2, 4, 6-trisubstituted 1, 3, 5-triazines as modulators of CX3CR1

Abstract

Disclosed are certain 2, 4, 6-trisubstituted 1, 3, 5-triazine compounds # imgabs0 # and pharmaceutically acceptable salts thereof of formula (I), as well as compositions containing them and their use in therapy. The compounds are modulators of CX3CR1 and thus are particularly useful in the treatment or prevention of cardiovascular disorders such as non-ischemic dilated cardiomyopathy and heart failure.

Description

[0001] Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 417,472, filed on October 19, 2022, which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] Chemokines play an important role in immune and inflammatory responses in a variety of diseases and conditions, including cardiovascular and respiratory diseases such as asthma, atherosclerosis and allergic diseases, as well as autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, lupus nephritis and inflammatory myopathies. These secreted small molecules are a growing superfamily of 8kDa-14kDa proteins characterized by a conserved cysteine ​​motif. Currently, the chemokine superfamily includes four groups that exhibit characteristic structural motifs; CXC, CC and CX 3 -C and XC families. The CXC and CC families have sequence similarity and are distinguished from each other based on a single amino acid insertion between the NH-proximal pair of cysteine ​​residues. 3 The -C family is distinguished from the other two families based on having a three 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.

[0004] CXC chemokines include several potent chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

[0005] CC chemokines include potent chemoattractants for monocytes, lymphocytes, and neutrophils.

[0006] CX 3 -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 monocytes, T cells, NK cells and mast cells. It also acts as an adhesion molecule on immunocompetent cells (such as monocytes and other cells) for cell infiltration from blood to tissues. Blocking the interaction has been shown to reduce atherosclerosis progression and plaque growth (Poupel et al., Arterioscler. Thromb. Vasc. Biol., 2013, 33, 2297-2305). In humans, CX 3CR1 and fractalkine are expressed in early and late atherosclerosis (Stolla et al., PLOS one 2012 (https: / / doi.org / 10.1371 / journal.pone.0043572) and Pucci et al., BioMed Res Int 2013 (http: / / dx.doi.org / 10.1155 / 2013 / 451349).

[0007] Fractalkine neutralization improves cardiac function in a murine myocardial infarction (MI) model by enhancing contractile function, ventricular remodeling, and reducing infarct size (Xuan et al. 2011, Cardiovascular Research 92, 385) and improves LVEF and survival at 2 weeks post-treatment after induction of MI in mice (Gu et al. 2015, Exp Physiol 100, 805).

[0008] In addition, fractalkine causes a cardiodepressant effect with impaired contractility observed in murine cardiomyocytes (Taube et al. 2013, PLOS ONE 8(7) (https: / / doi.org / 10.1371 / journal.pone.0069832)). Human serum soluble FKN (sFKN) levels are associated with NYHA heart failure functional class, with elevated soluble fractalkine levels in patients with HF (Husberg et al., J. of Mol. and Cellular Cardiology, 2008, 45(2), 261). sFKN concentration has prognostic value in patients with acute myocardial infarction treated with primary percutaneous coronary intervention (Xu Bing et al., Cytokine 2019 113(365 - 370). Elevated plasma sFKN levels are predictors of mortality in subjects with advanced systolic HF (Richter et al., 2012, Thrombosis & Haemostasis 108, 1220).

[0009] Studies have demonstrated that the actions of chemokines are mediated by a subfamily of G protein-coupled receptors, which include those named 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 CX 3 CR1 (for the C-X 3Receptors of the -C family. These receptors represent good targets for drug development because agents that modulate these receptors will be useful for treating disorders and diseases such as those mentioned above.

[0010] WO2005 / 070903 discloses certain triazine derivatives for treating chemokine-mediated diseases and disorders.

[0011] WO2006 / 107258 discloses certain 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives as CX 3 CR1 receptor antagonists.

[0012] WO2006 / 107257 and WO2009 / 120140 disclose certain 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidin-2(3H)-one derivatives as CX 3 CR1 receptor antagonists.

[0013] WO2013039057 discloses certain pyrrolidin-3-ylacetic acid derivatives that have inhibitory pathways in the fractalkine-CX 3 CR1 pathway.

[0014] Thus, the association of CX 3 CR1 activity with disease involves cardiovascular diseases (CVD), including those related to heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, stable coronary artery disease, and atherosclerotic disorders.

[0015] There is a need for orally active modulators of CX 3 CR1 for treating cardiovascular diseases (CVD), such as those related to heart failure, cardiomyopathy, and coronary artery disease. Detailed Description

[0016] Definition

[0017] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0018] The term "alkyl" or "alkane" is a fully saturated straight-chain or branched-chain non-aromatic hydrocarbon. Examples of straight-chain and branched-chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl.

[0019] The term "alkoxyalkyl" refers to an alkyl group attached to an alkoxy group, wherein the group is attached to the remainder of the molecule via a carbon on the alkyl group, i.e., a group having the structure -R-O-R', where R and R' are the same or different alkyl groups.

[0020] The term "aryl" refers to an aromatic hydrocarbon. The term aryl includes monocyclic aryls having a single ring, such as phenyl, and polycyclic aryls, including "bicyclic aryls" having two or more cyclic rings, where two or more atoms are common to two adjacent rings, where at least one ring is aromatic, such as the other ring being cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Examples of polycyclic aryl rings include naphthalene and tetrahydronaphthalene.

[0021] The term "cycloalkyl" refers to a partially or fully saturated monocyclic, bicyclic, polycyclic, or bridged hydrocarbon ring system.

[0022] The term "halogen" means fluorine, chlorine, bromine, and iodine. In one embodiment, the halogen is fluorine or chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is chlorine.

[0023] The term "haloalkoxy" means an alkoxy in which one or more hydrogens are replaced by a halogen.

[0024] The term "haloalkyl" means an alkyl group in which one or more hydrogens are replaced by a halogen.

[0025] As used herein, the terms "heteroaryl" and "heteroarylene" refer to substituted or unsubstituted aromatic ring structures, the ring structures of which contain at least one heteroatom selected from nitrogen, oxygen, and sulfur. Heteroaryl and heteroarylene groups can be attached to the remainder of the molecule via a carbon or nitrogen ring member atom. Heteroaryl / heteroarylene groups include monocyclic heteroaryls as well as polycyclic heteroaryls, such as bicyclic heteroaryls having two or more cyclic rings, where two or more atoms are common to two adjacent rings, where at least one ring is aromatic and at least one ring contains at least one heteroatom selected from nitrogen, oxygen, and sulfur. Examples of monocyclic heteroaryls or heteroarylenes include, but are not limited to, pyrrole, pyridine, pyrazine, pyridazine, pyrimidine, furan, triazole, thiophene, imidazole, iso azole, azole, diazole, thiazole, and pyrazole. Examples of bicyclic heteroaryls include, but are not limited to, purine, indole, indazole, quinoline, quinazoline, benzofuran, benzo azole, benzodioxolane, benzodioxane, pyrrolopyridine, indazole, 2H-indazole, isoquinoline, tetrahydroisoquinoline, dihydroquinazoline, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydrobenzo[d] Oxazoles, 3,4-dihydroquinazolines, 3,4-dihydro-2H-pyrido[3,2-b][1,4]

[0026] The term "monocyclic N-heteroaryl" refers to a monocyclic heteroaryl whose ring structure contains at least one nitrogen. Examples of monocyclic N-heteroaryl include, but are not limited to, imidazole, pyrrole, triazole, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0027] The term "heterocycle", "heterocyclic", or "heterocyclic group" refers to a partially or fully saturated hydrocarbon ring system in which at least one ring carbon atom is replaced by a heteroatom independently selected from nitrogen, oxygen, and sulfur. The heterocyclic group can be attached to the rest of the molecule via a carbon or nitrogen ring member atom. Heterocycles 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 is oxazolidine.

[0028] The term "hydroxy" refers to the -OH group.

[0029] The term "hydroxyalkyl" means an alkyl group in which one or more hydrogens are replaced by hydroxy groups.

[0030] The term "oxo group" refers to the "=O" group, i.e., a substituted oxygen atom that is attached to another atom by a double bond.

[0031] In this specification, in terms such as "C x-y alkyl" etc. (where x and y are integers), the prefix C x-y indicates the numerical range of carbon atoms present in the group. Examples of suitable C 1-3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl. Examples of suitable C 1-4 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In some cases, the group will have two instances of C x-y In this case, the prefix indicates the numerical range of carbon in each part of the group. For example, C 1-3 alkoxy-C 1-4 alkyl refers to an alkoxyalkyl group in which the alkyl group has 1 to 3 carbons and the alkoxy group has 1 to 4 carbons.

[0032] Compound

[0033] One embodiment disclosed herein provides a compound of formula (I)

[0034]

[0035] or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof,

[0036] wherein

[0037] R 1 is a C 3-6 branched alkyl or a C 3-6 branched haloalkyl;

[0038] R 2 is a C 1-3 alkyl or a C 1-3 haloalkyl;

[0039] m is 1 or 2;

[0040] R 3 and R 4 are independently selected from H, a halogen, C 1-3 alkyl and C 1-3 haloalkyl;

[0041] A is phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl;

[0042] p is 0, 1, 2, 3 or 4;

[0043] each R 5 is independently selected from a halogen, hydroxy, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkoxy-C 1-3 alkyl, C 1-3 hydroxyalkyl, -CN, -(CH 2 ) q CN, -C(O)NR 6 R 7 、-NS(O)R 6 R 7 、-(CH 2 ) q R 8 、-C(O)R 8 、-C(O)OR 9 、-OC(O)R 9 、-NR 6 C(O)R 7 、-NR 6 R 7 、C 3-6 cycloalkyl, 4- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl and phenyl,

[0044] wherein

[0045] the C 3-6 cycloalkyl or 4-6 membered heterocyclic group may optionally be substituted with 1 to 3 substituents selected from hydroxy, oxo, halo and -C(O)OR 9 .

[0046] the 4-6 membered heteroaryl may optionally be substituted with 1 to 3 halo substituents

[0047] the C 1-4 alkoxy may optionally be substituted with a 4-6 membered heterocyclic group

[0048] each R 6 and R 7 is independently selected from H and C 1-3 alkyl

[0049] each q is independently 1, 2 or 3

[0050] each R 8 is independently a 4-6 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with oxo, and

[0051] each R 9 is independently C 1-5 alkyl

[0052] Another embodiment disclosed herein provides a compound having the following structure:

[0053]

[0054] wherein R 1 , R 2 , R 3 , R 4 , R 5 , m, p and A are as defined above for formula (I).

[0055] Another embodiment disclosed herein provides a compound having the following structure:

[0056]

[0057] wherein R 1 , R 2 , R 3 , R 5 , m, p and A are as defined above for formula (I).

[0058] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is phenyl.

[0059] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is a monocyclic heteroaryl.

[0060] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is a monocyclic N - heteroaryl.

[0061] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is a 6 - membered monocyclic heteroaryl.

[0062] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is pyridyl.

[0063] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is pyrimidine.

[0064] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is pyrazine.

[0065] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is phenyl or a 6 - membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is para to the ring atom to which the compound is attached (e.g., R 5 is located relative to R 3 -R4 -substituted para to the carbon-bonded ring atom).

[0066] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is phenyl or a 6-membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is located ortho to the ring atom to which the compound is attached (e.g., R 5 is located ortho to R 3 -R 4 -substituted carbon-bonded ring atom).

[0067] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein A is phenyl or a 6-membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is located meta to the ring atom to which the compound is attached (e.g., R 5 is located meta to R 3 -R 4 -substituted carbon-bonded ring atom).

[0068] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least one R 5 is a halogen group.

[0069] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least one R 5 is F.

[0070] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least two R 5 are F.

[0071] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least three R5 It is F.

[0072] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R 5 is Cl.

[0073] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least two R 5 is Cl.

[0074] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R 5 is C 1-4 alkoxy.

[0075] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R 5 is -OCH 3 .

[0076] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R 5 is -OCH 2 CH 3 .

[0077] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R 5 is C 1-4 haloalkoxy.

[0078] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or stereoisomers, pharmaceutically acceptable salts or tautomers thereof, wherein at least one R5 is C 1 -C 3 alkyl.

[0079] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least one R 5 is methyl.

[0080] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein at least one R 5 is hydroxy or C 1 -C 3 hydroxyalkyl.

[0081] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein one of R 3 or R 4 is C 1-3 alkyl.

[0082] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein one of R 3 or R 4 is methyl.

[0083] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein one of R 3 or R 4 is ethyl.

[0084] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein one of R 3 or R 4 is H.

[0085] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 4 is H.

[0086] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 3 or R 4 is a halogen group.

[0087] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 1 is C 3-6 branched alkyl.

[0088] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 1 is C 4 branched alkyl.

[0089] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 1 is -CH 2 CH(CH 3 ) 2 .

[0090] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 2 is C 1-3 alkyl.

[0091] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R 2 is methyl.

[0092] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein p is 1, 2 or 3.

[0093] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein p is 1.

[0094] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein p is 2.

[0095] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein p is 3.

[0096] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein m is 1.

[0097] Some embodiments disclosed herein provide a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein m is 2.

[0098] Some embodiments disclosed herein provide a compound selected from the following:

[0099] N-(4-((R)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0100] N-(4-((S)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0101] N-(4-((R)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0102] N-(4-((S)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0103] N-(4-((R)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0104] N-(4-((S)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0105] N-(4-((R)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0106] N-(4-((S)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0107] N-(4-((R)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0108] N-(4-((S)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0109] N-(4-((R)-2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0110] N-(4-((S)-2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0111] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0112] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0113] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0114] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0115] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0116] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0117] N-(4-((R)-2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0118] N-(4-((S)-2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0119] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0120] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0121] N-(4-((R)-2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0122] N-(4-((S)-2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0123] N-(4-((R)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0124] N-(4-((S)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0125] N-(4-((R)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0126] N-(4-((S)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0127] N-(4-((R)-2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0128] N-(4-((S)-2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0129] N-(4-((R)-2-(4-Chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0130] N-(4-((S)-2-(4-chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0131] N-(4-((R)-2-(4-chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0132] N-(4-((S)-2-(4-chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0133] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0134] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0135] N-(4-((R)-2-(4-chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0136] N-(4-((S)-2-(4-chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0137] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0138] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0139] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0140] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0141] N-(4-((R)-2-(4-Chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0142] N-(4-((S)-2-(4-Chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0143] N-(4-((R)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0144] N-(4-((S)-2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0145] N-(4-((R)-2-(2,3-Difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0146] N-(4-((S)-2-(2,3-Difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0147] N-(4-(2-(4-Fluoro-6-methoxypyridin-3-yl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0148] N-(4-((R)-2-(6-Aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0149] N-(4-((S)-2-(6-Aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0150] N-(4-((R)-2-(2,6-Dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0151] N-(4-((S)-2-(2,6-Dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0152] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(piperazin-1-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0153] N-(4-(2-(4-(Cyanomethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0154] N-(4-(2-(3-Fluoro-4-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0155] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0156] N-(4-(2-(3-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0157] N-(4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)acetamide

[0158] N-(4-(2-(1H-Indol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0159] N-(4-(2-(benzo[d] oxazol-6-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0160] N-(4-(2-(benzo[d] N-(4-(2-(4-(1H-1,2,3-triazol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0161] N-(4-(2-(4-((dimethyl(oxo)-l 6 -sulfinyl)amino)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0162] N-(4-(2-(4-(1H-1,2,3-triazol-1-yl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0163] N-(4-((R)-2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0164] N-(4-((S)-2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0165] N-(4-(2-(2-ethoxypyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0166] N-(4-(2-(4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0167] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(methoxymethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0168] N-(4-(2-(3,4-dimethylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0169] N-(4-(2-(4-(1,1-difluoroethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0170] N-(4-(2-(3-chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0171] N-(4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)-N-methylacetamide

[0172] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(trifluoromethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0173] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0174] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0175] N-(4-((R)-2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0176] N-(4-((S)-2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0177] N-(4-((R)-2-(4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0178] N-(4-((S)-2-(4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0179] N-(4-((R)-2-(2-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0180] N-(4-((S)-2-(2-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0181] N-(4-((R)-2-(4-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0182] N-(4-((S)-2-(4-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0183] N-(4-((R)-2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0184] N-(4-((S)-2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0185] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0186] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0187] N-(4-(2-(2-Fluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0188] N-(4-((R)-2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0189] N-(4-((S)-2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0190] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0191] N-(4-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0192] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methylpyridin-4-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0193] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(morpholinomethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0194] N-(4-(2-(3,4-Dimethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0195] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(8-methoxyquinolin-5-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0196] N-(4-(2-(3-Chloro-4-ethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0197] N-(4-(2-(2-Fluoro-3-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0198] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d] oxazol-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0199] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-((3-oxoiso oxazolidin-2-yl)methyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0200] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0201] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(quinolin-8-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0202] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0203] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0204] N-(4-(2-(2,3-dimethyl-2H-indazol-6-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0205] N-(4-(2-(5-chloro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0206] N-(4-(2-(benzo[d][1,3]dioxol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0207] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0208] N-(4-(2-(3,5-difluoro-4-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0209] N-(4-(2-(4-fluoro-3-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0210] N-(4-(2-(4-aminophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0211] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0212] N-(4-(2-(3-amino-4-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0213] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(2-morpholinoethoxy)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0214] 2-fluoro-4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)-N,N-dimethylbenzamide,

[0215] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0216] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(3-oxomorpholino)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0217] N-(4-(2-(4-ethoxy-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0218] 2-fluoro-4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)-N-methylbenzamide,

[0219] N-(4-(2-(3-aminophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0220] N-(4-(2-(4-Fluoro-3-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0221] N-(4-(2-(4-Ethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0222] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0223] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4] azin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0224] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0225] N-(4-(2-(6-(Difluoromethoxy)pyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0226] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0227] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] azin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0228] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0229] N-(4-(2-(5-Amino-6-methylpyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0230] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-(2-hydroxyethyl)pyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0231] N-(4-(2-(3-Fluoro-4-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0232] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(quinolin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0233] N-(4-(2-(3-Fluoro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0234] N-(4-(2-(4-Amino-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0235] N-(4-(2-(3-Chloro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0236] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(2-morpholinoethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0237] N-(4-(2-(2-Hydroxy-3-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0238] N-(4-(2-(3-Fluoro-4-isopropoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0239] N-(4-(2-(4-cyano-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0240] N-(4-(2-(4-fluoro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0241] N-(4-((R)-2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0242] N-(4-((S)-2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0243] N-(4-((R)-2-(2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0244] N-(4-((S)-2-(2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0245] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0246] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0247] N-(4-((R)-2-(5-chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0248] N-(4-((S)-2-(5-chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0249] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide, and their pharmaceutically acceptable salts and tautomers.

[0250] Some embodiments disclosed herein provide compounds selected from:

[0251] (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-methyl-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0252] (R)-N-(4-(3-(4-chlorophenyl)-3,3-difluoropropyl)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0253] (R)-N-(4-(3,3-difluoro-3-(4-fluorophenyl)propyl)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0254] N-(4-(2-(3-fluoro-6-methylpyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0255] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(morpholine-4-carbonyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0256] N-(4-(2-([1,1'-biphenyl]-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0257] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-(1-hydroxycyclopropyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0258] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-isopropoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0259] N-(4-(2-(3-Fluoro-2-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0260] N-(4-(2-(3-Cyano-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0261] N-(4-(2-(4-Fluoro-2-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0262] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-oxodihydroindol-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0263] N-(4-((R)-2-(4-Cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0264] N-(4-((S)-2-(4-Cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0265] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-2-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0266] N-(4-(2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0267] N-(4-(2-([1,1'-Biphenyl]-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0268] N-(4-(2-(3-Chloro-4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0269] N-(4-((R)-2-(4-chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0270] N-(4-((S)-2-(4-chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and pharmaceutically acceptable salts and tautomers thereof.

[0271] Some embodiments disclosed herein provide compounds selected from:

[0272] N-(4-(2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0273] N-(4-(2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0274] N-(4-(2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0275] N-(4-(2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0276] N-(4-(2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0277] N-(4-(2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0278] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0279] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0280] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0281] N-(4-(2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0282] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0283] N-(4-(2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0284] N-(4-(2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0285] N-(4-(2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0286] N-(4-(2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0287] N-(4-(2-(4-Chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0288] N-(4-(2-(4-Chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0289] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0290] N-(4-(2-(4-Chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0291] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0292] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide,

[0293] N-(4-(2-(4-Chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0294] N-(4-(2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0295] N-(4-(2-(2,3-Difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0296] N-(4-(2-(6-Aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0297] N-(4-(2-(2,6-Dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0298] N-(4-(2-(3-Chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0299] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0300] N-(4-(2-(2,6-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0301] N-(4-(2-(4-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0302] N-(4-(2-(2-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0303] N-(4-(2-(4-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0304] N-(4-(2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0305] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0306] N-(4-(2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0307] N-(4-(2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0308] N-(4-(2-(2-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0309] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0310] N-(4-(2-(5-chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and their pharmaceutically acceptable salts and tautomers.

[0311] Some embodiments disclosed herein provide compounds selected from:

[0312] N-(4-(-2-(4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0313] N-(4-(2-(4-chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and their pharmaceutically acceptable salts and tautomers.

[0314] Some embodiments disclosed herein provide a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0315] For the avoidance of doubt, it should be understood that in this specification, when a group is limited by "as defined above", the group encompasses the first and broadest definition and each and all other definitions of the group. It should be understood that any definition, claim, aspect or embodiment of a variable group in a formula disclosed herein may be combined with any other definition, claim, aspect or embodiment herein (unless the context does not permit) to provide further embodiments of this specification.

[0316] It should be noted that any one of these specific compounds may be excluded from any one of the embodiments mentioned herein.

[0317] In one embodiment, there is provided a method for preparing a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and intermediates for preparing them.

[0318] Another embodiment is a product obtainable by any method or example disclosed herein.

[0319] Medical and pharmaceutical uses

[0320] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of cardiovascular diseases in mammals, particularly humans. Cardiovascular diseases include, but are not limited to, conditions associated with cardiac dysfunction and / or microvascular dysfunction and / or macrovascular lesions, such as atherosclerosis, arteriosclerosis, coronary artery disease including stable and high-risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or defined by biomarkers of microvascular and cardiac dysfunction), ischemic heart disease, myocardial infarction, restenosis after 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 ischemic attack (TIA) and reversible ischemic neurologic deficit (RIND), multi-infarct dementia, renovascular disease and renal artery disease.

[0321] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of non-ischemic dilated cardiomyopathy.

[0322] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of cardiovascular diseases in patients with comorbidities such as renal dysfunction.

[0323] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of cardiovascular diseases associated with chronic inflammatory diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and inflammatory arthropathy / multisystem diseases such as psoriatic arthritis).

[0324] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for the prevention or treatment of cardiovascular diseases associated with autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and inflammatory arthropathy / multisystem diseases such as psoriatic arthritis).

[0325] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating heart failure, including heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction.

[0326] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating inflammatory bowel disease.

[0327] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating lupus nephritis.

[0328] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating patients at risk of cardiovascular events despite standard of care (SoC) treatment, such as but not limited to lipid-lowering statins, antiplatelets, ACE inhibitors, mineralocorticoid receptor antagonists, and beta blockers.

[0329] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating chronic kidney disease.

[0330] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating type II diabetes and complications of type II diabetes in mammals, particularly humans. This includes but is not limited to diabetic microvascular and macrovascular lesions, neuropathy, and nephropathy.

[0331] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used for preventing or treating nephritic diseases and vascular diseases in mammals, particularly humans, and complications associated with kidney disease. Nephritic diseases and vascular diseases include but are not limited to chronic kidney disease, drug- and toxin-induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephropathy, reflux nephropathy, focal segmental glomerulosclerosis, purpura, and diabetic nephropathy.

[0332] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for preventing or treating autoimmune diseases such as, but not limited to, dermatomyositis, polymyositis and systemic lupus erythematosus (SLE).

[0333] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for preventing or treating non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and ASH (alcoholic steatohepatitis).

[0334] Treatment with compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can reduce the incidence and mortality of cardiovascular and / or cerebrovascular and / or renal and / or peripheral arterial diseases associated with cardiac dysfunction and / or atherosclerosis, and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular lesions due to their anti-inflammatory properties and effects on vascular activation mechanisms.

[0335] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for preventing or reducing the risk of developing cardiac dysfunction and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular lesions, and for stopping or slowing the progression and / or promoting the regression of atherosclerotic cardiovascular disease once it becomes clinically apparent, including administering a prophylactically or therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammal (including a human) at risk of developing atherosclerosis or having atherosclerotic cardiovascular disease.

[0336] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can be used for preventing or reducing the incidence or severity of acute events associated with atherosclerotic plaque rupture or erosion, which acute events include, but are not limited to, myocardial infarction, unstable angina and stroke.

[0337] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used to prevent or reduce the incidence or severity of acute events by improving microvascular function, macrovascular lesions and / or cardiac function.

[0338] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used to prevent or reduce the progression of abdominal aortic aneurysm (AAA) and the incidence of rupture.

[0339] A compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof can be used to prevent or treat respiratory inflammatory diseases and complications associated with respiratory inflammatory diseases in mammals, particularly humans. Respiratory inflammatory diseases include, but are not limited to, asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis.

[0340] Some embodiments disclosed herein provide a method of treating or preventing one or more of the diseases or disorders discussed herein, the method comprising administering to a human having or at risk of having the disease or disorder a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0341] Some embodiments disclosed herein provide a method of treating or preventing non-ischemic dilated cardiomyopathy, the method comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0342] Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease in a patient having a comorbidity such as renal dysfunction, the method comprising administering to a person in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0343] Some embodiments disclosed herein provide a method of treating or preventing cardiovascular diseases associated with chronic inflammatory diseases (such as rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and inflammatory arthropathy / multisystem diseases such as psoriatic arthritis), wherein the method comprises administering to a person in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0344] Some embodiments disclosed herein provide a method of treating or preventing heart failure, wherein the method comprises administering to a person in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

[0345] Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, wherein the method comprises administering to a person in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0346] Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, wherein the method comprises administering to a person in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0347] Some embodiments disclosed herein provide a method of treating or preventing respiratory inflammatory diseases and complications associated with respiratory inflammatory diseases, wherein the method comprises administering to a person in need a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue disease, and / or rhinitis.

[0348] The terms “preventing / prevention / prevent” are readily understood by a ordinarily skilled physician and, with respect to the treatment of a particular disorder, may include their ordinary meaning and include primary prevention which is intended to prevent the development of the disorder and secondary prevention in which the disorder has developed and the patient is temporarily or permanently protected against the progression or exacerbation of the disease or the development of new symptoms associated with the disorder.

[0349] The terms “treating / treatment / treat” are readily understood by a ordinarily skilled physician and, with respect to the treatment of a particular disorder, may include (1) reducing the extent or cause of the disorder being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with the disorder. Treatment of a cardiovascular disease may for example include stabilizing (i.e., not worsening), delaying or slowing the spread or progression of the cardiovascular disease; extending the survival period compared to the expected survival period if left untreated; and / or otherwise improving or alleviating in whole or in part the severity of the cardiovascular disease.

[0350] Compared to compounds known in the prior art, the compounds disclosed herein may have the following advantages: they may be more effective, less toxic, more selective, more potent, produce fewer side effects, be more readily absorbed and / or have better pharmacokinetic properties (e.g., higher oral bioavailability and / or lower clearance rate).

[0351] These and other embodiments are described in more detail below, and other aspects will be apparent to those skilled in the art upon reading this specification.

[0352] Pharmacological properties

[0353] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or compounds disclosed herein or pharmaceutically acceptable salts thereof or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of cardiovascular disorders in mammals, particularly humans, including but not limited to coronary artery disease, acute coronary syndrome, cardiomyopathy, non-ischemic dilated cardiomyopathy, heart failure, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction.

[0354] When the compounds or salts described herein are used to treat a disorder, a “therapeutically effective amount” means an amount sufficient to alleviate or completely relieve the symptoms or other adverse effects of the disorder, cure the disorder, reverse, completely stop or slow the progression of the disorder or reduce the risk of worsening of the disorder.

[0355] Accordingly, the compounds described herein are suitable for the therapeutic and / or prophylactic treatment of these disorders.

[0356] Pharmaceutical composition

[0357] There is provided a method for treating a disorder that requires modulation of CX 3 CR1, the method comprising administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0358] The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a compound disclosed herein or a pharmaceutically acceptable salt thereof will generally be administered in the form of a pharmaceutical formulation comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form, via oral, topical, parenteral, intravenous, intramuscular, subcutaneous or other injectable means, buccal, rectal, vaginal, transdermal and / or nasal routes and / or via inhalation. Depending on the disorder to be treated and the patient and the route of administration, these compositions may be administered in different doses. Conventional methods for the selection and preparation of suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, M.E. Aulton, Churchill Livingstone, 2nd Edition 2002.

[0359] The optimal dose and frequency of administration will depend on the specific disorder being treated and its severity; the type of patient; the age, sex, size and weight, diet and general physical condition of the specific patient; the brain / body weight ratio; other medications the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and other skilled persons in the art.

[0360] According to another aspect, there is thus provided a pharmaceutical formulation comprising a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof, mixed with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0361] The compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a compound disclosed herein or a pharmaceutically acceptable salt thereof may be present in the pharmaceutical formulation at a concentration of from 0.1% to 99.5% (such as from 0.5% to 95%) of the total formulation weight. Another embodiment encompasses a pharmaceutically acceptable salt of a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or a compound disclosed herein.

[0362] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or salts of the compounds disclosed herein may have advantages due to one or more of their chemical or physical properties, such as stability at different temperatures and humidities, or desired solubility in H 2 O, oil or other solvents. In some cases, salts can be used to assist in the separation or purification of the compound. In some embodiments (especially when the salt is intended to be administered to an animal (e.g., a human) or is a reagent for preparing a compound or salt intended to be administered to an animal), the salt is pharmaceutically acceptable.

[0363] The term "pharmaceutically acceptable" is used to characterize moieties (e.g., salts, dosage forms or excipients) suitable for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any harmful effects that the moiety may have. Harmful effects can include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0364] When a compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts. When a compound is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base addition salts.

[0365] For a review of 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.

[0366] It should also be understood that certain compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or the compounds disclosed herein may exist in solvated forms (e.g., hydrates, including solvates of pharmaceutically acceptable salts of compounds of formula (I)).

[0367] It should also be understood that certain compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or the compounds disclosed herein or their pharmaceutically acceptable salts may exist as mixtures of tautomers. "Tautomers" are structural isomers that exist in equilibrium due to the migration of a hydrogen atom, such as amide-imino acid tautomerism. The present disclosure includes all tautomers of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If) or the compounds disclosed herein or their pharmaceutically acceptable salts.

[0368] In certain embodiments, certain compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomeric mixtures. Certain compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may also contain linking bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where rotation about the bond of the particular linking bond is restricted, e.g., due to the presence of ring bonds or double bonds. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization, or stereoisomers can be prepared by stereoselective synthesis.

[0369] If R 3 and R 4 are the same, the compounds of formula (I) below contain one stereocenter, or if R 3 and R 4 are not the same, contain two stereocenters and can thus exist in the following stereoisomeric forms as shown in formula (Ib), (Ic), (Id) or (Ie).

