2,4,6-Trisubstituted 1,3,5-triazines as modulators of CXsub3CR1

Abstract

Disclosed are certain 2,4,6-trisubstituted 1,3,5-triazine compounds of formula (I), (I) and pharmaceutically acceptable salts thereof, as well as compositions containing them and their use in therapy. The compounds are modulators of CX3CR1 and are therefore particularly useful in the treatment or prevention of cardiovascular disorders such as non-ischemic dilated cardiomyopathy and heart failure. [Formula 1] JPEG2025537492000366.jpg39128

Description

[Technical Field]

[0001] (Related Applications) This application claims the benefit of priority to U.S. Provisional Application No. 63 / 417,472, filed October 19, 2022, which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Chemokines play important roles in immune and inflammatory responses in various diseases and disorders, including cardiovascular and respiratory diseases such as asthma, atherosclerosis, and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, lupus nephritis, and inflammatory myopathies. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterized by a conserved cysteine ​​motif. Currently, the chemokine superfamily includes four groups that exhibit characteristic structural motifs: the C-X-C, C-C, and C-X-C families, as well as the X-C family. The C-X-C and C-C families share sequence similarity and are distinguished from each other by a single amino acid insertion between the NH-proximal pair of cysteine ​​residues. The C-X-C family is distinguished from the other two families by a triple amino acid insertion between the NH-proximal pair of cysteine ​​residues. In contrast, members of the XC family lack one of the first two cysteine ​​residues.

[0003] CXC chemokines include several potent chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

[0004] CC chemokines include potent chemoattractants for monocytes, lymphocytes, and neutrophils.

[0005] The C-X3-C chemokine (also known as fractalkine, FKN, or CX3CL1) is a potent chemoattractant and activator of microglia, as well as monocytes, T cells, NK cells, and mast cells in the central nervous system (CNS). It also functions as an adhesion molecule on immune-activated cells, such as monocytes, for cellular infiltration from the blood into tissues. Blocking this interaction has been shown to reduce atherosclerosis progression and plaque growth (Poupel et al., Arterioscler. Thromb. Vasc. Biol., 2013, 33, 2297-2305). In humans, CX3CR1 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).

[0006] Neutralization of fractalkine improves cardiac function in a mouse myocardial infarction (MI) model by enhancing contractile function, ventricular remodeling, and reducing infarct size (Xuan et al. 2011, Cardiovascular Research 92, 385), and also improves LVEF and survival two weeks after treatment after inducing MI in mice (Gu et al. 2015, Exp Physiol 100, 805).

[0007] Additionally, fractalkine induces cardiac depressant effects with impaired contractility observed in mouse 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 the NYHA heart failure function score, and soluble fractalkine levels are increased in patients with HF (Husberg et al. J. of Mol. and Cellular Cardiology, 2008, 45(2), 261). sFKN concentrations have prognostic value in patients with acute myocardial infarction treated with primary percutaneous coronary intervention (Xu Bing et al. Cytokine 2019 113(365-370). Elevated sFKN plasma levels are a predictor of mortality in subjects with advanced systolic HF (Richter et al. 2012, Thrombosis & Haemostasis 108, 1220).

[0008] Studies have demonstrated that the actions of chemokines are mediated by subfamilies of G protein-coupled receptors, including CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, and CCR11 (for the CC family), CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5 (for the CXC family), and CX3CR1 for the C-X3-C family. These receptors represent good targets for drug development, as agents that modulate these receptors are useful in the treatment of disorders and diseases such as those mentioned above.

[0009] WO 2005 / 070903 discloses certain triazine derivatives for use in the treatment of chemokine-mediated diseases and disorders.

[0010] WO 2006 / 107258 discloses certain 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives as antagonists of the CX3CR1 receptor.

[0011] WO 2006 / 107257 and WO 2009 / 120140 disclose certain 5,7-disubstituted [1,3]thiazolo[4,5-d]pyrimidin-2(3H)one derivatives as antagonists of the CX3CR1 receptor.

[0012] WO2013039057 discloses certain pyrrolidin-3-ylacetic acid derivatives that have inhibitory activity in the fractalkine-CX3CR1 pathway.

[0013] Thus, the disease association of CX3CR1 activity has been implicated in cardiovascular disease (CVD), including heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, stable coronary artery disease, and atherosclerosis-related conditions.

[0014] There is a need for orally active modulators of CX3CR1 for the treatment of cardiovascular disease (CVD), such as heart failure, myocardial disease, and coronary artery disease-related conditions. DETAILED DESCRIPTION OF THE INVENTION

[0015] definition The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0016] The term "alkyl" or "alkane" refers to a straight-chain or branched non-aromatic hydrocarbon that is fully saturated. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl.

[0017] The term "alkoxyalkyl" refers to an alkyl group attached to an alkoxy group, where the group is attached to the remainder of the molecule through a carbon on the alkyl group, i.e., having the structure -RO-R', where R and R' are the same or different alkyl groups.

[0018] The term "aryl" refers to an aromatic hydrocarbon. The term aryl includes monocyclic aryls, such as phenyl, having a single ring, and polycyclic aryls, including bicyclic aryls, having two or more cyclic rings, where two or more atoms are common to two adjacent rings and at least one of the rings is aromatic, e.g., the other cyclic rings are cycloalkyl, cycloalkenyl, cycloalkynyl, and / or aryl. Examples of polycyclic aryl rings include naphthalene and tetrahydronaphthalene.

[0019] The term "cycloalkyl" refers to a partially or fully saturated monocyclic, bicyclic, polycyclic, or bridged hydrocarbon ring system.

[0020] The term "halo" refers to fluoro, chloro, bromo, and iodo. In one embodiment, halo is fluoro or chloro. In another embodiment, halo is fluoro. In yet another embodiment, halo is chloro.

[0021] The term "haloalkoxy" means an alkoxy in which one or more hydrogens have been replaced with halo.

[0022] The term "haloalkyl" means an alkyl group in which one or more hydrogens have been replaced with halo.

[0023] As used herein, the terms "heteroaryl" and "heteroarylene" refer to substituted or unsubstituted aromatic ring structures whose ring structures contain at least one heteroatom selected from nitrogen, oxygen, and sulfur. Heteroaryl and heteroarylene groups can be attached to the remainder of the molecule through a carbon or nitrogen ring atom. Heteroaryl / heteroarylene groups include monocyclic heteroaryls and polycyclic heteroaryls, e.g., bicyclic heteroaryls, having two or more cyclic rings in which two or more atoms are common to two adjacent rings, where at least one of the rings is aromatic and at least one of the rings 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, isoxazole, oxazole, oxadiazole, thiazole, and pyrazole. Examples of bicyclic heteroaryls include, but are not limited to, purine, indole, indazole, quinoline, quinazoline, benzofuran, benzoxazole, benzodioxole, benzodioxin, pyrrolopyridine, indazole, 2H-indazole, isoquinoline, tetrahydroisoquinoline, dihydroquinazoline, 1H-pyrrolo[2,3-b]pyridine, 2,3-dihydrobenzo[d]oxazole, 3,4-dihydroquinazoline, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-1,4-benzodioxin, and 2,3-dihydro-1-benzofuran. Additional polycyclic heteroaryls or heteroarylenes include, but are not limited to, carbazole and dibenzazepine.

[0024] The term "monocyclic N-heteroaryl" refers to a monocyclic heteroaryl whose ring structure contains at least one nitrogen. Examples of monocyclic N-heteroaryls include, but are not limited to, imidazole, pyrrole, triazole, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0025] The terms "heterocycle," "heterocyclic," or "heterocyclyl" refer to a partially or fully saturated hydrocarbon ring system in which at least one ring carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Heterocycle groups can be attached to the remainder of the molecule through a carbon or nitrogen ring atom. Heterocycles include monocyclic heterocycles and polycyclic heterocycles, such as bicyclic heterocycles. Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, piperidine, piperazine, oxetane, and isoxazolidine.

[0026] The term "hydroxy" refers to the group --OH.

[0027] The term "hydroxyalkyl" means an alkyl group in which one or more hydrogens have been replaced with hydroxy.

[0028] The term "oxo" refers to an "=O" group, ie, a substituted oxygen atom that is attached to another atom by a double bond.

[0029] As used herein, "C" refers to a compound in which x and y are integers. x~y The prefix C used in terms such as "alkyl" x~y indicates the range of the number of carbon atoms present in the group. 1~3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl. 1~4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In some cases, the group is C x~y In this case, the prefix indicates the range of carbon numbers in each part of the group, e.g., C 1~3 Alkoxy-C 1~4 Alkyl refers to alkoxyalkyl groups where the alkyl group has 1 to 3 carbons and the alkoxy group has 1 to 4 carbons.

[0030] compound One embodiment disclosed herein is a compound of formula (I):

[0031] [ka] During the ceremony, R 1 is C 3~6 Branched alkyl or C 3~6 is a branched haloalkyl; R 2 is C 1~3 Alkyl or C 1~3 is haloalkyl, m is 1 or 2; R 3 and R 4 are independently H, halo, and 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 are independently halo, 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, -(CH2) q CN, -C(O)NR 6 R 7 , -NS(O)R 6 R 7 , -(CH2) q R 8 , -C(O)R 8 , -C(O)OR 9 , -OC(O)R 9 , -NR 6 C(O)R 7 、 -NR 6 R7 , C 3~6 selected from cycloalkyl, 4- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl; During the ceremony, C 3~6 Cycloalkyl or 4-6 membered heterocyclyl includes hydroxy, oxy, halo, and -C(O)OR 9 may be optionally substituted with 1 to 3 substituents selected from the 4- to 6-membered heteroaryl is optionally substituted with 1 to 3 halo substituents; C 1~4 The alkoxy may be optionally substituted with a 4- to 6-membered heterocyclyl; Each R 6 and R 7 are independently H and C 1~3 alkyl, each q is independently 1, 2, or 3; Each R 8 is independently a 4- to 6-membered heterocyclyl, wherein the heterocyclyl is optionally substituted with oxy; Each R 9 independently, C 1~5 a compound, or a stereoisomer, a pharmaceutically acceptable salt, or a tautomer thereof.

[0032] Another embodiment disclosed herein is a compound having the following structure:

[0033] [ka] and In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , m, p, and A are as defined above for formula (I).

[0034] Another embodiment disclosed herein is a compound having the following structure:

[0035] [ka] wherein R 1 , R 2 , R 3 , R 5 , m, p, and A are as defined above for formula (I).

[0036] Some embodiments disclosed herein provide compounds 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.

[0037] Some embodiments disclosed herein provide compounds 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 monocyclic heteroaryl.

[0038] Some embodiments disclosed herein provide compounds 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 monocyclic N-heteroaryl.

[0039] Some embodiments disclosed herein provide compounds 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.

[0040] Some embodiments disclosed herein provide compounds 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.

[0041] 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.

[0042] 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.

[0043] Some embodiments disclosed herein include those in which A is phenyl or 6-membered monocyclic heteroaryl, p is at least 1, and R 5 is para to the ring atom attached to the compound (e.g., R 5 But R 3 -R 4 and para to the ring atom bonded to the substituted carbon), or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0044] Some embodiments disclosed herein include those in which A is phenyl or 6-membered monocyclic heteroaryl, p is at least 1, and R 5 is ortho to the ring atom attached to the compound (e.g., R 5 But R 3 -R 4 ortho to the ring atom bonded to the substituted carbon), or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0045] Some embodiments disclosed herein include those in which A is phenyl or 6-membered monocyclic heteroaryl, p is at least 1, and R 5is meta to the ring atom attached to the compound (e.g., R 5 But R 3 -R 4 wherein the carbon atom bonded to the substituted carbon is meta to the ring atom bonded to the substituted carbon, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0046] Some embodiments disclosed herein include at least one R 5 is halo, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0047] Some embodiments disclosed herein include at least one R 5 is F, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0048] Some embodiments disclosed herein include at least two R 5 is F, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0049] Some embodiments disclosed herein include at least three R 5 is F, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0050] Some embodiments disclosed herein include at least one R 5is Cl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0051] Some embodiments disclosed herein include at least two R 5 is Cl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0052] Some embodiments disclosed herein include at least one R 5 C 1~4 Provided is 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:

[0053] Some embodiments disclosed herein include at least one R 5 is —OCH3, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0054] Some embodiments disclosed herein include at least one R 5 is —OCH2CH3, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0055] Some embodiments disclosed herein include at least one R 5 C 1~4Provided is a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, which is haloalkoxy.

[0056] Some embodiments disclosed herein include at least one R 5 is C1-C3 alkyl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0057] Some embodiments disclosed herein include at least one R 5 is methyl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0058] Some embodiments disclosed herein include at least one R 5 is hydroxy or C1-C3 hydroxyalkyl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0059] Some embodiments disclosed herein include R 3 or R 4 One of them is C 1~3

[0013] Provided is 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:

[0060] Some embodiments disclosed herein include R 3 or R 4is methyl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0061] Some embodiments disclosed herein include R 3 or R 4 is ethyl, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof.

[0062] Some embodiments disclosed herein provide compounds 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 or R is H.

[0063] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), or (Ie) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R4 is H.

[0064] Some embodiments disclosed herein provide compounds 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 or R is halo.

[0065] Some embodiments disclosed herein are those in which R is C 3~6 Provided is 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:

[0066] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R1 is a C4 branched alkyl.

[0067] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R is —CHCH(CH).

[0068] Some embodiments disclosed herein are those in which R2 is C 1~3

[0013] Provided is 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:

[0069] Some embodiments disclosed herein provide compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R2 is methyl.

[0070] Some embodiments disclosed herein provide compounds 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.

[0071] Some embodiments disclosed herein provide compounds 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.

[0072] Some embodiments disclosed herein provide compounds 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.

[0073] Some embodiments disclosed herein provide compounds 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.

[0074] Some embodiments disclosed herein provide compounds 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.

[0075] Some embodiments disclosed herein provide compounds 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.

[0076] Some embodiments disclosed herein include: 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-(methylsulfonamido)-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 -sulfanylidene)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-(methylsulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)-N-methylacetamide, 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-oxoisoxazolidin-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-(methylsulfonamido)-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-(methylsulfonamido)-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]oxazin-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]oxazin-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, Provided is a compound selected from 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.

[0077] Some embodiments disclosed herein include: (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-oxoindolin-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, Provided is a compound selected from 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.

[0078] Some embodiments disclosed herein include: 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, Provided is a compound selected from 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 pharmaceutically acceptable salts and tautomers thereof.

[0079] Some embodiments disclosed herein include: N-(4-(-2-(4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Provided is a compound selected from N-(4-(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.

[0080] Some embodiments disclosed herein provide pharmaceutical compositions 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.

[0081] For the avoidance of doubt, when a group is modified herein by "as defined above," it is to be understood that this group encompasses the broadest definition occurring first, as well as each and every other definition for that group. It is to be understood that any definition, claim, aspect, or embodiment of a variable group of the formula disclosed herein may be combined (where context allows) with any other definition, claim, aspect, or embodiment herein to provide further embodiments of the present invention.

[0082] It should be noted that any one of these specific compounds may be dispensed with as a marker for any of the embodiments mentioned herein.

[0083] In one embodiment, provided are processes for the preparation of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, and intermediates used in their preparation.

[0084] Another embodiment is a product obtainable by any of the processes or examples disclosed herein.

[0085] Medical and Pharmaceutical Uses Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of cardiovascular disease in mammals, particularly humans. Cardiovascular disease includes, but is not limited to, conditions associated with cardiac dysfunction and / or microvascular dysfunction and / or macrovascular pathology, such as atherosclerosis, arteriosclerosis, coronary artery disease, including stable and high-risk coronary artery disease (defined as recent acute coronary syndrome (ACS) or by biomarkers of microvascular and cardiac dysfunction), ischemic heart disease, myocardial infarction, restenosis after revascularization, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD), including erectile dysfunction due to vascular disease, stroke, cardiomyopathies, including non-ischemic dilated cardiomyopathy, transient ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia, renovascular disease, and renal artery disease.

[0086] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of non-ischemic dilated cardiomyopathy.

[0087] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful for the prevention or treatment of cardiovascular disease in patients with co-morbidities such as renal insufficiency.

[0088] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of cardiovascular disease associated with chronic inflammatory diseases, for example, inflammatory arthropathies / multisystem diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and psoriatic arthropathy.

[0089] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of cardiovascular disease associated with autoimmune conditions, for example, inflammatory arthropathies / multisystem diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and psoriatic arthropathy.

[0090] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful for the prevention or treatment of heart failure, including heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction.

[0091] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of inflammatory bowel disease.

[0092] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of lupus nephritis.

[0093] The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of patients who remain at risk for cardiovascular events despite standard of care (SoC) treatment, including, but not limited to, lipid-lowering statins, antiplatelet agents, ACE inhibitors, mineralocorticoid receptor antagonists, and beta-blockers.

[0094] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of chronic kidney disease.

[0095] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of type II diabetes mellitus and complications of type II diabetes mellitus in mammals, particularly humans, including, but not limited to, diabetic micro- and macrovascular pathology, neuropathy, and nephropathy.

[0096] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of renal inflammatory and vascular diseases and complications associated with renal disease in mammals, particularly humans, including, but not limited to, chronic kidney disease, drug- and toxin-induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephritis, reflux nephropathy, focal segmental glomerulosclerosis, Henoch-Schönlein purpura, and diabetic nephropathy.

[0097] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of autoimmune diseases such as, but not limited to, dermatomyositis, polymyositis, and systemic lupus erythematosus (SLE).

[0098] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and ASH (alcoholic steatohepatitis).

[0099] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may reduce morbidity and mortality from cardiovascular and / or cerebrovascular and / or renal and / or peripheral arterial disease associated with cardiac dysfunction and / or atherosclerosis, and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology due to their anti-inflammatory properties and effects on vasoactive mechanisms.

[0100] 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 useful for preventing or reducing the risk of developing cardiac dysfunction and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology, as well as for halting or slowing the progression and / or promoting the regression of atherosclerotic cardiovascular disease once it has become clinically evident, comprising administering, as appropriate, 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 already having atherosclerotic cardiovascular disease.

[0101] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in preventing or reducing the occurrence or severity of acute events associated with atherosclerotic plaque rupture or erosion, including, but not limited to, myocardial infarction, unstable angina, and stroke.

[0102] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in preventing or reducing the occurrence or severity of acute events by improving microvascular function, macrovascular pathology, and / or cardiac function.

[0103] Compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in preventing or reducing the incidence of progression and rupture of abdominal aortic aneurysms (AAA).

[0104] Compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be useful in the prevention or treatment of respiratory inflammatory diseases and complications associated with respiratory inflammatory diseases in mammals, particularly humans, including, but not limited to, asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis.

[0105] Some embodiments disclosed herein provide methods of treating or preventing one or more of the diseases or conditions discussed herein, comprising administering to a person suffering from or at risk of the disease or condition 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.

[0106] Some embodiments disclosed herein provide a method of treating or preventing non-ischemic dilated cardiomyopathy, 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.

[0107] Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease in a patient with a co-morbid condition, such as renal insufficiency, 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.

[0108] Some embodiments disclosed herein provide a method of treating or preventing cardiovascular disease associated with chronic inflammatory diseases, e.g., inflammatory arthropathies / multisystem diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still's disease, and psoriatic arthropathy, 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.

[0109] Some embodiments disclosed herein provide a method of treating or preventing heart failure, 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. In further embodiments, the heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

[0110] Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, 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.

[0111] Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, 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.

[0112] Some embodiments disclosed herein provide methods of treating or preventing respiratory inflammatory diseases and complications associated with respiratory inflammatory diseases, 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. In further embodiments, the respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue disease, and / or rhinitis.

[0113] The terms "preventing," "prevention," and "prevent" are readily understood by an ordinarily skilled physician and are intended to have their ordinary meaning in relation to the treatment of a particular condition, and may include primary prevention, to prevent the onset of a condition, and secondary prevention, where the condition has already occurred and the patient is protected, either temporarily or permanently, from progression or worsening of the disease or the onset of new symptoms associated with the condition.

[0114] The terms "treating," "treatment," and "treat" are readily understood by an ordinarily skilled physician and, with respect to the treatment of a particular condition, can include (1) reducing the extent or cause of the condition being treated, and / or (2) alleviating or ameliorating one or more symptoms associated with the condition. Treating cardiovascular disease can include, for example, stabilizing (i.e., not worsening), slowing, or delaying the spread or progression of cardiovascular disease; prolonging survival compared to expected survival in the absence of treatment; and / or ameliorating or alleviating, in whole or in part, the severity of cardiovascular disease.

[0115] The compounds disclosed herein may have the advantage that they may be more effective, less toxic, more selective, more potent, produce fewer side effects, be more easily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than compounds known in the prior art.

[0116] These and other embodiments are described in more detail herein below, and further aspects will become apparent to those skilled in the art upon reading the present specification.

[0117] Pharmacological properties The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, are believed to be useful for the prevention or treatment of cardiovascular conditions, 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, in mammals, particularly humans.

[0118] When a compound or salt described herein is administered as therapy to treat a disorder, a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate the symptoms or other deleterious effects of the disorder, cure the disorder, reverse, halt entirely, or slow the progression of the disorder, or reduce the risk of the disorder worsening.

[0119] The compounds described herein are therefore indicated in both the therapeutic and / or prophylactic treatment of these conditions.

[0120] Pharmaceutical Composition Methods for treating a condition requiring modulation of CX3CR1 are provided, comprising administering to a person suffering from or susceptible to such a condition 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.

[0121] The compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or the compounds disclosed herein, or their pharmaceutically acceptable salts, are typically administered orally, topically, parenterally, intravenously, intramuscularly, subcutaneously, or via other injection methods, buccal, rectal, vaginal, transdermal, and / or nasal routes, and / or via inhalation, in the form of pharmaceutical preparations containing the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form. Depending on the disorder and patient to be treated and the route of administration, the composition may be administered in various dosage forms. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in Pharmaceuticals - The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2002. nd It is described in Ed.2002.

[0122] The optimal dosage and frequency of administration will depend on the particular condition being treated and its severity, the patient species, the age, sex, size and weight, diet, and general health of the particular patient, brain / body weight ratio, other medications the patient may be taking, the route of administration, the formulation, and a variety of other factors known to physicians and others skilled in the art.

