmol) in MeCN (10 mL) was stirred at rt for 15 h. (R)-2-Amino-4-methylpentan-1-ol (0.289 g, 2.47 mmol) was added and the reaction mixture was stirred at rt for 1 day. The solid 15 was removed by filtration and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC, PrepMethod G, (gradient: 45–90%) to give the title compound as a semi-solid foam (0.48 g, 74%). MS (ESI) m/z [M+H]+ 384.5/386.5. Intermediate 142 20 N-(2-(2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)pyrimidin- 4-yl)methanesulfonamide 181 201388-PCT01-NP OH F K2CO3 (553 mg, 4.0 mmol) was a of Ar(g) to a stirred mixture of (2R)- 2-((6-chloro-2-(2-(2,3-difluorophenyl)propyl)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 141 (990 mg, 2.58 mmol), methanesulfonamide (285 mg, 3.0 mmol), X-Phos (477 5 mg, 1 mmol), Pd2(dba)3 (229 mg, 0.25 mmol) in THF (16 mL). The reaction mixture was heated in a sealed vessel to 60°C for 19 h. The solvent was evaporated and EtOAc (15 mL) was added. This mixture was filtered through a pad of silica and CELITE, and the clear orange filtrate was concentrated in vacuo. DMSO (20 mL) was added to the remaining red foam and the mixture was stirred for 1 h and then purified by preparative HPLC, PrepMethod G, (gradient: 25–65%) to 10 give the title compound as a solid foam (733 mg, 64%). MS (ESI) m/z [M+H]+ 443.6. Intermediate 143 N-(2-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)pyrimidin-4- yl)methanesulfonamide 15 DIPEA (0.442 mL, 2.54 mmol) an (0.147 mL, 1.07 mmol) in DMF (0.15 ml) were added to a solution of (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercaptopyrimidin-4-yl)methanesulfonamide Example 134 step b (313 mg, 0.98 mmol) in DMF (3 mL) and the reaction mixture was stirred at ambient temperature for 2 h. Water and 20 EtOAc were added and the aqueous phase was extracted with EtOAc. The combined organic layer was washed with water, passed through a phase separator and concentrated to give a crude 182 201388-PCT01-NP product which was purified by preparative HPLC, PrepMethod G, (gradient: 25–65%) to give the title compound as a white solid (260 mg, 63%). MS (ESI) m/z [M+H]+ 425.3. Intermediate 144 5 (R)-2-((4,6-Dichloropyrimidin-2-yl)amino)pentan-1-ol H A solution of (2,3-difluorophenyl)meth g, 5.45 mmol) in THF (50 mL) was added dropwise over 20 min to a solution of 2,4,6-trichloropyrimidine (1 g, 5.45 mmol) and DIPEA (1.428 mL, 8.18 mmol) in THF (50 mL) at 0°C and under an atmosphere of N2(g). The reaction 10 mixture was stirred at 0°C to rt for 30 min and then at rt for 4 h. DIPEA (1.429 mL, 8.18 mmol) and (R)-2-aminopentan-1-ol (0.563 g, 5.45 mmol) were added and the reaction mixture was stirred at 65°C for 18 h. The mixture was purified by preparative HPLC, PrepMethod G, (gradient: 5–65%) to give the second eluted compound as the title compound (329 mg, 24%). MS (ESI) m/z [M+H]+ 250.0. 15 Intermediate 145 (R)-2-((4-Chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-2-yl)amino)pentan-1-ol F S-(2,3-Difluorobenzyl) ethanethioa 0 mg, 0.99 mmol) and K2CO3 (164 20 mg, 1.19 mmol) were added to a solution of (R)-2-(4,6-dichloropyrimidin-2-ylamino)pentan-1-ol Intermediate 144 (247 mg, 0.99 mmol) in MeOH (4 mL) and the reaction mixture was stirred at rt for 48 h. The mixture was concentrated in vacuo, DCM and water was added and the solvent 183 201388-PCT01-NP was concentrated in vacuo and the crude product was purified by preparative HPLC, PrepMethod G, (gradient: 20–95%) to give the title compound (178 mg, 48%). MS (ESI) m/z [M+H]+ 374.0. Intermediate 146 5 N-(6-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-2-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)pyrimidin-4-yl)methanesulfonamide Cl 1-(1-Bromoethyl)-4-chloro-2-fluo mmol) was added dropwise to a mixture of (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-4- 10 yl)methanesulfonamide Example 134 step b (200 mg, 0.62 mmol) and DIPEA (161 mg, 1.25 mmol) in DMF (2 mL) at rt and the reaction mixture was stirred for 2 h. The mixture was concentrated and diluted with EtOAc (100 mL), and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC to give the title compound as an off-white solid (140 mg, 47%). MS (ESI) m/z 15 [M+H]+ 477.1. Intermediate 147 2-((2,3-Difluorobenzyl)thio)pyrimidine-4,6-diol HO F 20 A solution of 1-(bromomethyl)-2,3- g, 10.0 mmol) in MeCN (1.8 mL) was added dropwise over 15 min to a rapidly stirred solution of 2-mercaptopyrimidine-4,6-diol (1.44 g, 10.0 mmol) and NaOAc (1.23 g, 15.0 mmol) in water (18 mL). The reaction mixture was stirred under an atmosphere of Ar(g) at 40°C for 18 h. The solid material was isolated by 184 201388-PCT01-NP filtration, washed with water (30 mL) and dried in vacuo to give the title compound (2.46 g, 91%). MS (ESI) m/z [M+H]+ 271.3. Intermediate 148 5 4,6-Dichloro-2-((2,3-difluorobenzyl)thio)pyrimidine Cl N F F POCl3 (8.48 mL, 91.3 mmol) and t ride (6.0 g, 36.2 mmol) were added to a stirred suspension of 2-((2,3-difluorobenzyl)thio)pyrimidine-4,6-diol Intermediate 147 (2.45 g, 9.1 mmol) in propionitrile (50 mL). The reaction mixture was heated at reflux 10 temperature for 3 h. The mixture was concentrated and the residue was suspended in toluene and concentrated again. The residue was suspended in water and EtOAc. NaHCO3(aq) was added to pH 2 and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and filtered. The organic layer was concentrated to give the title compound as a brown oil (2.7 g, 97%).1H NMR (400 MHz, CDCl3) 15 δ 4.64 (2H, s), 7.18-7.35 (2H, m), 7.45-7.54 (2H , m). Intermediate 149 (R)-2-((6-Chloro-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol F 20 (R)-2-Amino-4-methylpentan-1-ol , was added to a stirred mixture of 4,6- dichloro-2-((2,3-difluorobenzyl)thio)pyrimidine Intermediate 148 (2.7 g, 8.79 mmol) and NaHCO3 (0.80 g, 9.52 mmol) in MeCN (30 mL). The reaction mixture was heated to 55°C for 5 h. The mixture was concentrated and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, 185 201388-PCT01-NP filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod G (gradient: 45–85%) to give the title compound as a colorless solid (2.55 g, 75%). MS (ESI) m/z [M+H]+ 388.5/390.5. 5 Intermediate 150 N-(6-Chloro-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)methanesulfonamide Cl O O N F F The title compound was prepared -difluorobenzyl)thio)pyrimidine WO2004011443 in analogy with the description for Intermediate 153 to give the title compound 10 (3.2 g, 56%).1H NMR (400 MHz, CDCl3) δ 7.28–7.22 (1H, m).7.08–6.95 (2H, m), 6.78 (1H, s), 4.38 (2H, s), 3.24 (3H, s). Intermediate 151 2-(Benzylthio)pyrimidine-4,6-diol 15 OH N (Bromomethyl)benzene (9.92 g, 0.05 dropwise to a solution of 2- mercaptopyrimidine-4,6-diol (8 g, 0.056 mol) in 1 M NaOH (aq, 110 mL) on an ice bath. After complete addition, the reaction mixture was stirred at 50–55oC for 4 h. AcOH was added to the 20 mixture to adjust the pH to pH 2. The solid was collected by filtration and washed with PE to give the title compound (8.9 g, 68%).1H NMR (400 MHz, DMSO-d6) δ 7.42 (2H, d), 7.18-7.31 (4H, m), 4.34 (2H, s). Intermediate 152 25 2-(Benzylthio)-4,6-dichloropyrimidine 186 201388-PCT01-NP Cl N N, N-Diethylaniline (12.7 g, 85.4 mm wise at 0oC to a stirred suspension of 2- (benzylthio)pyrimidine-4,6-diol Intermediate 151 (10 g, 42.8 mmol) in POCl3 (100 mL). After complete addition, the reaction mixture was heated to reflux for 2 h and then concentrated under 5 reduced pressure. Ice water was added to the residue and the resulting mixture was stirred for 50 min. The crystalline precipitate was collected by filtration and washed with water to give the title compound (9.8 g, 84%). Intermediate 153 10 N-(2-(Benzylthio)-6-chloropyrimidin-4-yl)methanesulfonamide Cl O O N NaH (2.6 g, 65 mmol,) was added in to a stirred solution of methanesulfonamide (3.1 g, 32.6 mmol, 1.1 eq) in DMF (70 mL). The reaction mixture was stirred at 55-60oC for 30 min.2-(Benzylthio)-4,6-dichloropyrimidine Intermediate 152 (8.0 g, 15 30 mol) was added in portions, and the reaction mixture was stirred at rt for 18 h. The mixture was concentrated under reduced pressure. Water was added to the residue and the aqueous layer was extracted with EtOAc (×2). The aqueous layer was adjusted pH to 5 with AcOH, and then extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine (2×500 mL), dried, filtered and concentrated to give the title compound (2.3 g, 23%).1H NMR (400 20 MHz, CDCl3) δ 7.42 (2H, d), 7.08-7.34 (3H, m), 6.66 (1H, s), 4.39 (2H, s), 3.30 (3H, s). Intermediate 154 N-(6-Chloro-2-((2-cyanobenzyl)thio)pyrimidin-4-yl)methanesulfonamide 187 201388-PCT01-NP Cl N O O N The title compound was prepared -dihydroxypyrimidin-2- yl)thio)methyl)benzonitrile as described for Intermediate 152 and Intermediate 153 to give the title compound (2.3 g, 55%) as a brown solid.1H NMR (400 MHz, CDCl3) δ 7.68 (2H, d), 7.59 5 (1H, dt), 7.39 (1H, t), 6.93 (1H, s), 4.55 (2H, s), 3.28 (3H, s). Intermediate 155 N-(6-Chloro-2-((4-cyanobenzyl)thio)pyrimidin-4-yl)methanesulfonamide Cl O N N 10 The title compound was prepar hydroxypyrimidin-2- yl)thio)methyl)benzonitrile as described for Intermediate 152 and Intermediate 153 to give the title compound (2.2 g, 39%) as a brown solid.1H NMR (400 MHz, CDCl3) δ 7.77 (2H, d), 7.64 (2H, d) 6.68 (1H, s), 4.46 (2H, s), 3.29 (3H, s). 15 Intermediate 156 N-(6-Chloro-2-((pyridin-2-ylmethyl)thio)pyrimidin-4-yl)methanesulfonamide Cl The title compound was prepared aptopyrimidine-4,6-diol and 2- (bromomethyl)pyridine as described for Intermediate 151, Intermediate 152 and Intermediate 20 153 to give the title compound (2.8 g, 46%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.55 (1H, d), 7.77 (1H, t), 7.59 (1H, d), 7.30 (1H, t), 6.87 (2H, s), 4.51 (2H, s), 3.24 (3H, s). 188 201388-PCT01-NP Intermediate 157 N-(6-Chloro-2-(((3,5-dimethylisoxazol-4-yl)methyl)thio)pyrimidin-4-yl)methanesulfonamide Cl O O N N O 5 The title compound was prepared captopyrimidine-4,6-diol and 4- (bromomethyl)-3,5-dimethylisoxazole as described for Intermediate 151, Intermediate 152 and Intermediate 153 to give the title compound (2.7 g, 60%) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 6.86 (1H, s), 4.12 (2H, s), 3.23 (3H, s), 2.49 (3H, s), 2.34 (3H, s). 10 Intermediate 158 tert-Butyl 5-(((tert-butyldimethylsilyl)oxy)methyl)-7-methyl-3-oxooctanoate O LDA (16.6 mL, 0.0332 mol) was o a solution of tert-butyl acetate (3.85 g, 0.0332 mol) in THF (40 mL) and the reaction mixture was stirred at -78oC for 30 min.4- 15 Isobutyldihydrofuran-2(3H)-one (3.86 g, 27 mmol) was added dropwise, and the reaction mixture was stirred at -78oC for 2 h. The mixture was warmed to 20oC, and imidazole (2.76 g,40.6 mmol) followed by TBDMSCl (6.09 g, 40.6 mmol) were added. The reaction mixture was cooled to 0oC and 0.5 M HCl (aq) was added until pH<5. The mixture was extracted with EtOAc (3×500 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, 20 filtered and concentrated to give the title compound (8.2 g, 81%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 3.52-3.54 (m, 1H), 3.46 (s, 1H), 3.33 (s, 2H), 2.55-2.61 (m,1H), 2.34-2.40 (m, 1H), 2.13-2.15 (m, 1H), 1.64-1.66 (m, 1H), 1.53 (s, 9H), 1.16-1.18 (m, 1H), 1.01-1.02 (m, 1H), 0.84-0.86 (m, 15H), 0.00 (s, 6H). 25 Intermediate 159 189 201388-PCT01-NP 6-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-mercaptopyrimidin-4-ol BS A solution of tert-butyl 5-(((tert-butyld )methyl)-7-methyl-3-oxooctanoate Intermediate 158 (2.25 g, 6.04 mmol), thiourea (597 mg,7.86 mmol) and 0.5 M KOH in EtOH 5 (12 mL) was heated in a microwave reactor at 125oC for 30 min. The mixture was concentrated, and the crude product was purified by column chromatography on silica (gradient: 9–50% EtOAc in PE) to give the title compound (1.1 g, 51%) as a white solid. MS (ESI) m/z [M+H]+ 357.2. 10 Intermediate 160 6-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-((2,3- difluorobenzyl)thio)pyrimidin-4-ol F 1-(Bromomethyl)-2,3-difluoroben was added dropwise at 0oC to a15 solution of 6-(2-(((tert-butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-mercaptopyrimidin-4- ol Intermediate 159 (3.0 g, 8.42 mmol) and NaOH (404 mg,10.01 mmol) in EtOH (20 mL). The reaction mixture was stirred at 25oC for 12 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica (gradient: 9–50% of EtOAc in PE) to give the title compound (3.8 g, 92%) as a white solid. MS (ESI) m/z [M+H]+ 483.2. 20 Intermediate 161 6-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl methanesulfonate 190 201388-PCT01-NP F MsCl (354.4 mg, 3.11 mmol) w solution of 6-(2-(((tert- butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-((2,3-difluorobenzyl)thio)pyrimidin-4-ol Intermediate 160 (1.0 g, 2.07 mmol) and pyridine (327 mg, 4.14 mmol) in DCM (20 mL). The 5 reaction mixture was stirred at 25oC for 12 h. The reaction was quenched with sat NH4Cl (aq,10 mL) and the mixture was extracted with EtOAc (3×300 mL) The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated to give the title compound (1.15 g, 87%) as colorless oil. MS (ESI) m/z [M+H]+ 561.1. 10 Intermediate 162 N-(6-(2-(((tert-Butyldimethylsilyl)oxy)methyl)-4-methylpentyl)-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)methanesulfonamide F A mixture of 6-(2-(((tert-butyldi ethylpentyl)-2-((2,3- 15 difluorobenzyl)thio)pyrimidin-4-yl methanesulfonate Intermediate 161 (1.0 g, 1.78 mmol), methanesulfonamide (424 mg, 4.46 mmol), Pd2(dba)3 (311 mg,0.446 mmol), X-Phos (429 mg, 0.89 mmol) and Cs2CO3 (1.21 g,3.56 mmol) in dioxane (8 mL) was heated in a microwave reactor at 120oC for 30 min. The mixture was concentrated and the crude residue was purified by column chromatography on silica (PE:EtOAc, 1:1) to give the title compound (150 mg, 15%) as 20 white solid. MS (ESI) m/z [M+H]+ 506.2. Intermediate 163 191 201388-PCT01-NP Methyl (R)-2-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)pyrimidine-4-carboxylate OH DIPEA (8.41 mL, 48.31 mmol) and ( ylpentan-1-ol (6.17 mL, 48.31 mmol) were added to a solution of methyl 2,6-dichloropyrimidine-4-carboxylate (10.0 g, 48.31 mmol, 5 40% purity) in THF (100 mL) and the reaction mixture was heated at reflux for 19 h. The mixture was filtered to remove a colorless solid. The mother liquor was concentrated, and the residue was purified by straight phase flash chromatography on silica (heptane:EtOAc, 1:1) to give the title compound as a colourless solid (3.7 g, 27%).1H NMR (400 MHz, CD3OD) δ 0.96– 1.01 (6H, m), 1.43–1.57 (2H, m), 1.62–1.76 (1H, m), 3.52–3.65 (2H, m), 3.94 (3H, s), 4.3–4.4 10 (1H, m), 7.09 (1H, s). Intermediate 164 Methyl (R)-2-((2,3-difluorobenzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)pyrimidine- 4-carboxylate F 15 (R)-Methyl 2-chloro-6-(1-hydrox o)pyrimidine-4-carboxylate Intermediate 163 (3.23 g, 11.23 mmol) and DIPEA (2.15 mL, 12.36 mmol) were added to a solution of (2,3-difluorophenyl)methanethiol (1.8 g, 11.24 mmol) in THF (10 mL) and the reaction mixture was heated in a microwave reactor to 150°C for 3 h. The reaction mixture was 20 filtered, the solvent was evaporated and the residue was purified by straight phase flash chromatography on silica (gradient: 50–100% EtOAc in heptane) to give the title compound (1.55 g, 34%).1H NMR (400 MHz, CDCl3) δ 0.84–0.98 (6H, m), 1.36–1.5 (2H, m), 1.6–1.69 192 201388-PCT01-NP (1H, m), 2.00 (1H, s), 3.55–3.63 (1H, m), 3.66–3.74 (1H, m), 3.94 (3H, s), 4.33–4.47 (2H, m), 5.12 (1H, s), 6.77 (1H, s), 6.92–7.08 (2H, m), 7.3–7.39 (1H, m). Intermediate 165 5 (R)-2-((2,3-Difluorobenzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)pyrimidine-4- carboxylic acid F 2 M NaOH (aq, 1 mL) and MeO lution of methyl (R)-2-((2,3- difluorobenzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)pyrimidine-4-carboxylate 10 Intermediate 164 (540 mg, 1.31 mmol) in dioxane (6 mL) and the reaction mixture was stirred at ambient temperature for 2 h. The mixture was acidified to pH 4–5 by the addition of 1 M HCl. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was concentrated to give the title compound as a colorless solid (492 mg, 94%).1H NMR (400 MHz, CD3OD) δ 0.85–0.97 (6H, m), 1.38–1.5815 (2H, m), 1.66 (1H, tq), 3.48–3.6 (2H, m), 4.38 (1H, dt), 4.47–4.6 (2H, m), 6.86 (1H, s), 7.04– 7.22 (2H, m), 7.31–7.39 (1H, m). Intermediate 166 (R)-2-((2,3-Difluorobenzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)pyrimidine-4- 20 carboxamide F 201388-PCT01-NP TBTU (445 mg, 1.39 mmol) and DIPEA (0.323 mL, 1.85 mmol) were added to a solution of (R)- 2-(2,3-difluorobenzylthio)-6-(1-hydroxy-4-methylpentan-2-ylamino)pyrimidine-4-carboxylic acid Intermediate 165 (367 mg, 0.92 mmol) in DMF (10 mL) and the reaction mixture was stirred at ambient temperature for 10 min. NH4Cl (247 mg, 4.62 mmol) was added and the 5 reaction mixture was stirred for 19 h. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with 10% NaHCO3 (aq) and water, dried over MgSO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (heptane:EtOAc, 1:2) to give the title compound (145 mg, 40%). MS (ESI) m/z [M+H]+ 397.0. 10 Intermediate 167 (R)-2-((6-(Aminomethyl)-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1- ol F 15 BH3×Me2S (0.026 mL, 0.28 mm f (R)-2-(2,3-difluorobenzylthio)-6- (1-hydroxy-4-methylpentan-2-ylamino)pyrimidine-4-carboxamide Intermediate 166 (55 mg, 0.14 mmol) in THF (2 mL). The reaction mixture was stirred at ambient temperature for 4 h. BH3×Me2S (0.026 mL, 0.28 mmol) was added and the reaction mixture was stirred at ambient temperature for 19 h. MeOH was added and the mixture was concentrated(repeated once more). 20 DCM and 10% NaHCO3 (aq) were added and the two layers were separated. The aqueous layer was extracted with DCM and the combined organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by straight phase flash chromatography on silica (EtOAc as eluant) to give the title compound (22 mg, 42%). MS (ESI) m/z [M+H]+ 382.9. 25 Intermediate 168 tert-Butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-methyl-3-oxoheptanoate 194 201388-PCT01-NP O O O S tert-Butyl acetate (163.5 mg, 1.41m y at -78oC to a solution of LDA (158 mg, 1.48 mmol) in anhydrous THF (5 mL). After about 15 min a solution of 3- isobutyldihydrofuran-2(3H)-one (200 mg, 1.41 mmol) was added, and the reaction mixture was 5 stirred at -78oC about 2 h. The reaction was quenched with water and the mixture was extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude intermediate was dissolved in THF (2 mL) cooled to 0oC and imidazole (144 mg, 2.12 mmol) and TBDMSCl (319 mg, 2.12mmol) were added at 0oC. The reaction mixture was stirred at 25oC for 2 h. The reaction was quenched with water and the mixture was 10 extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica (gradient: 0.3–20% EtOAc in PE) to give the title compound (150 mg, 30%) as white solid.1H NMR (400MHz, CDCl3) δ 3.63 - 3.56 (m, 2H), 3.48 - 3.33 (m, 2H), 2.86 - 2.75 (m, 1H), 2.41 - 2.30 (m, 1H), 1.89 - 1.71 (m, 1H), 1.65 - 1.60 (m, 1H), 1.51 - 1.45 (m, 9H), 1.35 - 1.14 (m, 2H), 0.90 15 (s, 15H), 0.07 - 0.02 (m, 6H). Intermediate 169 6-(1-((tert-Butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-mercaptopyrimidin-4-ol OTBS 20 A solution of 0.5 M KOH in EtOH ( . , . and thiourea (265.7 mg, 3.49 mmol) was added to a solution of tert-butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-methyl-3- oxoheptanoate Intermedaite 168 (1 g, 2.67 mmol) in anhydrous EtOH (1 mL). The reaction mixture was heated in a microwave reactor at 125oC for 30 min. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and 25 concentrated. The crude product was purified by flash column chromatography on silica (PE:EtOAc, 5:1) to give the title compound (0.7 g, 78%) as white solid.1H NMR (400 MHz, 195 201388-PCT01-NP CDCl3) δ 9.86 - 9.70 (m, 1H), 9.42 - 9.26 (m, 1H), 5.72 (s, 1H), 3.78 - 3.65 (m, 2H), 2.78 - 2.63 (m, 1H), 1.94 - 1.81 (m, 1H), 1.58 (s, 1H), 1.46 - 1.34 (m, 1H), 1.27 (d, 2H), 0.98 - 0.90 (m, 15H), 0.15 (d, 6H). 5 Intermediate 170 6-(1-((tert-Butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-((2,3-difluorobenzyl)thio)pyrimidin- 4-ol OTBS F A solution of 0.5 M NaOH in EtO and thiourea (266 mg, 3.49 mmol) 10 were added to a solution of 6-(1-((tert-butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2- mercaptopyrimidin-4-ol Intermediate 169 (1g, 2.8mmol) in anhydrous EtOH (10 mL). The reaction mixture was stirred at 25oC for 3 h. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica (PE:EtOAc, 5:1) to give the title 15 compound (1.3 g, 87%) as white solid.1H NMR (400 MHz, CDCl3) δ 7.22 (t, 1H), 7.12 - 6.96 (m, 2H), 6.04 (s, 1H), 4.57 - 4.40 (m, 2H), 3.56 - 3.42 (m, 2H), 2.74 (td, 1H), 1.92 - 1.80 (m, 2H), 1.72 (dd, 2H), 1.66 - 1.55 (m, 2H), 0.96 - 0.76 (m, 15H), 0.02 (d, 6H). Intermediate 171 20 6-(1-((tert-Butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-((2,3-difluorobenzyl)thio)pyrimidin- 4-yl methanesulfonate OTBS F A solution of pyridine (0.2 mL, 1 . . , 0.93mmol) was added at 0oC to a solution of 6-(1-((tert-butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-((2,3- 25 difluorobenzyl)thio)pyrimidin-4-ol Intermediate 170 (0.3 g, 0.62 mmol) in anhydrous DCM (3 196 201388-PCT01-NP mL). The reaction mixture was stirred at 25oC for 2 h. The mixture was extracted with EtOAc (3×30 mL), and the combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica (PE:EtOAc, 3:1) to give the title compound (0.3 g, 86%) as yellow oil.1H NMR (400 MHz, CDCl3) δ 7.33 - 7.22 (m, 5 1H), 7.14 - 6.96 (m, 2H), 6.54 (s, 1H), 4.50 - 4.39 (m, 2H), 3.58 - 3.51 (m, 1H), 3.49 (s, 3H), 3.43 - 3.35 (m, 1H), 3.05 - 2.96 (m, 1H), 1.93 - 1.75 (m, 2H), 1.66 - 1.58 (m, 1H), 1.46 - 1.30 (m, 2H), 0.92 - 0.79 (m, 15H), -0.01 (d, 6H). Intermediate 172 10 N-(6-(1-((tert-Butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)methanesulfonamide OTBS F Methanesulfonamide (42 mg, 0. 0.36 mmol), Pd2(dba)3 (62 mg, 0.089 mmol) and X-Phos (42 mg, 0.089 mmol) were added to a solution of 6-(1-((tert- 15 butyldimethylsilyl)oxy)-5-methylhexan-3-yl)-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl methanesulfonate Intermediate 171 (0.1g, 0.18mmol) in anhydrous dioxane (2 mL). The reaction mixture was heated in a microwave reactor at 100oC for 30 min. The mixture was extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica 20 (PE:EtOAc, 3:1) to give the title compound (50 mg, 50%) as white solid.1H NMR (400 MHz, CDCl3) δ 7.50 - 7.40 (m, 1H), 7.08 - 7.00 (m, 2H), 6.59 (s, 1H), 4.43 (d, 2H), 3.56 - 3.49 (m, 2H), 3.24 (s, 3H), 2.90 (d, 1H), 1.86 (d, 1H), 1.79 - 1.74 (m, 2H), 1.27 (d, 2H), 0.91 - 0.85 (m, 15H), 0.00 (d, 6H). 25 Intermediate 173 1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methylbutan-1-ol 197 201388-PCT01-NP O (S)-2,2-Dimethyl-1,3-dioxolane-4-carba g, 55.3 mmol, 36 % w/w) in THF (30 mL) was added dropwise over 30 min to a solution of 2M iso-butylmagnesium bromide in Et2O (41.5 mL, 83.0 mmol) in THF (180 mL) at 0oC and the reaction mixture was stirred at 0°C for 2 h. The 5 reaction was quenched with NH4Cl (aq.200 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (3×150 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by straight phase flash chromatography on silica (PE:EtOAc, 20:1) to give the title compound (7.0 g, 67%).1H NMR (300 MHz, DMSO-d6): δ 0.75-0.95 (6H, m), 1.18-1.32 (8H, m), 1.70-1.90 (1H, m), 3.35-3.94 (1H, m, partially 10 overlapping with the water signal), 3.70-3.95 (3H, m), 4.67 (1H, d). Intermediate 174 (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methylbutyl 2-chloronicotinate 15 2-Chloronicotinoyl chloride (5.47 g, . ded dropwise to a cold (0oC) solution of TEA (6.50 mL, 46.6 mmol) and 1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutan-1-ol Intermediate 173 (3.90 g, 15.54 mmol) in THF (15 mL). The temperature was increased to rt, and the reaction mixture was stirred on. Two more batches (scale 17 mmol and 19 mmol, respectively) was prepared as described above. The combined reaction mixture from the three 20 batches was diluted with EtOAc (200 mL) and water (200 mL). The organic layer was washed with water (3×150 mL), dried over Na2SO4, filtered and concentrated. The crude product was first purified by preparative TLC (PE:EtOAc, 30:1) then by preparative SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 15% IPA (0.2 % ethanolamine) in CO2, at a flow rate of 170 mL/min as mobile phase to give the first eluting compound (R)-1-((S)- 198 201388-PCT01-NP 2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutyl 2-chloronicotinate Intermediate 174 (6.0 g, 35%) as a yellow liquid. Intermediate 175 5 (R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methylbutan-1-ol LiOH (0.438 g, 18.30 mmol) in water ( ded to a solution of (R)-1-((S)-2,2- dimethyl-1,3-dioxolan-4-yl)-3-methylbutyl 2-chloronicotinate Intermediate 174 (6.0 g, 18.30 mmol) in MeOH (150 mL) and the reaction mixture was stirred at rt for 1 h. The mixture was 10 diluted with EtOAc (100 mL) and water (100 mL). The organic layer was washed with water (3×50 mL), dried over Na2SO4, filtered and concentrated to give the title compound (3.00 g, 87%).1H NMR (300 MHz, DMSO-d6): δ 0.75-0.95 (6H, m), 1.18-1.32 (8H, m), 1.70-1.90 (1H, m), 3.35-3.94 (1H, m), 3.70-3.95 (3H, m), 4.67 (1H, d). 15 Intermediate 176 tert-Butyl (S)-2-methyl-4-sulfamoylpiperazine-1-carboxylate O S N NH2 Boc2O (5.60 g, 25.66 mmol) was adde piperazine-1-sulfonamide Intermediate 42 (4.6 g, 25.66 mmol) and NaHCO3 (aq, 40 mL) in DCM (40 mL) at rt and the reaction mixture 20 was stirred for 10 h. The mixture was diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (6.20 g, 86%). MS (ESI) m/z [M+H-Boc]+ 180. Intermediate 177 25 tert-Butyl (S)-4-(N-(4,6-dichloro-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate 199 201388-PCT01-NP Cl O N N Cl K2CO3 (2.57 g, 18.56 mmol) was a -tert-butyl 2-methyl-4- sulfamoylpiperazine-1-carboxylate Intermediate 176 (3.05 g, 10.9 mmol) and 2,4,6-trichloro- 1,3,5-triazine (2.01 g, 10.92 mmol) in dioxane (50 mL) at rt and the reaction mixture was stirred 5 at 65°C for 16 h. The mixture was filtered through a pad of CELITE and the filtrate was concentrated in vacuo. The crude product was purified by straight phase flash chromatography on silica (gradient: 0–60% EtOAc in heptane) to give the title compound as a yellow solid (2.0 g, 43%). MS (ESI) m/z [M+H-Boc]+ 327. 