[0370]

[0371]

[0372] Intermediate compounds may also exist in enantiomeric forms and can be used as purified enantiomers, diastereomers, racemates or mixtures.

[0373] In another embodiment, compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, encompass any isotopically labeled (or "radioactively labeled") derivatives of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof. Such derivatives are derivatives of the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, include but are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H,3 H, 11 C, 13 C, 14 C, 15 N, 35 S, 36 Cl and 125 I. The isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those conventional techniques described in the appended Examples using appropriate isotopically labeled reagents in place of the previously employed unlabeled reagents.

[0374] In another embodiment, a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be administered in the form of a prodrug which decomposes in a human or animal body to give a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie) or (If), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0375] Various forms of prodrugs are known in the art. Examples of prodrug derivatives can be found in: Nature Reviews Drug Discovery 2008, 7, 255 and the references cited therein.

[0376] Intermediate compounds can also exist in enantiomeric forms and can be used as purified enantiomers, diastereomers, racemates or mixtures.

[0377] Example

[0378] The following examples are non-limiting examples.

[0379] Synthesis method

[0380] General conditions (i) Operations are carried out at room temperature (rt) (i.e., in the range of 17 °C to 28 °C) and, if required, under an inert gas such as N 2 atmosphere, and optionally the reaction is carried out using an MBRAUN UNILab Plus ECO or MBRAUN UNILab SP Eco glove box workstation, in which case this will be indicated;

[0381] (ii) In cases where the reaction involves degassing or purging, this can be carried out, for example, by purging the reaction solvent with a constant stream of nitrogen for a suitable period of time (e.g., 5 minutes to 10 minutes) or by repeatedly evacuating the vessel and backfilling with an appropriate inert atmosphere (e.g., nitrogen (g) or argon (g));

[0382] (iii) In the case where the reaction involves the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry SmithCreator, or CEM Explorer;

[0383] (iv) Generally, monitor the progress of the reaction by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) usually coupled with a mass spectrometer (LCMS).

[0384] (v) If necessary, dry the organic solution over anhydrous MgSO 4 or Na 2 SO 4 , or dry it using a phase separator, and perform the work-up procedure using conventional phase separation techniques. When using a drying agent such as MgSO 4 or Na 2 SO 4 to dry the organic layer, it should be understood that the organic layer is filtered before concentrating the organic layer.

[0385] (vi) Evaporate by rotary evaporation under vacuum or by using a Genevac HT-4 / EZ-2 or Biotage V10;

[0386] (vii) Unless otherwise stated, perform flash column chromatography on normal phase silica using Merck silica gel (Art. 9385) or pre-packed cartridges such as SNAP cartridges (40μm - 63μm silica, 4g - 330g), silica HC D cartridges (20μm, 10g - 100g), Interchim puriFlash TM cartridges (25μm, 4g - 120g), Interchim puriFlash TM cartridges (50μm, 25g - 330g), Grace TM GraceResolv TM silica flash cartridges (4g - 120g) or Agela flash column silica-CS cartridges (80g - 330g), or perform it on reverse phase silica using Agela Technologies C-18 spherical cartridges (20μm - 35μm, 100A, 80g–330g) using a Grace X2 flash system or a similar system manually or automatically;

[0387] (viii) Use an isocratic or gradient mobile phase as described in the experimental section and use one of the following methods to perform preparative reverse-phase HPLC and preparative reverse-phase SFC using standard HPLC and SFC instruments equipped with MS and / or UV-triggered fraction collection instruments, respectively: Preparation method A: Purify the compound by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in H 2 O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation method B: Purify the compound by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in H 2 O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation method C: Purify the compound by preparative HPLC on an unspecified column using a gradient of MeCN in H 2 O / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparation method D: Purify the compound by preparative HPLC on an XBridge TM C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in H 2 O / MeCN / NH 3 (95 / 5 / 0.2) as the mobile phase; Preparation method E: Purify the compound by preparative HPLC on an Xbridge TM C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in H 2 O / NH 3 (0.2%, pH 10) buffer system as the mobile phase; Preparation method F: Purify the compound by preparative HPLC on an XBridge TM C18 ODB column (5 μm, 150 × 19 mm ID) using a gradient of MeCN in H 2 O / NH 3 (0.2%, pH 10) buffer system as the mobile phase; Preparation method G: Purify the compound by preparative HPLC on a Phenomenex Luna Hilic column (5 μm, 250 × 30) using MeOH / NH 3 20 mM as the mobile phase; Preparation method H: Purify the compound by preparative HPLC on a Waters Viridis 2-EP column (5 μm, 250 × 30) using MeOH / NH 3 20 mM as the mobile phase; Preparation method I: By preparative HPLC on an Xbridge TMPurify the compound using a gradient of MeCN in H 2 O / NH 3 (0.2%, pH 10) buffer system as the mobile phase on a C18 ODB column (5 μm, 100×10 mm ID); Preparation method J: Purify the compound by preparative HPLC on an Acquity TM UPC2 BEH column (3.5 μm, 100×3 mm ID) using MeOH / H 2 O / NH 3 (97 mM / 3 mM / 50 mM) buffer system as the mobile phase; Preparation method K: Purify the compound by preparative HPLC on a Virdis TM BEH OBD column (5 μm, 250×30 mm ID) using MeOH / H 2 O / NH 3 (97 mM / 3 mM / 50 mM) buffer system as the mobile phase; Preparation method L: Purify the compound by preparative HPLC on a Virdis TM BEH column (5 μm, 250×30 mm ID) using EtOH / FA 20 mM buffer system as the mobile phase; Preparation method M: Purify the compound by preparative HPLC on a Sunfire TM C18 ODB column (5 μm, 150×30 mm ID) using a gradient of MeCN in FA (0.1 M aqueous solution) buffer system as the mobile phase; Preparation method N: Purify the compound by preparative HPLC on a Sunfire TM C18 ODB column (5 μm, 100×10 mm ID) using a gradient of MeCN in FA (0.1 M aqueous solution) buffer system as the mobile phase; Preparation method O: Purify the compound by preparative HPLC on an XSelect CSH Prep C18OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN in FA (0.1 M aqueous solution) buffer system as the mobile phase; Preparation method P: Purify the compound by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN in FA (0.1 M aqueous solution) buffer system as the mobile phase; Preparation method Q: Purify the compound by preparative SFC on a Waters TM BEH (5 μm, 30×250 mm ID) using EtOH / FA (20 mM) in CO2 as the mobile phase;

[0388] ​​​​​​​​​​​​​​​​​​​​​​​​Collect the relevant fractions, combine and lyophilize or evaporate to obtain the purified compound, or collect the relevant fractions, combine and concentrate under reduced pressure, extract the aqueous layer with DCM or EtOAc, and dry the organic layer over 2 SO 4 or dry using a phase separator, then concentrate under reduced pressure and, if necessary, dry in vacuo to obtain the purified compound;

[0389] (ix) Perform chiral preparative chromatography using HPLC or SFC, respectively, on a standard HPLC or SFC instrument and using an isocratic or gradient run with a mobile phase as described in the Experimental section;

[0390] (x) The yield (where present) is not necessarily the maximum obtainable, and the reaction is repeated when more of the reaction product is required, if needed;

[0391] (xi) In cases where certain compounds are obtained as acid addition salts (e.g., the monohydrochloride or dihydrochloride), the stoichiometry of the salt is based on the number and nature of the basic groups in the compound and the exact stoichiometry of the salt cannot generally be determined, for example, from elemental analysis data;

[0392] (xii) In general, the structure of the end product of formula (I) is confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; use Bruker Avance III 300, 400, 500, and 600 spectrometers (at 300 MHz, 400 MHz, 500 MHz, and 600 MHz, respectively) 1The proton NMR chemical shift values are measured on the δ scale while operating at the H frequency. Experiments are usually recorded at 25 °C. The chemical shifts are given in ppm with the solvent as the internal standard. Protons on heteroatoms such as NH and OH protons are only reported if detected in the NMR and may thus be missing. In some cases, the protons may be masked or partially masked by the solvent peak and are thus either missing and not reported or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives such as dd, doublet of doublets, etc.) have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; qn, quintet; p, pentet. It should be understood that when the NMR spectrum contains residual impurities and / or residual solvent, such cases are not reported unless they partially overlap with the peaks of the intermediate and / or structure of formula (I), in which case the said peaks of the intermediate and / or structure of formula (I) are reported as a multiplet overlapping with the said solvent or impurity and the integration is omitted. In some cases, the structure of the end product of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peaks of the major rotamer are reported. In some cases, the structure of the end product of formula (I) may appear as rotamers in a more equal relationship, in which cases, if the signals of the rotamers partially overlap, the peaks of such rotamers are reported as a multiplet, or if the signals of the rotamers are well separated, the peaks of such rotamers are reported as separate peaks; Electrospray mass spectrometry data are obtained using Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar device, acquiring cationic and anionic data and usually only reporting ions related to the parent structure; High-resolution electrospray mass spectrometry data are obtained using a Waters XEVO qToF mass spectrometer or similar device coupled to Waters Acquity UPLC, acquiring cationic and anionic data and usually only reporting ions related to the parent structure;

[0393] (xiii) The intermediates are not necessarily fully purified, but their structures and purities are evaluated by TLC, analytical HPLC / UPLC and / or NMR analysis and / or mass spectrometry;

[0394] (xiv) Compounds containing asymmetric carbon and / or sulfur atoms are not resolved unless otherwise stated;

[0395] (xv) Generally, the examples and intermediate compounds are named using ChemDraw Professional version 20.1.1.125 or version 21.0.0 from PerkinElmer. ChemDraw Professional version 20.1.1.125 or version 21.0.0 uses the Cahn-Ingold-Prelog (CIP) rules for stereochemistry to generate names for chemical structures and adheres as strictly as possible to the IUPAC rules when generating chemical names. Stereoisomers are distinguished from each other by stereodescriptors cited in the name and are assigned according to the CIP rules.

[0396] ChemDraw optionally uses markers such as ‘&’ and ‘or’ in the illustration of stereocenters to describe the configuration of the stereochemical centers present in the structure. The numbers following the ‘&’ and ‘or’ markers are assigned to each stereocenter present in the structure. The numbers are incremented automatically to indicate that the stereocenters can vary independently of each other.

[0397] Generally, for the chemical structures of examples and intermediates in which there is more than one stereocenter and the stereocenters have a fixed relative configuration, the same number is used after the markers ‘&’ and ‘or’ to indicate that the stereocenters form one group. A third stereocenter present in the same chemical structure that varies independently of the previous stereocenters is represented by a unique new number after the markers ‘&’ and ‘or’.

[0398] Generally, for the chemical structures of examples and intermediates in which the stereocenter contains the marker ‘&’, it means that the configuration of such an example or intermediate at that stereocenter is a mixture of both (R) and (S); and the marker ‘or’ means that the configuration of such an example or intermediate at that stereocenter is (S) or (R). Absolute, unspecified, ‘&’ and ‘or’ stereocenters can all be present in a single structure.

[0399] Generally, for the structures of examples and intermediates in which all stereocenters are designated as ‘&’, the structure is named with the prefix “racemic-”.

[0400] The descriptors (RS) and (SR) are used to denote the general ‘&’ centers of chemical structures with multiple chiral centers, where only some are designated as ‘&’.

[0401] Generally, for the structures of examples and intermediates in which all stereocenters are designated as ‘or’, the structure is named with the prefix “rel-”.

[0402] Descriptors (R*) and (S*) are used to denote the general 'or' centers of chemical structures having multiple chiral centers, where only some are designated as 'or'. It should be understood that embodiments or intermediates having a stereocenter labeled (R*) or (S*) have an absolute configuration at said stereocenter, and when the stereocenter in a compound has been designated as (R*) or (S*), the actual stereochemistry of that particular isomer may be opposite to the label. For example, although in Example 1, the first eluted isomer from the chiral separation of N-(4-(2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Intermediate 6) is named "N-(4-((R*)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide)", it can be N-(4-((R)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-((S)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. Similar to Example 2, the second eluted isomer from the chiral separation of N-(4-(2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Intermediate 6) is named "N-(4-((S*)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide)", which can be N-(4-((S)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-((R)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide. It should be further understood that although Example 1 is shown as

[0403]

[0404] However, the actual structure of Example 1 (i.e., the first eluted isomer) can be

[0405]

[0406] Generally, for chemical structures of examples and intermediates in which the stereocenters present are racemic, no label is assigned to the stereocenters, and the bonds to the stereocenters are drawn as straight bonds.

[0407] Generally, on a given chiral HPLC column and eluent, the label "isomer 1" corresponds to the first eluting isomer, and "isomer 2" corresponds to the second eluting isomer, and is used to distinguish between two isomers containing one or more stereocenters with absolutely unknown configurations;

[0408] (xvi) In addition to those above, the following abbreviations and units are also used:

[0409] Abs anhydrous

[0410] AcOH acetic acid

[0411] Aq aqueous solution

[0412] 9-BBN 9-borabicyclo[3.3.1]nonane

[0413] B 2 pin 2 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)

[0414] tBu tert-butyl

[0415] n-BuLi 1-butyllithium

[0416] t-BuOH tert-butanol

[0417] KOtBu potassium tert-butoxide

[0418] Brine saturated aqueous sodium chloride solution

[0419] Calcd calculated value

[0420] DCM dichloromethane

[0421] DEA diethylamine

[0422] DIPE diisopropyl ether

[0423] DIPEA N-ethyl-N-isopropyl-propan-2-amine

[0424] DMA N,N-dimethylacetamide

[0425] DMF N,N-dimethylformamide

[0426] DMSO dimethyl sulfoxide

[0427] DPEphos (Oxybis(2,1-phenylene))bis(diphenylphosphine)

[0428] e.g. For example

[0429] ESI Electrospray ionization

[0430] Et 2 O Diethyl ether

[0431] EtOAc Ethyl acetate

[0432] EtOH Ethanol

[0433] eq Equivalent

[0434] FA Formic acid

[0435] HPLC High performance liquid chromatography

[0436] IPA 2-Propanol

[0437] HOAc Acetic acid

[0438] HRMS High resolution mass spectrometry

[0439] KOAc Potassium acetate

[0440] LCMS Liquid chromatography mass spectrometry

[0441] MeCN Acetonitrile

[0442] MeMgBr Methylmagnesium bromide

[0443] MeOH Methanol

[0444] MS Mass spectrometry

[0445] MTBE Methyl tert-butyl ether

[0446] 2-MeTHF 2-Methyltetrahydrofuran

[0447] m / z Mass-to-charge ratio

[0448] NaOtBu Sodium tert-butoxide

[0449] NMR Nuclear magnetic resonance

[0450] OAc O(CO)CH 3

[0451] OTf Trifluoromethanesulfonate

[0452] PE Petroleum ether

[0453] Pd / C Palladium on activated carbon

[0454] Pd(dtbpf)Cl2 Dichloropalladium(II) [1,1′-bis(di-tert-butylphosphino)ferrocene]

[0455] Pd 2 dba 3 Bis(tri(dibenzylideneacetone)) dipalladium(0)

[0456] Pd(dppf)Cl 2 Dichloropalladium(II) [1,1′-bis(diphenylphosphino)ferrocene]

[0457] Pd(dppf)Cl 2 ·DCM Dichloropalladium(II) [1,1′-bis(diphenylphosphino)ferrocene] CH 2 Cl 2 (1:1)

[0458] pTsOH p-Toluenesulfonic acid

[0459] [Rh(COD)Cl] 2 Dichlorobis(1,5-cyclooctadiene) dirhodium(I)

[0460] Rt Room temperature

[0461] sat Saturated

[0462] TBDMS tert-Butyldimethylsilyl

[0463] TBDMSCl tert-Butyldimethylsilyl chloride

[0464] TBTU 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate

[0465] TEA Triethylamine

[0466] THF Tetrahydrofuran

[0467] TLC Thin layer chromatography

[0468] UV Ultraviolet

[0469] X-Phos Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine

[0470] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

[0471] Unit

[0472] C Celsius

[0473] g gram

[0474] h hour

[0475] L liter

[0476] M mole per liter

[0477] mg milligram

[0478] MHz megahertz

[0479] min minute

[0480] mL milliliter

[0481] mm millimeter

[0482] mol mole

[0483] mmol millimole

[0484] μm micrometer

[0485] μmol micromole

[0486] μL microliter

[0487] nm nanometer

[0488] ppm parts per million

[0489] General synthesis scheme

[0490] The compound of formula (I) can be formed by reacting a compound of formula (II) in which R 1 and R 2 are as defined in formula (I) and LG 1 is a suitable leaving group such as a halogen or OTf, for example chlorine)

[0491]

[0492] with a coupling partner of formula (III) in which A, R 3 , R 5 and p are as defined in formula (I).

[0493]

[0494] The compounds of formula (II) can also be protected at the hydroxy moiety with a suitable protecting group (e.g., a silyl group such as TBDMS), and suitable methods are known to those skilled in the art (for the introduction and removal of such groups, see “Protective Groups in Organic Synthesis”, 4th Edition, T.W. Greene & P.G.M Wutz, Wiley-Interscience (2007)).

[0495] The compound of formula (III) can be premixed with an organoboron reagent (e.g., 9-BBN dimer or a solution of 9-BBN in an organic solvent such as THF) at room temperature for 1 hour - 24 hours, or at an elevated temperature (e.g., 35 °C to reflux) for 1 hour - 2 hours, and then the compound of formula (II) as defined above is added together with an inorganic salt (e.g., K 3 PO 4 ) or CsOH and a catalytic amount of a palladium source (e.g., Pd(dppf)Cl 2 ·DCM). The resulting reaction mixture is stirred at a temperature in the range of 35 °C to reflux for an extended period (e.g., 2 hours - 48 hours) until the reaction is complete to give the compound of formula (I).

[0496] The compound of formula (II) can be prepared by reacting the compound of formula (V) (wherein R 1 is as defined in formula (I)) and the compound of formula (VI) (wherein R 2 is as defined in formula (I)) with the compound of formula (IV) (wherein LG 1 is as defined in formula (II)) sequentially, as shown in Scheme 1.

[0497] Scheme 1

[0498]

[0499] At -35 °C to -10 °C, a solution of the compound of formula (V) in a suitable organic solvent (such as 2-MeTHF) is added to a solution of (IV) in an organic solvent (such as 2-MeTHF), then at -35 °C to 0 °C, an organic base (such as DIPEA dissolved in an organic solvent (e.g., 2-MeTHF)) is added to the reaction mixture, and the reaction mixture is stirred until complete, and then any solid is filtered. The filtrate is added to a solution of the compound of formula (VI) in an organic solvent (such as DMA) and an inorganic base (e.g., K 2 CO 3) and the reaction mixture is stirred for an extended period of time (e.g., 48 hours) at an elevated temperature (e.g., 70 °C to 80 °C) until the reaction is complete to obtain the compound of formula (II).

[0500] The compounds of formula (IV), (V) and (VI) are commercially available or can be prepared by those skilled in the art in a conventional manner.

[0501] The compound of formula (III) can be prepared from the compounds of formula (VII) or (VIII) and (IX) (wherein A, R 3 、R 5 and p are as defined in formula (I)) according to the method shown in Scheme 2.

[0502] Scheme 2

[0503]

[0504] Method a: The compound of formula (III) can be prepared by a Wittig reaction between the compound of formula (VII) and a suitable salt (such as methyltriphenylphosphonium bromide ) with a suitable base (such as KOtBu or n-BuLi) in an inert solvent (such as Et 2 O or THF). The base and the salt can be premixed in the solvent at -10 °C to 40 °C for 30 minutes to 1 hour, then the compound of formula (VII) is added, and the reaction is maintained at a temperature in the range of room temperature to 50 °C for a reaction time between 1 hour and 24 hours until the reaction is complete to obtain the compound of formula (III).

[0505] Method b: The compound of formula (VIII) can be reacted with the compound of formula (IX) to obtain the compound of formula (III). This reaction can use a catalytic amount of a palladium source (e.g., Pd(dppf)Cl 2 ·DCM or Pd(dtbpf)), in the presence of a base (e.g., an inorganic base such as K 2 CO 3 、Cs 2 CO 3 or CsOH), using an organic solvent (such as THF or 1,4-di ane) and water, and carried out at an elevated temperature (e.g., in the range of 50 °C to 95 °C) for an extended period of time (e.g., 2 hours to 24 hours) until the reaction is complete to obtain the compound of formula (III).

[0506] The compound of formula (VII) can be prepared from the compound of formula (X) (wherein A, R 5and p as defined in formula (I)) and are prepared as shown in Scheme 3.

[0507] Scheme 3

[0508]

[0509] Step 1: A compound of formula (X) can be reacted with a nucleophile (such as a Grignard reagent) containing a suitable R 3 - group (where R 3 is as defined in formula (I)) in an inert solvent (such as Et 2 O) to obtain an alcohol of formula (XI).

[0510] Step 2: A compound of formula (XI) (where A, R 3 , R 5 and p are as defined in formula (I)) can be reacted with a suitable oxidizing agent (such as Dess-Martin periodinane) in an inert solvent to obtain a compound of formula (VII).

[0511] The compound of formula (VII) can also be prepared from a compound of formula (XII) (where A, R 5 and p are as defined in formula (I)) in a two-step sequence as shown in Scheme 4.

[0512] Scheme 4

[0513]

[0514] Step 1: Using a suitable coupling reagent (such as TBTU), in the presence of an organic base (such as DIPEA), and using a solvent (such as DCM), a compound of formula (XII) can be reacted with N,O-dimethylhydroxylamine hydrochloride to obtain the corresponding Weinreb amide of formula (XIII).

[0515] Step 2: A compound of formula (XIII) (where A, R 5 and p are as defined in formula (I)) can be reacted with a nucleophile (such as a Grignard reagent) containing a suitable R 3 - group (where R 3 is as defined in formula (I)) in an inert solvent (such as THF) to obtain a compound of formula (VII).

[0516] Certain compounds of formula (VII), (VIII), (IX), (X), (X1), (XII), and (XIII) are commercially available or can be prepared by those skilled in the art in a conventional manner.

[0517] The compound of formula (I) can be obtained by reacting a compound of formula (XIV) (where A, R1 and R 3 and R 5 and p are as defined in formula (I), and LG 1 is a suitable leaving group such as a halogen or OTf, such as chlorine)

[0518]

[0519] react with a coupling partner of formula (VI) as defined above to form.

[0520] The compound of formula (I) can be prepared by reacting a compound of formula (XIV-a) in which A, R 1 and R 3 and R 4 and R 5 and p are as defined in formula (I), and LG 1 is a suitable leaving group such as a halogen or OTf, such as chlorine)

[0521]

[0522] react with a coupling partner of formula (VI) as defined above to form.

[0523] A catalytic amount of a phosphine ligand (e.g., X-Phos) and a palladium source (e.g., Pd 2 dba 3 ) are premixed in an inert atmosphere in a suitable solvent (such as THF), and then the compound of formula (XIV) or the compound of formula (XIV-a) and the compound of formula (VI) are added together with a base (such as K 2 CO 3 ), and the reaction is carried out in an inert atmosphere at an elevated temperature (e.g., 70 °C) for an extended period of time (such as overnight) until the reaction is complete to obtain the compound of formula (I).

[0524] The compound of formula (XIV) can be prepared by reacting a compound of formula (XV) (which can be a cis or trans isomer or a mixture of both, and in which R 1 and R 3 are as defined in formula (I), and LG 1 is a suitable leaving group such as a halogen or OTf, for example chlorine) and a compound of formula (XVI) in which A, R 5 and p are as defined in formula (I), and B is a boron substance, such as boric acid or a borate ester), as shown in Scheme 5.

[0525] Scheme 5

[0526]

[0527] Using an organic solvent (such as 1,4 - di ane) and water, a catalytic amount of a suitable organometallic catalyst (such as [Rh(COD)Cl] 2 ) is mixed with a compound of formula (XV), a compound of formula (XVI), and a base (such as KOH) at an elevated temperature (e.g., 50 °C to 95 °C) for an extended period of time (e.g., 2 hours to 24 hours) until the reaction is complete, to obtain a compound of formula (XIV).

[0528] The compound of formula (XV) (which can be a cis or trans isomer or a mixture of both) can be prepared by reacting a compound of formula (XVII) (where R 3 is as defined in formula (I) and M is a metal or a metal halide, typically MgBr) and a compound of formula (V) (as defined above) with a compound of formula (IV) (as defined above) in sequence, as shown in Scheme 6.

[0529] Scheme 6

[0530]

[0531] A solution of the compound of formula (XVII) in a suitable organic solvent (e.g., THF) is added to a cold solution of (IV) in an organic solvent (e.g., THF), and the mixture is allowed to reach room temperature over a short period (usually 30 minutes), then cooled, and a solution of the compound of formula (V) in a suitable organic solvent (e.g., THF) and an organic base (such as DIPEA) is added, and the reaction mixture is allowed to reach room temperature over an extended period until completion, to obtain the compound of formula (XV).

[0532] The compounds of formula (XVI) and (XVII) are commercially available or can be prepared by those skilled in the art in a conventional manner.

[0533] The compound of formula (I) can be prepared by reacting a compound of formula (XVIII) (where R 1 , R 2 and R 3 are as defined in formula (I))

[0534]

[0535] with a coupling partner of formula (XVI) as defined above. This reaction can be carried out in a manner similar to the preparation of formula (XIV).

[0536] The compound of formula (XIV) can also be prepared as follows: reacting a compound of formula (XIX) (where A, R 3 , R 5and p are as defined in formula (I), and LG 1 is a suitable leaving group such as a halogen or OTf, e.g., chlorine)

[0537]

[0538] is reacted with a compound of formula (V) as defined above in a suitable solvent (e.g., THF or MeCN) and a base (e.g., K 2 CO 3 ) at room temperature for an extended period of time (e.g., 2 hours to 24 hours) until the reaction is complete to give a compound of formula (XIV).

[0539] The compound of formula (XIX) can be prepared from a compound of formula (XX) (wherein A, R 3 , R 5 and p are as defined in formula (I)) in a two-step sequence as shown in Scheme 7.

[0540] Scheme 7

[0541]

[0542] Step 1: The compound of formula (XX) can be reacted with diphenyl iminodicarboxylate in a suitable solvent (e.g., MeCN) in the presence of a base (such as K 2 CO 3 ) at a temperature in the range from room temperature to 70 °C for an extended period of time (e.g., 2 hours to 24 hours) until the reaction is complete to give a compound of formula (XXI).

[0543] Step 2: The compound of formula (XXI) (wherein A, R 3 , R 5 and p are as defined in formula (I)) can be reacted with a suitable reagent (e.g., an excess of POCl 3 ) at an elevated temperature in the range from 70 °C to reflux, with or without an amine base (such as N,N - diethylaniline) as an additive, for an extended reaction time (e.g., 1.5 hours to 15 hours) until the reaction is complete to give a compound of formula (XIX).

[0544] The compound of formula (XX) as defined above can be prepared from a compound of formula (XXII) (wherein A, R 3 , R 5 and p are as defined in formula (I)) according to the method shown in Scheme 8.

[0545] Scheme 8

[0546]

[0547] Method a: The compound of formula (XX) can be prepared as follows: Add the compound of formula (XXII) to a mixture of AlMe 3 and NH 4 Cl in an inert solvent (such as toluene) at a temperature in the range of 70 °C to 90 °C and for an extended reaction time until the reaction is complete to obtain the compound of formula (XX).

[0548] Method b:

[0549] Step 1: The compound of formula (XXIII) (where A, R 3 、R 5 and p are as defined in formula (I)) can be prepared as follows: Add AcCl to a cold solution of the compound of formula (XXII) in a suitable solvent (such as EtOH) and allow the temperature to reach room temperature over an extended period of time (such as 15 hours to 24 hours).

[0550] Step 2: The compound of formula (XX) can be prepared as follows: Add a cold solution of NH 3 in a solvent (such as MeOH) to the compound of formula (XXIII) and allow the temperature to reach room temperature over an extended period of time (such as 22 hours).

[0551] The compound of formula (XXII) can be prepared from the compound of formula (VII) as defined above in a two-step sequence, as shown in Scheme 9.

[0552] Scheme 9

[0553]

[0554] Step 1: The compound of formula (VII) as defined above can be reacted with a solvent (such as anhydrous EtOH or THF), a suitable phosphonate (such as diethyl cyanomethylphosphonate), and a suitable base (such as NaOtBu or NaH). The base and the phosphonate can be premixed in the solvent for a short period of time, then the compound of formula (VII) is added, and the reaction is maintained at room temperature for a reaction time between 2 hours and 24 hours until the reaction is complete to obtain the compound of formula (XXIV).

[0555] Step 2: The compound of formula (XXIV) (where A, R 3 、R 5 and p are as defined in formula (I)) can be reduced by any of the methods described below;

[0556] Method a: The compound of formula (XXII) can be prepared as follows: React the compound of formula (XXIV) with Pd / C in a hydrogen atmosphere, in an inert solvent (such as EtOAc), at room temperature for an extended period of time until the reaction is complete.

[0557] Method b: The compound of formula (XXII) can be prepared as follows: reacting the compound of formula (XXIV) with NaBH 4 in a suitable solvent (such as MeOH) at room temperature for an extended period of time until the reaction is complete.

[0558] Method c: The compound of formula (XXII) can be prepared as follows: adding the compound of formula (XXIV) to a premixed slurry of diphenylsilane, Cu(OAc) 2 and DPEphos in a suitable solvent (such as toluene) at room temperature and maintaining for an extended period of time until the reaction is complete.

[0559] As shown in Scheme 10, the compound of formula (XIV-a) can be prepared as follows: reacting the compound of formula (XIX-a) (where A, R 3 、R 4 、R 5 and p are as defined in formula (I), and LG 1 is a suitable leaving group such as a halogen or OTf, for example chlorine)

[0560] Scheme 10

[0561]

[0562] with the compound of formula (V) as defined above in a suitable solvent (such as THF or MeCN) and a base (such as K 2 CO 3 ) at room temperature for an extended period of time (such as 2 hours to 24 hours) until the reaction is complete, to obtain the compound of formula (XIV-a).

[0563] The compound of formula (XIX-a) can be prepared from the compound of formula (XX-a) (where A, R 3 、R 4 、R 5 and p are as defined in formula (I)) in a two-step sequence, as shown in Scheme 11.

[0564] Scheme 11

[0565]

[0566] Step 1: The compound of formula (XX-a) can be reacted with diphenyl iminodicarboxylate in a suitable solvent (such as MeCN) in the presence of a base (such as K 2 CO 3) in the presence of, react at a temperature in the range of room temperature to 70 °C for an extended period of time (e.g., 2 hours to 24 hours) until the reaction is complete to obtain a compound of formula (XXI-a).

[0567] Step 2: The compound of formula (XXI-a) (wherein A, R 3 , R 4 , R 5 and p are as defined in formula (I)) can be reacted with a suitable reagent (e.g., an excess of POCl 3 ) in the presence or absence of an amine base (such as N,N-diethylaniline) as an additive at an elevated temperature in the range of 70 °C to reflux for an extended reaction time (e.g., 1.5 hours to 15 hours) until the reaction is complete to obtain a compound of formula (XIX-a).

[0568] The compound of formula (XX-a) as defined above can be prepared from a compound of formula (XXII-a) (wherein A, R 3 , R 4 , R 5 and p are as defined in formula (I)) according to the method shown in Scheme 12.

