THIO-substituted 1,3,5-triazine CX3CR1 modulators

Abstract

The present disclosure provides thio-substituted 1,3,5-triazine CX3CR1 modulators, pharmaceutical compositions thereof and uses thereof for the treatment of cardiovascular disease.

Description

[0001]201389-PCT01-NP THIO-SUBSTITUTED 1,3,5-TRIAZINE CX3CR1 MODULATORS RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional 5 Application No.63 / 635,709, filed April 18, 2024, which is incorporated by reference herein in its entirety for all purposes. BACKGROUND Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including cardiovascular and respiratory diseases such as asthma, 10 atherosclerosis and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis, multiple sclerosis, systemic sclerosis, systemic lupus erythematosus, lupus nephritis and inflammatory myopathy. These small, secreted molecules are a growing superfamily of 8- 14 kDa proteins characterized by a conserved cysteine motif. At the present time, the chemokine superfamily comprises four groups exhibiting characteristic structural motifs; the 15 C-X-C, C-C and C-X3-C and XC families. The C-X-C and C-C families have sequence similarity and are distinguished from one another on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues. The C-X3-C family is distinguished from the other two families on the basis of having a triple amino acid insertion between the NH- proximal pair of cysteine residues. In contrast, members of the XC family lack one of the first 20 two cysteine residues. The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2). The C-C chemokines include potent chemoattractants of monocytes, lymphocytes and neutrophils. 25 The C-X3-C chemokine (also known as fractalkine, FKN, or CX3CL1) is a potent chemoattractant and activator of microglia in the central nervous system (CNS) as well as of monocytes, T cells, NK cells and mast cells. It also functions as an adhesion molecule on immune active cells, such as monocytes and others for infiltration of cells from the blood to the tissue. Blocking the interaction has been proven to reduce atherosclerosis progression and 30 plaque growth (Poupel et al., Arterioscler. Thromb. Vasc. Biol., 2013, 33, 2297-2305). In humans, CX3CR1 and fractalkine is expressed in early and late atherosclerosis (Stolla et al. 1 201389-PCT01-NP 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). Fractalkine neutralisation improves cardiac function in mouse myocardial infarction (MI) models by enhanced systolic function, ventricular remodeling and decreased infarct size 5 (Xuan et al 2011, Cardiovascular Research 92, 385) and also LVEF and survival rate 2 weeks post treatment after an induced MI in mouse (Gu et al 2015, Exp Physiol 100, 805). Additionally, fractalkine cause cardio-depressive actions with impaired contractility observed in mouse cardiomyocytes (Taube et al 2013, PLOS ONE 8(7) (https: / / doi.org / 10.1371 / journal.pone.0069832)). Human serum soluble FKN (sFKN) levels 10 are associated with NYHA heart failure functional score where in patients with HF have an increased level of soluble fractalkine (Husberg et al. J. of Mol. and Cellular Cardiology, 2008, 45(2), 261). sFKN concentration has a prognostic value in patients with acute myocardial infarction treated with primary percutaneous coronary intervention (Xu Bing et al Cytokine 2019 113 (365-370). Elevated sFKN plasma levels predictor of mortality in subjects with 15 advanced systolic HF (Richter et al 2012, Thrombosis & Haemostasis 108, 1220). Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C 20 family) and CX3CR1 for the C-X3-C family. These receptors represent good targets for drug development since agents that modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. WO2005 / 070903 discloses certain triazine derivatives for use in the treatment of chemokine mediated diseases and disorders. 25 WO2006 / 107258 discloses certain 5-substituted 7-amino-[1,3]thiazolo[4,5- d]pyrimidine derivatives as antagonists of the CX3CR1 receptor. WO2006 / 107257 and WO2009 / 120140 disclose certain 5,7-disubstituted [l,3]thiazolo[4,5- d]pyrimidin-2(3H)one derivatives as antagonists of the CX3CR1 receptor. WO2013039057 discloses certain pyrrolidine-3-ylacetic acid derivatives having an 30 inhibitory pathway in the fractalkine-CX3CR1 pathway. 2 201389-PCT01-NP Linkage of CX3CR1 activity to diseases has thus been implicated in cardiovascular diseases (CVD) including heart failure, cardiomyopathy, acute coronary syndrome, myocardial infarction, stable coronary artery disease and atherosclerosis related conditions. There is a need for an orally active modulator of CX3CR1 for the treatment 5 cardiovascular diseases (CVD) e.g., heart failure, cardiac muscle diseases and coronary artery disease related conditions. SUMMARY In some embodiments, the present disclosure provides a compound of Formula (I) 10 wherein R1is a C3-6branched alkyl or C3-6branched haloalkyl; R2 is a C1-3 alkyl or C1-3 haloalkyl; n is 0 or 1; R3and R4are, independently, selected from H, halo, C1-3alkyl, and C1-3haloalkyl; 15 A is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl; p is 0, 1, 2, 3, or 4; each R5is independently selected from halo, hydroxy, oxo, C1-3alkyl, C1-3haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkoxy-C1-3alkyl, C1-3 hydroxyalkyl, -NO2, -(CH2)qCN, - C(O)NR6R7, -NS(O)R6R7, -NR6C(O)R7, -NR6R7, -NR6C(O)OR7, -(CH2)qC(O)NR6R7, - 20 (CH2)qNR6C(O)R7, -C(O)NR6COR7,–(CH2)qR8, -C(O)R8, -C(O)OR9,-OC(O)R9, C3-6cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, wherein the C3-6cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 substituents selected from hydroxy, oxy, halo, -C(O)NR6R7, and -C(O)OR9; 25 the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents; 3 201389-PCT01-NP the C1-4 alkoxy can be optionally substituted with a 4-6 member heterocyclyl; the C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl can be optionally substituted with -CH3; each R6 and R7 are, independently, selected from H, C1-3 alkyl, and -C1-3 alkoxy; 5 each q is, independently, 0, 1, 2, or 3; each R8is, independently, a C1-5alkyl or a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy; and each R9 is, independently, a C1-5 alkyl; or a pharmaceutically acceptable salt or tautomer thereof. 10 In some embodiments, the present disclosure provides a compound of Formula (Ia): In some embodiments, the present disclosure provides a compound of Formula (Ib): 15 In some embodiments, A is phenyl. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, A is a monocyclic N-heteroaryl. In some embodiments, A is a 6-member monocyclic heteroaryl. In some embodiments, the 6-member monocyclic 4 201389-PCT01-NP heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine or triazine. In some embodiments, A is a 5-member monocyclic heteroaryl. In some embodiments, the 5-member monocyclic heteroaryl is a monocyclic-N-heteroaryl. In some embodiments, the 5-member monocyclic heteroaryl is pyrrole, pyrazole, or imidazole. 5 In some embodiments, A is a bicyclic aryl. In some embodiments, the bicyclic aryl comprises two 6-membered rings. In some embodiments, the bicyclic aryl is a naphthalene or isoindene. In some embodiments, the bicyclic aryl is a bicyclic heteroaryl. In some embodiments, the bicyclic heteroaryl is benzodioxanyl, benzothioazolyl, benzodioxazolyl, indazolyl, indoxazinyl, indolyl, benzodihydrofuranyl, benzofuranyl, benzodihydropyrone, 10 benzoxazolyl, indolizinyl, benzothiazolyl, benzoxazinyl, benzodihydrothiophenyl, quinolinyl, phthalazinyl, purinyl, indazolyl, indolyl, naphthyridinyl, pteridinyl In some embodiments, p is at least 1. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1, 2, 3, or 4 and at least one R5 is para to the ring atom 15 bound to the R3R4- substituted carbon. In some embodiments, p is 1, 2, 3, or 4 and at least one R5is ortho to the ring atom bound to the R3R4- substituted carbon. In some embodiments, p is 1, 2, 3, or 4 and at least one R5is meta to the ring atom bound to the R3R4- substituted carbon. In some embodiments, p is 1, 2, 3 or 4 and at least one R5is halo. In some 20 embodiments, p is 2, 3, or 4 and at least two R5are F. In some embodiments, p is 3 or 4 and at least three R5 are F. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is Cl. In some embodiments, p is 2, 3 or 4 and at least two R5 are Cl. In some embodiments, p is 1, 2, 3 or 4 and at least one R5is oxo. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is a C1-C3 alkyl. In some 25 embodiments, p is 1, 2, 3 or 4 and at least one R5 is methyl or ethyl. In some embodiments, p is 1, 2, 3 or 4 and at least one R5is a C1-C3haloalkyl. In some embodiments, the C1-C3haloalkyl is fluoromethyl, fluoroethyl, difluoroethyl, fluoropropyl or difluoropropyl. 5 201389-PCT01-NP In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is a C1-4 alkoxy. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is -OCH3. In some embodiments, p is 1, 2, 3 or 4 and at least one R5is -OCH2CH3. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is a C1-4 haloalkoxy. 5 In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is a C1-4 alkoxy- C1-3 alkyl. In some embodiments, the C1-4alkoxy- C1-3alkyl is ethoxyalkyl or methoxyalkyl. In some embodiments, the ethoxyalkyl is ethoxymethyl or ethoxyethyl. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is a hydroxy or a C1-C3 hydroxyalkyl. In some embodiments, the C1-C3 hydroxyalkyl is hydroxymethyl or 10 hydroxyethyl. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is (CH2)qCN, -C(O)NR6R7, or -NS(O)R6R7. In some embodiments, R6 is H and R7 is C1-3 alkyl. In some embodiments, both R6and R7are C1-3alkyl. In some embodiments, both R6and R7are H. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is -NR6C(O)R7, -NR6R7, - 15 NR6C(O)OR7, -(CH2)qC(O)NR6R7, -(CH2)qNR6C(O)R7, -C(O)NR6COR7. In some embodiments, R6is H and R7is C1-3alkyl. In some embodiments, both R6and R7are C1-3alkyl. In some embodiments, both R6 and R7 are H. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is -(CH2)qR8, or -C(O)R8. In some embodiments, R8is a C1-5alkyl. 20 In some embodiments, p is 1, 2, 3 or 4 and at least one R5is -CR6NR7C(O)R8. In some embodiments, R6 is methyl or ethyl, R7 is H, and R8 is ethyl or methyl. In some embodiments, R8 is methyl, ethyl, or propyl. In some embodiments, R8 is a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy. In some embodiments, R3 or R4 is C1-3 alkyl. In some embodiments, the C1-3 alkyl is 25 methyl or ethyl. In some embodiments, one of R3 or R4 is H. In some embodiments, R4 is H. In some embodiments, R3or R4is halo. In some embodiments, R1 is a C3-C6 branched alkyl. In some embodiments, R1 is a C4 branched alkyl. In some embodiments, R1 is -CH2CH(CH3)2. In some embodiments, R2is a C1-3alkyl. In some embodiments, R2is methyl. 6 201389-PCT01-NP In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, the compound is selected from any of the compounds in Table 4. In some embodiments, the compound is selected from the compounds in Table 5. 5 In some embodiments, the compound is selected from the compounds in Table 6. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound disclosed herein. In some embodiments, the pharmaceutical composition is for use in the treatment of cardiovascular disease. In some embodiments, the cardiovascular disease is non-ischemic 10 dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. In some embodiments, the present disclosure provides a method of treating 15 cardiovascular disease comprising administering to a person suffering from or at risk of, said disease or condition, a therapeutically effective amount of a compound or composition disclosed herein. In some embodiments, the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart 20 failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. DETAILED DESCRIPTION Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in 25 the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. 7 201389-PCT01-NP The use of the term "or" in the claims is used to mean "and / or," unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and / or." As used herein, the terms "comprising" (and any variant or form of comprising, such 5 as "comprise" and "comprises"), "having" (and any variant or form of having, such as "have" and "has"), "including" (and any variant or form of including, such as "includes" and "include") or "containing" (and any variant or form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. 10 The use of the term "for example" and its corresponding abbreviation "e.g." means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. As used herein, "about" can mean plus or minus 10% of the provided value. Where 15 ranges are provided, they are inclusive of the boundary values. "About" can additionally or alternately mean either within 10% of the stated value, or within 5% of the stated value, or in some cases within 2.5% of the stated value; or, "about" can mean rounded to the nearest significant digit. As used herein, "between" is a range inclusive of the ends of the range. For example, 20 a number between x and y explicitly includes the numbers x and y and any numbers that fall within x and y. The term “alkoxy” refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy and the like. 25 The term “alkyl” or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. The term “alkoxyalkyl” refers to an alkyl group attached to an alkoxy group, where in 30 the group is attached to the rest of the molecule via a carbon on the alkyl group, i.e. a group having a structure of -R-O-R’ wherein R and R’ are the same or different alkyl groups. 