[0123] According to a further aspect, there is therefore 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, in admixture with a pharmaceutically acceptable adjuvant, diluent, and / or carrier.

[0124] A 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 0.1 to 99.5% by weight of the total formulation, such as 0.5 to 95% by weight. Further embodiments include a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a pharmaceutically acceptable salt of a compound disclosed herein.

[0125] Salts of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, may be advantageous due to one or more of their chemical or physical properties, such as stability at different temperatures and humidities, or desirable solubility in HO, oil, or other solvents. In some cases, salts may be used to aid in the isolation or purification of the compound. In some embodiments (particularly when the salt is intended for administration to animals, e.g., humans, or when the salt is a reagent for use in making compounds or salts intended for administration to animals), the salt is pharmaceutically acceptable.

[0126] The term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as appropriate for use according to sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0127] If the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid addition salts. If the compound is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base addition salts.

[0128] For a review on suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0129] It is also to be understood that certain compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, can exist in solvated forms, such as hydrates, including solvates of pharmaceutically acceptable salts of compounds of Formula (I).

[0130] It should also be understood that certain compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can exist as a mixture of tautomers. "Tautomers" are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom, e.g., amide-imidic acid tautomerism. The disclosure herein includes all tautomers of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof.

[0131] In certain embodiments, certain compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, can 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, can contain bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) where bond rotation is restricted about that particular bond, for example, by the presence of a ring bond or double bond. Stereoisomers can be separated using conventional techniques, such as chromatography or fractional crystallization, or stereoisomers can be made by stereoselective synthesis.

[0132] The compound of formula (I) below is R 3 and R 4 are identical, contain one stereocenter, or R 3 and R 4 are not identical, it contains two stereocenters and can therefore exist in the following stereoisomeric forms shown in formula (Ib), (Ic), (Id), or (Ie).

[0133] [ka]

[0134] Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.

[0135] In further embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or pharmaceutically acceptable salts thereof, include any isotopically labeled (or "radiolabeled") derivative 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 have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that may be incorporated into a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, include 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 Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0136] In a further embodiment, the compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or compounds disclosed herein, or a pharmaceutically acceptable salt thereof, may be administered in the form of a prodrug that is broken down in the human or animal body to yield a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), or (If), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0137] Various forms of prodrugs are known in the art, see Nature Reviews Drug Discovery 2008, 7, 255 and references cited therein for examples of prodrug derivatives.

[0138] Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures. [Example]

[0139] The following examples are non-limiting examples.

[0140] Synthesis method General conditions (i) the operation is carried out, if necessary, under an atmosphere of an inert gas such as N2, at room temperature (rt), i.e., in the range of 17-28°C; optionally, the reaction is carried out using an MBRAUN UNILab Plus ECO or MBRAUN UNILab SP Eco glovebox workstation (as shown in this case); (ii) where the reaction is referred to as being degassed or purged, this can be accomplished, for example, by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (e.g., 5-10 minutes), or by repeatedly evacuating the vessel and backfilling it with a suitable inert atmosphere (e.g., nitrogen(g) or argon(g)); (iii) if the reaction refers to the use of a microwave reactor, use one of the following microwave reactors: Biotage Initiator, Personal Chemistry Emrys Optimizer, Personal Chemistry Smith Creator, or CEM Explorer; (iv) the progress of the reaction is generally followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC), usually coupled to a mass spectrometer (LCMS); (v) If necessary, the organic solution was dried over anhydrous MgSO or NaSO, or dried using an ISOLUTE® Phase Separator, and work-up procedures were carried out using conventional phase separation techniques. For example, when using a drying agent such as MgSO or NaSO to dry the organic layer, it is understood that the organic layer will be filtered before being concentrated. (vi) evaporation was performed either by rotary evaporation in vacuo or in a Genevac HT-4 / EZ-2 or Biotage V10; (vii) Unless otherwise stated, flash column chromatography was performed on normal-phase silica using either Merck Silica Gel (Art. 9385) or preparatively packed cartridges such as Biotage® SNAP cartridges (40-63 μm silica, 4-330 g), Biotage® Sfar silica HC D cartridges (20 μm, 10-100 g), Interchim puriFlash™ cartridges (25 μm, 4-120 g), Interchim puriFlash™ cartridges (50 μm, 25-330 g), Grace® GraceResolv™ Silica Flash cartridges (4-120 g) or Agela Flash Column Silica-CS cartridges (80-330 g), or on reverse-phase silica, spherical cartridges (20-35 μm, 100 A, 80-330 g) using Agela Technologies C-18. performed manually or automated using the Reveleris® X2 Flash System or similar system; (viii) Preparative reversed-phase HPLC and preparative reversed-phase SFC were carried out using standard HPLC and SFC equipment, respectively, equipped with either MS and / or UV-triggered fraction collection equipment, using either an isocratic or gradient mobile phase as described in the experimental section, and one of the following methods: Preparative method A: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 50 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative method B: Compounds were purified by preparative HPLC on a Kromasil C8 column (10 μm, 250 × 20 mm ID) using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative Method C: The compound was purified by preparative HPLC on an unspecified column using a gradient of MeCN in HO / MeCN / FA (95 / 5 / 0.2) as the mobile phase; Preparative Method D: The compound was purified by preparative HPLC on an XBridge™ C18 column (10 μm, 250 × 19 mm ID) using a gradient of MeCN in HO / MeCN / NH3 (95 / 5 / 0.2) as the mobile phase; Preparative Method E: The compound was purified by preparative HPLC on an Xbridge™ C18 ODB column (5 μm, 150 × 30 mm ID) using a gradient of MeCN in HO / NH3 (0.2%, pH 10) buffer system as the mobile phase; Preparative Method F: The compound was purified by preparative HPLC on an XBridge™ C18 Preparative Method G: Compounds were purified by preparative HPLC on a Phenomenex Luna Hilic column (5 μm, 250×30) using a gradient of MeCN in a HO / NH (0.2%, pH 10) buffer system as the mobile phase; Preparative Method H: Compounds were purified by preparative HPLC on a Waters Viridis 2-EP column (5 μm, 250×30) using 20 mM MeOH / NH as the mobile phase; Preparative Method I: Compounds were purified by preparative HPLC on an Xbridge™ C18 ODB column (5 μm, 100×10 mm ID) using HO / NH (0.2%, pH 10) as the mobile phase.Preparative Method J: Compounds were purified by preparative HPLC on an Acquity™ UPC2 BEH column (3.5 μm, 100×3 mm ID) using a MeOH / H2O / NH3 (97 / 3 / 50 mM) buffer system as the mobile phase; Preparative Method K: Compounds were purified by preparative HPLC on a Virdis™ BEH OBD column (5 μm, 250×30 mm ID) using a MeOH / H2O / NH3 (97 / 3 / 50 mM) buffer system as the mobile phase; Preparative Method L: Compounds were purified by preparative HPLC on a Virdis™ BEH column (5 μm, 250×30 mm ID) using an EtOH / FA 20 mM buffer system as the mobile phase; Preparative Method M: Compounds were purified by preparative HPLC on a Sunfire™ C18 ODB column (5 μm, 150×30 mm ID) using an EtOH / FA 20 mM buffer system as the mobile phase. Preparative method N: Compounds were purified by preparative HPLC on a Sunfire™ C18 ODB column (5 μm, 100×10 mm ID) using a gradient of MeCN (0.1 M aq) buffer system in FA as the mobile phase; Preparative method O: Compounds were purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 250×19 mm ID) using a gradient of MeCN (0.1 M aq) buffer system in FA as the mobile phase; Preparative method P: Compounds were purified by preparative HPLC on an XSelect CSH Prep C18 OBD column (5 μm, 150×30 mm ID) using a gradient of MeCN (0.1 M aq) buffer system in FA as the mobile phase; Preparative method Q: Compounds were purified by preparative HPLC on a Waters™ BEH (5 μm, 30×250 mm ID) using a gradient of MeCN (0.1 M aq) buffer system in FA as the mobile phase. The purified product was purified by preparative SFC on a 1000 bp column using EtOH / FA (20 mM) in CO2 as the mobile phase; The relevant fractions were collected, combined, and lyophilized or evaporated to give the purified compound, or the relevant fractions were collected, combined, concentrated under reduced pressure, the aqueous layer extracted with DCM or EtOAc, and the organic layer dried over Na2SO4 or by using a phase separator, then concentrated under reduced pressure and dried in vacuo if necessary to give the purified compound. (ix) Chiral preparative chromatography was performed using HPLC or SFC on standard HPLC or SFC equipment, respectively, using either isocratic or gradient runs with mobile phases as described in the Experimental Section; (x) yields, if any, are not necessarily the maximum achievable and, if necessary, reactions were repeated when larger amounts of reaction product were required; (xi) When a particular compound is obtained as an acid addition salt (e.g., a 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 is not generally determined, for example, by elemental analysis data; (xii) In general, the structure of the final product of formula (I) was confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry techniques; proton NMR chemical shift values ​​were 300, 400, 500 and 600 MHz, respectively. 1Measurements were made on a Bruker Avance III 300, 400, 500, and 600 spectrometer operating at H frequencies on the delta scale. Experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the solvent as the internal standard. Protons on heteroatoms, such as NH and OH protons, are reported only if detected in the NMR and may therefore be missing. In certain instances, protons may be masked or partially masked by the solvent peak and therefore either missing and not reported, or reported as a multiplet overlapping with the solvent. The following abbreviations (and their derivatives, e.g., dd, doublet of doublet, etc.) are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. It is understood that if the NMR spectrum contains residual impurities and / or residual solvents, these will not be reported unless they partially coincide with the peaks of the intermediates and / or the structure of formula (I), in which case the peaks of the intermediates and / or the structure of formula (I) will be reported as multiplets that partially overlap with the solvent or impurities, and the integrals will be omitted. In some cases, the structure of the final product of formula (I) may appear as rotamers in the NMR spectrum, in which case only the peak of the major rotamer will be reported. In some cases, the structure of the final product of formula (I) may appear as more equally related rotamers, in which case the peaks of such rotamers will be reported either as multiplets if the signals of the rotamers partially overlap, or as individual peaks if the signals of the rotamers are sufficiently separated; Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar instrument, acquiring both positive and negative ion data, with generally only ions associated with the parent structure being reported; high-resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar instrument, acquiring either positive or negative ion data, with generally only ions associated with the parent structure being reported; (xiii) intermediates were not necessarily completely purified, but their structure and purity were assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; (xiv) Unless otherwise specified, compounds containing asymmetric carbon and / or sulfur atoms were not resolved; (xv) Examples and intermediate compounds are generally named using PerkinElmer's ChemDraw Professional Version 20.1.1.125 or Version 21.0.0. ChemDraw Professional Version 20.1.1.125 or Version 21.0.0 generates names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules whenever possible when generating chemical names. Stereoisomers are cited by name and distinguished from one another by stereodescriptors assigned according to the CIP rules.

[0141] ChemDraw optionally uses stereocenter indicators such as "&" and "or" in its drawings to describe the configuration of stereochemical centers present in a structure. A number following the "&" and "or" flag is assigned to each stereocenter present in the structure. The numbers are automatically incremented to indicate that the stereocenters can vary independently of each other.

[0142] In general, for chemical structures of examples and intermediates where two or more stereocenters are present and the stereocenters have fixed relative configurations, the same numbers are used after the labels "&" and "or" to indicate that the stereocenters form a group. A third stereocenter that is present in the same chemical structure and varies independently of the previous stereocenter is designated with a unique new number following the labels "&" and "or".

[0143] In general, chemical structures of examples and intermediates containing the label "&" at a stereocenter mean that the configuration of such example or intermediate at that stereocenter is a mixture of both (R) and (S); the label "or" means that the configuration of such example or intermediate is either (S) or (R) at the stereocenter. All unidentified absolute stereocenters "&" and "or" may be present in a single structure.

[0144] In general, for structures of examples and intermediates where all stereocenters are designated with "&", the structures are named with the prefix "rac-".

[0145] The descriptors (RS) and (SR) are used to indicate a generic "&" center for chemical structures with multiple chiral centers, only some of which are designated as "&".

[0146] In general, for structures of examples and intermediates where all of the stereocenters are designated "or," the structures are named with the prefix "rel-."

[0147] Descriptor (R * ) and (S * ) is used to indicate a general "or" center for chemical structures with multiple chiral centers, only some of which are designated as "or." (R * ) or (S * Examples or intermediates having a stereocenter labeled with (R) have the absolute configuration at that stereocenter, and the stereocenter in the compound is (R * ) or (S *), it is understood that the actual stereochemistry of that particular isomer may be the opposite of the label. For example, in Example 1, the first-eluting 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 designated "N-(4-((R * )-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide," but it may 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. Similarly, the second eluting isomer from the chiral separation of Example 2, 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 "N-(4-((S * )-2-(3,4-dichlorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide," but may 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. Furthermore, Example 1 is shown as follows,

[0148] [ka] The actual structure of Example 1 (i.e., the first-eluting isomer) is:

[0149] [ka] It should be understood that this may be the case.

[0150] Generally, for chemical structures of examples and intermediates where a stereocenter is present and is racemic, no label is assigned to the stereocenter and the bond to the stereocenter is drawn as a straight bond.

[0151] Generally, the label "Isomer 1" corresponds to the first eluting isomer and "Isomer 2" corresponds to the second eluting isomer on a given chiral HPLC column and eluent, and is used to distinguish between two isomers containing one or more stereocenters with unknown absolute configuration; (xvi) In addition to those above, the following abbreviations and units are used:

[0152] [Table 1-1]

[0153] [Table 1-2]

[0154] unit C Celsius g grams h time L liters M moles / liter mg milligram MHz Megahertz min mL milliliter mm millimeters mol mole mmol millimole μm micrometer μmol micromol μL microliter nm nanometer ppm (parts per million)

[0155] General synthetic scheme The compound of formula (I) can be prepared by reacting a compound of formula (II) 1 and R 2 is as defined in formula (I) and LG1 is a suitable leaving group such as halo or OTf, for example chloro,

[0156] [ka] Formula (III) (where A, R 3 , R 5 and p is as defined in formula (I)) with a coupling partner of formula (I).

[0157] [ka]

[0158] Compounds of formula (II) can also be protected at the hydroxyl moiety with suitable protecting groups, for example silyl groups 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", 4 th edition, T.W. Greene & P. ​​G.M. Wutz, Wiley-Interscience (2007).

[0159] The compound of formula (III) 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 1-24 hours or at elevated temperatures, such as 35°C to reflux, for 1-2 hours. The compound of formula (II), as defined above, is then added along with an inorganic salt, such as KPO or CsOH, and a catalytic amount of a palladium source, such as Pd(dppf)Cl·DCM. The resulting reaction mixture is stirred at temperatures ranging from 35°C to reflux for an extended period of time, such as 2-48 hours, until the reaction is complete, yielding the compound of formula (I).

[0160] Compounds of formula (II) can be prepared by reacting compounds of formula (V) (wherein R 1 is as defined in formula (I), and compounds of formula (VI) 2 is as defined in formula (I)) with a compound of formula (IV) where LG1 is as defined in formula (II).

[0161] Scheme 1

[0162] [ka]

[0163] A solution of a compound of formula (V) in a suitable organic solvent (e.g., 2-MeTHF) is added to a solution of (IV) in an organic solvent (e.g., 2-MeTHF) at −35° C. to −10° C., and then an organic base (e.g., DIPEA) dissolved in an organic solvent (e.g., 2-MeTHF) is added to the reaction mixture at −35° C. to 0° C. The reaction mixture is stirred until complete, after which any solids are filtered off. The filtrate is added to a compound of formula (VI) in an organic solvent (e.g., DMA) and an inorganic base (e.g., KCO), and the reaction mixture is stirred at an elevated temperature, e.g., 70° C. to 80° C., for an extended period of time, e.g., 48 hours, until the reaction is complete, to give a compound of formula (II).

[0164] Compounds of formula (IV), (V) and (VI) are commercially available or can be prepared by conventional methods by one skilled in the art.

[0165] Compounds of formula (III) can be prepared by the method shown in Scheme 2 from compounds of formula (VII) or (VIII) and (IX) (wherein A, R 3 , R 5 and p is as defined in formula (I).

[0166] Scheme 2

[0167] [ka]

[0168] Method a: The compound of formula (III) can be prepared by the Wittig reaction between the compound of formula (VII) and a suitable phosphonium salt, such as methyltriphenylphosphonium bromide, using a suitable base, such as KOTBu or n-BuLi, in an inert solvent, such as EtO or THF. Before adding the compound of formula (VII), the base and the phosphonium salt may be premixed in the solvent at -10°C to 40°C for 30 minutes to 1 hour, and the reaction is maintained at a temperature ranging from room temperature to 50°C for a reaction time of 1 hour to 24 hours until the reaction is complete, to obtain the compound of formula (III).

[0169] A compound of formula (VIII) can be reacted with a compound of formula (IX) to give a compound of formula (III). The reaction can be carried out in the presence of a base, for example, an inorganic base such as K2CO3, Cs2CO3, or CsOH, using an organic solvent such as THF or 1,4-dioxane together with water, at an elevated temperature, for example, in the range of 50°C to 95°C, for an extended period of time, for example, 2 hours to 24 hours, until the reaction is complete, using a catalytic amount of a palladium source, for example, Pd(dppf)Cl2·DCM or Pd(dtbpf), to give a compound of formula (III).

[0170] Compounds of formula (VII) can be prepared by reacting compounds of formula (X) (wherein A, R5 and p is as defined in formula (I)) in a two-step sequence.

[0171] Scheme 3

[0172] [ka]

[0173] Step 1: Compounds of formula (X) are reacted with a suitable R 3 Group(R 3 is as defined in formula (I)) to give an alcohol of formula (XI).

[0174] Step 2: Preparation of a compound of formula (XI) 3 , R 5 and p is as defined in formula (I)) can be reacted with a suitable oxidizing reagent, for example, Dess-Martin periodinane, in an inert solvent to give a compound of formula (VII).

[0175] Compounds of formula (VII) can be prepared by reacting compounds of formula (XII) (wherein A, R 5 and p is as defined in formula (I)) in a two-step sequence.

[0176] Scheme 4

[0177] [ka]

[0178] Step 1: A compound of formula (XII) can be reacted with N,O-dimethylhydroxylamine hydrochloride using a suitable coupling reagent, for example, TBTU, in the presence of an organic base such as DIPEA and using a solvent such as DCM to provide the corresponding Weinreb amide of formula (XIII).

[0179] Step 2: Preparation of a compound of formula (XIII) 5 and p is as defined in formula (I)) in an inert solvent such as THF, 3 -group(R 3 is as defined in formula (I)) to give a compound of formula (VII).

[0180] Certain compounds of formula (VII), (VIII), (IX), (X), (X1), (XII), and (XIII) are commercially available or can be prepared by conventional methods by one skilled in the art.

[0181] The compound of formula (I) can be prepared by reacting a compound of formula (XIV) 1 , R 3 , R 5 and p is as defined in formula (I), and LG1 is a suitable leaving group such as halo or OTf, e.g., chloro,

[0182] [ka] It can be formed by reaction with a coupling partner of formula (VI) as defined above.

[0183] The compound of formula (I) can be prepared by reacting a compound of formula (XIV-a) (wherein A, R 1 , R 3 , R 4 , R 5 and p is as defined in formula (I), and LG1 is a suitable leaving group such as halo or OTf, e.g., chloro,

[0184] [ka] It can be formed by reaction with a coupling partner of formula (VI) as defined above.

[0185] A catalytic amount of a phosphine ligand, e.g., X-Phos, and a palladium source, e.g., Pd2dba3, are premixed in a suitable solvent, e.g., THF, under an inert atmosphere, and then a compound of formula (XIV) or a compound of formula (XIV-a) and a compound of formula (VI) are added together with a base, e.g., K2CO3, and the reaction is carried out under an inert atmosphere at an elevated temperature, e.g., 70°C, for a long period of time, e.g., overnight, until the reaction is complete, to give a compound of formula (I).

[0186] Compounds of formula (XIV) can be prepared by the conversion of compounds of formula (XV) (wherein R 1 and R 3 is as defined in formula (I) and LG is a suitable leaving group such as halo or OTf, e.g., chloro), with a compound of formula (XVI) 5 and p is as defined in formula (I), and B is a boron species, for example, a boronic acid or boronic ester.

[0187] Scheme 5

[0188] [ka]

[0189] A catalytic amount of a suitable organometallic catalyst, for example, [Rh(COD)Cl], is added to the compound of formula (XV) and the compound of formula (XVI), together with a base such as KOH, and an organic solvent such as 1,4-dioxane is used together with water, and the mixture is heated at an elevated temperature, for example, 50°C to 95°C, for a long period of time, for example, 2 hours to 24 hours, until the reaction is complete, to obtain the compound of formula (XIV).

[0190] Compounds of formula (XV), which may be cis or trans isomers or a mixture of both, can be prepared by the conversion of compounds of formula (XVII), where R 3can be prepared by sequentially reacting a compound of formula (I), where M is a metal or halometal, usually MgBr, and formula (V), as defined above, with a compound of formula (IV), as defined above.

[0191] Scheme 6

[0192] [ka]

[0193] A solution of a 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), the mixture is allowed to reach room temperature for a short period of time (usually 30 minutes), then cooled, a solution of a compound of formula (V) in a suitable organic solvent (e.g., THF) and an organic base (e.g., DIPEA) is added, and the reaction mixture is allowed to reach room temperature over an extended period of time until complete, yielding a compound of formula (XV).

[0194] Compounds of formula (XVI) and (XVII) are commercially available or can be prepared by conventional methods by one skilled in the art.

[0195] The compound of formula (I) can be prepared by reacting a compound of formula (XVIII) 1 , R 2 , and R 3 is as defined in formula (I),

[0196] [ka] It can be prepared by reacting with a coupling partner of formula (XVI) as defined above, which reaction can be carried out in a similar manner to the preparation of formula (XIV).

[0197] The compound of formula (XIV) can also be prepared from a compound of formula (XIX) 3 , R 5and p is as defined in formula (I), and LG1 is a suitable leaving group such as halo or OTf, e.g., chloro,

[0198] [ka] It can be prepared by reacting a compound of formula (V) with a suitable solvent, such as THF or MeCN, and a base, such as K2CO3, for an extended period of time, such as 2 hours to 24 hours at room temperature, until the reaction is complete, to give a compound of formula (XIV).