[0569] Scheme 12

[0570]

[0571] Method a: The compound of formula (XX-a) can be prepared as follows: Add the compound of formula (XXII-a) to a mixture of AlMe 3 and NH 4 Cl in an inert solvent (such as toluene) at a temperature in the range of 70 °C to 90 °C for a continuously extended reaction time until the reaction is complete to obtain a compound of formula (XX-a).

[0572] Method b:

[0573] Step 1: The compound of formula (XXIII-a) (wherein A, R 3 , R 4 , R 5 and p are as defined in formula (I)) can be prepared as follows: Add AcCl to a cold solution of the compound of formula (XXII-a) in a suitable solvent (such as EtOH) and allow the temperature to reach room temperature over an extended period of time (e.g., 15 hours to 24 hours).

[0574] Step 2: The compound of formula (XX-a) can be prepared as follows: Add a cold solution of NH 3 in a solvent (such as MeOH) to the compound of formula (XXIII-a) and allow the temperature to reach room temperature over an extended period of time (e.g., 22 hours).

[0575] Certain compounds of formula (XXII-a) can be prepared from compounds of formula (XXVII-a) (wherein R 3 , R 4 , R 5 , A and p are as defined in formula (I)) in a two-step sequence as shown in Scheme 13.

[0576] Scheme 13

[0577]

[0578] Step 1: Compounds of formula (XXVI-a) can be prepared from compounds of formula (XXVII-a) by reaction with oxalyl chloride and a catalytic amount of DMF in a solvent (such as DCM) at low temperature to room temperature for 30 minutes to 12 hours. The product formed can be reacted with NH3 in a solvent (such as THF) at low temperature for a period of time, usually 1 hour to 24 hours, after concentration under reduced pressure.

[0579] Step 2: Compounds of formula (XXII-a) can be prepared from compounds of formula (XXVI-a) by reaction with PdCl 2 in a solvent (such as a mixture of MeCN and water) at room temperature for 12 hours to 24 hours.

[0580] Compounds of formula (XXII-a) and (XXVII-a) are commercially available or can be prepared by those skilled in the art in a conventional manner (for example, see the method described in Liebigs Annalen 1996, 8, 1289-1294).

[0581] Compounds of formula (I) (wherein A, R 1 , R 2 , R 3 , R 4 , R 5 and p are as defined in formula (I) and m is 2) can be formed by reacting a compound of formula (II) as defined above with a coupling partner of formula (XXV) (wherein A, R 3 , R 4 , R 5 and p are as defined in formula (I)) as shown in Scheme 14.

[0582] Scheme 14

[0583]

[0584] The compound of formula (XXV) can be premixed with an organoboron reagent (such as 9-BBN dimer or a solution of 9-BBN in an organic solvent (such as THF)) at room temperature for 1 hour to 24 hours, or at an elevated temperature (such as 35 °C to reflux) for 1 hour - 2 hours, and then the compound of formula (II) as defined above is added together with an inorganic salt (such as K 3 PO 4 ) or CsOH and a catalytic amount of a palladium source (such as Pd(dppf)Cl 2 ·DCM). The resulting reaction mixture is stirred at a temperature in the range of 35 °C to reflux for an extended period of time (such as 2 hours - 48 hours) until the reaction is complete to obtain the compound of formula (I).

[0585] Scheme 15

[0586]

[0587] The compound of formula (XXV) is commercially available or can be prepared by those skilled in the art in a conventional manner as described in Scheme 11 (for example, see the methods described in J. Org. Chem. 1958, 23, 1658; J. Am. Chem. Soc. 2012, 134, 17470; Angew. Chem. Int. Ed. 2021, 60, 25746).

[0588] Intermediate 1

[0589] (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0590]

[0591] Under a nitrogen atmosphere, 2,4,6-trichloro-1,3,5-triazine (50.0 g, 271.1 mmol) was dissolved in 2-MeTHF (500 mL), and the stirred solution was cooled to -30 °C. A solution of (R)-2-amino-4-methylpentan-1-ol (31.1 g, 265.7 mmol) in 2-MeTHF (125 mL) was added dropwise over about 45 minutes. A thick slurry was obtained, and a solution of DIPEA (47.2 mL, 271.1 mmol) in 2-MeTHF (125 mL) was added at -30 °C over 70 minutes. The reaction mixture was allowed to reach -5 °C over 30 minutes, then filtered and used directly without purification as described below. DMA (875 mL) was added to methanesulfonamide (77.0 g, 813.5 mmol), followed by K 2 CO3 (75.0 g, 542.4 mmol), and the mixture was stirred at 50 °C for 10 minutes, then the above-filtered reaction solution was added during 2 minutes. The reaction mixture was stirred at 75 °C for 48 hours and then allowed to reach room temperature. Water (1 L) was added and the pH was adjusted to about 3 by addition of 6 M HCl. The two phases were separated and the aqueous phase was extracted with 2-MeTHF (2 × 300 mL). The combined organic extracts were washed with saturated NH 4 Cl (aqueous solution) (2 × 500 mL) and concentrated in vacuo. The solid was dissolved in MTBE (250 mL) and the product was extracted with 5% K 2 CO 3 (aqueous solution) (3 × 200 mL). The pH of the aqueous phase was adjusted to about 4 by addition of 6 M HCl and extracted with MTBE (2 × 250 mL). The organic extracts were dried over MgSO 4 and filtered and evaporated to give the title compound as an off-white solid foam (57.4 g, 67%); MS (ESI) m / z [M+H] + 324.2.

[0592] Intermediate 2

[0593] (R)-N-(4-((1-((tert-Butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5-triazin-2-yl)methanesulfonamide

[0594]

[0595] TBDMSCl (1.4 g, 9.3 mmol) and imidazole (1.26 g, 18.5 mmol) were added to a solution of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 1 (1.0 g, 3.1 mmol) in DMF (5 mL). The reaction mixture was stirred at room temperature for 40 minutes and then poured into ice water and extracted with EtOAc (×3). The combined organic phases were washed with water and brine, dried over Na 2 SO 4 and filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (40%-100% EtOAc / heptane) to give the title compound as a colorless viscous oil (1.04 g, 77%); MS (ESI) m / z [M+H] + 438.4.

[0596] Intermediate 3

[0597] (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0598]

[0599] Over a 10-minute period at 0 °C, (E)-prop-1-en-1-ylmagnesium bromide (35.8 mL, 17.9 mmol, 0.5 M solution in THF) was added to a stirred suspension of 2,4,6-trichloro-1,3,5-triazine (3.0 g, 16.3 mmol) in THF (10 mL). The reaction mixture was allowed to reach room temperature over a 30-minute period and then cooled again to 0 °C. A solution of DIPEA (2.98 mL, 17.1 mmol) and (R)-2-amino-4-methylpentan-1-ol (1.91 g, 16.3 mmol) in THF (5 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Water and MTBE were added and the two phases were separated. The aqueous phase was acidified by addition of 1 M HCl and extracted twice with EtOAc. The organic extracts were evaporated and the product was used in the next step without further purification (2.23 g, 51%); MS (ESI) m / z [M+H] + 271.3. NMR showed a mixture of E- and Z-isomers.

[0600] Intermediate 4

[0601] (R,E)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)methanesulfonamide

[0602]

[0603] Under a nitrogen atmosphere, THF (20 mL) was added to (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (2.0 g, 7.39 mmol), methanesulfonamide (0.738 g, 7.76 mmol), Pd 2 dba 3 (271 mg, 0.30 mmol), X-Phos (0.563 g, 1.18 mmol) and K 2 CO 3(2.04 g, 14.8 mmol). The reaction mixture was stirred at 55 °C for 23 h, then water and MTBE were added and the two phases were separated. The organic phase was extracted with water and the pH of the combined aqueous extracts was adjusted to about 6 by adding 1 M HCl. EtOAc was added and the aqueous phase was extracted with EtOAc (×2). The combined organic phases were dried over MgSO 4 and filtered and evaporated, and the residue was purified by silica gel normal phase flash chromatography (EtOAc as eluent) to give the title compound (1.55 g, 64%); MS (ESI) m / z [M+H] + 330.2.

[0604] Intermediate 5

[0605] 1,2-Dichloro-4-(prop-1-en-2-yl)benzene

[0606]

[0607] KOtBu (2.37 g, 21.16 mmol) was added to a stirred suspension of methyltriphenylbromide (7.56 g, 21.16 mmol) in THF (17 mL), and the reaction mixture was stirred at 0 °C for 30 min. A solution of 1-(3,4-dichlorophenyl)ethanone (2.0 g, 10.6 mmol) in THF (10 mL) was added at 0 °C and stirring was continued at room temperature for 48 h.

[0608] The mixture was evaporated to 1 / 3 volume, diluted with EtOAc / heptane and filtered through a silica gel pad. The solvent was evaporated to give the title compound (1.6 g, 81%); 1 H NMR (500 MHz, CDCl 3 ) 2.12 (3H, dd), 5.14 (1H, p), 5.37 (1H, p), 7.28 (1H, dd), 7.38 (1H, d), 7.52 (1H, d).

[0609] Intermediate 6

[0610] N-(4-(2-(3,4-Dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0611]

[0612] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (1.54 mL, 0.77 mmol) was added to 2-dichloro-4-(prop-1-en-2-yl)benzene intermediate 5 (75 mg, 0.40 mmol), and the reaction mixture was stirred at room temperature for 1.5 h. A degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.62 mL, 1.85 mmol) was added, followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (100 mg, 0.31 mmol) and Pd(dppf)Cl 2 ·DCM (37.5 mg, 0.05 mmol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 1 h and then at 40 °C overnight. DCM and water were added, and the aqueous phase was acidified with 3 M HCl and extracted twice with DCM. The combined organic extracts were treated with SiliaMetS thiol, filtered, and evaporated. The residue was dissolved in a small amount of DCM and passed through a silica gel pad and SiliaMetS thiol, eluting with MeOH / EtOAc. The solvent was evaporated, and the residue was purified by preparative HPLC method C (gradient: 20% - 70%) to give the title compound (70 mg, 48%); MS(ESI) m / z [M+H] + 476.2.

[0613] Intermediate 7

[0614] 1-chloro-2-fluoro-3-(prop-1-en-2-yl)benzene

[0615]

[0616] At 0 °C, KOtBu (2.60 g, 23.18 mmol) was added to a stirred suspension of methyltriphenylbromide (8.28 g, 23.18 mmol) in THF (17 mL), and the reaction mixture was stirred at 0 °C for 30 min. A solution of 1-(3-chloro-2-fluorophenyl)ethan-1-one (2.0 g, 11.6 mmol) in THF (10 mL) was added at 0 °C, and stirring was continued at room temperature for 2 days. The mixture was evaporated to 1 / 3 volume, diluted with EtOAc / heptane, and passed through a silica gel pad. The fractions containing the product were evaporated to give the title compound as a colorless oil (1.0 g, 51%); 1 H NMR (500 MHz, CDCl 3) 2.13–2.15 (3H, m), 5.22–5.24 (1H, m), 5.25–5.28 (1H, m), 7.04 (1H, td), 7.19 (1H, ddd), 7.30 (1H, ddd).

[0617] Intermediate 8

[0618] N-(4-(2-(3-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0619]

[0620] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.19 mL, 1.10 mmol) was added to 1-chloro-2-fluoro-3-(prop-1-en-2-yl)benzene intermediate 7 (125 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 1 hour and then refluxed for 15 minutes. An aqueous solution of degassed 3M K 3 PO 4 (0.73 mL, 2.19 mmol) was added, followed by (R)-N-(4-((1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5-triazin-2-yl)methanesulfonamide intermediate 2 (160 mg, 0.37 mmol) and Pd(dppf)Cl 2 ·DCM (44.3 mg, 0.05 mmol). The reaction mixture was stirred at 35 °C under a nitrogen atmosphere for 42 hours. EtOAc and water were added, and the two phases were separated. The aqueous phase was acidified by adding 3M HCl and extracted with EtOAc. The organic extract was evaporated and redissolved in a small amount of DCM / EtOAc (1 / 1) and filtered through a short silica gel column (eluted with DCM / EtOAc). The solvent was evaporated, and the residue was dissolved in EtOH (2 mL) and HCl (0.4 mL), and the solution was stirred at room temperature for 30 minutes. The solvent was evaporated, and the residue was dissolved in DMSO and SiliaMetS thiol was added, stirred for one minute, filtered and purified by preparative HPLC method C (gradient: 20% - 75%) to give the title compound (158 mg, 94%); MS (ESI) m / z [M+H] + 460.3.

[0621] Intermediate 9

[0622] 2,4-Difluoro-1-(prop-1-en-2-yl)benzene

[0623]

[0624] At room temperature, KOtBu (1.44 g, 12.81 mmol) was added to a stirred suspension of methyltriphenylbromide (4.58 g, 12.81 mmol) in Et 2 O (8.0 mL). The reaction mixture was stirred at room temperature for 30 minutes and then at 40 °C for 10 minutes. 1-(2,4-Difluorophenyl)ethan-1-one (1.0 g, 6.4 mmol) was added and stirring was continued at room temperature for 30 minutes, then the reaction mixture was filtered and the solid was washed with Et 2 O. The combined organic extracts were carefully evaporated to about 4 mL (the product is volatile), then purified by silica gel normal phase flash chromatography (Et 2 O as eluent) to give the title compound (990 mg, 100%) containing some residual Et 2 O; 1 1H NMR (500 MHz, CDCl 3 ) 2.01–2.03 (3H, m), 5.08–5.10 (1H, m), 5.11–5.13 (1H, m), 6.65–6.76 (2H, m), 7.12–7.19 (1H, m).

[0625] Intermediate 10

[0626] N-(4-(2-(2,4-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0627]

[0628] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.19 mL, 1.10 mmol) was added to 2,4-difluoro-1-(prop-1-en-2-yl)benzene intermediate 9 (113 mg, 0.73 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then at 50 °C for 20 minutes. A degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.73 mL, 2.19 mmol) was added, followed by (R)-N-(4-((1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5-triazin-2-yl)methanesulfonamide intermediate 2 (160 mg, 0.37 mmol) and Pd(dppf)Cl 2· DCM (44.3 mg, 0.05 mmol). The reaction mixture was stirred at 35 °C for 42 h under a nitrogen atmosphere. EtOAc and water were added, and the two phases were separated. The aqueous phase was acidified to pH 4 with 3 M HCl and extracted with EtOAc. The organic extract was evaporated and redissolved in a small amount of DCM and filtered through a short silica gel column (eluted with DCM / EtOAc). The solvent was evaporated, and the residue was dissolved in EtOH (2 mL) and HCl (0.4 mL), and the solution was stirred at room temperature for 30 min. The solvent was evaporated, and the residue was purified by preparative HPLC method C to give the title compound (92 mg, 57%); MS (ESI) m / z [M+H] + 444.3.

[0629] Intermediate 11

[0630] 3-Fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0631]

[0632] At room temperature, KOtBu (0.663 g, 5.91 mmol) was added to a stirred suspension of methyltriphenylbromide (2.11 g, 5.91 mmol) in Et 2 O (4 mL), and the reaction mixture was stirred at room temperature for 30 min. A solution of 1-(5-fluoro-6-methoxypyridin-3-yl)ethan-1-one (0.50 g, 2.96 mmol) in THF (1.5 mL) was added, and stirring was continued at room temperature for 30 min. The reaction mixture was filtered, and the solid was washed with Et 2 O. The combined filtrates were carefully evaporated (the product is volatile), and the residue was purified by silica gel normal phase flash chromatography (pentane:Et 2 O, 4:1 as eluent) to give the title compound containing some residual solvent (530 mg, 107%); 1 1H NMR (500 MHz, CDCl 3 ) 2.11–2.13 (3H, m), 4.03 (3H, s), 5.08–5.10 (1H, m), 5.30–5.32 (1H, m), 7.45 (1H, dd), 8.01 (1H, d).

[0633] Intermediate 12

[0634] N-(4-(2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0635]

[0636] Under a nitrogen atmosphere, 9-BBN dimer (224 mg, 0.93 mmol) was added to a solution of 3-fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine intermediate 11 (112 mg, 0.67 mmol) in THF (2 mL), and the reaction mixture was stirred at room temperature for 1 h. A degassed solution of 3M K 3 PO 4 (aqueous solution, 0.74 mL, 2.22 mmol) was added, followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (120 mg, 0.37 mmol) and Pd(dppf)Cl 2 ·DCM (44.9 mg, 0.06 mmol). The reaction mixture was diluted with THF (1 mL) and stirred at 35 °C for 15 h. EtOAc and water were added, and the two phases were separated. The aqueous phase was neutralized and extracted with EtOAc several times, and the combined organic extracts were evaporated. The residue was filtered through silica, eluting with DCM, EtOAc, and MeOH. The solvent was evaporated, and the residue was purified by preparative HPLC method C (gradient: 15%-60%). Repurification by silica normal-phase flash chromatography (gradient: 35%-100% EtOAc / MeOH:20 / 1 / DCM as eluent) gave the title compound (33 mg, 20%); MS (ESI) m / z [M+H] + 457.3.

[0637] Intermediate 13

[0638] 3-Chloro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0639]

[0640] KOtBu (0.605 g, 5.39 mmol) was added to methyltriphenyl bromide (1.92 g, 5.39 mmol) in Et 2In a stirred suspension of O (4 mL), the reaction mixture was stirred at room temperature for 30 minutes. A solution of 1-(5-chloro-6-methoxypyridin-3-yl)ethan-1-one (0.50 g, 2.69 mmol) in THF (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes and then filtered. The solid was washed with Et 2 O, and the combined organic extracts were evaporated. The residue was purified by silica gel normal phase flash chromatography (pentane / Et 2 O: 4 / 1 as eluent) to give the title compound as a colorless oil (484 mg, 98%); 1 H NMR (500 MHz, CDCl 3 ) 2.10–2.13 (3H, m), 4.03 (3H, s), 5.07–5.10 (1H, m), 5.30–5.33 (1H, m), 7.74 (1H, d), 8.14 (1H, d).

[0641] Intermediate 14

[0642] N-(4-(2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0643]

[0644] Under a nitrogen atmosphere, 9-BBN dimer (224 mg, 0.93 mmol) was added to a solution of 3-chloro-2-methoxy-5-(prop-1-en-2-yl)pyridine intermediate 13 (122 mg, 0.67 mmol) in THF (2 mL), and the reaction mixture was stirred at room temperature for 1 hour. A degassed solution of 3M K 3 PO 4 (aqueous solution, 0.74 mL, 2.22 mmol) was added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0645] intermediate 1 (120 mg, 0.37 mmol) and Pd(dppf)Cl 2· DCM (44.9 mg, 0.06 mmol). The reaction mixture was diluted with THF (1 mL) and stirred at 35 °C for 15 h. Water and EtOAc were added, and the aqueous phase was neutralized and extracted with EtOAc several times. The combined organic extracts were evaporated and filtered through silica gel, eluting successively with EtOAc, MeOH, and DCM. The solvent was evaporated, and the residue was purified by preparative HPLC method C (gradient: 15% - 60%). Repurification by silica gel normal phase flash chromatography (gradient: 20% - 100% EtOAc / MeOH:20 / 1 / DCM as eluent) gave the title compound (24 mg, 14%); MS (ESI) m / z [M+H] + 473.2。

[0646] Intermediate 15

[0647] 2-Cyclopropyl-5-(prop-1-en-2-yl)pyrimidine

[0648]

[0649] Under a nitrogen atmosphere, a solution of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.04 mL, 5.53 mmol), 5-bromo-2-cyclopropylpyrimidine (1.0 g, 5.02 mmol) in THF (7 mL), and Pd(dppf)Cl 2 (44 mg, 0.06 mmol) was added to a degassed solution of K 2 CO 3 (2.08 g, 15.07 mmol) in water (2 mL). The reaction mixture was stirred at 95 °C overnight. Water and Et 2 O were added, and the two phases were separated. The organic phase was washed with brine and evaporated. The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 50% EtOAc / heptane) to give the title compound (0.95 g, 118%); 1 1H NMR (500 MHz, CDCl 3 ) 1.03–1.14 (4H, m), 2.10–2.13 (3H, m), 2.20–2.26 (1H, m), 5.13–5.15 (1H, m), 5.37–5.39 (1H, m), 8.61 (2H, s).

[0650] Intermediate 16

[0651] N-(4-(2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0652]

[0653] Under a nitrogen atmosphere, 9-BBN dimer (139 mg, 0.57 mmol) was added to a solution of 2-cyclopropyl-5-(prop-1-en-2-yl)pyrimidine intermediate 15 (89 mg, 0.56 mmol) in THF (1.5 mL), and the reaction mixture was stirred at 35 °C for 1 h. An air-free solution of CsOH monohydrate (187 mg, 1.11 mmol) in water (0.3 mL) was added, followed by addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (120 mg, 0.37 mmol) and Pd(dppf)Cl 2 ·DCM (24.0 mg, 0.03 mmol). The reaction mixture was stirred at 35 °C for 15 h, water (1 mL) was added, and the reaction mixture was neutralized by addition of HOAc. EtOAc was added, and the two phases were separated. The aqueous phase was further acidified by addition of dilute HCl and extracted with EtOAc. The aqueous phase was neutralized with NaHCO 3 (aqueous solution) and extracted twice with DCM. The combined organic extracts were evaporated, and the residue was purified by preparative HPLC method C (gradient: 15% - 75%) to afford the title compound (32 mg, 19%); MS (ESI) m / z [M + H] + 450.3.

[0654] Intermediate 17

[0655] 5-Bromo-2-methoxy-4-methylpyridine

[0656]

[0657] Sodium methoxide (30% solution in MeOH, 1.61 mL, 8.59 mmol) was added to a solution of 2,5-dibromo-4-methylpyridine (0.539 g, 2.15 mmol) in MeOH (3.75 mL), and the reaction mixture was heated at 100 °C for 1 h, then at 140 °C for 15 min in a single-mode microwave oven. The solvent was evaporated, and the residue was dissolved in EtOAc and washed with NH 4 Cl (aqueous solution) and brine, dried over Na 2 SO 4Dry and evaporate. The residue was purified by silica gel column flash chromatography (5% EtOAc / heptane as eluent) to afford the title compound as a colorless solid (328 mg, 76%); 1 H NMR (400 MHz, CDCl 3 ) 2.33 (3H, d), 3.89 (3H, s), 6.64 (1H, s), 8.17 (1H, s).

[0658] Intermediate 18

[0659] 2-Methoxy-4-methyl-5-(prop-1-en-2-yl)pyridine

[0660]

[0661] A degassed solution of 5-bromo-2-methoxy-4-methylpyridine intermediate 17 (300 mg, 1.48 mmol) in THF (3 mL) was added to a degassed solution of Cs 2 CO 3 (1.45 g, 4.45 mmol) in water (0.8 mL), followed by the addition of Pd(dppf)Cl 2 ·DCM (22 mg, 0.03 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.45 mL, 2.38 mmol), and the reaction mixture was stirred overnight at 80 °C under a nitrogen atmosphere. EtOAc and water were added. The two phases were separated, and the organic phase was washed with CsOH (aqueous solution) and water, then evaporated. The residue was purified by silica gel column flash chromatography (gradient: 0 - 25% EtOAc / heptane) to afford the title compound as a colorless oil (157 mg, 65%); 1 H NMR (400 MHz, CDCl 3 ) 2.00–2.03 (3H, m), 2.26 (3H, s), 3.91 (3H, s), 4.85–4.89 (1H, m), 5.20–5.24 (1H, m), 6.55 (1H, s), 7.89 (1H, s).

[0662] Intermediate 19

[0663] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0664]

[0665] Under a nitrogen atmosphere, 9-BBN dimer (239 mg, 0.99 mmol) was added to a solution of 2-methoxy-4-methyl-5-(prop-1-en-2-yl)pyridine intermediate 18 (150 mg, 0.92 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 15 minutes, then at 40 °C for 15 minutes, and left overnight at room temperature. A degassed solution of 3M K 3 PO 4 (aqueous solution, 1.03 ml, 3.09 mmol) was added, followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (200 mg, 0.62 mmol) and Pd(dppf)Cl 2 ·DCM (74.9 mg, 0.09 mmol). The reaction mixture was stirred at 35 °C under a nitrogen atmosphere for 15 hours. EtOAc and water were added. The aqueous phase was neutralized and extracted with EtOAc several times. SiliaMetS thiol was added to the combined organic extracts, and the mixture was stirred for a few minutes, filtered through silica, and eluted with EtOAc and MeOH. The filtrate was evaporated, and the residue was purified by preparative HPLC method C (gradient: 15%-60%). Repurification by preparative HPLC method C (gradient: 15%-60%) gave the title compound (42 mg, 15%); MS(ESI) m / z [M+H] + 453.4.

[0666] Intermediate 20

[0667] 2-Methoxy-3-methyl-5-(prop-1-en-2-yl)pyridine

[0668]

[0669] Under a nitrogen atmosphere, a degassed solution of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.75 mL, 3.96 mmol), 5-bromo-2-methoxy-3-methylpyridine (0.50 g, 2.47 mmol) in THF (4.2 mL) and Pd(dppf)Cl 2 ·DCM (36 mg, 0.05 mmol) was added to a degassed solution of Cs 2 CO 3 (2.42 g, 7.42 mmol) in water (1.21 mL). The reaction mixture was stirred at 80 °C for 2 hours. CsOH monohydrate (208 mg, 1.24 mmol) and Pd(dppf)Cl 2· DCM (36 mg, 0.05 mmol), and the reaction mixture was stirred at 80 °C overnight. EtOAc and water were added, and the two phases were separated. The organic phase was washed with CsOH (aqueous solution) and water, and then evaporated. The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 25% EtOAc / heptane) to give the title compound as a colorless oil (200 mg, 50%); 1 H NMR (500 MHz, CDCl 3 ) 2.08–2.17 (3H, m), 2.20 (3H, s), 3.96 (3H, s), 4.99–5.04 (1H, m), 5.26–5.31 (1H, m), 7.47–7.54 (1H, m), 8.06–8.12 (1H, m).

[0670] Intermediate 21

[0671] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0672]

[0673] Under a nitrogen atmosphere, 9-BBN dimer (239 mg, 0.99 mmol) was added to a solution of 2-methoxy-3-methyl-5-(prop-1-en-2-yl)pyridine intermediate 20 (144 mg, 0.88 mmol) in THF (2 mL), and the reaction mixture was stirred at room temperature for 15 minutes, at 35 °C for 15 minutes, and then left at room temperature overnight. A degassed solution of 3M K 3 PO 4 (aqueous solution, 1.03 mL, 3.09 mmol) was added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (200 mg, 0.62 mmol) and Pd(dppf)Cl 2· DCM (49.9 mg, 0.06 mmol). The reaction mixture was stirred at 35 °C for 35 h. EtOAc and water were added, and the aqueous phase was neutralized and the two phases were separated. The aqueous phase was extracted several times with EtOAc, and the combined organic extracts were partially evaporated. SiliaMetS thiol was added and the mixture was stirred for a few minutes. The residue was passed through silica, eluting with EtOAc and MeOH. The filtrate was evaporated and the residue was purified by preparative HPLC method C (gradient: 15% - 60%) to give the title compound (55 mg, 20%); MS (ESI) m / z [M+H] + 453.4

[0674] Intermediate 22

[0675] 2-Methoxy-3-(prop-1-en-2-yl)pyridine

[0676]

[0677] Under a nitrogen atmosphere, a degassed solution of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.00 g, 5.96 mmol), 3-bromo-2-methoxypyridine (0.70 g, 3.72 mmol) in THF (7.2 mL) and Pd(dppf)Cl 2 · DCM (2.72 g, 3.72 mmol) was added to Cs 2 CO 3 (3.64 g, 11.17 mmol) in a degassed solution of water (2.1 mL). The reaction mixture was stirred at 80 °C for 15 h. EtOAc and water were added and the two phases were separated. The organic phase was stirred with NaOH (aqueous solution), washed with water and then evaporated. The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 20% EtOAc / heptane). The fractions containing the product were combined, evaporated and dissolved in Et 2 O and stirred with CsOH (aqueous solution) for 1 h. The two phases were separated and the organic phase was washed with water and brine, dried over MgSO 4 and filtered and evaporated to give the title compound as a colorless oil (165 mg, 30%); 1 H NMR (500 MHz, CDCl 3 ) 2.11 (3H, dd), 3.97 (3H, s), 5.16–5.22 (2H, m), 6.85 (1H, dd), 7.47 (1H, dd), 8.07 (1H, dd).

[0678] Intermediate 23

[0679] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0680]

[0681] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (3.24 mL, 1.62 mmol) was added to 2-methoxy-3-(prop-1-en-2-yl)pyridine intermediate 22 (117 mg, 0.78 mmol). The reaction mixture was stirred overnight at room temperature and then a degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.93 mL, 2.78 mmol) was added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (150 mg, 0.46 mmol) and Pd(dppf)Cl 2 ·DCM (37.5 mg, 0.05 mmol). The reaction mixture was stirred at 38 °C for 20 h under a nitrogen atmosphere. EtOAc and water were added and the two phases were separated. The aqueous phase was acidified with dilute HCl and extracted twice with EtOAc. MgSO 4 and SiliaMetS thiol were added to the combined organic phases and the mixture was stirred for a few minutes and then filtered. The filtrate was evaporated and the residue was purified by preparative HPLC method A (gradient: 15%-60%) to give the title compound (176 mg, 87%); MS (ESI) m / z [M+H] + 439.3.

[0682] Intermediate 24

[0683] (2R)-2-((4-Chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0684]

[0685] Under a nitrogen atmosphere, 1,4-di Alkane (1.11 mL) and water (0.19 mL) were added to the intermediate 3 of (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (70 mg, 0.26 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (132 mg, 0.78 mmol), [Rh(COD)Cl] 2 (6.4 mg, 0.01 mmol) and KOH (43.5 mg, 0.78 mmol). The reaction mixture was stirred at 65 °C for 3.5 h. EtOAc and water were added, and the two phases were separated. The organic layer was washed with brine and evaporated. The residue was purified by preparative HPLC using Method A (gradient: 30%-80%) to give the title compound as a colorless solid (70 mg, 68%); MS (ESI) m / z [M+H] + 397.4.

[0686] Intermediate 25

[0687] N-(4-(2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0688]

[0689] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd 2 dba 3 (6.5 mg, 7.1 μmol) and X-Phos (13.5 mg, 0.03 mmol). The mixture was stirred for 10 min, then a solution of intermediate 24 of (2R)-2-((4-chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (56 mg, 0.14 mmol) in THF (0.75 mL), methanesulfonamide (32 mg, 0.34 mmol) and K 2 CO 3 (44 mg, 0.32 mmol) were added. The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc was added, and the mixture was washed with dilute HCl and brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and filtered and evaporated. The residue was purified by preparative HPLC using Method A (gradient: 30%-80%) to give the title compound as a colorless solid (54 mg, 84%); MS (ESI) m / z [M+H] + 456.4.

[0690] Intermediate 26

[0691] (2R)-2-((4-Chloro-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0692]

[0693] Under a nitrogen atmosphere, (3,4,5-trifluorophenyl)boronic acid (134 mg, 0.76 mmol) was added to a solution of (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (69 mg, 0.25 mmol) in 1,4-di ane (1.1 mL). [Rh(COD)Cl] 2 (6.3 mg, 0.01 mmol), KOH (42.9 mg, 0.76 mmol) and water (0.19 mL) were added, and the reaction mixture was stirred at 65 °C overnight. EtOAc and water were added, and the two phases were separated. The organic extract was washed with brine and evaporated. The residue (combined with two other batches prepared in a similar manner starting from a total of 138 mg of intermediate 3) was purified by preparative HPLC method A (gradient: 30%-90%) to give the title compound as a colorless solid (90 mg, 44% total); MS (ESI) m / z [M+H] + 403.3.