8 201389-PCT01-NP The term “aryl” refers to an aromatic hydrocarbon. The term aryl includes monocyclic aryls, with a single ring, such as phenyl, as well as polycyclic aryls, including “bicyclic aryls” having two or more cyclic rings, in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic, for example, the other cyclic 5 ring is cycloalkyl, cycloalkenyl, cycloalkynyl and / or aryl. Examples of polycyclic aryl rings include naphthalene and tetrahydronaphthalene. The term “cycloalkyl” refers to a partially or completely saturated monocyclic, bicyclic, polycyclic or bridged hydrocarbon ring system. The term “halo” means fluoro, chloro, bromo, and iodo. In an embodiment, halo is 10 fluoro or chloro. In another embodiment, halo is fluoro. In yet another embodiment, halo is chloro. The term “haloalkoxy” means an alkoxy in which one or more hydrogens has been substituted with a halo. The term “haloalkyl” means an alkyl group in which one or more hydrogens has been 15 substituted with a halo. The term “heteroaryl” as used herein, refers to substituted or unsubstituted aromatic ring structures whose ring structures include, e.g., at least one heteroatom selected from nitrogen, oxygen, and sulphur. Heteroaryl groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atom. Heteroaryl groups can include monocyclic 20 heteroaryls as well as polycyclic heteroaryls such as bicyclic heteroaryls, having two or more cyclic rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic and at least one of the rings includes at least one heteroatom selected from nitrogen, oxygen, and sulphur. In some embodiments, the heteroatom in the heteroaryl is sulfur, and the sulfur can be oxidized with 1 or 2 oxygens. For examples, the 25 term heteroaryl would encompass dihydro-isothiazole-dioxide, in which the sulfur has been oxidized with two oxygen. In other some embodiments, the sulphur heteroatom is not oxidized. Examples of monocyclic heteroaryls include, but are not limited to, pyrrole, pyridine, pyrazine, pyridazine, pyrimidine, furan, triazole, thiophene, imidazole, isoxazole, oxazole, 30 oxadiazole, thiazole and pyrazole. Examples of bicyclic heteroaryls, include, but are not limited to purine, indole, indazole, quinoline, quinazoline, benzofuran, benzoxazole, 9 201389-PCT01-NP 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 5 heteroaryls include, but are not limited to, carbazole and dibenzazepine. The term “monocyclic N-heteroaryl” refers to a monocyclic heteroaryl whose ring structures include at least one nitrogen. Examples of monocyclic N-heteroaryls include, but are not limited to imidazole, pyrrole, triazole, pyridine, pyrazine, pyridazine, pyrimidine, and triazine. 10 The term “heterocycle” “heterocyclic” or “heterocyclyl” refers to a partially or completely saturated hydrocarbon ring system wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen and sulphur. Heterocyclic groups can be attached to the rest of the molecule via a carbon or nitrogen ring- member atoms. Heterocycles include monocyclic heterocycles as well as polycyclic 15 heterocycles such as bicyclic heterocycles. Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, piperidine, piperazine, oxetane, and isoxazolidine. The term “hydroxy” refers to an -OH group. The term “hydroxyalkyl” means an alkyl group in which one or more hydrogens has 20 been substituted with a hydroxy. The term “oxo” refers to an “=O” group, i.e., a substituent oxygen atom connected to another atom by a double bond. In this specification the prefix Cx-yas used in terms such as “Cx-yalkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in 25 the group. Examples of suitable C1-3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl. Examples of suitable C1-4alkyl 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, a group will have two instances of Cx-y in which case the prefix indicates the numerical range of carbons in each part of the group, e.g., C1-3alkoxy- C1-4alkyl, refers to an 30 alkoxyalkyl group wherein the alkyl group has 1 to 3 carbons and the alkoxy group has 1-4 carbons. 10 201389-PCT01-NP Compounds: In some embodiments, the present disclosure provides a compound of Formula (I) wherein 5 R1 is a C3-6 branched alkyl or C3-6 branched haloalkyl; R2 is a C1-3 alkyl or C1-3 haloalkyl; n is 0 or 1; R3 and R4 are, independently, selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; A is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl; 10 p is 0, 1, 2, 3, or 4; each R5is independently selected from halo, hydroxy, oxo, C1-3alkyl, C1-3haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkoxy-C1-3alkyl, C1-3 hydroxyalkyl, -NO2, -(CH2)qCN, - C(O)NR6R7, -NS(O)R6R7, -NR6C(O)R7, -NR6R7,-NR6C(O)OR7, -(CH2)qC(O)NR6R7, - (CH2)qNR6C(O)R7, -C(O)NR6COR7,-(CH2)qR8, -C(O)R8, -C(O)OR9,-OC(O)R9, C3-615 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, wherein the C3-6cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 substituents selected from hydroxy, oxy, halo, -C(O)NR6R7, and -C(O)OR9; the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents; 20 the C1-4alkoxy can be optionally substituted with a 4-6 member heterocyclyl; the C3-6cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl can be optionally substituted with -CH3; each R6and R7are, independently, selected from H, -C1-3alkyl, and -C1-3alkoxy; each q is, independently, 0, 1, 2, or 3; 11 201389-PCT01-NP each R8 is, independently, a C1-5 alkyl or a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy; and each R9is, independently, a C1-5alkyl; or a pharmaceutically acceptable salt or tautomer thereof. 