[0199] Compounds of formula (XIX) can be prepared by reacting compounds of formula (XX) (wherein A, R 3 , R 5 and p is as defined in formula (I)) in a two-step sequence.

[0200] Scheme 7

[0201] [ka]

[0202] Step 1: A compound of formula (XX) can be reacted with diphenyl iminodicarboxylate in a suitable solvent, such as MeCN, in the presence of a base such as K2CO3, at a temperature ranging from room temperature to 70°C for a long period of time, such as 2 hours to 24 hours, until the reaction is complete, to give a compound of formula (XXI).

[0203] Step 2: Preparation of a compound of formula (XXI) 3 , R 5 and p is as defined in formula (I)) can be reacted with a suitable reagent, for example, excess POCl, with or without an amine base such as N,N-diethylaniline as an additive, at an elevated temperature ranging from 70°C to reflux for a long reaction time, for example, 1.5 hours to 15 hours, until the reaction is complete, to give the compound of formula (XIX).

[0204] The compound of formula (XX) defined above can be prepared by reacting a compound of formula (XXII) 3 , R 5 and p can be prepared from formula (I) according to the method shown in Scheme 8.

[0205] Scheme 8

[0206] [ka]

[0207] Method a: The compound of formula (XX) can be prepared by adding the compound of formula (XXII) to a mixture of AlMe3 and NH4Cl in an inert solvent, such as toluene, at a temperature ranging from 70°C to 90°C for an extended reaction time until the reaction is complete to give the compound of formula (XX).

[0208] Method b: Step 1: Preparation of a compound of formula (XXIII) (A, R 3 , R 5 and p is as defined in formula (I)) can be prepared by adding AcCl to a cold solution of a compound of formula (XXII) in a suitable solvent, for example, EtOH, and allowing the temperature to reach room temperature over an extended period of time, for example, 15 to 24 hours.

[0209] Step 2: Compounds of formula (XX) can be prepared by adding a cold solution of NH3 in a solvent such as MeOH to a compound of formula (XXIII) and allowing the temperature to reach room temperature over an extended period of time, for example 22 hours.

[0210] Compounds of formula (XXII) can be prepared in a two-step sequence from compounds of formula (VII) defined above, as shown in Scheme 9.

[0211] Scheme 9

[0212] [ka]

[0213] Step 1: A compound of formula (VII) as defined above can be reacted with a suitable phosphonate, such as diethyl cyanomethyl phosphonate, using a suitable base, such as NaOtBu or NaH, in a solvent, such as absolute EtOH or THF. The base and phosphonate may be briefly premixed in the solvent before adding the compound of formula (VII), and the reaction is maintained at room temperature for a reaction time of 2 hours to 24 hours until the reaction is complete, to give a compound of formula (XXIV).

[0214] Step 2: Preparation of a compound of formula (XXIV) 3 , R 5 and p is as defined in formula (I)) can be reduced by any of the following methods:

[0215] Method a: Compounds of formula (XXII) can be prepared by reacting compounds of formula (XXIV) with Pd / C under a hydrogen atmosphere in an inert solvent such as EtOAc at room temperature for an extended period of time until the reaction is complete.

[0216] Method b: Compounds of formula (XXII) can be prepared by reacting compounds of formula (XXIV) with NaBH4 in a suitable solvent such as MeOH at room temperature for an extended period of time until the reaction is complete.

[0217] Method c: Compounds of formula (XXII) can be prepared by adding compounds of formula (XXIV) to a pre-mixed slurry of diphenylsilane, Cu(OAc)2, and DPEphos in a suitable solvent such as toluene at room temperature and maintaining at room temperature for an extended period of time until the reaction is complete.

[0218] The compound of formula (XIV-a) can be prepared by reacting a compound of formula (XIX-a) (wherein A, R 3 , R 4 , R 5and p is as defined in formula (I), and LG1 is halo or a suitable leaving group such as OTf, e.g., chloro, Scheme 10

[0219] [ka] It can be prepared by reacting a compound of formula (V) with a suitable solvent, such as THF or MeCN, and a base, such as K2CO3, for an extended period of time, such as 2 hours to 24 hours at room temperature, until the reaction is complete, to give a compound of formula (XIV-a).

[0220] Compounds of formula (XIX-a) can be prepared by reacting compounds of formula (XX-a) (wherein A, R 3 , R 4 , R 5 and p is as defined in formula (I)) can be prepared in a two-step sequence.

[0221] Scheme 11

[0222] [ka]

[0223] Step 1: 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 K2CO3 at a temperature ranging from room temperature to 70°C for a long period of time, such as 2 hours to 24 hours, until the reaction is complete, to give compound of formula (XXI-a).

[0224] Step 2: Preparation of a compound of formula (XXI-a) (wherein A, R 3 , R 4 , R 5and p is as defined in formula (I)) can be reacted with a suitable reagent, for example, excess POCl, with or without an amine base such as N,N-diethylaniline as an additive, at an elevated temperature ranging from 70°C to reflux for a long reaction time, for example, 1.5 hours to 15 hours, until the reaction is complete, to give the compound of formula (XIX-a).

[0225] Compounds of formula (XX-a) as defined above can be prepared by the method shown in Scheme 12 to give compounds of formula (XXII-a) (wherein A, R 3 , R 4 , R 5 and p is as defined in formula (I).

[0226] Scheme 12

[0227] [ka]

[0228] Method a: The compound of formula (XX-a) can be prepared by adding the compound of formula (XXII-a) to a mixture of AlMe3 and NH4Cl in an inert solvent, such as toluene, at a temperature ranging from 70°C to 90°C for an extended reaction time until the reaction is complete to give the compound of formula (XX-a).

[0229] Method b: Step 1: Preparation of Compound (A, R) of Formula (XXIII-a) 3 , R 4 , R 5 , and p is as defined in formula (I)) can be prepared by adding AcCl to a cold solution of a compound of formula (XXII-a) in a suitable solvent, for example, EtOH, and allowing the temperature to reach room temperature over an extended period of time, for example, 15 to 24 hours.

[0230] Step 2: Compounds of formula (XX-a) can be prepared by adding a cold solution of NH in a solvent such as MeOH to compounds of formula (XXIII-a) and allowing the temperature to reach room temperature over an extended period of time, e.g., 22 hours.

[0231] Certain compounds of formula (XXII-a) can be prepared by reacting a compound of formula (XXVII-a) (wherein R 3 , R 4 , R 5 , A, and p are as defined in formula (I)) can be prepared in a two-step sequence.

[0232] Scheme 13

[0233] [ka]

[0234] Step 1: Compounds of formula (XXVI-a) can be prepared from compounds of formula (XXVII-a) by reacting them with oxalyl chloride and a catalytic amount of DMF in a solvent (e.g., DCM) at low to room temperature for 30 minutes to 12 hours. The formed product can be concentrated under reduced pressure and then reacted with NH3 in a solvent (e.g., THF) at low temperature for a period of time, typically 1 hour to 24 hours.

[0235] Step 2: Compounds of formula (XXII-a) can be prepared from compounds of formula (XXVI-a) by reacting with PdCl in a solvent such as a mixture of MeCN and water at room temperature for 12 to 24 hours.

[0236] Compounds of formula (XXII-a) and (XXVII-a) are commercially available or can be prepared by conventional methods by those skilled in the art (see, for example, the methods described in Liebigs Annalen 1996, 8, 1289-1294).

[0237] A compound of formula (I) 1 , R 2 , R3 , R 4 , R 5 and p is as defined in formula (I) and m is 2), can be prepared by reacting a compound of formula (II) as defined above with a compound of formula (XXV) (wherein A, R 3 , R 4 , R 5 and p is as defined in formula (I)) with a coupling partner of formula (I).

[0238] Scheme 14

[0239] [ka]

[0240] 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, before adding the compound of formula (II) defined above along with an inorganic salt, such as KPO or CsOH, and a catalytic amount of a palladium source, such as Pd(dppf)Cl·DCM, at room temperature for 1-24 hours or at elevated temperatures, such as 35°C to reflux, for 1-2 hours. The resulting reaction mixture is stirred at temperatures ranging from 35°C to reflux for an extended period of time, such as 2-48 hours, until the reaction is complete, yielding the compound of formula (I).

[0241] Scheme 15

[0242] [ka]

[0243] Compounds of formula (XXV) are commercially available or can be prepared by those skilled in the art using conventional methods as described in Scheme 11 (see, for example, the methods described in J. Org. Chem. 1958, 23, 1658; J. Am. Chem. Soc. 2012, 134, 17470; Angew. Chem. Int. Ed. 2021, 60, 25746).

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

[0245] [ka]

[0246] 2,4,6-Trichloro-1,3,5-triazine (50.0 g, 271.1 mmol) was dissolved in 2-MeTHF (500 mL) under a nitrogen atmosphere, 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 approximately 45 minutes. A thick slurry was obtained, and 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 K2CO3 (75.0 g, 542.4 mmol). The mixture was stirred at 50 °C for 10 min, and then the filtered reaction solution from above was added over 2 min. The reaction mixture was stirred at 75 °C for 48 h and then allowed to reach room temperature. Water (1 L) was added, and the pH was adjusted to approximately 3 by adding 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 NH4Cl(aq) (2 × 500 mL) and concentrated in vacuo. The solid was dissolved in MTBE (250 mL), and the product was extracted with 5% K2CO3(aq) (3 × 200 mL). The pH of the aqueous phase was adjusted to approximately 4 by adding 6 M HCl and extracted with MTBE (2 × 250 mL). The organic extract was dried over MgSO4, filtered and evaporated to give the title compound (57.4 g, 67%) as an off-white solid foam; MS (ESI) m / z [M+H] + 324.2.

[0247] Intermediate 2 (R)-N-(4-((1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-yl)amino)-6-chloro-1,3,5-triazin-2-yl)methanesulfonamide

[0248] [ka]

[0249] 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 min, then poured into ice water and extracted with EtOAc (×3). The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by normal-phase flash chromatography on silica (40 to 100% EtOAc in heptane) to give the title compound as a colorless viscous oil (1.04 g, 77%); MS (ESI) m / z [M+H] + 438.4.

[0250] Intermediate 3 (R,E)-2-((4-chloro-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0251] [ka]

[0252] (E)-Prop-1-en-1-ylmagnesium bromide (35.8 mL, 17.9 mmol, 0.5 M in THF) was added over 10 min to a stirred suspension of 2,4,6-trichloro-1,3,5-triazine (3.0 g, 16.3 mmol) in THF (10 mL) at 0 °C. The reaction mixture was allowed to reach room temperature over 30 min and then cooled back to 0 °C. A solution of (R)-2-amino-4-methylpentan-1-ol (1.91 g, 16.3 mmol) in DIPEA (2.98 mL, 17.1 mmol) and THF (5 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. Water and MTBE were added, and the two phases were separated. The aqueous phase was acidified by adding 1 M HCl and extracted twice with EtOAc. The organic extract was 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 shows a mixture of E and Z-isomers.

[0253] Intermediate 4 (R,E)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-(prop-1-en-1-yl)-1,3,5-triazin-2-yl)methanesulfonamide

[0254] [ka]

[0255] 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), Pd2dba3 (271 mg, 0.30 mmol), X-Phos (0.563 g, 1.18 mmol), and K2CO3 (2.04 g, 14.8 mmol) under a nitrogen atmosphere. 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 approximately 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 MgSO4, filtered, evaporated and the residue purified by normal phase flash chromatography on silica (EtOAc as eluent) to give the title compound (1.55 g, 64%); MS (ESI) m / z [M+H] + 330.2.

[0256] Intermediate 5 1,2-Dichloro-4-(prop-1-en-2-yl)benzene

[0257] [ka]

[0258] KOtBu (2.37 g, 21.16 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (7.56 g, 21.16 mmol) in THF (17 mL), and the reaction mixture was stirred for 30 min at 0° C. 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 for 48 h at room temperature.

[0259] The mixture was evaporated to 1 / 3 volume, diluted with EtOAc / heptane and filtered through a silica pad. The solvent was evaporated to give the title compound (1.6 g, 81%); 1H NMR (500MHz, CDCl3) 2.12 (3H, dd), 5.14 (1H, p), 5.37 (1H, p), 7.28 (1H, dd), 7.38 (1H, d), 7.52 (1H, d).

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

[0261] [ka]

[0262] A 0.5 M solution of 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) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1.5 h. A degassed solution of 3 M KPO (aq, 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·DCM (37.5 mg, 0.05 mmol). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 1 h, then at 40 °C overnight. DCM and water were added, and the aqueous phase was acidified with 3M 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 pad of silica, and the SiliaMetS thiol was eluted with MeOH / EtOAc. The solvent was evaporated, and the residue was purified by preparative HPLC, Prep Method C (gradient: 20-70%) to give the title compound (70 mg, 48%); MS (ESI) m / z [M+H] + 476.2.

[0263] Intermediate 7 1-chloro-2-fluoro-3-(prop-1-en-2-yl)benzene

[0264] [ka]

[0265] KOtBu (2.60 g, 23.18 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (8.28 g, 23.18 mmol) in THF (17 mL) at 0° C., 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 pad. Evaporation of the product-containing fractions gave the title compound as a colorless oil (1.0 g, 51%); 1 H NMR (500MHz, CDCl3) 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).

[0266] Intermediate 8 N-(4-(2-(3-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0267] [ka]

[0268] A 0.5 M solution of 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour and then under reflux for 15 minutes. A degassed solution of 3 M KPO (aq, 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·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, redissolved in a small amount of DCM / EtOAc (1 / 1), and filtered through a short column of silica (eluted with DCM / EtOAc). The solvent was evaporated, 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, the residue was dissolved in DMSO, SiliaMetS thiol was added, stirred for 1 min, filtered, and purified by preparative HPLC, preparative method C (gradient: 20-75%) to give the title compound (158 mg, 94%); MS (ESI) m / z [M+H] + 460.3.

[0269] Intermediate 9 2,4-Difluoro-1-(prop-1-en-2-yl)benzene

[0270] [ka]

[0271] KOtBu (1.44 g, 12.81 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (4.58 g, 12.81 mmol) in EtO (8.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then at 40° C. for 10 minutes. 1-(2,4-Difluorophenyl)ethan-1-one (1.0 g, 6.4 mmol) was added, stirring was continued at room temperature for 30 minutes, and the reaction mixture was then filtered and the solid was washed with EtO. The combined organic extracts were carefully evaporated to approximately 4 mL (the product is volatile) and then purified by normal-phase flash chromatography on silica (EtO as eluent) to give the title compound (990 mg, 100%) containing some residual EtO; 1 H NMR (500MHz, CDCl3)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).

[0272] Intermediate 10 N-(4-(2-(2,4-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0273] [ka]

[0274] A 0.5 M solution of 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes and then at 50 °C for 20 minutes. A degassed 3 M solution of KPO (aq, 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·DCM (44.3 mg, 0.05 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 35 °C for 42 hours. EtOAc and water were added and the two phases were separated. The aqueous phase was acidified to pH 4 with 3M HCl and extracted with EtOAc. The organic extract was evaporated, redissolved in a small amount of DCM and filtered through a short column of silica (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, Prep Method C, to give the title compound (92 mg, 57%); MS (ESI) m / z [M+H] + 444.3.

[0275] Intermediate 11 3-Fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0276] [ka]

[0277] KOtBu (0.663 g, 5.91 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (2.11 g, 5.91 mmol) in EtO (4 mL) at room temperature, and the reaction mixture was stirred at room temperature for 30 minutes. 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 minutes. The reaction mixture was filtered, and the solid was washed with EtO. The combined filtrate was carefully evaporated (the product is volatile), and the residue was purified by normal-phase flash chromatography on silica (pentane:EtO, 4:1 as eluent) to give the title compound (530 mg, 107%) containing some residual solvent. 1 H NMR (500MHz, CDCl3) 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).

[0278] Intermediate 12 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

[0279] [ka]

[0280] 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) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 h. A degassed solution of 3 M KPO (aq, 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 Intermediate 1 (120 mg, 0.37 mmol) and Pd(dppf)Cl·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 several times with EtOAc, and the combined organic extracts were evaporated. The residue was filtered through silica and eluted with DCM, EtOAc, and MeOH. The solvent was evaporated, and the residue was purified by preparative HPLC, Prep Method C (gradient: 15-60%). Repurification by normal phase flash chromatography on silica (gradient: 35-100% EtOAc / MeOH in DCM: 20 / 1 as eluent) gave the title compound (33 mg, 20%); MS (ESI) m / z [M+H] + 457.3.

[0281] Intermediate 13 3-chloro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0282] [ka]

[0283] KOtBu (0.605 g, 5.39 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (1.92 g, 5.39 mmol) in EtO (4 mL), and 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, then filtered. The solid was washed with EtO, and the combined organic extracts were evaporated. The residue was purified by normal-phase flash chromatography on silica (pentane / EtO: 4 / 1 as eluent) to give the title compound (484 mg, 98%) as a colorless oil; 1 H NMR (500MHz, CDCl3)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).

[0284] Intermediate 14 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

[0285] [ka]

[0286] 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) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 1 h. A degassed solution of 3 M KPO (aq, 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 intermediate 1 (120 mg, 0.37 mmol) and Pd(dppf)Cl·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 several times with EtOAc. The combined organic extracts were evaporated and filtered through silica, eluting successively with EtOAc, MeOH, and DCM. The solvent was evaporated, and the residue was purified by preparative HPLC, Prep Method C (gradient: 15-60%). Repurification by normal phase flash chromatography on silica (gradient: 20-100% EtOAc / MeOH in DCM: 20 / 1 as eluent) gave the title compound (24 mg, 14%); MS (ESI) m / z [M+H] + 473.2.

[0287] Intermediate 15 2-Cyclopropyl-5-(prop-1-en-2-yl)pyrimidine

[0288] [ka]

[0289] 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 (44 mg, 0.06 mmol) was added to a degassed solution of KCO (2.08 g, 15.07 mmol) in water (2 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 95 °C. Water and EtO were added, and the two phases were separated. The organic phase was washed with brine and evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 0-50% EtOAc in heptane) to give the title compound (0.95 g, 118%). 1 H NMR (500MHz, CDCl3) 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).

[0290] Intermediate 16 N-(4-(2-(2-cyclopropylpyrimidin-5-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0291] [ka]

[0292] 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) under a nitrogen atmosphere, and the reaction mixture was stirred at 35 °C for 1 h. A degassed solution of CsOH monohydrate (187 mg, 1.11 mmol) in water (0.3 mL) 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 (120 mg, 0.37 mmol) and Pd(dppf)Cl·DCM (24.0 mg, 0.03 mmol). The reaction mixture was stirred at 35°C for 15 hours, water (1 mL) was added, and the reaction mixture was neutralized by adding HOAc. EtOAc was added and the two phases were separated. The aqueous phase was further acidified by adding dilute HCl and extracted with EtOAc. The aqueous phase was neutralized with NaHCO3(aq) and extracted twice with DCM. The combined organic extracts were evaporated and the residue was purified by preparative HPLC, preparative method C (gradient: 15-75%) to give the title compound (32 mg, 19%); MS (ESI) m / z [M+H] + 450.3.

[0293] Intermediate 17 5-Bromo-2-methoxy-4-methylpyridine

[0294] [ka]

[0295] Sodium methoxide (30% in MeOH, 1.61 mL, 8.59 mmol) was added to 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, followed by heating at 140 °C for 15 min in a single-node microwave. The solvent was evaporated, and the residue was dissolved in EtOAc, washed with NH4Cl(aq) and brine, dried over Na2SO4, and evaporated. The residue was purified by normal-phase flash chromatography on silica (5% EtOAc in heptane as eluent) to give the title compound (328 mg, 76%) as a colorless solid; 1 H NMR (400MHz, CDCl3) 2.33 (3H, d), 3.89 (3H, s), 6.64 (1H, s), 8.17 (1H, s).

[0296] Intermediate 18 2-Methoxy-4-methyl-5-(prop-1-en-2-yl)pyridine

[0297] [ka]

[0298] 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 CsCO (1.45 g, 4.45 mmol) in water (0.8 mL), followed by Pd(dppf)Cl·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). 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 (aq) and water, then evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 0-25% EtOAc in heptane) to afford the title compound (157 mg, 65%) as a colorless oil; 1H NMR (400MHz, CDCl3)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).

[0299] Intermediate 19 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

[0300] [ka]

[0301] 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 minutes, then at 40 °C for 15 minutes, and left at room temperature overnight. A degassed solution of 3 M KPO (aq, 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·DCM (74.9 mg, 0.09 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 35 °C for 15 hours. EtOAc and water were added. The aqueous phase was neutralized and extracted several times with EtOAc. SiliaMetS thiol was added to the combined organic extracts, and the mixture was stirred for several minutes and filtered through silica, eluting with EtOAc and MeOH. The filtrate was evaporated and the residue was purified by preparative HPLC, Preparative Method C (gradient: 15-60%). Repurification by preparative HPLC, Preparative Method C (gradient: 15-60%) gave the title compound (42 mg, 15%); MS (ESI) m / z [M+H] + 453.4.

[0302] Intermediate 20 2-Methoxy-3-methyl-5-(prop-1-en-2-yl)pyridine

[0303] [ka]

[0304] 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·DCM (36 mg, 0.05 mmol) was added to a degassed solution of CsCO (2.42 g, 7.42 mmol) in water (1.21 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 2 h. CsOH monohydrate (208 mg, 1.24 mmol) and Pd(dppf)Cl·DCM (36 mg, 0.05 mmol) were added, 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(aq) and water, then evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 0-25% EtOAc in heptane) to give the title compound as a colorless oil (200 mg, 50%); 1 H NMR (500MHz, CDCl3)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).

[0305] Intermediate 21 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

[0306] [ka]

[0307] 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 min, at 35 °C for 15 min, and then left at room temperature overnight. A degassed solution of 3 M KPO (aq, 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·DCM (49.9 mg, 0.06 mmol). The reaction mixture was stirred at 35 °C for 35 h. EtOAc and water were added to neutralize the aqueous phase, 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 several minutes. The residue was passed through silica eluting with EtOAc and MeOH. The filtrate was evaporated, and the residue was purified by preparative HPLC, preparative method C (gradient: 15-60%) to give the title compound (55 mg, 20%); MS (ESI) m / z [M+H] + 453.4.