[0694] Intermediate 27

[0695] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0696]

[0697] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd 2 dba 3 (5.1 mg, 5.6 μmol) and X-Phos (10.6 mg, 0.02 mmol). The mixture was stirred for 10 minutes, then a solution of (2R)-2-((4-chloro-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 26 (56 mg, 0.14 mmol) in THF (0.75 mL), methanesulfonamide (30 mg, 0.32 mmol) and K2 CO 3 (39 mg, 0.28 mmol). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc was added, and the mixture was washed with dilute HCl and brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 4, filtered, and evaporated. The residue was purified by preparative HPLC using Method A (gradient: 30% - 80%) to give the title compound as a colorless solid (60 mg, 94%); MS (ESI) m / z [M+H] + 462.4.

[0698] Intermediate 28

[0699] (2R)-2-((4-Chloro-6-(2-(2,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0700]

[0701] Under a nitrogen atmosphere, 1,4-d ane (1.11 mL) and water (0.19 mL) were added to the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (70 mg, 0.26 mmol), (2,5-difluorophenyl)boronic acid (122 mg, 0.78 mmol), [Rh(COD)Cl] 2 (6.4 mg, 0.01 mmol), and KOH (43.5 mg, 0.78 mmol). The reaction mixture was stirred at 50 °C for 3.5 h. EtOAc and dilute HCl were added, the organic phase was washed with water and brine, and evaporated. The residue was purified by preparative HPLC using Method B (gradient: 30% - 80%) to give the title compound as a colorless solid (36 mg, 36%); MS (ESI) m / z [M+H] + 385.3.

[0702] Intermediate 29

[0703] N-(4-(2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0704]

[0705] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd2 dba 3 (3.1 mg, 3.4 μmol) and X-Phos (6.3 mg, 0.01 mmol) in. The mixture was stirred for 10 minutes, then a solution of (2R)-2-((4-chloro-6-(2-(2,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 28 (32 mg, 0.08 mmol) in THF (0.75 mL), methanesulfonamide (17.8 mg, 0.19 mmol) and K 2 CO 3 (23.6 mg, 0.17 mmol) were added. The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc was added and the mixture was washed with dilute HCl and brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 , filtered and evaporated. The residue was purified by preparative HPLC Method A (gradient: 30%-80%) to give the title compound as a colorless solid (29 mg, 79%); MS (ESI) m / z [M+H] + 444.4.

[0706] Intermediate 30

[0707] 2-chloro-4-(prop-1-en-2-yl)pyridine

[0708]

[0709] KOtBu (0.620 g, 5.53 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (1.98 g, 5.53 mmol) in Et 2 O (4 mL), and the reaction mixture was stirred at room temperature for 30 minutes. A solution of 1-(2-chloropyridin-4-yl)ethan-1-one (0.43 g, 2.76 mmol) in Et 2 O (1.5 mL) was added and stirring was continued at room temperature for 30 minutes. The reaction mixture was filtered, the solid was washed with Et 2 O, and the combined filtrates were carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (pentane / Et 2 O: 4 / 1 as eluent) to give the title compound as a colorless oil (350 mg, 82%); 1 1H NMR (400 MHz, CDCl 3)2.11–2.14(3H,m),5.29–5.33(1H,m),5.56–5.60(1H,m),7.25(1H,dd),7.35(1H,dd),8.32(1H,dd).

[0710] Intermediate 31

[0711] N-(4-(2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0712]

[0713] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.16 mL, 1.08 mmol) was added to 2-chloro-4-(prop-1-en-2-yl)pyridine intermediate 30 (89 mg, 0.58 mmol). The reaction mixture was stirred at room temperature overnight, then a degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.62 mL, 1.85 mmol) was added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (100 mg, 0.31 mmol) and Pd(dppf)Cl 2 ·DCM (25.0 mg, 0.03 mmol). The reaction mixture was stirred at 35 °C under a nitrogen atmosphere for 20 h. EtOAc and water were added, and the two phases were separated. The aqueous phase was acidified with dilute HCl and extracted with EtOAc. SiliaMetS thiol was added to the organic phase and stirred for a few minutes, then filtered. The filtrate was collected and evaporated, and the residue was purified by preparative HPLC method A (gradient: 20%-75%). Repurification by preparative HPLC method D (gradient: 0-50%) gave the title compound (23 mg, 17%); 1 1H NMR (500 MHz, CDCl 3 ) 0.88–0.98 (6H, m), 1.21–1.77 (8H, m), 2.85–3.06 (2H, m), 3.29–3.46 (4H, m), 3.54–3.85 (2H, m), 4.15–4.30 (1H, m), 7.15 (1H, dd), 7.24–7.27 (m, overlapping with solvent portion), 8.31 (1H, dd).

[0714] Intermediate 32

[0715] (2R)-2-((4-chloro-6-(2-(6-ethoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0716]

[0717] Under a nitrogen atmosphere, a solution of (6-ethoxypyridin-3-yl)boronic acid (126 mg, 0.75 mmol) and KOH (62.2 mg, 1.11 mmol) in water (0.27 mL) was added to (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (100 mg, 0.37 mmol) in 1,4-di ane (1.58 mL). [Rh(COD)Cl] 2 (9.1 mg, 0.02 mmol) was added, and the reaction mixture was stirred at 70 °C overnight. EtOAc and water were added, and the two phases were separated. The organic extract was washed with brine and evaporated. The residue was purified by preparative HPLC method A (gradient: 40%-100%) to give the title compound as a colorless solid (18 mg, 12%); MS(ESI) m / z [M+H] + 394.4.

[0718] Intermediate 33

[0719] N-(4-(2-(6-ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0720]

[0721] Under a nitrogen atmosphere, THF (0.15 mL) was added to Pd 2 dba 3 (2.1 mg, 2.3 μmol) and X-Phos (4.5 mg, 9.34 μmol). The mixture was stirred for 10 minutes, then a solution of (2R)-2-((4-chloro-6-(2-(6-ethoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 32 (23 mg, 0.06 mmol) in THF (0.50 mL), methanesulfonamide (12.5 mg, 0.13 mmol) and K 2 CO 3(16.5 mg, 0.12 mmol). The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc was added, and the mixture was washed with dilute HCl and brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and filtered and evaporated. The residue was purified by preparative HPLC using Method B (gradient: 25% - 70%) to afford the title compound as a colorless solid (24 mg, 89%); MS (ESI) m / z [M+H] + 453.4.

[0722] Intermediate 34

[0723] (2R)-2-((4-Chloro-6-(2-(5-chloro-2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0724]

[0725] Under a nitrogen atmosphere, 1,4-d ane (1.1 mL) and water (0.12 mL) were added to the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (70 mg, 0.26 mmol), (5-chloro-2-fluorophenyl)boronic acid (135 mg, 0.78 mmol), [Rh(COD)Cl] 2 (6.4 mg, 0.01 mmol) and KOH (43.5 mg, 0.78 mmol). The reaction mixture was stirred at 65 °C for 3.5 h. EtOAc and dilute HCl were added, and the two phases were separated, and the organic phase was washed with water and brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were evaporated, and the residue was purified by preparative HPLC using Method B (gradient: 30% - 80%) to afford the title compound (14.6 mg, 14%); MS (ESI) m / z [M+H] + 401.3.

[0726] Intermediate 35

[0727] N-(4-(2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0728]

[0729] Under a nitrogen atmosphere, THF (0.15 mL) was added to Pd2 dba 3 (1.3 mg, 1.4 μmol) and X-Phos (2.7 mg, 5.6 μmol), and the reaction mixture was stirred for 10 minutes. A solution of (2R)-2-((4-chloro-6-(2-(5-chloro-2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 34 (14.0 mg, 0.03 mmol) in THF (0.50 mL), methanesulfonamide (7.5 mg, 0.08 mmol) and K 2 CO 3 (9.9 mg, 0.07 mmol) were added, and the reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc and dilute HCl were added, and the two phases were separated. The organic phase was washed with brine. The combined aqueous phases were extracted with EtOAc, and the combined organic extracts were evaporated. The residue was purified by preparative HPLC method D (gradient: 25%-70%) to give the title compound as a colorless solid (12.6 mg, 79%); MS (ESI) m / z [M+H] + 460.4.

[0730] Intermediate 36

[0731] (2R)-2-((4-chloro-6-(2-(4-chloro-3,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0732]

[0733] A solution of 2-(4-chloro-3,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (203 mg, 0.74 mmol) and KOH (62.2 mg, 1.11 mmol) in water (0.26 mL) was added to (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (100 mg, 0.37 mmol) in 1,4-di ane (1.58 mL), followed by the addition of [Rh(COD)Cl] 2 (9.1 mg, 0.02 mmol). The reaction mixture was stirred overnight at 70 °C, then EtOAc and water were added. The two phases were separated, and the organic extract was washed with brine and evaporated. The residue was purified by preparative HPLC method A (gradient: 30%-90%) to give the title compound (20 mg, 13%); 1 1H NMR (400 MHz, CDCl3 ) 0.86–0.98 (6H, m), 1.21–1.70 (7H, m), 2.76–2.95 (2H, m), 3.31–3.52 (1H, m), 3.52–3.84 (2H, m), 4.10–4.27 (1H, m), 5.56–5.69 (1H, d), 6.81–6.89 (2H, m).

[0734] Intermediate 37

[0735] N-(4-(2-(4-Chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0736]

[0737] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd 2 dba 3 (4.3 mg, 4.8 μmol) and X-Phos (9.1 mg, 0.02 mmol). The mixture was stirred for 10 minutes and then (2R)-2-((4-chloro-6-(2-(4-chloro-3,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 36 (50 mg, 0.12 mmol) in THF (0.75 mL), methanesulfonamide (26.1 mg, 0.27 mmol) and K 2 CO 3 (33.8 mg, 0.24 mmol) were added. The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc and dilute HCl were added and the two phases were separated. The organic phase was washed with brine and the combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 and filtered and evaporated. The residue was purified by preparative HPLC method A (gradient: 30%-80%) to give the title compound as a colorless solid (25 mg, 44%); MS (ESI) m / z [M+H] + 478.3.

[0738] Intermediate 38

[0739] (2R)-2-((4-Chloro-6-(2-(4-chloro-2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0740]

[0741] Under a nitrogen atmosphere, 1,4-diiodo ethane (3.66 mL) and water (0.41 mL) were added to the intermediate 3 of (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (220 mg, 0.81 mmol), (4-chloro-2,3-difluorophenyl)boronic acid (313 mg, 1.63 mmol), [Rh(COD)Cl] 2 (20 mg, 0.04 mmol) and KOH (91 mg, 1.63 mmol). The reaction mixture was stirred at 50 °C overnight. EtOAc and water were added, and the two phases were separated, and the organic extract was evaporated. The residue was purified by preparative HPLC method A (gradient: 40%-85%) to give the title compound (87 mg, 26%); MS(ESI) m / z [M+H] + 419.3.

[0742] Intermediate 39

[0743] N-(4-(2-(4-chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0744]

[0745] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd 2 dba 3 (7.6 mg, 8.3 μmol) and X-Phos (15.8 mg, 0.03 mmol). The mixture was stirred for 10 minutes, then a solution of intermediate 38 of (2R)-2-((4-chloro-6-(2-(4-chloro-2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (87 mg, 0.21 mmol) in THF (0.75 mL), methanesulfonamide (45.4 mg, 0.48 mmol) and K 2 CO 3 (58.8 mg, 0.43 mmol) were added. The reaction mixture was stirred at 70 °C under a nitrogen atmosphere overnight. EtOAc and dilute HCl were added, and the two phases were separated. The organic phase was washed with brine, and the combined aqueous phase was extracted with EtOAc. The combined organic extracts were dried over MgSO 4 filtered and evaporated. The residue was purified by preparative HPLC method A (gradient: 30%-75%) to give the title compound as a colorless solid (64 mg, 65%); MS(ESI) m / z [M+H]+ 478.4。

[0746] Intermediate 40

[0747] 1,2,4-Trifluoro-5-(prop-1-en-2-yl)benzene

[0748]

[0749] Add Cs 2 CO 3 (4.63 g, 14.22 mmol) in a degassed solution of water (2.38 mL) to a degassed solution of 1-bromo-2,4,5-trifluorobenzene (1.0 g, 4.7 mmol) in THF (8.3 mL), followed by the addition of Pd(dppf)Cl 2 ·DCM (69 mg, 0.09 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.16 mL, 6.16 mmol). Stir the reaction mixture at 70 °C for 20 h, then add MTBE and water. Separate the two phases, and wash the organic extract with water and carefully evaporate (the product is volatile). Purify the residue by silica gel normal-phase flash chromatography (gradient: 0 - 15% Et 2 O / pentane) to give the title compound (0.64 g, 78%); 1 1H NMR (500 MHz, CDCl 3 ) 2.09–2.12 (3H, m), 5.22–5.24 (1H, m), 5.25–5.28 (1H, m), 6.86–6.94 (1H, m), 7.07–7.14 (1H, m).

[0750] Intermediate 41

[0751] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0752]

[0753] Add a solution of 0.5 M 9-BBN in THF (2.96 mL, 1.48 mmol) to a solution of 1,2,4-trifluoro-5-(prop-1-en-2-yl)benzene intermediate 40 (170 mg, 0.99 mmol) in THF (0.5 mL), and stir the reaction mixture at room temperature overnight. Add 3 M K 3 PO 4The degassed solution (aqueous solution, 0.99 mL, 2.96 mmol), followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (160 mg, 0.49 mmol) and Pd(dppf)Cl 2 ·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere, then EtOAc and dilute HCl were added. The two phases were separated, and the organic phase was washed with water and brine. The organic extract was treated with SILIAMES thiol, filtered and dried over MgSO 4 4, filtered and evaporated. The residue was purified by preparative HPLC method A (gradient: 30%-85%). Repurification by silica gel normal-phase flash chromatography (eluting with DCM and EtOAc) gave the title compound (120 mg, 53%); 1 1H NMR (400 MHz, CDCl 3 ) 0.81–0.98 (6H, m), 1.05–1.70 (9H, m), 2.85–3.01 (2H, m), 3.20–3.30 (3H, m), 3.50–4.30 (4H, m), 6.75–7.20 (3H, m).

[0754] Intermediate 42

[0755] 1-chloro-2,5-difluoro-4-(prop-1-en-2-yl)benzene

[0756]

[0757] At 10 °C, KOtBu (1.18 g, 10.49 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (3.75 g, 10.49 mmol) in Et 2 2O (6 mL), followed by the addition of a solution of 1-(4-chloro-2,5-difluorophenyl)ethan-1-one (1.0 g, 5.3 mmol) in Et 2 2O (6 mL). The reaction mixture was stirred overnight at room temperature, then diluted with Et 2 2O and filtered. The filtrate was washed with water, dilute HCl, water and brine, dried over MgSO 4 4, filtered and carefully evaporated (the product is volatile). Pentane was added, and the solid was filtered, and the solvent was evaporated. The residue was purified by silica gel normal-phase flash chromatography (using pentane / EtOAc: 10 / 1 as the eluent) to give the title compound (688 mg, 70%); 1 1H NMR (400 MHz, CDCl3 ) 2.29 (3H, s), 5.47 (2H, s), 7.21–7.35 (2H, m).

[0758] Intermediate 43

[0759] N-(4-(2-(4-Chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0760]

[0761] A solution of 0.5 M 9-BBN in THF (2.78 mL, 1.39 mmol) was added to 1-chloro-2,5-difluoro-4-(prop-1-en-2-yl)benzene intermediate 42 (175 mg, 0.93 mmol), and the reaction mixture was stirred at 70 °C under nitrogen for 1 hour. A degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.93 mL, 2.78 mmol) was then added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (150 mg, 0.46 mmol) and Pd(dppf)Cl 2 ·DCM (56.7 mg, 0.07 mmol). The reaction mixture was stirred at 40 °C under a nitrogen atmosphere overnight, then EtOAc and dilute HCl were added, and the two phases were separated. The organic extract was treated with SILIAMES thiol, filtered and evaporated. The residue was purified by preparative HPLC method E (gradient: 5% - 95%) to give the title compound (99 mg, 48%); MS (ESI) m / z [M+H] + 478.2.

[0762] Intermediate 44

[0763] 2,4,6-Trifluoro-N-methoxy-N-methylbenzamide

[0764]

[0765] N,O-Dimethylhydroxylamine hydrochloride (1.11 g, 11.36 mmol) was added, followed by TBTU (4.38 g, 13.63 mmol), to a solution of 2,4,6-trifluorobenzoic acid (2.0 g, 11.4 mmol) in DIPEA (7.9 mL, 45.4 mmol) and DCM (20.5 mL), and the reaction mixture was stirred at room temperature overnight. DCM and saturated NaHCO3 (aqueous solution), and the two phases were separated. The organic extract was washed with water, dilute HCl, water and brine and evaporated to give the title compound (2.40 g, 96%); 1 H NMR (500 MHz, CDCl 3 ) 3.39 (3H, s), 3.54 (3H, s), 6.67–6.76 (2H, m).

[0766] Intermediate 45

[0767] 1-(2,4,6-Trifluorophenyl)ethan-1-one

[0768]

[0769] A solution of 3M MeMgBr in Et 2 O (11.0 mL, 32.85 mmol) was added dropwise to a cold solution of 2,4,6-trifluoro-N-methoxy-N-methylbenzamide intermediate 44 (2.4 g, 10.95 mmol) in THF (60 mL), and the reaction mixture was stirred at 0 °C for 4 h and at room temperature overnight. 0.5M HCl and Et 2 O were added. The phases were separated, and the organic extract was washed with water and brine, dried over MgSO 4 , filtered and carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (gradient: 0-15% Et 2 O / pentane) to give the title compound as a colorless oil (1.73 g, 91%); 1 H NMR (500 MHz, CDCl 3 ) 2.58 (3H, t), 6.67–6.78 (2H, m).

[0770] Intermediate 46

[0771] 1,3,5-Trifluoro-2-(prop-1-en-2-yl)benzene

[0772]

[0773] KOtBu (1.29 g, 11.49 mmol) was added to methyltriphenyl bromide (4.10 g, 11.49 mmol) in Et 2In a stirred suspension of O (5 mL), THF (1 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes. 1-(2,4,6-Trifluorophenyl)ethan-1-one intermediate 45 (1.0 g, 5.7 mmol) was added, and stirring was continued at room temperature overnight. Pentane was added and the mixture was filtered. The solid was washed with Et 2 O, and the combined filtrates were washed with water and brine and carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 15% Et 2 O / pentane) to give the title compound as a colorless oil (760 mg, 77%); 1 H NMR (400 MHz, CDCl 3 ) 2.04–2.09 (3H, m), 5.06–5.11 (1H, m), 5.39–5.44 (1H, m), 6.59–6.73 (2H, m).

[0774] Intermediate 47

[0775] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0776]

[0777] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.96 mL, 1.48 mmol) was added to a solution of 1,3,5-trifluoro-2-(prop-1-en-2-yl)benzene intermediate 46 (170 mg, 0.99 mmol) in THF (0.5 mL), and the reaction mixture was stirred at 40 °C for 2 hours. Another portion of a solution of 0.5 M 9-BBN in THF (1.98 mL, 0.99 mmol) was added, and stirring was continued at 40 °C for 1 hour. A degassed solution of 3 M K 3 PO 4 (aqueous solution, 1.32 mL, 3.95 mmol) was added, followed by (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (160 mg, 0.49 mmol) and Pd(dppf)Cl 2 ·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred at 40 °C overnight under a nitrogen atmosphere. EtOAc and 3.8 M HCl were added, and the two phases were separated. The organic extract was washed with water and brine, dried over MgSO 4Drying with SILIAMES thiol. The mixture was filtered and evaporated. The residue was purified by preparative HPLC using Method A (gradient: 35% - 75%) to give the title compound (150 mg, 66%); MS (ESI) m / z [M+H] + 462.4

[0778] Intermediate 48

[0779] 2,3,6-Trifluoro-N-methoxy-N-methylbenzamide

[0780]

[0781] N,O-Dimethylhydroxylamine hydrochloride (1.11 g, 11.36 mmol) was added to a solution of 2,3,6-trifluorobenzoic acid (2.0 g, 11.4 mmol) in DIPEA (7.9 mL, 45.4 mmol) and DCM (20.5 mL), followed by the addition of TBTU (4.38 g, 13.63 mmol). The reaction mixture was stirred overnight at room temperature, then DCM and saturated NaHCO 3 (aqueous solution) were added, and the two phases were separated. The organic extract was washed with water, dilute HCl, water, and brine and evaporated to give the title compound (3.60 g, 140%); 1 1H NMR (500 MHz, CDCl 3 ) 3.40 (3H, s), 3.56 (3H, s), 6.85–6.93 (1H, m), 7.14–7.23 (1H, m).

[0782] Intermediate 49

[0783] 1-(2,3,6-Trifluorophenyl)ethan-1-one

[0784]

[0785] A solution of 3M MeMgBr in Et 2 2O (11.0 mL, 32.85 mmol) was added dropwise to a cold solution of 2,3,6-trifluoro-N-methoxy-N-methylbenzamide intermediate 48 (2.4 g, 10.95 mmol) in THF (60 mL), and the reaction mixture was stirred at 0 °C for 3 hours and then at room temperature overnight. 0.5M HCl and Et 2 2O were added. The organic extract was washed with water and brine, dried over MgSO 4 4, filtered, and carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 15% Et 2Purified with O / pentane to obtain the title compound as a colorless oil (1.78 g, 93%); 1 HNMR(500MHz,CDCl 3 ) 2.61 (3H, t), 6.87–6.94 (1H, m), 7.19–7.29 (1H, m).

[0786] Intermediate 50

[0787] 1,2,4-Trifluoro-3-(prop-1-en-2-yl)benzene

[0788]

[0789] KOtBu (1.29 g, 11.49 mmol) was added to a stirred suspension of methyltriphenylbromide (4.10 g, 11.49 mmol) in THF (14.4 mL), and the reaction mixture was stirred at room temperature for 30 minutes. 1-(2,3,6-Trifluorophenyl)ethan-1-one intermediate 49 (1.0 g, 5.7 mmol) was added, and stirring was continued at room temperature overnight. Pentane was added and the mixture was filtered. The solid was washed with pentane, and the combined filtrates were washed with water and brine. The organic extract was filtered again and the filtrate was carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (gradient: 0-15% Et 2 O / pentane) to obtain the title compound as a colorless oil (750 mg, 76%); 1 H NMR(400MHz,CDCl 3 ) 2.07–2.12 (3H, m), 5.11–5.16 (1H, m), 5.43–5.48 (1H, m), 6.75–6.85 (1H, m), 6.96–7.09 (1H, m).

[0790] Intermediate 51

[0791] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0792]

[0793] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.96 mL, 1.48 mmol) was added to a solution of 1,2,4-trifluoro-3-(prop-1-en-2-yl)benzene intermediate 50 (170 mg, 0.99 mmol) in THF (0.5 mL), and the reaction mixture was stirred at 40 °C for 2 h. Another portion of a solution of 0.5 M 9-BBN in THF (1.98 mL, 0.99 mmol) was added, and stirring was continued at 40 °C for 1 h. A degassed solution of 3 M K 3 PO 4 (aqueous solution, 1.32 mL, 3.95 mmol) was added, followed by the addition of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (160 mg, 0.49 mmol) and Pd(dppf)Cl 2 ·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred at 40 °C overnight under a nitrogen atmosphere. EtOAc and 3.8 M HCl were added, and the two phases were separated. The organic extract was washed with water and brine and dried over MgSO 4 . SiliaMetS thiol and silica were added, and the mixture was filtered and evaporated, and the residue was purified by preparative HPLC method A (gradient: 35%-75%). Repurification by preparative HPLC method B (gradient: 15%-65%) gave the title compound (54 mg, 24%); MS (ESI) m / z [M+H] + 462.4.

[0794] Intermediate 52

[0795] 1-(4-chloro-2,6-difluorophenyl)ethan-1-ol

[0796]

[0797] Under a nitrogen atmosphere, a solution of 3 M MeMgBr in Et 2 O (5.66 mL, 16.99 mmol) was added dropwise to a stirred ice-cold solution of 4-chloro-2,6-difluorobenzaldehyde (2.0 g, 11.33 mmol) in Et 2 O (32.1 mL). The reaction mixture was allowed to reach room temperature over a 4 h period, then an NH 4 Cl solution (aqueous solution, 10%) was added. The mixture was acidified by the addition of 3.8 M HCl. The two phases were separated, and the organic extract was washed with water and brine, dried over MgSO 4 , filtered and evaporated to give the title compound (1.0 g, 46%);1 H NMR (400 MHz, CDCl 3 ) 1.61 (3H, d), 2.19 (1H, br s), 5.20 (1H, p), 6.87–6.97 (2H, m).

[0798] Intermediate 53

[0799] 1-(4-Chloro-2,6-difluorophenyl)ethan-1-one

[0800]

[0801] Dess-Martin periodinane (2.42 g, 5.71 mmol) was added to a solution of 1-(4-chloro-2,6-difluorophenyl)ethan-1-ol intermediate 52 (1.0 g, 5.19 mmol) in DCM (51.9 mL), and the reaction mixture was stirred overnight at room temperature. NaHCO 3 (aqueous solution, 20 mL) was added, and the reaction mixture was stirred vigorously for 2 h, then filtered. The solid was washed with DCM, and the two phases were separated. The organic extract was washed with NaHCO 3 (aqueous solution), Na 2 S 2 O 5 (aqueous solution), water, and brine. The organic extract was evaporated, and the residue was purified by silica gel normal-phase flash chromatography (heptane / EtOAc: 10 / 1 as eluent) to give the title compound (0.87 g, 88%); 1 H NMR (400 MHz, CDCl 3 ) 2.58 (3H, t), 6.95–7.04 (2H, m).

[0802] Intermediate 54

[0803] 5-Chloro-1,3-difluoro-2-(prop-1-en-2-yl)benzene

[0804]

[0805] At 10 °C, KOtBu (1.03 g, 9.13 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (3.26 g, 9.13 mmol) in Et 2 O (6 mL), followed by addition of a solution of 1-(4-chloro-2,6-difluorophenyl)ethan-1-one intermediate 53 (1.0 g, 5.3 mmol) in Et 2 O (6 mL). The reaction mixture was stirred overnight at room temperature, then with Et 2Dilute and filter. Wash the filtrate with water, dilute HCl, water and brine, dry over MgSO 4 and filter, and carefully evaporate (the product is volatile). Add pentane, filter the solid, and evaporate the solvent. Purify the residue by silica gel normal phase flash chromatography (pentane / EtOAc: 10 / 1 as eluent) to give the title compound (315 mg, 37%); 1 1H NMR (400 MHz, CDCl 3 ) 2.05–2.08 (3H, m), 5.08–5.12 (1H, m), 5.42 (1H, p), 6.87–6.97 (2H, m).

[0806] Intermediate 55

[0807] N-(4-(2-(4-Chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0808]

[0809] Add a solution of 0.5 M 9-BBN in THF (2.78 mL, 1.39 mmol) to 5-chloro-1,3-difluoro-2-(prop-1-en-2-yl)benzene intermediate 54 (175 mg, 0.93 mmol), and stir the reaction mixture at 70 °C for 1 h under a nitrogen atmosphere. Add a degassed solution of 3 M K 3 PO 4 (aqueous solution, 0.926 mL, 2.78 mmol), then add (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (150 mg, 0.46 mmol) and Pd(dppf)Cl 2 ·DCM (56.7 mg, 0.07 mmol), and stir the reaction mixture at 40 °C overnight under a nitrogen atmosphere. Add EtOAc and dilute HCl, and separate the two phases. Acidify the aqueous phase with 3.8 M HCl and extract with EtOAc. Treat the combined organic extracts with SiliaMetS thiol and dry over MgSO 4 . Filter the mixture, evaporate the filtrate, and purify the residue by preparative HPLC method E (gradient: 5% - 95%) to give the title compound (59 mg, 27%); MS(ESI) m / z [M+H] + 478.2.

[0810] Intermediate 56

[0811] 5-Bromo-4-fluoro-2-methoxypyridine

[0812]

[0813] A solution of dibromide (56.6 g, 354.0 mmol) in HOAc (100 mL) was added dropwise over 15 minutes to a solution of 4-fluoro-2-methoxypyridine (30.0 g, 236.0 mmol) in HOAc (150 mL), and the reaction mixture was stirred overnight at room temperature. EtOAc and water were added, followed by Na 2 S 2 O 5 (aqueous solution) until the bromine color disappeared, and the two phases were separated. The aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with 2M NaOH and water, dried over MgSO 4 4, filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (heptane / EtOAc: 10 / 1 as eluent) to give the title compound as a colorless oil which solidified on standing (25.6 g, 53%); 1 1H NMR (500 MHz, CDCl 3 ) 3.93 (3H, s), 6.52 (1H, d), 8.23 (1H, d).

[0814] Intermediate 57

[0815] 4-Fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0816]

[0817] Under a nitrogen atmosphere, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (27.4 ml, 145.6 mmol) was added to 5-bromo-4-fluoro-2-methoxypyridine intermediate 56 (25.0 g, 121.4 mmol), K 2 2 3 CO 2 3 (41.9 g, 303.4 mmol) and Pd(dtbpf)Cl 2 2 (4.75 g, 7.28 mmol) in a mixture of THF (240 mL) and water (60 mL). The reaction mixture was stirred at 50 °C for 2 hours and then allowed to reach room temperature. Water and Et 2 2O were added, and the two phases were separated. The aqueous phase was extracted with Et 4Dry, filter and evaporate. Purify the residue by silica gel normal phase flash chromatography (heptane / MTBE: 20 / 1 as eluent) to afford the title compound as an oil (17.1 g, 84%); 1 H NMR (500 MHz, CDCl 3 ) 2.10–2.12 (3H, m), 3.94 (3H, s), 5.19–5.21 (1H, m), 5.22–5.24 (1H, m), 6.42 (1H, d), 8.10 (1H, d).

[0818] Intermediate 58

[0819] N-(4-(2-(4-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0820]

[0821] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (7.41 mL, 3.71 mmol) was added to 4-fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine intermediate 57 (341 mg, 2.04 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (600 mg, 1.85 mmol), Pd(dppf)Cl 2 ·DCM (151 mg, 0.19 mmol) and K 3 PO 4 (1.57 g, 7.41 mmol), and the reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 1 h. Water and EtOAc were added, and the two phases were separated. The organic extract was washed with water and brine. The combined aqueous phases were acidified by addition of 1 M HCl and extracted with EtOAc (×3). The combined organic extracts were dried over MgSO 4 , filtered and evaporated. Purify the residue by silica gel normal phase flash chromatography (EtOAc as eluent) to afford the title compound (498 mg, 59%); MS (ESI) m / z [M+H] + 457.4.