5 In some embodiments, the compounds described herein can be a single isomer. In some embodiments, the compounds can be a racemic mixture. In some embodiments, the present disclosure provides a compound of 10 wherein R1, R2, R3, R4, R5, n, p, and A are defined as above for Formula (I). In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein A is phenyl. In some embodiments, A is a monocyclic heteroaryl. In some 15 embodiments, A is a monocyclic N-heteroaryl. In some embodiments, A is a 6-member monocyclic heteroaryl. In some embodiments, the 6-member monocyclic heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine or triazine. In some embodiments, A is a 5- 12 201389-PCT01-NP member monocyclic heteroaryl. In some embodiments, the 5-member monocyclic heteroaryl is a monocyclic-N-heteroaryl. In some embodiments, the 5-member monocyclic heteroaryl is pyrrole, pyrazole, or imidazole. In some embodiments, the present disclosure provides a compound of Formulae (I), 5 (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein A is a bicyclic aryl. In some embodiments, the bicyclic aryl comprises two 6-membered rings. In some embodiments, the bicyclic aryl is a naphthalene or isoindene. In some embodiments, the bicyclic aryl is a bicyclic heteroaryl. In some embodiments, the bicyclic heteroaryl is benzodioxanyl, benzothioazolyl, benzodioxazolyl, indazolyl, 10 indoxazinyl, indolyl, benzodihydrofuranyl, benzofuranyl, benzodihydropyrone, benzoxazolyl, indolizinyl, benzothiazolyl, benzoxazinyl, benzodihydrothiophenyl, quinolinyl, phthalazinyl, purinyl, indazolyl, indolyl, naphthyridinyl, pteridinyl In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer 15 thereof, wherein p is at least 1. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3, or 4 and at least one R5is para to the ring atom bound to the 20 R3R4- substituted carbon. In some embodiments, p is 1, 2, 3, or 4 and at least one R5is ortho to the ring atom bound to the R3R4- substituted carbon. In some embodiments, p is 1, 2, 3, or 4 and at least one R5is meta to the ring atom bound to the R3R4- substituted carbon. In some embodiments, the disclosure provides a compound of Formulae (I), (Ia), or (Ib), p is 1, and R5is para to the ring atom bound to the R3R4- substituted carbon. 25 In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5is halo. In some embodiments, p is 2, 3, or 4 and at least two R5 are halo. In some embodiments, p is 3 or 4 and at least three R5 are halo. In some embodiments, p is 1, 2, 3 or 4 and at least one R5is F. In some embodiments, 30 p is 2, 3, or 4 and at least two R5are F. In some embodiments, p is 3 or 4 and at least three R5are F. p is 1, 2, 3 or 4 and at least one R5 is Cl. In some embodiments, p is 2, 3, or 4 and at least two R5are Cl. In some embodiments, p is 3 or 4 and at least three R5are Cl. In some 13 201389-PCT01-NP embodiments, p is 1, 2, 3 or 4 and at least one R5 is Br. In some embodiments, p is 2, 3, or 4 and at least two R5 are Br. In some embodiments, p is 3 or 4 and at least three R5 are Br. In some embodiments, p is 2, and one R5is F and one is Cl. In some embodiments, p is 2, 3, or 4 and at least two R5 are halo. In some embodiments, p is 3 or 4 and at least three R5 are 5 halo. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is oxo. In some embodiments, one R5 is oxo. In some embodiments, two R5are oxo. In some embodiments, three R5are oxo. In some 10 embodiments, four R5are oxo. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5is a C1-C3alkyl. In some embodiments, p is 1, 2, 3 or 4 and at least one R5 is methyl, ethyl, or propyl. In some embodiments, p is 1 and 15 R5 is methyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is a C1-C3 haloalkyl. In some embodiments, the C1-C3haloalkyl is chloromethyl, bromomethyl, fluoromethyl, chloroethyl, 20 bromoethyl, fluoroethyl, dichloroethyl, dibromoethyl, difluoroethyl, chloropropyl, bromopropyl, fluoropropyl, dichloropropyl, dibromopropyl, or difluoropropyl. In some embodiments, p is 1 and R5is a C1-C3haloalkyl, e.g., fluoromethyl or chloromethyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer 25 thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is alkoxy, e.g., C1-4 alkoxy. In some embodiments, the C1-4alkoxy is methoxy, i.e., -OCH3 or ethoxy, i.e., -OCH2CH3. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1 or 2 and at least one R5is -OCH3. In some embodiments, p is 1 or 2 and at30 least one R5is -OCH2CH3. In some embodiments, p is 1 or 2 and at least one R5is - O(CH2)2CH3. 14 201389-PCT01-NP In some embodiments, the C1-4 alkoxy is optionally substituted with a 4-6 member heterocycle, e.g., optionally substituted with tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, or morpholinyl. In some embodiments, the present disclosure provides a compound of Formulae (I), 5 (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5is a C1-4haloalkoxy. The term “haloalkoxy” refers to an alkoxy group substituted with one or more halos. In some embodiments, the term “haloalkoxy” refers to an alkoxy group substituted with one or more halos on the terminal carbon, e.g., a trifluoromethoxy. However, in other embodiments, the 10 term haloalkoxy includes halo substituted on a secondary carbon in the carbon chain. In some embodiments, at least one R5 is a halomethoxy. In some embodiments, at least one R5 is a haloethoxy. In some embodiments, at least one R5 is a halopropoxy, i.e., halo- isopropoxy. In some embodiments, at least one R5is a halobutoxy. In some embodiments at least one R5 is a chloroalkoxy, comprising one, two or three Cl. In some embodiments, at 15 least one R5 is a bromoalkoxy, comprising one, two or three Br. In some embodiments, at least one R5is a fluoroalkoxy, comprising one, two or three F. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5is a C1-4alkoxy-C1-3alkyl. In some 20 embodiments, the C1-4alkoxy- C1-3alkyl is methoxyalkyl, ethoxyalkyl, propoxyalkyl, or butoxyalkyl. In some embodiments, the methoxyalkyl is methoxymethyl, methoxyethyl, or methoxypropyl. In some embodiments, the ethoxyalkyl is ethoxymethyl, ethoxyethyl, or ethoxypropyl. In some embodiments, the propoxyalkyl is propoxymethyl, propoxyethyl, or propoxypropyl. In some embodiments, the butoxyalkyl is butoxymethyl, butoxyethyl, or 25 butoxypropyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is a hydroxy or a C1-3 hydroxyalkyl. In some embodiments, the C1-3hydroxyalkyl is hydroxymethyl, hydroxyethyl, or 30 hydroxypropyl, e.g., hydroxy-isopropyl. In some embodiments, p is 1 or 2, and R5 is independently hydroxy or a C1-3 hydroxyalkyl. 