10 Intermediate 178 tert-Butyl (2S)-4-(N-(4-chloro-6-((1-(2,6-difluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)sulfamoyl)-2-methylpiperazine-1-carboxylate Cl N N NaH (131 mg, 3.28 mmol, 60% ution of 1-(2,6- 15 difluorophenyl)ethanethiol (400 mg, 2.29 mmol) in THF (6 mL) and the reaction mixture was stirred at 0°C for 30 min. The mixture was added dropwise in 3 portions over a period of 1 h to a solution of (S)-tert-butyl 4-(N-(4,6-dichloro-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1- carboxylate Intermediate 177 (700 mg, 1.64 mmol) in THF (20 mL) at 5°C and under an atmosphere of N2(g). The reaction mixture was stirred at 5°C for 30 min. The solvent was 20 removed under reduced pressure to give a crude product which was purified by straight phase flash chromatography on silica (gradient: 0–80% EtOAc in heptane) to give the title compound as a yellow solid (380 mg, 41%). MS (ESI) m/z [M+H]+ 565. Intermediate 179 200 201388-PCT01-NP tert-Butyl (2S)-4-(N-(4-((1-(2,6-difluorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3- dioxolan-4-yl)-3-methylbutoxy)-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate O (R)-1-((S)-2,2-Dimethyl-1,3-dio ol Intermediate 175 (112 mg, 0.60 5 mmol) was added dropwise to a solution of (2S)-tert-butyl 4-(N-(4-chloro-6-((1-(2,6- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate Intermediate 178 (310 mg, 0.55 mmol) and NaH (43.9 mg, 1.10 mmol, 60% w/w in oil) in THF (8 mL) at 0°C under an atmosphere of N2(g) and the reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was diluted with EtOAc (100 10 mL) and washed with brine (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to afford the title compound as a yellow oil which solidified upon standing (324 mg, 82%). MS (ESI) m/z [M+H]+ 717. 15 Intermediate 180 tert-Butyl (2S)-4-(N-(4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)sulfamoyl)-2- methylpiperazine-1-carboxylate Cl NaH (140 mg, 3.51 mmol, 60% ution of 1-phenylethanethiol (340 20 mg, 2.46 mmol) in THF (6 mL) at 0°C and the resulting mixture was stirred at 0°C for 30 min. The mixture was added dropwise in 3 portions over a period of 1 h to (S)-tert-butyl 4-(N-(4,6- dichloro-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate Intermediate 177 (750 201 201388-PCT01-NP mg, 1.76 mmol) in THF (20 mL) at 5°C under an atmosphere of N2(g). The reaction mixture was stirred at 5°C for 30 min. The solvent was removed under reduced pressure and the crude product was purified by straight phase flash chromatography on silica (gradient: 0–50% EtOAc in heptane) to give the title compound as a white solid (520 mg, 56%). MS (ESI) m/z [M+H- 5 Boc]+ 429/431. Intermediate 181 tert-Butyl (2S)-4-(N-(4-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate 10 (R)-1-((S)-2,2-Dimethyl-1,3-di l Intermediate 175 (116 mg, 0.62 mmol) was added dropwise to a mixture of (2S)-tert-butyl 4-(N-(4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate Intermediate 15 180 (300 mg, 0.57 mmol) and NaH (45.4 mg, 1.13 mmol, 60% w/w in oil) in THF (8 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at rt for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in DCM (60 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to give the title compound as a 20 yellow oil which solidified on standing (319 mg, 83%). MS (ESI) m/z [M+H]+ 682.3. Intermediate 182 N-(4-Chloro-6-((1-(3,4-dichlorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 202 201388-PCT01-NP Cl O O N N Cl Cl NaH (120 mg, 3.00 mmol, 60% lution of N-(4,6-dichloro-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 43 (486 mg, 2.00 mmol) in THF (15 mL) at 0°C and the resulting slurry was stirred at 0°C for 5 min.1-(3,4-Dichlorophenyl)ethanethiol (414 mg, 5 2.00 mmol) was added dropwise over 1 h at 0°C and the reaction mixture was stirred at rt for 2 h. The reaction was quenched with 30% AcOH (25 mL) and the mixture was extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Z5 (using decreasingly polar mixtures of water (containing FA) and MeCN as eluents) to give the title compound as a white 10 solid (190 mg, 23%). MS (ESI) m/z [M+H]+ 413. Intermediate 183 N-(4-((1-(3,4-Dichlorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3- methylbutoxy)-1,3,5-triazin-2-yl)methanesulfonamide Cl 15 Cl (R)-1-((S)-2,2-Dimethyl-1,3-diox y y -ol Intermediate 175 (130 mg, 0.69 mmol) was added dropwise to a mixture of N-(4-chloro-6-((1-(3,4-dichlorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 182 (260 mg, 0.63 mmol) and NaH (50 mg, 1.26 mmol, 60% w/w in oil) in THF (8 mL) at 0°C under an atmosphere of N2(g). The 20 reaction mixture was stirred at 0oC for 1 h and then at rt for 16 h. The mixture was concentrated and diluted with EtOAc (50 mL) and washed with brine (2×50 mL). The organic layer was dried 203 201388-PCT01-NP over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 5:1) to afford the title compound as a yellow oil which solidified upon standing (274 mg, 77 %). MS (ESI) m/z [M+H]+ 565.1. 5 Intermediate 184 (R)-4-Methylpentane-1,2-diol OH BH3×Me2S (1.44 mL, 15.13 mmol) dissol F (15 mL) was added dropwise over 45 min to an ice cooled solution of (R)-2-hydroxy-4-methylpentanoic acid (1.00 g, 7.57 mmol) in THF 10 (50 mL) under an atmosphere of N2(g) (Gas evolution observed). The reaction mixture was stirred under an atmosphere of N2(g) at rt on. The colorless reaction solution was cooled in dry ice/acetone bath and then added dropwise over 20 min to an ice cold solution of 1 M NaOH (100 mL). The reaction mixture was allowed to reach rt and stirred for 1.5 h. EtOAc (80 mL) was added and the layers were separated. The water layer was extracted with EtOAc (×2). The 15 combined organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (0.80 g, 89%).1H NMR (500 MHz, CDCl3) δ 0.87–0.99 (6H, m), 1.15–1.26 (1H, m), 1.35–1.41 (1H, m), 1.72–1.86 (1H, m), 3.37–3.45 (1H, m), 3.62–3.68 (1H, m), 3.76–3.85 (1H, m). 20 Intermediate 185 (R)-1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-ol BS TBDMSCl (1.122 g, 7.45 mmol) was ad cooled solution of (R)-4-methylpentane- 1,2-diol Intermediate 184 (0.80 g, 6.77 mmol), TEA (1.13 mL, 8.12 mmol) and DMAP (0.033 25 g, 0.27 mmol) in DCM (100 mL) and the reaction mixture was stirred on. The precipitated Et3N×HCl was filtered off and the filtrate was diluted with DCM (20 mL) and washed with water (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound (1.38 g, 88 %).1H NMR (500 MHz, CDCl3) δ 0.08 (6H, s), 0.85–0.98 (15H, m), 1.14 204 201388-PCT01-NP (1H, td), 1.33–1.41 (1H, m), 1.75–1.86 (1H, m), 2.39 (1H, d), 3.37 (1H, dd), 3.61 (1H, dd), 3.72 (1H, ddt). Intermediate 186 5 2,4-Dichloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazine Cl N N F F DIPEA (1.69 mL, 9.69 mmol) was ,4,6-trichloro-1,3,5-triazine (1.19 g, 6.46 mmol) in THF (30 mL) at 0oC under an atmosphere of N2(g). A solution of (2,3- difluorophenyl)methanethiol (1.035 g, 6.46 mmol) in THF (10 mL) was added dropwise over 40 10 min and the mixture was stirred at 0oC for an additional 2 h. The mixture was concentrated and the residue was purified by straight phase flash chromatography on silica (gradient: 0–30% EtOAc in heptane) and then by straight phase flash chromatography on silica (gradient: 0–25% EtOAc in heptane) to give the title compound (1.17 g, 59%).1H NMR (400 MHz, CDCl3) δ 4.46 (2H, s), 7–7.18 (2H, m), 7.21–7.26 (1H, m, partially overlapping with the solvent peak). 15 Intermediate 187 (R)-2-((1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)oxy)-4-chloro-6-((2,3- difluorobenzyl)thio)-1,3,5-triazine F 20 The title compound was prepared i bed for Intermediate 191 from 2,4- dichloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazine Intermediate 186 and (R)-1-((tert- butyldimethylsilyl)oxy)-4-methylpentan-2-ol Intermediate 185. Intermediate 188 205 201388-PCT01-NP (R)-N-(4-((1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)oxy)-6-((2,3- difluorobenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide F The title compound was prepare ed for Intermediate 124 from (R)- 5 2-((1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)oxy)-4-chloro-6-((2,3- difluorobenzyl)thio)-1,3,5-triazine Intermediate 187. Intermediate 189 1-(Dimethylamino)-2-(sulfamoylamino)ethan O O N S N NH2 10 A mixture of N1,N1-dimethylethane- 30.0 mmol) and sulfuric diamide (2.36 g, 24.6 mmol) in dioxane (30 mL) was heated at reflux for 3 d. The mixture was partitioned between EtOAc and water and the aqueous layer was extracted with EtOAc. The combined organic layer was concentrated to give the title compound as an amber coloured oil (2.50 g, 61%) 15 which was used without further purification.1H NMR (500 MHz, CD3OD) δ 2.49 (6H,s), 2.73 (2H, t), 3.31 (2H, t). Intermediate 190 1-(Dimethylamino)-3-(sulfamoylamino)propane O O S H2 20 Prepared in a similar way as Interm ,N1-dimethylpropane-1,2-diamine (3.13 g, 30.6 mmol) and sulfuric diamide (2.41 g, 25.1 mmol) to give the title compound as an amber coloured oil (2.60 g, 57%).1H NMR (500 MHz, CD3OD) δ 1.68–1.79 (2H, m), 2.25 (6H, s), 2.39 (2H, t), 2.98 (2H, t). 206 201388-PCT01-NP Intermediate 191 N-(4-((R)-1-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-6-((1-phenylethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide 5 (R)-1-((S)-2,2-Dimethyl-1,3-dioxola n-1-ol Intermediate 175 (180 mg, 0.96 mmol) was added dropwise to a mixture of N-(4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 190 (300 mg, 0.87 mmol) and NaH (70 mg, 1.74 mmol, 10 60% w/w in oil) in THF (20 mL) at 0°C and the reaction mixture was stirred for 1 h at 0oC and then at rt for 16 h. The mixture was concentrated and the residue was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to give the title compound (400 mg, 93%) as a yellow oil which solidified on standing.1H NMR (300 MHz, 15 DMSO-d6): δ 0.84-0.90 (6H, m), 1.24-1.73 (12H, m), 3.26 (3H, s), 3.79-3 m), 3.97-4.01 (1H, m), 4.18-4.21 (1H, m), 5.01-5.05 (1H, m), 5.41-5.43 (1H, m), 7.27-7.47 (5H, m), 12.0 (1H, br s). Intermediate 192 20 N-(4-(((2S,3R)-1,2-Dihydroxy-5-methylhexan-3-yl)oxy)-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide 207 201388-PCT01-NP OH FeCl3×6 H2O (569 mg, 2.11 mmol) n of N-(4-((R)-1-((S)-2,2-dimethyl-1,3- dioxolan-4-yl)-3-methylbutoxy)-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 191 (300 mg, 0.60 mmol) in DCM (15 mL) at 0oC and the reaction mixture was 5 stirred at 0°C for 16 h. The mixture was concentrated and the residue was diluted with EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (100 mg, 36%) as a yellow oil which solidified on standing. MS (ESI) m/z [M+H]+ 457.3. 10 Intermediate 193 N-(4-Chloro-6-((1-(2,3-difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl F NaH (120 mg, 3.00 mmol, 60% ,6-dichloro-1,3,5-triazin-2- 15 yl)methanesulfonamide Intermediate 43 (486 mg, 2.00 mmol) in THF (15 mL) at 0°C. The reaction mixture was stirred at 0°C for 5 min. A solution of 1-(2,3-difluorophenyl)ethanethiol (348 mg, 2.00 mmol) in THF (5 mL) was added dropwise over 1 h at 0°C. The resulting slurry was allowed to reach rt and stirred for 2 h. The reaction was quenched with 30% AcOH (25 mL) and extracted with EtOAc (3×25 mL). The combined organic layer was dried over Na2SO4, 20 filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Z5 (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound (280 mg, 37%) as a white solid. MS (ESI) m/z [M+H]+ 381.1/383.1. 208 201388-PCT01-NP Intermediate 194 N-(4-((1-(2,3-Difluorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3- methylbutoxy)-1,3,5-triazin-2-yl)methanesulfonamide O F 5 (R)-1-((S)-2,2-Dimethyl-1,3-dioxol -1-ol Intermediate 175 (152 mg, 0.81 mmol) was added dropwise to a mixture of N-(4-chloro-6-((1-(2,3-difluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 193 (280 mg, 0.74 mmol) and NaH (59 mg, 1.47 mmol, 60% w/w in oil) in THF (8 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at 0oC for 1 h and then at rt for 16 h. The mixture was concentrated 10 and the residue was diluted with DCM (20 mL) and washed with brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 5:1) to give the title compound (294 mg, 75 %) as a yellow oil which solidified on standing. MS (ESI) m/z [M+H]+ 533.2. 15 Intermediate 195 N-(4-Chloro-6-((1-(2,6-difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Cl NaH (120 mg, 3.00 mmol, 60 % w/ N-(4,6-dichloro-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 43 (486 mg, 2.00 mmol) in THF (15 mL) at 0°C. The 20 reaction mixture was stirred at 0°C for 5 min. A solution of 1-(2,6-difluorophenyl)ethanethiol (348 mg, 2.00 mmol) in THF (5 mL) was added dropwise over 1 h at 0°C, and the resulting slurry was allowed to reach rt and stirred for 2 h. The reaction was quenched with 30% AcOH 209 201388-PCT01-NP (25 mL) and extracted with EtOAc (3×15 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Z5, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound as a white solid (100 mg, 13%). MS (ESI) m/z [M+H]+ 5 381/383 Intermediate 196 N-(4-((1-(2,6-Difluorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3- methylbutoxy)-1,3,5-triazin-2-yl)methanesulfonamide 10 (R)-1-((S)-2,2-Dimethyl-1,3-dioxo -1-ol Intermediate 175 (152 mg, 0.81 mmol) was added dropwise to N-(4-chloro-6-((1-(2,6-difluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 195 (280 mg, 0.74 mmol) and NaH (59 mg, 1.47 mmol, 15 60 % w/w in oil) in THF (8 mL) under an atmosphere of N2(g) at 0°C. The reaction mixture was stirred at 0oC for 1 h and then at rt for 16 h. The mixture was concentrated, and the residue was diluted with DCM (20 mL) and washed with brine (2×50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 5:1) to give the title compound as a yellow oil which solidified on standing 20 (330 mg, 84%). MS (ESI) m/z [M+H]+ 533.2. Synthesis of Example CX3CR1 Modulators: Example 1 210 201388-PCT01-NP N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)-1,1,1-trifluoromethanesulfonamide F amide (56 mg, 0.37 mmol) followed by K2CO3 (40 mg, 0.37 5 mmol) were added to (R)-2-((4-chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2- yl)amino)pentan-1-ol, Intermediate 1 (70 mg, 0.19 mmol) dissolved in DMF (1 mL). The reaction mixture was stirred at rt for 2 h, then at 90°C on. DCM (5 mL) and water (1 mL) were added followed by 1% HCl (aq) to acidify the aqueous layer to pH 3. The layers were separated, and the organic layer was washed with sat brine (20 mL), filtered, and concentrated at reduced pressure. 10 The crude residue was purified by preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (17 mg, 19%); HRMS (ESI) m/z [M+H]+ calcd for C16H19F5N5O3S2: 488.0844, found: 488.0864; 1H NMR (600 MHz, DMSO-d6, mixture of two rotamers, 1:1) δ 0.80–0.88 (m, 3H, rotamers), 1.11–1.36 (m, 2H), 1.36–1.57 (m, 2H), 3.37–3.46 (m, partly overlapping with solvent), 3.92–4.09 (m, 1H, rotamers), 4.39–4.57 (m, 2H), 4.77 (s, 1H), 7.11–7.2 (m, 1H), 7.29– 15 7.55 (m, 2H, rotamers). Example 2 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)ethanesulfonamide F 20 201388-PCT01-NP A mixture of (R)-2-(4-chloro-6-(2,3-difluorobenzylthio)-1,3,5-triazin-2-ylamino)pentan-1-ol Intermediate 1 (50 mg, 0.13 mmol), ethansulfonamide (14 mg, 0.13 mmol), Pd2(dba)3 (12 mg, 0.01 mmol), K2CO3 (28 mg, 0.20 mmol) and X-Phos were suspended in THF (2 mL) and the reaction mixture was stirred at 60°C overnight. Water and DCM were added to the mixture and 5 the organic layer was concentrated in vacuo. The crude residue was dissolved in DMSO and purified by preparative HPLC, PrepMethod F (gradient: 30–80%) to give the title compound (2.3 mg, 3.6%). HRMS (ESI) m/z [M+H]+ calcd for C17H24F2N5O3S2: 448.1282, found: 448.1312. Example 3 10 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)cyclopropanesulfonamide F The title compound was prepar from (R)-2-(4-chloro-6-(2,3- difluorobenzylthio)-1,3,5-triazin-2-ylamino)pentan-1-ol Intermediate 1 (50 mg, 0.13 mmol) and 15 cyclopropanesulfonamide (16 mg, 0.13 mmol). The crude product was purified by preparative HPLC, PrepMethod A (gradient: 0–50%) to give the title compound (1.3 mg, 2%). HRMS (ESI) m/z [M+H]+ calcd for C18H24F2N5O3S2: 460.1282, found: 460.1304. Example 4 20 N-(4-{[(4-Fluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)sulfuric diamide F 201388-PCT01-NP The title compound was made in a similar way to Example 24 from (R)-2-((4-chloro-6-((4- fluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 31. (100 mg, 0.27 mmol). The crude residue was purified by preparative HPLC, PrepMethod A, (gradient: 5– 95%) to give the title compound (16 mg, 13%): HRMS (ESI) m/z [M+H]+ calcd for 5 C16H24FN6O3S2: 431.1330, found: 431.1344.1H NMR (600 MHz, DMSO-d6, mixture of rotamers) δ 0.8–0.89 (6H, m), 1.16–1.48 (2H, m), 1.51–1.69 (1H, m), 3.34–3.46 (2H, m, overlapping with the water signal), 3.9–4.16 (1H, m), 4.21–4.43 (2H, m), 4.67–4.89 (1H, m), 6.91–7.22 (4H, m), 7.37–7.72 (3H, m), 11.02 (1H, s). 10 Example 5 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)methanesulfonamide F 15 A mixture of (R)-2-((4-chloro-6- 3,5-triazin-2-yl)amino)pentan-1-ol Intermediate 1 (80 mg, 0.21 mmol), methanesulfonamide (41 mg, 0.43 mmol), Cs2CO3 (139 mg, 0.43 mmol), X-Phos (21 mg, 0.04 mmol) and Pd2(dba)3 (22 mg, 0.02 mmol) in a closed vial was flushed with N2(g). THF (3 mL) was added, and the vial was flushed with N2(g) and then heated to 64°C in an oil bath for 18 h. The mixture was concentrated and DCM (10 mL) and 20 water (1 mL) were added to the residue. The pH of the mixture was adjusted to pH 3–4 with 1 M HCl (aq). The layers were separated, and the organic layer was concentrated and the crude product was purified by preparative HPLC, PrepMethod J, (gradient: 5–95%) to give the title compound (41 mg, 44%). HRMS (ESI) m/z [M+H]+ calcd for C16H22F2N5O3S2: 434.1126, found: 434.1108.1H NMR (600 MHz, DMSO-d6, mixture of rotamers 1/1) δ 0.8–0.88 (3H, m), 1.11– 25 1.34 (2H, m), 1.34–1.46 (1H, m), 1.47–1.54 (1H, m), 3.3–3.33 (3H, MeSO2, overlapping with the water signal), 3.37–3.45 (2H, m, overlapping with the water signal), 3.81–4.06 (1H, m), 213 201388-PCT01-NP 4.28–4.57 (2H, m), 4.70 (1H, t), 7.11–7.18 (1H, m), 7.3–7.38 and 7.38–7.43 (1H, m, rotamers), 7.46–7.52 (1H, m). Example 6 5 N-(4-{[3-(2-Fluorophenoxy)propyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide 1-(3-Bromopropoxy)-2-fluoro added to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 10 Intermediate 4 (64 mg, 0.20 mmol) and DIPEA (76 µL, 0.44 mmol) in THF (2 mL). The reaction mixture was stirred at 50oC overnight. The mixture was concentrated, and the crude product was purified by preparative TLC to give the title compound (11.4 mg, 12%). HRMS (ESI) m/z [M+H]+ calcd for C19H29FN5O4S2: 474.1640, found: 474.1654. 15 Example 7 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({[(4S)-3-methyl-2-oxoimidazolidin-4- yl]methyl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide H 20 201388-PCT01-NP The title compound was prepared and purified as described for Example 6 from (S)-5- (bromomethyl)-1-methylimidazolidin-2-one Intermediate 34 (42 mg, 0.22 mmol) and (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (7.6 mg, 9%). HRMS (ESI) m/z 5 [M+H]+ calcd for C15H28N7O4S2: 434.1638, found: 434.1644. Example 8 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({[(2R)-1-methyl-6-oxopiperidin-2- yl]methyl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide 10 The title compound was prepared for Example 6 from (R)-6- (bromomethyl)-1-methylpiperidin-2-one Intermediate 35 (45 mg, 0.22 mmol) and (R)-N-(4-((1- 15 hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (31.2 mg, 35%). HRMS (ESI) m/z [M+H]+ calcd for C17H31N6O4S2: 447.1842, found: 447.1846. Example 9 20 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(2E)-3-phenylprop-2-en-1- yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 215 201388-PCT01-NP The title compound was prepar Example 6 from (E)-(3- bromoprop-1-en-1-yl)benzene (43 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 5 mmol) to give the title compound (15.6 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O3S2: 438.1628, found: 438.1638. Example 10 N-[4-({[(4S)-1,3-dimethyl-2-oxoimidazolidin-4-yl]methyl}sulfanyl)-6-{[(2R)-1-hydroxy-4- 10 methylpentan-2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide The title compound was prepared or Example 6 from (S)-4- (iodomethyl)-1,3-dimethylimidazolidin-2-one Intermediate 39 (54 mg, 0.22 mmol) and (R)-N- (4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 15 Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (8.8 mg, 9.8%). HRMS (ESI) m/z [M+H]+ calcd for C16H30N7O4S2: 448.1796, found: 448.1804. Example 11 N-(4-{[(3,3-Difluorocyclobutyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 20 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 216 201388-PCT01-NP F (R)-N-(4-(1-Hydroxy-4-methylpe o-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (40 mg, 0.12 mmol) was dissolved in DMF (1 mL) and 3-(bromomethyl)-1,1-difluorocyclobutane (23 mg, 0.12 mmol) and DIPEA (0.043 mL, 0.25 5 mmol) were added. The reaction mixture was heated in a microwave reactor to 70°C for 30 min. The mixture was filtered and purified by preparative HPLC , PrepMethod F, (gradient 5–95%) to give the title compound (12 mg, 22%). HRMS (ESI) m/z [M+H]+ calcd for C15H26F2N5O3S2: 426.1440, found: 426.1422.1H NMR (600 MHz, DMSO-d6) δ 0.79–0.97 (6H, m), 1.22–1.53 (2H, m), 1.53–1.63 (1H, m), 2.24–2.43 (2H, m), 2.5-2.55 (1H, m, overlapping with the solvent 10 peak), 2.58–2.76 (2H, m), 3.17-3.44 (7H, m, overlapping with the water signal), 3.96–4.07 (1H, m). Example 12 N-(4-{[(2E)-But-2-en-1-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-1,3,5- 15 triazin-2-yl)methanesulfonamide The title compound was prepared a p for Example 6 from (E)-1-bromobut- 2-ene (29.7 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto- 20 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (9.3 mg, 12%). HRMS (ESI) m/z [M+H]+ calcd for C14H26N5O3S2: 376.1472, found: 376.1482. 217 201388-PCT01-NP Example 13 N'-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)-N,N-dimethylsulfuric diamide F 5 A mixture of (R)-2-(4-chloro-6 triazin-2-ylamino)pentan-1-ol Intermediate 1 (80 mg, 0.21 mmol), N,N-dimethylsulfamid (53 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol), X-Phos (44 mg, 0.09 mmol) and Pd2(dba)3 (41 mg, 0.04 mmol) in a sealed vial was flushed with N2(g). THF (3 mL) was added, and the vial was flushed with N2(g) and then heated 10 to 64°C in an oil bath for 90 h. The mixture was concentrated. DCM (10 mL) and water (1 mL) were added and pH was adjusted to pH 4 with 1 M HCl (aq). The two layers were separated and the organic layer was concentrated to afford a crude product which was purified by preparative HPLC, PrepMethod F, (gradient 5–95%), to give the title compound (7 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C17H25F2N6O3S2: 463.1392, found: 463.1354.1H NMR (600 MHz, 15 DMSO-d6) δ 0.81–0.87 (3H, m), 1.05–1.32 (2H, m), 1.32–1.45 (1H, m), 1.45–1.57 (1H, m), 2.80 (6H, s), 3.35–3.47 (2H, m, overlapping with the water signal), 3.89–4.04 (1H, m), 4.33–4.43 (2H, m), 4.67 (1H, t, OH), 7.02–7.17 (1H, m), 7.33 (1H, q), 7.38–7.58 (1H, m). Example 14 20 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(3E)-4-phenylbut-3-en-1-yl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP DIPEA (0.097 mL, 0.56 mmol) followed by a mixture of (chloro(cyclopropyl)methyl)benzene and (E)-(4-chlorobut-1-en-1-yl)benzene Intermediate 40 (2.4:1, 80 mg, crude product) dissolved in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (204 mg, 0.51 5 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 20 h and then heated at 100°C for 30 min and finally heated at 110°C for 1 h in a microwave reactor. Water and MTBE were added, and the two layers were separated. The organic layer was washed with water and brine and concentrated. The residue was purified by flash column chromatography on silica (DCM then DCM:MeOH, 10:1) to give the title compound (17 mg, 7%). HRMS (ESI) m/z 10 [M+H]+ calcd for C20H30N5O3S2: 452.1784, found: 452.1788.1H NMR (400 MHz, CD3OD, mixture of rotamers 1/1) δ 0.88–0.98 (6H, m), 1.36–1.55 (2H, m), 1.6–1.75 (1H, m), 2.56–2.68 (2H, m), 3.24 (2H, td), 3.32 (3H, apparent d), 3.5–3.61 (2H, m), 4.15–4.33 (1H, m), 6.29 (1H, dt), 6.49 (1H, dd), 7.12–7.23 (1H, m), 7.27 (2H, td), 7.34 (2H, dt). 15 Example 15 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(3-methyl-2-oxo-1,3-oxazinan-4- yl)methyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide O The title compound was prepared or Example 6 from 4- 20 (bromomethyl)-3-methyl-1,3-oxazinan-2-one JACS, (1983), 105 (23), 6985–6986 (45.8 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (7.6 mg, 8%). HRMS (ESI) m/z [M+H]+ calcd for C16H29N6O5S2: 449.1636, found: 449.1646. 25 Example 16 219 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(oxan-4-yl)methyl]sulfanyl}-1,3,5- triazin-2-yl)methanesulfonamide O The title compound was prepared or Example 6 from 4- 5 (bromomethyl)tetrahydro-2H-pyran (39.4 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (16.4 mg, 19%). HRMS (ESI) m/z [M+H]+ calcd for C16H30N5O4S2: 420.1734, found: 420.1742. 10 Example 17 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(4-methylpent-3-en-1-yl)sulfanyl]- 1,3,5-triazin-2-yl)methanesulfonamide A solution of 5-bromo-2-methylp ol) in DMF (0.6 mL), followed by15 DIPEA (0.057 mL, 0.33 mmol), were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol). The reaction mixture was stirred at rt for 20 h. Water (2 mL) and DCM (2 mL) were added, and the phases were separated. The organic layer was passed through a phase separator. The filtrate was concentrated and purified by preparative HPLC, PrepMethod Z6 (gradient: 0– 20 50%) to give the title compound (27.7 mg, 53%). HRMS (ESI) m/z [M+H]+ calcd for C16H30N5O3S2: 404.1784, found: 404.1764. 220 201388-PCT01-NP Example 18a N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide F 5 Example 18a may be prepar ed herein, for example according to the method described for Example 18, using Intermediate 41 and 3- methylpiperazine-1-sulfonamide. HRMS data for Example 18a is expected to be consistent with that of Example 18, e.g. the HRMS may be: HRMS (ESI) m/z [M+H]+ calcd for C21H32F2N7O3S2: 532.1970, found: 532.1990. 10 Example 18 (3S)-N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide F THF (4 mL) was added to a fluorobenzylthio)-1,3,5-triazin-15 2-ylamino)-4-methylpentan-1-ol Intermediate 41 (80 mg, 0.21 mmol), (S)-3-methylpiperazine- 1-sulfonamide Intermediate 42 (74 mg, 0.41 mmol), Cs2CO3 (134 mg, 0.41 mmol), X-Phos (21 mg, 0.04 mmol) and Pd2(dba)3 (21 mg, 0.02 mmol) in a sealed vessel and the reaction mixture was flushed with N2(g) and heated to 64oC for 18 h. The mixture was concentrated, water and DCM were added and the pH was adjusted to pH 5 with 1 M HCl (aq). The two layers were 20 separated and the organic layer was concentrated to afford a crude product which was purified by preparative HPLC, PrepMethod F, (gradient 5–95%) to give the title compound (9 mg, 8%). HRMS (ESI) m/z [M+H]+ calcd for C21H32F2N7O3S2: 532.1970, found: 532.1990.1H NMR (600 221 201388-PCT01-NP MHz, CD3OD, mixture of rotamers 1/1) δ 0.88–1.03 (6H, m), 1.19–1.22 (3H, m), 1.36–1.51 (2H, m), 1.61–1.73 (1H, m), 2.71–2.89 (1H, m), 2.96–3.23 (4H, m), 3.47–3.6 (2H, m), 3.78 (2H, dd), 4.18–4.25 (1H, m), 4.37–4.48 (2H, m), 7.02–7.11 (1H, m), 7.11–7.17 (1H, m), 7.32–7.43 (1H, m). 