[0822] Intermediate 59

[0823] 1-(But-1-en-2-yl)-2,3-difluorobenzene

[0824]

[0825] KOtBu (523 mg, 4.66 mmol) was added to a solution of methyltriphenylbromide (1.47 g, 4.10 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature for 30 minutes and then added to a solution of 1-(2,3-difluorophenyl)propan-1-one (635 mg, 3.73 mmol) in THF (2 mL). The reaction mixture was stirred at room temperature for 2 hours and then water and pentane were added. The two phases were separated and the aqueous phase was extracted with pentane. The combined organic extracts were washed with water, dried over MgSO 4 and filtered and carefully evaporated (the product is volatile). The residue was purified by silica gel normal phase flash chromatography (pentane as eluent) to give the title compound as a colorless oil (233 mg, 37%); 1 1H NMR (500 MHz, CDCl 3 ) 1.05 (3H, t), 2.44–2.51 (2H, m), 5.15–5.18 (1H, m), 5.24–5.28 (1H, m), 6.96–7.12 (3H, m).

[0826] Intermediate 60

[0827] N-(4-(2-(2,3-Difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0828]

[0829] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.97 mL, 1.48 mmol) was added to 1-(but-1-en-2-yl)-2,3-difluorobenzene intermediate 59 (125 mg, 0.74 mmol). The reaction mixture was stirred at room temperature for 1 hour and then added to (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (240 mg, 0.74 mmol), Pd(dppf)Cl 2 ·DCM (60.5 mg, 0.07 mmol) and K 3 PO 4(629 mg, 2.96 mmol). The reaction mixture was stirred at 50 °C for 2.5 h under a nitrogen atmosphere, then water and EtOAc were added. The two phases were separated, and the organic extract was washed with water and brine. The combined aqueous phases were acidified by adding 1 M HCl, and the aqueous phases were extracted with EtOAc (×3). The combined organic extracts were dried over MgSO 4 and filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (EtOAc as the eluent) to give the title compound (75 mg, 22%); MS (ESI) m / z [M + H] + 458.3.

[0830] Intermediate 61

[0831] 2-(But-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0832]

[0833] Under a nitrogen atmosphere, 1,4-d ane (10 mL) was added to B 2 pin 2 (4.51 g, 17.78 mmol), KOAc (4.36 g, 44.44 mmol) and Pd(dppf)Cl 2 ·DCM (0.968 g, 1.19 mmol). A solution of 2-bromobut-1-ene (2.0 g, 14.81 mmol) in d ane (5 mL) was added, and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled, then water and Et 2 O were added, and the two phases were separated. The organic extract was dried over MgSO 4 and filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (pentane / MTBE: 20 / 1 as the eluent) to give the title compound as a colorless oil (0.68 g, 25%); 1 1H NMR (500 MHz, CDCl 3 ) 1.01 (3H, t), 1.27 (12H, s), 2.13–2.20 (2H, m), 5.60 (1H, s), 5.72–5.77 (1H, m).

[0834] Intermediate 62

[0835] 5-(But-1-en-2-yl)-4-fluoro-2-methoxypyridine

[0836]

[0837] Under a nitrogen atmosphere, 2-(but-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane intermediate 61 (610 mg, 3.35 mmol) was added to 5-bromo-4-fluoro-2-methoxypyridine (575 mg, 2.79 mmol), K 2 CO 3 (964 mg, 6.98 mmol) and Pd(dtbpf)Cl 2 (182 mg, 0.28 mmol) in a mixture of water (1.5 mL) and THF (6 mL). The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was allowed to reach room temperature, then water and Et 2 O were added, and the two phases were separated. The aqueous phase was extracted with Et 2 O, and the combined organic extracts were washed with water, dried over MgSO 4 , filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (heptane / MTBE: 20 / 1 as eluent). The fractions containing the product were combined and repurified by silica gel normal phase flash chromatography (heptane / MTBE: 25 / 1 as eluent) to give the title compound as a colorless oil (172 mg, 34%); 1H NMR (500 MHz, CDCl 3 ) 1.04 (3H, t), 2.44 (2H, q), 3.94 (3H, s), 5.11–5.15 (1H, m), 5.18–5.21 (1H, m), 6.41 (1H, d), 8.04 (1H, d).

[0838] Intermediate 63

[0839] (5-(prop-1-en-2-yl)pyridin-2-yl)carbamic acid tert-butyl ester

[0840]

[0841] Under a nitrogen atmosphere, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.24 mL, 6.59 mmol) was added to (5-bromopyridin-2-yl)carbamic acid tert-butyl ester (1.50 g, 5.49 mmol), K 2 CO 3 (1.90 g, 13.73 mmol) and Pd(dtbpf)Cl 2 (0.358 g, 0.55 mmol) in a mixture of water (3 mL) and THF (12 mL). The reaction mixture was stirred at 60 °C for 1.5 h, then water and Et 2O, and separate the two phases. The aqueous phase was extracted with Et 2 O, and the combined organic extracts were washed with water, dried over MgSO 4 , filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (heptane / MTBE: 10 / 1 as eluent) to give the title compound as a colorless solid (514 mg, 40%); 1 1H NMR (500 MHz, CDCl 3 ) 1.54 (9H, s), 2.11–2.15 (3H, m), 5.06–5.09 (1H, m), 5.33–5.36 (1H, m), 7.75 (1H, dd), 7.91 (1H, d), 8.12 (1H, br s), 8.37 (1H, d).

[0842] Intermediate 64

[0843] (5-(1-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(methylsulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)pyridin-2-yl)carbamic acid tert-butyl ester

[0844]

[0845] Under a nitrogen atmosphere, a solution of 0.5 M 9-BBN in THF (2.47 mL, 1.24 mmol) was added to (5-(prop-1-en-2-yl)pyridin-2-yl)carbamic acid tert-butyl ester intermediate 63 (139 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 1 h, then added to (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (160 mg, 0.49 mmol), Pd(dppf)Cl 2 ·DCM (40.4 mg, 0.05 mmol) and K 3 PO 4 (420 mg, 1.98 mmol) under a nitrogen atmosphere, and the reaction mixture was heated to 50 °C for 2 h. Water and EtOAc were added. The two phases were separated, and the organic phase was extracted with water. The combined aqueous extracts were acidified to pH 5 with 1 M HCl, then extracted with EtOAc (×3). The combined organic extracts were dried over MgSO 4 , filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (gradient: 0-10% MeOH / EtOAc) to give the title compound (125 mg, 48%); MS (ESI) m / z [M+H] + 524.4.

[0846] Intermediate 65

[0847] N-(4-(2-(6-Aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0848]

[0849] A solution of 4M HCl in di ane (2.0 mL, 8.0 mmol) was added to tert-butyl (5-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)pyridin-2-yl)carbamate intermediate 64 (105 mg, 0.20 mmol), and the reaction mixture was stirred at 40 °C for 1 h. Et 2 O was added to precipitate the product and the solvent was decanted. Another portion of Et 2 O was added to wash the solid. The solid residue was dried in vacuo to give the title compound as the HCl salt (107 mg, 100% if 3HCl); MS (ESI) m / z [M+H] + 424.3.

[0850] Intermediate 66

[0851] 2,6-Dimethoxy-3-(prop-1-en-2-yl)pyridine

[0852]

[0853] 3-Bromo-2,6-dimethoxypyridine (1.0 g, 4.59 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.38 mL, 7.34 mmol), K 2 CO 3 (1.90 g, 13.76 mmol), and Pd(dppf)Cl 2 (40 mg, 0.06 mmol) were added to 1,4-di ane (7 mL) and water (2 mL). The reaction mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. Another portion of Pd(dppf)Cl 2(40 mg, 0.06 mmol), followed by the addition of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.89 mL, 4.76 mmol), and stirring was continued at 100 °C until the reaction was complete. Add Et 2 O and water, and the two phases were separated. The aqueous phase was extracted with Et 2 O, and the combined organic extracts were evaporated. The residue was purified by silica gel normal-phase flash chromatography (gradient: 1% - 7% EtOAc / heptane) to give the title compound as an oil (190 mg, 23%); 1 1H NMR (500 MHz, CDCl 3 ) 2.08–2.10 (3H, m), 3.92 (3H, s), 3.96 (3H, s), 5.10–5.14 (1H, m), 5.17–5.20 (1H, m), 6.27 (1H, d), 7.44 (1H, d).

[0854] Intermediate 67

[0855] N-(4-(2-(2,6-Dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0856]

[0857] Under a nitrogen atmosphere, 9-BBN dimer (44.8 mg, 0.18 mmol) was added to 2,6-dimethoxy-3-(prop-1-en-2-yl)pyridine (31.4 mg, 0.18 mmol) intermediate 66 (31.4 mg, 0.18 mmol) dissolved in Et 2 O (1 mL), and the reaction mixture was stirred at room temperature for 45 minutes. Add a degassed solution of 3M K 3 PO 4 (aqueous solution, 0.274 ml, 0.82 mmol), followed by the addition of (R)-N-(4-((1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5-triazin-2-yl)methanesulfonamide intermediate 2 (60 mg, 0.14 mmol) and Pd(dppf)Cl 2· DCM (16.6 mg, 0.02 mmol). The reaction mixture was stirred overnight at 35 °C under a nitrogen atmosphere, then EtOAc and water were added. The mixture was acidified with dilute HCl and the two phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine and evaporated. The residue was dissolved in EtOH (2 mL) and concentrated HCl (0.4 mL) was added, and the mixture was stirred at room temperature for 1 hour, then the solvent was evaporated. The residue (combined with two other batches prepared in a similar manner starting from a total of 176 mg of Intermediate 2) was purified by preparative HPLC Method A (gradient: 20% - 65%) to give the title compound (57.0 mg, 30% total); MS (ESI) m / z [M+H] + 469.4.

[0858] Intermediate 68

[0859] tert-Butyl 4-(4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)piperazine-1-carboxylate

[0860]

[0861] A solution of Intermediate 3 (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (45 mg, 0.17 mmol) in 1,4-d ane (1.5 mL) and 4 M KOH solution (aqueous, 83 μL, 0.33 mmol), followed by [Rh(COD)Cl] 2 (4.1 mg, 0.01 mmol) was added to (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (51 mg, 0.17 mmol), and the reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad and evaporated to give the crude title compound (yield assumed to be quantitative), which was used in the next step without further purification; MS (ESI) m / z [M+H] + 533.5.

[0862] Intermediate 69

[0863] tert-Butyl 4-(4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methylsulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)piperazine-1-carboxylate

[0864]

[0865] Add THF (0.3 mL) to Pd 2 dba 3 (10.6 mg, 0.01 mmol) and X-Phos (22 mg, 0.05 mmol), and stir the mixture at room temperature under a nitrogen atmosphere for 10 minutes. Add a solution of tert-butyl 4-(4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)piperazine-1-carboxylate intermediate 68 (90 mg, 0.17 mmol) in THF (1 mL), a solution of methanesulfonamide (55 mg, 0.58 mmol) in THF (0.5 mL), and K 2 CO 3 (82 mg, 0.59 mmol), and stir the reaction mixture at 70 °C overnight. Add EtOAc and water. Acidify the mixture with 3.8 M HCl and separate the two phases. Extract the aqueous phase with EtOAc, and dry the combined organic extracts over MgSO 4 dry, treat with SiliaMetS thiol for 30 minutes, filter and evaporate to give the crude title compound (yield assumed to be quantitative), which is used in the next step without further purification; MS (ESI) m / z [M+H] + 592.6.

[0866] Intermediate 70

[0867] 2-(4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)acetonitrile

[0868]

[0869] A solution of (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) in 1,4-d ane (1.5 mL) and 4 M KOH solution (aqueous, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] 2(7.1 mg, 0.01 mmol) was added to (4-(cyanomethyl)phenyl)boronic acid (93 mg, 0.58 mmol), and the reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (yield assumed quantitative), which was used in the next step without further purification; MS (ESI) m / z [M+H] + 388.4.

[0870] Intermediate 71

[0871] (2R)-2-((4-Chloro-6-(2-(3-fluoro-4-methylphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0872]

[0873] A solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) in 1,4-di ane (1.5 mL) and 4 M KOH solution (aqueous, 0.18 mL, 0.72 mmol) were followed by [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (3-fluoro-4-methylphenyl)boronic acid (89 mg, 0.58 mmol), and the reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (yield assumed quantitative), which was used in the next step without further purification; MS (ESI) m / z [M+H] + 381.3.

[0874] Intermediate 72

[0875] (2R)-2-((4-Chloro-6-(2-(4-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0876]

[0877] A solution of intermediate 3, (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (78 mg, 0.29 mmol) in 1,4-d ane (1.5 mL) and 4 M KOH solution (aqueous, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (4-(oxetan-3-yl)phenyl)boronic acid (103 mg, 0.58 mmol), and the reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h. EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (yield assumed to be quantitative), which was used in the next step without further purification; MS (ESI) m / z [M+H] + 405.4.

[0878] Intermediate 73

[0879] (2R)-2-((4-chloro-6-(2-(3-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0880]

[0881] A solution of intermediate 3, (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (78 mg, 0.29 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (3-fluorophenyl)boronic acid (81 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h, then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 367.3.

[0882] Intermediate 74

[0883] N-(4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)acetamide

[0884]

[0885] A solution of the intermediate (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol 3 (81 mg, 0.30 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol) was added to N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (118 mg, 0.45 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (presumed quantitative yield); MS (ESI) m / z [M+H] + 406.4.

[0886] Intermediate 75

[0887] (2R)-2-((4-(2-(1H-indol-5-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0888]

[0889] A solution of the intermediate (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol 3 (81 mg, 0.30 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2(7.4 mg, 0.02 mmol) was added to (1H-indol-5-yl)boronic acid (95 mg, 0.59 mmol). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 388.3

[0890] Intermediate 76

[0891] (2R)-2-((4-(2-(benzo[d] oxazol-6-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0892]

[0893] A solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (81 mg, 0.30 mmol) in 1,4-di ane (1.5 mL), 4 M KOH solution (aqueous, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol) was added to 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d] oxazole (102 mg, 0.42 mmol). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 390.3

[0894] Intermediate 77

[0895] (2R)-2-((4-(2-(benzo[d] oxazol-5-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0896]

[0897] A solution of intermediate 3 ((R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol, 81 mg, 0.30 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous solution, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol) were added to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d] azole (99 mg, 0.40 mmol). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 390.3.

[0898] Intermediate 78

[0899] ((4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)prop-2-yl)phenyl)imino)dimethyl-λ 6 -sulfone

[0900]

[0901] A solution of intermediate 3 ((R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol, 81 mg, 0.30 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous solution, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol) were added to dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino)-λ 6 -sulfone (96 mg, 0.33 mmol). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 440.4.

[0902] Intermediate 79

[0903] (2R)-2-((4-(2-(4-(1H-1,2,3-triazol-1-yl)phenyl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0904]

[0905] A solution of the intermediate 3 of (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (81 mg, 0.30 mmol) in 1,4-di ane (1.5 mL), 4 M KOH solution (aqueous solution, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol) was added to 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,3-triazole (96 mg, 0.35 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours, and then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc, and the combined organic extracts were filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 416.4.

[0906] Intermediate 80

[0907] (2R)-2-((4-chloro-6-(2-(3-chloro-4-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0908]

[0909] 1,4-Di ane (0.65 mL) and water (72 μL) were added to (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (39 mg, 0.14 mmol), (3-chloro-4-fluorophenyl)boronic acid (50.2 mg, 0.29 mmol), [Rh(COD)Cl] 2(3.6 mg, 7.2 μmol) and KOH (16.2 mg, 0.29 mmol), and the reaction mixture was stirred at 50 °C for 3.5 h and then at 60 °C overnight. EtOAc and water were added, and the two phases were separated. The organic extract was evaporated, and the residue was purified by preparative HPLC method A (gradient: 40% - 85%) to give the title compound (30 mg, 51%); MS (ESI) m / z [M+H] + 401.3

[0910] Intermediate 81

[0911] N-(4-(2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0912]

[0913] Under a nitrogen atmosphere, THF (0.25 mL) was added to Pd 2 dba 3 (2.7 mg, 2.9 μmol) and X-Phos (5.5 mg, 0.01 mmol). The mixture was stirred for 10 min, then a mixture of (2R)-2-((4-chloro-6-(2-(3-chloro-4-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 80 (29 mg, 0.07 mmol) in THF (0.5 mL), methanesulfonamide (15.5 mg, 0.16 mmol) and K 2 CO 3 (20.47 mg, 0.15 mmol) was added. The reaction mixture was stirred overnight at 70 °C under a nitrogen atmosphere. EtOAc and dilute HCl were added, and the two phases were separated. The organic phase was washed with brine. The combined aqueous phases were extracted with EtOAc. The combined organic extracts were dried over MgSO 4 , filtered and evaporated. The residue was purified by preparative HPLC method A (gradient: 30% - 80%) to give the title compound as a colorless solid (23.8 mg, 72%); MS (ESI) m / z [M+H] + 478.3

[0914] Intermediate 82

[0915] 2-ethoxy-4-(prop-1-en-2-yl)pyridine

[0916]

[0917] A solution of 4-bromo-2-ethoxypyridine (860 mg, 4.26 mmol) in THF (7.47 mL) was subsequently added with Pd(dppf)Cl 2 ·DCM (62 mg, 0.09 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.04 mL, 5.53 mmol) to a solution of Cs 2 CO 3 (4.16 g, 12.77 mmol) in water (2.13 mL), and the reaction mixture was degassed and stirred at 80 °C under a nitrogen atmosphere for 20 h. Et 2 O and water were added, and the two phases were separated. The organic phase was washed with CsOH (aqueous solution) and water and evaporated. The residue was purified by silica gel column chromatography (gradient: 5% - 80% Et 2 O / pentane) to give the title compound as a colorless oil (647 mg, 93%); 1 1H NMR (400 MHz, CDCl 3 ) 1.40 (3H, t), 2.09–2.12 (3H, m), 4.36 (2H, q), 5.19–5.23 (1H, m), 5.51–5.54 (1H, m), 6.74 (1H, d), 6.94 (1H, dd), 8.08 (1H, dd).

[0918] Intermediate 83

[0919] 4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)benzonitrile

[0920]

[0921] (4-Cyanophenyl)boronic acid (90 mg, 0.61 mmol) and 4 M KOH solution (aqueous solution, 0.15 mL, 0.61 mmol) were added to a 1,4-d ane (1.38 mL) solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (83 mg, 0.31 mmol). The mixture was degassed and then [Rh(COD)Cl] 2(7.56 mg, 0.02 mmol). The reaction mixture was stirred at 55 °C for 2.5 h under a nitrogen atmosphere. EtOAc and dilute acid were added, and the two phases were separated. The organic extract was washed with brine and evaporated. The residue was purified by preparative HPLC method A (gradient: 40% - 85%) to give the title compound (89 mg, 78%); MS (ESI) m / z [M+H] + 374.3.

[0922] Intermediate 84

[0923] (2R)-2-((4-Chloro-6-(2-(4-(methoxymethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0924]

[0925] A solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) in 1,4-di ane (1.5 mL), 4 M KOH solution (aqueous, 0.18 mL, 0.72 mmol), and then [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) were added to (4-(methoxymethyl)phenyl)boronic acid (96 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere, then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 393.4.

[0926] Intermediate 85

[0927] (2R)-2-((4-Chloro-6-(2-(3,4-dimethylphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0928]

[0929] A solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) in 1,4-di A solution in hexane (1.5 mL), 4 M KOH solution (aqueous solution, 0.18 mL, 0.72 mmol), and then [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (3,4-dimethylphenyl)boronic acid (87 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours, and then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (presumed quantitative yield); MS (ESI) m / z [M+H] + 377.4.

[0930] Intermediate 86

[0931] (2R)-2-((4-Chloro-6-(2-(4-(1,1-difluoroethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0932]

[0933] A solution of the (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) in 1,4-di hexane (1.5 mL), 4 M KOH solution (aqueous solution, 0.18 mL, 0.72 mmol), and then [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (4-(1,1-difluoroethyl)phenyl)boronic acid (108 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours, and then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was dried over MgSO 4 and filtered through a short silica gel pad. The eluate was evaporated to give the crude title compound (presumed quantitative yield); MS (ESI) m / z [M+H] + 413.4.

[0934] Intermediate 87

[0935] (2R)-2-((4-Chloro-6-(2-(3-chlorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0936]

[0937] (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) was reacted with 1,4-dihydrochloric acid to obtain (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (78 mg, 0.29 mmol) A solution in oxane (1.5 mL), 4 M KOH solution (aq., 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] 2 (7.1 mg, 0.01 mmol) was added to (3-chlorophenyl)boronic acid (91 mg, 0.58 mmol). The reaction mixture was stirred at 50 °C for 2 hours under nitrogen atmosphere, then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic extract was purified by MgSO 4 Dry and filter through a short pad of silica gel. Evaporate the eluate to give the crude title compound (assumed quantitative yield); MS (ESI) m / z [M+H] + 383.3.

[0938] Intermediate 88

[0939] N-(4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)-N-methylacetamide

[0940]

[0941] (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 3 (81 mg, 0.30 mmol) was reacted with 1,4-dihydro- A solution of 1,2-dioxaborolan-2-yl in 2-oxane (1.5 mL) and 4 M KOH solution (aqueous solution, 0.15 mL, 0.60 mmol) were added to N-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (116 mg, 0.42 mmol), followed by the addition of [Rh(COD)Cl] 2 (7.4 mg, 0.02 mmol). The reaction mixture was stirred at 50 °C for 2 hours under nitrogen atmosphere, then DCM and water were added. The aqueous phase was acidified and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic extracts were filtered through a short pad of silica gel. The eluate was evaporated and the residue containing the crude title compound was used in the next step without further purification. The yield was assumed to be quantitative; MS (ESI) m / z [M+H] + 420.4.

[0942] Intermediate 89

[0943] (2R)-2-((4-chloro-6-(2-(4-(trifluoromethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0944]

[0945] A solution of the intermediate (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol 3 (81 mg, 0.30 mmol) in 1,4-d ane (1.5 mL), 4 M KOH solution (aqueous, 0.15 mL, 0.60 mmol), and then [Rh(COD)Cl] 2 (7.4 mg, 0.01 mmol) was added to (4-(trifluoromethyl)phenyl)boronic acid (57 mg, 0.30 mmol). The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 1.5 h, then EtOAc and water were added. The aqueous phase was acidified and the phases were separated. The organic phase was extracted with EtOAc, and the combined organic extracts were dried over MgSO 4 , filtered, and evaporated. The residue was purified by silica gel normal-phase flash chromatography (gradient: 15% - 75% EtOAc / heptane) to give the title compound (80 mg, 64%); MS (ESI) m / z [M+H] + 417.3.

[0946] Intermediate 90

[0947] 2-methoxy-5-(prop-1-en-2-yl)pyridine

[0948]

[0949] Under a nitrogen atmosphere, at -20 °C, methyltriphenylbromide (23.6 g, 66.2 mmol) was added to a suspension of KOtBu (7.42 g, 66.2 mmol) in THF (50 mL). The reaction mixture was stirred at -20 °C for 1 h. 1-(6-Methoxypyridin-3-yl)ethan-1-one (5.0 g, 33 mmol) was added at -20 °C, and stirring was continued at room temperature for 14 h. The mixture was concentrated, diluted with EtOAc (200 mL), and washed successively with saturated NH 4 Cl (2 × 200 mL), brine (2 × 200 mL), and water (3 × 200 mL). The organic layer was dried over Na 2 SO 4Dry, filter and evaporate. Purify the residue by silica gel normal phase flash chromatography (gradient: 10%-20% EtOAc / PE) to afford the title compound as a dark oil (3.4 g, 69%); 1 H NMR (300 MHz, DMSO-d 6 ) 2.10 (3H, dd), 3.86 (3H, s), 5.00–5.10 (1H, m), 5.30–5.40 (1H, m), 6.80 (1H, dd), 7.87 (1H, dd), 8.29 (1H, dd).

[0950] Intermediate 91

[0951] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0952]

[0953] Add a solution of 9-BBN (0.5 M, 72.9 mL, 36.5 mmol) in THF (40 mL) to the 2-methoxy-5-(prop-1-en-2-yl)pyridine intermediate 90 (3.20 g, 21.4 mmol), and stir the reaction mixture at 70 °C for 1 h. Add the degassed (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (3.47 g, 10.7 mmol), Pd(dppf)Cl 2 ·DCM (1.31 g, 1.61 mmol) and 3 M K 3 PO 4 (aqueous solution, 21.4 mL, 64.4 mmol) to the solution. Purge the resulting mixture and stir at 40 °C for 20 h. Pour the reaction mixture into saturated brine (250 mL), acidify with 0.3 M HCl (to pH 1) and extract with EtOAc (2 × 200 mL). Adjust the pH of the aqueous phase to approximately 7 by adding saturated NaHCO 3 (50 mL), then extract with EtOAc (3 × 200 mL). Dry the combined organic layers over MgSO 4 and concentrate (40 °C). Purify the residue by reverse phase flash chromatography on a C18-column (gradient: 10%-80% water / CH 3 CN) to afford the title compound as a colorless solid (2.80 g, 60%); MS (ESI) m / z [M+H] + 439.20

[0954] Intermediate 92

[0955] 1,3 - Difluoro - 2 - (prop - 1 - en - 2 - yl)benzene

[0956]

[0957] At room temperature, KOtBu (1.72 g, 15.4 mmol) was added to a stirred suspension of methyltriphenylammonium bromide (5.49 g, 15.4 mmol) in Et 2 O (8.6 mL), and the resulting mixture was stirred at room temperature for 30 minutes. 1 - (2,6 - Difluorophenyl)ethanone (1.0 mL, 7.7 mmol) was added, and stirring was continued at room temperature for 30 minutes. The reaction mixture was filtered and evaporated. The crude product was purified by flash chromatography on silica gel (20 g), eluting with Et 2 O to give the title compound as an oil (1.3 g, 110%); 1 1H NMR (400 MHz, CDCl 3 ) 2.07–2.11 (3H, s), 5.08–5.13 (1H, m), 5.39–5.43 (1H, m), 5.15–5.20 (1H, m), 5.39–5.43 (1H, m), 6.83–6.91 (2H, m), 7.13–7.22 (1H, m).

[0958] Intermediate 93

[0959] N - (4 - (2 - (2,6 - Difluorophenyl)propyl)-6 - (((R)-1 - hydroxy - 4 - methylpentan - 2 - yl)amino)-1,3,5 - triazin - 2 - yl)methanesulfonamide

[0960]

[0961] 9 - BBN (0.5 M solution in THF, 1.69 mL, 0.840 mmol) was added to 1,3 - difluoro - 2 - (prop - 1 - en - 2 - yl)benzene intermediate 92 (65 mg, 0.42 mmol), and the mixture was stirred at 60 °C under a nitrogen atmosphere for 2 hours. Degassed (R)-N - (4 - chloro - 6 - ((1 - hydroxy - 4 - methylpentan - 2 - yl)amino)-1,3,5 - triazin - 2 - yl)methanesulfonamide intermediate 1 (137 mg, 0.420 mmol), 3 M K 3 PO 4 (aqueous solution, 422 μL, 1.26 mmol) and PdCl 2(dppf)·DCM (15 mg, 0.02 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. Water and DCM were added, the aqueous layer was acidified with 1 M KHSO 4 and extracted with DCM. The organic portion was concentrated and filtered through SiliaMetS thiol applied on top of a silica plug, eluting with a mixture of DCM and a small amount of MeOH. The organic layer was concentrated, and the residue was purified by preparative HPLC using method F (gradient: 5% - 95%) to give the title compound (15 mg, 8%); MS (ESI) m / z [M+H] + 444.19

[0962] Intermediate 94

[0963] N-(4-(2-(4-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0964]

[0965] Under a nitrogen atmosphere, 9-BBN (0.5 M solution in THF, 1.24 mL, 0.620 mmol) was added to a cold solution of 1-fluoro-4-(prop-1-en-2-yl)benzene (42 mg, 0.31 mmol) in THF (0.5 ml). The mixture was stirred at room temperature for 1.5 h. A degassed mixture of (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (100 mg, 0.310 mmol), 3 M K 3 PO 4 (aqueous solution, 309 μL, 0.930 mmol) and DMF (250 μl) was added, followed by addition of degassed PdCl 2 (dppf)·DCM (11 mg, 0.02 mmol). The resulting mixture was stirred at room temperature for 2 days under a nitrogen atmosphere. Water and DCM were added, the aqueous layer was acidified with 1 M KHSO 4 and extracted with DCM. The organic portion was concentrated and filtered through SiliaMetS thiol applied on top of a silica plug, eluting with a mixture of DCM and a small amount of MeOH. The organic layer was concentrated, and the residue was purified by preparative HPLC using method F (gradient: 5% - 95%) to give the title compound (29 mg, 22%); MS (ESI) m / z [M+H] + 426.2

[0966] Intermediate 95

[0967] 2-Fluoro-4-methoxy-1-(prop-1-en-2-yl)benzene

[0968]

[0969] At room temperature, KOtBu (1.34 g, 11.9 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (4.25 g, 11.9 mmol) in Et 2 O (15 ml), and the resulting mixture was stirred at room temperature for 30 minutes. 1-(2-Fluoro-4-methoxyphenyl)ethanone (1.0 g, 5.95 mmol) was added dropwise, and stirring was continued at room temperature overnight. The reaction mixture was diluted with Et 2 O, filtered and evaporated. The residue was purified by silica gel flash column chromatography (gradient: 5%–30% EtOAc / heptane) to give the title compound as an oil (0.78 g, 79%); 1 H NMR (500 MHz, CDCl 3 ) 2.12 (3H, s), 3.80 (3H, s), 5.14–5.18 (1H, m), 5.18–5.21 (1H, m), 6.57–6.68 (2H, m), 7.22 (1H, t).

[0970] Intermediate 96

[0971] N-(4-(2-(2-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0972]

[0973] Under a nitrogen atmosphere, 9-BBN dimer (139 mg, 0.570 mmol) was added to a solution of 2-fluoro-4-methoxy-1-(prop-1-en-2-yl)benzene intermediate 95 (92 mg, 0.56 mmol) in THF (1.5 mL). The mixture was stirred at room temperature for 1 hour. Degassed K 3 PO 4 (371 μL, 1.11 mmol), (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (120 mg, 0.370 mmol) and Pd(dppf)Cl 2· DCM (14 mg, 0.02 mmol) was added to the solution. The reaction mixture was degassed and stirred at 35 °C under a nitrogen atmosphere for 3 days. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC method F (gradient: 5% - 95%) to give the title compound (23 mg, 14%); MS (ESI) m / z [M+H] + 456.21

[0974] Intermediate 97

[0975] 4-Chloro-2-fluoro-1-(prop-1-en-2-yl)benzene

[0976]

[0977] At about 10 °C, KOtBu (1.33 g, 11.8 mmol) was added to

[0978] methyltriphenylbromide (4.14 g, 11.6 mmol) in a suspension of Et 2 O (10 mL). A solution of 1-(4-chloro-2-fluorophenyl)ethanone (1.01 g, 5.83 mmol) in Et 2 O (3 mL) was added dropwise, the mixture was brought to room temperature, and stirring was continued overnight. The reaction mixture was diluted with Et 2 O, filtered and washed successively with water, KHSO 4 (aqueous solution), water and brine. The organic layer was dried over MgSO 4 , filtered and evaporated (24 °C). The residue was purified by silica gel normal phase flash chromatography (gradient: 0 - 5% Et 2 O / pentane) to give the title compound (0.89 g, 89%); 1 1H NMR (400 MHz, THF-d 8 ) 2.07–2.14 (3H, m), 5.21–5.27 (2H, m), 7.11–7.23 (2H, m), 7.28–7.38 (1H, m).