15 201389-PCT01-NP In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5is -(CH2)qCN, -C(O)NR6R7, or - NS(O)R6R7. In some embodiments, R6 is H and R7 is methyl, ethyl, or propyl. In some 5 embodiments, both R6 and R7 are independently methyl, ethyl, or propyl. In some embodiments, both R6and R7are H. In some embodiments, R5is (CH2)qCN, wherein q is 0, i.e., R5is cyano. In some embodiments, R5is cyanomethyl or cyanoethyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer10 thereof, wherein p is 1, 2, 3 or 4 and at least one R5is -NR6C(O)R7, -NR6R7,- NR6C(O)OR7, -(CH2)qC(O)NR6R7, -(CH2)qNR6C(O)R7, or -C(O)NR6COR7. In some embodiments, R6 is H and R7 is methyl, ethyl, or propyl. In some embodiments, both R6 and R7are independently methyl, ethyl, or propyl. In some embodiments, both R6and R7are H. In some embodiments, p is 1 or 2, at least one R5 is –(CH2)qC(O)NR6R7 and q is 0 or 1. In 15 some embodiments, p is 1 or 2, at least one R5 is –(CH2)qC(O)NR6R7 and R6 is H and R7 is methyl. In some embodiments, p is 1 or 2, at least one R5is –(CH2)qNR6C(O)R7and q is 0 or 1. In some embodiments, p is 1 or 2, at least one R5is –(CH2)qNR6C(O)R7and R6is H and R7 is methyl. In some embodiments, the present disclosure provides a compound of Formulae (I), 20 (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is –(CH2)qR8, or -C(O)R8. In some embodiments, R8 is a C1-5 alkyl. In some embodiments, R8 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments, R8is a 4-6 member heterocycle, optionally substituted with an oxy. For example, in some embodiments, R8 is tetrahydrofuranyl, pyrrolidinyl, piperidinyl, 25 dioxanyl, or morpholinyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein p is 1, 2, 3 or 4 and at least one R5 is -CR6NR7C(O)R8. In some embodiments, R6is H or C1-C3alkyl, e.g., methyl or ethyl. In some embodiments, R7is H or 30 C1-C3alkyl, e.g., methyl or ethyl. In some embodiments, R8is ethyl or methyl. In some embodiments, R6 is methyl or ethyl, R7 is H, and R8 is methyl, ethyl, or propyl. In some embodiments, R8is a 4-member, 5-member, or 6-member heterocyclyl, wherein the 16 201389-PCT01-NP heterocyclyl is optionally substituted with an oxy. For example, in some embodiments, R5 is -CR6NR7C(O)R8, R8 is tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, or morpholinyl. In some embodiments, R5is -C(O)OR9or -OC(O)R9wherein R9is C1-5alkyl. In some embodiments, R5 is -C(O)OR9 and R9 is C1-5 alkyl, e.g., methyl or ethyl. In some 5 embodiments, p is 1 or 2, R5 is -C(O)OR9, and R9 is methyl. In some embodiments, R5 is - OC(O)R9wherein R9is C1-5alkyl, e.g., methyl or ethyl. In some embodiments, p is 1 or 2, R5is -OC(O)R9, and R9is methyl. In some embodiments, R5 is C3-6 cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, R5is a 4-6 member heteroaryl, 10 comprising one or more heteroatoms. In some embodiments, R5is a 4-6 member heterocycyl. In some embodiments, p is 1 and R5 is phenyl. In some embodiments, p is 1 and R5 is C3-6 cycloalkyl, 4-6 member heteroaryl, or 4-6 member heterocycyl. In some embodiments, when R5C3-6cycloalkyl, the cycloalkyl group can be optionally substituted with one to three substitutions selected from hydroxy, oxy, halo, - 15 C(O)NR6R7 and -C(O)OR9, wherein R6, R7 and R9 are defined as described herein. In some embodiments, when R5is C3-6cycloalkyl, the cycloalkyl group substituted with one substitution is selected from hydroxy, oxy, halo, -C(O)NR6R7and -C(O)OR9.In some embodiments, when R5 is C3-6 cycloalkyl, the cycloalkyl group is substituted with one substitution selected from hydroxy, and halo. 20 In some embodiments, when R54-6 member heterocycyl, the 4-6 member heterocycyl group can be optionally substituted with 1 to 3 substitutions selected from hydroxy, oxy, halo, -C(O)NR6R7 and -C(O)OR9, wherein R6, R7 and R9 are defined as described herein. In some embodiments, when R5is 4-6 member heterocycyl, the 4-6 member heterocycyl group is substituted with one substitution selected from hydroxy, oxy, halo, -C(O)NR6R7 and - 25 C(O)OR9. In some embodiments, when R5 is 4-6 member heterocycyl, the 4-6 member heterocycyl group is substituted with one substitution selected from hydroxy, and halo. In some embodiments, when R5is 4-6 member heterocycyl, the 4-6 member heterocycyl group is substituted with methyl. In some embodiments, the 4-6 member heterocycyl is not substituted. 30 In some embodiments, when R5is a 4-6 member heteroaryl, the heteroaryl can be optionally substituted with one to three halo substituents. In some embodiments, R5 is a 4-6 member heteroaryl, the heteroaryl can be optionally substituted with one to three F 17 201389-PCT01-NP substituents. In some embodiments, R5 is a 4-6 member heteroaryl, the heteroaryl can be optionally substituted with one to three Cl. In some embodiments, R5 is a 4-6 member unsubstituted heteroaryl. In some embodiments, R5is a 4-6 member heteroaryl, the heteroaryl can be optionally substituted with methyl. 5 In some embodiments, when R5 is phenyl, the pheyl is optionally substituted with one or more methyl. In some embodiments, when R5is C3-6cycloalkly, the C3-6cycloalkly is optionally substituted with one ore more methyl. In some embodiments, R5 can be -NO2. For example, in some embodiments, p is 1 and R5is -NO2. 10 One of skill in the art will appreciate that when p is 2 or greater, each of the R5substituents can independently be present. For example, when p is 2, R5 can be both halo and C1-4 alkoxy; when p is 3, R5 can be hydroxy, and two halo; etc. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer 15 thereof, wherein R3 and R4 are independently H, halo, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R3and R4are independently C1-3alkyl. In some embodiments, the C1-3alkyl is methyl or ethyl. In some embodiments, one of R3or R4is H. In some embodiments, both of R3 or R4 is H. In some embodiments, one of R3 or R4 is H, and the other is halo, C1-3 alkyl, In some embodiments, R3and R4are independently halo, e.g., fluoro or difluoro, chloro or 20 dichloro. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R1is a C3, C4, C5, or C6branched alkyl. In some embodiments, R1is - CH2CH(CH3)2. 25 In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer thereof, wherein R2 is methyl, ethyl, or propyl. In some embodiments, the present disclosure provides a compound of Formulae (I), (Ia), or (Ib) as defined above, or a stereoisomer, pharmaceutically acceptable salt, or tautomer 30 thereof, wherein n is 0. In some embodiments, n is 1. 18 201389-PCT01-NP In some embodiments, R2 is methyl, R3 is isobutyl, n is 1, R3 and R4 are both halo, e.g., F. In some embodiments, R2 is methyl, R3 is isobutyl, n is 1, R3 and R4 are both halo, e.g., F, R5is phenyl or pyridinyl, optionally substituted with one or more halo, -NO2, or cyano, In some embodiments, R2 is methyl, R3 is isobutyl, n is 0, R3 and R4 are 5 independently H or halo, e.g., F, R5 is phenyl or pyridinyl, optionally substituted with one or more halo, -NO2, methyl or cyano. In some embodiments, the compound is selected from Table 5. 19 201389-PCT01-NP 20 201389-PCT01-NP 21 201389-PCT01-NP 22 201389-PCT01-NP In some embodiments, the compound is selected from Table 6. Table 6 23 201389-PCT01-NP 24 201389-PCT01-NP Medical and Pharmaceutical Use: The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease in a mammal, particularly a human. Cardiovascular disease includes, 5 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 following 10 revascularization procedures, heart failure, abdominal aortic aneurysm (AAA), peripheral artery disease (PAD) including erectile dysfunction due to vascular disease, stroke, cardiomyopathy, including non-ischemic dilated cardiomyopathy, transient ischemic attack (TIA) and reversible ischemic neurologic disease (RIND), multi-infarct dementia, renovascular disease, and renal arterial disease. 