[0308] Intermediate 22 2-Methoxy-3-(prop-1-en-2-yl)pyridine

[0309] [ka]

[0310] 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·DCM (2.72 g, 3.72 mmol) was added to a degassed solution of CsCO (3.64 g, 11.17 mmol) in water (2.1 mL) under a nitrogen atmosphere. 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 (aq), washed with water, and then evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 0 to 20% EtOAc in heptane). The product-containing fractions were combined, evaporated, dissolved in EtO and stirred with CsOH(aq) for 1 h. The two phases were separated and the organic phase was washed with water and brine, dried over MgSO, filtered and evaporated to give the title compound (165 mg, 30%) as a colorless oil; 1 H NMR (500MHz, CDCl3) 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).

[0311] Intermediate 23 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0312] [ka]

[0313] A 0.5 M solution of 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) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature, and then a degassed solution of 3 M KPO (aq, 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·DCM (37.5 mg, 0.05 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 38 °C for 20 h. EtOAc and water were added, and the two phases were separated. The aqueous phase was acidified with dilute HCl and extracted twice with EtOAc. MgSO4 and SiliaMetS thiol were added to the combined organic phase, and the mixture was stirred for several minutes and then filtered. The filtrate was evaporated, and the residue was purified by preparative HPLC, Prep Method A (gradient: 15-60%) to give the title compound (176 mg, 87%); MS (ESI) m / z [M+H] + 439.3.

[0314] Intermediate 24 (2R)-2-((4-chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0315] [ka]

[0316] 1,4-Dioxane (1.11 mL) and water (0.19 mL) 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 (70 mg, 0.26 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (132 mg, 0.78 mmol), [Rh(COD)Cl] (6.4 mg, 0.01 mmol), and KOH (43.5 mg, 0.78 mmol) under a nitrogen atmosphere. 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, Preparative Method A (gradient: 30-80%) to give the title compound (70 mg, 68%) as a colorless solid; MS (ESI) m / z [M+H] + 397.4.

[0317] Intermediate 25 N-(4-(2-(3-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0318] [ka]

[0319] THF (0.25 mL) was added to Pd2dba3 (6.5 mg, 7.1 μmol) and X-Phos (13.5 mg, 0.03 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and then (2R)-2-((4-chloro-6-(2-(3-fluoro-4-methoxyphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 24 (56 mg, 0.14 mmol), methanesulfonamide (32 mg, 0.34 mmol), and K2CO3 (44 mg, 0.32 mmol) in THF (0.75 mL) 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 phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC, Preparative Method A (gradient: 30-80%) to give the title compound (54 mg, 84%) as a colorless solid; MS (ESI) m / z [M+H] + 456.4.

[0320] Intermediate 26 (2R)-2-((4-chloro-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0321] [ka]

[0322] (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-dioxane (1.1 mL) under a nitrogen atmosphere. [Rh(COD)Cl] (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 made in a similar manner starting from a total of 138 mg of intermediate 3) was purified by preparative HPLC, Prep Method A (gradient: 30-90%) to give the title compound (total 90 mg, 44%) as a colorless solid; MS (ESI) m / z [M+H] + 403.3.

[0323] Intermediate 27 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(3,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0324] [ka]

[0325] THF (0.25 mL) was added to Pd2dba3 (5.1 mg, 5.6 μmol) and X-Phos (10.6 mg, 0.02 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and then (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), methanesulfonamide (30 mg, 0.32 mmol), and K2CO3 (39 mg, 0.28 mmol) in THF (0.75 mL) 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 phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC, Preparative Method A (gradient: 30-80%) to give the title compound (60 mg, 94%) as a colorless solid; MS (ESI) m / z [M+H] + 462.4.

[0326] Intermediate 28 (2R)-2-((4-chloro-6-(2-(2,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0327] [ka]

[0328] 1,4-Dioxane (1.11 mL) and water (0.19 mL) 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 (70 mg, 0.26 mmol), (2,5-difluorophenyl)boronic acid (122 mg, 0.78 mmol), [Rh(COD)Cl] (6.4 mg, 0.01 mmol), and KOH (43.5 mg, 0.78 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 3.5 h. EtOAc and dilute HCl were added, and the organic phase was washed with water and brine and evaporated. The residue was purified by preparative HPLC, Prep Method B (gradient: 30-80%) to give the title compound (36 mg, 36%) as a colorless solid; MS (ESI) m / z [M+H] + 385.3.

[0329] Intermediate 29 N-(4-(2-(2,5-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0330] [ka]

[0331] THF (0.25 mL) was added to Pd2dba3 (3.1 mg, 3.4 μmol) and X-Phos (6.3 mg, 0.01 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and then (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), methanesulfonamide (17.8 mg, 0.19 mmol), and K2CO3 (23.6 mg, 0.17 mmol) in THF (0.75 mL) 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 phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC, Preparative Method A (gradient: 30-80%) to give the title compound (29 mg, 79%) as a colorless solid; MS (ESI) m / z [M+H] + 444.4.

[0332] Intermediate 30 2-chloro-4-(prop-1-en-2-yl)pyridine

[0333] [ka]

[0334] KOtBu (0.620 g, 5.53 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (1.98 g, 5.53 mmol) in EtO (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 EtO (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 EtO, and the combined filtrate was carefully evaporated (the product is volatile). The residue was purified by normal-phase flash chromatography on silica (pentane / EtO: 4 / 1 as eluent) to give the title compound (350 mg, 82%) as a colorless oil; 1H NMR (400MHz, CDCl3) 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).

[0335] Intermediate 31 N-(4-(2-(2-chloropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0336] [ka]

[0337] A 0.5 M solution of 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) under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature, and then a degassed solution of 3 M KPO (aq, 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·DCM (25.0 mg, 0.03 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 35 °C 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, stirred for a few minutes, and then filtered. The filtrate was collected and evaporated, and the residue was purified by preparative HPLC, preparative method A (gradient: 20-75%). Repurification by preparative HPLC, preparative method D (gradient: 0-50%) gave the title compound (23 mg, 17%). 1H NMR(500MHz,CDCl3)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, partially overlaps with solvent),8.31(1H,dd).

[0338] Intermediate 32 (2R)-2-((4-chloro-6-(2-(6-ethoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0339] [ka]

[0340] (6-Ethoxypyridin-3-yl)boronic acid (126 mg, 0.75 mmol) and KOH (62.2 mg, 1.11 mmol) in water (0.27 mL) were 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 (100 mg, 0.37 mmol) in 1,4-dioxane (1.58 mL) under a nitrogen atmosphere. [Rh(COD)Cl] (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, Preparative Method A (gradient: 40-100%) to give the title compound (18 mg, 12%) as a colorless solid; MS (ESI) m / z [M+H] + 394.4.

[0341] Intermediate 33 N-(4-(2-(6-ethoxypyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0342] [ka]

[0343] THF (0.15 mL) was added to Pd2dba3 (2.1 mg, 2.3 μmol) and X-Phos (4.5 mg, 9.34 μmol) under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and then (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), methanesulfonamide (12.5 mg, 0.13 mmol), and K2CO3 (16.5 mg, 0.12 mmol) in THF (0.50 mL) 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 phase was extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method B (gradient: 25-70%) to give the title compound (24 mg, 89%) as a colorless solid; MS (ESI) m / z [M+H] + 453.4.

[0344] Intermediate 34 (2R)-2-((4-chloro-6-(2-(5-chloro-2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0345] [ka]

[0346] 1,4-Dioxane (1.1 mL) and water (0.12 mL) 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 (70 mg, 0.26 mmol), (5-chloro-2-fluorophenyl)boronic acid (135 mg, 0.78 mmol), [Rh(COD)Cl] (6.4 mg, 0.01 mmol), and KOH (43.5 mg, 0.78 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 65 °C for 3.5 h. EtOAc and dilute HCl were added, 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, Prep Method B (gradient: 30-80%) to give the title compound (14.6 mg, 14%); MS (ESI) m / z [M+H] + 401.3.

[0347] Intermediate 35 N-(4-(2-(5-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0348] [ka]

[0349] THF (0.15 mL) was added to Pd2dba3 (1.3 mg, 1.4 μmol) and X-Phos (2.7 mg, 5.6 μmol) under a nitrogen atmosphere, and the reaction mixture was stirred for 10 min. (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), methanesulfonamide (7.5 mg, 0.08 mmol), and K2CO3 (9.9 mg, 0.07 mmol) in THF (0.50 mL) 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 phase was extracted with EtOAc, and the combined organic extracts were evaporated. The residue was purified by preparative HPLC, Prep Method D (gradient: 25-70%) to give the title compound (12.6 mg, 79%) as a colorless solid; MS (ESI) m / z [M+H] + 460.4.

[0350] Intermediate 36 (2R)-2-((4-chloro-6-(2-(4-chloro-3,5-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0351] [ka]

[0352] 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) were 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 (100 mg, 0.37 mmol) in 1,4-dioxane (1.58 mL), followed by the addition of [Rh(COD)Cl] (9.1 mg, 0.02 mmol). The reaction mixture was stirred at 70 °C overnight, and 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, preparative method A (gradient: 30-90%) to give the title compound (20 mg, 13%); 1 H NMR(400MHz,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).

[0353] Intermediate 37 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,

[0354] [ka]

[0355] THF (0.25 mL) was added to Pd2dba3 (4.3 mg, 4.8 μmol) and X-Phos (9.1 mg, 0.02 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 min, 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), methanesulfonamide (26.1 mg, 0.27 mmol), and K2CO3 (33.8 mg, 0.24 mmol) in THF (0.75 mL) 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, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient: 30-80%) to give the title compound (25 mg, 44%) as a colorless solid; MS (ESI) m / z [M+H] + 478.3.

[0356] Intermediate 38 (2R)-2-((4-chloro-6-(2-(4-chloro-2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0357] [ka]

[0358] 1,4-Dioxane (3.66 mL) and water (0.41 mL) 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 (220 mg, 0.81 mmol), (4-chloro-2,3-difluorophenyl)boronic acid (313 mg, 1.63 mmol), [Rh(COD)Cl] (20 mg, 0.04 mmol), and KOH (91 mg, 1.63 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C overnight. EtOAc and water were added, the two phases were separated, and the organic extract was evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient: 40-85%) to give the title compound (87 mg, 26%); MS (ESI) m / z [M+H] + 419.3.

[0359] Intermediate 39 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

[0360] [ka]

[0361] THF (0.25 mL) was added to Pd2dba3 (7.6 mg, 8.3 μmol) and X-Phos (15.8 mg, 0.03 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 min, and then (2R)-2-((4-chloro-6-(2-(4-chloro-2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 38 (87 mg, 0.21 mmol), methanesulfonamide (45.4 mg, 0.48 mmol), and K2CO3 (58.8 mg, 0.43 mmol) in THF (0.75 mL) 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, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient: 30-75%) to give the title compound (64 mg, 65%) as a colorless solid; MS (ESI) m / z [M+H] + 478.4.

[0362] Intermediate 40 1,2,4-trifluoro-5-(prop-1-en-2-yl)benzene

[0363] [ka]

[0364] A degassed solution of Cs2CO3 (4.63 g, 14.22 mmol) in water (2.38 mL) was added 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)Cl2·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). The reaction mixture was stirred at 70 °C for 20 h, followed by the addition of MTBE and water. The two phases were separated, and the organic extract was washed with water and carefully evaporated (the product is volatile). The residue was purified by normal-phase flash chromatography on silica (gradient: 0–15% Et2O in pentane) to give the title compound (0.64 g, 78%). 1 H NMR (500MHz, CDCl3)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).

[0365] Intermediate 41 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,5-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0366] [ka]

[0367] 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-5-(prop-1-en-2-yl)benzene Intermediate 40 (170 mg, 0.99 mmol) in THF (0.5 mL), and the reaction mixture was stirred overnight at room temperature. A degassed solution of 3 M KPO (aq, 0.99 mL, 2.96 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·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere, followed by the addition of EtOAc and dilute HCl. The two phases were separated and the organic phase was washed with water and brine. The organic extract was treated with SILIAMES thiol, filtered, dried over MgSO4, filtered and evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient 30-85%). Repurification by normal phase flash chromatography on silica (eluted with DCM and EtOAc) gave the title compound (120 mg, 53%); 1 H NMR (400MHz, CDCl3) 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).

[0368] Intermediate 42 1-chloro-2,5-difluoro-4-(prop-1-en-2-yl)benzene

[0369] [ka]

[0370] KOtBu (1.18 g, 10.49 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (3.75 g, 10.49 mmol) in EtO (6 mL) at 10° C., followed by the addition of 1-(4-chloro-2,5-difluorophenyl)ethan-1-one (1.0 g, 5.3 mmol) in EtO (6 mL). The reaction mixture was stirred overnight at room temperature, then diluted with EtO and filtered. The filtrate was washed with water, dilute HCl, water, and brine, dried over MgSO, filtered, and carefully evaporated (the product is volatile). Pentane was added, the solid was filtered, and the solvent was evaporated. The residue was purified by normal-phase flash chromatography on silica (pentane / EtOAc: 10 / 1 as eluent) to give the title compound (688 mg, 70%). 1 H NMR (400MHz, CDCl3) 2.29 (3H, s), 5.47 (2H, s), 7.21-7.35 (2H, m).

[0371] Intermediate 43 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

[0372] [ka]

[0373] A 0.5 M solution of 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 under nitrogen at 70 °C for 1 h. A degassed solution of 3 M KPO (aq, 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·DCM (56.7 mg, 0.07 mmol). The reaction mixture was stirred under nitrogen at 40 °C overnight, then EtOAc and dilute HCl were added, and the two phases were separated. The organic extract was treated with Silames thiol, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method E (gradient: 5-95%) to give the title compound (99 mg, 48%); MS (ESI) m / z [M+H] + 478.2.

[0374] Intermediate 44 2,4,6-trifluoro-N-methoxy-N-methylbenzamide

[0375] [ka]

[0376] N,O-Dimethylhydroxylamine hydrochloride (1.11 g, 11.36 mmol) followed by TBTU (4.38 g, 13.63 mmol) were added 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 overnight at room temperature. DCM and saturated NaHCO3(aq) 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 (2.40 g, 96%). 1 H NMR (500MHz, CDCl3) 3.39 (3H, s), 3.54 (3H, s), 6.67-6.76 (2H, m).

[0377] Intermediate 45 1-(2,4,6-trifluorophenyl)ethan-1-one

[0378] [ka]

[0379] A solution of 3M MeMgBr in EtO (11.0 mL, 32.85 mmol) was added dropwise to an ice-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. 0.5 M HCl and EtO were added. The phases were separated, and the organic extract was washed with water and brine, dried over MgSO, filtered, and carefully evaporated (the product is volatile). The residue was purified by normal-phase flash chromatography on silica (gradient: 0-15% EtO in pentane) to give the title compound (1.73 g, 91%) as a colorless oil. 1 H NMR (500MHz, CDCl3) 2.58 (3H, t), 6.67-6.78 (2H, m).

[0380] Intermediate 46 1,3,5-trifluoro-2-(prop-1-en-2-yl)benzene

[0381] [ka]

[0382] KOtBu (1.29 g, 11.49 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (4.10 g, 11.49 mmol) in EtO (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 EtO, and the combined filtrate was washed with water and brine and carefully evaporated (the product is volatile). The residue was purified by normal-phase flash chromatography on silica (gradient: 0-15% EtO in pentane) to give the title compound (760 mg, 77%) as a colorless oil. 1 H NMR (400MHz, CDCl3) 2.04-2.09 (3H, m), 5.06-5.11 (1H, m), 5.39-5.44 (1H, m), 6.59-6.73 (2H, m).

[0383] Intermediate 47 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,4,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0384] [ka]

[0385] A solution of 0.5 M 9-BBN in THF (2.96 mL, 1.48 mmol) was added to 1,3,5-trifluoro-2-(prop-1-en-2-yl)benzene intermediate 46 (170 mg, 0.99 mmol) in THF (0.5 mL) under a nitrogen atmosphere, and the reaction mixture was stirred for 2 h at 40° C. Another portion of a 0.5 M solution of 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 3M KPO (aq, 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·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred overnight at 40 °C 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 and Silames thiol. The mixture was filtered and evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient: 35-75%) to give the title compound (150 mg, 66%); MS (ESI) m / z [M+H] + 462.4.

[0386] Intermediate 48 2,3,6-trifluoro-N-methoxy-N-methylbenzamide

[0387] [ka]

[0388] 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 TBTU (4.38 g, 13.63 mmol). The reaction mixture was stirred overnight at room temperature, then added to DCM and saturated NaHCO. 3(aq) was 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 H NMR (500MHz, CDCl3) 3.40 (3H, s), 3.56 (3H, s), 6.85-6.93 (1H, m), 7.14-7.23 (1H, m).

[0389] Intermediate 49 1-(2,3,6-trifluorophenyl)ethan-1-one

[0390] [ka]

[0391] A solution of 3M MeMgBr in EtO (11.0 mL, 32.85 mmol) was added dropwise to an ice-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 h and at room temperature overnight. 0.5 M HCl and EtO were added. The organic extract was washed with water and brine, dried over MgSO, filtered, and carefully evaporated (the product is volatile). The residue was purified by normal-phase flash chromatography on silica (gradient: 0-15% EtO in pentane) to give the title compound (1.78 g, 93%) as a colorless oil. 1 H NMR (500MHz, CDCl3) 2.61 (3H, t), 6.87-6.94 (1H, m), 7.19-7.29 (1H, m).

[0392] Intermediate 50 1,2,4-trifluoro-3-(prop-1-en-2-yl)benzene

[0393] [ka]

[0394] KOtBu (1.29 g, 11.49 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (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 filtrate was 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 normal-phase flash chromatography on silica (gradient: 0-15% EtO in pentane) to give the title compound (750 mg, 76%) as a colorless oil. 1 H NMR (400MHz, CDCl3)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).

[0395] Intermediate 51 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,6-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0396] [ka]

[0397] A solution of 0.5 M 9-BBN in THF (2.96 mL, 1.48 mmol) was added to 1,2,4-trifluoro-3-(prop-1-en-2-yl)benzene intermediate 50 (170 mg, 0.99 mmol) in THF (0.5 mL) under a nitrogen atmosphere, and the reaction mixture was stirred for 2 h at 40° C. 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 KPO (aq, 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·DCM (32.3 mg, 0.04 mmol). The reaction mixture was stirred overnight at 40 °C 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. SiliaMetS thiol and silica were added, the mixture was filtered and evaporated, and the residue was purified by preparative HPLC, Prep Method A (gradient: 35–75%). Repurification by preparative HPLC, Prep Method B (gradient: 15-65%) gave the title compound (54 mg, 24%); MS (ESI) m / z [M+H] + 462.4.

[0398] Intermediate 52 1-(4-chloro-2,6-difluorophenyl)ethan-1-ol

[0399] [ka]

[0400] A solution of 3M MeMgBr in EtO (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 EtO (32.1 mL) under a nitrogen atmosphere. The reaction mixture was allowed to reach room temperature over 4 hours, and then a solution of NHCl (aq, 10%) was added. The mixture was acidified by adding 3.8 M HCl. The two phases were separated, and the organic extract was washed with water and brine, dried over MgSO, filtered, and evaporated to give the title compound (1.0 g, 46%). 1 H NMR (400MHz, CDCl3) 1.61 (3H, d), 2.19 (1H, br s), 5.20 (1H, p), 6.87-6.97 (2H, m).

[0401] Intermediate 53 1-(4-chloro-2,6-difluorophenyl)ethan-1-one

[0402] [ka]

[0403] 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 at room temperature overnight. NaHCO (aq, 20 mL) was added, and the reaction mixture was stirred vigorously for 2 h and then filtered. The solid was washed with DCM, and the two phases were separated. The organic extract was washed with NaHCO (aq), NaSO (aq), water, and brine. The organic extract was evaporated, and the residue was purified by normal-phase flash chromatography on silica (heptane / EtOAc: 10 / 1 as eluent) to give the title compound (0.87 g, 88%). 1 H NMR (400MHz, CDCl3) 2.58 (3H, t), 6.95-7.04 (2H, m).

[0404] Intermediate 54 5-chloro-1,3-difluoro-2-(prop-1-en-2-yl)benzene

[0405] [ka]

[0406] KOtBu (1.03 g, 9.13 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (3.26 g, 9.13 mmol) in EtO (6 mL) at 10° C., followed by the addition of 1-(4-chloro-2,6-difluorophenyl)ethan-1-one intermediate 53 (1.0 g, 5.3 mmol) in EtO (6 mL). The reaction mixture was stirred overnight at room temperature, then diluted with EtO and filtered. The filtrate was washed with water, dilute HCl, water, and brine, dried over MgSO, filtered, and carefully evaporated (the product is volatile). Pentane was added, the solid was filtered, and the solvent was evaporated. The residue was purified by normal-phase flash chromatography on silica (pentane / EtOAc: 10 / 1 as eluent) to give the title compound (315 mg, 37%). 1 H NMR (400MHz, CDCl3) 2.05-2.08 (3H, m), 5.08-5.12 (1H, m), 5.42 (1H, p), 6.87-6.97 (2H, m).

[0407] Intermediate 55 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

[0408] [ka]

[0409] A 0.5 M solution of 9-BBN in THF (2.78 mL, 1.39 mmol) was added to 5-chloro-1,3-difluoro-2-(prop-1-en-2-yl)benzene Intermediate 54 (175 mg, 0.93 mmol), and the reaction mixture was stirred at 70 °C for 1 h under a nitrogen atmosphere. A degassed solution of 3 M KPO (aq, 0.926 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·DCM (56.7 mg, 0.07 mmol), and the reaction mixture was stirred overnight at 40 °C under a nitrogen atmosphere. EtOAc and dilute HCl were added, and the two phases were separated. The aqueous phase was acidified with 3.8 M HCl and extracted with EtOAc. The combined organic extracts were treated with SiliaMetS thiol and dried over MgSO. The mixture was filtered, the filtrate evaporated, and the residue purified by preparative HPLC, Prep Method E (gradient: 5-95%) to give the title compound (59 mg, 27%); MS (ESI) m / z [M+H] + 478.2.