[0979] Intermediate 98

[0980] N-(4-(2-(4-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0981]

[0982] Under a nitrogen atmosphere, 9-BBN (a 0.5 M solution in THF, 2.78 mL, 1.39 mmol) was added to the 4-chloro-2-fluoro-1-(prop-1-en-2-yl)benzene intermediate 97 (190 mg, 0.930 mmol). The reaction mixture was stirred at room temperature for 2.5 h and then at 40 °C for 1 h. Degassed K 3 PO 4 (0.926 mL, 2.78 mmol), (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (150 mg, 0.460 mmol), and Pd(dppf)Cl 2 ·DCM (57 mg, 0.07 mmol) were added to the solution. The reaction mixture was stirred at 40 °C under a nitrogen atmosphere for 16 h. EtOAc and 0.3 M HCl were added. The aqueous phase was acidified with 4 M HCl (to pH 4) and extracted once with EtOAc. The organic phases were combined, treated with SiliaMetS thiol, filtered, and evaporated (40 °C). The residue was purified by preparative HPLC method A (gradient: 30% - 70%) to give the title compound (128 mg, 60%); MS(ESI) m / z [M+H] + 460.3

[0983] Intermediate 99

[0984] 2-Fluoro-6-methoxy-3-(prop-1-en-2-yl)pyridine

[0985]

[0986] n-BuLi (a 1.6 M solution in hexanes, 44.3 mL, 70.9 mmol) was added to a solution of methyltriphenylphosphonium bromide (25.3 g, 70.9 mmol) in THF (150 mL). The reaction mixture was stirred at room temperature for 10 min, then a solution of 1-(2-fluoro-6-methoxypyridin-3-yl)ethan-1-one (10.0 g, 59.1 mmol) in THF (50 mL) was added, and the reaction mixture was stirred at 40 °C for 1 h. Water and Et 2 O were added, and the two phases were separated. The organic extract was washed with water, dried over MgSO 4 4, filtered, and evaporated. The residue was dissolved in boiling heptane. The heptane solution was allowed to reach room temperature and then filtered. The filtrate was evaporated, and the residue was purified by silica gel normal phase flash chromatography (heptane / EtOAc, 15 / 1) to give the title compound as a colorless oil (8.5 g, 86%); 11H NMR (500 MHz, CDCl 3 ) 2.10–2.13 (3H, m), 3.92 (3H, s), 5.19–5.21 (1H, m), 5.23–5.26 (1H, m), 6.59 (1H, dd), 7.63 (1H, dd).

[0987] Intermediate 100

[0988] N-(4-(2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0989]

[0990] A solution of 9-BBN (0.5 M in THF, 56.5 mL, 28.3 mmol) in THF (30 mL) was added to 2-fluoro-6-methoxy-3-(prop-1-en-2-yl)pyridine intermediate 99 (2.70 g, 16.2 mmol), and the mixture was stirred overnight at room temperature. Degassed 3 M K 3 PO 4 (aqueous solution, 16.2 mL, 48.4 mmol), (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (2.61 g, 8.07 mmol), and Pd(dppf)Cl 2 ·DCM (0.989 g, 1.21 mmol) were added to the solution. The reaction mixture was purged and stirred at 38 °C for 20 h. The reaction mixture was poured into saturated brine (100 mL), acidified with 0.3 M HCl (to pH 1) and extracted with EtOAc (3 × 150 mL). The pH of the aqueous phase was adjusted to approximately 7 by adding saturated NaHCO 3 , and then extracted with EtOAc (2 × 50 mL). The combined organic layers were treated with SiliaMetS thiol, dried over MgSO 4 , filtered and concentrated. The residue was purified by reverse-phase flash chromatography on a C18-column [gradient: 0–50% MeCN / water (0.2% FA)] to afford the title compound as a colorless solid (1.70 g, 46%); MS (ESI) m / z [M+H] + 457.15

[0991] Intermediate 101

[0992] 1,2,3-Trifluoro-4-(prop-1-en-2-yl)benzene

[0993]

[0994] At approximately 10 °C (ice-water bath), K 3 PO 4 (1.93 g, 17.2 mmol) was added to a suspension of methyltriphenylphosphonium bromide (6.15 g, 17.2 mmol) in Et 2 O (8 mL). A solution of 1-(2,3,4-trifluorophenyl)ethanone (1.50 g, 8.61 mmol) in Et 2 O (8 mL) was added dropwise, and the mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was diluted with Et 2 O, filtered and washed successively with water, 0.4 M HCl, water and brine. The organic layer was dried over MgSO 4 , filtered and carefully concentrated (24 °C). Pentane was added and the precipitate was filtered off. The filtrate was evaporated and the residue was purified by silica gel normal phase flash chromatography (10% EtOAc / pentane) to give the title compound (1.16 g, 78%); 1 1H NMR (400 MHz, CDCl 3 ) 2.09–2.15 (3H, m), 5.20–5.30 (2H, m), 6.85–7.05 (2H, m).

[0995] Intermediate 102

[0996] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0997]

[0998] Under a nitrogen atmosphere, 9-BBN (0.5 M solution in THF, 5.31 mL, 2.66 mmol) was added to 1,2,3-trifluoro-4-(prop-1-en-2-yl)benzene intermediate 101 (229 mg, 1.33 mmol). The reaction mixture was stirred at room temperature for 1 h and then added under a nitrogen atmosphere to (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (430 mg, 1.33 mmol), Pd(dppf)Cl 2 ·DCM (108 mg, 0.130 mmol) and K 3 PO 4(1.13 g, 5.31 mmol) in the mixture. The reaction mixture was heated at 50 °C for 2.5 h. Water and EtOAc were added, and the two phases were separated. The organic layer was extracted with water and brine. The combined aqueous layers were acidified with 1 M HCl (to pH 5) and extracted with EtOAc (×3). The organic extracts were dried over MgSO 4 dried, filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography using EtOAc as the eluent to give the title compound (75 mg, 12%); MS (ESI) m / z [M+H] + 462.33

[0999] Intermediate 103

[1000] 1-(but-1-en-2-yl)-2-fluorobenzene

[1001]

[1002] KOtBu (0.796 g, 7.10 mmol) was added to a stirred suspension of methyltriphenylbromide (2.54 g, 7.10 mmol) in Et 2 O (15 ml), and the mixture was stirred at room temperature for 30 min. 1-(2-Fluorophenyl)propan-1-one (0.503 mL, 3.55 mmol) was added dropwise, and stirring was continued at room temperature overnight. The reaction mixture was filtered and evaporated. The residue was purified by silica gel normal phase flash chromatography (gradient: 5%–20% EtOAc / heptane) to give the title compound (0.387 g, 73%); 1 1H NMR (400 MHz, CDCl 3 ) 1.05 (3H, td), 2.44–2.53 (2H, m), 5.12–5.15 (1H, m), 5.19–5.24 (1H, m), 6.98–7.13 (2H, m), 7.19–7.28 (m, overlapping with CDCl 3 portion).

[1003] Intermediate 104

[1004] 2-fluoro-4-(prop-1-en-2-yl)pyridine

[1005]

[1006] Under a nitrogen atmosphere, at 10 °C, within a 1-minute period, 4-bromo-2-fluoropyridine (5.00 g, 28.4 mmol) was added to 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.25 g, 31.2 mmol), Cs 2 CO 3 (18.5 g, 56.8 mmol) and Pd(dppf)Cl 2 ·DCM (2.32 g, 2.84 mmol) in 1,4-di ane (50 mL). The resulting solution was stirred at 100 °C for 14 hours. The reaction mixture was extracted with EtOAc (3 × 150 mL), and the organic layer was dried over Na 2 SO 4 , filtered and evaporated. The residue was purified by preparative TLC (PE / EtOAc, 5 / 1) to give the title compound as an oil (3.70 g, 95%) which solidified on standing; 1 1H NMR (400 MHz, CDCl 3 ) 1.95–2.12 (m, 3H), 5.17 (d, 1H), 5.46 (d, 1H), 6.75–6.85 (m, 1H), 7.05–7.20 (m, 1H), 8.00 (d, 1H).

[1007] Intermediate 105

[1008] N-(4-(2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[1009]

[1010] A solution of 9-BBN (0.5 M in THF, 77.0 mL, 38.3 mmol) in THF (30 mL) was added to 2-fluoro-4-(prop-1-en-2-yl)pyridine intermediate 104 (3.0 g, 21.9 mmol), and the mixture was stirred at 70 °C overnight. Degassed K 3 PO 4 (21.9 mL, 65.6 mmol), (R)-N-(4-chloro-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 1 (3.54 g, 10.9 mmol) and Pd(dppf)Cl 2· DCM (1.34 g, 1.64 mmol) was added to the solution. The reaction mixture was purged and stirred at 38 °C for 20 h. The reaction mixture was poured into saturated brine (250 mL) and extracted with EtOAc (3 × 150 mL). The aqueous phase was acidified with 0.3 M HCl (to pH 5) and extracted with EtOAc (150 mL). The combined organic layers were treated with SiliaMetS thiol, dried over MgSO 4 and filtered and concentrated (40 °C). The residue was purified by reverse-phase flash chromatography on a C18-column (gradient: 10%-70% MeCN / water) to afford the title compound as a colorless solid (2.19 g, 47%); MS (ESI) m / z [M+H] + 427.15

[1011] Intermediate 106

[1012] 2-(3-Bromobenzyl)is oxazolidin-3-one

[1013]

[1014] K 2 CO 3 (105 g, 0.812 mol), followed by 3-bromobenzyl bromide (105 g, 0.377 mol) was added to a solution of is oxazolidin-3-one (35 g, 0.40 mol) in MeCN (750 mL). The mixture was stirred at room temperature for 16 h, then filtered and concentrated. The residue was purified by silica gel flash chromatography (PE:EtOAc, 1:1) to afford the title compound as a pale yellow solid (74 g, 70%); MS (ESI) m / z [M+H] + 255.8.

[1015] Intermediate 107

[1016] 2-(3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)is oxazolidin-3-one

[1017]

[1018] Under a nitrogen atmosphere, Pd(dppf)Cl 2 (10 g, 0.013 mol) was added to 2-(3-bromobenzyl)is oxazolidin-3-one intermediate 106 (74 g, 0.29 mol), B 2 pin 2(92.5 g, 0.36 mol) and KOAc (113 g, 1.15 mol) were in a solution of 1,4-d ane (750 mL), and the reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (PE:EtOAc, 4:1) to afford the title compound as a colorless solid (30 g, 34%); MS (ESI) m / z [M+H] + 304.1

[1019] Intermediate 108

[1020] 2-((5,6,7,8-Tetrahydronaphthalen-1-yl)oxy)tetrahydro-2H-pyran

[1021]

[1022] Pyridine pTsOH (0.397 g, 1.58 mmol) was added to a solution of 3,4-dihydro-2H-pyran (2.8 mL, 30.7 mmol) and 5,6,7,8-tetrahydronaphthalen-1-ol (2.3 g, 15.5 mmol) in DCM (60 mL). The resulting mixture was stirred at room temperature for 6 h, then saturated NaHCO 3 (aqueous solution, 50 mL) was added. The layers were separated, and the organic portion was washed with saturated NaHCO 3 (aqueous solution, 50 mL) and brine, dried over MgSO 4 , filtered and evaporated. The residue was purified by flash chromatography on silica gel (0-20% EtOAc / heptane) to afford the title compound as a colorless oil (3.40 g, 94%); 1 H NMR (400 MHz, CDCl 3 ) δ 1.56–1.84 (7H, m), 1.84–1.91 (2H, m), 1.97–2.11 (1H, m), 2.64–2.83 (4H, m), 3.60 (1H, dtd), 3.91 (1H, ddd), 5.42 (1H, t), 6.73 (1H, d), 6.89 (1H, d), 7.03 (1H, t).

[1023] Intermediate 109

[1024] 4,4,5,5-Tetramethyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane

[1025]

[1026] Add MTBE (20 mL) to a purge mixture of 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.017 g, 0.06 mmol) and di-μ-methoxybis(1,5-cyclooctadiene)diiridium(I) (0.021 g, 0.03 mmol). Add B under a nitrogen atmosphere 2 pin 2 (1.72 g, 6.77 mmol), and then add a solution of 2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)tetrahydro-2H-pyran intermediate 108 (1.5 g, 6.46 mmol) in MTBE (5 mL). Heat the reaction mixture in a microwave reactor at 80 °C for 4 h. After cooling and standing overnight, concentrate the reaction mixture and purify the residue by flash column chromatography on silica gel (0 - 25% EtOAc / heptane) twice to give the title compound as a colorless crystalline solid (1.1 g, 45%); 1 H NMR (400 MHz, CDCl 3 3) δ 1.32 (12H, s), 1.59 - 1.83 (7H, m), 1.86 (2H, dt), 1.95 - 2.1 (1H, m), 2.74 (4H, dt), 3.62 (1H, dtd), 3.89 (1H, ddd), 5.57 (1H, t), 7.20 (1H, s), 7.26 (1H, s).

[1027] Intermediate 110

[1028] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-1-ol

[1029]

[1030] Add a solution of CuBr 2 (4.30 g, 19.3 mmol) in water (40 mL) to a suspension of 4,4,5,5-tetramethyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane intermediate 109 (2.3 g, 6.42 mmol) in MeOH (40 mL). Heat the mixture at 80 °C for 4 h, then stir at room temperature for 16 h. Treat the reaction mixture with Et 2 O (75 mL) and water (20 mL). Separate the layers and extract the aqueous phase with Et 2 O (2 × 75 mL). Wash the combined organic phases with brine, over MgSO 4Dry, filter and evaporate. Purify the residue by silica gel flash chromatography (0 - 50% EtOAc / heptane) to afford the title compound as a colorless solid (0.539 g, 30.6%); MS (ESI) m / z [M-H] - 273.

[1031] Intermediate 111

[1032] (6-(2-Hydroxyethyl)pyridin-3-yl)boronic acid

[1033]

[1034] A suspension of 2-(5-bromopyridin-2-yl)ethan-1-ol (50 g, 0.25 mol), Pd(dppf)Cl 2 (18.1 g, 25 mmol), KOAc (48.6 g, 0.49 mol) and B 2 pin 2 (81.7 g, 0.32 mol) in 1,4-dioxane (1000 mL) was stirred at 80 °C for 16 h. The mixture was filtered and concentrated. 2 M HCl (300 mL) was added and the solution was washed with EtOAc (3 × 150 mL). The aqueous layer was concentrated to afford the HCl salt of the title compound as a pale yellow solid (25 g, 50%); MS (ESI) m / z [M+H] 168.1. + 168.1.

[1035] Intermediate 112

[1036] Diphenyl iminodicarbonate

[1037]

[1038] Step a) Phenyl isocyanatoformate

[1039]

[1040] Under a nitrogen atmosphere, oxalyl chloride (20.8 mL, 246 mmol) was added to a stirred suspension of phenyl carbamate (30.7 g, 224 mmol) in DCM (165 mL). The mixture was heated to gentle reflux under a nitrogen atmosphere for 18 h to obtain a solution. After evaporation, the residue was treated with toluene (150 mL). The slurry was stirred for 20 min and the insoluble material was removed by filtration. The toluene filtrate containing the subtitle compound (224 mmol) was used immediately.

[1041] Step b) Diphenyl iminodicarbonate

[1042] Phenol (23.2 g, 246 mmol) was added in portions to the ice-cold toluene filtrate intermediate 112 step a) (224 mmol) over 10 minutes. The mixture was stirred in a cooling bath for 30 minutes and then at room temperature for 20 hours. The mixture was concentrated, the residue was dissolved in DCM and concentrated, and after repeating once more, the residue was solidified. Toluene (200 mL) was added to the solid and the mixture was stirred at room temperature for 20 minutes. Heptane (50 mL) was added to the mixture and stirring was continued overnight to obtain a slurry. The crude product was filtered out and the solid was washed with heptane until the filtrate was clear. The mother liquor and washings were combined and concentrated. Toluene (50 mL) and heptane (20 mL) were added to the residue. The mixture was stirred overnight to obtain a slurry. The residue was filtered out and the solid was washed with heptane until the filtrate was clear. The two batches of product were combined to give the title compound (38.8 g, 93%). MS (ESI) m / z [M+H] + 257.9

[1043] Intermediate 113

[1044] (E)-3-(2,3-Difluorophenyl)but-2-enenitrile

[1045]

[1046] At 0 °C, diethyl cyanomethylphosphonate (4.45 mL, 27.5 mmol) was added to a solution of NaOtBu (2.64 g, 27.5 mmol) in anhydrous EtOH (33 mL). After stirring for 15 minutes, 1-(2,3-difluorophenyl)ethanone (3.90 g, 25.0 mmol) was added and the mixture was stirred at room temperature for 2 hours. 10% Citric acid (33 mL) was added and the mixture was extracted with PE×3 (boiling point 40 - 60) (×3, 100 mL, 50 mL and 50 mL). The combined colorless extracts were washed with brine, dried over Na 2 SO 4 dried and concentrated to give the title compound (3.94 g, 88%). According to 1 1H NMR, a mixture of E- and Z-isomers (approx. 4:1) was obtained; 1 1H NMR (400 MHz, CDCl 3 ) 2.28–2.48 (3H, m), 5.54–5.66 (1H, m), 7.03–7.25 (3H, m).

[1047] Intermediate 114

[1048] 3-(2,3-Difluorophenyl)butanenitrile

[1049]

[1050] Under an argon atmosphere, Pd / C 10% (1.20 g, 1.13 mmol) was added to a stirred solution of crude (E)-3-(2,3-difluorophenyl)but-2-enenitrile intermediate 113 (9.92 g, 55.4 mmol) (E / Z-mixture) in EtOAc (240 mL). The mixture was hydrogenated (atmospheric pressure) at room temperature for 14 h. The catalyst was removed by filtration through silica and diatomaceous earth. The filtrate was concentrated to give the title compound as a colorless oil (9.62, 96%), which was used without further purification; 1 HNMR(400MHz,CDCl 3 ) 1.48 (3H, dd), 2.58–2.75 (2H, m), 3.45–3.57 (1H, m), 6.94–7.15 (3H, m).

[1051] Intermediate 115

[1052] 3-(2,3-Difluorophenyl)butyramide

[1053]

[1054] Under an argon atmosphere, AlMe 3 (2 M solution in toluene, 4.8 mL, 9.6 mmol) was added dropwise to a cold suspension of NH 4 Cl (0.551 g, 10.3 mmol) in toluene (6 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. 3-(2,3-Difluorophenyl)butyronitrile intermediate 114 (1.09 g, 6.01 mmol) was added, and the mixture was stirred at 80 °C overnight. After cooling to room temperature, the mixture was slowly poured into a cold slurry of silica (4 g) in CHCl 3 (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 with HCl (1.25 M solution in MeOH, 4 mL) for 5 min and then concentrated. The colorless residue was stirred with 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), HCl (1.25 M solution in MeOH, 0.5 mL) was added with stirring, followed by the dropwise addition (ca. 10 min) of Et 2 O (ca. 20 mL). The mixture was stirred at room temperature for 30 min and then cooled to 5 °C for 1 h. The colorless precipitate was collected by filtration, washed with Et 2Wash and dry under vacuum to obtain the HCl salt of the title compound (0.79 g, 56%); 1 H NMR (400 MHz, D 2 O) 1.41 (3H, d), 2.68–2.9 (2H, m), 3.53–3.66 (1H, m), 7.12–7.26 (3H, m).

[1055] Intermediate 116

[1056] 6-(2-(2,3-Difluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1057]

[1058] Suspend K 2 CO 3 (462 mg, 3.35 mmol) and the 3-(2,3-difluorophenyl)butyramide intermediate 115 (785 mg, 3.35 mmol) in MeCN (15 mL) in an argon atmosphere and stir for 5 minutes. Add the diphenyl iminodicarbonate intermediate 112 (862 mg, 3.35 mmol), and continue stirring at room temperature for 1 hour. Add another equivalent of K 2 CO 3 (462 mg, 3.35 mmol), and continue stirring at room temperature for 1 hour and at 60 °C for 2 hours. After cooling to room temperature, dissolve the resulting thick suspension in 1 M HCl (15 mL) and EtOAc (50 mL). Separate the layers, extract the aqueous phase with EtOAc (2 × 25 mL), and wash the combined organic layers with brine and dry over Na 2 SO 4 . Evaporate the solvent and dry the remaining solid under vacuum. Stir the material containing phenol (ca. 20 mol%) as an impurity with PE / Et 2 O (2 / 1, 30 mL) for 10 minutes, filter and dry under vacuum to obtain the title compound (791 mg, 88%); MS (ESI) m / z [M+H] + 268.4.

[1059] Intermediate 117

[1060] (2R)-2-((4-Chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1061]

[1062] Step a) 2,4-Dichloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine

[1063]

[1064] A mixture of 6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione intermediate 116 (0.27 g, 1.0 mmol), POCl 3 (0.28 ml, 3.0 mmol) and N,N-diethylaniline (0.16 ml, 1.0 mmol) was heated at 70 °C for 1.5 h. After cooling to room temperature, the mixture was diluted with CHCl 3 (10 mL) and toluene (10 mL). The mixture was concentrated to give the subtitle compound as an oil used in step b) (yield assumed to be quantitative).

[1065] Step b) (2R)-2-((4-Chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1066] K 2 CO 3 (270 mg, 1.95 mmol) was added in 3 portions over 2 h to a stirred solution of 2,4-dichloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine intermediate 117 step a) and (R)-2-amino-4-methylpentan-1-ol (150 μl, 1.17 mmol) in anhydrous THF (6 mL). Stirring was continued for 1 h, additional (R)-2-amino-4-methylpentan-1-ol (100 μl, 0.780 mmol) was added, and the mixture was stirred overnight. The mixture was diluted with Et 2 O (40 mL) and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was purified by preparative HPLC method A (gradient: 40%–80%) to give the title compound (80 mg, 21%); MS (ESI) m / z [M+H] + 385.5

[1067] Intermediate 118

[1068] N-(4-(2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[1069]

[1070] Under an argon atmosphere, Cs2 CO 3 (132 mg, 0.410 mmol) was added to a suspension of methanesulfonamide (39 mg, 0.41 mmol), Pd 2 (dba) 3 (21 mg, 0.020 mmol), X-Phos (21 mg, 0.040 mmol) and the intermediate 117 of (2R)-2-((4-chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (80 mg, 0.21 mmol) in THF (3.1 mL), and the reaction mixture was stirred at 64 °C for 6.5 h. After cooling to room temperature, the mixture was diluted with THF (7 mL) and filtered through celite. The filtrate was acidified with HOAc (50 μL) and concentrated. The remaining oil was purified by preparative HPLC method F (gradient: 5% - 95%) to give the title compound (37 mg, 40%); MS (ESI) m / z [M+H] + 444.19.

[1071] Intermediate 119

[1072] (E)-3-(2-fluorophenyl)but-2-enenitrile

[1073]

[1074] As described for intermediate 125, the title compound was prepared from 1-(2-fluorophenyl)ethanone (18.2 mL, 150 mmol) to give the title compound (24.0 g, 99%). According to 1 H NMR, a mixture of E-isomer and Z-isomer (about 4:1) was obtained; 1 HNMR (400 MHz, CDCl 3 ) 2.27–2.50 (3H, m), 5.49–5.65 (1H, m), 7.07–7.24 (2H, m), 7.28–7.43 (2H, m).

[1075] Intermediate 120

[1076] 3-(2-fluorophenyl)butanenitrile

[1077]

[1078] Under argon, Pd / C 10% (1.50 g, 1.41 mmol) was added to a solution of crude (E)-3-(2-fluorophenyl)but-2-enenitrile intermediate 119 (24.0 g, 149 mmol) (E / Z-mixture) in EtOAc (300 mL). The mixture was hydrogenated at room temperature and at 1.3 bar for 17 h, then at 1.6 bar for 5 h. The catalyst was removed by filtration through diatomaceous earth and the solvent was evaporated (30 °C) to give the title compound as a colorless oil (24.0 g, 89%); 1 H NMR (400 MHz, CDCl 3 ) 1.47 (3H, d), 2.54–2.75 (2H, m), 3.40–3.56 (1H, m), 6.7–7.41 (4H, m, overlapping with CDCl 3 ).

[1079] Intermediate 121

[1080] 3-(2-Fluorophenyl)butyramide

[1081]

[1082] Step a) Ethyl 3-(2-fluorophenyl)butyramidate

[1083]

[1084] Acetyl chloride (82.3 mL, 1160 mmol) was added dropwise to a cold solution of crude 3-(2-fluorophenyl)butanenitrile intermediate 120 (23.9 g, 146 mmol) in anhydrous EtOH (106 mL). The solution was kept at about 4 °C for 1 h, then allowed to reach room temperature and left standing at room temperature for 22 h. The clear solution was concentrated to leave the HCl salt of the subtitle compound as a colorless solid (34.6 g). The crude compound was stored in the refrigerator.

[1085] Step b) 3-(2-Fluorophenyl)butyramide

[1086] Cold NH 3 (7 M solution in MeOH, 170 ml, 1190 mmol) was added to 3-(2-fluorophenyl)butyramidate intermediate 121 step a) (34.6 g, 140.8 mmol). After stirring for 15 min, a clear solution was formed. After standing at room temperature for 22 h, the solvent was evaporated and the residue was dried in vacuo to give the HCl salt of the title compound as a colorless solid (30.2 g, 99%); 1 H NMR (400 MHz, DMSO-d 6)1.24(3H,d),2.65–2.83(2H,m),3.51–3.64(1H,m),7.12–7.44(4H,m),8.73(2H,br s),9.11(2H,br s).

[1087] Intermediate 122

[1088] 6-(2-(2-Fluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1089]

[1090] Add K 2 CO 3 (6.05 g, 43.8 mmol) and the 3-(2-fluorophenyl)butyramide intermediate 121 (8.67 g, 40.0 mmol) in a suspension in MeCN (200 ml) were stirred for 5 minutes under an argon atmosphere. Add the diphenyl iminodicarbonate intermediate 112 (12.4 g, 45.0 mmol), and continue stirring at room temperature for 1 hour. Add K 2 CO 3 (6.05 g, 43.8 mmol), and continue stirring at room temperature for 1 hour, then continue stirring at 60 °C for 2 hours. Cool the mixture to room temperature and then concentrate. Add 2 M HCl (70 mL) and heptane (70 mL), and stir the resulting mixture for 1 hour. Collect the resulting solid by filtration, wash it twice with heptane, dry it in vacuo, wash it twice with water and dry it again to obtain a colorless solid (6.27 g). Combine the filtrates and discard the top layer. Concentrate the two bottom layers to a volume of about 70 mL at 60 °C. Add DIPE (50 mL), and precipitation occurs immediately. After stirring at room temperature for 1 hour, collect the precipitate by filtration, wash it with heptane and water, dry it in vacuo and recrystallize it from IPA (35 mL). Obtain another pure material (1.99 g), and combine the two batches of products to obtain the title compound (8.26 g, 83%); MS (ESI) m / z [M+H] + 250.1

[1091] Intermediate 123

[1092] (2R)-2-((4-Chloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1093]

[1094] Step a) 2,4-Dichloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazine

[1095]

[1096] A mixture of 6-(2-(2-fluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione intermediate 122 (6.23 g, 25.0 mmol) and POCl 3 (80.0 mL, 861 mmol) was heated to gentle reflux for 15 h. After cooling to room temperature, the POCl 3 was evaporated. The residue was dissolved twice in toluene (20 mL) and evaporated to give a brown liquid. The resulting liquid was diluted with anhydrous DCM (130 mL) under an argon atmosphere. The mixture was cooled to 0 °C and a solution of DIPEA (18 mL) in DCM (10 mL) was added dropwise. After addition was complete (ca. 15 min), the still cold solution was shaken with ice / saline 1 / 1 (100 mL). The layers were separated, the aqueous phase was extracted with DCM (30 mL), and the combined organic layers were washed twice with a mixture of water / saturated NaHCO 3 / saline (5 / 2 / 2, 90 mL), dried over Na 2 SO 4 , filtered and concentrated. The residual oil was dissolved in toluene (50 mL) and decanted. The clear toluene solution was concentrated to give the subtitle compound as a dark orange solid (6.42 g, 22.4 mmol).

[1097] Step b) (2R)-2-((4-chloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1098] At 5 °C, (R)-2-amino-4-methylpentan-1-ol (3.16 mL, 24.7 mmol) was added to a stirred suspension of K 2 CO 3 (3.48 g, 25.2 mmol) and 2,4-dichloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazine intermediate 123 step a) (6.42 g, 22.4 mmol) in MeCN (70 mL). A precipitate formed and the cooling bath was removed. After stirring for 90 min, the reaction mixture was concentrated. The residue was stirred with toluene (60 mL) for 5 min. The insoluble material was removed by filtration and the filtrate was washed twice with 10% citric acid and brine, dried over Na 2 SO 4 , filtered and concentrated. The remaining oil was dissolved in EtOAc (25 mL) and filtered through silica. The filtrate was concentrated to give the title compound as an orange oil (6.74 g, 82%); MS (ESI) m / z [M+H]+ 367.3

[1099] Intermediate 124

[1100] N-(4-(2-(2-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[1101]

[1102] A mixture of methanesulfonamide (3.11 g, 32.7 mmol), (2R)-2-((4-chloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 123 (6.73 g, 18.3 mmol), X-phos (1.41 g, 2.96 mmol), Pd 2 (dba) 3 (1.25 g, 1.37 mmol) and THF (80 mL) was stirred at room temperature under an argon atmosphere for 10 minutes. K 2 CO 3 (4.52 g, 32.7 mmol) was added and the mixture was heated at 65 °C for 21 hours. After cooling to room temperature, the mixture was partitioned between water (180 mL) and MTBE (50 mL). The dark upper layer was extracted with a mixture of 2M K 2 CO 3 (20 mL) and THF (10 mL). The combined aqueous layers were washed with MTBE (2 × 30 mL). The aqueous layer was concentrated to remove THF, the remaining mixture was cooled to 8 °C and neutralized by dropwise addition of concentrated HCl. MTBE (80 mL) was added and the two layers were separated. The aqueous layer was extracted with MTBE (60 mL). The combined extracts were washed with brine (50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC Method B (gradient: 20% - 65%) to give the title compound (3.83 g, 49%); MS (ESI) m / z [M+H] + 426.3

[1103] Intermediate 125

[1104] (E)-3-Phenylbut-2-enenitrile

[1105]

[1106] At 0 °C, diethyl cyanomethylphosphonate (26.7 mL, 165 mmol) was added to a solution of NaOtBu (15.8 g, 165 mmol) in anhydrous EtOH (230 mL). After stirring for 15 minutes, while still cooling in an ice bath, acetophenone (17.6 mL, 150 mmol) was added in two equal portions over 10 minutes. The mixture was stirred at 0 °C for an additional 30 minutes, then allowed to reach room temperature and stirred overnight. The mixture was concentrated and the residue was cooled to precipitate. EtOH (30 mL), 10% citric acid (100 mL) and heptane (120 mL) were added, and the mixture was shaken well until all solids dissolved. Upon standing, three liquid layers were separated, the lower two layers were combined and extracted with heptane (100 mL, 80 mL and 50 mL). The combined colorless extracts were washed with brine, dried over Na 2 SO 4 dried and concentrated to give the title compound (20.7 g, 96%). According to 1 H NMR, a mixture of E- and Z-isomers (ca. 9:1) was obtained; 1 H NMR (400 MHz, CDCl 3 ) 2.26–2.51 (3H, m), 5.38–6.66 (1H, m), 7.37–7.56 (5H, m).