5 Example 19 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)azetidine-1-sulfonamide F 10 THF (4 mL) was added to a m ifluorobenzylthio)-1,3,5-triazin- 2-ylamino)-4-methylpentan-1-ol Intermediate 41 (80 mg, 0.21 mmol), azetidine-1-sulfonamide (56 mg, 0.41 mmol), Cs2CO3 (134 mg, 0.41 mmol), X-Phos (21 mg, 0.04 mmol) and Pd2(dba)3 (21 mg, 0.02 mmol) in a sealed vessel and the vessel was flushed with N2(g) and heated to 64oC for 18 h. The solvent was evaporated, water and DCM were added and the pH of the mixture was 15 adjusted to pH 5 with 1 M HCl (aq). The two layers were separated and the organic layer was concentrated to afford a crude product which was purified by preparative HPLC, PrepMethod F, (gradient 5–95%) to give the title compound (17 mg, 17%). MS (ESI) m/z [M+H]+ 489.2.1H NMR (600 MHz, DMSO, mixture of rotamers 1/1) δ 0.79–0.9 (6H, m), 1.27–1.36 (1H, m), 1.36– 1.45 (1H, m), 1.51–1.61 (1H, m), 2.02–2.16 (2H, m), 3.3–3.37 (2H, m, overlapping with the 20 water signal), 3.85–4.14 (5H, m), 4.38–4.48 (2H, m), 4.6–4.79 (1H, m, OH), 7.05–7.2 (1H, m), 7.33 (1H, q), 7.38–7.52 (1H, m). Example 20 N-(4-{[(4-Fluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 25 1,3,5-triazin-2-yl)-3-methylazetidine-1-sulfonamide 222 201388-PCT01-NP F A mixture of (R)-2-((4-chloro azin-2-yl)amino)-4- methylpentan-1-ol Intermediate 31 (50 mg, 0.13 mmol), 3-methylazetidine-1-sulfonamide (40 mg, 0.27 mmol), Pd2(dba)3 (25 mg, 0.03 mmol), X-Phos (26 mg, 0.05 mmol), Cs2CO3 (88 mg, 5 0.27 mmol) and THF (2 mL) in a sealed vessel was heated to 70oC for 55 min. An additional amount of 3-methylazetidine-1-sulfonamide (6 mg, 0.04mmol) was added and the reaction was heated again to 70°C for 2.5 h. The solvent was evaporated to afford a crude product which was purified by preparative HPLC, PrepMethod F, (gradient 5–95%) to give the title compound (3 mg, 4%). HRMS (ESI) m/z [M+H]+ calcd for C20H30FN6O3S2: 485.1800, found: 485.1820. 10 Example 21 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)morpholine-4-sulfonamide F 15 THF (4 mL) was added to a m ifluorobenzylthio)-1,3,5-triazin- 2-ylamino)-4-methylpentan-1-ol Intermediate 41 (80 mg, 0.21 mmol), morpholine-4- sulfonamide (68 mg, 0.41 mmol), Cs2CO3 (134 mg, 0.41 mmol), X-Phos (21 mg, 0.04 mmol) and Pd2(dba)3 (20.7 mg, 0.02 mmol) in a closed vessel and the vessel was flushed with N2(g) and heated to 64oC for 18 h. The solvent was evaporated, water and DCM were added and pH was 20 adjusted to pH 5 with 1 M HCl (aq). The two layers were separated and the organic layer was concentrated to afford a crude product which was purified by preparative HPLC, PrepMethod F, 223 201388-PCT01-NP (gradient 5–95%) to give the title compound (60 mg, 56%). HRMS (ESI) m/z [M+H]+ calcd for C20H29F2N6O4S2: 519.1654, found: 519.1654.1H NMR (600 MHz, DMSO-d6) δ 0.79–0.89 (6H, m), 1.23–1.44 (2H, m), 1.48–1.64 (1H, m), 3.18–3.29 (4H, m), 3.31–3.36 (2H, m, overlapping with the water signal), 3.5–3.65 (4H, m), 3.96–4.14 (1H, m), 4.29–4.49 (2H, m), 4.54–4.87 (1H, 5 m, OH), 7.11–7.17 (1H, m), 7.29–7.37 (1H, m), 7.37–7.53 (1H, m). Example 22 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5- triazin-2-yl)thiophene-2-sulfonamide F 10 The title compound was prepa rom (R)-2-(4-chloro-6-(2,3- difluorobenzylthio)-1,3,5-triazin-2-ylamino)pentan-1-ol Intermediate 1 (50 mg, 0.13 mmol) and thiophene-2-sulfonamide (21 mg, 0.13 mmol). The crude product was purified by preparative HPLC, PrepMethod F (gradient: 30–80%) to give the title compound (1.7 mg, 3%). HRMS (ESI) 15 m/z [M+H]+ calcd for C19H22F2N5O3S3: 502.0848, found: 502.0874. Example 23 N-(4-{[(4-Fluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)azetidine-1-sulfonamide 20 F 201388-PCT01-NP THF (3 mL) was added to a mixture of (R)-2-(4-chloro-6-(4-fluorobenzylthio)-1,3,5-triazin-2- ylamino)-4-methylpentan-1-ol Intermediate 31 (100 mg, 0.27 mmol), azetidine-1-sulfonamide (73 mg, 0.54 mmol), Pd2(dba)3 (49 mg, 0.05 mmol), X-Phos (51 mg, 0.11 mmol) and Cs2CO3 (163 mg, 0.50 mmol) in a closed vessel and the vessel was flushed with N2(g) and heated to 65oC 5 for 20 h. The solvent was evaporated and the crude product was purified by preparative HPLC , PrepMethod K, (gradient 10–45%) to give the title compound (33 mg, 26%). HRMS (ESI) m/z [M+H]+ calcd for C19H28FN6O3S2: 471.1642, found: 471.1664.1H NMR (600 MHz, DMSO-d6) δ 0.8–0.89 (6H, m), 1.27–1.37 (1H, m), 1.37–1.45 (1H, m), 1.52–1.62 (1H, m), 1.99–2.23 (2H, m), 3.37–3.4 (2H, m, overlapping with the water signal), 3.89–4.16 (5H, m), 4.31–4.38 (2H, m), 10 4.58–4.76 (1H, m, OH), 7.08–7.15 (2H, m), 7.46–7.52 (2H, m). Example 24 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin- 2-yl)sulfuric diamide 15 Pd2(dba)3·CHCl3 (21 mg, 0.02 m mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol) and sulfuric diamide (79 mg, 0.82 mmol) in THF (8 mL) in a sealed tube. The reaction mixture was stirred at 100°C for 3 20 h and then EtOAc (50 mL) was added. The organic layer was washed with water (50 mL) and brine (2×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC, PrepMethod B, (gradient: 20–80%) to give the title compound (40 mg, 23%); HRMS (ESI) m/z [M+H]+ calcd for C17H27N6O3S2: 427.1580, found: 427.1564; 1H NMR (300 MHz, CDCl3) δ 0.86–0.94 (m, 6H), 1.26–1.71 (m, 6H), 3.43– 25 3.77 (m, 2H), 4.22 (s, 1H), 4.89–4.96 (m, 1H), 5.15– 5.70 (m, 2H), 7.16–7.42 (m, partly overlapping with solvent). 225 201388-PCT01-NP Example 25 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin- 2-yl)-N'-methylsulfuric diamide 5 Pd2(dba)3×CHCl3 (21 mg, 0.02 m mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added to a mixture of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol), (methylsulfamoyl)amine (90 mg, 0.82 mmol) and THF (8 mL). The vessel was sealed and heated to 100°C for 3 h. The 10 reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a crude product which was purified by preparative HPLC, PrepMethod B, (gradient 30–70%) to give the title compound as a yellow solid (65 mg, 36%): HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O3S2: 441.1738, found: 441.1734.1H NMR (300 MHz, CDCl3-D2O): δ 0.87-0.94 (6H, 15 m), 1.25-1.70 (6H, m), 2.46-2.55 (3H, m), 3.45-3.78 (2H, m), 4.21 (1H, d), 4.79-4.95 (1H, m), 7.24-7.45 (5H, m). Example 26 N-(4-{[(2R)-1-Hydroxy-3-methylbutan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin-2- 20 yl)methanesulfonamide 201388-PCT01-NP K2CO3 (405 mg, 2.93 mmol) was added to (R)-N-(4-((1-hydroxy-3-methylbutan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 46 (300 mg, 0.98 mmol) in DMF (10 mL) at rt under an atmosphere of N2(g) and the mixture was stirred for 15 min at rt. (1- Bromoethyl)benzene (217 mg, 1.17 mmol) was added dropwise, and the reaction mixture was 5 stirred at 40°C on. The mixture was acidified to pH 4–5 with 20% AcOH (aq), diluted with DCM (150 mL), and washed with brine (3×150 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound as a white solid (22 mg, 6%): HRMS (ESI) m/z [M+H]+ calcd for C17H26N5O3S2: 412.1472, found: 412.1462.1H NMR (400 MHz, DMSO-d6): δ 0.85-0.90 (6H, m), 1.69-1.71 (3H, m), 1.86-1.90 (1H, m), 3.28-3.35 (3H, m), 3.41-3.60 (2H, m), 10 3.67-3.88 (1H, m), 4.96-5.04 (1H, m), 7.26-7.28 (1H, m), 7.32-7.37 (2H, m), 7.44-7.49 (2H, m). Example 27 N-(4-{[(2R)-1-Hydroxybutan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin-2- yl)methanesulfonamide 15 OH K2CO3 (501 mg, 3.62 mmol) was 1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 47 (250 mg, 0.72 mmol) in DMF (5 mL) at rt under an atmosphere of N2(g). (R)-2-Aminobutan-1-ol (323 mg, 3.62 mmol) was added and the reaction 20 mixture was stirred at 50°C on. The mixture was acidified with a mixture of AcOH:H2O (5:1, v/v), diluted with DCM (200 mL) and washed with brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod K, (gradient 22–100%) to afford the title compound as a white solid (180 mg, 62%). HRMS (ESI) m/z [M+H]+ calcd for C16H24N5O3S2: 398.1314, found: 398.1346.1H NMR (400 25 MHz, DMSO-d6): δ 0.80-0.88 (3H, m), 1.31-1.46 (1H, m), 1.55-1.65 (1H, m), 1.66-1.71 (3H, m), 3.34-3.43 (5H, m), 3.75-3.95 (1H, m), 4.65-4.75 (1H, m), 4.95-5.05 (1H, m), 7.22-7.36 (3H, m), 7.44-7.48 (2H, m), 7.65-7.85 (1H, m), 11.20 (1H, brs). 227 201388-PCT01-NP Example 28 (R*)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonimidoamide Isomer 2 5 The isomers of N-(4-{[(2R)-1-hyd ]amino}-6-[(1-phenylethyl)sulfanyl]- 1,3,5-triazin-2-yl)methanesulfonimidoamide Example 29 (340 mg, 0.8 mmol) were separated by preparative chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 15% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase, at a flow rate of 130 mL/min. The first eluting compound 10 mixture was collected and further separated by preparative chiral HPLC on a Chiralpak IC column (5µm, 250×20 mm ID) using a heptane:EtOH:TEA (80:20:0.1) mobile system as eluant, at a flow rate of 20 mL/min. The second eluting compound was collected to give the title compound (R*)-N-(4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- phenylethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonimidoamide Isomer 2, Example 28, (70 15 mg, 20%): HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O2S2: 425.1788, found: 425.1768.1H NMR (500 MHz, CD3OD) δ 0.9–0.99 (6H, m), 1.37–1.53 (2H, m), 1.64–1.81 (4H, m), 3.34–3.39 (3H, m), 3.39–3.6 (2H, m), 4.09–4.3 (1H, m), 5.01–5.1 (1H, m), 7.17–7.26 (1H, m), 7.27–7.35 (2H, m), 7.4–7.46 (2H, m). 20 Example 29 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin- 2-yl)methanesulfonimidoamide 228 201388-PCT01-NP N'-(tert-Butyldimethylsilyl)-N-(4- pentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonimidamide Intermediate 49 (620 mg, 1.15 mmol) was treated with 3.8 M HCl (aq) (3.03 mL, 11.50 mmol). DCM was added when the 5 reaction was complete, and the organic layer was separated and concentrated. The crude product was purified by preparative HPLC, PrepMethod E, (gradient 10–55%), to give the title compound (340 mg, 70 %): HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O2S2: 425.1788, found: 425.1780.1H NMR (500 MHz, CDCl3) δ 0.86–0.94 (6H, m), 1.28–1.53 (2H, m), 1.66–1.76 (4H, m), 3.19–3.37 (3H, m), 3.43–3.86 (2H, m), 4.01–4.32 (1H, m), 4.91–5.25 (1H, m), 7.21–7.25 10 (1H, m), 7.29–7.35 (2H, m), 7.36–7.44 (2H, m). Example 30 N'-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin- 2-yl)-N,N-dimethylsulfuric diamide 15 Pd2(dba)3 xCHCl3 (21 mg, 0.02 mmol) followed by Cs2CO3 (200 mg, 0.61 mmol) were added to a mixture of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol), N,N- dimethylsulfamide (102 mg, 0.82 mmol) and THF (8 mL). The vessel was sealed and heated to 20 100°C for 3 h. The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The 229 201388-PCT01-NP crude product was purified by preparative HPLC, PrepMethod M, (gradient 30–70%) to give the title compound as a yellow solid (64 mg, 34%): HRMS (ESI) m/z [M+H]+ calcd for C19H31N6O3S2: 455.1894, found: 455.1870.1H NMR (300 MHz, CDCl3, mixture of rotamers ca 1/1): δ 0.85-0.95(6H, m), 1.33-1.75 (6H, m), 2.97 (6H, s), 3.44-3.76 (2H, m), 4.30 (1H, apparent 5 br s), 4.92-4.96 (1H, m), 6.74-6.79 (1H, t, OH), 7.24-7.41 (5H, m). Example 31 (3S)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)-3-methylpiperazine-1-sulfonamide 10 Pd2(dba)3×CHCl3 (21 mg, 0.02 mol) followed by Cs2CO3 (200 mg, 0.61 mmol) were added to a mixture of (2R)-2-((4-Chloro-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol), (S)-3- 15 methylpiperazine-1-sulfonamide Intermediate 42 (147 mg, 0.82 mmol) and THF (8 mL). The vessel was sealed and heated to 65°C on. The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod M, (gradient 30–70%), to give the title compound as a white solid (35 mg, 17%). HRMS (ESI) m/z 20 [M+H]+ calcd for C22H36N7O3S2: 510.2316, found: 510.2320.1H NMR (300 MHz, CD3OD, mixture of rotamers): δ 0.91-0.99 (6H, m), 1.16 (3H, d), 1.39-1.50 (2H, m), 1.69-1.96 (4H, m), 2.65-2.76 (1H, m), 2.90-3.15 (4H, m), 3.32-3.76 (4H, m), 4.20-4.26 (1H, m), 5.06-5.18 (1H, m), 7.22-7.46 (5H, m). 25 Example 32 (R*)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonimidoamide Isomer 1 230 201388-PCT01-NP OH The isomers of N-(4-{[(2R)-1-hyd l]amino}-6-[(1-phenylethyl)sulfanyl]- 1,3,5-triazin-2-yl)methanesulfonimidoamide Example 29 (340 mg, 0.8 mmol) were separated by preparative chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 15 % EtOH/DEA 5 (100/0.5 mM) in CO2 as mobile phase at a flow rate of 130 mL/min. The first eluting compound mixture was collected and further separated by preparative chiral HPLC on a Chiralpak IC column (5µm, 250×20 mm ID) using a heptane:EtOH:TEA (80:20:0.1) mobile system as eluant at a flow rate of 20 mL/min. The first eluting compound was collected to give the title compound (R*)-N-(4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1-phenylethyl]sulfanyl}- 10 1,3,5-triazin-2-yl)methanesulfonimidoamide, Isomer 1, Example 32, (62 mg, 18%): HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O2S2: 425.1788, found: 425.1768.1H NMR (500 MHz, CD3OD, mixture of rotamers) δ 0.89–1 (6H, m), 1.33–1.53 (2H, m), 1.68–1.76 (4H, m), 3.36 and 3.41 (3H, s, rotamers), 3.42–3.59 (2H, m), 4.14–4.34 (1H, m), 5.07 (1H, p), 7.18–7.26 (1H, m), 7.26–7.35 (2H, m), 7.4–7.46 (2H, m). 15 Example 33 N-(4-{[(2R)-1-Cyclopentyl-3-hydroxypropan-2-yl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F 20 The isomers of N-(4-(((R)-1-cyclopentyl-3-hydroxypropan-2-yl)amino)-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 52 (200 mg, 231 201388-PCT01-NP 0.41 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(2R)-1-cyclopentyl-3- hydroxypropan-2- yl]amino}-6-{[(1R*)-1-(2,4-difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2- 5 yl)methanesulfonamide Isomer 1, Example 33 as a white solid (95 mg, 48%). HRMS (ESI) m/z [M+H]+ calcd for C20H28F2N5O3S2: 488.1596, found: 488.1618.1H NMR (300 MHz, DMSO-d6) δ 1.07 (2H, br s), 1.29 – 1.59 (6H, m), 1.59-1.86 (6H, m), 3.2-3-4 (5H, m), 3.94-4.03 (1H, m), 4.69 (1H, t), 5.15-5.21 (1H, m), 7.03-7.10 (1H, m), 7.21-7.29 (1H, t), 7.54 – 7.81 (H, m), 11.22 (1 H, s). 10 Example 34 N-(4-{[(1R)-1-Cyclobutyl-2-hydroxyethyl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F 15 The isomers of N-(4-(((R)-1-cycl o)-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 53 (250 mg, 0.54 mmol) were separated by preparative HPLC, PrepMethod P, (gradient 30–50%) to give the first eluting compound N-(4-{[(1R)-1-cyclobutyl-2-hydroxyethyl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 34 as 20 a white solid (100 mg, 40%). HRMS (ESI) m/z [M+H]+ calcd for C18H24F2N5O3S2: 460.1282, found: 460.1292.1H NMR (400 MHz, DMSO-d6) δ 1.75-1.95 (9H, m), 2.4-2.55 (1H, m, overlapping with the DMSO peak), 3.29-3.37 (5H, m), 3.9-4.05 (1H, m), 4.56 (1H, t), 5.18-5.21 (1H, m), 7.06- 7.09 (1H, m), 7.23-7.28 (1H, m), 7.62-7.69 (2H, m), 11.21 (1H, s). 25 Example 35 232 201388-PCT01-NP N-(4-{[(1R)-1-Cyclopentyl-2-hydroxyethyl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 2 F The isomers of N-(4-(((R)-1-cycl no)-6-((1-(2,4- 5 difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 54 (100 mg, 0.21 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 60% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the second eluting compound N-(4-{[(1R)-1-cyclopentyl-2-hydroxyethyl]amino}- 6-{[(1R*)-1-(2,4-difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 10 2, Example 35, as a white solid (25 mg, 25%). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N5O3S2: 474.1440, found: 474.1434.1H NMR (400 MHz, DMSO-d6) δ 1.20-1.72 (11H, m), 2.03-2.06 (1H, m), 3.26-3.50 (5H, m), 3.85-3.87 (1H, m), 4.57 (1H, t), 5.16-5.22 (1H, m), 7.03-7.11 (1H, m), 7.22-7.28 (1H, m), 7.61-7.75 (2H, m), 11.25 (1H, s). 15 Example 36 N-(4-{[(2R)-1-Cyclopropyl-3-hydroxypropan-2-yl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F The isomers of N-(4-(((R)-1-cyc opropy - - y roxypropan- -yl)amino)-6-((1-(2,4- 20 difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 55 (200 mg, 233 201388-PCT01-NP 0.44 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 modified with 0.1% DEA at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(2R)-1-cyclopropyl-3- hydroxypropan-2-yl]amino}-6-{[(1R*)-1-(2,4-difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2- 5 yl)methanesulfonamide Isomer 1, Example 36 as a white solid (76 mg, 38%). HRMS (ESI) m/z [M+H]+ calcd for C18H24F2N5O3S2: 460.1282, found: 460.1276.1H NMR (300 MHz, DMSO-d6) δ -0.21–0.18 (2H, m), 0.26–0.52 (2H, m), 0.56–0.93 (1H, m), 1.24–1.52 (2H, m), 1.65–1.76 (3H, m), 3.31–3.51 (5H, m), 3.82–4.25 (1H, m), 4.48–4.8 (1H, m), 5.1–5.35 (1H, m), 7–7.15 (1H, m), 7.25 (1H, t), 7.55–7.85 (2H, m), 11.22 (1H, br s). 10 Example 37 N-(4-{[(2R,3R)-1,2-Dihydroxyhexan-3-yl]amino}-6-{[(1R*)-1-phenylethyl]sulfanyl}-1,3,5- triazin-2-yl)methanesulfonamide Isomer 1 OH 15 The isomers of N-(4-(((2R,3R)-1, ino)-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 61 (310 mg, 0.70 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 50% MeOH in CO2 at a flow rate of 170 mL/min as mobile phase to give the first eluting compound N-(4-{[(2R,3R)-1,2-dihydroxyhexan-3-yl]amino}-6-{[(1R*)-1- 20 phenylethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 37 as a white solid (110 mg, 36 %). HRMS (ESI) m/z [M+H]+ calcd for C18H28N5O4S2: 442.1578, found: 442.1574.1H NMR (300 MHz, DMSO-d6, mixture of rotamers about 1/1): δ 0.82-0.88 (3H, m), 1.19-1.49 (3H, m), 1.58-1.72 (4H, m), 3.32-3.49 (6H, m, partially overlapping with the water signal), 3.89-4.18 (1H, m), 4.45-4.58 (1H, m), 4.65-4.78 (1H, m), 4.97-5.05 (1H, m), 7.25-7.37 25 (3H, m), 7.43-7.49 (2H, m), 7.66-7.69 (1H, m), 11.22 (1H, brs). 234 201388-PCT01-NP Example 38 N-(4-{[(1R)-1-Cyclopropyl-2-hydroxyethyl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 OH F 5 The isomers of N-(4-(((R)-1-cyc no)-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 62 (160 mg, 0.36 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 modified with 0.1% DEA at a flow rate of 170 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R)-1-cyclopropyl-2-10 hydroxyethyl]amino}-6-{[(1R*)-1-(2,4-difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 38 as a white solid (67 mg, 42%). HRMS (ESI) m/z [M+H]+ calcd for C17H22F2N5O3S2: 446.1126, found: 446.1106.1H NMR (300 MHz, DMSO- d6): δ 0.25-0.45 (4H, m), 0.95 (1H, apparent br s), 1.68 (3H, apparent dd, two rotamers), 3.37- 3.54 (5H, m, partially overlapping with the water signal), 4.68 (1H, apparent br s), 5.11-5.21(1H, 15 m), 7.07 (1H, t), 7.22-7.32 (1H, m), 7.56-7.69 (1H, m), 7.89-7.97 (1H, m), 11.21 (1H, br s). Example 39 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclobutyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 20 Cl 201388-PCT01-NP The isomers of N-(4-((1-(4-chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclobutyl-2- hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 66 (200 mg, 0.42 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 170 mL/min as mobile 5 phase to give the second eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclobutyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 39 as a white solid (40 mg, 20%). HRMS (ESI) m/z [M+H]+ calcd for C18H24ClFN5O3S2: 476.0988, found: 476.0982.1H NMR (400 MHz, DMSO- d6) δ 1.77-1.94 (9H, m), 2.49-2.53 (1H, m), 3.26-3.41 (5H, m), 3.93-3.98 (1H, m), 4.54-4.57 10 (1H, m), 5.14-5.21 (1H, m), 7.26 (1H, t), 7.40 (1H, d), 7.58-7.66 (2H, m), 11.25 (1H, s). Example 40 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R,3R)-1,2-dihydroxyhexan-3- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 OH 15 Cl The isomers of N-(4-((1-(4-chlo 6-(((2R,3R)-1,2-dihydroxyhexan- 3-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 67 (310 mg, 0.60 mmol) were separated by preparative chiral SFC on a Phenomenex Lux Cellulose-4 column (5 µm, 250×50 mm ID) using an isocratic system of 50% MeOH in CO2 at a flow rate of 180 mL/min to give the20 first eluting compound N-(4-{[(1R*)-1-(4-chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R,3R)- 1,2-dihydroxyhexan-3-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 40 as a brown solid (130 mg, 42%). HRMS (ESI) m/z [M+H]+ calcd for C18H26ClFN5O4S2: 494.1094, found: 494.1092.1H NMR (300 MHz, DMSO-d6): δ 0.81-0.88 (3H, m), 1.13-1.46 (3H, m), 1.58-1.71 (4H, m), 3.34-3.48 (6H, m), 3.85-4.10 (1H, m), 4.52 (1H, t), 4.77 (1H, d), 25 5.16-5.21 (1H, m), 7.25 (1H, t), 7.43 (1H, d), 7.60-7.67 (2H, m), 11.22 (1H, br s). 236 201388-PCT01-NP Example 41 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylbut-3-en-1-yl)sulfanyl]-1,3,5- triazin-2-yl)methanesulfonamide 5 1-Phenylbut-3-en-1-yl methanesu 0.109 g, 0.48 mmol) dissolved in DMF (0.6 mL) was added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (0.129 g, 0.4 mmol) in DMF (0.6 mL). DIPEA (0.174 mL, 1.00 mmol) was added, and the reaction mixture was left at rt on and then heated in a microwave reactor at 100°C for 30 min. Water (2 mL) and DCM (6 mL) 10 were added and the mixture was shaken vigorously and the phases were separated using a phase separator. The organic layer was concentrated and the residue was purified by preparative SFC, PrepMethod G (gradient: 15–20%) to give (19 mg, 10%) of the title compound. HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O3S2: 452.1784, found: 452.1788; 1H NMR (600 MHz, DMSO-d6, mixture of diasteromers and rotamers) δ 0.82–0.9 (6H, m), 1.24–1.47 (2H, m), 1.52–1.64 (1H, 15 m), 2.69–2.8 (1H, m), 2.84 (1H, ddt), 3.3–3.43 (5H, m, overlapping with the solvent), 3.96–4.17 (1H, m), 4.65–4.77 (1H, m), 4.9–5.01 (2H, m), 5.01–5.11 (1H, m), 5.6–5.74 (1H, m), 7.2–7.27 (1H, m), 7.28–7.36 (2H, m), 7.37–7.46 (2H, m), 7.71 (1H, s). Example 42 20 N-(4-{[(2R)-1-Cyclobutyl-3-hydroxypropan-2-yl]amino}-6-{[(1R*)-1-(2,4- difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 237 201388-PCT01-NP F The isomers of N-(4-(((R)-1-cycl l)amino)-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 69 (200 mg, 0.42 mmol) were separated by preparative chiral SFC on a Chiralpak IC-3 column (5 µm, 5 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(2R)-1-cyclobutyl-3-hydroxypropan-2- yl]amino}-6-{[(1R*)-1-(2,4-difluorophenyl)ethyl]sulfanyl}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 42 as a white solid (90 mg, 45%). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N5O3S2: 474.1440, found: 474.1430.1H NMR (300 MHz, DMSO-d6) 10 δ 1.45 - 1.83 (9H, m), 1.93-1.98 (2H, m), 2.19 - 2.35 (1H, m), 3.28-3.37 (2 H, m, overlapping with the water signal), 3.36 (3H, s), 3.8-4.0 (1H, m), 4.67 (1H, t), 5.18 (1H, q), 7.0-7.1 (1H, m), 7.21-7.29 (1H, m), 7.55 - 7.77 (2H, m), 11.21 (1H, br s). Example 43 15 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopentyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 2 Cl The isomers of N-(4-((1-(4-chlor o- - uo op e y e y o -6-(((R)-1-cyclopentyl-2- hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 70 (100 mg, 0.2 20 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm 238 201388-PCT01-NP ID) using an isocratic system of 40% MeOH (0.1% DEA) in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopentyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 2, Example 43 as a white solid (20 mg, 20%). HRMS (ESI) m/z 5 [M+H]+ calcd for C19H26ClFN5O3S2: 490.1144, found: 490.1162.1H NMR (400 MHz, DMSO- d6) δ 1.24-1.32 (2H, m), 1.46-1.71 (9H, m), 1.94-2.10 (1H, m), 3.30-3.41 (5H, m, partially overlapping with the DMSO signal), 3.80-3.91 (1H, m), 4.55-4.65 (1H, m), 5.14-5.20 (1H, m), 7.27-7.29 (1H, m), 7.41-7.45 (1H, m), 7.45-7.65 (1H, m), 7.78 (1H, br s), 11.17 (1H, br s). 10 Example 44 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopentyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 Cl The isomers of N-(4-((1-(4-chlo 6-(((R)-1-cyclopentyl-3- 15 hydroxypropan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 71 (140 mg, 0.28 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 µm, 250×50 mm ID) using an isocratic system of 25% MeOH (0.1% DEA) in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopentyl-3-hydroxypropan-2-yl]amino}-1,3,5- 20 triazin-2-yl)methanesulfonamide Isomer 1, Example 44 as a white solid (50 mg, 36%). HRMS (ESI) m/z [M+H]+ calcd for C20H28ClFN5O3S2: 504.1300, found: 504.1288.1H NMR (300 MHz, DMSO-d6) δ 0.95-1.15 (2H, m), 1.37 - 1.59 (6H, m), 1.59-1.85 (6H, m), 3.23-3.38 (5H, m, partially overlapping with the DMSO signal), 4.00 (1H, s), 4.68 (1H, t), 5.13-5.22 (1H, m), 7.27 (1H, dt), 7.40 (1H, dd), 7.55 - 7.77 (2H, m), 11.21 (1H, br s). 25 Example 45 239 201388-PCT01-NP N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclobutyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 Cl The isomers of N-(4-((1-(4-chlo 6-(((R)-1-cyclobutyl-3- 5 hydroxypropan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 72 (140 mg, 0.28 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH (0.1% DEA) in CO2 at a flow rate of 170 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclobutyl-3-hydroxypropan-2-yl]amino}-1,3,5-triazin- 10 2-yl)methanesulfonamide Isomer 1, Example 45 as a white solid (55 mg, 37%). HRMS (ESI) m/z [M+H]+ calcd for C19H26ClFN5O3S2: 490.1144, found: 490.1130.1H NMR (300 MHz, DMSO-d6) δ 1.46 – 1.81 (9H, m), 1.8-2.0 (2H, m), 2.21 – 2.35 (1H, m), 3.2-3.4 (5H, m, partially overlapping with the water signal), 3.8-4.0 (1H, m), 4.68 (1H, t), 5.17 (1H, q), 7.24-7.29 (1H, m), 7.44 (1H, dd), 7.56 – 7.71 (2H, m), 11.25 (1H, br s). 