15 The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of non- ischemic dilated cardiomyopathy. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of 20 cardiovascular disease in a patient having co-morbidities such as renal dysfunction. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, 25 and inflammatory arthropathies / multisystem diseases such as psoriatic arthropathy. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of cardiovascular disease associated with autoimmune conditions, e.g., rheumatoid arthritis, AZinflammatory arthropathies / multisystem diseases such as psoriatic arthropathy. 30 The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of 25 201389-PCT01-NP heart failure, including heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of 5 inflammatory bowel disease. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of lupus nephritis. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a 10 pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of patients with remaining risk for a cardiovascular event despite standard of care (SoC) treatment, such as, but not limited to, lipid lowering statins, anti-platelets, ACE inhibitors, mineralocorticoid receptor antagonists, and beta blockers. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a 15 pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of chronic kidney disease. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of type II diabetes mellitus and complications of type II diabetes mellitus in a mammal, particularly a 20 human. This includes and is not restricted to, diabetic micro and macrovascular pathology, neuropathy and nephropathy. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of renal inflammatory and vascular diseases and complications associated with renal disease in a 25 mammal, particularly a human. Renal inflammatory and vascular disease includes, but is not limited to chronic kidney disease, drug and toxin induced nephrotoxicity, lupus nephritis, glomerulonephritis, nephrotic syndrome, IgA nephritis, reflux nephropathy, focal segmental glomerulosclerosis, Henoch-Schönleins purpura, and diabetic nephropathy. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a 30 pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of 26 201389-PCT01-NP autoimmune diseases, such as, but not limited to, dermatomyositis, polymyositis, and systemic lupus erythematosus (SLE). The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of non- 5 alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and ASH (alcoholic steatohepatitis). Treatment with the compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may lower the cardiovascular and / or cerebrovascular and / or renal and / or peripheral arterial disease morbidity and mortality 10 associated with cardiac dysfunction and / or atherosclerosis, and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology due to their anti-inflammatory properties and influence on vasoactive mechanisms. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may serve to prevent or reduce the risk of 15 developing cardiac dysfunction and / or renal dysfunction and / or microvascular dysfunction and / or macrovascular pathology, as well as for halting or slowing the progression and / or promoting the regression of atherosclerotic cardiovascular disease once it has become clinically evident, comprising the administration of a prophylactically or therapeutically effective amount, as appropriate, of a compound of formulae (I), (Ia), (Ib), or a compound 20 disclosed herein, or a pharmaceutically acceptable salt thereof, to a mammal, including a human, who is at risk of developing atherosclerosis or who already has atherosclerotic cardiovascular disease. Compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in preventing or reducing the 25 incidence or severity of acute events related to atherosclerotic plaque rupture or erosion, including, but not limited to, myocardial infarction, unstable angina and stroke. Compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in preventing or reducing the incidence or severity of acute events by improving microvascular function, macrovascular 30 pathology and / or cardiac function. 27 201389-PCT01-NP Compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be useful in preventing or reducing the progression of abdominal aortic aneurysms (AAA) and incidence of rupture. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a 5 pharmaceutically acceptable salt thereof, may be useful in the prevention or treatment of respiratory inflammatory disease and complications associated with respiratory inflammatory disease in a mammal, particularly a human. Respiratory inflammatory disease includes, but is not limited to asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and rhinitis. 10 Some embodiments disclosed herein provide a method of treating or preventing one or more of the diseases or conditions discussed herein, wherein the method comprises administering to a person suffering from, or at risk of, said disease or condition, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 15 Some embodiments disclosed herein provide a method of treating or preventing non- ischemic dilated cardiomyopathy, wherein the method comprises administering to a person in need thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing 20 cardiovascular disease in a patient having co-morbidities such as renal dysfunction, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing 25 cardiovascular disease associated with chronic inflammatory diseases, e.g., rheumatoid arthritis, systemic lupus erythematosus (SLE), polymyositis, dermatomyositis, Still’s disease, and inflammatory arthropathies / multisystem diseases such as psoriatic arthropathy, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a 30 pharmaceutically acceptable salt thereof. 