[1107] Intermediate 126

[1108] 3-Phenylbutyronitrile

[1109]

[1110] Under an argon atmosphere, 10% Pd / C (2.0 g, 1.88 mmol) was added to a well-stirred solution of the crude (E)-3-phenylbut-2-enenitrile intermediate 125 (20.7 g, 144 mmol) (E / Z-mixture) in EtOAc (300 mL). The mixture was hydrogenated at room temperature (1.3 bar) for 5 h. The catalyst was removed by filtration through diatomaceous earth, and the solvent was evaporated (30 °C) to give the title compound as a colorless oil (20.8 g, 99%); 1 H NMR (400 MHz, CDCl 3 ) 1.46 (3H, d), 2.5–2.67 (2H, m), 3.10–3.23 (1H, m), 7.2–7.41 (5H, m, overlapping with CDCl 3 ).

[1111] Intermediate 127

[1112] 3-Phenylbutyramide

[1113]

[1114] Step a) Ethyl 3-phenylbutanimidate

[1115]

[1116] Acetyl chloride (38.7 mL, 544 mmol) was added dropwise to a cold solution of 3-phenylbutanenitrile intermediate 126 (10.0 g, 68.9 mmol) in anhydrous EtOH (50 mL). The solution was allowed to stand at room temperature for 18 h. The clear solution was concentrated, leaving the HCl salt (15.2 g) of the subtitle compound as a colorless solid; 1 H NMR (400 MHz, CD 3 CN) 1.27 (3H, t), 1.32 (3H, d), 2.91–3.05 (2H, m), 3.27–3.41 (1H, m), 4.29–4.43 (2H, m), 7.2–7.38 (5H, m).

[1117] Step b) 3-Phenylbutanimide

[1118] Cold NH 3 (7 M solution in MeOH, 86.0 mL, 600 mmol) was added to ethyl 3-phenylbutanimidate intermediate 127 step a) (15.2 g, 66.8 mmol). After stirring for 15 min, a clear solution was formed. After standing at room temperature for 22 h, the solvent was evaporated, leaving a colorless solid which was stirred with DIPE (100 mL) for 1 h. The solid was collected by filtration and dried in vacuo to give the HCl salt (12.7 g, 96%) of the title compound; 1 H NMR (400 MHz, DMSO-d 6 ) 1.22 (3H, d), 2.62–2.7 (2H, m), 3.21–3.36 (1H, m, overlapping partially with water in DMSO-d 6 ), 7.19–7.37 (5H, m), 8.66 (2H, br s), 9.03 (2H, br s).

[1119] Intermediate 128

[1120] 6-(2-Phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1121]

[1122] K 2 CO 3(6.05 g, 43.8 mmol) and the 3-phenylbutyric imide intermediate 127 (7.55 g, 38.0 mmol) in a suspension in MeCN (190 mL) were stirred for 5 minutes under an argon atmosphere. The iminodicarbonic acid diphenyl ester intermediate 112 (12.1 g, 43.7 mmol) was added, and stirring was continued at room temperature for 1 hour. K 2 CO 3 (6.05 g, 43.8 mmol) was added, and stirring was continued at room temperature for 1 hour and then at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. 2 M HCl (68 mL), followed by heptane / Et 2 O (2 / 1, 90 mL) was added to the resulting suspension, and it was stirred for 1 hour. The resulting solid was collected by filtration, washed with heptane, dried in vacuo, washed with water and dried again to give the title compound (5.62 g, 64%); 1 HNMR (400 MHz, DMSO-d 6 ) 1.23 (3H, d), 2.59–2.73 (2H, m), 3.22–3.34 (m, overlapping with the water portion in DMSO-d 6 ), 7.15–7.35 (5H, m), 11.19 (1H, s), 12.08 (1H, s).

[1123] Intermediate 129

[1124] (2R)-2-((4-chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1125]

[1126] Step a) 2,4-dichloro-6-(2-phenylpropyl)-1,3,5-triazine

[1127]

[1128] A mixture of 6-(2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione intermediate 128 (5.62 g, 24.3 mmol) in distilled POCl 3 (80.0 mL, 861 mmol) was heated to gentle reflux for 15 hours. After cooling to room temperature, POCl 3Evaporation. The residue was dissolved twice in toluene (30 mL) and evaporated to give an orange liquid. The resulting liquid was diluted with anhydrous DCM (130 mL) under an argon atmosphere. The mixture was cooled to 0 °C, and a solution of DIPEA (17 mL) in DCM (15 mL) was added dropwise. After the addition was complete, the still cold solution was shaken with ice / saline (1 / 1, 100 mL). The layers were separated, and the aqueous phase was extracted with DCM (30 mL). The combined organic layers were washed with saturated NaHCO 3 / brine solution (1 / 3, ×2), dried over Na 2 SO 4 , filtered, and concentrated. The residual oil was dissolved in toluene / EtOAc (1 / 1, 120 mL) and washed with water and NaHCO 3 (aqueous solution). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated to give the titled compound (yield assumed to be quantitative); 1 H NMR (500 MHz, CDCl 3 ) 1.31–1.35 (3H, m), 3.11–3.24 (2H, m), 3.46–3.57 (1H, m), 7.17–7.32 (m, overlapping with the CDCl 3 portion).

[1129] Step b) (2R)-2-((4-Chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol At room temperature, (R)-2-amino-4-methylpentan-1-ol (3.44 mL, 26.9 mmol) was added to K 2 CO 3 (3.77 g, 27.3 mmol) and the 2,4-dichloro-6-(2-phenylpropyl)-1,3,5-triazine intermediate 129 step a) in a stirred suspension in MeCN (70 mL). The mixture was heated to about 30 °C. After 21 h, the mixture was concentrated, and the residue was partitioned between toluene (100 mL) and water (100 mL). HCl (12 M, ca. 25 mL) was added to facilitate layer separation. The aqueous phase was extracted with toluene (50 mL). The combined organic layers were washed twice with water and brine, dried over Na 2 SO 4 , filtered, and concentrated. The remaining oil was dissolved in EtOAc (25 mL) and filtered through silica, and the filtrate was concentrated to give the title compound as an orange oil (6.12 g, 72%); MS (ESI) m / z [M+H] + 349.2

[1130] Intermediate 130

[1131] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide

[1132]

[1133] Under a nitrogen atmosphere, a solution of the intermediate 129 ((2R)-2-((4-chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol, 5.95 g, 17.1 mmol) in THF (6 mL) (degassed with argon) was added to a mixture of Pd 2 (dba) 3 (0.607 g, 0.670 mmol), X-Phos (1.25 g, 2.62 mmol) and K 2 CO 3 (3.54 g, 25.6 mmol) and the mixture was stirred at room temperature for about 10 minutes. Then a degassed solution of methanesulfonamide (1.95 g, 20.5 mmol) in THF (20 mL) was added and the reaction mixture was heated at 60 °C overnight under a nitrogen atmosphere. After cooling to room temperature, the mixture was partitioned between water (180 mL) and MTBE (50 mL). The organic layer was extracted with a mixture of 2M K 2 CO 3 (aqueous solution, 20 mL) and THF (10 mL). Additional water (20 mL), MTBE (30 mL) and brine (10 mL) were added. The aqueous phase was washed with MTBE (30 mL) and concentrated. The aqueous phase was acidified with 4M HCl (to pH 4.7) and the precipitated compound was extracted into EtOAc (×2, 130 mL and 60 mL). The organic layer was dried over Na 2 SO 4 and filtered and evaporated to give the title compound as a solid (4.51 g, 65%); MS (ESI) m / z [M+H] + 408.4

[1134] Intermediate 131

[1135] (E)-3-(5-Chloropyridin-2-yl)but-2-enenitrile

[1136]

[1137] At 0 °C, diethyl cyanomethylphosphonate (4.45 mL, 27.5 mmol) was added to a solution of NaOtBu (2.64 g, 27.5 mmol) in anhydrous EtOH (33 mL). After stirring for 15 minutes, 1-(5-chloropyridin-2-yl)ethanone (3.89 g, 25.0 mmol) was added and the mixture was stirred at room temperature for 14 hours. 10% Citric acid (33 mL) was added, the mixture was cooled to 5 °C for 1 hour, and the precipitate was collected by filtration, washed with EtOH (aqueous solution, 50%) and dried in vacuo to give the title compound (4.02 g, 90%). According to 1 1H NMR, only one (E / Z)-configuration was observed, probably the E-isomer; 1 1H NMR (400 MHz, CDCl 3 ) 2.48 (3H, d), 6.45 (1H, q), 7.46 (1H, dd), 7.73 (1H, dd), 8.57 (1H, dd).

[1138] Intermediate 132

[1139] 3-(5-Chloropyridin-2-yl)butanenitrile

[1140]

[1141] Under an argon atmosphere, at room temperature, diphenylsilane (7.98 mL, 43.0 mmol) was added to a stirred mixture of Cu(OAc) 2 (118 mg, 0.650 mmol) and DPEphos (0.35 g, 0.65 mmol) in toluene (22 mL), and the reaction mixture was stirred at room temperature for 30 minutes. Solid (E)-3-(5-chloropyridin-2-yl)but-2-enenitrile intermediate 131 (3.84 g, 21.5 mmol) and t-BuOH (8 mL) were added and the reaction mixture was stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL) under vigorous stirring and gas evolution, followed by saturated NaHCO 3 . EtOAc (30 mL) was added and the layers were separated. The organic portion was extracted with 1 M HCl (5 × 50 mL). The combined acidic extracts were washed with pentane (20 mL) and neutralized with concentrated NH 3 . The milky mixture was extracted with Et 2 O (2 × 50 mL). The combined extracts were dried over Na 2 SO 4Dry, filter, and concentrate (24 °C). Dissolve the remaining black oil in DCM (15 mL) and filter through silica gel (5 g), eluting with DCM (45 mL), and concentrate the combined filtrates to give the title compound (2.96 g, 76%); MS (ESI) m / z [M+H] + 181.2

[1142] Intermediate 133

[1143] 3-(5-Chloropyridin-2-yl)butyramide

[1144]

[1145] Under an argon atmosphere, add AlMe 3 (2 M solution in toluene, 13.1 mL, 26.2 mmol) dropwise to a cold suspension of NH 4 Cl (1.51 g, 28.2 mmol) in toluene (16 mL) (gas evolution). Warm the resulting mixture to room temperature and stir for 1 h. Add 3-(5-chloropyridin-2-yl)butyronitrile intermediate 132 (2.96 g, 16.4 mmol), and stir the mixture at 80 °C overnight. After cooling to room temperature, slowly pour the mixture into a cold slurry of silica gel (15 g) in CHCl 3 (40 mL) and continue stirring at room temperature for 15 min. Filter the mixture, and wash the residue with MeOH (2 × 60 mL). Concentrate the combined filtrates, and stir the residue in a solution of 1.25 M HCl in MeOH (13.1 mL) for 10 min, then concentrate. Stir the residue with IPA / acetone (4 / 1, 45 mL) for 10 min, filter off the colorless insoluble material, and concentrate the filtrate to a volume of approximately 20 mL. Add Et 2 O (20 mL) dropwise with vigorous stirring (ca. 15 min). Continue stirring at room temperature for 30 min, and let the mixture stand at 5 °C for 1 h. Collect the precipitate by filtration, wash with IPA / Et 2 O (1 / 1), Et 2 O, and dry in vacuo to give the HCl salt of the title compound (2.17 g, 57%); 1 H NMR (400 MHz, D 2 O) 1.49 (3H, d), 2.86–2.95 (2H, m), 3.54–3.68 (1H, m), 7.82 (1H, d), 8.36 (1H, dd), 8.74 (1H, d).

[1146] Intermediate 134

[1147] 6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1148]

[1149] Add K 2 CO 3 (1.17 g, 8.50 mmol) and a suspension of 3-(5-chloropyridin-2-yl)butanimide intermediate 133 (1.98 g, 8.44 mmol) in MeCN (35 mL) were stirred for 1 h under an argon atmosphere. Di(phenyl) iminodicarbonate intermediate 112 (2.17 g, 8.44 mmol) was added and stirring was continued for 1 h at room temperature. K 2 CO 3 (1.17 g, 8.50 mmol) was added and stirring was continued for 1 h at room temperature and then for 2 h at 60 °C. After cooling to room temperature, the resulting thick suspension was dissolved in 0.4 M citric acid (aqueous solution, 50 mL) and concentrated to a volume of about 60 mL. The remaining solution was extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine and dried over Na 2 SO 4 , filtered, and the solvent was evaporated. The remaining solid was dried in vacuo for 3 h. The semi-solid residue was stirred with PE / Et 2 O (2 / 1, 60 mL) for 20 min, filtered, washed with DIPE and dried in vacuo to give the title compound (1.59 g, 71%); MS (ESI) m / z [M+H] + 267.4

[1150] Intermediate 135

[1151] (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1152]

[1153] Step a) 2,4-dichloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine

[1154]

[1155] 6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1156] Intermediate 134 (267 mg, 1.00 mmol), POCl3 (280 μL, 3.00 mmol) and a mixture of N,N - diethylaniline (159 μL, 1.00 mmol) were heated at 70 °C for 1.5 hours. After cooling to room temperature, the mixture was diluted with CHCl 3 (10 mL) and toluene (10 mL). The mixture was concentrated to give the titled compound (assumed quantitative yield) as an oil used in step b).

[1157] Step b) (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1158] K 2 CO 3 (270 mg, 1.95 mmol) was added in 3 portions over 2 hours to a stirred solution of 2,4-dichloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine intermediate 135 step a) and (R)-2-amino-4-methylpentan-1-ol (150 μl, 1.17 mmol) in anhydrous THF (6 mL). Stirring was continued for 1 hour, additional (R)-2-amino-4-methylpentan-1-ol (100 μl, 0.780 mmol) was added, and the mixture was stirred overnight. Three further portions of (R)-2-amino-4-methylpentan-1-ol (100 μL each) were added over an 8-hour period and stirring was continued overnight. The mixture was diluted with Et 2 O (40 mL) and the insoluble gum was removed by decantation and filtration through diatomaceous earth. The filtrate was concentrated and the residue was purified by preparative HPLC method B (gradient: 35%–75%) to give the title compound (58 mg, 15%); MS (ESI) m / z [M + H] + 384.5 / 386.5

[1159] Intermediate 136

[1160] N-(4-(2-(5-chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[1161]

[1162] As described for Example 118, the title compound was prepared from the intermediate 135 (58 mg, 0.15 mmol) of (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol; the title compound was obtained (33 mg, 49%); MS (ESI) m / z [M+H] + 443.17

[1163] Intermediate 137

[1164] (Z)-4,4,4-Trifluoro-3-phenylbut-2-enenitrile

[1165]

[1166] Under a nitrogen atmosphere, at room temperature, over a period of 15 minutes, a solution of diethyl cyanomethylphosphonate (4.52 g, 25.5 mmol) in THF (5 mL) was added to a slurry of NaH (1.02 g, 25.5 mmol) in THF (10 mL), and the resulting yellow solution was stirred for 1 hour. 2,2,2-Trifluoro-1-phenylethan-1-one (2.96 g, 17 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. THF (10 mL) was added to the thick reaction mixture and it was stirred at room temperature overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (×2, 150 mL and 50 mL). The combined organic layers were dried over Na 2 SO 4 dried, filtered and concentrated. The residue was purified by silica gel normal phase flash chromatography (gradient: 5%-40% EtOAc / heptane) to give the title compound as two separated E-isomers and Z-isomers (total 1.80 g, 54%). First eluted isomer (1.07 g): 1 H NMR (400 MHz, CDCl 3 ) 6.15–6.19 (1H, m), 7.46–7.59 (5H, m); Second eluted isomer (0.728 g): 1 H NMR (400 MHz, CDCl 3 ) 5.92–5.96 (1H, m), 7.41–7.56 (5H, m).

[1167] Intermediate 138

[1168] 4,4,4-Trifluoro-3-phenylbutanenitrile

[1169]

[1170] At 0 °C, NaBH 4 (0.616 g, 16.3 mmol) was added to a mixture of the (Z)-4,4,4-trifluoro-3-phenylbut-2-enenitrile intermediate 137 first eluted isomer (1.07 g, 5.43 mmol) (E or Z-isomer) in MeOH (20 mL). After 5 minutes, the mixture was allowed to reach room temperature and stirred for 2 h. The reaction mixture was quenched with 2 M HCl (10 mL), stirred for 45 minutes and then concentrated. Brine (10 mL) was added and the aqueous phase was extracted with DCM (50 mL). The organic phase was dried over a phase separator and concentrated to give the title compound as a colorless oil (1.0 g, 92%); 1 H NMR (400 MHz, CDCl 3 ) 2.88–3.11 (2H, m), 3.63–3.78 (1H, m), 7.31–7.49 (5H, m).

[1171] Intermediate 139

[1172] 4,4,4-Trifluoro-3-phenylbutanimide

[1173]

[1174] Under a nitrogen atmosphere, AlMe 3 (2 M solution in toluene, 12.5 mL, 25.0 mmol) was added dropwise (over ca. 10 minutes) to a cold suspension of NH 4 Cl (1.62 g, 30.2 mmol) in toluene (10 mL). The resulting mixture was warmed to room temperature and stirred for 1 h. A solution of 4,4,4-trifluoro-3-phenylbutanenitrile intermediate 138 (1.66 g, 8.33 mmol) in toluene (5 mL) was added and the clear solution was heated at 70 °C overnight. The mixture was allowed to reach room temperature and then cooled in an ice-bath. MeOH (24 mL) was added slowly and the resulting mixture was stirred for 15 minutes and then allowed to reach room temperature. Silica (2 g) was added as a filtering agent and the insoluble material was removed by filtration. The insoluble material was washed with MeOH (44 mL) and the combined filtrates were concentrated to give a solid. MeOH (25 mL), followed by HCl (4 M solution in di ane, 4 mL) was added to the solid and the suspension was concentrated. The residue was stirred with a mixture of IPA / acetone (4 / 1, 50 mL) for ca. 45 minutes. The insoluble precipitate was removed by filtration and the filtrate was concentrated. The oily residue was dried under vacuum overnight to give a syrupy foam. Et 2O (10 mL), and concentrate the mixture. Add MTBE to the residue, and concentrate the mixture to obtain a gummy solid. Vacuum dry the gummy solid over the weekend to obtain the HCl salt of the title compound (1.96 g, 93%); 1 H NMR (400 MHz, DMSO-d 6 ) 3.1–3.29 (2H, m), 4.38–4.53 (1H, m), 7.39–7.46 (5H, m). According to 1 H NMR, the product contains some TBME.

[1175] Intermediate 140

[1176] 2,4-Dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine

[1177]

[1178] Add K 2 CO 3 (1.26 g, 9.13 mmol) and the 4,4,4-trifluoro-3-phenylbutyramide intermediate 139 (1.96 g, 7.76 mmol) in MeCN (40 mL) as a suspension and stir for 5 minutes under a nitrogen atmosphere. Add the iminodicarbonic acid diphenyl ester intermediate 112 (2.36 g, 9.19 mmol), and continue stirring at room temperature for 1.5 h. Add K 2 CO 3 (1.26 g, 9.13 mmol), and continue stirring at room temperature for 20 minutes, then continue stirring at 60 °C overnight. Stir the mixture with MTBE (35 mL) for 1 h. Filter the solid, wash with MTBE (10 mL) and dry in vacuo. Add 2 M HCl (24 mL) to the solid, and stir the mixture for 45 minutes. Collect the precipitate by filtration, wash with 0.2 M HCl (15 mL) and water (10 mL), then dry in vacuo at 50 °C overnight to obtain the title compound as a colorless solid (1.98 g, 89%); MS (ESI) m / z [M+H] + 286.2

[1179] Intermediate 141

[1180] (2R)-2-((4-Chloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1181]

[1182] Step a) 2,4-Dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine

[1183]

[1184] A mixture of 6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione intermediate 140 (1.97 g, 6.91 mmol) and POCl 3 (31.5 mL, 338 mmol) was heated to gentle reflux for 48 h. After cooling to room temperature, the mixture was concentrated and co-evaporated twice from toluene. The residue was dissolved in DCM (85 mL), and the solution was cooled to 0 °C in an ice bath. DIPEA (4.83 mL, 27.6 mmol) was carefully added over 15 min, followed by slow addition of water (1 mL). The orange solution was diluted with DCM (25 mL) and water (12 mL). The organic layer was washed with water (18 mL), then with saturated NaHCO 3 (12 mL) and water (18 mL), dried over a phase separator and concentrated to give the subtitle compound as a dark oil (assumed quantitative yield).

[1185] Step b) (2R)-2-((4-Chloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1186] K 2 CO 3 (1.05 g, 7.60 mmol) was added to a cold solution of 2,4-dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine intermediate 141 step a) in MeCN (25 mL). At 0 °C, (R)-2-amino-4-methylpentan-1-ol (0.927 mL, 7.26 mmol) was added dropwise over ca. 1 min, and the reaction mixture was stirred at 0 °C for 20 min. The mixture was allowed to reach room temperature and stirred for 1.5 h, then DCM (150 mL) and water (20 mL) were added. The organic layer was washed with water / brine (2 / 1, 30 mL), dried over MgSO 4 filtered and concentrated. The residue was purified by silica gel normal phase flash chromatography (gradient: 12 - 100% EtOAc / heptane) to give the title compound as a thick yellow oil (0.526 g, 19%); MS (ESI) m / z [M+H] + 403.4.

[1187] Intermediate 142

[1188] (3-(1-Hydroxycyclopropyl)phenyl)boronic acid

[1189]

[1190] At -65 °C and under N 2 (g) atmosphere, n-BuLi (291 mL, 0.73 mol) was added dropwise to a solution of 1-(3-bromophenyl)cyclopropan-1-ol (70 g, 0.33 mol) in THF (1.5 L). The reaction mixture was stirred at -65 °C for 30 minutes. A solution of triisopropyl borate (75.2 g, 0.40 mol) in THF (200 mL) was added dropwise at -65 °C. The reaction mixture was slowly warmed to -30 °C and maintained for 2 hours. The reaction was quenched with NH 4 Cl (aqueous solution). The organic layer was separated, dried over anhydrous Na 2 SO 4 , filtered and evaporated to give a crude solid product, which was washed with 2-methoxy-2-methylpropane to give the title compound (27 g, 46%); MS (ESI) m / z [M - 18 + H] + 161.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.05 (m, 2H), 1.32 (m, 2H), 2.38 (brs, 1H), 7.18 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H).

[1191] Intermediate 143

[1192] 6-(2-Methyl-2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione

[1193]

[1194] K 2 CO 3 (374 mg, 2.71 mmol) and 3-methyl-3-phenylbutanimide HCl US20140194431 (0.490 g, 2.30 mmol) in anhydrous MeCN (13 mL) were stirred at room temperature for 5 minutes under N 2 (g) atmosphere. Di(phenyl) iminodicarbonate (0.702 g, 2.73 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour. K 2 CO 3(374 mg, 2.71 mmol), and the reaction mixture was stirred at room temperature for 20 minutes and then at 60 °C for 2 hours 20 minutes. The reaction mixture was cooled to room temperature and concentrated in vacuo. MTBE (10 mL) was added to the residue, and the mixture was stirred for 30 minutes. The insoluble material was separated by filtration, washed with MTBE (2 mL - 3 mL), and dried in vacuo. The solid was stirred with 2N HCl (8 mL) for 45 minutes. The precipitate was collected by filtration, washed with 0.2N HCl (5 mL), and dried in vacuo to give the title compound as an off-white solid (0.302 g, 54%); MS (ESI) m / z [M+H] + 246.3

[1195] Intermediate 144

[1196] 2,4-Dichloro-6-(2-methyl-2-phenylpropyl)-1,3,5-triazine

[1197]

[1198] POCl 3 (5.38 mL, 57.73 mmol) was added to 6-(2-methyl-2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione intermediate 143 (0.289 g, 1.18 mmol), and the reaction mixture was heated to gentle reflux for 18 hours and then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo, co-evaporated twice from toluene, and dried overnight under N 2 (g) atmosphere and then solidified. The crude product was dissolved in DCM (15 mL), and the solution was cooled to 0 °C in an ice bath. DIPEA (0.823 mL, 4.71 mmol) was added very carefully over 15 minutes, followed by slow addition of water (1 mL) over 10 minutes. The mixture was partitioned between DCM (4 mL) and water (2 mL). The organic phase was washed with water (3 mL), saturated aqueous NaHCO 3 (2 mL), and water (3 mL). The organic layer was dried over MgSO 4 filtered, and concentrated to give the crude title compound as a brown oil (386 mg), which solidified upon standing at room temperature; 1 1H NMR (400 MHz, CD 3 3CN) δ 1.45 (6H, s), 3.15 (2H, s), 7.16–7.21 (1H, m), 7.26–7.32 (2H, m), 7.35–7.4 (2H, m). The crude product was used in the next step without further purification.

[1199] Intermediate 145

[1200] (R)-2-((4-chloro-6-(2-methyl-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[1201]

[1202] Add K 2 CO 3 (0.179 g, 1.30 mmol) to a cooled solution of 2,4-dichloro-6-(2-methyl-2-phenylpropyl)-1,3,5-triazine intermediate 144 (0.333 g, 1.18 mmol) in MeCN (4 mL). At 0 °C, (R)-2-amino-4-methylpentan-1-ol (0.158 mL, 1.24 mmol) was added dropwise and the reaction mixture was stirred at 0 °C for 15 minutes. The reaction mixture was allowed to reach room temperature and DCM (60 mL) and water (10 mL) were added. The organic layer was washed with water (10 mL), dried over MgSO 4 filtered and concentrated. The crude product was purified by silica gel normal phase flash chromatography (heptane: EtOAc, 1:1) to give the title compound as a yellow oil (211 mg, 49%); MS (ESI) m / z [M+H] + 363.4.

[1203] Intermediate 146

[1204] 1-(1,1-difluoroallyl)-4-fluorobenzene

[1205]

[1206] Add 3-bromo-3,3-difluoroprop-1-ene (235 mg, 1.50 mmol) to (4-fluorophenyl)boronic acid (140 mg, 1 mmol), Pd 2 dba 3 (5 mg, 5.46 μmol) and K 2 CO 3 (415 mg, 3.00 mmol) in a mixture of dioxane (5 mL) and water (8.65 μl). The vessel was sealed and heated at 80 °C overnight and then stirred at room temperature for 20 hours. The reaction mixture was diluted with Et O and filtered through a MgSO 2 pad. The filtrate was washed several times with water and then concentrated. The crude product was dissolved in pentane, washed with water and concentrated. The crude product was purified by silica gel normal phase flash chromatography (0 - 5% Et 4 OAc) 2Purified with O / pentane to obtain the title compound (60 mg, 35%); 1 H NMR (400 MHz, CDCl 3 ) δ 5.46–5.61 (2H, m), 6.06–6.22 (1H, m), 7.11 (2H, t), 7.49 (2H, dd).

[1207] Intermediate 147

[1208] 3-Fluoro-6-methyl-2-(prop-1-en-2-yl)pyridine

[1209]

[1210] Add Et 2 O (7 mL) and PdCl 2 (dppf) (0.046 g, 0.06 mmol) to a degassed solution of K 2 CO 3 (2.182 g, 15.79 mmol) in water (2 mL), and degas the reaction mixture. Add 2-bromo-3-fluoro-6-methylpyridine (1 g, 5.26 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.088 mL, 5.79 mmol) in one portion, then add THF (1.5 mL), and reflux the reaction mixture under N 2 (g) atmosphere for 72 h. Dilute the reaction mixture with Et 2 O and wash with water and brine. Concentrate the organic layer carefully, and purify the residue by silica gel normal phase flash chromatography (2% - 5% Et 2 O / pentane). Collect the fraction containing the first compound and heat it with K 2 CO 3 (aqueous solution) at 100 °C for 15 min, then partition between Et 2 O and water. Treat the organic layer at room temperature with a solution of CsOH monohydrate (0.23 g, 1.37 mmol) in water (0.5 mL). Extract the aqueous layer with Et 2 O, and concentrate the combined organic layers carefully. Collect the fraction containing the second compound and treat it with CsOH monohydrate (0.23 g, 1.37 mmol) at room temperature, then extract with Et 2 O. Concentrate the organic layer carefully, and combine the residues to obtain the title compound as a colorless liquid (0.505 g, 64%); 1 H NMR (500 MHz, CDCl 3)δ 2.20 (3H, td), 2.51 (3H, d), 5.45 (1H, h), 5.66 (1H, tq), 6.99 (1H, dd), 7.24 (1H, dd).

[1211] Example 1

[1212] N-(4-((S*)-2-(3,4-Dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1213]

[1214] Example 2

[1215] N-(4-((R*)-2-(3,4-Dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1216]

[1217] The diastereomers of N-(4-(2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 6 (70 mg, 0.15 mmol) were separated by preparative chiral HPLC on a Chiralpak IA column (250×30 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 150 mL / min and detected at 220 nm) containing 15% MeOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((S*)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 1 (28 mg, 40%); HRMS (ESI) m / z [M+H] + C 19 H 28 Cl 2 N 5 O 3 Calculated for C 1 H NMR (500 MHz, CDCl 3) 0.91 (6H, dd), 1.25 (m, overlapping with the DEA residue part), 1.31–1.47 (2H, m), 1.57–1.75 (1H, m), 2.64–2.82 (2H, m), 3.13 (3H, s), 3.33 (1H, sext), 3.55 (1H, dd), 3.69 (1H, dd), 4.07 (1H, br s), 6.10 (2H, br s), 7.05 (1H, dd), 7.28–7.33 (2H, m), and the second eluted compound N-(4-((R*)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 2 (27 mg, 39%); HRMS (ESI) m / z [M+H] + C 19 H 28 Cl 2 N 5 O 3 Calculated for 1 H NMR (500 MHz, CDCl 3 ) 0.85 - 0.98 (6H, m), 1.21–1.49 (m, overlapping with the DEA residue part), 1.54–1.75 (1H, m), 2.69–2.91 (2H, m), 2.97–3.10 (2H, m), 3.16 (3H, s), 3.26–3.40 (1H, m), 3.51–3.63 (1H, m), 3.64–3.77 (1H, m), 4.14 (1H, br s), 6.80 (1H, br s), 7.07 (1H, d), 7.28–7.34 (2H, m).