[0410] Intermediate 56 5-Bromo-4-fluoro-2-methoxypyridine

[0411] [ka]

[0412] Dibromine (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 NaSO(aq) 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 2 M NaOH and water, dried over MgSO, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (heptane / EtOAc: 10 / 1 as eluent) to give the title compound as a colorless oil that solidified on standing (25.6 g, 53%); 1 H NMR (500MHz, CDCl3) 3.93 (3H, s), 6.52 (1H, d), 8.23 ​​(1H, d).

[0413] Intermediate 57 4-Fluoro-2-methoxy-5-(prop-1-en-2-yl)pyridine

[0414] [ka]

[0415] 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (27.4 mL, 145.6 mmol) was added to a mixture of 5-bromo-4-fluoro-2-methoxypyridine intermediate 56 (25.0 g, 121.4 mmol), K2CO3 (41.9 g, 303.4 mmol), and Pd(dtbpf)Cl2 (4.75 g, 7.28 mmol) in THF (240 mL) and water (60 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 50 °C for 2 h, then allowed to reach room temperature. Water and Et2O were added, and the two phases were separated. The aqueous phase was extracted with Et2O, and the combined organic extracts were washed with water (×2) and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica (heptane / MTBE:20 / 1 as eluent) to give the title compound as an oil (17.1 g, 84%); 1 H NMR (500MHz, CDCl3) 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).

[0416] Intermediate 58 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

[0417] [ka]

[0418] 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) under a nitrogen atmosphere, 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)Cl₂·DCM (151 mg, 0.19 mmol), and K₃PO₄ (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 adding 1M HCl and extracted with EtOAc (x3). The combined organic extracts were dried over MgSO4, filtered and evaporated. The residue was purified by normal phase flash chromatography on silica (EtOAc as eluent) to give the title compound (498 mg, 59%); MS (ESI) m / z [M+H] + 457.4.

[0419] Intermediate 59 1-(but-1-en-2-yl)-2,3-difluorobenzene

[0420] [ka]

[0421] KOtBu (523 mg, 4.66 mmol) was added to methyltriphenylphosphonium bromide (1.47 g, 4.10 mmol) in THF (8 mL). The reaction mixture was stirred at room temperature for 30 minutes, and then it was 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 MgSO4, filtered, and carefully evaporated (the product is volatile). The residue was purified by normal phase flash chromatography on silica (pentane as eluent) to give the title compound (233 mg, 37%) as a colorless oil; 1 H NMR (500MHz, CDCl3) 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).

[0422] Intermediate 60 N-(4-(2-(2,3-difluorophenyl)butyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0423] [ka]

[0424] A 0.5 M solution of 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h 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·DCM (60.5 mg, 0.07 mmol), and KPO (629 mg, 2.96 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 50 °C for 2.5 h, and 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 1M HCl, and the aqueous phase was extracted with EtOAc (x3). The combined organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica (EtOAc as eluent) to give the title compound (75 mg, 22%); MS (ESI) m / z [M+H] + 458.3.

[0425] Intermediate 61 2-(but-1-en-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0426] [ka]

[0427] 1,4-Dioxane (10 mL) was added to B2pin2 (4.51 g, 17.78 mmol), KOAc (4.36 g, 44.44 mmol), and Pd(dppf)Cl2·DCM (0.968 g, 1.19 mmol) under a nitrogen atmosphere. 2-Bromobut-1-ene (2.0 g, 14.81 mmol) in dioxane (5 mL) was added, and the reaction mixture was stirred at 60 °C for 18 h. The reaction mixture was cooled, then water and Et2O were added, and the two phases were separated. The organic extract was dried over MgSO4, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (pentane / MTBE: 20 / 1 as eluent) to give the title compound (0.68 g, 25%) as a colorless oil. 1 H NMR (500MHz, CDCl3) 1.01 (3H, t), 1.27 (12H, s), 2.13-2.20 (2H, m), 5.60 (1H, s), 5.72-5.77 (1H, m).

[0428] Intermediate 62 5-(but-1-en-2-yl)-4-fluoro-2-methoxypyridine

[0429] [ka]

[0430] 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 a mixture of 5-bromo-4-fluoro-2-methoxypyridine (575 mg, 2.79 mmol), K2CO3 (964 mg, 6.98 mmol), and Pd(dtbpf)Cl2 (182 mg, 0.28 mmol) in water (1.5 mL) and THF (6 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was allowed to reach room temperature, then water and Et2O were added, and the two phases were separated. The aqueous phase was extracted with Et2O, and the combined organic extracts were washed with water, dried over MgSO4, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (heptane / MTBE: 20 / 1 as eluent). The product-containing fractions were combined and repurified by normal phase flash chromatography on silica (heptane / MTBE:25 / 1 as eluent) to give the title compound (172 mg, 34%) as a colorless oil; H NMR (500 MHz, CDCl) 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).

[0431] Intermediate 63 tert-Butyl (5-(prop-1-en-2-yl)pyridin-2-yl)carbamate

[0432] [ka]

[0433] 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.24 mL, 6.59 mmol) was added to a mixture of tert-butyl(5-bromopyridin-2-yl)carbamate (1.50 g, 5.49 mmol), K2CO3 (1.90 g, 13.73 mmol), and Pd(dtbpf)Cl2 (0.358 g, 0.55 mmol) in water (3 mL) and THF (12 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 1.5 h, then water and Et2O were added and the two phases were separated. The aqueous phase was extracted with Et2O, and the combined organic extracts were washed with water, dried over MgSO4, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica (heptane / MTBE: 10 / 1 as eluent) to give the title compound (514 mg, 40%) as a colorless solid; 1 H NMR(500MHz,CDCl3)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).

[0434] Intermediate 64 tert-Butyl (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)carbamate

[0435] [ka]

[0436] A 0.5 M solution of 9-BBN in THF (2.47 mL, 1.24 mmol) was added to tert-butyl 5-(prop-1-en-2-yl)pyridin-2-ylcarbamate Intermediate 63 (139 mg, 0.59 mmol) under a nitrogen atmosphere. 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 (160 mg, 0.49 mmol), Pd(dppf)Cl₂·DCM (40.4 mg, 0.05 mmol), and K₃PO₄ (420 mg, 1.98 mmol) under a nitrogen atmosphere. The reaction mixture was heated to 50 °C for 2 hours. 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 1M HCl and then extracted with EtOAc (x3). The combined organic extracts were dried over MgSO, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 0-10% MeOH in EtOAc) to give the title compound (125 mg, 48%); MS (ESI) m / z [M+H] + 524.4.

[0437] Intermediate 65 N-(4-(2-(6-aminopyridin-3-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0438] [ka]

[0439] A solution of 4 M HCl in dioxane (2.0 mL, 8.0 mmol) was added to tert-butyl (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)carbamate Intermediate 64 (105 mg, 0.20 mmol), and the reaction mixture was stirred at 40 °C for 1 h. EtO was added to precipitate the product, and the solvent was decanted. Another portion of EtO was added to wash the solid. The solid residue was dried under vacuum to give the title compound as the HCl salt (107 mg, 100% for 3HCl); MS (ESI) m / z [M+H] + 424.3.

[0440] Intermediate 66 2,6-Dimethoxy-3-(prop-1-en-2-yl)pyridine

[0441] [ka]

[0442] 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), KCO (1.90 g, 13.76 mmol), and Pd(dppf)Cl (40 mg, 0.06 mmol) were added to 1,4-dioxane (7 mL) and water (2 mL). The reaction mixture was stirred at 100° C. under a nitrogen atmosphere for 2 hours. Another portion of Pd(dppf)Cl2 (40 mg, 0.06 mmol) was added, followed by 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. Et2O and water were added, and the two phases were separated. The aqueous phase was extracted with Et2O, and the combined organic extracts were evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 1-7% EtOAc in heptane) to give the title compound (190 mg, 23%) as an oil;1 H NMR (500MHz, CDCl3)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).

[0443] Intermediate 67 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

[0444] [ka]

[0445] 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 EtO (1 mL) under a nitrogen atmosphere, and the reaction mixture was stirred at room temperature for 45 min. A degassed solution of 3 M KPO (aq, 0.274 mL, 0.82 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 (60 mg, 0.14 mmol) and Pd(dppf)Cl·DCM (16.6 mg, 0.02 mmol). The reaction mixture was stirred overnight at 35°C under a nitrogen atmosphere, and 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), concentrated HCl (0.4 mL) was added, and the mixture was stirred at room temperature for 1 h, and the solvent was evaporated. The residue (combined with two other batches made in a similar manner starting from a total of 176 mg of intermediate 2) was purified by preparative HPLC, Preparative Method A (gradient: 20-65%) to give the title compound (total 57.0 mg, 30%); MS (ESI) m / z [M+H] + 469.4.

[0446] Intermediate 68 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

[0447] [ka]

[0448] 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 (45 mg, 0.17 mmol) in 1,4-dioxane (1.5 mL) and a solution of 4 M KOH (aq, 83 μL, 0.33 mmol) followed by [Rh(COD)Cl] (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 h. 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 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.

[0449] Intermediate 69 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

[0450] [ka]

[0451] THF (0.3 mL) was added to Pd2dba3 (10.6 mg, 0.01 mmol) and X-Phos (22 mg, 0.05 mmol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. 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), methanesulfonamide (55 mg, 0.58 mmol), and K2CO3 (82 mg, 0.59 mmol) in THF (0.5 mL) were added, and the reaction mixture was stirred at 70 °C overnight. EtOAc and water were added. The mixture was acidified with 3.8 M HCl, and the two phases were separated. The aqueous phase was extracted with EtOAc and the combined organic extracts were dried over MgSO4, treated with SiliaMetS thiol for 30 min, filtered 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] + 592.6.

[0452] Intermediate 70 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

[0453] [ka]

[0454] 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) and 4 M KOH (aq, 0.18 mL, 0.72 mmol) followed by [Rh(COD)Cl] (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 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 and filtered through a short pad of silica. Evaporation of the eluate gave 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] + 388.4.

[0455] Intermediate 71 (2R)-2-((4-chloro-6-(2-(3-fluoro-4-methylphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0456] [ka]

[0457] 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) and 4 M KOH (aq, 0.18 mL, 0.72 mmol) followed by [Rh(COD)Cl] (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 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 and filtered through a short pad of silica. Evaporation of the eluate gave 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] + 381.3.

[0458] Intermediate 72 (2R)-2-((4-chloro-6-(2-(4-(oxetan-3-yl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0459] [ka]

[0460] 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) and 4 M KOH (aq, 0.18 mL, 0.72 mmol) followed by [Rh(COD)Cl] (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 and filtered through a short pad of silica. Evaporation of the eluate gave 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.

[0461] Intermediate 73 (2R)-2-((4-chloro-6-(2-(3-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0462] [ka]

[0463] 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-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] (7.1 mg, 0.01 mmol) was added to (3-fluorophenyl)boronic acid (81 mg, 0.58 mmol). The reaction mixture was stirred under nitrogen at 50 °C 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 and filtered through a short pad of silica. Evaporation of the eluate gave the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 367.3.

[0464] Intermediate 74 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

[0465] [ka]

[0466] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (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 under a nitrogen atmosphere at 50 °C 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 pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 406.4.

[0467] Intermediate 75 (2R)-2-((4-(2-(1H-indol-5-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0468] [ka]

[0469] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (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 under nitrogen atmosphere at 50 °C 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 pad of silica. Evaporation of the eluate gave the crude title compound (estimated quantitative yield). MS (ESI) m / z [M+H] + 388.3.

[0470] Intermediate 76 (2R)-2-((4-(2-(benzo[d]oxazol-6-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0471] [ka]

[0472] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (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 under a nitrogen atmosphere at 50 °C 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 pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 390.3.

[0473] Intermediate 77 (2R)-2-((4-(2-(benzo[d]oxazol-5-yl)propyl)-6-chloro-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0474] [ka]

[0475] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (7.4 mg, 0.02 mmol) was added to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (99 mg, 0.40 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 50 °C 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 pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 390.3.

[0476] Intermediate 78 (4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)imino)dimethyl-λ 6 -Sulfanone

[0477] [ka]

[0478] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol) followed by [Rh(COD)Cl]2 (7.4 mg, 0.02 mmol) was added to dimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)imino-λ 6-sulfanone (96 mg, 0.33 mmol) was added. The reaction mixture was stirred under nitrogen atmosphere at 50°C for 2 hours, 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. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 440.4.

[0479] Intermediate 79 (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

[0480] [ka]

[0481] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (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 under a nitrogen atmosphere at 50 °C 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 pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 416.4.

[0482] Intermediate 80 (2R)-2-((4-chloro-6-(2-(3-chloro-4-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0483] [ka]

[0484] 1,4-Dioxane (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] (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, Prep Method A (gradient: 40-85%) to give the title compound (30 mg, 51%); MS (ESI) m / z [M+H] + 401.3.

[0485] Intermediate 81 N-(4-(2-(3-chloro-4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0486] [ka]

[0487] THF (0.25 mL) was added to Pd2dba3 (2.7 mg, 2.9 μmol) and X-Phos (5.5 mg, 0.01 mmol) under a nitrogen atmosphere. The mixture was stirred for 10 minutes, and 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), methanesulfonamide (15.5 mg, 0.16 mmol), and K2CO3 (20.47 mg, 0.15 mmol) in THF (0.5 mL) 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, filtered, and evaporated. The residue was purified by preparative HPLC, Prep Method A (gradient: 30-80%) to give the title compound (23.8 mg, 72%) as a colorless solid; MS (ESI) m / z [M+H] + 478.3.

[0488] Intermediate 82 2-ethoxy-4-(prop-1-en-2-yl)pyridine

[0489] [ka]

[0490] A solution of 4-bromo-2-ethoxypyridine (860 mg, 4.26 mmol) in THF (7.47 mL) followed by Pd(dppf)Cl·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) was added to a solution of CsCO (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. EtO and water were added, and the two phases were separated. The organic phase was washed with CsOH(aq) and water and evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 5-80% Et2O in pentane) to give the title compound (647 mg, 93%) as a colorless oil; 1 H NMR (400MHz, CDCl3) 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).

[0491] Intermediate 83 4-(1-(4-chloro-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)propan-2-yl)benzonitrile

[0492] [ka]

[0493] A solution of (4-cyanophenyl)boronic acid (90 mg, 0.61 mmol) and 4 M KOH (aq, 0.15 mL, 0.61 mmol) 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 (83 mg, 0.31 mmol) in 1,4-dioxane (1.38 mL). The mixture was degassed, and then [Rh(COD)Cl] (7.56 mg, 0.02 mmol) was added. The reaction mixture was stirred under a nitrogen atmosphere at 55 °C for 2.5 h. 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, Preparative Method A (gradient: 40-85%) to give the title compound (89 mg, 78%); MS (ESI) m / z [M+H] + 374.3.

[0494] Intermediate 84 (2R)-2-((4-chloro-6-(2-(4-(methoxymethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0495] [ka]

[0496] 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-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] (7.1 mg, 0.01 mmol) was added to (4-(methoxymethyl)phenyl)boronic acid (96 mg, 0.58 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 50 °C 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 and filtered through a short pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 393.4.

[0497] Intermediate 85 (2R)-2-((4-chloro-6-(2-(3,4-dimethylphenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0498] [ka]

[0499] 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-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] (7.1 mg, 0.01 mmol) was added to (3,4-dimethylphenyl)boronic acid (87 mg, 0.58 mmol). The reaction mixture was stirred under nitrogen at 50 °C 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 and filtered through a short pad of silica. Evaporation of the eluate gave the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] +377.4.

[0500] Intermediate 86 (2R)-2-((4-chloro-6-(2-(4-(1,1-difluoroethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0501] [ka]

[0502] 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-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] (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 under a nitrogen atmosphere at 50 °C 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 and filtered through a short pad of silica. The eluate was evaporated to give the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 413.4.

[0503] Intermediate 87 (2R)-2-((4-chloro-6-(2-(3-chlorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0504] [ka]

[0505] 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-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.18 mL, 0.72 mmol), followed by [Rh(COD)Cl] (7.1 mg, 0.01 mmol) was added to (3-chlorophenyl)boronic acid (91 mg, 0.58 mmol). The reaction mixture was stirred under nitrogen at 50 °C 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 and filtered through a short pad of silica. Evaporation of the eluate gave the crude title compound (estimated quantitative yield); MS (ESI) m / z [M+H] + 383.3.

[0506] Intermediate 88 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

[0507] [ka]

[0508] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL) and a 4 M solution of KOH (aq, 0.15 mL, 0.60 mmol) was 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 [Rh(COD)Cl] (7.4 mg, 0.02 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 50 °C 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 pad of silica. 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 quantitative; MS(ESI) m / z [M+H] + 420.4.

[0509] Intermediate 89 (2R)-2-((4-chloro-6-(2-(4-(trifluoromethyl)phenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0510] [ka]

[0511] 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 (81 mg, 0.30 mmol) in 1,4-dioxane (1.5 mL), a solution of 4 M KOH (aq, 0.15 mL, 0.60 mmol), followed by [Rh(COD)Cl] (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, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica (gradient: 15-75% EtOAc in heptane) to give the title compound (80 mg, 64%); MS (ESI) m / z [M+H] + 417.3.

[0512] Intermediate 90 2-Methoxy-5-(prop-1-en-2-yl)pyridine

[0513] [ka]

[0514] Methyltriphenylphosphonium bromide (23.6 g, 66.2 mmol) was added to a suspension of KOtBu (7.42 g, 66.2 mmol) in THF (50 mL) at −20° C. under a nitrogen atmosphere. 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 sequentially with saturated NH4Cl (2 × 200 mL), brine (2 × 200 mL), and water (3 × 200 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 10–20% EtOAc in PE) to give the title compound (3.4 g, 69%) as a dark oil.1 H NMR(300MHz,DMSO-d6)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).

[0515] Intermediate 91 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(6-methoxypyridin-3-yl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0516] [ka]

[0517] 9-BBN (0.5 M, 72.9 mL, 36.5 mmol) in THF (40 mL) was added to 2-methoxy-5-(prop-1-en-2-yl)pyridine Intermediate 90 (3.20 g, 21.4 mmol), and the reaction mixture was stirred at 70 °C for 1 h. 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)Cl2 DCM (1.31 g, 1.61 mmol), and 3 M K3PO4 (aq, 21.4 mL, 64.4 mmol) were added to the solution. The resulting mixture was purged and stirred at 40 °C for 20 h. The reaction mixture was poured into saturated brine (250 mL), acidified with 0.3 M HCl (to pH 1), and extracted with EtOAc (2 × 200 mL). The pH of the aqueous phase was adjusted to approximately 7 by adding saturated NaHCO (50 mL), and then extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over MgSO, filtered, and evaporated (40 °C). The residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 10-80% water in CHCN) to give the title compound (2.80 g, 60%) as a colorless solid; MS (ESI) m / z [M+H] + 439.20

[0518] Intermediate 92 1,3-Difluoro-2-(prop-1-en-2-yl)benzene

[0519] [ka]

[0520] KOtBu (1.72 g, 15.4 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (5.49 g, 15.4 mmol) in EtO (8.6 mL) at room temperature, 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 (20 g) eluted with EtO to give the title compound (1.3 g, 110%) as an oil; 1 H NMR(400MHz,CDCl3)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).

[0521] Intermediate 93 N-(4-(2-(2,6-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0522] [ka]

[0523] 9-BBN (0.5 M 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 for 2 h under a nitrogen atmosphere. 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 KPO (aq, 422 μL, 1.26 mmol), and PdCl(dppf)·DCM (15 mg, 0.02 mmol) were added to the solution. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. Water and DCM were added, and the aqueous layer was acidified with 1M KHSO4 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, Prep Method F (gradient: 5-95%) to give the title compound (15 mg, 8%); MS (ESI) m / z [M+H] + 444.19

[0524] Intermediate 94 N-(4-(2-(4-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0525] [ka]

[0526] 9-BBN (0.5 M in THF, 1.24 mL, 0.620 mmol) was added to an ice-cold solution of 1-fluoro-4-(prop-1-en-2-yl)benzene (42 mg, 0.31 mmol) in THF (0.5 mL) under a nitrogen atmosphere. 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 KPO (aq, 309 μL, 0.930 mmol), and DMF (250 μL) was added, followed by degassed PdCl(dppf)·DCM (11 mg, 0.02 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 days. Water and DCM were added, and the aqueous layer was acidified with 1M KHSO4 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, Prep Method F (gradient: 5-95%) to give the title compound (29 mg, 22%); MS (ESI) m / z [M+H] + 426.2

[0527] Intermediate 95 2-Fluoro-4-methoxy-1-(prop-1-en-2-yl)benzene

[0528] [ka]

[0529] KOtBu (1.34 g, 11.9 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (4.25 g, 11.9 mmol) in EtO (15 ml) at room temperature, 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 EtO, filtered, and evaporated. The residue was purified by normal-phase flash chromatography on silica (gradient: 5-30% EtOAc in heptane) to give the title compound (0.78 g, 79%) as an oil; 1 H NMR (500MHz, CDCl3) 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).

[0530] Intermediate 96 N-(4-(2-(2-fluoro-4-methoxyphenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide,

[0531] [ka]

[0532] 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) under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. Degassed KPO (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·DCM (14 mg, 0.02 mmol) were 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, Prep Method F (gradient: 5-95%) to give the title compound (23 mg, 14%); MS (ESI) m / z [M+H] + 456.21

[0533] Intermediate 97 4-chloro-2-fluoro-1-(prop-1-en-2-yl)benzene

[0534] [ka]

[0535] KOtBu (1.33 g, 11.8 mmol) was added to a suspension of methyltriphenylphosphonium bromide (4.14 g, 11.6 mmol) in EtO (10 mL) at approximately 10 °C. A solution of 1-(4-chloro-2-fluorophenyl)ethanone (1.01 g, 5.83 mmol) in EtO (3 mL) was added dropwise, the mixture was allowed to reach room temperature, and stirring was continued overnight. The reaction mixture was diluted with EtO and washed successively with water, KHSO(aq), water, and brine. The organic layer was dried over MgSO, filtered, and evaporated (24 °C). The residue was purified by normal-phase flash chromatography on silica (gradient: 0-5% EtO in pentane) to give the title compound (0.89 g, 89%). 1H NMR (400MHz,THF-d8)2.07-2.14(3H,m),5.21-5.27(2H,m),7.11-7.23(2H,m),7.28-7.38(1H,m).