28 201389-PCT01-NP Some embodiments disclosed herein provide a method of treating or preventing heart failure wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In further embodiments the 5 heart failure is heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction Some embodiments disclosed herein provide a method of treating or preventing inflammatory bowel disease, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a 10 compound disclosed herein, or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein provide a method of treating or preventing lupus nephritis, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 15 Some embodiments disclosed herein provide a method of treating or preventing respiratory inflammatory disease and complications associated with respiratory inflammatory disease, wherein the method comprises administering to a person in need of thereof, a therapeutically effective amount of a compound of formulae (I), (Ia), (Ib), a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In further embodiments, the 20 respiratory inflammatory disease is asthma, chronic obstructive pulmonary disease, emphysema, interstitial lung disease associated with connective tissue diseases, and / or rhinitis. The terms “preventing”, “prevention”, and “prevent” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can 25 include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition. 30 The terms "treating”, “treatment”, and “treat” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include (1) diminishing the extent or cause of the condition being treated, and / or (2) alleviating or 29 201389-PCT01-NP ameliorating one or more symptoms associated with that condition. Treatment of cardiovascular disease, for example, can include stabilizing (i.e., not worsening), delaying, or slowing the spread or progression of the cardiovascular disease; prolonging survival as compared to expected survival if not receiving treatment; and / or otherwise ameliorating or 5 palliating the severity of the cardiovascular disease, in whole or in part. The compounds disclosed herein may have the advantage that they may be more efficacious, be less toxic, be more selective, be more potent, produce fewer side effects, be more 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. 10 These and other embodiments are described in greater detail herein below, where further aspects will be apparent to one skilled in the art from reading this specification. Pharmacological Properties: The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or pharmaceutically acceptable salts thereof are 15 believed to be useful in the prevention or treatment of cardiovascular conditions, including but not limited to coronary artery disease, acute coronary syndrome, cardiomyopathy, non- ischemic dilated cardiomyopathy, heart failure, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, and heart failure with preserved ejection fraction in a mammal, particularly a human. 20 When a compound or salt described herein is administered as therapy for treating a disorder, a “therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder, cure the disorder, reverse, completely stop, or slow the progress of the disorder or reduce the risk of the disorder getting worse. 25 The compounds described herein are thus indicated both in the therapeutic and / or prophylactic treatment of these conditions. Pharmaceutical Compositions: There is provided a method of treatment of a condition where modulation of CX3CR1 is required, which method comprises administration of a therapeutically effective amount of a 30 201389-PCT01-NP compound of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to a person suffering from, or susceptible to, such a condition. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, will normally be administered via the oral, topical, 5 parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be 10 administered at varying doses. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, Pharmaceuticals - The Science of Dosage Form Designs, M. E. Aulton, Churchill Livingstone, 2ndEd. 2002.The optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and 15 weight, diet, and general physical condition of the particular patient; brain / body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians and others skilled in the art. According to a further aspect there is thus provided a pharmaceutical formulation comprising a compound of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a 20 pharmaceutically acceptable salt thereof, or pharmaceutically acceptable derivatives thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier. The compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be present in the pharmaceutical formulation in a concentration from 0.1 to 99.5%, such as from 0.5 to 95%, by weight of the total 25 formulation. A further embodiment encompasses pharmaceutically acceptable salts of the compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein. A salt of a compound of formulae (I), (Ia), (Ib), or a compound disclosed herein, may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in H2O, oil, or other solvent. 30 In some instances, a salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly where the salt is intended for administration to an animal, 31 201389-PCT01-NP e.g. a human, or is a reagent for use in making a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable. The term “pharmaceutically acceptable” is used to characterize a moiety (e.g. a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical 5 judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications. Where the compound is sufficiently basic, pharmaceutically acceptable salts include, 10 but are not limited to, inorganic or organic acid addition salts. Where the compound is sufficiently acidic, pharmaceutically acceptable salts include, but are not limited to, inorganic or organic base addition salts. For reviews on suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19 or Handbook of Pharmaceutical Salts: Properties, selection and use, P.H. Stahl, P.G. Vermuth, 15 IUPAC, Wiley-VCH, 2002. It is also to be understood that certain compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, may exist in solvated form, e.g. hydrates, including solvates of a pharmaceutically acceptable salt of a compound of formula (I). It is also to be understood that certain compounds of formulae (I), (Ia), (Ib), or a 20 compound disclosed herein, or a pharmaceutically acceptable salt thereof, may exist as a mixture of tautomers. “Tautomers” are structural isomers that exist in equilibrium resulting from the migration of a hydrogen atom, e.g., amide-imidic acid tautomerism. The disclosure herein includes all tautomers of compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof. 25 In particular embodiments, certain compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Certain compounds of formulae (I), (Ia), (Ib), or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may also contain linkages 30 (e.g. carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence 32 201389-PCT01-NP of a ring bond or double bond. Stereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallization, or the stereoisomers may be made by stereoselective