15 Example 46 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopropyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 Cl 20 The isomers of N-(4-((1-(4-chlor o- - uorop eny )e y ) o)-6-(((R)-1-cyclopropyl-3- hydroxypropan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 73 (140 mg, 240 201388-PCT01-NP 0.28 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH (0.1% DEA) in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopropyl-3-hydroxypropan-2-yl]amino}-1,3,5- 5 triazin-2-yl)methanesulfonamide Isomer 1, Example 46 as a white solid (55 mg, 34%). HRMS (ESI) m/z [M+H]+ calcd for C18H24ClFN5O3S2: 476.0988, found: 476.0996.1H NMR (300 MHz, DMSO-d6): δ 0.00-0.07 (1H, m), 0.09-0.11 (1H, m), 0.33-0.44 (2H, m), 0.66-0.69 (1H, m), 1.36-1.44 (2H, m), 1.68 (3H, apparent t, two rotamers), 3.40-3.47 (5H, m, partially overlapping with the water signal), 3.89-4.12 (1H, m), 4.68 (1H, t), 5.19 (1H, q), 7.25-7.30 (1H, m), 7.43 10 (1H, dd), 7.58-7.68 (1H, m), 7.75 (1H, d), 11.22 (1H, br s). Example 47 N-(4-{[1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide 15 Cl DIPEA (0.051 mL, 0.29 mmol) )-N-(4-((1-hydroxypentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 76 (60 mg, 0.20 mmol) and 1-(1-bromoethyl)-4-chloro-2-fluorobenzene (46 mg, 0.20 mmol) in DMF (5 mL) at 15°C under an atmosphere of N2(g) and the reaction mixture was stirred at rt for 1 h. The solvent 20 was removed under reduced pressure to give a crude product that was purified by preparative HPLC, PrepMethod Q, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound as a white solid (35 mg, 39%). HRMS (ESI) m/z [M+H]+ calcd for C17H24ClFN5O3S2: 464.0988, found: 464.0996.1H NMR (300 MHz, DMSO- d6): δ 1.80-1.92 (3H, m), 1.29-1.51 (4H, m), 1.63-1.71 (3H, m), 3.38-3.40 (5H, m, partially 25 overlapping with the water signal), 3.91 (1H, apparent br s), 4.66-4.69 (1H, m), 5.16-5.20 (1H, m), 7.26-7.29 (1H, m), 7.42 (1H, dd), 7.45-7.58 (1H, m), 7.60-7.64 (1H, m), 11.20 (1H, br s). 241 201388-PCT01-NP Example 48 N-(4-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopropyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 OH 5 Cl The isomers of N-(4-((1-(4-chlo 6-(((R)-1-cyclopropyl-2- hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 77 (130 mg, 0.28 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile10 phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-2- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopropyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 48 as a white solid (38 mg, 29%). HRMS (ESI) m/z [M+H]+ calcd for C17H22ClFN5O3S2: 462.0830, found: 462.0834.1H NMR (300 MHz, DMSO- d6, mixture of rotamers): δ 0.24-0.46 (4H, m), 0.92-0.95 (1H, m), 1.67 (3H, apparent dd), 3.29- 15 3.56 (6H, m, partially overlapping with the water signal), 4.67 (1H, t), 5.10-5.21 (1H, m), 7.27 (1H, d), 7.40-7.47 (1H, m), 7.56-7.64 (1H, m), 7.85 (1H, br d), 11.22 (1H, br s). Example 49 N-(4-{[(1R*)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclobutyl-2- 20 hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F Cl 201388-PCT01-NP The isomers of N-(4-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-cyclobutyl-2- hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 81 (100 mg, 0.28 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 50% MeOH in CO2 at a flow rate of 150 mL/min as mobile 5 phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-3- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclobutyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 49 as a white solid (30 mg, 30%). HRMS (ESI) m/z [M+H]+ calcd for C18H24ClFN5O3S2: 476.0988, found: 476.0960.1H NMR (400 MHz, DMSO- d6) δ 1.66-1.94 (9H, m), 2.50-2.55 (1H, m, overlapping with the DMSO signal), 3.30-3.42 (5H, 10 m, partially overlapping with the water signal), 3.91-3.98 (1H, m), 4.55 (1H, t), 4.95-5-05 (1H, m), 7.39 (1H, t), 7.50-7.82 (3H, m), 11.19 (1H, br s). Example 50 N-(4-{[(1R*)-1-(2,4-Dichlorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}- 15 1,3,5-triazin-2-yl)methanesulfonamide Isomer 2 Cl DIPEA (0.085 mL, 0.49 mmol) -N-(4-((1-hydroxypentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 76 (100 mg, 0.33 mmol) and 1-(1-bromoethyl)-2,4-dichlorobenzene (83 mg, 0.33 mmol) in DMF (5 mL) at rt 20 under an atmosphere of N2(g) and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure to give a crude product which was purified by preparative HPLC, PrepMethod Q, (gradient 40–52%) to give the second eluting compound N-(4-{[(1R*)-1- (2,4-dichlorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 2, Example 50 as a white solid (25 mg, 16%). HRMS (ESI) m/z25 [M+H]+ calcd for C17H24Cl2N5O3S2: 480.0692, found: 480.0686.1H NMR (400 MHz, DMSO- d6): δ 0.81 and 0.86 (3H, t, two rotamers), 1.23-1.42 (4H, m), 1.65 and 1.74 (3H, d, two 243 201388-PCT01-NP roamers), 3.33-3.40 (5H, m), 3.94 (1H, m), 4.69 (1H, t), 5.28-5.32 (1H, m), 7.43-7.47 (1H, m), 7.63-7.68 (3H, m), 11.27 (1H, br s). Example 51 5 N-(4-{[(1R*)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopentyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F Cl The isomers of N-(4-((1-(4-chlo 6-(((R)-1-cyclopentyl-2- hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 83 (100 mg, 0.20 10 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-3- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopentyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 51 as a white solid. (30 mg, 30%). HRMS (ESI) m/z15 [M+H]+ calcd for C19H26ClFN5O3S2: 490.1144, found: 490.1160.1H NMR (400 MHz, DMSO- d6, mixture of rotamers) δ 1.17-1.69 (11H, m), 2.0-2.1 (1H, m), 3.32-3..51 (5H, m, partially overlapping with the water signal), 3.8-3.9 (1H, m), 4.55-4.65 (1H, m), 4.95-5.01 (1H, m), 7.36- 7.50 (1H, m), 7.52-7.66 (2H, m), 7.73-7.93 (1H, m), 11.21 (1H, br s). 20 Example 52 N-(4-{[(1R*)-1-(4-Chlorophenyl)ethyl]sulfanyl}-6-{[(2R,3R)-1,2-dihydroxyhexan-3-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 244 201388-PCT01-NP OH Cl The isomers of N-(4-((1-(4-chloro ,3R)-1,2-dihydroxyhexan-3- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 84 (330 mg, 0.69 mmol) were separated by a preparative chiral SFC on a Phenomenex Lux Cellulose-3 column (5 mm, 250×50 5 mm ID) using an isocratic system of 50% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chlorophenyl)ethyl]sulfanyl}-6- {[(2R,3R)-1,2-dihydroxyhexan-3-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 52 as a white solid (73 mg, 22%). HRMS (ESI) m/z [M+H]+ calcd for C18H27ClN5O4S2: 476.1188, found: 476.1190.1H NMR (300 MHz, DMSO-d6): δ 0.81-0.88 (3H, 10 m), 1.16-1.47 (3H, m), 1.58-1.69 (4H, m), 3.33-3.51 (6H, m), 3.85-4.15 (1H, m), 4.35-4.60 (1H, m), 4.65-4.79 (1H, m), 4.97-5.02 (1H, m), 7.35-7.40 (2H, m), 7.48-7.55 (2H, m), 7.67-7.76 (1H, m), 11.21 (1H, brs). Example 53 15 N-(4-{[1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopentyl-3-hydroxypropan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F Cl Methanesulfonamide (443 mg, 4. ixture of (2R)-2-((4-chloro-6-((1-(4- chloro-3-fluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)amino)-3-cyclopentylpropan-1-ol 20 Intermediate 85 (290 mg, 0.47 mmol), Cs2CO3 (304 mg, 0.93 mmol), Pd2(dba)3 (85 mg, 0.09 mmol) and X-Phos (178 mg, 0.37 mmol) in THF (50 mL) at rt and the reaction mixture was 245 201388-PCT01-NP stirred at 60°C for 15 h. The mixture was filtered and the filtrate was concentrated to dryness to give a crude product which was first purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC, PrepMethod Q, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN) to give the title compound as a white solid (30 mg, 13%). HRMS (ESI) 5 m/z [M+H]+ calcd for C20H28ClFN5O3S2: 504.1300, found: 504.1312.1H NMR (400 MHz, DMSO-d6) δ 1.06 (2H, s), 1.43 - 1.54 (6H, m), 1.62 - 1.77 (6H, m), 3.25-3.45 (5H, m, partially overlapping with the water signal), 3.85-4.05 (1H, m), 4.65-4.75 (1H, m), 4.95-5.05 (1H, m), 7.35 - 7.48 (1H, m), 7.50 - 7.72 (3H, m), 11.20 (1H, br s). 10 Example 54 N-(4-{[(1R*)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopropyl-2- hydroxyethyl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 OH F Cl The isomers of N-(4-((1-(4-chlo 6-(((R)-1-cyclopropyl-2- 15 hydroxyethyl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 87 (60 mg, 0.13 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-3- fluorophenyl)ethyl]sulfanyl}-6-{[(1R)-1-cyclopropyl-2-hydroxyethyl]amino}-1,3,5-triazin-2- 20 yl)methanesulfonamide Isomer 1, Example 54 as a white solid (30 mg, 50%). HRMS (ESI) m/z [M+H]+ calcd for C17H22ClFN5O3S2: 462.0830, found: 462.0870.1H NMR (400 MHz, DMSO- d6, mixture of two rotamers) δ 0.23-0.45 (4H, m), 0.92-0.96 (1H, m), 1.65 (3H, apparent dd, two rotamers), 3.27-3.55 (6H, m, partially overlapping with the water signal), 4.68 (1H, t), 4.92-5.01 (1H, m), 7.33-7.39 (1H, m), 7.40-7.63 (2H, m), 7.85 (1H, br s), 11.22 (1H, br s). 25 Example 55 246 201388-PCT01-NP N-(4-{[(1R*)-1-(4-Chloro-3-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopropyl-3- hydroxypropan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F Cl 5 The isomers of N-(4-((1-(4-c io)-6-(((R)-1-cyclopropyl-3- hydroxypropan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 89 (130 mg, 0.27 mmol) were separated by a preparative chiral SFC on a Chiralpak IC column (5 mm, 250×50 mm ID) using an isocratic system of 40% MeOH in CO2 at a flow rate of 150 mL/min as mobile phase to give the first eluting compound N-(4-{[(1R*)-1-(4-chloro-3-10 fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-cyclopropyl-3-hydroxypropan-2-yl]amino}-1,3,5- triazin-2-yl)methanesulfonamide Isomer 1, Example 55 as a white solid ( (42 mg, 32%). HRMS (ESI) m/z [M+H]+ calcd for C18H24ClFN5O3S2: 476.0988, found: 476.0990.1H NMR (400 MHz, DMSO-d6) δ -0.03-0.02 (1H, m), 0.07-0.11 (1H, m), 0.34 (2H, t), 0.66-0.68 (1H, m), 1.35-1.43 (2H, m), 1.65 (3H, d), 3.35-3.46 (5H, m, partially overlapping with the water 15 signal), 3.87-4.13 (1H, m), 4.69 (1H, t), 4.98 (1H, q), 7.35-7.42 (1H, m), 7.49-7.64 (2H, m), 7.80 (1H, br s), 11.20 (1H, br s). Example 56 N-(4-{[(1R)-2-Hydroxy-1-phenylethyl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5-triazin-2- 20 yl)methanesulfonamide 201388-PCT01-NP (2R)-2-Amino-2-phenylethan-1-ol (240 mg, 1.75 mmol) and K2CO3 (242 mg, 1.75 mmol) were added to a solution of N-(4-chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 47 (120 mg, 0.35 mmol) in dioxane (5 mL) and the reaction mixture was stirred for 2 h at 80oC. The reaction was quenched by the addition of 5 30% AcOH (aq) (5 mL). The mixture was extracted with EtOAc (3×10 mL) and the combined organic layer was concentrated. The crude product was purified by preparative HPLC, PrepMethod Y, (gradient 30–70%) to give the title compound as an off-white solid (66 mg, 43%). HRMS (ESI) m/z [M+H]+ calcd for C20H24N5O3S2: 446.1314, found: 446.1302.1H NMR (400 MHz, DMSO-d6, diastereomeric mixture) δ 1.46 and 1.49 (3H, d, 10 isomers), 302 and 3.29 (3H, s, isomers), 3.61-3.68 (2H, m), 4.81-5.08 (3H, m), 7.20-7.48 (10H, m), 8.20 (1H, br s), 11.26 (1H, br s). Example 57 N-(4-[(3,4-Dihydro-2H-1-benzopyran-4-yl)sulfanyl]-6-{[(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.105 mL, 0.60 mmol) f (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 20 4 (96 mg, 0.30 mmol) and 4-bromochroman (76 mg, 0.36 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 72 h . The solvent was evaporated to give a crude product which was purified by preparative HPLC, PrepMethod A, (gradient 5–95%) to give the title compound (56 mg, 35%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O4S2: 454.1578, found: 454.1576.1H NMR (600 MHz, DMSO-d6) δ 0.83–0.9 (6H, m), 1.27–1.44 25 (2H, m), 1.56–1.64 (1H, m), 2.23–2.32 (1H, m), 2.35–2.46 (1H, m), 3.30-3.42 (5H, m, overlapping with the water signal), 4.01–4.1 (1H, m), 4.19–4.27 (1H, m), 4.28–4.35 (1H, m), 248 201388-PCT01-NP 4.68–4.74 (1H, m), 5.11–5.17 (1H, m), 6.76–6.81 (1H, m), 6.85–6.91 (1H, m), 7.13–7.19 (1H, m), 7.29–7.35 (1H, m), 7.65–7.88 (1H, m), 11.23 (1H, br s). Example 58 5 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)-1-phenylmethanesulfonamide Pd2(dba)3×CHCl3 (21 mg, 0. 4 mmol) and Cs2CO3 (200 mg,10 0.61 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol) and phenylmethanesulfonamide (140 mg, 0.82 mmol) in dioxane (8 mL) in a closed vessel and heated to 100°C for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, filtered 15 and concentrated to give a crude product which was purified by preparative HPLC, PrepMethod M, (gradient 30–70%) to give the title compound as a yellow solid (117 mg, 57%). HRMS (ESI) m/z [M+H]+ calcd for C24H32N5O3S2: 502.1940, found: 502.1922.1H NMR (300 MHz, CDCl3): δ 0.87-0.95 (6H, m), 1.29-1.39 (2H, m), 1.55-1.60 (1H, m), 1.73- 1.79 (3H, m), 3.41-3.67 (2H, m), 4.15-4.18 (1H, m), 4.66-4.73 (2H, m), 4.98-5.02 (1H, m), 20 6.90-7.00 (1H, m), 7.22-7.44 (10H, m). Example 59 N-(4-{[(1S)-2-Hydroxy-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]amino}-6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide 249 201388-PCT01-NP N O N 2-Amino-2-(3-methyl-1,2,4-oxa e base of Intermediate 91) (501 mg, 3.50 mmol) and K2CO3 (484 mg, 3.50 mmol) were added to a solution of N-(4-chloro-6- ((1-phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 47 (241 mg, 0.70 5 mmol) in DMF (5 mL) and the reaction mixture was stirred at 80oC for 1 h. The reaction was quenched with 30% AcOH (aq) (5 mL). The resulting solution was extracted with EtOAc (3×10 mL) and the combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Y, (gradient 30–70%) to give the title compound as an off-white solid (57 mg, 16%). HRMS (ESI) m/z [M+H]+ calcd 10 for C17H22N7O4S2: 452.1170, found: 452.1178.1H NMR (300 MHz, DMSO-d6, mixture of diastereomers): δ 1.50- 1.72 (3H, m), 2.31 and 2.33 (3H, s, two isomers), 3.16 and 3.37 (3H, s, two isomers, partially overlapping with the water peak), 3.88-3.91 (2H, m), 4.83-5.04 (1H, m), 5.22-5.32 (2H, m), 7.26-7.49 (5H, m), 8.55 (1H, br s), 11.44 (1H, br s): 15 Example 60 1-Cyclobutyl-N-(4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide 20 Pd2(dba)3×CHCl3 (21 mg, 0.0 p g, 0.04 mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5- 250 201388-PCT01-NP triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol) and cyclobutylmethanesulfonamide (122 mg, 0.82 mmol) in dioxane (8 mL) in a sealed tube and heated to 100°C for 3 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (1×50 mL) and brine (2×50 mL). The organic layer was dried over Na2SO4, 5 filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod M, (gradient 20-70%) to give the title compound as a yellow solid (120 mg, 61%). HRMS (ESI) m/z [M+H]+ calcd for C22H34N5O3S2: 480.2098, found: 480.2088.1H NMR (300 MHz, CDCl3): δ 0.88-0.94 (6H, m), 1.35 - 1.48(2H, m), 1.64-1.94 (8H, m), 2.11-2.15 (2H, m), 2.77-2.80 (1H, m), 3.51-3.74 (4H, m), 4.1-4.3 (1H, m), 4.96-5.00 (1H, m), 7.25-7.43 (6H, m). 10 Example 61 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)cyclopropanesulfonamide 15 Pd2(dba)3×CHCl3 (28 mg, 0.03 .055 mmol) and Cs2CO3 (294 mg, 0.82 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (150 mg, 0.41 mmol) and cyclopropanesulfonamide (99 mg, 0.82 mmol) in degassed dioxane (6 mL) in a sealed tube and the reaction mixture was heated to 100°C for 3 h under an atmosphere of N2(g). The 20 mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod M, (gradient 20–50%) to give the title compound as a yellow solid (119 mg, 48%). HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O3S2: 452.1784, found: 452.1790. 1H NMR (300 MHz, CDCl3) δ 0.87-1.02 (8H, m), 1.25-1.48 (5H, m), 1.63-1.75 (5H, m), 25 3.00-3.12 (1H, m), 3.40-3.75 (2H, m), 4.12-4.21 (1H, m), 4.92-5.05 (1H, t), 7.01-7.03 (1H, m),7.22-7.43 (5H, m). 251 201388-PCT01-NP Example 62 N-(4-{[(1R)-2-Hydroxy-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}-6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide N N 5 (2R)-2-Amino-2-(1-methyl-1H-p 94 mg, 3.50 mmol) and K2CO3 (484 mg, 3.50 mmol) were added to a solution of N-(4-chloro-6-((1-phenylethyl)sulfanyl)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 47 (241 mg, 0.70 mmol) in DMF (5 mL) and the reaction mixture was stirred at 50oC on. The reaction was quenched by the 10 addition of 30% AcOH (aq) (5 mL) and the resulting solution was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Y, (gradient 30–70%) to give the title compound as an off-white solid (135 mg, 43%). HRMS (ESI) m/z [M+H]+ calcd for C18H24N7O3S2: 450.1376, found: 450.1382.1H NMR (400 MHz, DMSO-d6, mixture of 15 diastereomers) δ 1.60-1.71 (3H, m), 3.24 and 3.3 (3H, s, partially overlapping with the water signal), 3.64-3.79 (5H, m), 4.86-5.23 (3H, m), 6.16 (1H, dd), 7.22-7.60 (6H, m), 8.08 (1H, br s), 11.30 (1H, br s). Example 63 20 N-(4-{[(1S)-2-Hydroxy-1-(3-methyl-1,2-oxazol-5-yl)ethyl]amino}-6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide 252 201388-PCT01-NP N O (2S)-2-Amino-2-(3-methyl-1,2- 9 mg, 1.75 mmol) and K2CO3 (242 mg, 1.75 mmol) were added to a solution of N-(4-chloro-6-((1-phenylethyl)sulfanyl)-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 47 (120 mg, 0.35 mmol) in dioxane (5 mL) 5 and the reaction mixture was stirred at 80oC for 2 h. The reaction was then quenched by the addition of 30% AcOH (aq) (5 mL) and the resulting solution was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Y, (gradient 30–70%), to give the title compound a light yellow solid (44 mg, 28%). HRMS (ESI) m/z [M+H]+ calcd 10 for C18H23N6O4S2: 451.1216, found: 451.1208.1H NMR (400 MHz, DMSO-d6, mixture of diastereomers): δ 1.58-1.71 (3H, m), 2.18 and 2.20 (3H, s, two isomers), 3.08 and 3.26 (3H, s, two isomers, partially overlapping with the water signal), 3.74-3.75 (2H, m), 4.92-5.08 (1H, m), 5.13-5.30 (2H, m), 6.20-6.24 (1H, m), 7.24-7.46 (5H, m). 15 Example 64 (R*)-N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- phenylethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonimidoamide Isomer 3 20 The isomers of N-(4-{[(2R)-1-hy roxy- -me ypen an- -yl]amino}-6-[(1- phenylethyl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonimidoamide Example 29 (340 mg, 0.8 253 201388-PCT01-NP mmol) were separated by preparative chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 15% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 130 mL/min to give the second eluting compound (R*)-N-(4-{[(2R)-1-hydroxy-4-methylpentan- 2-yl]amino}-6-{[(1R*)-1-phenylethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonimidoamide 5 Isomer 3, Example 64 (61 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O2S2: 425.1788, found: 425.1778.1H NMR (500 MHz, CD3OD, mixture of rotamers) δ 0.87–0.99 (7H, m), 1.38–1.54 (2H, m), 1.64–1.75 (4H, m), 3.36 and 3.37 (3H, s, rotamers), 3.37 (1H, s), 3.51–3.61 (2H, m), 4.12–4.23 (1H, m), 4.60 (1H, s), 5.07 (1H, dq), 7.18–7.27 (1H, m), 7.28– 7.33 (2H, m), 7.39–7.44 (2H, m). 10 Example 65 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)methanesulfinamide 15 Pd2(dba)3×CHCl3 (42 mg, 0.04 0.08 mmol) and Cs2CO3 (400 mg, 1.23 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 2 (300 mg, 0.82 mmol) and methanesulfinamide (129 mg, 1.64 mmol) in dioxane (8 mL) under an atmosphere of N2(g) 20 and the reaction mixture was heated to 64°C for 10 h. The mixture was filtered and the filtrate was concentrated to afford a crude product which was first purified by preparative TLC (PE:EtOAc, 1:3) followed by preparative HPLC, PrepMethod Y, (gradient 35–72%) to give the title compound as a white solid (35 mg, 10%). HRMS (ESI) m/z [M+H]+ calcd for C18H28N5O2S2: 410.1678, found: 410.1674.1H NMR (300 MHz, CDCl3): δ 0.85-0.91 (6H, 25 m), 1.25-1.74 (6H, m), 2.78-2.86 (3H, m), 3.49-3.79 (2H, m), 4.16-4.17 (1H, m), 4.93-5.00 (1H, m), 7.23-7.43 (5H, m). 254 201388-PCT01-NP Example 66 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(2R*)-1-phenylpropan-2- yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 5 The isomers of N-(4-(((R)-1-hyd mino)-6-((1-phenylpropan-2- yl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 93 (168 mg, 0.38 mmol) were separated by preparativen chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 25% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 80 mL/min. The first 10 eluting compound was collected and dissolved in DCM (4 mL) and extracted with citric acid (2 mL) to remove traces of DEA. The organic layer was concentrated to give N-(4-{[(2R)-1- hydroxy-4-methylpentan-2-yl]amino}-6-{[(2R*)-1-phenylpropan-2-yl]sulfanyl}-1,3,5-triazin-2- yl)methanesulfonamide Isomer 1, Example 66 (69 mg, 41%). HRMS (ESI) m/z [M+H]+ calcd for C19H30N5O3S2: 440.1784, found: 440.1784.1H NMR (400 MHz, CDCl3, mixture of rotamers) 15 δ 0.86–0.96 (6H, m), 1.3–1.46 (4H, m), 1.46–1.57 (1H, m), 1.57–1.7 (1H, m), 2.75–2.89 (1H, m), 3.07–3.19 (1H, m), 3.31 and 3.37 (3H, s, rotamers), 3.58 (1H, dd), 3.74 (1H, dd), 3.98–4.15 (1H, m), 4.22–4.35 (1H, m), 7.19–7.25 (3H, m), 7.27–7.35 (2H, m), 7.66 (1H, d). Example 67 20 N-[4-({(Z)-2-Fluoro-2-[4-(trifluoromethyl)phenyl]ethenyl}sulfanyl)-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide F F 201388-PCT01-NP 1-(2-Bromo-1,1-difluoroethyl)-4-(trifluoromethyl)benzene (45 mg, 0.15 mmol) dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (54 mg, 0.14 mmol) and DIPEA (0.062 mL, 0.35 mmol). The reaction mixture was heated in a microwave reactor at 140°C for 30 min. 5 Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod C, (gradient: 20–25%) to give the title compound (3 mg, 3%). HRMS (ESI) m/z [M+H]+ calcd for C19H24F4N5O3S2: 510.1252, found: 510.1266. 10 Example 68 N-(4-{[2-(2,4-Dichlorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cl 2-Chloro-1-(2,4-dichloropheny ol) dissolved in DMF (0.6 mL) 15 was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol) and DIPEA (0.057 mL, 0.33 mmol) and the reaction mixture was stirred at rt for 20 h. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative HPLC, PrepMethod 20 A, (gradient: 5–95%) to give the title compound (40 mg, 57%). HRMS (ESI) m/z [M+H]+ calcd for C18H24Cl2N5O4S2: 508.0642, found: 508.0622; 1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) δ 0.70–0.94 (m, 6H), 1.17–1.45 (m, 2H), 1.46–1.64 (m, 1 H, rotamers), 3.20–3.40 (m, partly overlapping with solvent), 3.88–4.07 (m, 1H, rotamers), 4.52–4.74 (m, 2H), 7.52–7.78 (m, 3H, rotamers), 7.83–7.88 (m, 1H, rotamers), 11.16 (s, 1 H). 25 Example 69 256 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-nitrophenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide - O A solution of 2-bromo-1-(2-nitr , 0.14 mmol) in DMF (0.6 mL) 5 was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol). DIPEA (0.057 mL, 0.33 mmol) was added, and the reaction mixture was stirred at rt for 19 h. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The filtrate was concentrated and purified by preparative SFC, PrepMethod C 10 (gradient: 25–30%) to give the title compound (18.5 mg, 29%). HRMS (ESI) m/z [M+H]+ calcd for C18H25N6O6S2: 485.1272, found: 485.1248. Example 70 N-(4-{[2-(2,6-Dichlorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide l A solution of 2-bromo-1-(2,6-dic 5 mg, 0.17 mmol) in DMF (0.6 mL), followed by DIPEA (0.061 mL, 0.35 mmol), were added to (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 20 (50 mg, 0.14 mmol). The reaction mixture was stirred at rt for 20 h. Water (2 mL) and DCM (2 mL) were added, and the phases were separated. The organic layer was passed through a phase separator. The filtrate was concentrated and purified by preparative SFC, PrepMethod A 257 201388-PCT01-NP (gradient: 20–25%) to give the title compound (48 mg, 67%). HRMS (ESI) m/z [M+H]+ calcd for C18H24Cl2N5O4S2: 508.0642, found: 508.0636.1H NMR (600 MHz, DMSO-d6) δ 0.75 – 0.92 (m, 6H), 1.23 – 1.62 (m, 3H), 3.24 – 3.52 (m, 5H), 3.95 – 4.11 (m, 1H), 4.57 – 4.75 (m, 2H), 7.49 – 7.55 (m, 1H), 7.55 – 7.61 (m, 2H). 5 Example 71 N-(4-{[2-(2-Chlorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide l 10 The title compound was prepared or Example 70 from 2-bromo-1-(2- chlorophenyl)ethan-1-one (39.7 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol) to give the title compound (32 mg, 45%). HRMS (ESI) m/z [M+H]+ calcd for C18H25ClN5O4S2: 474.1030, found: 474.1034.1H NMR (600 MHz, DMSO-d6) δ 0.67 – 0.96 (m, 15 6H), 1.16 – 1.66 (m, 3H), 3.21 – 3.51 (m, 5H), 3.91 – 4.06 (m, 1H), 4.55 – 4.72 (m, 2H), 7.44 – 7.49 (m, 1H), 7.53 – 7.59 (m, 2H), 7.78 – 7.84 (m, 1H). Example 72 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-oxo-2-(thiophen-2- 20 yl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide S 201388-PCT01-NP The title compound was prepared and purified as described for Example 6 from 2-bromo-1- (thiophen-2-yl)ethan-1-one (45.1 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (8.7 mg, 10%). HRMS (ESI) m/z [M+H]+ calcd for 5 C16H24N5O4S3: 446.0984, found: 446.0992. Example 73 N-(4-{[2-(4-Fluorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 10 F 2-Bromo-1-(4-fluorophenyl)eth nd DIPEA (0.054 mL, 0.31 mmol) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol, 80% w/w) 15 in DMF (0.6 mL) and the reaction mixture was stirred at ambient temperature on. Water (1.5 mL) and DCM (2.5 mL) were added. The two layers were separated, and the organic layer was passed through a phase separator and concentrated to give a crude product which was purified by preparative SFC, PrepMethod Z, (gradient 5–95%) to give the title compound (41 mg, 73%). HRMS (ESI) m/z [M+H]+ calcd for C18H25FN5O4S2: 458.1326, found: 458.1312.1H NMR (600 20 MHz, DMSO-d6, two rotamers about 1/1) δ 0.57–0.89 (6H, m), 1.04–1.68 (3H, m), 3.04–3.35 (5H, m), 3.61–3.84 and 3.9–4.1 (1H, m, rotamers), 4.55–4.85 (3H, m), 7.34–7.42 (2H, m), 7.53– 7.75 (1H, m), 8.09–8.15 (2H, m). Example 74 25 N-[4-({1-[4-(Difluoromethoxy)phenyl]-1-oxopropan-2-yl}sulfanyl)-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide 259 201388-PCT01-NP F The title compound was prepa Example 70 from 2-bromo-1-(4- (difluoromethoxy)phenyl)propan-1-one (47.4 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 5 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C (gradient: 20–25%) to give the title compound (18.9 mg, 26%). HRMS (ESI) m/z [M+H]+ calcd for C20H28F2N5O5S2: 520.1494, found: 520.1492.1H NMR (600 MHz, DMSO-d6) δ 0.59 – 0.92 (m, 6H), 1.06 – 1.65 (m, 6H), 3.12 – 3.55 (m, 5H), 3.7 – 4.08 (m, 1H), 5.57 – 5.76 (m, 1H), 7.24 – 7.55 (m, 3H), 8.08 – 8.16 (m, 2H). 10 Example 75 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(4-methylphenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 15 The title compound was prepare Example 6 from 2-bromo-1-(p- tolyl)ethan-1-one (46.9 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (20.2 mg, 10%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O4S2: 454.1578, found: 454.1584. 