[0536] Intermediate 98 N-(4-(2-(4-chloro-2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0537] [ka]

[0538] 9-BBN (0.5 M in THF, 2.78 mL, 1.39 mmol) was added to 4-chloro-2-fluoro-1-(prop-1-en-2-yl)benzene Intermediate 97 (190 mg, 0.930 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2.5 hours and at 40 °C for 1 hour. Degassed KPO (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·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 hours. EtOAc and 0.3 M HCl were added. The aqueous phase was acidified with 4M 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, Preparative Method A (gradient: 30-70%) to give the title compound (128 mg, 60%); MS (ESI) m / z [M+H] + 460.3

[0539] Intermediate 99 2-Fluoro-6-methoxy-3-(prop-1-en-2-yl)pyridine

[0540] [ka]

[0541] n-BuLi (1.6 M in hexane, 44.3 mL, 70.9 mmol) was added to methyltriphenylphosphonium bromide (25.3 g, 70.9 mmol) in THF (150 mL). The reaction mixture was stirred at room temperature for 10 minutes, and 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 hour. Water and EtO were added, and the two phases were separated. The organic extract was washed with water, dried over MgSO, 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 normal-phase flash chromatography on silica (heptane / EtOAc, 15 / 1) to give the title compound as a colorless oil (8.5 g, 86%); 1 H NMR (500MHz, CDCl3) 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).

[0542] Intermediate 100 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

[0543] [ka]

[0544] 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 at room temperature overnight. Degassed 3 M KPO (aq, 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·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 NaHCO3, and then extracted with EtOAc (2 × 50 mL). The combined organic layers were treated with SiliaMetS thiol, dried over MgSO4, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography on a C18-column [gradient: 0-50% MeCN in water (0.2% FA)] to give the title compound (1.70 g, 46%) as a colorless solid; MS (ESI) m / z [M+H] + 457.15

[0545] Intermediate 101 1,2,3-trifluoro-4-(prop-1-en-2-yl)benzene

[0546] [ka]

[0547] K3PO4 (1.93 g, 17.2 mmol) was added to a suspension of methyltriphenylphosphonium bromide (6.15 g, 17.2 mmol) in Et2O (8 mL) at approximately 10 °C (ice-water bath). A solution of 1-(2,3,4-trifluorophenyl)ethanone (1.50 g, 8.61 mmol) in Et2O (8 mL) was added dropwise, and the mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was diluted with Et2O, filtered, and washed successively with water, 0.4 M HCl, water, and brine. The organic layer was dried over MgSO4, 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 normal-phase flash chromatography on silica (gradient: 10% EtOAc in pentane) to give the title compound (1.16 g, 78%). 1 H NMR (400MHz, CDCl3) 2.09-2.15 (3H, m), 5.20-5.30 (2H, m), 6.85-7.05 (2H, m).

[0548] Intermediate 102 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-(2,3,4-trifluorophenyl)propyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0549] [ka]

[0550] 9-BBN (0.5 M 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) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour and then added to a mixture of (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·DCM (108 mg, 0.130 mmol), and KPO (1.13 g, 5.31 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 50 °C for 2.5 hours. 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 1M HCl (to pH 5) and extracted with EtOAc (x3). The organic extracts were dried over MgSO4, filtered, and evaporated. The residue was purified by normal phase flash chromatography on silica using EtOAc as eluent to give the title compound (75 mg, 12%); MS (ESI) m / z [M+H] + 462.33

[0551] Intermediate 103 1-(but-1-en-2-yl)-2-fluorobenzene

[0552] [ka]

[0553] KOtBu (0.796 g, 7.10 mmol) was added to a stirred suspension of methyltriphenylphosphonium bromide (2.54 g, 7.10 mmol) in EtO (15 ml), and the mixture was stirred at room temperature for 30 minutes. 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 normal-phase flash chromatography on silica (gradient: 5-20% EtOAc in heptane) to give the title compound (0.387 g, 73%). 1H NMR (400MHz, CDCl3) 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, partially overlaps with CDCl3).

[0554] Intermediate 104 2-Fluoro-4-(prop-1-en-2-yl)pyridine

[0555] [ka]

[0556] 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), CsCO (18.5 g, 56.8 mmol), and Pd(dppf)Cl·DCM (2.32 g, 2.84 mmol) in 1,4-dioxane (50 mL) under a nitrogen atmosphere at 10 °C over 1 minute. The resulting solution was stirred at 100 °C for 14 h. The reaction mixture was extracted with EtOAc (3 × 150 mL), and the organic layer was dried over NaSO, filtered, and evaporated. The residue was purified by preparative TLC (PE / EtOAc, 5 / 1) to give the title compound (3.70 g, 95%) as an oil that solidified upon standing. 1 H NMR (400MHz, CDCl3) 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).

[0557] Intermediate 105 N-(4-(2-(2-fluoropyridin-4-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0558] [ka]

[0559] 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 KPO (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 DCM (1.34 g, 1.64 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 (250 mL) and extracted with EtOAc (3 x 150 mL). The aqueous phase was adjusted (to pH 5) with 0.3 M HCl and extracted with EtOAc (150 mL). The combined organic layers were treated with SiliaMetS thiol, dried over MgSO4, filtered, and concentrated (40 °C). The residue was purified by reverse-phase flash chromatography on a C18 column (gradient: 10-70% MeCN in water) to give the title compound (2.19 g, 47%) as a colorless solid; MS (ESI) m / z [M+H] + 427.15

[0560] Intermediate 106 2-(3-Bromobenzyl)isoxazolidin-3-one

[0561] [ka]

[0562] K2CO3 (105 g, 0.812 mol) followed by 3-bromobenzyl bromide (105 g, 0.377 mol) were added to a solution of isoxazolidin-3-one (35 g, 0.40 mol) in MeCN (750 mL). The mixture was stirred at room temperature for 16 hours, then filtered and concentrated. The residue was purified by flash chromatography on silica (PE: EtOAc, 1:1) to give the title compound (74 g, 70%) as a pale yellow solid; MS (ESI) m / z [M+H] + 255.8.

[0563] Intermediate 107 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isoxazolidin-3-one

[0564] [ka]

[0565] Pd(dppf)Cl (10 g, 0.013 mol) was added to a solution of 2-(3-bromobenzyl)isoxazolidin-3-one intermediate 106 (74 g, 0.29 mol), B2pin2 (92.5 g, 0.36 mol), and KOAc (113 g, 1.15 mol) in 1,4-dioxane (750 mL) under a nitrogen atmosphere, 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 (PE: EtOAc, 4:1) to give the title compound (30 g, 34%) as a colorless solid; MS (ESI) m / z [M+H] + 304.1

[0566] Intermediate 108 2-((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)tetrahydro-2H-pyran

[0567] [ka]

[0568] Pyridinium 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 hours, and then saturated NaHCO3 (aq, 50 mL) was added. The layers were separated, and the organic portion was washed with saturated NaHCO3 (aq, 50 mL) and brine, dried over MgSO4, filtered, and evaporated. The residue was purified by flash chromatography on silica (0-20% EtOAc in heptane) to give the title compound (3.40 g, 94%) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ1.56-1.84(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).

[0569] Intermediate 109 4,4,5,5-tetramethyl-2-(4-((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane

[0570] [ka]

[0571] MTBE (20 mL) was added to a purged mixture of 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (0.017 g, 0.06 mmol) and di-mu-metaoxobis(1,5-cyclooctadiene)diiridium(I) (0.021 g, 0.03 mmol). B2pin2 (1.72 g, 6.77 mmol) was added, followed by 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) under a nitrogen atmosphere. The reaction mixture was heated at 80 °C in a microwave reactor for 4 h. After cooling and standing overnight, the reaction mixture was concentrated and the residue was purified twice by flash chromatography on silica (0-25% EtOAc in heptane) to give the title compound (1.1 g, 45%) as a colorless crystalline solid; 1 H NMR(400MHz,CDCl3)δ1.32(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).

[0572] Intermediate 110 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydronaphthalen-1-ol

[0573] [ka]

[0574] A solution of CuBr (4.30 g, 19.3 mmol) in water (40 mL) was added 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). The mixture was heated at 80 °C for 4 h and then stirred at room temperature for 16 h. The reaction mixture was treated with EtO (75 mL) and water (20 mL). The layers were separated and the aqueous phase was extracted with EtO (2 × 75 mL). The combined organic phases were washed with brine, dried over MgSO, filtered, and evaporated. The residue was purified by flash chromatography on silica (0-50% EtOAc in heptane) to give the title compound (0.539 g, 30.6%) as a colorless solid; MS (ESI) m / z [M−H] - 273.

[0575] Intermediate 111 (6-(2-hydroxyethyl)pyridin-3-yl)boronic acid

[0576] [ka]

[0577] A suspension of 2-(5-bromopyridin-2-yl)ethan-1-ol (50 g, 0.25 mol), Pd(dppf)Cl (18.1 g, 25 mmol), KOAc (48.6 g, 0.49 mol), and B2pin2 (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 give the HCl salt of the title compound (25 g, 50%) as a pale yellow solid; MS (ESI) m / z [M+H] + 168.1.

[0578] Intermediate 112 Diphenyliminodicarbonate

[0579] [ka]

[0580] Step a) Phenylcarbonoisocyanatide acid

[0581] [ka]

[0582] Oxalyl dichloride (20.8 mL, 246 mmol) was added to a stirred suspension of phenyl carbamate (30.7 g, 224 mmol) in DCM (165 mL) under a nitrogen atmosphere. The mixture was heated to gentle reflux under a nitrogen atmosphere for 18 hours to give a solution. After evaporation, the residue was treated with toluene (150 mL). The slurry was stirred for 20 minutes and the insoluble material was removed by filtration. The toluene filtrate, containing the subtitle compound (224 mmol), was used immediately.

[0583] Step b) Diphenyliminodicarbonate Phenol (23.2 g, 246 mmol) was added portionwise to the ice-cold toluene filtrate Intermediate 112, step a) (224 mmol) within 10 minutes. The mixture was stirred in the cooling bath for 30 minutes, then at room temperature for 20 hours. The mixture was concentrated, and the residue was dissolved in DCM and concentrated. After one more cycle, the residue 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 off, 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 off, and the solid was washed with heptane until the filtrate was clear. Both crops were combined to give the title compound (38.8 g, 93%). MS(ESI) m / z[M+H] + 257.9.

[0584] Intermediate 113 (E)-3-(2,3-difluorophenyl)but-2-enenitrile

[0585] [ka]

[0586] Diethyl cyanomethylphosphonate (4.45 mL, 27.5 mmol) was added to a solution of NaOtBu (2.64 g, 27.5 mmol) in absolute EtOH (33 mL) at 0 °C. After stirring for 15 min, 1-(2,3-difluorophenyl)ethanone (3.90 g, 25.0 mmol) was added, and the mixture was stirred at room temperature for 2 h. 10% citric acid (33 mL) was added, and the mixture was extracted with PE (bp 40-60) × 3 (× 3, 100, 50, and 50 mL). The combined colorless extracts were washed with brine, dried over NaSO, and concentrated to give the title compound (3.94 g, 88%). 1 According to H NMR, a mixture of E and Z isomers (approximately 4:1) was obtained; 1 H NMR (400MHz, CDCl3) 2.28-2.48 (3H, m), 5.54-5.66 (1H, m), 7.03-7.25 (3H, m).

[0587] Intermediate 114 3-(2,3-difluorophenyl)butanenitrile

[0588] [ka]

[0589] 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) under an argon atmosphere. The mixture was hydrogenated (atmospheric pressure) at room temperature for 14 hours. The catalyst was removed by filtration through silica and Celite. The filtrate was concentrated to give the title compound (9.62, 96%) as a colorless oil, which was used without further purification;1 H NMR (400MHz, CDCl3) 1.48 (3H, dd), 2.58-2.75 (2H, m), 3.45-3.57 (1H, m), 6.94-7.15 (3H, m).

[0590] Intermediate 115 3-(2,3-difluorophenyl)butanimidamide

[0591] [ka]

[0592] AlMe3 (2 M in toluene, 4.8 mL, 9.6 mmol) was added dropwise to an ice-cooled suspension of NH4Cl (0.551 g, 10.3 mmol) in toluene (6 mL) under an argon atmosphere. The resulting mixture was warmed to room temperature and stirred for 1 h. 3-(2,3-Difluorophenyl)butanenitrile 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 an ice-cooled slurry of silica (4 g) in CHCl3 (15 mL) and stirred for 15 min. The slurry was filtered, and the residue was washed with MeOH (2 × 40 mL). The combined filtrate was concentrated. The residue was stirred with HCl (1.25 M 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), and HCl (1.25 M in MeOH, 0.5 mL) was added under stirring, followed by dropwise addition of EtO (approximately 20 mL) (approximately 10 min). 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 EtO, and dried in vacuo to give the HCl salt of the title compound (0.79 g, 56%); 1 H NMR (400MHz, D2O) 1.41 (3H, d), 2.68-2.9 (2H, m), 3.53-3.66 (1H, m), 7.12-7.26 (3H, m).

[0593] Intermediate 116 6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0594] [ka]

[0595] A suspension of K2CO3 (462 mg, 3.35 mmol) and 3-(2,3-difluorophenyl)butanimidamide intermediate 115 (785 mg, 3.35 mmol) in MeCN (15 mL) was stirred for 5 min under an argon atmosphere. Diphenyliminodicarbonate intermediate 112 (862 mg, 3.35 mmol) was added, and stirring was continued at room temperature for 1 h. An additional equivalent of K2CO3 (462 mg, 3.35 mmol) was added, and stirring was continued at room temperature for 1 h and at 60 °C for 2 h. After cooling to room temperature, the resulting thick suspension was dissolved in 1 M HCl (15 mL) and EtOAc (50 mL). The layers were separated, the aqueous phase was extracted with EtOAc (2 × 25 mL), and the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated, and the remaining solid was dried in vacuo. The material, containing phenol (approximately 20 mol%) as an impurity, was stirred with PE / Et2O (2 / 1, 30 mL) for 10 min, filtered, and dried in vacuo to give the title compound (791 mg, 88%); MS (ESI) m / z [M+H] + 268.4.

[0596] Intermediate 117 (2R)-2-((4-chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0597] [ka]

[0598] Step a) 2,4-dichloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazine

[0599] [ka]

[0600] 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 (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 (10 mL) and toluene (10 mL). The mixture was concentrated to give the subtitle compound as an oil (yield assumed quantitative) which was used in step b).

[0601] Step b) (2R)-2-((4-chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol KCO (270 mg, 1.95 mmol) was added in three 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 dry THF (6 mL). Stirring was continued for an additional 1 h, and 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 EtO (40 mL) and the insoluble material was removed by filtration. The filtrate was concentrated and the residue was purified by preparative HPLC, Prep Method A (gradient: 40-80%) to give the title compound (80 mg, 21%); MS (ESI) m / z [M+H] + 385.5

[0602] Intermediate 118 N-(4-(2-(2,3-difluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0603] [ka]

[0604] CsCO (132 mg, 0.410 mmol) was added to a suspension of methanesulfonamide (39 mg, 0.41 mmol), Pd(dba) (21 mg, 0.020 mmol), X-Phos (21 mg, 0.040 mmol), and (2R)-2-((4-chloro-6-(2-(2,3-difluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 117 (80 mg, 0.21 mmol) in THF (3.1 mL) under an argon atmosphere, 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 residual oil was purified by preparative HPLC, Prep Method F (gradient: 5-95%) to give the title compound (37 mg, 40%); MS (ESI) m / z [M+H] + 444.19.

[0605] Intermediate 119 (E)-3-(2-fluorophenyl)but-2-enenitrile

[0606] [ka]

[0607] The title compound was prepared from 1-(2-fluorophenyl)ethanone (18.2 mL, 150 mmol) as described in Intermediate 125 to afford the title compound (24.0 g, 99%). 1 According to H NMR, a mixture of E and Z isomers (approximately 4:1) was obtained; 1 H NMR (400MHz, CDCl3) 2.27-2.50 (3H, m), 5.49-5.65 (1H, m), 7.07-7.24 (2H, m), 7.28-7.43 (2H, m).

[0608] Intermediate 120 3-(2-fluorophenyl)butanenitrile

[0609] [ka]

[0610] 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) under argon. The mixture was hydrogenated at room temperature and 1.3 bar for 17 hours, then at 1.6 bar for 5 hours. The catalyst was removed by filtration through Celite, and the solvent was evaporated (30 °C) to give the title compound (24.0 g, 89%) as a colorless oil. 1 H NMR (400MHz, CDCl3) 1.47 (3H, d), 2.54-2.75 (2H, m), 3.40-3.56 (1H, m), 6.7-7.41 (overlapping with 4H, m, CDCl3).

[0611] Intermediate 121 3-(2-fluorophenyl)butanimidamide

[0612] [ka]

[0613] Step a) Ethyl 3-(2-fluorophenyl)butanimidate

[0614] [ka]

[0615] Acetyl chloride (82.3 mL, 1160 mmol) was added dropwise to an ice-cold solution of crude 3-(2-fluorophenyl)butanenitrile intermediate 120 (23.9 g, 146 mmol) in absolute EtOH (106 mL). The solution was maintained at approximately 4° C. for 1 h, then allowed to reach room temperature and left 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 freezer.

[0616] Step b) 3-(2-Fluorophenyl)butanimidamide Cold NH3 (7 M in MeOH, 170 ml, 1190 mmol) was added to ethyl 3-(2-fluorophenyl)butanimidate Intermediate 121, Step a) (34.6 g, 140.8 mmol). After stirring for 15 minutes, a clear solution was formed. After standing at room temperature for 22 hours, the solvent was evaporated and the residue was dried in vacuo to give the HCl salt of the title compound (30.2 g, 99%) as a colorless solid; 1 H NMR (400MHz, DMSO-d6) 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).

[0617] Intermediate 122 6-(2-(2-fluorophenyl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0618] [ka]

[0619] A suspension of K2CO3 (6.05 g, 43.8 mmol) and 3-(2-fluorophenyl)butanimidamide Intermediate 121 (8.67 g, 40.0 mmol) in MeCN (200 mL) was stirred under an argon atmosphere for 5 minutes. Diphenyliminodicarbonate Intermediate 112 (12.4 g, 45.0 mmol) was added, and stirring was continued at room temperature for 1 hour. K2CO3 (6.05 g, 43.8 mmol) was added, and stirring was continued at room temperature for 1 hour, then at 60 °C for 2 hours. The mixture was cooled to room temperature and then concentrated. 2 M HCl (70 mL) and heptane (70 mL) were added, and the resulting mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed twice with heptane, dried in vacuo, washed twice with water, and dried again to give a colorless solid (6.27 g). The filtrates were combined, and the upper layer was discarded. Both lower layers were concentrated at 60° C. to a volume of approximately 70 mL. DIPE (50 mL) was added, resulting in immediate precipitation. After stirring at room temperature for 1 h, the precipitate was collected by filtration, washed with heptane and water, dried in vacuo, and recrystallized from IPA (35 mL). Another pure material (1.99 g) was obtained, and both crops were combined to give the title compound (8.26 g, 83%); MS (ESI) m / z [M+H] + 250.1

[0620] Intermediate 123 (2R)-2-((4-chloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0621] [ka]

[0622] Step a) 2,4-dichloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazine

[0623] [ka]

[0624] 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 POCl3 (80.0 mL, 861 mmol) was heated to gentle reflux for 15 h. After cooling to room temperature, POCl3 was evaporated. The residue was taken up twice in toluene (20 mL) and evaporated to give a brown liquid. The resulting liquid was diluted with dry 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 complete addition (approximately 15 min), the still-cold solution was shaken with ice / brine 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 NaHCO3 / brine (5 / 2 / 2, 90 mL), dried over Na2SO4, filtered, and concentrated. The remaining oil was taken up in toluene (50 mL) and decanted. The clear toluene solution was concentrated to give the subtitle compound (6.42 g, 22.4 mmol) as a dark orange solid.

[0625] Step b) (2R)-2-((4-chloro-6-(2-(2-fluorophenyl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (R)-2-amino-4-methylpentan-1-ol (3.16 mL, 24.7 mmol) was added to a stirred suspension of KCO (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) at 5 °C. 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 Na2SO4, 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 (6.74 g, 82%) as an orange oil; MS (ESI) m / z [M+H] + 367.3

[0626] Intermediate 124 N-(4-(2-(2-fluorophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0627] [ka]

[0628] 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(dba) (1.25 g, 1.37 mmol), and THF (80 mL) was stirred at room temperature for 10 minutes under an argon atmosphere. KCO (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 2 M KCO (20 mL) and THF (10 mL). The combined aqueous layers were washed with MTBE (2 x 30 mL). The aqueous layer was concentrated to remove THF, and the remaining mixture was cooled to 8 °C and neutralized by dropwise addition of concentrated HCl. MTBE (80 mL) was added, and the two phases were separated. The aqueous layer was extracted with MTBE (60 mL). The combined extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC, Prep Method B (gradient: 20-65%) to give the title compound (3.83 g, 49%); MS (ESI) m / z [M+H] + 426.3

[0629] Intermediate 125 (E)-3-phenylbut-2-enenitrile

[0630] [ka]

[0631] Diethyl cyanomethylphosphonate (26.7 mL, 165 mmol) was added to a solution of NaOtBu (15.8 g, 165 mmol) in absolute EtOH (230 mL) at 0 °C. After stirring for 15 min, acetophenone (17.6 mL, 150 mmol) was added in two equal portions within 10 min while cooling in an ice bath. The mixture was stirred at 0 °C for an additional 30 min, then allowed to reach room temperature and stirred overnight. The mixture was concentrated, and the residue was precipitated by cooling. EtOH (30 mL), 10% citric acid (100 mL), and heptane (120 mL) were added, and the mixture was shaken thoroughly until all solids were dissolved. Upon standing, three liquid layers separated; the bottom two were combined and extracted with heptane (100, 80, and 50 mL). The combined colorless extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to give the title compound (20.7 g, 96%). 1 According to H NMR, a mixture of E and Z isomers (approximately 9:1) was obtained; 1 H NMR (400MHz, CDCl3) 2.26-2.51 (3H, m), 5.38-6.66 (1H, m), 7.37-7.56 (5H, m).