[1218] Example 3

[1219] N-(4-((S*)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1220]

[1221] Example 4

[1222] N-(4-((R*)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1223]

[1224] The diastereomers of N-(4-(2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 8 (150 mg, 0.33 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250×30 mm, 5 μm) eluted with CO 2 (120 bar, flow rate 80 mL / min and detected at 220 nm) containing 15% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((S*)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 3, which was dissolved in EtOAc and washed with acidic water (pH 4) and brine. The organic extract was evaporated to give (36 mg, 24%); HRMS (ESI) m / z [M+H] + C 19 H 28 ClFN 5 O 3 S calculated: 460.1580, found: 460.1580; 1 1H NMR (500 MHz, MeOD) 0.83–0.97 (6H, m), 1.31–1.53 (5H, m), 1.56–1.69 (1H, m), 2.84 (1H, d), 2.88–2.98 (1H, m), 3.16 (3H, d), 3.45–3.59 (2H, m), 3.67–3.82 (1H, m), 4.13–4.27 (1H, m), 7.07–7.13 (1H, m), 7.23–7.28 (1H, m), 7.28–7.34 (1H, m). The second eluted compound from the chiral separation, N-(4-((R*)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 4, was dissolved in EtOAc and washed with acidic water (pH 4) and brine. The organic extract was evaporated to give (38 mg, 26%); HRMS (ESI) m / z [M+H] + C 19 H 28 ClFN 5 O 3 S calculated: 460.1580, found: 460.1580; 11H NMR (500 MHz, MeOD) 0.89 - 0.96 (6H, m), 1.31–1.53 (5H, m), 1.57–1.71 (1H, m), 2.84 (1H, d), 2.87–2.98 (1H, dd), 3.16 (3H, d), 3.41–3.61 (2H, m), 3.70–3.81 (1H, m), 4.17–4.27 (1H, m), 7.07–7.13 (1H, m), 7.23–7.28 (1H, m), 7.28–7.34 (1H, m).

[1225] Example 5

[1226] N-(4-((S*)-2-(2,4-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1227]

[1228] Example 6

[1229] N-(4-((R*)-2-(2,4-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1230]

[1231] The diastereomers of N-(4-(2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 10 (90 mg, 0.20 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250 × 30 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 80 mL / min and detected at 220 nm) containing 15% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((S*)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 5 which was dissolved in EtOAc and washed with dilute HCl. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (22 mg, 24%); HRMS (ESI) m / z [M+H] + C 19 H28 F 2 N 5 O 3 Calculated value of S: 444.1876, measured value: 444.1894; 1 H NMR (500 MHz, MeOD) 0.86–0.97 (6H, m), 1.34 (3H, d), 1.36–1.51 (2H, m), 1.57–1.68 (1H, m), 2.77–2.85 (1H, m), 2.85–2.93 (1H, m), 3.15 (3H, d), 3.45–3.59 (2H, m), 3.60–3.75 (1H, m), 4.15–4.27 (1H, m), 6.82–6.93 (2H, m), 7.28–7.36 (1H, m). The second eluted compound N-(4-((R*)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) from chiral separation was dissolved in EtOAc and washed with dilute HCl. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (14 mg, 16%); HRMS (ESI) m / z [M+H] + C 19 H 28 F 2 N 5 O 3 Calculated value of S: 444.1876, measured value: 444.1856; 1 H NMR (500 MHz, MeOD) 0.87–0.97 (6H, m), 1.30–1.35 (3H, m), 1.36–1.55 (2H, m), 1.50–1.69 (1H, m), 2.82 (1H, d), 2.89 (1H, d), 3.16 (3H, d), 3.48 (1H, d), 3.50–3.60 (1H, m), 3.64–3.74 (1H, m), 4.23 (1H, hept), 6.83–6.93 (2H, m), 7.29–7.37 (1H, m).

[1232] Example 7

[1233] N-(4-((R*)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1234]

[1235] Example 8

[1236] N-(4-((S*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1237]

[1238] The diastereomers of N-(4-(2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 12 (33 mg, 0.07 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 70 mL / min and detected at 230 nm) containing 20% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((R*)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 7, which was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to give (15 mg, 45%); HRMS (ESI) m / z [M+H] + C 19 H 30 FN 6 O 4 S calculated: 457.2028, found: 457.2020; 11H NMR (400 MHz, MeOD) 0.84–0.99 (6H, m), 1.31–1.54 (5H, m), 1.54–1.71 (1H, m), 2.67–2.98 (m, overlapping with the citrate residue), 3.16 (3H, d), 3.37–3.63 (3H, m), 3.95 (3H, d), 4.18–4.28 (1H, m), 7.44 (1H, ddd), 7.77 (1H, dd). The second eluted compound from chiral separation, N-(4-((S*)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 8, was dissolved in EtOAc and washed with aqueous citric acid solution and brine. The organic extract was dried over Na 2 SO 4 , filtered and evaporated to give (13 mg, 39%); HRMS (ESI) m / z [M+H] + C 19 H 30 FN 6 O 4 S calculated: 457.2028, found: 457.2010; 1 1H NMR (400 MHz, MeOD) 0.87–0.99 (6H, m), 1.31–1.53 (5H, m), 1.55–1.71 (1H, m), 2.68–2.97 (m, overlapping with the citrate residue), 3.16 (3H, d), 3.34–3.61 (3H, m), 3.95 (3H, d), 4.15–4.27 (1H, m), 7.44 (1H, dt), 7.74–7.79 (1H, m).

[1239] Example 9

[1240] N-(4-((R*)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1241]

[1242] Example 10

[1243] N-(4-((S*)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1244]

[1245] The diastereomers of N-(4-(2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 14 (23 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 μm) eluted with CO 2 (120 bar, flow rate 70 mL / min and detected at 230 nm) containing 20% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((R*)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 9, which was dissolved in EtOAc and washed with aqueous citric acid solution and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to give (7.9 mg, 34%); HRMS (ESI) m / z [M+H] + C 19 H 30 ClN 6 O 4 S calculated: 473.1732, found: 473.1724; 1 H NMR (500 MHz, MeOD) 0.83–0.99 (6H, m), 1.32–1.54 (5H, m), 1.55–1.73 (1H, m), 2.68–2.94 (m, partially overlapping with citrate residue), 3.16 (3H, d), 3.35–3.43 (1H, m), 3.47–3.60 (2H, m), 3.94 (3H, d), 4.17–4.28 (1H, m), 7.70 (1H, dd), 7.91 (1H, dd). The second eluted compound from the chiral separation N-(4-((S*)-2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 10 was dissolved in EtOAc and washed with aqueous citric acid solution and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to give (8.2 mg, 36%); HRMS (ESI) m / z [M+H] + C 19H 30 ClN 6 O 4 Calculated value of S: 473.1732, measured value: 473.1734; 1 H NMR (500 MHz, MeOD) 0.87–0.98 (6H, m), 1.32–1.52 (5H, m), 1.58–1.69 (1H, m), 2.69–2.93 (m, overlapping with the citrate residue), 3.16 (3H, d), 3.35–3.43 (1H, m), 3.46–3.60 (2H, m), 3.95 (3H, d), 4.15–4.26 (1H, m), 7.68–7.71 (1H, m), 7.88–7.92 (1H, m).

[1246] Example 11

[1247] N-(4-((S*)-2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1248]

[1249] Example 12

[1250] N-(4-((R*)-2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1251]

[1252] The diastereomers of N-(4-(2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 16 (49 mg, 0.11 mmol) were separated by preparative chiral HPLC on a Chiralpak AD column (250×20 mm, 5 μm) using CO containing 20% EtOH / DEA (100 / 0.5) 2(Eluted at 120 bar, flow rate of 70 mL / min and detected at 230 nm) to separate, obtaining the first eluted compound N-(4-((S*)-2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 11, which was dissolved in EtOAc and washed with aqueous citric acid solution and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to obtain (28 mg, 57%); HRMS (ESI) m / z [M+H] + C 20 H 32 N 7 O 3 S calculated value: 450.2282, found value: 450.2276; 1 1H NMR (500 MHz, MeOD) 0.84–0.97 (6H, m), 1.04–1.09 (4H, m), 1.33–1.53 (5H, m), 1.57–1.68 (1H, m), 2.14–2.22 (1H, m), 2.76–2.96 (m, partially overlapping with the citric acid residue), 3.16–3.19 (3H, m), 3.37–3.60 (3H, m), 4.09–4.26 (1H, m), 8.50–8.53 (2H, m). The second eluted compound N-(4-((R*)-2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 12 from the chiral separation was dissolved in EtOAc and washed with aqueous citric acid solution and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to obtain (28 mg, 57%); HRMS (ESI) m / z [M+H] + C 20 H 32 N 7 O 3 S calculated value: 450.2282, found value: 450.2292; 11H NMR (500 MHz, MeOD) 0.85–0.98 (6H, m), 1.03–1.10 (4H, m), 1.33–1.53 (5H, m), 1.55–1.70 (1H, m), 2.13–2.22 (1H, m), 2.76–2.98 (m, overlapping with the citrate residue), 3.16–3.19 (3H, m), 3.39–3.63 (3H, m), 4.15–4.26 (1H, m), 8.50–8.53 (2H, m).

[1253] Example 13

[1254] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1255]

[1256] Example 14

[1257] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1258]

[1259] The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 19 (52 mg, 0.11 mmol) were separated by preparative chiral HPLC on a Chiralpak IB column (250×30 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 150 mL / min and detected at 230 nm) containing 15% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 13 which was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was passed through Na 2 SO 4Dry, filter and evaporate to obtain (25 mg, 48%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 Calculated for C H N O S: 453.2278, found: 453.2254; 1 H NMR (500 MHz, CDCl 3 ) 0.85–0.98 (6H, m), 1.24–1.51 (5H, m), 1.56–1.73 (1H, m), 2.30 (3H, s), 2.78–3.04 (2H, m), 3.27 (3H, d), 3.46–3.61 (2H, m), 3.63–3.81 (1H, m), 3.87 (3H, d), 4.15–4.26 (1H, d), 6.51 (1H, s), 8.00 (1H, d). The second eluted compound from chiral separation, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 14 was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was dried over Na 2 SO 4 Dry, filter and evaporate to obtain (17 mg, 33%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 Calculated for C H N O S: 453.2278, found: 453.2274; 1 H NMR (500 MHz, CDCl 3 ) 0.86–0.97 (6H, m), 1.24–1.51 (5H, m), 1.56–1.72 (1H, m), 2.26–2.32 (3H, m), 2.80–3.04 (2H, m), 3.28 (3H, d), 3.47–3.61 (2H, m), 3.63–3.81 (1H, m), 3.87 (3H, d), 4.16–4.26 (1H, m), 6.51 (1H, d), 8.02 (1H, d).

[1260] Example 15

[1261] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1262]

[1263] Example 16

[1264] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1265]

[1266] The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 21 (52 mg, 0.11 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 60 mL / min and detected at 230 nm) containing 35% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 15 which was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was dried over Na 2 SO 4 dried, filtered and evaporated to give (23 mg, 44%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 S calculated: 453.2278, found: 453.2272; 1 1H NMR (500 MHz, CDCl 3) 0.86–0.97 (6H, m), 1.24–1.32 (3H, m), 1.33–1.49 (2H, m), 1.56–1.72 (1H, m), 2.13–2.17 (3H, m), 2.89 (2H, dd), 3.20–3.40 (4H, m), 3.45–3.80 (2H, m), 3.88–3.93 (3H, m), 4.16–4.27 (1H, m), 7.28

[1267] –7.33 (1H, m), 7.81 (1H, dd). The second eluted compound from chiral separation, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 16, was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was dried over Na 2 SO 4 and filtered and evaporated to give (24 mg, 46%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 S calculated: 453.2278, found: 453.2270; 0.85–0.97 (6H, m), 1.24–1.50 (5H, m), 1.55–1.72 (1H, m), 2.15 (3H, s), 2.80–2.95 (2H, m), 3.21–3.32 (4H, m), 3.51–3.80 (2H, m), 3.91 (3H, s), 4.09–4.25 (1H, m), 7.30 (1H, ddd), 7.80 (1H, dd).

[1268] Example 17

[1269]

[1270]

[1271] Example 18

[1272] N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1273]

[1274] The diastereomers of N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 23 (166 mg, 0.38 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250×30 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 130 mL / min and detected at 230 nm) containing 15% EtOH / TEA (100 / 0.5) to give the first eluted compound N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 17 which was dissolved in EtOAc and washed with dilute HCl (aqueous solution) and brine. The organic extract was dried over MgSO 4 and filtered and evaporated to give (50 mg, 30%); HRMS (ESI) m / z [M+H] + C 19 H 31 N 6 O 4 S calculated: 439.2122, found: 439.2126; 1 H NMR (500 MHz, MeOD) 0.86–0.97 (6H, m), 1.29–1.52 (5H, m), 1.57–1.72 (1H, m), 2.73–2.91 (2H, m), 3.08–3.18 (m, partially overlapping with TEA residue), 3.44–3.70 (3H, m), 3.89 (3H, d), 4.10–4.28 (1H, m), 6.90 (1H, dd), 7.58 (1H, d), 7.96 (1H, d). The second eluted compound from the chiral separation N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) Example 18 was dissolved in EtOAc and washed with dilute HCl (aqueous solution) and brine. The organic extract was dried over MgSO 4Dry, filter and evaporate to obtain (42 mg, 25%); HRMS (ESI) m / z [M+H] + C 19 H 31 N 6 O 4 Calculated for C H N O S: 439.2122, found: 439.2124; 1 H NMR (500 MHz, MeOD) 0.87–0.97 (6H, m), 1.31–1.52 (m, partially overlapping with TEA residue), 1.55–1.72 (1H, m), 2.72–2.91 (2H, m), 3.15 (3H, d), 3.44–3.72 (3H, m), 3.89 (3H, d), 4.12–4.27 (1H, m), 6.91 (1H, dd), 7.58 (1H, dt), 7.97 (1H, dt).

[1275] Example 19

[1276] N-(4-((R*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1277]

[1278] Example 20

[1279] N-(4-((S*)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1280]

[1281] The diastereomers of N-(4-(2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 25 (64 mg, 0.14 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×20 mm, 5 μm) using CO containing 30% EtOH / DEA (100 / 0.5). 2(Eluted at 120 bar, flow rate 80 mL / min and detected at 254 nm) to separate, obtaining the first eluted compound N-(4-((R*)-2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 19, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (30 mg, 47%); HRMS (ESI) m / z [M+H] + C 20 H 31 FN 5 O 4 S calculated: 456.2076, found: 456.2088; 1 1H NMR (400 MHz, CDCl 3 ) 0.87–0.98 (6H, m), 1.22–1.54 (m, partially overlapping with solvent residues), 1.55–1.73 (1H, m), 2.86–2.98 (2H, m), 3.19–3.40 (4H, m), 3.52–3.89 (5H, m), 4.16–4.31 (1H, m), 6.80–7.01 (3H, m). The second eluted compound from the chiral separation, N-(4-((S*)-2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 20, was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (28 mg, 44%); HRMS (ESI) m / z [M+H] + C 20 H 31 FN 5 O 4 S calculated: 456.2076, found: 456.2092; 1 1H NMR (400 MHz, CDCl 3 ) 0.88–0.98 (6H, m), 1.22–1.54 (m, partially overlapping with solvent residues), 1.55–1.73 (1H, m), 2.81–2.95 (2H, m), 3.18–3.36 (4H, m), 3.53–3.87 (5H, m), 4.17–4.29 (1H, d), 6.80–7.02 (3H, m).

[1282] Example 21

[1283] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1284]

[1285] Example 22

[1286] N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1287]

[1288] The diastereomers of N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 27 (98 mg, 0.21 mmol) were separated by preparative chiral HPLC on a Chiralpak IA column (250×20 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 70 mL / min and detected at 254 nm) containing 15% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S*)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 21 which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (22 mg, 22%); HRMS (ESI) m / z [M+H] + C 19 H 27 F 3 N 5 O 3 S calculated: 462.1780, found: 462.1792; 1 H NMR (400 MHz, CDCl 3) 0.85–1.01 (6H, m), 1.22–1.54 (m, partially overlapping with solvent residues), 1.55–1.74 (1H, m), 2.84–2.99 (2H, m), 3.22–3.41 (4H, m), 3.53–3.65 (1H, m), 3.66–3.83 (1H, m), 4.16–4.30 (1H, m), 6.82–6.94 (2H, m). The second eluted compound from chiral separation, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R*)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 22, was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (27 mg, 28%); HRMS (ESI) m / z [M+H] + C 19 H 27 F 3 N 5 O 3 S calculated: 462.1780, found: 462.1792; 0.85–1.01 (6H, m), 1.22–1.54 (m, partially overlapping with solvent residues), 1.55–1.74 (1H, m), 2.81–3.00 (2H, m), 3.23–3.43 (4H, m), 3.54–3.65 (1H, m), 3.66–3.84 (1H, m), 4.18–4.32 (1H, m), 6.83–6.95 (2H, m).

[1289] Example 23

[1290] N-(4-((S*)-2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1291]

[1292] Example 24

[1293] N-(4-((R*)-2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1294]

[1295] The diastereomers of N-(4-(2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 29 (28 mg, 0.06 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250×30 mm, 5 μm) eluting with CO 2 (120 bar, flow rate 70 mL / min and detected at 260 nm) containing 15% EtOH / DEA (100 / 0.5) to give the first eluted compound N-(4-((S*)-2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1) Example 23 which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 , filtered and evaporated to give (10 mg, 36%); HRMS (ESI) m / z [M+H] + C 19 H 28 F 2 N 5 O 3 S calculated: 444.1876, found: 444.1900; 1 H NMR (400 MHz, CDCl 3 ) 0.84–1.00 (6H, m), 1.28–1.53 (5H, m), 1.55–1.73 (1H, m), 2.87–3.03 (2H, m), 3.23–3.34 (3H, m), 3.52–3.81 (3H, m), 4.15–4.26 (1H, m), 6.77–6.86 (1H, m), 6.89–7.01 (2H, m). The second eluted compound from the chiral separation N-(4-((R*)-2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2) Example 24 was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 , filtered and evaporated to give (11 mg, 39%); HRMS (ESI) m / z [M+H] + C 19 H 28 F 2 N 5 O 3 S calculated: 444.1876, found: 444.1888; 1H NMR (400 MHz, CDCl 3 ) 0.85–0.98 (6H, m), 1.25–1.53 (m, overlapping with solvent residue), 1.54–1.70 (1H, m), 2.83–3.04 (2H, m), 3.22–3.31 (3H, m), 3.52–3.80 (3H, m), 4.16–4.28 (1H, m), 6.77–6.86 (1H, m), 6.88–7.01 (2H, m).

[1296] Example 25

[1297] N-(4-((S*)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1298]

[1299] Example 26

[1300] N-(4-((R*)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1301]

[1302] The diastereomers of N-(4-(2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 31

[1303] (23 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250×30 mm, 5 μm) eluting with CO 2 containing 20% EtOH / TEA (100 / 0.5) (120 bar, flow rate 87.5 mL / min and detected at 230 nm) to give the first eluted compound N-(4-((S*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 25, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4Dry, filter and evaporate. The residue was purified by preparative HPLC method C (gradient: 20%-60%) to give (4.6 mg, 20%); HRMS (ESI) m / z [M+H] + C 18 H 28 ClN 6 O 3 Calculated for C H ClN O S: 443.1626, found: 443.1626; 1 H NMR (400 MHz, CDCl 3 ) 0.87–0.99 (6H, m), 1.30–1.54 (5H, m), 1.55–1.71 (1H, m), 2.82–3.02 (2H, m), 3.29–3.45 (m, partially overlapped with by-products), 3.56–3.64 (1H, m), 3.66–3.83 (1H, m), 4.13–4.28 (1H, m), 7.12 (1H, dd), 7.20–7.24 (1H, m), 8.24–8.32 (1H, m). The second eluted compound from the chiral separation, N-(4-((R*)-2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 26, was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dry, filtered and evaporated to give (5.6 mg, 24%); HRMS (ESI) m / z [M+H] + C 18 H 28 ClN 6 O 3 Calculated for C H ClN O S: 443.1626, found: 443.1618; 1 H NMR (500 MHz, CDCl 3 ) 0.87–0.98 (6H, m), 1.28–1.52 (5H, m), 1.55–1.71 (1H, m), 2.82–3.02 (2H, m), 3.25–3.45 (4H, m), 3.53–3.61 (1H, m), 3.63–3.81 (1H, m), 4.16–4.26 (1H, m), 7.09–7.14 (1H, m), 7.22 (1H, d), 8.26 (1H, d).

[1304] Example 27

[1305] N-(4-((R*)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1)

[1306]

[1307] Example 28

[1308] N-(4-((S*)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2)

[1309]

[1310] The diastereomers of N-(4-(2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 33 (23.5 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralpak IC column (250×30 mm, 5 μm) eluted with CO 2 (100 bar, flow rate 160 mL / min and detected at 230 nm) to give the first eluted compound N-(4-((R*)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) Example 27, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (10.6 mg, 45%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 S calculated: 453.2278, found: 453.2306; 1 H NMR (400 MHz, CDCl 3) 0.86–0.97 (6H, m), 1.22–1.50 (8H, m), 1.54–1.70 (1H, m), 2.86–3.00 (2H, m), 3.21–3.40 (4H, m), 3.46–3.82 (2H, m), 4.16–4.33 (3H, m), 6.65 (1H, d), 7.46–7.52 (1H, m), 7.95–8.00 (1H, m). The second eluted compound from chiral separation, N-(4-((S*)-2-(6-ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2), Example 28, was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO 4 dried, filtered and evaporated to give (10.6 mg, 45%); HRMS (ESI) m / z [M+H] + C 20 H 33 N 6 O 4 S calculated: 453.2278, found: 453.2302; 1 H NMR (400 MHz, CDCl 3 ) 0.84–0.98 (6H, m), 1.22–1.51 (8H, m), 1.54–1.72 (1H, m), 2.81–2.98 (2H, m), 3.21–3.38 (4H, m), 3.50–3.60 (1H, m), 3.61–3.82 (1H, m), 4.09–4.23 (1H, m), 4.28 (2H, q), 6.65 (1H, d), 7.44–7.53 (1H, m), 7.92–7.99 (1H, m).

[1311] Example 29

[1312] N-(4-((S*)-2-(5-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 1)

[1313]

[1314] Example 30

[1315] N-(4-((R*)-2-(5-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (isomer 2)

[1316]

[1317] The diastereomers of N-(4-(2-(5-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide intermediate 35 (12.8 mg, 0.03 mmol) were separated by pr...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or tautomer thereof, wherein R 1 is C 3-6 branched alkyl or C 3-6 branched haloalkyl; R 2 is C 1-3 alkyl or C 1-3 haloalkyl; m is 1 or 2; R 3 and R 4 are independently selected from H, a halogen group, C 1-3 alkyl, and C 1-3 haloalkyl; A is phenyl, monocyclic heteroaryl, bicyclic aryl or bicyclic heteroaryl; p is 0, 1, 2, 3 or 4; Each R 5 is independently selected from a halogen group, a hydroxyl group, an oxo group, a C 1-3 alkyl group, a C 1-3 haloalkyl group, a C 1-4 alkoxy group, a C 1-4 haloalkoxy group, a C 1-4 alkoxy-C 1-3 alkyl group, a C 1-3 hydroxyalkyl group, -CN, -(CH 2 ) q CN, -C(O)NR 6 R 7 , -NS(O)R 6 R 7 , -(CH 2 ) q R 8 , -C(O)R 8 , -C(O)OR 9 , -OC(O)R 9 , -NR 6 C(O)R 7 , -NR 6 R 7 , C 3-6 cycloalkyl group, a 4-6 membered heteroaryl group, a 4-6 membered heterocyclic group and a phenyl group, wherein The said C 3-6 The cycloalkyl or 4-6 membered heterocyclic group can optionally be substituted by 1 to 3 substituents selected from hydroxy, oxo, halo and -C(O)OR 9 substituents. the 4- to 6-membered heteroaryl may optionally be substituted with 1 to 3 halo substituents, The said C 1-4 alkoxy group can optionally be substituted by a 4- to 6-membered heterocyclic group, Each R 6 and R 7 are independently selected from H and C 1-3 alkyl groups, each q is independently 1, 2 or 3, Each R 8 independently is a 4- to 6-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with an oxy group, and Each R 9 is independently C 1-5 alkyl.

2. The compound according to claim 1, having the following structure 3. The compound according to claim 1 or 2, wherein A is phenyl.

4. The compound according to claim 1 or 2, wherein A is monocyclic heteroaryl.

5. The compound according to claim 4, wherein A is monocyclic N-heteroaryl.

6. The compound according to claim 4 or 5, wherein A is a 6-membered monocyclic heteroaryl.

7. The compound according to claim 5, wherein A is pyridyl.

8. The compound according to claim 5, wherein A is pyrimidine.

9. A compound according to any one of claims 1 to 8, wherein A is phenyl or a 6-membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is located para to the carbon-bonded ring atom substituted with R 4 -R 5 -substituted carbon-bonded ring atom.

10. A compound according to any one of claims 1 to 8, wherein A is phenyl or a 6-membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is located ortho to the carbon-bonded ring atom substituted with R 4 -R 5 -substituted carbon-bonded ring atom.

11. A compound according to any one of claims 1 to 8, wherein A is phenyl or a 6-membered monocyclic heteroaryl, wherein p is at least 1 and R 5 is located at the meta position of the carbon-bonded ring atom substituted with R 4 -R 5 -substituted carbon-bonded ring atom.

12. The compound according to any one of claims 1 to 11, wherein at least one R 5 is a halogenated group.

13. The compound according to claim 12, wherein at least one R 5 is F.

14. The compound according to claim 13, wherein at least two Rs 5 are F.

15. The compound according to claim 14, wherein at least three Rs 5 are F.

16. The compound according to any one of claims 9 to 15, wherein at least one R 5 is Cl.

17. The compound according to claim 16, wherein at least two Rs 5 are Cl.

18. A compound according to any one of claims 1 to 17, wherein at least one R 5 is C 1-4 alkoxy.

19. The compound according to claim 18, wherein at least one R 5 is -OCH 3 .

20. The compound according to claim 18, wherein at least one R 5 is -OCH 2 CH 3 .

21. The compound according to any one of claims 1 to 20, wherein at least one R 5 is C 1-4 haloalkoxy.

22. The compound according to any one of claims 1 to 21, wherein at least one R 5 is C 1 -C 3 alkyl.

23. The compound according to claim 22, wherein at least one R 5 is methyl.

24. A compound according to any one of claims 1 to 23, wherein at least one R 5 is a hydroxyl group or a C 1 -C 3 hydroxyalkyl group.

25. A compound according to any one of claims 1 to 24, wherein R 3 or R 4 is one of C 1-3 alkyl.

26. The compound according to claim 25, wherein said C 1-3 alkyl group is a methyl group.

27. The compound according to claim 25, wherein said C 1-3 alkyl group is ethyl.

28. A compound according to any one of claims 1 to 27, wherein one of R 3 or R 4 is H.

29. The compound according to claim 28, wherein R 4 is H.

30. A compound according to any one of claims 1 to 29, wherein one of R 3 or R 4 is a halogenated group.

31. The compound according to any one of claims 1 to 30, wherein R 1 is C 3-6 branched alkyl.

32. The compound according to claim 31, wherein R 1 is C 4 branched alkyl.

33. The compound according to claim 32, wherein R 1 is -CH 2 CH(CH 3 ) 2 .

34. A compound according to any one of claims 1 to 33, wherein R 2 is C 1-3 alkyl.

35. The compound according to claim 34, wherein R 2 is methyl.

36. The compound according to any one of claims 1 to 35, wherein p is 1, 2 or 3.

37. The compound according to claim 36, wherein p is 1.

38. The compound according to claim 36, wherein p is 2.

39. The compound according to claim 36, wherein p is 3.

40. The compound according to any one of claims 1 to 39, wherein m is 1.

41. The compound according to any one of claims 1 to 38, wherein m is 2.

42. The compound according to claim 1, selected from: N-(4-((R)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((S)-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((R)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((S)-2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((R)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((S)-2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((R)-2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-((S)-2-(5-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(5-Chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(5-Chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-Cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-Methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-Methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-Methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-Methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2-Methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2-Methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(3-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2,5-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-Chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(5-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-Chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-Chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-Chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2,3-difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2,3-difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-fluoro-6-methoxypyridin-3-yl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(6-aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(6-aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2,6-dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2,6-dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(piperazin-1-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-(cyanomethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-fluoro-4-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)acetamide N-(4-(2-(1H-indol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(benzo[d] oxazol-6-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(2-(Benzo[d] oxazol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(2-(4-((Dimethyl(oxo)-l 6 -sulfinylidene)amino)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(2-(4-(1H-1,2,3-triazol-1-yl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-ethoxypyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(methoxymethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3,4-dimethylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-(1,1-difluoroethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)-N-methylethanamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(trifluoromethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-fluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methylpyridin-4-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(morpholinomethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3,4-Dimethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(8-methoxyquinolin-5-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Chloro-4-ethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Fluoro-3-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-2-oxo-2,3-dihydrobenzo[d] oxazol-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-((3-oxois oxazolidin-2-yl)methyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(quinolin-8-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,3-Dimethyl-2H-indazol-6-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-Chloro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(Benzo[d][1,3]dioxol-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-8-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3,5-Difluoro-4-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Fluoro-3-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Aminophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Amino-4-methylphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(2-morpholinoethoxy)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide 2-Fluoro-4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)-N,N-dimethylbenzamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(3-oxomorpholino)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Ethoxy-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 2-Fluoro-4-(1-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(methanesulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)-N-methylbenzamide N-(4-(2-(3-Aminophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Fluoro-3-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Ethoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4] azin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-methyl-4-oxo-3,4-dihydroquinazolin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(6-(Difluoromethoxy)pyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4] thiazin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide, N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-Amino-6-methylpyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-(2-hydroxyethyl)pyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Fluoro-4-(hydroxymethyl)phenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(quinolin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Fluoro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Amino-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Chloro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(2-morpholinoethyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Hydroxy-3-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Fluoro-4-isopropoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Cyano-3-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Fluoro-2-hydroxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(2-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(2-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((R)-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((S)-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(5-Chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(5-Chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide, and pharmaceutically acceptable salts and tautomers thereof 43. The compound according to claim 1, wherein the compound is selected from: (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-methyl-2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-(3-(4-Chlorophenyl)-3,3-difluoropropyl)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-(3,3-Difluoro-3-(4-fluorophenyl)propyl)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Fluoro-6-methylpyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(4-(morpholine-4-carbonyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-([1,1'-Biphenyl]-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3-(1-hydroxycyclopropyl)phenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-isopropoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Fluoro-2-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Cyano-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Fluoro-2-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-oxodihydroindol-7-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-Cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-Cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-2-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(6-Ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-([1,1'-Biphenyl]-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-Chloro-4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((R)-2-(4-Chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-((S)-2-(4-Chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and pharmaceutically acceptable salts and tautomers thereof.

44. The compound according to claim 1, wherein the compound is selected from:[[]] N-(4-(2-(3,4-Dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-chloro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-4-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxy-5-methylpyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(6-ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-chloro-3,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-chloro-2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-chloro-2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-chloro-2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,3-difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(6-aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,6-dimethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Fluoro-6-methoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2,3-Difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(2-Fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(5-Chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and their pharmaceutically acceptable salts and tautomers.

45. The compound according to claim 1, wherein the compound is selected from: N-(4-(-2-(4-Cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(2-(4-Chlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, and their pharmaceutically acceptable salts and tautomers.

46. A pharmaceutical composition comprising the compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt or tautomer thereof.

47. The compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt or tautomer thereof for use in the treatment of cardiovascular diseases.

48. The compound according to claim 47, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, a cardiovascular disease associated with an autoimmune disorder, a cardiovascular disease associated with a chronic inflammatory disease, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

49. A method of treating a cardiovascular disease, comprising administering to a human being suffering from or at risk of said disease or disorder a therapeutically effective amount of a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt or tautomer thereof.

50. The method according to claim 49, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, a cardiovascular disease associated with an autoimmune disorder, a cardiovascular disease associated with a chronic inflammatory disease, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

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