20 Example 76 260 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(2-oxo-2-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)methanesulfonamide 5 The title compound was prepare or Example 70 from 2-bromo-1- phenylethan-1-one (33.8 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C (gradient: 25–30%) to give the title compound (27 mg, 44%). HRMS (ESI) m/z [M+H]+ calcd for C18H26N5O4S2: 10 440.1420, found: 440.1408.1H NMR (600 MHz, DMSO-d6) δ 0.61 – 0.9 (m, 6H), 1.02 – 1.62 (m, 3H), 3.07 – 3.46 (m, 5H), 3.69 – 4.06 (m, 1H), 4.53 – 4.85 (m, 2H), 7.56 (q, 2H), 7.59 – 7.72 (m, 1H), 8 – 8.07 (m, 2H). Example 77 15 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({2-oxo-2-[2- (trifluoromethyl)phenyl]ethyl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide F A solution of 2-bromo-1-(2-(trifl y p y - -one (37 mg, 0.14 mmol) in DMF (0.6 mL), followed by DIPEA (0.054 mL, 0.31 mmol), were added to (R)-N-(4-((1-hydroxy-4- 20 methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol). The reaction mixture was stirred at rt for 20 h. Water (2 mL) and DCM (2 261 201388-PCT01-NP mL) were added, and the phases were separated. The organic layer was passed through a phase separator. The filtrate was concentrated and purified by preparative SFC, PrepMethod Z1 (gradient: 20–25%) to give the title compound (35 mg, 54%). HRMS (ESI) m/z [M+H]+ calcd for C19H25F3N5O4S2: 508.1294, found: 508.1298.1H NMR (600 MHz, DMSO-d6) δ 0.68 – 0.92 (m, 5 6H), 1.2 – 1.64 (m, 3H), 3.21 – 3.54 (m, 5H), 3.92 – 4.07 (m, 1H), 4.59 – 4.76 (m, 2H), 7.74 – 7.79 (m, 1H), 7.79 – 7.85 (m, 1H), 7.88 (d, 1H), 8.01 (dd, 1H). Example 78 N-(4-{[2-(2-Bromophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide r The title compound was prepare or Example 77 from 2-bromo-1-(2- bromophenyl)ethan-1-one (39 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 15 mmol) to give the title compound (32 mg, 48%). HRMS (ESI) m/z [M+H]+ calcd for C18H25BrN5O4S2: 518.0526, found: 518.0546.1H NMR (600 MHz, DMSO-d6) δ 0.71 – 0.93 (m, 6H), 1.2 – 1.64 (m, 3H), 3.16 – 3.49 (m, 5H), 3.93 – 4.06 (m, 1H), 4.53 – 4.74 (m, 2H), 7.42 – 7.53 (m, 2H), 7.73 (dt, 1H), 7.78 (ddd, 1H). 20 Example 79 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({2-[4-(methylsulfonyl)phenyl]-2- oxoethyl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide 262 201388-PCT01-NP O 2-Bromo-1-(4-(methylsulfony .14 mmol) dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol). DIPEA (0.057 mL, 0.33 mmol) 5 was added, and the reaction mixture was stirred at rt for 21 h. Water (2 mL) and DCM (2 mL) were added. The two layers were separated, and the organic layer was passed through a phase separator. The solvent was evaporated to give the crude product, which was purified by preparative SCF, PrepMethod Z1, (gradient 5–95%) to give the title compound (12 mg, 17%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O6S3: 518.1196, found: 518.1200.1H NMR (600 10 MHz, DMSO-d6, mixture of two rotamers about 1/1) δ 0.61–0.87 (6H, m), 1.03–1.6 (3H, m), 3.1–3.33 (8H, m), 3.56–3.84 and 3.85–4.1 (1H, m, rotamers), 4.53–4.91 (3H, m), 7.66 (1H, apparent br s), 8.07–8.13 (2H, m), 8.23–8.29 (2H, m). Example 80 15 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(2-methyl-1-oxo-1-phenylpropan-2- yl)sulfanyl]-1,3,5-triazin-2-yl)methanesulfonamide The title compound was prepared p 77 from 2-bromo-2-methyl-1-20 phenylpropan-1-one (32 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol). The crude product was purified by preparative SFC PrepMethod Z1 (gradient: 10–15%) to give the 263 201388-PCT01-NP title compound (30 mg, 51%). HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O4S2: 468.1734, found: 468.1724.1H NMR (600 MHz, DMSO-d6) δ 0.74 – 0.93 (m, 6H), 1.21 – 1.61 (m, 3H), 1.61 – 1.88 (m, 6H), 3.11 – 3.5 (m, 5H), 3.8 – 4 (m, 1H), 7.33 (t, 1H), 7.37 – 7.47 (m, 2H), 7.47 – 7.53 (m, 1H), 8.10 (d, 1H). 5 Example 81 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-hydroxyphenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide H 10 The title compound was prepared 77 from 2-bromo-1-(2- hydroxyphenyl)ethan-1-one (30 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol). The crude product was purified by preparative HPLC, PrepMethod A (gradient: 0–50%) to give the title compound (36 mg, 60%). HRMS (ESI) m/z [M+H]+ calcd for C18H26N5O5S2: 15 456.1370, found: 456.1340.1H NMR (600 MHz, DMSO-d6) δ 0.61 – 0.93 (m, 6H), 1.02 – 1.64 (m, 3H), 3.01 – 3.59 (m, 5H), 3.71 – 4.1 (m, 1H), 4.52 – 4.84 (m, 2H), 6.92 – 7.02 (m, 2H), 7.48 – 7.57 (m, 1H), 7.92 (ddd, 1H). Example 82 20 N-(4-{[2-(2-Fluorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP The title compound was prepared as described for Example 77 from 2-bromo-1-(2- fluorophenyl)ethan-1-one (30 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol). The crude product was purified by preparative HPLC, PrepMethod A (gradient: 0–50%) 5 to give the title compound (32 mg, 53%). HRMS (ESI) m/z [M+H]+ calcd for C18H25FN5O4S2: 458.1326, found: 458.1332.1H NMR (600 MHz, DMSO-d6) δ 0.66 – 0.92 (m, 6H), 1.06 – 1.63 (m, 3H), 3.12 – 3.54 (m, 5H), 3.76 – 4.06 (m, 1H), 4.55 – 4.75 (m, 2H), 7.32 – 7.44 (m, 2H), 7.67 – 7.74 (m, 1H), 7.86 – 7.93 (m, 1H). 10 Example 83 N-(4-{[2-(2-Fluoropyridin-3-yl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide N 15 A solution of 2-bromo-1-(2-fluor 37 mg, 0.17 mmol) in DMF (0.6 mL), followed by DIPEA (0.068 mL, 0.39 mmol), were added to (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.16 mmol). The reaction mixture was stirred at rt for 4 days. Water (2 mL) and DCM (2 mL) were added, and the phases were separated. The organic layer was passed through a phase 20 separator. The filtrate was concentrated and purified by preparative SFC, PrepMethod Z1 (gradient: 20–25%) to give the title compound (14.8 mg, 20%). HRMS (ESI) m/z [M+H]+ calcd for C17H24FN6O4S2: 459.1278, found: 459.1276.1H NMR (600 MHz, DMSO-d6) δ 0.67 – 0.92 (m, 6H), 1.1 – 1.62 (m, 3H), 3.15 – 3.47 (m, 5H), 3.77 – 4.04 (m, 1H), 4.58 – 4.73 (m, 3H), 7.51 – 7.59 (m, 1H), 7.59 – 7.76 (m, 1H), 8.4 – 8.47 (m, 1H), 8.50 (d, 1H), 11.12 (s, 1H). 25 Example 84 265 201388-PCT01-NP N-(4-{[1-(2-Bromophenyl)-1-oxopropan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide r Prepared in a similar way as desc (R)-N-(4-((1-hydroxy-4- 5 methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (100 mg, 0.31 mmol) and 2-bromo-1-(2-bromophenyl)propan-1-one (91 mg, 0.31 mmol). The crude product was purified by preparative HPLC, PrepMethod Z, (gradient: 20–25%) to give the title compound (58 mg, 35%). HRMS (ESI) m/z [M+H]+ calcd for C19H27BrN5O4S2: 532.0682, found: 532.0688.1H NMR (500 MHz, CD3OD) δ 0.84 – 0.98 (6H, m), 1.32 – 1.52 (2H, m), 1.54 10 – 1.73 (4H, m), 3.15 – 3.28 (3H, m), 3.47 – 3.57 (2H, m), 4.09 – 4.24 (1H, m), 7.27 – 7.43 (2H, m), 7.52 – 7.69 (2H, m). Note: The proton α to the carbonyl is also exchanged for deuterium. Example 85 N-(4-{[2-(4-Chlorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cl Prepared in a similar way as de )-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 20 (50 mg, 0.12 mmol, 80% w/w) and 2-bromo-1-(4-chlorophenyl)ethan-1-one (29 mg, 0.12 mmol). The crude product was purified by preparative HPLC, PrepMethod Z, (gradient: 20–25%) to give the title compound (41 mg, 70%). HRMS (ESI) m/z [M+H]+ calcd for C18H25ClN5O4S2: 266 201388-PCT01-NP 474.1030, found: 474.1016.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers) δ 0.59– 0.96 (6H, m), 1.05–1.67 (3H, m), 3.11–3.35 (5H, m, partially overlapping with the water signal), 3.68–3.77 and 3.94–4.05 (1H, m, rotamers), 4.53–4.88 (3H, m), 7.6–7.66 (2H, m), 8.02–8.08 (2H, m). 5 Example 86 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-methylphenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 10 The title compound was prepare or Example 70 from 2-bromo-1-(o- tolyl)ethan-1-one (36.2 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C (gradient: 20–25%) to give the title compound (34.3 mg, 50%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O4S2: 454.1578, 15 found: 454.1566.1H NMR (600 MHz, DMSO-d6) δ 0.67 – 0.95 (m, 6H), 1.12 – 1.64 (m, 3H), 2.38 (d, 3H), 3.2 – 3.46 (m, 5H), 3.84 – 4.06 (m, 1H), 4.54 – 4.77 (m, 2H), 7.29 – 7.37 (m, 2H), 7.43 – 7.49 (m, 1H), 7.92 (dd, 1H). Example 87 20 N-(4-{[1-(4-Chlorophenyl)-1-oxopropan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cl 201388-PCT01-NP The title compound was prepared and purified as described for Example 70 from 22-bromo-1- (4-chlorophenyl)propan-1-one (42.1 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C (gradient: 20–25%) 5 to give the title compound (21.8 mg, 31%). HRMS (ESI) m/z [M+H]+ calcd for C19H27ClN5O4S2: 488.1188, found: 488.1186.1H NMR (600 MHz, DMSO-d6) δ 0.58 – 0.94 (m, 6H), 1.06 – 1.63 (m, 6H), 3.12 – 3.52 (m, 5H), 3.67 – 4.08 (m, 1H), 5.54 – 5.71 (m, 1H), 7.55 – 7.62 (m, 2H), 8.01 – 8.08 (m, 2H). 10 Example 88 N-(4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-{[2-oxo-2-(thiophen-3- yl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide S The title compound was prepare or Example 6 from 2-bromo-1-15 (thiophen-3-yl)ethan-1-one (45.1 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (25.3 mg, 28%). HRMS (ESI) m/z [M+H]+ calcd for C16H24N5O4S3: 446.0984, found: 446.0990. 20 Example 89 N-[4-({2-[2-(Difluoromethoxy)-5-methylphenyl]-2-oxoethyl}sulfanyl)-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide 268 201388-PCT01-NP F The title compound was prepar Example 70 from 2-bromo-1-(2- (difluoromethoxy)-5-methylphenyl)ethan-1-one (47.4 mg, 0.17 mmol) and (R)-N-(4-((1- hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 5 Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod A (gradient: 0–50%) to give the title compound (40 mg, 52%). HRMS (ESI) m/z [M+H]+ calcd for C20H28F2N5O5S2: 520.1494, found: 520.1504.1H NMR (600 MHz, DMSO-d6) δ 0.67 – 0.93 (m, 6H), 1.09 – 1.63 (m, 3H), 2.33 (d, 3H), 3.15 – 3.5 (m, 5H), 3.82 – 4.06 (m, 1H), 4.48 – 4.71 (m, 2H), 7.04 – 7.37 (m, 2H), 7.43 – 7.49 (m, 1H), 7.60 (dd, 1H). 10 Example 90 N-[4-({2-[4-(Dimethylamino)phenyl]-2-oxoethyl}sulfanyl)-6-{[(2R)-1-hydroxy-4-methylpentan- 2-yl]amino}-1,3,5-triazin-2-yl]methanesulfonamide 15 The title compound was prep xample 70 from 2-bromo-1-(4- (dimethylamino)phenyl)ethan-1-one (41.2 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod A (gradient: 20–25%) to give the title compound (44.8 mg, 63%). HRMS (ESI) m/z [M+H]+ calcd 20 for C20H31N6O4S2: 483.1842, found: 483.1862.1H NMR (600 MHz, DMSO-d6) δ 0.69 – 0.91 (m, 269 201388-PCT01-NP 6H), 1.11 – 1.63 (m, 3H), 3.03 (d, 6H), 3.15 – 3.48 (m, 5H), 3.81 – 4.07 (m, 1H), 4.52 – 4.73 (m, 2H), 6.69 – 6.77 (m, 2H), 7.81 – 7.9 (m, 2H). Example 91 5 N-(4-{[2-(2,5-Dimethoxyphenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide The title compound was prepare or Example 6 from 2-bromo-1-(2,5-10 dimethoxyphenyl)ethan-1-one (57.0 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (8.7 mg, 9%). HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O6S2: 500.1632, found: 500.1640. 15 Example 92 N-(4-{[2-(2,4-Difluorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F The title compound was prepare p r Example 70 from 22-bromo-1-20 (2,4-difluorophenyl)ethan-1-one (40.0 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C 270 201388-PCT01-NP (gradient: 20–25%) to give the title compound (16.6 mg, 23%). HRMS (ESI) m/z [M+H]+ calcd for C18H24F2N5O4S2: 476.1232, found: 476.1244.1H NMR (600 MHz, DMSO-d6) δ 0.66 – 0.92 (m, 6H), 1.09 – 1.62 (m, 3H), 3.14 – 3.5 (m, 5H), 3.75 – 4.06 (m, 1H), 4.54 – 4.72 (m, 2H), 7.22 – 7.29 (m, 1H), 7.43 – 7.51 (m, 1H), 7.95 – 8.03 (m, 1H). 5 Example 93 N-(4-{[(2R)-1-Hydroxy-4-methylpentan -2-yl]amino}-6-[(1-oxo-1-phenylpropan-2-yl)sulfanyl]- 1,3,5-triazin-2-yl)methanesulfonamide 10 The title compound was prepare r Example 77 from 2-bromo-1- phenylpropan-1-one (30 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol) to give the title compound (32 mg, 56%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O4S2: 454.1578, found: 454.1594.1H NMR (600 MHz, DMSO-d6) δ 0.59 – 0.93 (m, 6H), 1.06 – 1.65 (m, 6H), 15 3.09 – 3.52 (m, 5H), 3.75 – 4.08 (m, 1H), 5.61 – 5.78 (m, 1H), 7.49 – 7.58 (m, 2H), 7.64 – 7.7 (m, 1H), 8 – 8.08 (m, 2H). Example 94 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(4-methoxyphenyl)-2- 20 oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP The title compound was prepared and purified as described for Example 6 from 2-bromo-1-(4- methoxyphenyl)ethan-1-one (50.4 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (21.1 mg, 22%). HRMS (ESI) m/z [M+H]+ calcd for 5 C19H28N5O5S2: 470.1526, found: 470.1532. Example 95 N-(4-{[2-(2,4-Dimethoxyphenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 10 The title compound was prepa Example 6 from 2-bromo-1-(2,4- dimethoxyphenyl)ethan-1-one (57.0 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 15 mmol) to give the title compound (14.7 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O6S2: 500.1632, found: 500.1644. Example 96 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(2-methoxyphenyl)-2- 20 oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 201388-PCT01-NP The title compound was prepared as described for Example 77 from 2-bromo-1-(2- methoxyphenyl)ethan-1-one (32 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol). The crude product was purified by preparative HPLC, PrepMethod A (gradient: 0–50%) 5 to give the title compound (35 mg, 58%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O5S2: 470.1526, found: 470.1520.1H NMR (600 MHz, DMSO-d6) δ 0.68 – 0.93 (m, 6H), 1.11 – 1.62 (m, 3H), 3.14 – 3.49 (m, 5H), 3.86 – 4.06 (m, 4H), 4.5 – 4.74 (m, 2H), 7 – 7.07 (m, 1H), 7.21 (d, 1H), 7.51 – 7.69 (m, 2H). 10 Example 97 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-(3-methoxyphenyl)-2- oxoethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide The title compound was prepa xample 6 from 2-bromo-1-(3-15 methoxyphenyl)ethan-1-one (50.4 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 mmol) to give the title compound (17.3 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for C19H28N5O5S2: 470.1526, found: 470.1536. 20 Example 98 N-(4-{[1-(4-Bromophenyl)-1-oxopropan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 273 201388-PCT01-NP Br The title compound was prepa from 2-bromo-1-(4- bromophenyl)propan-1-one (41 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 5 mmol). The crude product was purified by preparative HPLC, PrepMethod Z6 (gradient: 10– 60%) to give the title compound (50.3 mg, 72%). HRMS (ESI) m/z [M+H]+ calcd for C19H27BrN5O4S2: 532.0682, found: 532.0660. Example 99 10 N-(4-{[2-(3-Fluorophenyl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F The title compound was prepar from 2-bromo-1-(3- fluorophenyl)ethan-1-one (36.9 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- 15 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.14 mmol). The crude product was purified by preparative SFC, PrepMethod C (gradient: 25–30%) to give the title compound (4.8 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C18H25FN5O4S2: 458.1326, found: 458.1334.1H NMR (600 MHz, DMSO-d6) δ 0.59 – 0.92 (m, 6H), 1 – 1.64 (m, 3H), 3.05 – 3.51 (m, 5H), 3.64 – 4.09 (m, 1H), 4.53 – 4.85 (m, 2H), 7.51 – 7.57 (m, 1H), 7.58 – 20 7.74 (m, 1H), 7.78 – 7.83 (m, 1H), 7.87 – 7.93 (m, 1H). Example 100 274 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[1-(4-methoxyphenyl)-1-oxopropan-2- yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide The title compound was prepa rom 2-bromo-1-(4- 5 methoxyphenyl)propan-1-one (34 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol). The crude product was purified by preparative HPLC, PrepMethod A (gradient: 0–50%) to give the title compound (47.5 mg, 45%). HRMS (ESI) m/z [M+H]+ calcd for C20H30N5O5S2: 484.1682, found: 484.1672. 10 Example 101 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[2-oxo-2-(2-oxo-1,2,3,4- tetrahydroquinolin-6-yl)ethyl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide O 15 The title compound was pre om 6-(2-bromoacetyl)-3,4- dihydroquinolin-2(1H)-one (38 mg, 0.14 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.13 mmol). The crude product was purified by preparative HPLC, PrepMethod Z6 (gradient: 0–50%) 20 to give the title compound (17 mg, 26%). HRMS (ESI) m/z [M+H]+ calcd for C21H29N6O5S2: 509.1636, found: 509.1632 275 201388-PCT01-NP Example 102 N-(4-{[(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(methylsulfonyl)amino]-1,3,5- triazin-2-yl)sulfanyl]acetyl}phenyl)acetamide 5 Prepared in a similar way as -N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.12 mmol, 90% w/w) and N-(4-(2-chloroacetyl)phenyl)acetamide (33 mg, 0.15 mmol). The crude product was purified by preparative SFC, PrepMethod Z1 (gradient: 25–30%) to give the title compound (9 mg, 13%). HRMS (ESI) m/z [M+H]+ calcd for C20H29N6O5S2: 497.1636, 10 found: 497.1662.1H NMR (600 MHz, DMSO-d6) δ 0.63–0.88 (6H, m), 1.05–1.63 (3H, m), 2.09 (3H, s), 3.02–3.33 (5H, m, partially overlapping with the water signal), 3.72–3.83 and 3.97–4.05 (1H, m. two rotamers), 4.55–4.77 (3H, m), 7.64 (1H, br s), 7.71–7.75 (2H, m), 7.96–8.02 (2H, m), 10.31 (1H, apparent d), 11.14 (1H, br s). 15 Example 103 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({1-oxo-1-[2- (trifluoromethyl)phenyl]propan-2-yl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide F 20 Prepared in a similar way as desc r e or xamp e rom (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 276 201388-PCT01-NP (100 mg, 0.31 mmol) and 2-bromo-1-(2-(trifluoromethyl)phenyl)propan-1-one (87 mg, 0.31 mmol). The crude product was purified by preparative SFC, PrepMethod C, (gradient: 20–25%) to give the title compound (71 mg, 44%). HRMS (ESI) m/z [M+H]+ calcd for C20H27F3N5O4S2: 522.1450, found: 522.1464.1H NMR (500 MHz, CDCl3, mixture of two rotamers) δ 0.83 – 0.96 5 (6H, m), 1.3 – 1.53 (2H, m), 1.54 – 1.69 (4H, m), 3.22 – 3.33 (3H, m), 3.51 – 3.75 (2H, m), 4.05 – 4.26 (1H, m), 5.16 – 5.39 (1H, m), 7.53 – 7.76 (4H m). Example 104 N-(4-{[2-(6-Chloropyridin-3-yl)-2-oxoethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cl The title compound was prepar from 2-bromo-1-(6- chloropyridin-3-yl)ethan-1-one (40 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.16 15 mmol). The crude product was purified by preparative SFC, PrepMethod Z (gradient: 20–25%) to give the title compound (6 mg, 1.2%). HRMS (ESI) m/z [M+H]+ calcd for C17H24ClN6O4S2: 475.0984, found: 475.0982. Example 105 20 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-({2-oxo-2-[4- (trifluoromethyl)phenyl]ethyl}sulfanyl)-1,3,5-triazin-2-yl]methanesulfonamide F F 201388-PCT01-NP The title compound was prepared as described for Example 83 from 2-bromo-1-(4- (trifluoromethyl)phenyl)ethan-1-one (45 mg, 0.17 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (50 mg, 0.16 mmol). The crude product was purified by preparative SFC, PrepMethod Z1 5 (gradient: 15–20%) to give the title compound (24.5 mg, 4.8%). HRMS (ESI) m/z [M+H]+ calcd for C19H25F3N5O4S2: 508.1294, found: 508.1312. Example 106 N-(4-{[2-(2,3-Difluorophenoxy)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F 1-(2-Chloroethoxy)-2,3-difluo d DIPEA (0.043 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- 15 triazin-2-yl)methanesulfonamide, Intermediate 4 (40 mg, 0.12 mmol) dissolved in DMF (1 mL). The reaction mixture was heated in a microwave reactor at 110°C for 1 h, filtered and purified by preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (36 mg, 60%). HRMS (ESI) m/z [M+H]+ calcd for C18H26F2N5O4S2: 478.1388, found: 478.1410; 1H NMR (600 MHz, DMSO-d6) δ 0.75–0.91 (m, 6H), 1.26–1.43 (m, 2H), 1.50–1.63 (m, 1H), 3.25– 20 3.51 (m, partly overlapping with solvent), 3.96–4.10 (m, 1H), 4.28–4.39 (m, 2H), 4.62–4.75 (m, 1H), 6.96–7.08 (m, 2H), 7.09–7.16 (m, 1 H), 7.69 (1H, s), 11.19 (s, 1 H). Example 107 N-(4-{[(2R*)-1-(2,3-Difluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4- 25 methylpentan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 4 278 201388-PCT01-NP F The isomers from the mixture )propan-2-yl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamideand and N-(4-((2- (2,3-difluorophenoxy)propyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 5 2-yl)methanesulfonamide, Intermediate 98 and Intermediate 99 (300 mg) were separated by preparative chiral SFC on a Chiralpac IC column (5 µm, 250×30 mm ID) using 30% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 80 mL/min. The first eluting compound mixture was collected and separated by preparative chiral SFC on a Chiralpak IA column (5 um, 250×20 mm ID) using 18% EtOH in CO2 as mobile phase at a flow rate of 80 mL/min. The10 second eluting compound was collected to give the title compound N-(4-{[(2R*)-1-(2,3- difluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-1,3,5- triazin-2-yl)methanesulfonamide Isomer 4 Example 107 (21 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O4S2: 492.1546, found: 492.1538.1H NMR (600 MHz, CDCl3, mixture of two rotamers) δ 0.88–0.99 (6H, m), 1.33–1.53 (2H, m), 1.56 (3H, d), 1.61–1.67 (1H, m), 3.36 15 and 3.40 (3H, s, rotamers), 3.5–3.64 (1H, m), 3.64–3.8 (1H, m), 4.01–4.12 (1H, m), 4.16–4.3 (2H, m), 4.33–4.41 (1H, m), 6.73–6.84 (2H, m), 6.96–7.03 (1H, m), 7.38 (1H, s). Example 108 N-(4-{[(2R*)-2-(2,3-Difluorophenoxy)propyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 20 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F 201388-PCT01-NP The isomers from the mixture of N-(4-((1-(2,3-difluorophenoxy)propan-2-yl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide and N-(4-((2-(2,3- difluorophenoxy)propyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Intermediate 98 and Intermediate 99 (300 mg) were separated by 5 preparative chiral SFC on a Chiralpac IC column (5 µm, 250×30 mm ID) using 30% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 80 mL/min. The first eluting compound mixture was collected and separated by preparative chiral SFC on a Chiralpak IA column (5um, 250×20 mm ID) using 18% EtOH in CO2 as mobile phase at a flow rate of 80 mL/min. The first eluting compound was collected to give the title compound N-(4-{[(2R*)-1-(2,3-10 difluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-1,3,5- triazin-2-yl)methanesulfonamide Isomer 1 Example 108 (4 mg, 1%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O4S2: 492.1546, found: 492.1542. Example 109 15 N-(4-{[(2S)-1-(4-Fluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F DIPEA (0.073 mL, 0.42 mmol ophenoxy)propan-2-yl methanesulfonate Intermediate 100 (95 mg, 0.38 mmol) in DMF (0.5 mL) were added to a20 solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (154 mg, 0.38 mmol) in DMF (2 mL). The reaction mixture was stirred for 2 h at ambient temperature and then at 60°C for 18 h. An additional amount of (R)-1-(4-fluorophenoxy)propan-2-yl methanesulfonate Intermediate 100 (50 mg, 0.20 mmol) was added and the reaction mixture was heated to 90oC for 3 h. Water and MTBE 25 were added and the two layers were separated. The organic layer was washed with water and concentrated to give a crude product which was purified by straight phase flash chromatography 280 201388-PCT01-NP on silica (DCM:EtOAc, 5:1) to afford the title compound (67 mg, 37%). HRMS (ESI) m/z [M+H]+ calcd for C19H29FN5O4S2: 474.1640, found: 474.1654.1H NMR (400 MHz, CD3OD, mixture of rotamers) δ 0.87–0.97 (6H, m), 1.3–1.75 (6H, m), 3.23–3.32 (3H, m, overlapping with the water solvent signal), 3.43–3.58 (2H, m), 3.97–4.3 (4H, m), 6.88–6.94 (2H, m), 6.94–7.02 5 (2H, m). Example 110 N-(4-{[(2S)-1-(2,4-Difluorophenoxy) propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 10 F A mixture of (R)-N-(4-((1-hyd )-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (133 mg, 0.41 mmol), (R)-1-(2,4- difluorophenoxy)propan-2-yl methanesulfonate Intermediate 103 (121 mg, 0.46 mmol), DIPEA 15 (0.217 mL, 1.24 mmol) and MeCN (1.3 mL) in a sealed vessel was heated to 95oC on. The solvent was evaporated to give a crude product which was purified by preparative HPLC, PrepMethod C, (gradient: 20–25%) to give the title compound (73 mg, 36%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O4S2: 492.1546, found: 492.1536.1H NMR (600 MHz, DMSO-d6, mixture of rotamers about 1/1) δ 0.81 - 0.88 (6H, m), 1.24 - 1.34 (1H, m), 1.34 - 1.42 (1H, m), 20 1.42 - 1.48 (3H, m), 1.51 - 1.64 (m, 1H), 3.28-3.40 (5H, s and m, overlapping with the water signal) , 3.96 - 4.08 (1H, m), 4.08 - 4.23 (2H, m), 4.25 - 4.36 (1H, m), 4.68 (1H, t), 6.96 - 7.02 (1H, m), 7.19 - 7.25 (1H, m), 7.25 - 7.31 (1H, m), 7.7 (br. s, 1H), 11.18 (br. s, 1H). Example 111 25 N-(4-{[(2S)-1-(3-Fluoro-4-methoxyphenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 281 201388-PCT01-NP H The title compound was prep the procedure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 4 (128 mg, 0.40 mmol) and (R)-1-(3-fluoro-4- 5 methoxyphenoxy)propan-2-yl methanesulfonate Intermediate 105 (122 mg, 0.44 mmol) to give the title compound (64 mg, 32%). HRMS (ESI) m/z [M+H]+ calcd for C20H31FN5O5S2: 504.1744, found: 504.1770.1H NMR (600 MHz, DMSO-d6, mixture of rotamers about 1/1) δ 0.85 (6H, m), 1.30 (1H, dtd), 1.35 – 1.47 (4H, m), 1.57 (1H, m), 3.28-3.42 (5H, s and m overlapping with the water signal), 3.77 (3H, s), 3.96 – 4.24 (4H, m), 4.61 – 4.74 (1H, m), 6.7 – 6.77 (1H, m), 6.90 10 (1H, dt), 7.06 (1H, t), 7.69 (1H, br s) 11.18 (1H, br s). Example 112 N-(4-{[(2S)-1-(3,4-Difluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan- 2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide F 15 F The title compound was prepa o the procedure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 4 (133 mg, 0.41 mmol) and (R)-1-(3,4- difluorophenoxy)propan-2-yl methanesulfonate Intermediate 107 (121 mg, 0.46 mmol) to give 20 the title compound (79 mg, 39%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O4S2: 492.1546, found: 492.1540.1H NMR (600 MHz, DMSO-d6) δ 0.79 – 0.92 (6H, m), 1.24 – 1.34 282 201388-PCT01-NP (1H, m), 1.35 – 1.48 (4H, m), 1.51 – 1.64 (1H, m), 3.27-3.40 (5H, s and m, overlapping with the water peak), 3.98 – 4.06 (1H, m), 4.06 – 4.18 (2H, m), 4.19 – 4.27 (1H, m), 4.63 – 4.72 (1H, m), 6.76 – 6.84 (1H, m), 7.05 – 7.13 (1H, m), 7.3 – 7.37 (1H, m), 7.67 (1H, br s), 11.19 (1H, s). 5 Example 113 N-(4-{[(2S)-1-(3-Chlorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cl The title compound was prepar to the procedure described in 10 Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 4 (146 mg, 0.45 mmol) and (R)-1-(3- chlorophenoxy)propan-2-yl methanesulfonate Intermediate 109 (132 mg, 0.50 mmol) to give the title compound (66 mg, 30%). HRMS (ESI) m/z [M+H]+ calcd for C19H29ClN5O4S2: 490.1344, found: 490.1330.1H NMR (600 MHz, DMSO-d6) δ 0.81 – 0.89 (6H, m), 1.25 – 1.34 15 (1H, m), 1.34 – 1.42 (1H, m), 1.42 – 1.48 (3H, m), 1.52 – 1.64 (1H, m), 3.27-3.40 (5H, s and m, overlapping with the water peak), 3.97 – 4.08 (1H, m), 4.09 – 4.21 (2H, m), 4.21 – 4.32 (1H, m), 4.68 (1H, t), 6.94 (1H, dd), 6.98 – 7.02 (1H, m), 7.02 – 7.07 (1H, m), 7.27 – 7.33 (1H, m), 7.66 (1H, br s), 11.17 (1H, br s). 