[0632] Intermediate 126 3-Phenylbutanenitrile

[0633] [ka]

[0634] Pd / C 10% (2.0 g, 1.88 mmol) was added to a well-stirred solution of crude (E)-3-phenylbut-2-enenitrile intermediate 125 (20.7 g, 144 mmol) (E / Z-mixture) in EtOAc (300 mL) under an argon atmosphere. The mixture was hydrogenated at room temperature (1.3 bar) for 5 hours. The catalyst was removed by filtration through Celite, and the solvent was evaporated (30 °C) to give the title compound (20.8 g, 99%) as a colorless oil. 1H NMR (400 MHz, CDCl3) 1.46 (3H, d), 2.5-2.67 (2H, m), 3.10-3.23 (1H, m), 7.2-7.41 (5H, m, overlap with CDCl3).

[0635] Intermediate 127 3-phenylbutanimidamide

[0636] [ka]

[0637] Step a) Ethyl 3-phenylbutanimidate

[0638] [ka]

[0639] Acetyl chloride (38.7 mL, 544 mmol) was added dropwise to an ice-cold solution of 3-phenylbutanenitrile intermediate 126 (10.0 g, 68.9 mmol) in absolute EtOH (50 mL). The solution was allowed to stand at room temperature for 18 hours. The clear solution was concentrated to leave the HCl salt of the subtitle compound as a colorless solid (15.2 g). 1 H NMR(400MHz,CD3CN)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).

[0640] Step b) 3-Phenylbutamidamide Cold NH3 (7 M 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 minutes, a clear solution formed. After standing at room temperature for 22 hours, the solvent was evaporated to leave a colorless solid, which was stirred with DIPE (100 mL) for 1 hour. The solid was collected by filtration and dried in vacuo to give the HCl salt of the title compound (12.7 g, 96%); 1H NMR (400MHz, DMSO-d6) 1.22 (3H, d), 2.62-2.7 (2H, m), 3.21-3.36 (1H, m, partially overlapped with water in DMSO-d6), 7.19-7.37 (5H, m), 8.66 (2H, br s), 9.03 (2H, br s).

[0641] Intermediate 128 6-(2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0642] [ka]

[0643] A suspension of K2CO3 (6.05 g, 43.8 mmol) and 3-phenylbutanimidamide intermediate 127 (7.55 g, 38.0 mmol) in MeCN (190 mL) was stirred under an argon atmosphere for 5 minutes. Diphenyliminodicarbonate intermediate 112 (12.1 g, 43.7 mmol) was added, and stirring was continued at room temperature for 1 hour. K2CO3 (6.05 g, 43.8 mmol) was added, and stirring was continued at room temperature for 1 hour and at 60 °C for 2 hours. The reaction mixture was cooled to room temperature and concentrated. 2 M HCl (68 mL) followed by heptane / Et2O (2 / 1, 90 mL) was added to the resulting suspension, which 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 H NMR (400 MHz, DMSO-d₆): 1.23 (3H, d), 2.59-2.73 (2H, m), 3.22-3.34 (m, partially overlapped with water in DMSO-d₆), 7.15-7.35 (5H, m), 11.19 (1H, s), 12.08 (1H, s).

[0644] Intermediate 129 (2R)-2-((4-chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0645] [ka]

[0646] Step a) 2,4-dichloro-6-(2-phenylpropyl)-1,3,5-triazine

[0647] [ka]

[0648] 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 POCl3 (80.0 mL, 861 mmol) was heated to gentle reflux for 15 h. After cooling to room temperature in between, POCl3 was evaporated. The residue was taken up twice in toluene (30 mL) and evaporated to give an orange liquid. The resulting liquid was diluted with dry 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 complete addition, the still-cold solution was shaken with ice / brine (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 a solution of saturated NaHCO3 / brine (1 / 3, ×2), dried over Na2SO4, filtered, and concentrated. The remaining oil was taken up in toluene / EtOAc (1 / 1, 120 mL) and washed with water and NaHCO3(aq). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (yield assumed quantitative); 1 H NMR (500 MHz, CDCl3) 1.31-1.35 (3H, m), 3.11-3.24 (2H, m), 3.46-3.57 (1H, m), 7.17-7.32 (m, partial overlap with CDCl3).

[0649] Step b) (2R)-2-((4-chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol. (R)-2-Amino-4-methylpentan-1-ol (3.44 mL, 26.9 mmol) was added to a stirred suspension of KCO (3.77 g, 27.3 mmol) and 2,4-dichloro-6-(2-phenylpropyl)-1,3,5-triazine, Intermediate 129, Step a) in MeCN (70 mL) at room temperature over 2 minutes. The mixture was heated to approximately 30°C. After 21 hours, the mixture was concentrated and the residue was partitioned between toluene (100 mL) and water (100 mL). HCl (12 M, approximately 25 mL) was added to accelerate layer separation. The aqueous phase was extracted with toluene (50 mL). The combined organic layers were washed twice with water and brine, dried over Na2SO4, filtered, and concentrated. The remaining oil was dissolved in EtOAc (25 mL), filtered through silica, and the filtrate was concentrated to give the title compound (6.12 g, 72%) as an orange oil; MS (ESI) m / z [M+H] + 349.2

[0650] Intermediate 130 N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)methanesulfonamide

[0651] [ka]

[0652] A solution of (2R)-2-((4-chloro-6-(2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol intermediate 129 (5.95 g, 17.1 mmol) in THF (6 mL) (degassed with argon) was added to a mixture of Pd(dba) (0.607 g, 0.670 mmol), X-Phos (1.25 g, 2.62 mmol), and KCO (3.54 g, 25.6 mmol) under a nitrogen atmosphere with stirring at room temperature for about 10 minutes. A degassed solution of methanesulfonamide (1.95 g, 20.5 mmol) in THF (20 mL) was then added, and the reaction mixture was heated at 60 °C under a nitrogen atmosphere overnight. 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 K2CO3 (aq, 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 (x2, 130 and 60 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (4.51 g, 65%) as a solid; MS (ESI) m / z [M+H] + 408.4

[0653] Intermediate 131 (E)-3-(5-chloropyridin-2-yl)but-2-enenitrile

[0654] [ka]

[0655] Diethyl cyanomethylphosphonate (4.45 mL, 27.5 mmol) was added to a solution of NaOtBu (2.64 g, 27.5 mmol) in absolute EtOH (33 mL) at 0° C. 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 (aq, 50%), and dried in vacuo to give the title compound (4.02 g, 90%). 1 According to H NMR, only one (E / Z) configuration was observed, such as the E isomer; 1 H NMR (400MHz, CDCl3) 2.48 (3H, d), 6.45 (1H, q), 7.46 (1H, dd), 7.73 (1H, dd), 8.57 (1H, dd).

[0656] Intermediate 132 3-(5-chloropyridin-2-yl)butanenitrile

[0657] [ka]

[0658] Diphenylsilane (7.98 mL, 43.0 mmol) was added to a stirred mixture of Cu(OAc) (118 mg, 0.650 mmol) and DPEphos (0.35 g, 0.65 mmol) in toluene (22 mL) at room temperature under an argon atmosphere, and the reaction mixture was stirred at room temperature for 30 min. 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 h. The reaction was quenched with vigorous stirring and gassed with water (20 mL), followed by saturated NaHCO. EtOAc (30 mL) was added, the layers were separated, and 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. The milky mixture was extracted with EtO (2 x 50 mL). The combined extracts were dried over NaSO, filtered, and concentrated (24 °C). The remaining black oil was dissolved in DCM (15 mL), filtered through silica (5 g), eluted with DCM (45 mL), and the combined filtrate was concentrated to give the title compound (2.96 g, 76%); MS (ESI) m / z [M+H] + 181.2

[0659] Intermediate 133 3-(5-chloropyridin-2-yl)butanimidamide

[0660] [ka]

[0661] AlMe3 (2 M in toluene, 13.1 mL, 26.2 mmol) was added dropwise to an ice-cooled suspension of NH4Cl (1.51 g, 28.2 mmol) in toluene (16 mL) under an argon atmosphere (gas evolution). The resulting mixture was warmed to room temperature and stirred for 1 h. 3-(5-chloropyridin-2-yl)butanenitrile intermediate 132 (2.96 g, 16.4 mmol) was added, and the mixture was stirred at 80 °C overnight. After cooling to room temperature, the mixture was slowly poured into an ice-cooled slurry of silica (15 g) in CHCl3 (40 mL), and stirring was continued at room temperature for 15 min. The mixture was filtered, and the residue was washed with MeOH (2 × 60 mL). The combined filtrates were concentrated, and the residue was stirred in 1.25 M HCl in MeOH (13.1 mL) for 10 min and then concentrated. The residue was stirred with IPA / acetone (4 / 1, 45 mL) for 10 minutes, the colorless insoluble matter was removed by filtration, and the filtrate was concentrated to a volume of approximately 20 mL. EtO (20 mL) was added dropwise with vigorous stirring (approximately 15 minutes). Stirring was continued at room temperature for 30 minutes, and the mixture was allowed to stand at 5°C for 1 hour. The precipitate was collected by filtration, washed with IPA / EtO (1 / 1), EtO, and dried in vacuo to give the HCl salt of the title compound (2.17 g, 57%). 1 H NMR (400MHz, D2O) 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).

[0662] Intermediate 134 6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0663] [ka]

[0664] A suspension of K2CO3 (1.17 g, 8.50 mmol) and 3-(5-chloropyridin-2-yl)butanimidamide Intermediate 133 (1.98 g, 8.44 mmol) in MeCN (35 mL) was stirred under an argon atmosphere for 1 h. Diphenyliminodicarbonate Intermediate 112 (2.17 g, 8.44 mmol) was added, and stirring was continued at room temperature for 1 h. K2CO3 (1.17 g, 8.50 mmol) was added, and stirring was continued at room temperature for 1 h and then at 60 °C for 2 h. After cooling to room temperature, the resulting thick suspension was dissolved in 0.4 M citric acid (aq, 50 mL) and concentrated to a volume of approximately 60 mL. The remaining solution was extracted with EtOAc (3 × 50 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered, and the solvent was evaporated. The remaining solid was dried in vacuo for 3 h. The semi-solid residue was stirred with PE / Et2O (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

[0665] Intermediate 135 (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0666] [ka]

[0667] Step a) 2,4-dichloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine

[0668] [ka]

[0669] A mixture of 6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazine-2,4(1H,3H)-dione, Intermediate 134 (267 mg, 1.00 mmol), POCl (280 μL, 3.00 mmol), and N,N-diethylaniline (159 μL, 1.00 mmol) was heated at 70° C. for 1.5 h. After cooling to room temperature, the mixture was diluted with CHCl (10 mL) and toluene (10 mL). The mixture was concentrated to give the subtitle compound (estimated quantitative yield) as an oil, which was used in step b).

[0670] Step b) (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol KCO (270 mg, 1.95 mmol) was added in three portions over 2 h 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 dry THF (6 mL). Stirring was continued for an additional 1 h, and 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 8 h and stirring was continued overnight. The mixture was diluted with EtO (40 mL) and the insoluble gum was removed by decantation and filtration through Celite. The filtrate was concentrated and the residue was purified by preparative HPLC, Prep Method B (gradient: 35-75%) to give the title compound (58 mg, 15%); MS (ESI) m / z [M+H] + 384.5 / 386.5

[0671] Intermediate 136 N-(4-(2-(5-chloropyridin-2-yl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide

[0672] [ka]

[0673] The title compound was prepared from (2R)-2-((4-chloro-6-(2-(5-chloropyridin-2-yl)propyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 135 (58 mg, 0.15 mmol) as described in Example 118 to give the title compound (33 mg, 49%); MS (ESI) m / z [M+H] + 443.17

[0674] Intermediate 137 Z-4,4,4-trifluoro-3-phenylbut-2-enenitrile

[0675] [ka]

[0676] 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) at room temperature under a nitrogen atmosphere for 15 minutes, 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 concentrated reaction mixture, which was stirred at room temperature overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (×2, 150 and 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by normal-phase flash chromatography on silica (gradient: 5–40% EtOAc in heptane) to afford the title compound as two distinct E and Z isomers (total 1.80 g, 54%). First eluting isomer (1.07 g): 1 H NMR (400 MHz, CDCl) 6.15-6.19 (1H, m), 7.46-7.59 (5H, m); second eluting isomer (0.728 g): 1H NMR (400MHz, CDCl3) 5.92-5.96 (1H, m), 7.41-7.56 (5H, m).

[0677] Intermediate 138 4,4,4-trifluoro-3-phenylbutanenitrile

[0678] [ka]

[0679] NaBH4 (0.616 g, 16.3 mmol) was added to a mixture of the first eluted isomer of (Z)-4,4,4-trifluoro-3-phenylbut-2-enenitrile intermediate 137 (1.07 g, 5.43 mmol) (E or Z isomer) in MeOH (20 mL) at 0 °C. After 5 min, 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 min, and then concentrated. Brine (10 mL) was added, and the aqueous phase was extracted with DCM (50 mL). The organic phase was dried by passing through a phase separator and concentrated to give the title compound (1.0 g, 92%) as a colorless oil; 1 H NMR (400MHz, CDCl3) 2.88-3.11 (2H, m), 3.63-3.78 (1H, m), 7.31-7.49 (5H, m).

[0680] Intermediate 139 4,4,4-trifluoro-3-phenylbutanimidamide

[0681] [ka]

[0682] AlMe3 (2 M in toluene, 12.5 mL, 25.0 mmol) was added dropwise (approximately 10 min) to an ice-cooled suspension of NH4Cl (1.62 g, 30.2 mmol) in toluene (10 mL) under a nitrogen atmosphere. 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 on an ice-water bath. MeOH (24 mL) was added slowly, and the resulting mixture was stirred for 15 min 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 filtrate was concentrated to give a solid. MeOH (25 mL) followed by HCl (4 M in dioxane, 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 about 45 minutes. The insoluble precipitate was removed by filtration, and the filtrate was concentrated. The oily residue was dried in vacuo overnight to give a syrup-like foam. EtO (10 mL) was added, and the mixture was concentrated. MTBE was added to the residue, and the mixture was concentrated to give a gummy solid, which was dried in vacuo over the weekend to give the HCl salt of the title compound (1.96 g, 93%); 1 H NMR (400MHz, DMSO-d6) 3.1-3.29 (2H, m), 4.38-4.53 (1H, m), 7.39-7.46 (5H, m). 1 By H NMR, the product contains some TBME.

[0683] Intermediate 140 2,4-Dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine

[0684] [ka]

[0685] A suspension of K2CO3 (1.26 g, 9.13 mmol) and 4,4,4-trifluoro-3-phenylbutanimidamide intermediate 139 (1.96 g, 7.76 mmol) in MeCN (40 mL) was stirred under a nitrogen atmosphere for 5 minutes. Diphenyliminodicarbonate intermediate 112 (2.36 g, 9.19 mmol) was added, and stirring was continued at room temperature for 1.5 hours. K2CO3 (1.26 g, 9.13 mmol) was added, and stirring was continued at room temperature for 20 minutes, then at 60 °C overnight. The mixture was stirred with MTBE (35 mL) for 1 hour. The solid was filtered, washed with MTBE (10 mL), and dried in vacuo. 2 M HCl (24 mL) was added to the solid, and the mixture was stirred for 45 minutes. The precipitate was collected by filtration, washed with 0.2 M HCl (15 mL) and water (10 mL), and then dried in vacuo at 50° C. overnight to give the title compound (1.98 g, 89%) as a colorless solid; MS (ESI) m / z [M+H] + 286.2

[0686] Intermediate 141 (2R)-2-((4-chloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0687] [ka]

[0688] Step a) 2,4-dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine

[0689] [ka]

[0690] 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 (31.5 mL, 338 mmol) was heated to gentle reflux for 48 h. After cooling to room temperature, the mixture was concentrated and coevaporated twice from toluene. The residue was dissolved in DCM (85 mL), and the solution was cooled to 0 °C on an ice bath. DIPEA (4.83 mL, 27.6 mmol) was carefully added over 15 min, followed by the 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), followed by saturated NaHCO (12 mL) and water (18 mL), dried by passing through a phase separator, and concentrated to give the subtitle compound (estimated quantitative yield) as a dark oil.

[0691] Step b) (2R)-2-((4-chloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol KCO (1.05 g, 7.60 mmol) was added to an ice-cooled solution of 2,4-dichloro-6-(3,3,3-trifluoro-2-phenylpropyl)-1,3,5-triazine intermediate 141, step a) in MeCN (25 mL). (R)-2-Amino-4-methylpentan-1-ol (0.927 mL, 7.26 mmol) was added dropwise at 0° C. for approximately 1 minute, and the reaction mixture was stirred at 0° C. for 20 minutes. The mixture was allowed to reach room temperature and stirred for 1.5 hours, 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, filtered, and concentrated. The residue was purified by normal phase flash chromatography on silica (gradient: 12 to 100% EtOAc in heptane) to give the title compound (0.526 g, 19%) as a thick yellow oil; MS (ESI) m / z [M+H] + 403.4.

[0692] Intermediate 142 (3-(1-hydroxycyclopropyl)phenyl)boronic acid

[0693] [ka]

[0694] 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) at −65° C. under an atmosphere of N (g). 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 allowed to warm slowly to −30° C. over 2 hours. The reaction was quenched with NH4Cl(aq). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to give the 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 (400MHz, DMSO-d6) δ1.05 (m, 2H), 1.32 (m, 2H), 2.38 (brs, 1H), 7.18 (m, 2H), 7.34 (m, 1H), 7.46 (m, 1H).

[0695] Intermediate 143 6-(2-methyl-2-phenylpropyl)-1,3,5-triazine-2,4(1H,3H)-dione

[0696] [ka]

[0697] A suspension of K2CO3 (374 mg, 2.71 mmol) and 3-methyl-3-phenylbutanimidamide, HCl (US Patent Application Publication No. 20140194431) (0.490 g, 2.30 mmol) in dry MeCN (13 mL) was stirred at room temperature for 5 minutes under an atmosphere of N2 (g). Diphenyliminodicarbonate (0.702 g, 2.73 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. K2CO3 (374 mg, 2.71 mmol) was added, and the reaction mixture was stirred at room temperature for 20 minutes, then at 60 °C for 2 hours and 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 isolated by filtration, washed with MTBE (2-3 mL), and dried in vacuo. The solid was stirred with 2 N HCl (8 mL) for 45 minutes. The precipitate was collected by filtration, washed with 0.2 N HCl (5 mL), and dried in vacuo to give the title compound (0.302 g, 54%) as an off-white solid; MS (ESI) m / z [M+H] + 246.3.

[0698] Intermediate 144 2,4-Dichloro-6-(2-methyl-2-phenylpropyl)-1,3,5-triazine

[0699] [ka]

[0700] POCl3 (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 h and then cooled to room temperature. The reaction mixture was concentrated to dryness in vacuo, coevaporated twice from toluene, and dried overnight under a N2(g) atmosphere, at which time it solidified. The crude product was dissolved in DCM (15 mL), and the solution was cooled to 0 °C on an ice bath. DIPEA (0.823 mL, 4.71 mmol) was added very carefully over 15 min, followed by the slow addition of water (1 mL) over 10 min. The mixture was partitioned between DCM (4 mL) and water (2 mL). The organic phase was washed with water (3 mL), aqueous NaHCO3 (saturated, 2 mL), and water (3 mL). The organic layer was dried over MgSO4, filtered, and concentrated to give the crude title compound (386 mg) as a brown oil that solidified upon standing at room temperature; 1 H NMR (400 MHz, CD3CN) 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.

[0701] Intermediate 145 (R)-2-((4-chloro-6-(2-methyl-2-phenylpropyl)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol

[0702] [ka]

[0703] K2CO3 (0.179 g, 1.30 mmol) was added 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). (R)-2-Amino-4-methylpentan-1-ol (0.158 mL, 1.24 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 15 min. 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 MgSO4, filtered, and concentrated. The crude product was purified by normal-phase flash chromatography on silica (gradient: heptane: EtOAc, 1:1) to give the title compound (211 mg, 49%) as a yellow oil; MS (ESI) m / z [M+H] + 363.4.

[0704] Intermediate 146 1-(1,1-difluoroallyl)-4-fluorobenzene

[0705] [ka]

[0706] 3-Bromo-3,3-difluoroprop-1-ene (235 mg, 1.50 mmol) was added to a mixture of (4-fluorophenyl)boronic acid (140 mg, 1 mmol), Pd2dba3 (5 mg, 5.46 μmol), and K2CO3 (415 mg, 3.00 mmol) in dioxane (5 mL) and water (8.65 μL) in a microwave vial. The vessel was sealed and heated at 80 °C overnight, then stirred at room temperature for 20 h. The reaction mixture was diluted with Et2O and filtered through a pad of MgSO4. 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 normal-phase flash chromatography on silica (gradient: 0-5% Et2O in pentane) to give the title compound (60 mg, 35%). 1H NMR (400MHz, CDCl3) δ5.46-5.61(2H,m), 6.06-6.22(1H,m), 7.11(2H,t), 7.49(2H,dd).

[0707] Intermediate 147 3-Fluoro-6-methyl-2-(prop-1-en-2-yl)pyridine

[0708] [ka]

[0709] EtO (7 mL) and PdCl(dppf) (0.046 g, 0.06 mmol) were added to a degassed solution of KCO (2.182 g, 15.79 mmol) in water (2 mL), and the reaction mixture was degassed. 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) were added in one portion, followed by THF (1.5 mL), and the reaction mixture was refluxed under an atmosphere of N for 72 h. The reaction mixture was diluted with EtO and washed with water and brine. The organic layer was carefully concentrated, and the residue was purified by normal-phase flash chromatography on silica (2–5% EtO in pentane). The fractions containing the first compound were collected and heated with K2CO3(aq) in a microwave reactor at 100 °C for 15 minutes, then partitioned between Et2O and water. The organic layer was treated with CsOH monohydrate (0.23 g, 1.37 mmol) in water (0.5 mL) at room temperature. The aqueous layer was extracted with Et2O, and the combined organic layers were carefully concentrated. The fractions containing the second compound were collected and treated with CsOH monohydrate (0.23 g, 1.37 mmol) at room temperature, then extracted with Et2O. The organic layer was carefully concentrated, and the residues were combined to give the title compound (0.505 g, 64%) as a colorless liquid; 1 H NMR (500MHz, CDCl3) δ2.20 (3H, td), 2.51 (3H, d), 5.45 (1H, h), 5.66 (1H, tq), 6.99 (1H, dd), 7.24 (1H, dd).