20 Example 114 N-(4-{[(2S)-1-(4-Chloro-2-fluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 283 201388-PCT01-NP Cl DIPEA (0.072 mL, 0.41 mmo noxy)propan-2-yl methanesulfonate Intermediate 111 (106 mg, 0.37 mmol) were added to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 5 Intermediate 4 (150 mg, 0.37 mmol) in MeCN (2 mL) and the reaction mixture was heated to 90°C for 18 h. Water and MTBE were added. The two layers were separated and the organic layer was washed with water and concentrated to give a crude product which was first purified by straight phase flash chromatography on silica (gradient: 10–50% EtOAc in DCM) followed by preparative chiral SFC on a CelluCoat column (5 µm, 250×30 mm ID) using 10% IPA/DEA 10 (100/0.5 mM) in CO2 as mobile phase at a flow rate of 160 mL/min. The product containing fractions were collected, concentrated, dissolved in DCM (4 mL). The organic layer was washed with 1 M citric acid (aq) to remove traces of DEA and concentrated to give the title compound (64 mg, 34%). HRMS (ESI) m/z [M+H]+ calcd for C19H28ClFN5O4S2: 508.1250, found: 508.1264.1H NMR (400 MHz, CDCl3) δ 0.72–0.82 (6H, m), 1.1–1.27 (1H, m), 1.28–1.56 (5H,15 m), 3.15 (3H, s), 3.3–3.42 (1H, m), 3.53 (1H, dd), 3.85–3.92 (1H, m), 3.97–4.04 (1H, m), 4.04– 4.13 (1H, m), 4.17 (1H, dd), 6.71–6.82 (1H, m), 6.82–6.98 (2H, m), 7.15–7.3 (2H, m), 7.45 (1H, d). Example 115 20 N-[4-{[(2R)-1-Hydroxy-4-methylpentan-2 -yl]amino}-6-({[(2R)-oxolan-2-yl]methyl}sulfanyl)- 1,3,5-triazin-2-yl]methanesulfonamide 284 201388-PCT01-NP The title compound was prepared for Example 6 from (R)-2- (iodomethyl)tetrahydrofuran (46.6 mg, 0.22 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 4 (64 mg, 0.20 5 mmol) to give the title compound (17.3 mg, 21%). HRMS (ESI) m/z [M+H]+ calcd for C15H28N5O4S2: 406.1578, found: 406.1586. Example 116 N-(4-{[1-(2,6-Difluorophenoxy )propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 10 yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.091 mL, 0.52 mmol) rophenoxy)propan-2-yl methanesulfonate Intermediate 113 (126 mg, 0.47 mmol) in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 15 yl)methanesulfonamide Intermediate 4 (190 mg, 0.47 mmol) in DMF (2 mL) and the reaction mixture was stirred at 60°C for 19 h and then heated in a microwave reactor to 140°C for 30 min. An additional amount of (2,6-difluorophenoxy)propan-2-yl methanesulfonate Intermediate 113 (50 mg, 0.19 mmol) was added and the reaction mixture was heated to 140°C for 20 min. Water and MTBE were added and the two layers were separated. The aqueous layer was extracted with 20 MTBE and the combined organic layer was washed with water and concentrated. The crude product was purified by straight phase flash chromatography on silica (5% MeOH in DCM) to 285 201388-PCT01-NP give the title compound (42 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O4S2: 492.1546, found: 492.1532.1H NMR (400 MHz, CD3OD) δ 0.78–1.04 (6H, m), 1.27–1.57 (5H, m), 1.57–1.73 (1H, m), 3.3–3.33 (3H, m), 3.4–3.62 (2H, m), 4.17 (3H, tdd), 4.31–4.61 (1H, m), 6.88–7.1 (3H, m). 5 Example 117 N-(4-{[(2R*)-1-(4-Chlorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 Cl 10 The isomers of N-(4-((1-(4-ch (((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 115 (118 mg, 0.24 mmol) were separated by preparative chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 15% EtOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 80 mL/min. The first eluting compound was collected, dissolved in DCM and washed with citric acid to remove15 traces of DEA. The organic layer was concentrated to give the title compound N-(4-{[(2R*)-1- (4-chlorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 117 (45 mg, 38%). HRMS (ESI) m/z [M+H]+ calcd for C19H29ClN5O4S2: 490.1344, found: 490.1372.1H NMR (400 MHz, CDCl3) δ 0.85 – 0.96 (6H, m), 1.27 – 1.7 (6H, m), 3.28 (3H, s), 3.46 – 3.6 (1H, m), 3.62 – 3.71 (1H, m), 20 3.9 – 4.03 (1H, m), 4.06 – 4.32 (3H, m), 6.79 – 6.9 (2H, m), 7.2 – 7.25 (2H, m), 7.47 – 7.72 (1H, m). Example 118 N-(4-{[(2R)-1-Hydroxy -4-methylpentan-2-yl]amino}-6-{[(2S)-1-(3,4,5- 25 trifluorophenoxy)propan-2-yl]sulfanyl}-1,3,5-triazin-2-yl)methanesulfonamide 286 201388-PCT01-NP H F F The title compound was prepa ure described in Example 110 from (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 4 (131 mg, 0.41 mmol) and (R)-1-(3,4,5- 5 trifluorophenoxy)propan-2-yl methanesulfonate Intermediate 117 (127 mg, 0.45 mmol). The crude product was purified by preparative HPLC, PrepMethod C, (gradient: 15–20%), to give the title compound (76 mg, 36%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F3N5O4S2: 510.1450, found: 510.1456.1H NMR (600 MHz, DMSO-d6) δ 0.85 (6H apparent dd), 1.29 (1H, ddt), 1.34 – 1.48 (4H, m), 1.57 (1H, m), 3.27-3.40 (5H, s and m, overlapping with the water peak), 3.98- 10 4.05 (1H, m), 4.06 – 4.19 (2H, m), 4.25 (1H, m), 4.68 (1H, m), 6.84 – 7.14 (2H, m), 7.68 (1H, br s), 11.18 (1H, br s). Example 119 N-(4-{[(2S)-1-(4-Chloro-3-fluorophenoxy)propan-2-yl]sulfanyl}-6-{[(2R)-1-hydroxy-4- 15 methylpentan-2-yl]amino }-1,3,5-triazin-2-yl)methanesulfonamide F Cl DIPEA (0.06 mL, 0.34 mmol oxy)propan-2-yl methanesulfonate Intermediate 119 (88 mg, 0.31 mmol) were added to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 20 Intermediate 4 (125 mg, 0.31 mmol) in MeCN (2 mL) and the reaction mixture was heated to 90°C for 18 h. Water and MTBE were added. The two layers were separated and the organic 287 201388-PCT01-NP layer was washed with water and concentrated. The crude product was first purified by straight phase flash chromatography on silica (gradient: 10–50% EtOAc in DCM) followed by preparative chiral SFC on a CelluCoat column (5 µm, 250×30 mm ID) using 10% IPA/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 160 mL/min. The compound containing 5 fractions were collected, concentrated and dissolved in DCM (4 mL). The organic layer was washed with 1 M citric acid (aq) to remove traces of DEA and concentrated to give the title compound (63 mg, 40%). HRMS (ESI) m/z [M+H]+ calcd for C19H28ClFN5O4S2: 508.1250, found: 508.1252.1H NMR (400 MHz, CDCl3) δ 0.88–0.92 (6H, m), 1.26–1.37 (1H, m), 1.42– 1.49 (1H, m), 1.51 (3H, d), 1.53–1.66 (1H, m), 3.28 (3H, s), 3.46–3.54 (1H, m), 3.68 (1H, dd), 10 3.99 (1H, dd), 4.1–4.16 (1H, m), 4.22 (2H, dd), 6.65 (1H, ddd), 6.72 (1H, dd), 7.25 (1H, t), 7.60 (1H, d). Example 120 N-(4-{[(2-Fluorophenyl)sulfanyl]methyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 15 1,3,5-triazin-2-yl)methanesulfonamide A suspension of (R)-2-((4-chloro- methyl)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol Intermediate 122 (76 mg, 0.20 mmol), THF (3 mL), methanesulfonamide (39 mg, 0.41 mmol), X-Phos (40 mg, 0.08 mmol), Pd2(dba)3 (20 mg, 0.022 mmol) and Cs2CO3 20 (132 mg, 0.41 mmol) was heated in a sealed vessel under an atmosphere of Ar(g) to 65°C for 12 h. After cooling to rt the mixture was diluted with THF (7 mL) and filtered through CELITE. The filtrate was acidified with AcOH (50 µL), and concentrated to give a crude product which was purified by preparative SFC, PrepMethod Z2, to give the title compound (20 mg, 22%). HRMS (ESI) m/z [M+H]+ calcd for C17H25FN5O3S2: 430.1378, found: 430.1390.1H NMR (600 25 MHz, DMSO-d6) δ 0.89 – 0.75 (6H, m), 1.43 – 1.25 (2H, m), 1.54 (1H, m), 3.23 – 3.09 (3H, m), 288 201388-PCT01-NP 3.40 – 3.25 (2H, m, overlapping with the water signal), 4.05 – 3.87 (3H, m), 4.67 (1H, br s), 7.34 – 7.11 (3H, m), 7.61 – 7.51 (1H, m), 7.73 (1H, br d), 11.70 (1H, br s). Example 121 5 N-(4-{1-[(2-Fluorophenyl)sulfanyl]ethyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}- 1,3,5-triazin-2-yl)methanesulfonamide (2R)-2-((4-Chloro-6-(1-((2-fluoro iazin-2-yl)amino)-4-methylpentan-1- ol Intermediate 7 (150 mg, 0.39 mmol), X-Phos (40 mg, 0.08 mmol), Pd2(dba)3 (40 mg, 0.04 10 mmol) and Cs2CO3 (254 mg, 0.78 mmol) were added to methanesulfonamide (74 mg, 0.78 mmol) in THF (6 mL). The reaction mixture was stirred at 65°C for 12 h under an atmosphere of Ar(g), and then diluted with THF (7 mL) and filtered through Celite. The filtrate was acidified with AcOH (24 µL) and concentrated under reduced pressure. The crude residue was dissolved in DMSO (4 mL), filtered through Celite, and purified by preparative HPLC, PrepMethod D, 15 (gradient: 20–60%). The compound containing fractions were collected and concentrated. AcOH (118 µL, 2 mmol) was added to the residue and the mixture was extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (120 mg, 69%). HRMS (ESI) m/z [M+H]+ calcd for C18H27FN5O3S2: 444.1534, found: 444.1558; 1H NMR (600 MHz, DMSO- 20 d6, mixture of rotamers and diastereomers) δ 7.48–7.42 (m, 1H), 7.35–7.28 (m, partly overlapping with solvent), 7.10–7.03 (m, 2H), 6.56 (s, 1H), 5.85–5.78 (m, 1H), 4.24–4.05 (m, 2H), 3.80–3.50 (m, 2H), 3.38–3.31 (m, 3H), 1.69–1.58 (m, partly overlapping with solvent), 1.50–1.31 (m, 2H), 0.98–0.87 (m, 6H). 25 Example 122 N-(4-[3-(2,3-Difluorophenoxy)-2-methylpropyl]-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide 289 201388-PCT01-NP F 9-BBN dimer (0.188 g, 0.78 m 1,2-difluoro-3-((2- methylallyl)oxy)benzene, Intermediate 8 (0.141 g, 0.77 mmol) in THF-d8 (2.25 mL). The reaction mixture was stirred at rt for 1.3 h under an atmosphere of N2(g). (R)-N-(4-Chloro-6-((1- 5 hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 9 (0.162 g, 0.5 mmol), Pd(dppf)Cl2·DCM (0.018 g, 0.03 mmol) and 3 M K3PO4 (0.50 mL, 1.50 mmol) were added and the reaction mixture was stirred at 65°C for 20 h, then at 100°C for 3 h. DCM (20 mL) and water (5 mL) were added, and the organic layer was passed through a phase separator and concentrated. The crude residue was purified by preparative HPLC, PrepMethod F, 10 (gradient: 5–95%) and then by preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (19 mg, 8%). HRMS (ESI) m/z [M+H]+ calcd for C20H30F2N5O4S: 474.1980, found: 474.1984; 1H NMR (600 MHz, DMSO-d6) δ 0.75–0.89 (m, 6H), 0.95–1.05 (m, 3H), 1.21–1.62 (m, 3H), 2.35–2.70 (m, partly overlapping with solvent), 3.30–3.50 (m, partly overlapping with solvent), 3.91–4.16 (m, 3H), 4.61–4.79 (m, 1H), 6.91–7.04 (m, 2H), 7.08–7.16 15 (m, 1H), 8.21 (s, 1H), 12.45 (s, 1H). Example 123 N-(4-[1-(2-Fluorophenyl)ethoxy]-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-1,3,5-triazin- 2-yl)methanesulfonamide 20 A solution of TMAF (100 mg, 1.0 o was added to N-(4-(((R)-1-((tert- butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-(1-(2-fluorophenyl)ethoxy)-1,3,5-triazin- 290 201388-PCT01-NP 2-yl)methanesulfonamide Intermediate 12 (205 mg, 0.38 mmol) in THF (2 mL). The reaction mixture was stirred at rt for 4 d under an atmosphere of Ar(g) and then concentrated. The crude residue was purified by preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (95 mg, 59%). HRMS (ESI) m/z [M+H]+ calcd for C18H27FN5O4S: 428.1762, found: 5 428.1766; 1H NMR (500 MHz, DMSO-d6) δ 7.60–7.40 (m, 2H), 7.40–7.30 (m, 1H), 7.26–7.14 (m, 2H), 6.36–6.23 (m, 1H), 4.76–4.62 (m, 1H), 4.08–3.86 (m, 1H), 3.37–3.14 (m, partly overlapping with solvent), 1.61–1.22 (m, 6H), 0.91–0.64 (m, 6H). Example 124 10 N-(4-[1-(3-Cyanophenyl)ethoxy]-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-1,3,5-triazin- 2-yl)methanesulfonamide N A solution of tetramethylamm mol) in EtOH (1.5 mL) and AcOH (60 µL) was added to a solution of crude N-(4-(((R)-1-((tert-butyldimethylsilyl)oxy)-4- 15 methylpentan-2-yl)amino)-6-(1-(3-cyanophenyl)ethoxy)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 124 (331 mg, 0.60 mmol) in DMSO (1.7 mL) and the reaction mixture was stirred under an atmosphere of Ar(g) at rt for 3 d. The solvent was evaporated, and the crude product was purified by preparative HPLC, PrepMethod A, (gradient 5–95%) to give the title compound (85 mg, 32%). HRMS (ESI) m/z [M+H]+ calcd for C19H27N6O4S: 435.1808, found: 435.1818.1H 20 NMR (500 MHz, DMSO-d6) δ 0.60-0.90 (6H, m), 1.22-1.60 (6H, m), 3.09-3.40 (5H, m, overlap with solvent signal), 3.84-4.08 (1H, m), 4.64-4.79 (1H, m), 6.00-6.14 (1H, m), 7.27-7.53 (1H, br s), 7.53-7.62 (1H, m), 7.69-7.81 (2H, m), 7.83-7.91 (1H, m). Example 125 25 N-(4-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]oxy}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 2 291 201388-PCT01-NP F The isomers of N-(4-(1-(2,3-difl -hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 127 (53 mg, 0.12 mmol) were separated by preparative chiral SFC on a Chiralsel OJ column (5 µm, 250×30 mm ID) using 15% 5 MeOH/DEA (100/0.5 mM) in CO2 as mobile phase at a flow rate of 80 mL/min to give the second eluting compound N-(4-{[(1R*)-1-(2,3-difluorophenyl)ethyl]oxy}-6-{[(2R)-1-hydroxy-4- methylpentan-2-yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 2, Example 125. HRMS (ESI) m/z [M+H]+ calcd for C18H26F2N5O4S: 446.1668, found: 446.1652.1H NMR (400 MHz, DMSO) δ 0.77-0.94 (6H, m), 1.23-1.39 (2H, m), 1.47-1.67 (4H, m), 2.82-2.97 (3H, m), 10 3.28 (2H, m, overlapping with the water signal), 3.87-4.03 (1H, m), 6.20-6.31 (1H, m), 6.41-6.73 (m, 1H), 7.16-7.38 (3H, m), 8.28 (1H, br s). Example 126 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-[(1S)-1-(pyridin-2-yl)ethoxy]-1,3,5- 15 triazin-2-yl)methanesulfonamide A degassed solution of (R)-2-(4-ch yl)ethoxy)-1,3,5-triazin-2-ylamino)- 4-methylpentan-1-ol Intermediate 128 (0.120 g, 0.34 mmol) in THF (6 mL) was added to K2CO3 (0.071 g, 0.51 mmol), Pd2(dba)3 (0.062 g, 0.07 mmol) and X-Phos (0.130 g, 0.27 mmol) 20 under an atmosphere of N2(g). The reaction mixture was stirred for 5 min. Methanesulfonamide (0.049 g, 0.51 mmol) was added under a flow of N2(g). The reaction mixture was heated to 65°C 292 201388-PCT01-NP for 6 h. The reaction was cooled, diluted with DCM (30 mL) and extracted with water (30 mL). The aqueous layer was separated and extracted with DCM (30 mL). The combined organic layer was passed over a phase separator.10% NH4Cl (aq) (100 mL) was added to the aqueous layer to provide a pH of about 6.5, and the aqueous layer was extracted with DCM (4×50 mL) which was 5 pooled with the previous organic layer. Silicycle Si-Thiol (1 g, 1.4 mmol/g) was added, and the mixture was stirred for 1 h. Filtration followed by evaporation of the solvent gave a crude product which was purified by preparative HPLC, PrepMethod E, (gradient 4–45%) to give the title compound as a white solid (48 mg, 34%). HRMS (ESI) m/z [M+H]+ calcd for C17H27N6O4S: 411.1808, found: 411.1812.1H NMR (400 MHz, CDCl3) δ 0.85–0.95 (6H, m), 10 1.29–1.41 (1H, m), 1.43–1.54 (1H, m), 1.56–1.74 (4H, m), 3.21 (3H, s), 3.40 (1H, dd), 3.51 (1H, dd), 4.09–4.19 (1H, m), 6.10 (1H, q), 7.20 (1H, ddd), 7.38–7.45 (1H, m), 7.63 (1H, s), 7.69 (1H, td), 8.53 (1H, ddd). Example 127 15 N-(4-{[(2-Fluorophenyl)(methyl)amino]methyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}-1,3,5-triazin-2-yl)methanesulfonamide Cs2CO3 (111 mg, 0.34 mmol) was -6-(((2- 20 fluorophenyl)(methyl)amino)methyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol, Intermediate 16 (61 mg, 0.17 mmol), methanesulfonamide (32 mg, 0.34 mmol), X-Phos (16 mg, 0.034 mmol) and Pd2(dba)3 (16 mg, 0.17 mmol) in THF (7 mL) under an atmosphere of Ar(g). The reaction mixture was stirred at 65°C for 13 h. THF (5 mL) was added, and the solids were removed by filtration through Celite. The filtrate was concentrated and the crude residue 25 was purified by preparative SFC, PrepMethod H, (gradient: 10–40%) to give the title compound (12 mg, 17%). HRMS (ESI) m/z [M+H]+ calcd for C18H28FN6O3S: 427.1922, found: 427.1942; 293 201388-PCT01-NP 1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) δ 7.08–6.92 (m, 3H), 6.90– 6.70 (m, 1 H), 4.69–4.60 (m, 1H, rotamers), 4.36–4.24 (m, 1H), 4.20 (s, 1H), 4.07–3.87 (m, 1H, rotamers), 3.31–2.89 (m, partly overlapping with solvent), 1.60–1.12 (m, 3H), 0.87–0.66 (m, 6H). 5 Example 128 N-(4-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-2-yl)methanesulfonamide Isomer 2 F 10 The isomers of N-(4-((1-(2,3-dif R)-1-hydroxy-4-methylpentan-2- yl)amino)pyrimidin-2-yl)methanesulfonamide, Intermediate 21 (152 mg, 0.33 mmol) were separated by preparative chiral HPLC on a Chiralpak AD column (5 µm, 250×20 mm ID) using a heptane/IPA/TEA (60/40/0.1) buffer system as mobile phase, to give the second eluting compound N-(4-{[1-(2,3-difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino}pyrimidin-2-yl)methanesulfonamide Isomer 2, Example 128 (68 mg, 45%); HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O3S2: 461.1488, found: 461.1468, 1H NMR (400 MHz, CD3CN, mixture of two rotamers about 1:1) δ 0.84–093 (6H, m, rotamers), 1.12 (2H, t), 1.32– 1.40 (2H, m), 1.56–1.66 (1H, m), 1.69 (3H, d), 3.31 (3 H, s), 3.40–3.45 (1H, m) 3.46–3.57 (2H, m), 5.32 (1H, q), 5.66 (1H, d), 5.95 (1H, s), 7.04–7.27 (2H, m), 7.3–7.4 (1H, m). 20 Example 129 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-2-yl)methanesulfonamide 294 201388-PCT01-NP F A mixture of (R)-2-((4-chloro-6 imidin-2-yl)amino)-4- methylpentan-1-ol and (R)-2-((2-chloro-6-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)-4- methylpentan-1-ol Intermediate 130 and Intermediate 131 (34.0 mg, 0.08 mmol), 5 methanesulfonamide (16.7 mg, 0.18 mmol), Cs2CO3 (57.1 mg, 0.18 mmol), X-Phos (8.8 mg, 0.02 mmol) and Pd2(dba)3 (8.8 mg, 9.64 µmol) in THF (2 mL) was flushed with N2(g) for 5 min and then heated to 65oC for 18 h. The solvent was evaporated, and the residue dissolved in DCM and diluted with water. The pH was adjusted with 1 M HCl (aq) to pH 3. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layer was 10 passed over a phase separator and concentrated. The crude product was purified by preparative HPLC, PrepMethod E, (gradient 20–60%) to give the first eluting compound N-(6-{[(2,3- difluorophenyl)methyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin-4- yl)methanesulfonamide, Example 135 (2 mg, 6%) followed by the second eluting compound N- (4-{[(2,3-difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- 15 yl]amino}pyrimidin-2-yl)methanesulfonamide, Example 129 (7 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for C18H25F2N4O3S2: 447.1330, found: 447.1312.1H NMR (400 MHz, CD3OD) δ 0.86–0.97 (6H, m), 1.36–1.49 (2H, m), 1.62–1.71 (1H, m), 3.17 (3H, s), 3.47–3.54 (2H, m), 4.26 (1H, s), 4.44 (2H, s), 5.86 (1H, s), 7.02–7.19 (2H, m), 7.35 (1H, t). 20 Example 130 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin- 2-yl)methanesulfonamide 295 201388-PCT01-NP F A mixture of (R)-2-(2-chloro-6-( idin-4-ylamino)pentan-1-ol Intermediate 23 (35 mg, 0.09 mmol), methanesulfonamide (8.9 mg, 0.09 mmol), Pd2(dba)3 (8.6 mg, 9.4 µmol), K2CO3 (19.4 mg, 0.14 mmol), X-Phos (66,2 mg, 0,14 mmol) and THF (2 mL) 5 were heated under an atmosphere of N2(g) at 60°C on. Water and DCM were added, and the organic layer was concentrated in vacuo. The residue was dissolved in DMSO (1 mL). K2CO3 (19.4 mg, 0.14 mmol) and methanesulfonamide (8.9 mg, 0.09 mmol) were added and the reaction mixture was heated at 120°C for 3 d. The crude product was first purified by preparative HPLC, PrepMethod A, (gradient 5–95%) followed by PrepMethod F, (gradient 5–95%) to give 10 the title compound (3 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C17H23F2N4O3S2: 433.1174, found: 433.1196. Example 131 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- 15 phenylethyl]sulfanyl}pyrimidin-2-yl)methanesulfonamide Isomer 2 The isomers of N-(4-(((R)-1-hydro y y y amino)-6-((1- phenylethyl)thio)pyrimidin-2-yl)methanesulfonamide Intermediate 132 (179 mg, 0.42 mmol) were separated by preparative chiral SFC on a Chiralpak IA column (5 µm, 250×30 mm ID) 20 using 20% MeOH in CO2 as mobile phase at a flow rate of 120 mL/min to give the second eluting compound N-(4-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- 296 201388-PCT01-NP phenylethyl]sulfanyl}pyrimidin-2-yl)methanesulfonamide Isomer 2, Example 131 (72 mg, 40%). HRMS (ESI) m/z [M+H]+ calcd for C19H29N4O3S2: 425.1676, found: 425.1670.1H NMR (500 MHz, CDCl3) δ 0.86 - 0.97 (6H, m), 1.34 - 1.46 (2H, m), 1.59 - 1.7 (1H, m), 1.74 (3H, d), 3.25 (3H, s), 3.5 - 3.57 (1H, m), 3.64 - 3.72 (1H, m), 5.01 - 5.11 (1H, m), 5.85 (1H, s), 7.22 - 7.3 5 (1H, m), 7.3 - 7.38 (2H, m), 7.4 - 7.48 (2H, m). Example 132 N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[1-(5-methylpyrazin-2- yl)ethyl]sulfanyl}pyrimidin-2-yl)methanesulfonamide 10 DIPEA (1.416 g, 10.95 mmol) w ure of (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercaptopyrimidin-2-yl)methanesulfonamide Intermediate 20 (1.17 g, 3.65 mmol) and 2-(1-bromoethyl)-5-methylpyrazine (0.734 g, 3.65 mmol) in DMF (20 15 mL) at rt and the reaction mixture was stirred for 1 h. The mixture was concentrated and diluted with DCM (125 mL) and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was first purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC, PrepMethod Q, (gradient 3–100%) to give the title compound as an orange solid (0.059 g, 4%). HRMS (ESI) m/z [M+H]+ calcd for20 C18H29N6O3S2: 441.1738, found: 441.1752.1H NMR (400 MHz, DMSO-d6) δ 0.86 (6H, d), 1.3- 1.4 (2H, m), 1.65-1.54(4H, m), 2.50 (3H, 2), 3.3-3-4 (5H, s + m, overlapping with the water signal), 4.06 (1H, d), 4.67(1H, br s), 5.1- 5.3 (1H, m), 5.96 (s, 1H), 7.14 (1H, br s), 8.49 (1H, s), 8.72(1H, s), 10.65(1H, br s). 25 Example 133 297 201388-PCT01-NP N-(4-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(5-methylpyrazin-2- yl)methyl]sulfanyl}pyrimidin-2-yl)methanesulfonamide DIPEA (605 mg, 4.68 mmol) wa re of (R)-N-(4-((1-hydroxy-4- 5 methylpentan-2-yl)amino)-6-mercaptopyrimidin-2-yl)methanesulfonamide Intermediate 20 (500 mg, 1.56 mmol) and 2-(chloromethyl)-5-methylpyrazine (222 mg, 1.56 mmol) in DMF (10 mL) and the reaction mixture was stirred at rt for 1.5 h. The mixture was concentrated and diluted with DCM (150 mL) and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was first purified by preparative TLC 10 (DCM:MeOH, 10:1) followed by preparative HPLC, PrepMethod Q, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound as a white solid (35 mg, 5%). HRMS (ESI) m/z [M+H]+ calcd for C17H27N6O3S2: 427.1580, found: 427.1570.1H NMR (400 MHz, DMSO-d6) δ 0.8-0.9 (6H, m), 1.39-1.23 (2H, m), 1.64-1.54 (1H, m), 2.50 (3H, s), 3.3-3-4 (5H, s + m, overlapping with the water signal), 4.06 (1H, br s), 4.41 15 (2H, s), 5.98 (1H, s), 7.05 (1H, br s), 8.45 (1H, s), 8.70(1H, s). Example 134 N-(6-{[1-(2,3-Difluorophenyl)ethyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide F 20 Step a) 1-(2,3-Difluorophenyl)et y 298 201388-PCT01-NP O O F S F O MsCl (0.161 mL, 2.09 mmol) was ad -(2,3-difluorophenyl)ethan-1-ol (300 mg, 1.90 mmol) and DIPEA (0.364 mL, 2.09 mmol) in DCM (4 mL). The reaction mixture was stirred at rt for 2.5 h.5% NaHCO3 (aq) was added, the phases were separated, and the organic 5 layer was filtered through a short pad of silica and eluted with DCM to give the crude subtitle compound, which was used in the next step without further purification. Step b) (R)-N-(2-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-4- yl)methanesulfonamide H 10 (R)-N-(2-((1-Hydroxy-4-methylpenta -methoxybenzyl)thio)pyrimidin-4- yl)methanesulfonamide, Intermediate 25 (527 mg, 1.20 mmol) was added to a solution of TFA (4 ml, 51.92 mmol) and anisole (0.157 ml, 1.44 mmol). The reaction mixture was stirred at rt for 2 d then at 70°C on and concentrated.10% NaHCO3 (aq) and EtOAc were added, and the two phases were separated. The organic layer was extracted with 10% NaHCO3 (aq) and the 15 combined aqueous layer was acidified to pH 3. The aqueous layer was extracted with EtOAc (×6) and the combined organic layer was dried over MgSO4, filtered and concentrated to give the hydrochloride of the crude subtitle compound, which was used in the next step without further purification. Step c) N-(6-{[1-(2,3-Difluorophenyl)ethyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan-2- 20 yl]amino}pyrimidin-4-yl)methanesulfonamide 1-(2,3-Difluorophenyl)ethyl methanesulfonate, Example 134 Step a (36.9 mg, 0.16 mmol) was added to a solution of (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin- 4-yl)methanesulfonamide HCl Example 134 Step b (50 mg, 0.16 mmol) and DIPEA (60.0 µl, 0.34 mmol) in DMF. The reaction mixture was heated in a microwave reactor at 70°C for 30 25 min. Water and DCM were added and the two phases were separated. The aqueous layer was 299 201388-PCT01-NP extracted with DCM and the combined organic layer was washed with water (×2), dried and concentrated. The residue was purified preparative HPLC, PrepMethod A, (gradient: 5–95%) to give the title compound (62 mg, 86%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O3S2: 461.1488, found: 461.1492; 1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) 5 δ 0.76–0.98 (m, 6H), 1.30–1.48 (m, 2H, rotamers), 1.58–1.75 (m, 4H), 3.20–3.50 (m, partly overlapping with solvent), 3.90–4.15 (m, 1H, rotamers), 4.50–4.80 (s, 1H), 5.15–6.03 (m, 1H, rotamers), 6.73–6.95 (m, 1H), 7.19 (q, 1H), 7.3–7.46 (m, 2H), 10.60 (s, 1H). Example 135 10 N-(6-{[(2,3-Difluorophenyl)methyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide F For the preparation of this comp 15 HRMS (ESI) m/z [M+H]+ calcd for C18H25F2N4O3S2: 447.1330, found: 447.1322.1H NMR (500 MHz, CD3OD) δ 0.89–0.99 (6H, m), 1.38–1.52 (2H, m), 1.61–1.75 (1H, m), 3.36 (3H, s), 3.51 (1H, dd), 3.58 (1H, dd), 4.29 (1H, s), 4.46 (2H, s), 6.12 (1H, s), 7.07–7.15 (1H, m), 7.15–7.23 (1H, m), 7.28–7.35 (1H, m). 20 Example 136 N-(2-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(5-methylpyrazin-2- yl)methyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide 300 201388-PCT01-NP H 2-(Chloromethyl)-5-methylpyraz added dropwise to a mixture of (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-4- yl)methanesulfonamide Example 134 step b (200 mg, 0.62 mmol) and DIPEA (161 mg, 1.25 5 mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated and diluted with EtOAc (100 mL) and washed with brine (3× 50 mL). The organic layer was dried over Na2SO4. filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod Z3, (using decreasingly polar mixtures of water (containing 0.5 % NH4HCO3) and MeCN as eluents) to give the title compound as a white solid (101 mg, 38%). 10 HRMS (ESI) m/z [M+H]+ calcd for C17H27N6O3S2: 427.1580, found: 427.1594.1H NMR (400 MHz, DMSO-d6) δ 0.7-0.9 (6H,m), 1.3-1.5 (2H, m), 1.55-1.75 (1H, m), 2.503H, s), 3.3-3-4 (5H, s + m, overlapping with the water signal), 3.98 (1H, apparent br s), 4.42 (2H, apparent br s), 4.75 (1H, br s), 5.9-6.1 (1H, d), 6.8-7.0 (1H, m), 8.45 (1H, s), 8.5-8.75 (1H, m), 10.75 (1H, br s). 15 Example 137 N-(2-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1-(5-methylpyrazin-2- yl)ethyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide Isomer 2 2-(1-Bromoethyl)-5-methylpyraz e g, . o was added dropwise to a mixture of20 (R)-N-(2-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercaptopyrimidin-4- yl)methanesulfonamide Example 134 step b (200 mg, 0.62 mmol) and DIPEA (161 mg, 1.25 301 201388-PCT01-NP mmol) in DMF (2 mL) and the reaction mixture was stirred at rt for 2 h. The mixture was concentrated and diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was first purified by preparative TLC (DCM:MeOH 10:1) followed by chiral preparative HPLC on Venusil Chiral 5 OD-H column (5 µm) using n-hexane/IPA (7/3) as mobile phase to give the first eluting compound as a white solid (20 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C18H29N6O3S2: 441.1738, found: 441.1752.1H NMR (400 MHz, DMSO-d6, mixture of two rotamers) δ 0.8- 0.95 (6H, m), 1.3-1.5 (2H, s), 1.66-1.7 (4H, m), 2.50 (3H, s), 3.2-3.4 (5H, m, overlapping with the water signal), 3.9-4.1 (1H, m), 4.4-4.75 (1H, m), 5.21 (1H, br s), 5.8-6.0 (1H, m), 6.8-7.0 10 (1H, m), 8.49 (1H, s), 8.55-8.75 (1H, m), 10.64 (1H, br s), Example 138 N-(2-{[2-(2,3-Difluorophenoxy)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide 15 F (R)-N-(6-((1-Hydroxy-4-meth pyrimidin-4- yl)methanesulfonamide Intermediate 29 (48 mg, 0.15 mmol) was dissolved in DMF (0.5 mL) and DIPEA (0.031 mL, 0.18 mmol) followed by a solution of 1-(2-chloroethoxy)-2,3- 20 difluorobenzene (30.3 mg, 0.16 mmol) in DMF (0.5 mL) were added. The reaction mixture was heated at 100°C for 1.5 h in a microwave reactor. Water and EtOAc were added, and the two phases were separated. The aqueous layer was extracted with EtOAc, and the combined organic layer was washed with water (×2), dried over MgSO4, filtered and concentrated. The residue was purified by straight phase flash column chromatography on silica (increasing amounts of MeOH 25 in EtOAc as eluent) to yield the title compound (32 mg, 45%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O4S2: 477.1436, found: 477.1434.1H NMR (400 MHz, CDCl3, mixture of 302 201388-PCT01-NP rotamers, 1:1) δ 0.89 (6H, d, rotamers), 1.32–1.53 (2H, m, rotamers), 1.63 (1H, dp), 3.20 (3H, s), 3.39–3.5 (2H, m), 3.54 (1H, dd), 3.71 (1H, dd), 4.28 (2H, t), 5.38 (1H, d), 5.90 (1H, s), 6.71– 6.82 (2H, m), 6.95 (1H, tdd). 5 Example 139 N-(2-{[1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide F K2CO3 (138 mg, 1.00 mmol) wa of Ar(g) to a stirred mixture of10 (2R)-2-((6-chloro-2-((1-(2,3-difluorophenyl)ethyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1- ol Intermediate 135 (260 mg, 0.65 mmol), methanesulfonamide (69 mg, 0.73 mmol), X-Phos (128 mg, 0.27 mmol), Pd2(dba)3 (61 mg, 0.07 mmol) and THF (4 mL). The reaction mixture was heated in a sealed vessel in an oil bath to 60°C for 18 h. The mixture was concentrated, and the residue was suspended EtOAc (10 mL). The insoluble was removed by filtration through 15 CELITE. The orange solution was concentrated to dryness, and the residue was purified by preparative SFC, PrepMethod Z1, to give the title compound (255 mg, 86%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O3S2: 461.1488, found: 461.1504.1H NMR (600 MHz, DMSO-d6) δ 0.75-0.91 (6H, m), 1.29-1.38 (2H, m), 1.54-1.72 (4H, m), 3.23 (3H, s), 3.3-3.5 (2H, m, overlapping with the water signal), 3.98-4.17 (1H, m), 4.63 (1H, d), 5.21 (1H, q), 5.78 (1H , br 20 s), 6.97-7.40 (4H, m), 10.53 (1H, br s). Example 140 N-(2-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide Isomer 1 303 201388-PCT01-NP F The isomers of N-(2-(2-(2,3-difl -hydroxy-4-methylpentan-2- yl)amino)pyrimidin-4-yl)methanesulfonamide Intermediate 142 (300 mg, 0.68 mmol) were separated by preparative chiral SFC on a Lux C2 column (5 µm, 250×30 mm ID) using 30% 5 MeOH in CO2 as mobile phase at a flow rate of 80 mL/min to give the first eluting compound N- (2-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide Isomer 1, Example 140, (131 mg, 44%). HRMS (ESI) m/z [M+H]+ calcd for C20H29F2N4O3S: 443.1922, found: 443.1940. 10 Example 141 N'-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin- 2-yl)-N,N-dimethylsulfuric diamide F A mixture of (R)-2-((2-chloro-6 imidin-4-yl)amino)pentan-1-ol, 15 Intermediate 23 (22.0 mg, 0.06 mmol), N,N-dimethylsulfamide (7.0 mg, 0.06 mmol), Pd2(dba)3 (5.0 mg, 5.88 µmol), K2CO3 (12 mg, 0.09 mmol) and X-Phos (66 mg, 0.14 mmol) in THF (2 mL) was stirred under an atmosphere of N2(g) at 60°C on. Pd2(dba)3 (5.0 mg, 5.88 µmol), X- Phos (11.2 mg, 0.02 mmol) and N,N-dimethylsulfamide (7 mg, 0.06 mmol) were added and the reaction mixture was stirred at 60°C for 2 d. Water and DCM were added and the phases were 20 separated. The organic layer was concentrated, and the crude residue was purified by preparative 304 201388-PCT01-NP HPLC, PrepMethod I, (gradient: 30–95%) to give the title compound (2 mg, 8%). HRMS (ESI) m/z [M+H]+ calcd for C18H26F2N5O3S2: 462.1440, found: 462.1452. Example 142 5 N-(4-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin- 2-yl)azetidine-1-sulfonamide F A mixture of (R)-2-(2-chloro-6 din-4-ylamino)pentan-1-ol Intermediate 23 (30.0 mg, 0.08 mmol), Pd2(dba)3 (7.4 mg, 8.02 µmol), K2CO3 (16.6 mg, 0.12 10 mmol), azetidine-1-sulfonamide (10.9 mg, 0.08 mmol) and X-Phos (66.2 mg, 0,14 mmol) in THF (2 mL) was stirred under an atmosphere of N2(g) at 60°C on. Additional Pd2(dba)3 (7.4 mg, 8.02 µmol) and X-Phos (66.2 mg, 0,14 mmol) were added and the reaction mixture was stirred at 60oC for 72 h. Water and DCM were added. The organic layer was separated and concentrated. The crude product was purified by preparative HPLC, PrepMethod I, (gradient 30–95%) to give 15 the title compound (3 mg, 8%). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N5O3S2: 474.1440, found: 474.1468. Example 143 N-(4-{[1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan -2- 20 yl]amino}pyrimidin-2-yl)methanesulfonamide Cl 201388-PCT01-NP DIPEA (605 mg, 4.68 mmol) was added dropwise to a mixture of (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercaptopyrimidin-2-yl)methanesulfonamide Intermediate 20 (500 mg, 1.56 mmol) and 1-(1-bromoethyl)-4-chloro-2-fluorobenzene (371 mg, 1.56 mmol) in DMF (10 mL) at 20°C. The reaction mixture was stirred at rt for 2 h. The mixture was 5 concentrated and diluted with EtOAc (125 mL) and washed with brine (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was first purified by preparative TLC (DCM:MeOH, 10:1) followed by preparative HPLC, PrepMethod Q, (using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents) to give the title compound as a white solid (30 mg, 4%). HRMS (ESI) m/z [M+H]+ calcd for 10 C19H27ClFN4O3S2: 477.1192, found: 477.1218.1H NMR (400MHz, CD3OD,）δ 0.81-0.97 (6H, m), 1.31 (2H, apparent t), 1.65-1.75 (4H, m), 3.30 (3H, s), 3.47-3,57 (2H, m), 4.20 (1H, apparent br s), 5.20-5.32 (1H, m), 5.93 (1H, d), 7.18-7.22 (2H, m), 7.53-7.57 (1H, m). Example 144 15 N-(2-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- phenylethyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide Isomer 2 The isomers of N-(2-(((R)-1-hydro amino)-6-((1- phenylethyl)thio)pyrimidin-4-yl)methanesulfonamide Intermediate 143 (345 mg, 0.81 mmol) 20 were separated by preparative chiral SFC on a Chiralpak IA column (5 µm, 250×30 mm ID) using 15% MeOH/DEA (100/0.5) in CO2 as mobile phase at a flow rate of 120 mL/min to give the second eluting compound N-(2-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}-6-{[(1R*)-1- phenylethyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide Isomer 2, Example 144 (139 mg, 40%). HRMS (ESI) m/z [M+H]+ calcd for C19H29N4O3S2: 425.1676, found: 425.1690.1H NMR 25 (500 MHz, CDCl3) δ 0.83 - 0.95 (6H, m), 1.27 - 1.36 (1H, m), 1.38 - 1.49 (1H, m), 1.59 - 1.71 306 201388-PCT01-NP (4H, m), 2.8 - 2.91 (3H, m), 3.41 - 3.48 (1H, m), 3.55 - 3.63 (1H, m), 4.16 (1H, br s), 4.89 (1H, q), 6.28 (1H, br s), 7.15 - 7.23 (1H, m), 7.24 - 7.33 (2H, m), 7.34 - 7.42 (2H, m). Example 145 5 N'-(6-{[(2,3-Difluorophenyl)methyl]sulfanyl}-2-{[(2R)-1-hydroxypentan -2- yl]amino}pyrimidin-4-yl)-N,N-dimethylsulfuric diamide F A mixture of (R)-2-(4-chloro-6 din-2-ylamino)pentan-1-ol Intermediate 145 (59 mg, 0.16 mmol), N,N-dimethylsulfamid (20 mg, 0.16 mmol), Pd2(dba)3 10 (14 mg, 0.02 mmol), K2CO3 (32 mg, 0.24 mmol) and X-Phos (66 mg, 0,14 mmol) in THF (2 mL) was stirred under an atmosphere of N2(g) at 60°C for 3 h. Water and DCM were added, the organic layer was concentrated in vacuo and the residue was purified by PrepMethod A, (gradient 5–95%) to give the title compound (5 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for C18H26F2N5O3S2: 462.1440, found: 462.1438; 15 Example 146 N-(6-{[(2,3-Difluorophenyl)methyl]sulfanyl}-2-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin- 4-yl)azetidine-1-sulfonamide F 20 201388-PCT01-NP A mixture of (R)-2-(4-chloro-6-(2,3-difluorobenzylthio)pyrimidin-2-ylamino)pentan-1-ol Intermediate 145 (59 mg, 0.16 mmol), azetidine-1-sulfonamide (22 mg, 0.16 mmol), Pd2(dba)3 (14 mg, 0.02 mmol), K2CO3 (33 mg, 0.24 mmol) and X-Phos (30 mg, 0.06 mmol) in THF (2 mL) was stirred under an atmosphere of N2(g) at 60°C for 3 h. Additional Pd2(dba)3 (14 mg, 0.02 5 mmol) and X-Phos (30 mg, 0.06 mmol) were added and the reaction mixture was stirred at 60°C on. Water and DCM were added, the organic layer was concentrated in vacuo and the crude product was purified by preparative HPLC, PrepMethod A, (gradient 5–95%) to give the title compound (11 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N5O3S2: 474.1440, found: 474.1460.1H NMR (600 MHz, DMSO-d6) δ 0.84 (3H, t), 1.18–1.37 (2H, m), 1.37–1.46 (1H, m), 10 1.48–1.57 (1H, m), 2.06 (2H, p), 3.37–3.45 (2H, m), 3.57–4.16 (5H, m), 4.29–4.51 (2H, m), 6.15 (1H, s), 6.73 (1H, s), 7–7.26 (1H, m), 7.23–7.43 (2H, m). Example 147 N-(6-{[(1R*)-1-(4-Chloro-2-fluorophenyl)ethyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan- 15 2-yl]amino}pyrimidin-4-yl)methanesulfonamide Isomer 1 Cl The isomers of N-(6-((1-(4-chlo 2-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)pyrimidin-4-yl)methanesulfonamide Intermediate 146 (140 mg, 0.29 20 mmol) were separated by preparative chiral HPLC on a Chiralpak IA column (5 µm, 250×30 mm ID) using 20% EtOH in heptane as mobile phase to give the first eluting compound N-(6- {[(1R*)-1-(4-chloro-2-fluorophenyl)ethyl]sulfanyl}-2-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide Isomer 1, Example 147 as a white solid (35 mg, 25%). HRMS (ESI) m/z [M+H]+ calcd for C19H27ClFN4O3S2: 477.1192, found: 477.1196.1H 25 NMR (400 MHz, DMSO-d6) δ 0.85-0-95 (6H, m), 1.26-1.46 (2H, m), 1.63 (4H, apparent br s), 3.2-3.4 (5H, m, partially overlapping with the water signal), 3.9-4.1(1H, m), 4.65(1H, br s), 5.15- 308 201388-PCT01-NP 5.35 (1H, m), 5.75-5.95 (1H, m), 6.75-6.9 (1H, m), 7.26 (1H, apparent d), 7.42 (1H, dd), 7.5-7.7 (1H, m), 10.62 (1H, br s). Example 148 5 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide F K2CO3 (138 mg, 1.00 mmol) wa of Ar(g) to a stirred mixture of (R)- 10 2-((6-chloro-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (260 mg, 0.67 mmol), methanesulfonamide (70 mg, 0.74 mmol), X-Phos (128 mg, 0.27 mmol), Pd2(dba)3 (61 mg, 0.07 mmol) in THF (4 mL). The reaction mixture was heated in a sealed vessel in an oil bath to 60°C on. The mixture was concentrated, and the residue was suspended in EtOAc (10 mL). The insoluble was removed by filtration through CELITE. The 15 orange solution was concentrated, and the residue was purified by preparative HPLC, PrepMethod E, (gradient 15–55%) to give the title compound as a solid (167 mg, 56%). HRMS (ESI) m/z [M+H]+ calcd for C18H25F2N4O3S2: 447.1330, found: 447.1332.1H NMR (400 MHz, CD3CN) δ 0.85-0.96 (6H, m), 1.33-1.45 (2H, m), 1.59-1.71 (1H, m), 3.19 (3H, s), 3.40-3.56 (2H, m), 4.24 (1H, br s), 4.42 (2H, s), 5.74 (1H, d), 5.89 (1H, s), 7.07-7.22 (m, 2H), 7.38 (1H, t), 7.83 20 (1H, br s). Example 149 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-3-methylbutan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide 309 201388-PCT01-NP OH HN F A mixture of N-(6-chloro-2-((2,3 din-4-yl)methanesulfonamide Intermediate 150 (80.5 mg, 0.22 mmol), (R)-2-amino-3-methylbutan-1-ol (34 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120℃ for 5 d. The mixture 5 was concentrated, and the crude product was purified by preparative HPLC to give the title compound (3.4 mg, 3.6%). HRMS (ESI) m/z [M+H]+ calcd for C17H23F2N4O3S2: 433.1174, found: 433.1182. Example 150 10 N-[2-(Benzylsulfanyl)-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin-4- yl]methanesulfonamide A mixture of N-(2-(benzylthio)-6- hanesulfonamide Intermediate 153 (73 mg, 0.22 mmol), (R)-2-amino-4-methylpentan-1-ol (39 mg, 0.33 mmol) and DIPEA (85 mg, 15 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120℃ for 5 d. The mixture was concentrated, and the crude product was purified by preparative HPLC to give the title compound (13.6 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C18H27N4O3S2: 411.1518, found: 411.1532. Example 151 20 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin- 4-yl)methanesulfonamide 310 201388-PCT01-NP F The title compound was prepare fluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (R)-2-aminopentan-1-ol as described for Example 149 to give the title compound (10.1 mg, 11%). HRMS (ESI) m/z [M+H]+ calcd for 5 C17H23F2N4O3S2: 433.1174, found: 433.1184. Example 152 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2S,3S)-1,3-dihydroxybutan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide OH OH F 10 The title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (2S,3S)-2-aminobutane-1,3-diol as described for Example 149 to give the title compound (9.4 mg, 10%). HRMS (ESI) m/z [M+H]+ calcd for C16H21F2N4O4S2: 435.0966, found: 435.0972. 15 Example 153 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4- yl)methanesulfonamide 311 201388-PCT01-NP F The title compound was prepare fluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and 2-aminopentan-1-ol as described for Example 149 to give the title compound (16.9 mg, 18%). HRMS (ESI) m/z [M+H]+ calcd for 5 C17H23F2N4O3S2: 433.1174, found: 433.1184. Example 154 N-{2-(Benzylsulfanyl)-6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4-yl}methanesulfonamide 10 The title compound was prepared -chloropyrimidin-4- yl)methanesulfonamide Intermediate 153 and 2-aminopentan-1-ol as described for Example 150 to give the title compound (12.4 mg, 14%). HRMS (ESI) m/z [M+H]+ calcd for C17 H25 N4 O3 S2: 397.1362, found: 397.1366. 15 Example 155 N-(2-{[(2-Cyanophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide 312 201388-PCT01-NP A mixture of N-(6-chloro-2-((2-cy -4-yl)methanesulfonamide Intermediate 154 (78 mg, 0.22 mmol), (R)-2-amino-4-methylpentan-1-ol (39 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120℃ for 5 d. The mixture 5 was concentrated, and the crude product was purified by preparative HPLC to give the title compound (14.1 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C19H26N5O3S2: 436.1472, found: 436.1480. Example 156 10 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxybutan-2-yl]amino}pyrimidin- 4-yl)methanesulfonamide OH F The title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (R)-2-aminobutan-1-ol as described for Example 15 149 to give the title compound (13.4 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C16H21F2N4O3S2: 419.1018, found: 419.1028. Example 157 N-[2-(Benzylsulfanyl)-6-{[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}pyrimidin-4- 20 yl]methanesulfonamide 313 201388-PCT01-NP OH HN The title compound was prepared chloropyrimidin-4- yl)methanesulfonamide Intermediate 153 and (R)-2-amino-3-methylbutan-1-ol as described for Example 150 to give the title compound (6.2 mg, 7%). HRMS (ESI) m/z [M+H]+ calcd for 5 C17H25N4O3S2: 397.1362, found: 397.1364. Example 158 N-(2-{[(4-Cyanophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin-4- yl)methanesulfonamide 10 N A mixture of N-(6-chloro-2-((4 -yl)methanesulfonamide Intermediate 155 (78 mg, 0.22 mmol), (R)-2-aminopentan-1-ol (34 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120℃ for 5 d. The mixture was concentrated, and the crude product was purified by preparative HPLC to give the title 15 compound (11.3 mg, 12%). HRMS (ESI) m/z [M+H]+ clad for C18H24N5O3S2: 422.1314, found: 422.1324. Example 159 N-(2-{[(2-Cyanophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxypentan-2-yl]amino}pyrimidin-4- 20 yl)methanesulfonamide 314 201388-PCT01-NP The title compound was prepared anobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 154 and (R)-2-aminopentan-1-ol as described for Example 155 to give the title compound (3.2 mg, 3%). HRMS (ESI) m/z [M+H]+ calcd for 5 C18H24N5O3S2: 422.1314, found: 422.1332. Example 160 N-[2-(Benzylsulfanyl)-6-{[(2S)-1-hydroxy-4-methylpentan-2-yl]amino}pyrimidin-4- yl]methanesulfonamide 10 The title compound was prepared chloropyrimidin-4- yl)methanesulfonamide Intermediate 153 and (S)-2-amino-4-methylpentan-1-ol as described for Example 150 to give the title compound (8.6 mg, 10%). HRMS (ESI) m/z [M+H]+ calcd for C18 H27 N4 O3 S2: 411.1518, found: 411.1542. 15 Example 161 N-(6-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-2-{[(pyridin-2- yl)methyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide 315 201388-PCT01-NP A mixture of N-(6-chloro-2-((pyri idin-4-yl)methanesulfonamide Intermediate 156 (73 mg, 0.22 mmol), (R)-2-amino-4-methylpentan-1-ol (39 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 120℃ for 5 d. The mixture 5 was concentrated, and the crude product was purified by preparative HPLC to give the title compound (8.3 mg, 9%). HRMS (ESI) m/z [M+H]+ calcd for C17H26N5O3S2: 412.1472, found: 412.1484. Example 162 10 N-(2-{[(2-Cyanophenyl)methyl]sulfanyl}-6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4- yl)methanesulfonamide The title compound was prepared yanobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 154 and 2-aminopentan-1-ol as described for Example 15 155 to give the title compound (6 mg, 6%). HRMS (ESI) m/z [M+H]+ calcd for C18H24N5O3S2: 422.1314, found: 422.1332. Example 163 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(1S,2S)-2- 20 hydroxycyclohexyl]amino}pyrimidin-4-yl)methanesulfonamide 316 201388-PCT01-NP HO HN F The title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (1S,2S)-2-aminocyclohexan-1-olas described for Example 149 to give the title compound (4.4 mg, 5%). HRMS (ESI) m/z [M+H]+ calcd for C18 5 H23 F2 N4 O3 S2: 445.1174, found: 445.1178. Example 164 N-(2-{[(2-Cyanophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-3-methylbutan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide OH 10 The title compound was prepared anobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 154 and (R)-2-amino-3-methylbutan-1-olas described for Example 155 to give the title compound (8.6 mg, 9%). HRMS (ESI) m/z [M+H]+ calcd for C18H24N5O3S2: 422.1314, found: 422.1326. 15 Example 165 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(1S,2S)-2- hydroxycyclopentyl]amino}pyrimidin-4-yl)methanesulfonamide 317 201388-PCT01-NP HO F The title compound was prepare fluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (1S,2S)-2-aminocyclopentan-1-ol as described for Example 149 to give the title compound (10.7 mg, 11%). HRMS (ESI) m/z [M+H]+ calcd for 5 C17H21F2N4O3S2: 431.1018, found: 431.1032. Example 166 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2S)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide 10 A F The title compound was prepare ifluorobenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 150 and (S)-2-amino-4-methylpentan-1-ol as described for Example 149 to give the title compound (2.5 mg, 3%). HRMS (ESI) m/z [M+H]+ calcd for 15 C18H25F2N4O3S2: 447.1330, found: 447.1336. Example 167 N-(2-{[(4-Cyanophenyl)methyl]sulfanyl}-6-[(1-hydroxypentan-2-yl)amino]pyrimidin-4- yl)methanesulfonamide 318 201388-PCT01-NP N The title compound was prepar obenzyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 155 and 2-aminopentan-1-ol as described for Example 158 to give the title compound (4.9 mg, 5%). HRMS (ESI) m/z [M+H]+ calcd for C1 H24N5O3S2: 5 422.1314, found: 422.1330. Example 168 N-(6-{[(2R)-1-Hydroxypentan-2-yl]amino}-2-{[(pyridin-2-yl)methyl]sulfanyl}pyrimidin-4- yl)methanesulfonamide 10 The title compound was prepared din-2-ylmethyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 156 and (R)-2-aminopentan-1-ol as described for Example 161 to give the title compound. 15 Example 169 N-(2-{[(3,5-Dimethyl-1,2-oxazol-4-yl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methanesulfonamide 319 201388-PCT01-NP N A mixture of N-(6-chloro-2-(((3,5 thyl)thio)pyrimidin-4- yl)methanesulfonamide Intermediate 157 (77 mg, 0.22 mmol,), (R)-2-amino-4-methylpentan-1- ol (39 mg, 0.33 mmol) and DIPEA (85 mg, 0.66 mmol) in n-BuOH (2.5 mL) was stirred at 5 120℃ for 5 d. The mixture was concentrated, and the crude product was purified by preparative HPLC to give the title compound (10.1 mg, 11%). HRMS (ESI) m/z [M+H]+ calcd for C17H28N5O4S2: 430.1578, found: 430.1602. Example 170 10 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)morpholine-4-sulfonamide F A mixture of K2CO3 (52 mg, 2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (98 mg, 0.25 15 mmol), morpholine-4-sulfonamide (85 mg, 0.46 mmol), X-Phos (19.3 mg, 0.04 mmol), Pd2(dba)3 (32 mg, 0.03 mmol) in THF was heated under an atmosphere of N2(g) at 65°C on. The reaction mixture was concentrated and the residue was dissolved in DCM and water and acidified with AcOH. The organic layer was concentrated and the crude product was purified by preparative HPLC, PrepMethod D, (gradient 20–60%) to give the title compound (65 mg, 50%). 20 HRMS (ESI) m/z [M+H]+ calcd for C21H30F2N5O4S2: 518.1702, found: 518.1690.1H NMR (500 MHz, CD3OD) δ 0.87–0.96 (6H, m), 1.4–1.49 (2H, m), 1.63–1.72 (1H, m), 3.21–3.27 (4H, m), 320 201388-PCT01-NP 3.48–3.55 (2H, m), 3.65–3.7 (4H, m), 4.27 (1H, s), 4.39–4.49 (2H, m), 5.98 (1H, s), 7.03–7.18 (2H, m), 7.31–7.38 (1H, m). Example 171 5 N'-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)-N,N-dimethylsulfuric diamide F Prepared in a similar way as de R)-2-((6-chloro-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (278 mg, 10 0.72 mmol) and N,N-dimethylsulfamid (133 mg, 1.08 mmol). The crude product was purified by preparative HPLC, PrepMethod D (gradient 15–55%) to give the title compound (135 mg, 40%). HRMS (ESI) m/z [M+H]+ calcd for C19H28F2N5O3S2: 476.1596, found: 476.1570.1H NMR (500 MHz, DMSO-d6) δ 0.76–1 (6H, m), 1.29–1.5 (2H, m), 1.5–1.68 (1H, m), 2.77 (6H, s), 3.30 (2H, s), 4.10 (1H, s), 4.38 (2H, s), 4.63 (1H, s), 5.87 (1H, s), 7.13 (1H, q), 7.23 (1H, apparent br s), 15 7.31 (1H, q), 7.36–7.47 (1H, m), 10.39 (1H, br s). Example 172 (3S)-N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)-3-methylpiperazine-1-sulfonamide F 20 201388-PCT01-NP Prepared in a similar way as described in Example 170 from (R)-2-((6-chloro-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (104 mg, 0.27 mmol) and (S)-3-methylpiperazine-1-sulfonamide (80 mg, 0.40 mmol). The crude product was purified by preparative HPLC, PrepMethod D (gradient 20–65%) to give the title compound 5 (28 mg, 20%). HRMS (ESI) m/z [M+H]+ calcd for C22H33F2N6O3S2: 531.2018, found: 531.2020. 1H NMR (500 MHz, CD3OD) δ 0.83–0.93 (6H, m), 1.01 (3H, d), 1.39 (2H, t), 1.61–1.73 (1H, m), 2.33 (1H, t), 2.6–2.79 (3H, m), 2.86–2.94 (1H, m), 3.41–3.52 (4H, m), 3.90 (1H, s), 4.33– 4.43 (2H, m), 5.90 (1H, s), 6.95–7.1 (2H, m), 7.31–7.37 (1H, m). 10 Example 173 N-(6-{[(2R)-1-Hydroxy-4-methylpentan-2-yl]amino}-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrimidin-4-yl)methanesulfonamide A degassed solution of (R)-2-(( thio)pyrimidin-4-yl)amino)-4- 15 methylpentan-1-ol Intermediate 28 (736 mg, 1.93 mmol) in THF (6 mL) was added to K2CO3 (0.174 mL, 2.89 mmol), Pd2(dba)3 (353 mg, 0.39 mmol) and X-Phos (735 mg, 1.54 mmol) under an atmosphere of N2(g). The reaction mixture was stirred a few min and then a solution of methanesulfonamide (202 mg, 2.12 mmol) in THF (4 mL) was added. The reaction mixture was heated at 60°C for 5 h. Water and EtOAc were added, and the two phases were separated. The 20 aqueous layer was extracted with EtOAc (×2), and the combined organic layer was washed with water, dried over MgSO4 and concentrated. The residue was purified by straight phase flash column chromatography on silica (0–100% EtOAc in heptane) to yield the title compound (522 mg, 62%). HRMS (ESI) m/z [M+H]+ calcd for C19H29N4O4S2: 441.1624, found: 441.1630; 1H NMR (400 MHz, CDCl3) δ 0.88–0.97 (6H, m), 1.37–1.45 (2H, m), 1.62–1.72 (1H, m), 3.15 (3H, 25 s), 3.56 (1H, dd), 3.71 (1H, dd), 3.79 (3H, s), 4.28 (2H, s), 4.96 (1H, s), 5.93 (1H, s), 6.83 (2H, d), 7.30 (2H, d). 322 201388-PCT01-NP Example 174 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)azetidine-1-sulfonamide 5 F Prepared in a similar way as de )-2-((6-chloro-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (177 mg, 0.41 mmol, 90 % w/w) and azetidine-1-sulfonamide (126 mg, 0.74 mmol, 80% w/w). The crude 10 product was purified by preparative HPLC, PrepMethod D (gradient 15–55%) to give the title compound (106 mg, 53%). HRMS (ESI) m/z [M+H]+ calcd for C20H28F2N5O3S2: 488.1596, found: 488.1596.1H NMR (500 MHz, CD3OD) δ 0.88–0.97 (6H, m), 1.4–1.49 (2H, m), 1.64– 1.72 (1H, m), 2.19 (2H, p), 3.43–3.57 (2H, m), 3.91–3.98 (4H, m), 4.28 (1H, s), 4.42–4.49 (2H, m), 6.04 (1H, s), 7.03–7.18 (2H, m), 7.32–7.39 (1H, m). 15 Example 175 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)-N'-[2-(dimethylamino)ethyl]sulfuric diamide F 20 Prepared in a similar way as 2-((6-chloro-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (160 mg, 323 201388-PCT01-NP 0.41 mmol, 90 % w/w) and 1-(dimethylamino)-2-(sulfamoylamino)ethan Intermediate 189 (115 mg, 0.62 mmol, 90% w/w). The crude product was first purified by, preparative HPLC, PrepMethod Z4 (gradient 25–65%) followed by PrepMethod D to give the title compound (9 mg, 4%). HRMS (ESI) m/z [M+H]+ calcd for C21H33F2N6O3S2: 519.2018, found: 519.2024.1H NMR 5 (500 MHz, CD3OD) δ 0.87–0.96 (6H, m), 1.43 (2H, ddd), 1.67 (1H, dq), 2.25 (6H, d), 2.53 (2H, t), 3.12 (2H, t), 3.50 (2H, qd), 4.05–4.34 (1H, m), 4.38–4.47 (2H, m), 5.83 (1H, s), 7.02–7.18 (2H, m), 7.3–7.39 (1H, m). Example 176 10 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)-N'-[3-(dimethylamino)propyl]sulfuric diamide F Prepared in a similar way ((6-chloro-2-((2,3- difluorobenzyl)thio)pyrimidin-4-yl)amino)-4-methylpentan-1-ol Intermediate 149 (226 mg, 15 0.58 mmol) and 1-(dimethylamino)-3-(sulfamoylamino)propane Intermediate 190 (260 mg, 1.29 mmol, 90% w/w). The crude product was purified by preparative HPLC, PrepMethod I (gradient 15–55%) to give the title compound (27 mg, 9%). HRMS (ESI) m/z [M+H]+ calcd for C22H35F2N6O3S2: 533.2174, found: 533.2176.1H NMR (500 MHz, CD3OD) δ 0.83–0.93 (6H, m), 1.34–1.44 (2H, m), 1.64 (3H, h), 2.18 (6H, s), 2.3–2.37 (2H, m), 2.99 (2H, t), 3.4–3.52 (2H, 20 m), 4.16 (1H, br s), 4.33–4.43 (2H, m), 5.82 (1H, s), 6.98–7.13 (2H, m), 7.32 (1H, t). Example 177 N-(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-[2-(hydroxymethyl)-4-methylpentyl]pyrimidin- 4-yl)methanesulfonamide 25 324 201388-PCT01-NP F TFA (1 mL) was added at 0oC to butyldimethylsilyl)oxy)methyl)-4- methylpentyl)-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)methanesulfonamide Intermediate 162 (200 mg, 0.357 mmol) in DCM (5 mL). The reaction mixture was stirred at 25oC for 16 h. 5 The mixture was concentrated, and the residue was purified by preparative HPLC to give the title compound (81 mg, 51%) as a white solid.1H NMR (400 MHz, CD3OD) δ 7.35-7.41 (m, 1H), 7.07-7.17 (m, 2H), 6.56 (s, 1H), 4.51 (s, 1H) 344-3.47 (m, 2H), 3.29 (s, 3H), 2.72-2.77 (m, 1H).2.52-2.57 (m, 1H), 2.08-2.11 (m, 1H), 1.64-1.68 (m, 1H), 1.29-1.32 (m, 1H), 1.07-1.10 (m, 1H), 0.85-0.90 (m, 6H). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N3O3S2: 446.1378, found: 10 446.1390. Example 178 N-[(2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2- yl]amino}pyrimidin-4-yl)methyl]methanesulfonamide F 15 DIPEA (9.11 µL, 0.05 mmol) a were added to a solution of (R)-2- (6-(aminomethyl)-2-(2,3-difluorobenzylthio)pyrimidin-4-ylamino)-4-methylpentan-1-ol Intermediate 167 (20 mg, 0.05 mmol) in DCM (1 mL) and the reaction mixture was stirred for 2 h. Water and DCM were added and the two layers were separated. The organic layer was 20 concentrated and the crude product was purified by straight phase flash column chromatography on silica (EtOAc:DCM, 2:1) to give the title compound (5 mg, 21%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O3S2: 461.1488, found: 461.1476.1H NMR (400 MHz, CDCl3, 25°C) δ 325 201388-PCT01-NP 0.84–0.98 (6H, m), 1.35–1.48 (2H, m), 1.61–1.69 (1H, m), 2.93 (3H, s), 3.56 (1H, dd), 3.71 (1H, dd), 4.12 (2H, d), 4.3–4.42 (2H, m), 5.00 (1H, br s), 5.31–5.38 (1H, m), 6.05 (1H, s), 6.96–7.1 (2H, m), 7.2–7.26 (1H, m, partially overlapping with the solvent). 5 Example 179 N-[2-{[(2,3-Difluorophenyl)methyl]sulfanyl}-6-(1-hydroxy-5-methylhexan-3-yl)pyrimidin-4- yl]methanesulfonamide OH F TFA (0.5 mL) was added to a sol dimethylsilyl)oxy)-5-methylhexan- 10 3-yl)-2-((2,3-difluorobenzyl)thio)pyrimidin-4-yl)methanesulfonamide Intermediate 172 (50 mg, 0.089 mmol) in DCM (2 mL) and the reaction mixture was stirred at 25oC for 3 h. The mixture was extracted with DCM (2×50 mL) and the combined organic layer was washed with sat NaHCO3 (30 mL), dried, filtered and concentrated to give the title compound (20 mg, 50%).1H NMR: (400 MHz, CDCl3) δ 7.25 (m, 1H), 7.10 - 6.96 (m, 2H), 6.62 (s, 1H), 4.43 (d, 2H), 3.58 - 15 3.55 (m, 1H), 3.46 - 3.43 (m, 1H), 3.26 (s, 3H), 2.92 (d, 1H), 1.88 (q, 2H), 1.70 - 1.66 (m, 1H), 1.42 - 1.36 (m, 2H), 0.91 - 0.81 (m, 6H). HRMS (ESI) m/z [M+H]+ calcd for C19H26F2N3O3S2: 446.1378, found: 446.1390. Example 180 20 N-(4-{[(2R,3R)-1,2-Dihydroxy-5-methylhexan-3-yl]oxy}-6-{[(1R*)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 HRMS (ESI) m/z [M+H]+ calcd fo r 19 29 4 5 2: . 4, found: 457.1578 326 201388-PCT01-NP Example 181 N-(4-{[(1R*)-1-(2,3-difluorophenyl)ethyl]sulfanyl}-6-{[(2R,3R)-1,2-dihydroxy-5-methylhexan- 3-yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 5 F HRMS (ESI) m/z [M+H]+ calcd 6, found: 493.1384. Example 182 10 N-(4-{[1-(2,6-Difluorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,3-dihydroxy-5-methylhexan-2- yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide HRMS (ESI) m/z [M+H]+ calcd fo 386, found: 493.1376. 15 Example 183 (3S)-N-(4-{[1-(2,6-Difluorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,2-dihydroxy-5-methylhexan-3- yl]oxy}-1,3,5-triazin-2-yl)-3-methylpiperazine-1-sulfonamide 327 201388-PCT01-NP TFA (2 mL) was added to a s ((1-(2,6- difluorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-1,3,5- triazin-2-yl)sulfamoyl)-2-methylpiperazine-1-carboxylate Intermediate 179 (324 mg, 0.45 5 mmol) in DCM (8 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated and diluted with DCM (13 mL) and washed with brine (2×5 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to give the title compound as a yellow oil which solidified on standing. (153 mg, 59%). HRMS (ESI) m/z [M+H]+ calcd for 10 C23H35F2N6O5S2: 577.2072, found: 577.2082; 1H NMR (400 MHz, DMSO-d6, mixture of isomers) δ 0.80-0.88 (6H, m), 1.15-1.83 (9H m), 3.78-2.58 (9H, m), 4.07-4.91 (4H, m), 5.4-5.5 (1H, m), 7.13 (2H, t), 7.33-7.43 (1H, m), 8.40 (1H, s). Example 184 15 (3S)-N-(4-{[(2S,3R)-1,2-Dihydroxy-5-methylhexan-3-yl]oxy}-6-[(1-phenylethyl)sulfanyl]-1,3,5- triazin-2-yl)-3-methylpiperazine-1-sulfonamide TFA (2.0 mL) was added to a -((R)-1-((S)-2,2-dimethyl-1,3-20 dioxolan-4-yl)-3-methylbutoxy)-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)sulfamoyl)-2- methylpiperazine-1-carboxylate Intermediate 181 (319 mg, 0.47 mmol) in DCM (8 mL) at rt under an atmosphere of N2(g) and the reaction mixture was stirred at rt for 16 h. The reaction 328 201388-PCT01-NP mixture was concentrated and diluted with DCM (23 mL) and washed with brine (15 mL) and water (15 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to give the title compound as a yellow oil which solidified on standing (134 mg, 53%). HRMS (ESI) m/z [M+H]+ calcd for 5 C23H37N6O5S2: 541.2262, found: 541.2284.1H NMR (400 MHz, DMSO-d6, mixture of isomers) δ 0.79-0.89 (6H, m), 1.14-1.83 (9H, m), 2.57-2.67 (1H, m), 2.85 (1H, t), 3.04 (1H, t), 3.21-3.58 (5H, m, partially overlapping with the water signal), 4.03-4.89 (3H, m), 4.98-5.06 (1H, m), 5.11- 5.20 (1H, m), 7.20-7.34 (m, 3H), 7.45 (2H, d), 8.45 (1H, br s). 10 Example 185 N-(4-{[1-(3,4-Dichlorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,2-dihydroxy-5-methylhexan-3- yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide Cl Cl FeCl3×6 H2O (456 mg, 1.70 mm 4-dichlorophenyl)ethyl)thio)-6-15 ((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 183 (274 mg, 0.48 mmol) in DCM (15 mL) at 0oC and the reaction mixture was stirred at 0oC for 16 h. The reaction mixture was concentrated and diluted with DCM (25 mL) and washed with brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative TLC 20 (DCM:MeOH, 10:1) to give the title compound as a yellow oil which solidified upon standing (40 mg, 16%). HRMS (ESI) m/z [M+H]+ calcd for C19H27Cl2N4O5S2: 525.0794, found: 525.0790.1H NMR (300 MHz, DMSO-d6): δ 0.77-0.88 (6H, m), 1.36-1.67 (6H, m), 3.14 (3H, s), 3.6-3.7 (2H, m), 4.54-4.78 (1H, m), 4.86-5.28 (3H, m), 7.49-7.59 (2H, m), 7.77 (1H, s), 11.9 (1H, br s). 25 Example 186 329 201388-PCT01-NP N-(4-{[1-(3,4-Dichlorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,3-dihydroxy-5-methylhexan-2- yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide HO Cl 5 HRMS (ESI) m/z [M+H]+ calcd 94, found: 525.0770. Example 187 N-(4-{[(2,3-Difluorophenyl )methyl]sulfanyl}-6-{[(2R)-1-hydroxy-4-methylpentan-2-yl]oxy}- 1,3,5-triazin-2-yl)methanesulfonamide 10 F Prepared in a similar way as des Intermediate 188 to give the title compound (19 mg, 15%). HRMS (ESI) m/z [M+H]+ calcd for C17H23F2N4O4S2: 449.1124, found: 449.1128. 15 Example 188 N-(4-{[(2S,3R)-1,2-Dihydroxy-5-methylhexan-3-yl]oxy}-6-{[(1S)-1-phenylethyl]sulfanyl}- 1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 330 201388-PCT01-NP The isomers of N-(4-(((2S,3R)-1,2 n-3-yl)oxy)-6-((1-phenylethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 192 (110 mg, 0.24 mmol) was separated by preparative chiral SFC on a ChiralPak IC column (5 µm, 250×20 mm ID) using 40% MeOH in 5 CO2 as mobile phase at a flow rate of 40 mL/min to give the first eluting compound N-(4- {[(2S,3R)-1,2-dihydroxy-5-methylhexan-3-yl]oxy}-6-{[(1S)-1-phenylethyl]sulfanyl}-1,3,5- triazin-2-yl)methanesulfonamide Isomer 1, Example 188 (20 mg, 18%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H29N4O5S2: 457.1574, found: 457.1578; 1H NMR(300 MHz, CDCl3): δ 0.88-0.98 (6H, m), 1.25-1.83 (6H, m), 3.32 (3H, s), 3.59-3.87 (3H, m), 4.98-5.06 (1H, 10 m), 5.31-5.32 (1H, m), 7.24-7.44 (5H, m). Example 189 N-(4-{[(1R*)-1-(2,3-Difluorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,2-dihydroxy-5-methylhexan- 3-yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1 F 15 FeCl3×6 H2O (520 mg, 1.93 mm o ) was a e o -( -(( -( ,3-difluorophenyl)ethyl)thio)-6- ((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 194 (294 mg, 0.55 mmol) in DCM (15 mL). The reaction mixture was stirred at 0°C for 16 h. The solvent was removed under reduced pressure and the 20 residue was diluted with DCM (25 mL) and washed with brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified and the 331 201388-PCT01-NP isomers were separated by preparative chiral SFC on a Chiralpak AD-H column (5 µm, 250×25 mm ID) using 30% MeOH in CO2 as mobile phase at a flow rate of 160 mL/min to give the first eluting compound N-(4-{[(1R*)-1-(2,3-difluorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,2- dihydroxy-5-methylhexan-3-yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide Isomer 1, Example 5 189 (30 mg, 11%) as a white solid. HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O5S2: 493.1386, found: 493.1384.1H NMR (300 MHz, DMSO-d6): δ 0.83-0.89 (6H, m), 1.44-1.74 (6H, m), 3.2-3.4 (5H, m, partially overlapping with the water signal), 3.63-3.66 (1H, m), 4.5-4.6 (1H, m), 4.92 (1H, d), 5.25-5.35 (2H, m), 7.19-7.24 (1H, m), 7.35-7.42 (2H, m).11.92 (1H, br s). 10 Example 190 N-(4-{[1-(2,6-Difluorophenyl)ethyl]sulfanyl}-6-{[(2S,3R)-1,2-dihydroxy-5-methylhexan-3- yl]oxy}-1,3,5-triazin-2-yl)methanesulfonamide FeCl3×6 H2O (583 mg, 2.17 mmo of N-(4-((1-(2,6-15 difluorophenyl)ethyl)thio)-6-((R)-1-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylbutoxy)-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 196 (330 mg, 0.62 mmol) in DCM (15 mL) at 0oC and the reaction mixture was stirred at 0°C for 16 h. The solvent was removed under reduced pressure and the residue was diluted with DCM (25 mL) and washed with brine (2×20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified 20 by preparative chiral SFC on a Chiralpak AD-H column (5 µm, 250×25 mm ID) using 30% MeOH in CO2 as mobile phase to give the title compound as a white solid (35 mg, 11%). HRMS (ESI) m/z [M+H]+ calcd for C19H27F2N4O5S2: 493.1386, found: 493.1376.1H NMR (300 MHz, DMSO-d6): δ 0.83-0.89 (6H, m), 1.41-1.72 (6H, m), 3.08 (3H, s), 3.30-3.50 (2H, m, partially overlapping with the water signal), 3.60-3.65 (1H, m), 4.47-4.51 (1H, m), 4.86-4.88 (1H, m), 25 5.26-5.29 (1H, m), 5.49-5.53 (1H, m), 7.10-7.16 (2H, m), 7.35-7.45 (1H, m), 12.00 (1H, s). 332 201388-PCT01-NP Pharmacological Activity: Materials Adherent CHO-K1 cells stably expressing hCX3CR1 (ES-137-C) were purchased from 5 PerkinElmer. The RPMI-8226 cell line (CCL-155) was purchased from A.T.C.C. The CHO-K1 CX3CR1 β-arrestin cell line (93-0290C2) was from DiscoveRx. hWB was collected from healthy volunteers. The work was performed in accordance with the Declaration of Helsinki (2013) of the World Medical Association and has been approved by the relevant ethical committee. AZD8797 (CAS911715-90-7) was synthesized as described previously (J. Med. 10 Chem (2013), 56(8), 3177-3190; J, Labelled Comp. and Radiopharmaceuticals, (2012), 55(10), 387-392). [ 3H]AZD8797 (50 Ci/mmol, 52.932 μM) was labelled in-house, 125I-CX3CL1 (2200 C/mmol) and [35S]GTPγ S (guanosine 5’- [γ-thio]triphosphate) (1250 Ci/mmol) were purchased from PerkinElmer, CX3CL1 (8.5 kDa, soluble chemokine domain, unless otherwise stated, was the ligand used) was from Peprotech and recombinant His-tagged full-length human CX3CL1 15 (365-FR-025/CF) was from R&D Systems. Pertussis toxin (PTX), polyethyleneimine (PEI), GTPγ S, GDP and gelatin type A were purchased from Sigma Aldrich. Vena8 Fluoro+ Biochips for cell adhesion assays were purchased from Cellix.3,3’- dihexyloxacarbocyanine iodide (DiOC6) was from Molecular Probes and Hoechst 33342 was from Invitrogen. HEPES, Roswell Park Memorial Institute 1640 (RPMI 1640) medium, Ham’s F12 (Nutrient mixture F-12 Ham) 20 medium, Dulbecco’s modified eagle medium (DMEM), geneticin, phosphate-buffered saline 200898-US-PSP 14 (PBS), Hanks’ balanced salt solution (HBSS) and Opti-MEM were purchased from Gibco (Life Technologies). Abbreviations and units used: A.T.C.C. American Type Culture Collection; distributes reference microorganisms/cell lines for R&D BSA Bovine serum albumin derived from cows and used as a protein concentration standard in lab and protein supplement in in vitro assays. CHO-K1 an immortalized cell line isolated from the ovary of an adult, female Chinese hamster 333 201388-PCT01-NP Ci Curie = 3.7mmol-1 x 1010 atoms that decay/second; Ci/mmol = amount radiolabeled mass in a sample DiOC6 Dihexyloxacarbocyanine iodide DMEM Dulbecco’s modified eagle medium (cell medium) FBS Fetal bovine serum GDP Guanosine diphosphate GTP Guanosine-5'-triphosphate HBSS Hanks’ balanced salt solution HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); zwitterionic sulfonic acid buffering agent Hoechst 33342 a fluorescent stain for labeling DNA in fluorescence microscopy kDa Kilodalton Opti-MEM™ Reduced-Serum Medium; contains insulin, transferrin, hypoxanthine, thymidine, and trace elements PBS Phosphate-buffered saline 200898-US-PSP 14 PEI Polyethyleneimine PTX Pertussis toxin RPMI 1640 Roswell Park Memorial Institute 1640 cell medium WGA coated PVT Wheat germ agglutinin PEI-coated SPA beads for proximity-based radiometric scintillation assays 334 201388-PCT01-NP hCX3CR1 [3H]-AZD8797 competitive binding assay (filter) CHO-hCX3CR1 membranes (9 μg per well) together with 2 nM [3H]-AZD8797 and different concentrations of competitor compound were incubated in 25 mM HEPES (pH 7.4), 10 mM MgCl2, 1mM CaCl2 and 0.5% BSA in a Corning polystyrene flat-bottom 96-well plate. The plate 5 was incubated for 2 h at room temperature before free radioligand was separated from bound by vacuum filtration on to a Multiscreen HTS + HiFlow FB (Millipore) filter plate, using a Biomek FX (Beckman Coulter). The filter plate was washed in ice-cold 25 mM HEPES (pH 7.4), 5 mM MgCl2, 1 mM CaCl2 and 500 mM NaCl and dried at 50ºC for 1 h. Scintillation cocktail, Optiphase Supermix (PerkinElmer) was added to each well and the radioactivity was measured 10 using a MicroBeta Trilux reader (PerkinElmer). The DMSO concentration was held constant at 1%. The results from this assay are shown below in Table 1. hCX3CR1 [125I]-CX3CL1 displacement binding (SPA) CHO-hCX3CR1 membranes (3 μg per well) together with 75 pM [125I]-CX3CL1 (Perkin Elmer) and different concentrations of competitor compound were incubated together with 400 µg/well 15 WGA coated PVT SPA beads (Perkin Elmer) in 50 mM HEPES (pH 7.4), 10 mM MgCl2, 1mM EDTA and 0.1% Gelatin in a Greiner polystyrene flat-bottom 384-well plate. The plate was incubated for 20 h at room temperature before the radioactivity was measured using a MicroBeta Trilux reader (PerkinElmer). The DMSO concentration was held constant at 1%. Results are shown below in Table 1. 20 Table 1 Filter SPA Filter SPA E l Bi di Bi di E l Bi di Bi di ) 335 201388-PCT01-NP Filter SPA Filter SPA Example Binding Binding Example Binding Binding ) 336 201388-PCT01-NP Filter SPA Filter SPA Example Binding Binding Example Binding Binding ) 337 201388-PCT01-NP Filter SPA Filter SPA Example Binding Binding Example Binding Binding ) 338 201388-PCT01-NP Filter SPA Filter SPA Example Binding Binding Example Binding Binding ) 339

Claims

201388-PCT01-NP CLAIMS What is claimed: 1. A compound of formula (I) 1 OH R R11 ), 5 and pha alts thereof, wherein j , S-(CR3R4)k–, –(CR3R4)m-CR3=CR3–, –S-(CR3R4)k-CR3=CR3–, –CR3aR4a-CR3R4–, –(CR3R4)n-S–, –(CR3R4)n-O–, –(CH2)-NR3–, –S-(CR3R4)n-O–, –S-(CR3R4)- C(O) –, –O-(CR3R4) j–, j is 1 or 2, 10 k is 0, 1 or 2, m is 0 or 1, n is 1, 2, or 3; R1 is C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, C3-6 branched alkyl, C3-6 branched haloalkyl, -C1-3 alkyl-C3-6 cycloalkyl, phenyl, or monocyclic heteroaryl, wherein the R1 C1-3 alkyl 15 or C3-6 branched alkyl is optionally substituted with -OH and the R1 monocyclic heteroaryl is optionally substituted with -CH3; R11 is H or -CH2OH; or R1 and R11 together form a 4-6-membered carbocycle; R2 is O O O O NH O O O S S HN NH O O ) 20 , w ere n Ra is C1-3 alkyl, C1-3 haloalkyl, C3-6 carbocycle, 5-6 membered heteroaryl, C1-3 alkyl- phenyl, C1-3 alkyl-C3-6 carbocycle, S-heterocycyl, each Rb is, independently, H, C1-3 alkyl, C1-3 haloalkyl, or C1-3 alkyl-N(CH3)2, 340 201388-PCT01-NP Rc is C1-3 alkyl, and B is a 4-6 member heterocycle comprising at least one N, wherein the heterocycle is bound to the S via a ring N, optionally substituted by a C1-3 alkyl; Z is -NH-, CH2 or -O- 5 each R3, R3a, R4 and R4a are, independently, selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl; X is a bond or A; A is 4-6 member cycloalkyl, 4-6 member heterocycle, phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl; 10 p is 0, 1, 2, 3, or 4; each R5 is independently selected from halo, hydroxy, oxo, C1-3 alkyl, C1-3 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -C1-4alkoxy-C1-3alkyl, -C1-3hydroxyalkyl, -CN, -(CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, -(CH2)qR8, -C(O)R8, -C(O)OR9 , -OC(O)R9, -NR6C(O)R7 , -NO2, -NR6R7, -S(O)2R6, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, 15 wherein the C3-6 cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 substituents selected from hydroxy, oxo, halo, -CH3, and -C(O)OR9, the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents, the C1-4 alkoxy can be optionally substituted with a 4-6 member heterocyclyl, 20 each R6 and R7 are, independently, selected from H and C1-3 alkyl, each q is, independently, 1, 2, or 3, each R8 is, independently, a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy, and each R9 is, independently, a C1-5 alkyl; 25 G1, G2, and G3 are independently selected from N or CH, provided that at least two are N, wherein if L is (a) –S-CR3R4–, (b) –S-CH2-R3R4–, (c) –CH2-CR3R4–, or 30 (d) –(CH2)2-CR3R4–, and 341 201388-PCT01-NP R3 and R4 are, independently, H, halo, C1-3 alkyl, and C1-3 haloalkyl then (i) R1 is not a C3-6 branched alkyl or C3-6 branched haloalkyl; (ii) R2 is not wherein Ra is a C1-3 alkyl or C1-3 haloalkyl; 5 (iii) Z is not -N , (iv) R11 is not H, and (v) G1, G2, and G3 are not all N. 2. The compound of claim 1, wherein Z is C. 3. The compound of claim 1, wherein Z is O. 10 4. The compound of claim 1, wherein Z is -NH-. 5. The compound of claim 1, wherein Z is C or O, and wherein the compound has the formula: OH R p . 6. The compound of claim 1, wherein Z is C or O, and wherein the compound has the 15 formula: 342 201388-PCT01-NP OH R1 p . 7. e co pou o c a 4, wherein the compound has the formula . 8. The compound of claim 4, wherein the compound has the formula 5 . 9. The compound of claim 4, wherein the compound has the formula 343 201388-PCT01-NP OH R1 p . 10. , wherein the compound has the formula OH R1 p . 11. The compound of any one of claims 1 to 10, wherein L is –S-(CR3R4)k–, –S-(CR3R4)k- 5 CR3=CR3–, –(CR3R4)n-S–, –S-(CR3R4)n-O–, or –S– (CR3R4) –C(O). 12. The compound of claim 11, wherein L is –S-(CR3R4)k–. 13. The compound of claim 12, wherein k is 1. 14. The compound of 1 to 13, wherein compound has the formula . 10 15. The compound of claim 1 to 13, wherein compound has the formula 344 201388-PCT01-NP . 16. Th e co pou o c a , w erein the compound has the formula . 17. The compound of claim 8, wherein the compound has the formula 5 . 18. The compound of claim 9, wherein the compound has the formula 345 201388-PCT01-NP . 19. , wherein the compound has the formula . 20. The compound of claim 11, wherein L is –S-(CR3R4)k– and k is 0 or 2. 5 21. The compound of claim 11, wherein L is –S-(CR3R4)k-CR3=CR3–. 22. The compound of claim 21, wherein m is 1. 23. The compound of claim 11, wherein L is–(CR3R4)n-S, or –S-(CR3R4)n-O–. 24. The compound of claim 23, wherein n is 1. 25. The compound of claim 11, wherein L is –S-(CR3R4)-C(O) –. 10 26. The compound of claim 25, wherein R3 and R4 are H. 27. The compound of any one of claims 1 to 10, wherein L is –(CH2)j-CR3R4–, –(CR3R4)k- CR3=CR3–, – CR3aR4a-CR3R4–, or –(CH2)-NR3–. 28. The compound of claim 27, wherein j is 1 or m is 1. 346 201388-PCT01-NP 29. The compound of any one of claims 1 to 10, wherein L is –(CR3R4)n-O–, or –O- (CR3R4)j-. 30. The compound of claim 29, wherein R3 and R4 are not H. 31. The compound of claim 29 or 30, wherein j is 1. 5 32. The compound of claim 29, wherein n is 2. 33. The compound of any one of claims 1 to 32, wherein R1 is C1-3 alkyl or C1-3 haloalkyl. 34. The compound of claim 33, wherein R1 is propyl or isopropyl. 35. The compound of claim 33, wherein R1 is hydroxymethyl or ethyl optionally substituted with one hydroxy. 10 36. The compound of any one of claims 1 to 32, wherein R1 is C3-6 cycloalkyl. 37. The compound of claim 36, wherein R1 is cyclopropyl, cyclobutyl, or cyclopentyl. 38. The compound of any one of claims 1 to 32, wherein R1 is C3-6 branched alkyl or C3-6 branched haloalkyl. 39. The compound of claim 38, wherein R1 is isopropyl. 15 40. The compound of claim 38, wherein R1 is isobutyl. 41. The compound of any one of claims 1 to 32, wherein R1 is -C1-3 alkyl-C3-6 cycloalkyl. 42. The compound of claim 41, wherein R1 is -methyl-C3-6 cycloalkyl. 43. The compound of claim 42, wherein R1 is -methyl-cyclopropyl, -methyl-cyclobutyl, or - methyl-clyclopentyl. 20 44. The compound of any of claims 1 to 43, wherein R11 is H. 45. The compound of any one of claims 1 to 44, wherein R2 is 347 201388-PCT01-NP . 46. The compound of claim 45, wherein Ra is C1-3 alkyl. 47. The compounds of any one of claims 1 to 44, wherein R2 is . 5 48. The compound of claim 47, wherein Ra is methyl. 49. The compound of claim 47, wherein Ra is C1-3 haloalkyl. 50. The compound of claim 47, wherein Ra is C1-3 haloalkyl is trifluoromethyl. 51. The compound of claim 47, wherein Ra is C1-3 alkylphenyl, C1-3 carbocycle or S- heterocyclyl. 10 52. The compound of claim 51, wherein the C1-3 alkylphenyl is methylphenyl. 53. The compound of claim 51, wherein the C1-3 carbocyclyl is cyclopropyl. 54. The compounds of claim 51, wherein the S-hetercycyl is tetrahydrothiophene. 55. The compounds of any one of claims 1 to 44, wherein R2 is . 15 56. The compound of claim 55, wherein each Rb is independently C1-3 alkyl or H. 57. The compound of claim 55, wherein both Rb is H. 348 201388-PCT01-NP 58. The compound of claim 55, wherein one Rb is H, and one Rb is C1-3 alkyl-N-(CH2)2. 59. The compounds of any one of claims 1 to 44, wherein R2 is . 60. of claim 59, wherein the B is tetrahydro oxazine, piperazinyl, 5 . 61. one o 2 f claims 1 to 44, wherein R is . 62. T he compound of claim 61, wherein Rc is methyl. 63. The compounds of any one of claims 1 to 44, wherein R2 is 10 . 64. The compound of any one of claims 1 to 63, wherein X is A. 65. The compound of claim 64, wherein A is phenyl. 66. The compound of claim 64, wherein A is a 4-6 membered heterocyclyl. 67. The compound of claim 66, wherein the 4-6 membered heterocyclyl is dithiolyl, thianyl,15 thiolanyl, oxetanyl, azetidinyl, thetanyl, tetrahydrofuranyl, dioxanyl, pyrrolinyl, piperidinyl. 349 201388-PCT01-NP 68. The compound of claim 64, wherein A is a 4-6 member cycloalkyl. 69. The compound of claim 68, wherein the 4-6 member cycloalklyl is cyclobutyl, cyclopentyl, or cyclohexyl. 70. The compound of claim 64, wherein A is a monocyclic heteroaryl. 5 71. The compound of claim 70, wherein the monocyclic heteroaryl is pyridinyl, pyrimidinyl, purinyl, furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazinyl, oxazinyl, or pyranyl, 72. The compound of claim 64, wherein A is a bicyclic heteroaryl. 73. The compound of compound of claim 72, wherein the bicyclic heteroaryl comprises benzofuranyl, benzothiophenyl, chromanyl, chromenyl, purinyl, indolyl, quinazolinyl, 10 pteridinyl, or pyrrolizinyl. 74. The compound of any one of claims 1 to 73, wherein p is 0. 75. The compound of any one of claims 1 to 73, wherein p is 1, 2 or 3 and R5 is independently selected from halo, hydroxy, and oxo. 76. The compound of claim 75, wherein R5 is halo, oxo or hydroxy and p is 1. 15 77. The compound of claim 75, wherein R5 is halo, oxo or hydroxy and p is 2. 78. The compound of claim 75, wherein R5 is F and p is 1 or 2. 79. The compound of claim 75, wherein one R5 is F and one R5 is Cl. 80. The compound of claim 75, wherein R5 is oxo and p is 1 or 2. 81. The compound of any one of claims 1 to 75, wherein R5 is independently selected from20 C1-3 alkyl, C1-3 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -C1-4alkoxy-C1-3alkyl, -C1- 3hydroxyalkyl, -CN, -(CH2)qR8, -C(O)R8, -C(O)OR9, and -OC(O)R9. 350 201388-PCT01-NP 82. The compound of any one of claims 1 to 75, wherein R5 is independently selected from - (CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, -NR6C(O)R7, -NO2, -NR6R7, -S(O)2R6, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, 83. The compound of any one of claims 1 to 82, wherein R3 and R4 are independently 5 methyl. 84. The compound of any one of claims 1 to 82, wherein R3 and R4 are independently H. 85. The compound of any one of claims 1 to 82, wherein R3a and R4a are independently methyl. 86. The compound of any one of claims 1 to 82, wherein R3a and R4a are independently H. 10 87. The compound of claim 1, selected from any of the compounds in Table 1 and pharmaceutically acceptable salts thereof. 88. The compound of claim 1, selected from the following compounds: 24 28 201388-PCT01-NP 35 77 and pharmaceutically acceptable salts thereof. 89. The compound of claim 1, selected from one of the following compounds: 1 24 201388-PCT01-NP 69 70 F F 353 201388-PCT01-NP 139 148 90. e compoun o c a m , se ecte rom any o t e compoun s n a e an pharmaceutically acceptable salts thereof. 91. A pharmaceutical composition comprising a compound of any one of claims 1 to 90 and a 5 pharmaceutically acceptable excipient. 92. A compound of any one of claims 1 to 90 or a pharmaceutical composition of claim 91, for use in the treatment of cardiovascular disease. 93. The compound or composition of claim 92, wherein the cardiovascular disease is non- ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with 10 autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. 94. A method of treating cardiovascular disease administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound or 15 composition of any one of claims 1 to 92. 354 201388-PCT01-NP 95. The method of claim 94, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, 5 or heart failure with preserved ejection fraction. 355
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