[0710] Example 1 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)

[0711] [ka]

[0712] Example 2 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)

[0713] [ka]

[0714] 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) eluted with 15% MeOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 150 mL / min, and detected at 220 nm to give the following: the first eluting 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 28Calculated for Cl2N5O3S: 476.1284, Found: 476.1292; 1 H NMR (500 MHz, CDCl3) 0.91 (6H, dd), 1.25 (m, partially overlapping with DEA ​​residue), 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-eluting 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 Calculated for Cl2N5O3S: 476.1284, Found: 476.1280; 1 H NMR (500MHz, CDCl3) 0.85-0.98 (6H, m), 1.21-1.49 (m, partially overlapped with DEA ​​residue), 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).

[0715] Example 3 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)

[0716] [ka]

[0717] Example 4 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)

[0718] [ka]

[0719] 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 15% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 80 mL / min, and detected at 220 nm, revealing that the first-eluting 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 was obtained, 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 Calculated for ClFN5O3S: 460.1580, Found: 460.1580; 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-eluting 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 acidified 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 Calculated for ClFN5O3S: 460.1580, Found: 460.1580; 1 H NMR(500MHz,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).

[0720] Example 5 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)

[0721] [ka]

[0722] Example 6 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)

[0723] [ka]

[0724] 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) eluted with 15% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 80 mL / min, and detected at 220 nm, revealing the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl. The organic extract was dried over MgSO4, filtered, and evaporated to give (22 mg, 24%); HRMS (ESI) m / z [M+H] + C 19 H 28 Calculated value for F2N5O3S: 444.1876, Found value: 444.1894; 1H 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-eluting compound from the chiral separation, 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) Example 6 was dissolved in EtOAc and washed with dilute HCl. The organic extract was dried over MgSO4, filtered, and evaporated to give (14 mg, 16%); HRMS (ESI) m / z [M+H] + C 19 H 28 Calculated value for F2N5O3S: 444.1876, Found value: 444.1856; 1 H NMR(500MHz,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).

[0725] Example 7 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)

[0726] [ka]

[0727] Example 8 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)

[0728] [ka]

[0729] 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) eluted with 20% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 70 mL / min, and detected at 230 nm, revealing that the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (15 mg, 45%); HRMS (ESI) m / z [M+H] + C 19 H 30 Calculated value for FN6O4S: 457.2028, Measured value: 457.2020; 1H 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, partially overlapping with citric acid 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-eluting compound from the 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 and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (13 mg, 39%); HRMS (ESI) m / z [M+H] + C 19 H 30 Calculated value for FN6O4S: 457.2028, Measured value: 457.2010; 1 H 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, partially overlapping with citric acid residues), 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).

[0730] Example 9 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)

[0731] [ka]

[0732] Example 10 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)

[0733] [ka]

[0734] 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 20% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 70 mL / min, and detected at 230 nm, revealing that the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (7.9 mg, 34%); HRMS (ESI) m / z [M+H] + C 19 H 30 Calculated for ClN6O4S: 473.1732, Found: 473.1724; 1H 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 citric acid 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-eluting 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 and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (8.2 mg, 36%); HRMS (ESI) m / z [M+H] + C 19 H 30 Calculated for ClN6O4S: 473.1732, Found: 473.1734; 1 H NMR(500MHz,MeOD)0.87-0.98(6H,m),1.32-1.52(5H,m),1.58-1.69(1H,m),2.69-2.93(m, partially overlapped with citric acid 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).

[0735] Example 11 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)

[0736] [ka]

[0737] Example 12 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)

[0738] [ka]

[0739] 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) eluted with 20% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 70 mL / min, and detected at 230 nm, revealing the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (28 mg, 57%); HRMS (ESI) m / z [M+H] + C 20 H 32 Calculated value for N7O3S: 450.2282, Measured value: 450.2276; 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 citric acid residues), 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-eluting compound from the chiral separation, 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 was dissolved in EtOAc and washed with aqueous citric acid and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (28 mg, 57%); HRMS (ESI) m / z [M+H] + C 20 H 32 Calculated value for N7O3S: 450.2282, Measured value: 450.2292; 1 H NMR(500MHz,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,partially overlapped with citric acid 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).

[0740] Example 13 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)

[0741] [ka]

[0742] Example 14 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)

[0743] [ka]

[0744] 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) eluted with 15% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 150 mL / min, and detected at 230 nm, with the first eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (25 mg, 48%); HRMS (ESI) m / z [M+H] + C 20 H 33 Calculated value for N6O4S: 453.2278, Measured value: 453.2254; 1H NMR (500 MHz, CDCl3) 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-eluting compound from the 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 Na2SO4, filtered, and evaporated to give (17 mg, 33%); HRMS (ESI) m / z [M+H] + C 20 H 33 Calculated value for N6O4S: 453.2278, Measured value: 453.2274; 1 H NMR(500MHz,CDCl3)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).

[0745] Example 15 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)

[0746] [ka]

[0747] Example 16 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)

[0748] [ka]

[0749] 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) eluted with 35% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 60 mL / min, and detected at 230 nm, with the first eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute acetic acid (0.5%) and brine. The organic extract was dried over Na2SO4, filtered, and evaporated to give (23 mg, 44%); HRMS (ESI) m / z [M+H] + C 20 H 33 Calculated value for N6O4S: 453.2278, Measured value: 453.2272; 1H NMR (500 MHz, CDCl3) 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), 7.28-7.33 (1H, m), 7.81 (1H, dd). The second eluting compound from the 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 Na2SO4, filtered, and evaporated to give (24 mg, 46%); HRMS (ESI) m / z [M+H] + C 20 H 33 Calculated for N6O4S: 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).

[0750] Example 17 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)

[0751] [ka]

[0752] Example 18 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)

[0753] [ka]

[0754] 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) eluted with 15% EtOH / TEA (100 / 0.5) in CO at 120 bar, a flow rate of 130 mL / min, and detected at 230 nm, with the first eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl (aq) and brine. The organic extract was dried over MgSO4, filtered and evaporated to give (50 mg, 30%); HRMS (ESI) m / z [M+H] + C 19 H 31 Calculated value for N6O4S: 439.2122, Measured value: 439.2126; 1H 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-eluting 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 (aq) and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (42 mg, 25%); HRMS (ESI) m / z [M+H] + C 19 H 31 Calculated value for N6O4S: 439.2122, Measured value: 439.2124; 1 H NMR(500MHz,MeOD)0.87-0.97(6H,m),1.31-1.52(m,partially overlapped 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).

[0755] Example 19 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)

[0756] [ka]

[0757] Example 20 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)

[0758] [ka]

[0759] 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) eluted with 30% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 80 mL / min, and detected at 254 nm, revealing that the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (30 mg, 47%); HRMS (ESI) m / z [M+H] + C 20 H 31 Calculated value for FN5O4S: 456.2076, Measured value: 456.2088; 1 H NMR (400 MHz, CDCl3) 0.87-0.98 (6H, m), 1.22-1.54 (m, partially overlapping with solvent residue), 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-eluting 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 MgSO4, filtered, and evaporated to give (28 mg, 44%); HRMS (ESI) m / z [M+H] + C 20 H 31 Calculated value for FN5O4S: 456.2076, Measured value: 456.2092; 1 H NMR (400MHz, CDCl3)0.88-0.98(6H,m),1.22-1.54(m, partially overlapped with solvent residue),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).

[0760] Example 21 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)

[0761] [ka]

[0762] Example 22 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)

[0763] [ka]

[0764] 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) eluted with 15% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 70 mL / min, and detected at 254 nm, with the first eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (22 mg, 22%); HRMS (ESI) m / z [M+H] + C 19 H 27 Calculated value for F3N5O3S: 462.1780, Measured value: 462.1792; 1 H NMR (400 MHz, CDCl3) 0.85-1.01 (6H, m), 1.22-1.54 (m, partially overlapping with solvent residue), 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-eluting compound from the 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 MgSO4, filtered, and evaporated to give (27 mg, 28%); HRMS (ESI) m / z [M+H] + C 19 H27 Calculated for F3N5O3S: 462.1780, found: 462.1792; 0.85-1.01 (6H, m), 1.22-1.54 (m, partially overlapping with solvent residue), 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).

[0765] Example 23 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)

[0766] [ka]

[0767] Example 24 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)

[0768] [ka]

[0769] 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) eluted with 15% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 70 mL / min, and detected at 260 nm, revealing the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (10 mg, 36%); HRMS (ESI) m / z [M+H] + C 19 H 28 Calculated value for F2N5O3S: 444.1876, Found value: 444.1900; 1 H NMR (400 MHz, CDCl3) 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-eluting 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 MgSO4, filtered, and evaporated to give (11 mg, 39%); HRMS (ESI) m / z [M+H] + C 19 H 28Calculated value for F2N5O3S: 444.1876, Found value: 444.1888; 1 H NMR (400MHz, CDCl3) 0.85-0.98(6H,m), 1.25-1.53(m, partially overlapped 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).

[0770] Example 25 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)

[0771] [ka]

[0772] Example 26 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)

[0773] [ka]

[0774] 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 (23 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250 × 30 mm, 5 μm) eluted with 20% EtOH / TEA (100 / 0.5) in CO at 120 bar, a flow rate of 87.5 mL / min, and detected at 230 nm, revealing the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated. The residue was purified by preparative HPLC Prep Method C (gradient 20-60%) to give (4.6 mg, 20%); HRMS (ESI) m / z [M+H] + C 18 H 28 Calculated for ClN6O3S: 443.1626, Found: 443.1626; 1 H NMR (400 MHz, CDCl3) 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 overlapping with by-product), 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-eluting 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 MgSO4, filtered, and evaporated to give (5.6 mg, 24%); HRMS (ESI) m / z [M+H] + C 18 H 28 Calculated for ClN6O3S: 443.1626, Found: 443.1618; 1 H NMR(500MHz,CDCl3)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).

[0775] Example 27 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)

[0776] [ka]

[0777] Example 28 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)

[0778] [ka]

[0779] 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 27% EtOH / DEA (100 / 0.5) in CO at 100 bar, a flow rate of 160 mL / min, and detected at 230 nm, revealing that the first-eluting 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 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (10.6 mg, 45%); HRMS (ESI) m / z [M+H] + C 20 H 33 Calculated value for N6O4S: 453.2278, Measured value: 453.2306; 1 H NMR (400 MHz, CDCl3) 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-eluting compound from the 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 MgSO4, filtered, and evaporated to give (10.6 mg, 45%); HRMS (ESI) m / z [M+H] + C20 H 33 Calculated value for N6O4S: 453.2278, Measured value: 453.2302; 1 H NMR(400MHz,CDCl3)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).

[0780] Example 29 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)

[0781] [ka]

[0782] Example 30 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)

[0783] [ka]

[0784] 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 preparative chiral HPLC on a Chiralcel OJ column (250 × 30 mm, 5 μm) eluted with 15% EtOH / DEA (100 / 0.5) in CO at 100 bar, a flow rate of 70 mL / min, and detected at 260 nm, revealing that the first-eluting compound, 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) Example 29 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (4.2 mg, 33%); HRMS (ESI) m / z [M+H] + C 19 H 28 Calculated for ClFN5O3S: 460.1580, Found: 460.1610; 1 H NMR (400 MHz, CDCl3) 0.85-0.99 (6H, m), 1.29-1.53 ​​(5H, m), 1.55-1.73 (1H, m), 2.85-3.03 (2H, m), 3.26-3.35 (3H, m), 3.54-3.79 (3H, m), 4.15-4.26 (1H, m), 6.88-6.96 (1H, m), 7.08-7.15 (1H, m), 7.24 (1H, dd). The second-eluting compound from the chiral separation, 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) Example 30 was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (4.5 mg, 35%); HRMS (ESI) m / z [M+H] + C 19 H 28Calculated for ClFN5O3S: 460.1580, Found: 460.1608; 1 H NMR(400MHz,CDCl3)0.86-0.98(6H,m),1.28-1.53(5H,m),1.55-1.73(1H,m),2.85-3.01(2H,m),3.2 6-3.35(3H,m),3.52-3.81(3H,m),4.16-4.30(1H,m),6.92(1H,dd),7.08-7.15(1H,m),7.23(1H,dd).

[0785] Example 31 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 (Isomer 1)

[0786] [ka]

[0787] Example 32 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 (Isomer 2)

[0788] [ka]

[0789] The diastereomers of 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 intermediate 37 (25 mg, 0.05 mmol) were separated by preparative chiral HPLC on a Chiralcel IA column (250 × 30 mm, 5 μm) eluted with 10% EtOH / DEA (100 / 0.5) in CO at 120 bar, a flow rate of 100 mL / min, and detected at 230 nm, with the first eluting compound, 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 (Isomer 1) Example 31 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (10.3 mg, 41%); HRMS (ESI) m / z [M+H] + C 19 H 27 Calculated for ClF2N5O3S: 478.1486, Found: 478.1516; 1 H NMR (400 MHz, CDCl3) 0.85-0.98 (6H, m), 1.27-1.53 ​​(5H, m), 1.54-1.74 (1H, m), 2.83-3.00 (2H, m), 3.22-3.46 (4H, m), 3.53-3.64 (1H, m), 3.65-3.83 (1H, m), 4.16-4.30 (1H, m), 6.84-6.95 (2H, m). The second-eluting compound from the chiral separation, 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 (Isomer 2) Example 32 was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (8.2 mg, 33%); HRMS (ESI) m / z [M+H] + C 19 H 27Calculated for ClF2N5O3S: 478.1486, Found: 478.1466; 1 H NMR(400MHz,CDCl3)0.85-0.98(6H,m),1.27-1.54(5H,m),1.55-1.72(1H,m),2.83-2.96(2H,m) ,3.25-3.42(4H,m),3.54-3.64(1H,m),3.66-3.82(1H,m),4.15-4.26(1H,m),6.83-6.92(2H,m).

[0790] Example 33 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 (Isomer 1)

[0791] [ka]

[0792] Example 34 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 (Isomer 2)

[0793] [ka]

[0794] The diastereomers of 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 intermediate 39 (60 mg, 0.13 mmol) were separated by preparative chiral HPLC on a Chiralcel OJ column (250 × 30 mm, 5 μm) eluted with 10% IPA / TEA (100 / 0.5) in CO at 120 bar, a flow rate of 80 mL / min, and detected at 230 nm, revealing that the first-eluting compound, 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 (Isomer 1) Example 33 was obtained, which was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (23 mg, 38%); HRMS (ESI) m / z [M+H] + C 19 H 27 Calculated for ClF2N5O3S: 478.1486, Found: 478.1484; 1 H NMR (400 MHz, CDCl3) 0.82-0.99 (6H, m), 1.28-1.74 (6H, m), 2.89-3.08 (2H, m), 3.23-3.36 (3H, m), 3.52-3.63 (1H, m), 3.64-3.81 (2H, m), 4.08-4.26 (1H, m), 6.92-7.14 (2H, m). The second eluting compound from the chiral separation, 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 (Isomer 2) Example 34 was dissolved in EtOAc and washed with dilute HCl and brine. The organic extract was dried over MgSO4, filtered, and evaporated to give (20 mg, 33%); HRMS (ESI) m / z [M+H] + C 19 H 27Calculated for ClF2N5O3S: 478.1486, Found: 478.1488; 1 H NMR(400MHz,CDCl3)0.87-0.99(6H,m),1.28-1.72(6H,m),2.91-3.07(2H,m) ,3.24-3.38(3H,m),3.53-3.83(3H,m),4.16-4.30(1H,m),6.93-7.14(2H,m).

[0795] Example 35 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 (Isomer 1)

[0796] [ka]

[0797] Example 36 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 (isomer 2)

[0798] [ka...

Claims

1. A compound of formula (I) 【Chemistry 1】 During the ceremony, R １ is C ３～６ Branched alkyl or C ３～６ is a branched haloalkyl; R ２ is C １～３ Alkyl or C １～３ is haloalkyl, m is 1 or 2; R ３ and R ４ are independently H, halo, 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 are independently halo, 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 selected from cycloalkyl, 4- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and phenyl; where: Said C ３～６ Cycloalkyl or 4- to 6-membered heterocyclyl includes hydroxy, oxy, halo, and —C(O)OR ９ optionally substituted with 1 to 3 substituents selected from said 4-6 membered heteroaryl optionally substituted with 1 to 3 halo substituents; Said C １～４ The alkoxy may be optionally substituted with a 4- to 6-membered heterocyclyl; Each R ６ and R ７ are independently H and C １～３ alkyl, each q is independently 1, 2, or 3; Each R ８ is independently a 4- to 6-membered heterocyclyl, said heterocyclyl being optionally substituted with oxy; Each R ９ are independently １～５ a compound, or a pharmaceutically acceptable salt or tautomer thereof.

2. The following structure 【Chemistry 2】 【Transformation 3】 2. The compound of claim 1 having the formula:

3. 3. The compound of claim 1 or 2, wherein A is phenyl.

4. 3. The compound of claim 1 or 2, wherein A is a monocyclic heteroaryl.

5. The compound of claim 4, wherein A is a monocyclic N-heteroaryl.

6. 6. The compound of claim 4 or 5, wherein A is a 6-membered monocyclic heteroaryl.

7. 6. The compound of claim 5, wherein A is pyridyl.

8. 6. The compound of claim 5, wherein A is pyrimidine.

9. A is phenyl or a 6-membered monocyclic heteroaryl, p is at least 1, and R ５ But, R ４ -R ５ The compound of any one of claims 1 to 8, wherein the ring atom is para to the ring atom attached to the substituted carbon.

10. A is phenyl or a 6-membered monocyclic heteroaryl, p is at least 1, and R ５ But, R ４ -R ５ The compound of any one of claims 1 to 8, wherein the ring atom is ortho to the ring atom attached to the substituted carbon.

11. A is phenyl or a 6-membered monocyclic heteroaryl, p is at least 1, and R ５ But, R ４ -R ５ The compound of any one of claims 1 to 8, wherein the compound is meta to the ring atom attached to the substituted carbon.

12. At least one R ５ The compound of any one of claims 1 to 11, wherein is halo.

13. At least one R ５ The compound of claim 12, wherein is F.

14. At least two R ５ The compound of claim 13, wherein is F.

15. At least three R's ５ The compound of claim 14 , wherein is F.

16. At least one R ５ The compound according to any one of claims 9 to 15, wherein is Cl.

17. At least two R ５ The compound of claim 16, wherein is Cl.

18. At least one R ５ But C １～４ The compound of any one of claims 1 to 17, which is alkoxy.

19. At least one R ５ But, -OCH ３ 19. The compound of claim 18, wherein:

20. At least one R ５ But, -OCH ２ CH ３ 19. The compound of claim 18, wherein:

21. At least one R ５ But C １～４ The compound of any one of claims 1 to 20, which is haloalkoxy.

22. At least one R ５ But C １ ~C ３ The compound of any one of claims 1 to 21, which is alkyl.

23. At least one R ５ 23. The compound of claim 22, wherein is methyl.

24. At least one R ５ is hydroxy or C １ ~C ３ The compound of any one of claims 1 to 23, which is hydroxyalkyl.

25. R ３ or R ４ One of them is C １～３ The compound of any one of claims 1 to 24, which is alkyl.

26. Said C １～３ 26. The compound of claim 25, wherein the alkyl is methyl.

27. Said C １～３ 26. The compound of claim 25, wherein the alkyl is ethyl.

28. R ３ or R ４ The compound of any one of claims 1 to 27, wherein one of

29. R ４ 29. The compound of claim 28, wherein is H.

30. R ３ or R ４ The compound of any one of claims 1 to 29, wherein one of is halo.

31. R １ But C ３～６ The compound of any one of claims 1 to 30, which is a branched alkyl.

32. R １ But C ４ 32. The compound of claim 31, which is a branched alkyl.

33. R １ But -CH ２ CH (CH ３ ) ２ 33. The compound of claim 32, wherein:

34. R ２ But C １～３ The compound of any one of claims 1 to 33, which is alkyl.

35. R ２ 35. The compound of claim 34, wherein is methyl.

36. The compound of any one of claims 1 to 35, wherein p is 1, 2, or 3.

37. 37. The compound of claim 36, wherein p is 1.

38. 37. The compound of claim 36, wherein p is 2.

39. 37. The compound of claim 36, wherein p is 3.

40. 40. The compound of any one of claims 1 to 39, wherein m is 1.

41. The compound of any one of claims 1 to 38, wherein m is 2.

42. 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-(methylsulfonamido)-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 -sulfanylidene)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-(methylsulfonamido)-1,3,5-triazin-2-yl)propan-2-yl)phenyl)-N-methylacetamide, 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-oxoisoxazolidin-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-(methylsulfonamido)-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-(methylsulfonamido)-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]oxazin-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]oxazin-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, 2. The compound of claim 1, which is selected from 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. (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-oxoindolin-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, 2. The compound of claim 1, wherein the compound is selected from 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. 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, 2. The compound of claim 1, wherein the compound is selected from 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 pharmaceutically acceptable salts and tautomers thereof.

45. N-(4-(-2-(4-cyanophenyl)propyl)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, 2. The compound of claim 1, which is selected from N-(4-(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.

46. 46. ​​A pharmaceutical composition comprising a compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt or tautomer thereof.

47. 46. ​​A 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 disease.

48. 48. The compound of claim 47, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with an autoimmune condition, 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. 46. ​​A method of treating cardiovascular disease, comprising administering to a person suffering from or at risk of said disease or condition a therapeutically effective amount of a compound of any one of claims 1 to 45, or a pharmaceutically acceptable salt or tautomer thereof.

50. 50. The method of claim 49, wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with an autoimmune condition, 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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