synthesis. EXAMPLES 5 The following examples are non-limiting examples. SYNTHETIC METHODS: General conditions Operations were carried out at room temperature (rt), i.e. in the range 17 to 28oC and 10 where needed under an atmosphere of an inert gas such as N2; optionally reactions were carried out using a MBRAUN UNILab Plus ECO or a MBRAUN UNILab SP Eco glovebox workstation or a KitAlysis™ Benchtop Inertion Box from Sigma-Aldrich, in which case it is indicated. Where reactions refer to being degassed or purged, this can be performed for example 15 by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g)). Where reactions refer to the use of a microwave reactor, one of the following microwave reactors were used: Biotage Initiator, Personal Chemistry Emrys Optimizer, 20 Personal Chemistry Smith Creator or CEM Explorer. In general, the course of reactions was followed by thin layer chromatography (TLC) and / or analytical high performance liquid chromatography (HPLC or UPLC) which was usually coupled to a mass spectrometer (LCMS). When necessary, organic solutions were dried over anhydrous MgSO4 or Na2SO4, or 25 by using ISOLUTE® Phase Separator, and workup procedures were carried out using traditional phase separating techniques. When a drying agent such as e.g. MgSO4or Na2SO4is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer. 33 201389-PCT01-NP It is understood that washing solutions used in the work-up procedures or reagent used for acidifying such as e.g. Brine, NaHCO3, NH4Cl , HCl, NaH2PO4 are presumed to be aqueous solutions unless otherwise stated. Evaporations were carried out either by rotary evaporation in vacuo or in a Genevac 5 HT-4 / EZ-2 or Biotage V10. Unless otherwise stated, flash column chromatography was performed on straight phase silica, using either Merck Silica Gel (Art.9385) or prep-packed cartridges such as BIOTAGE SNAP cartridges (40-63 μm silica, 4–330 g), BIOTAGE Sfär Silica HC D cartridges (20 µm, 10–100 g), INTERCHIM PURIFLASH cartridges (25 µm, 4–120 g), 10 INTERCHIM PURIFLASH cartridges (50 µm, 25–330 g), GRACE GRACERESOLVE Silica Flash Cartridges (4–120 g) or Agela Flash Colum Silica-CS cartridges (80–330g), or on reversed phase silica using Agela Technologies C-18, spherical cartridges (20–35µm, 100A, 80–330g), manually or automated using a GRACE REVELERIS X2 Flash system or similar system. 15 Ion exchange column purification was performed on SCX ion exchange column from Isolute, using the appropriate solvent or solvent mixtures as eluant as stated in the experimental description; Preparative TLC was performed on glass-backed silica plates (20×20 cm) covered with a 1 mm thick silica gel (particle size of 10–40 µm), in a glass chamber, using the 20 appropriate solvent or solvent mixtures as eluant as stated in the experimental description. Preparative reverse phase HPLC and preparative reverse phase SFC were performed using standard HPLC and SFC instruments, respectively, equipped with either a MS and / or UV triggered fraction collecting instrument, using either isocratic or a gradient of the mobile phase as described in the experimental section and using one of the following methods: 25 PrepMethod A; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / NH4HCO3(8 mM) buffer system as mobile phase; PrepMethod B; The compound was purified by preparative HPLC on a Waters XSelect CSH PrepC18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O as mobile phase; PrepMethod C; The compound was purified by 30 preparative HPLC on a Xbridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / 0.05% TFA buffer system as mobile phase; PrepMethod D; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) 34 201389-PCT01-NP using a gradient of MeCN in H2O / FA (0.1%) as mobile phase; PrepMethod E; The compound was purified by preparative SFC on a SuperSep 1, Viridis 2-EP column (5 μm, 250×30) using MeOH in CO2as mobile phase; PrepMethod F; The compound was purified by preparative SFC on a Phenomenex Luna®HILIC column (5 μm, 250×30 mm ID) using 5 MeOH / NH3 (20 mM) in CO2 as mobile phase; PrepMethod G; The compound was purified by preparative SFC on a Viridis 2-EP column (5 μm, 250×30) using MeOH / NH3 (20 mM) in CO2as mobile phase; PrepMethod H; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / NH3 (0.2%) as mobile phase; PrepMethod I; The compound was purified by preparative HPLC 10 on a XBridge C18 column (10 μm, 250×19 mm ID) using a gradient of MeCN in H2O / MeCN / NH3 (95 / 5 / 0.2) as mobile phase; PrepMethod J; The compound was purified by preparative HPLC on a XBridge C18 column (5 μm, 150×30 mm ID) using a gradient of MeCN in H2O / MeCN / NH3(95 / 5 / 0.2) as mobile phase; PrepMethod K; The compound was purified by preparative SFC on a Viridis 2-EP column (5 μm, 250×4.6) using MeOH in CO2 15 as mobile phase; PrepMethod L; The compound was purified by preparative HPLC on a Waters Sunfire C18 ODB column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / FA (0.1 M) as mobile phase; PrepMethod M; The compound was purified by preparative HPLC on a XBridge C18 column (10 μm, 250×50 mm ID) using a gradient of MeCN in H2O / MeCN / NH3(95 / 5 / 0.2) as mobile phase; PrepMethod N; The compound was 20 purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / FA (0.1%) as mobile phase; PrepMethod O; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / NH4HCO3(0.5%) buffer system as mobile phase; PrepMethod P; The compound was purified by preparative HPLC on a 25 XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / NH4HCO3(0.1%) buffer system as mobile phase; PrepMethod Q; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / NH3 (0.1%) as mobile phase; PrepMethod R; The compound was purified by preparative HPLC on a XBridge C18 OBD column (5 μm, 150×30 mm ID) 30 using a gradient of MeCN in H2O / NH3(0.2%) as mobile phase; PrepMethod S; The compound was purified by preparative HPLC on a Xbridge C18 column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / 0.05% NH3buffer system as mobile phase; PrepMethod T; The compound was purified by preparative HPLC on a Waters XSelect CSH C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in a H2O / 0.05% NH3 35 201389-PCT01-NP buffer system as mobile phase; PrepMethod U; The compound was purified by preparative SFC on a Phenomenex Luna HILIC column (5 μm, 250×4.6 mm ID) using MeOH / NH3 (20 mM) in CO2as mobile phase; PrepMethod V; The compound was purified by preparative HPLC on an XBridge C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in 5 H2O / MeCN (95 / 5) with 20 mM NH3, pH10, as mobile phase; PrepMethod X; The compound was purified by preparative HPLC on a Waters Sunfire C18 OBD column (5 μm, 150×19 mm ID) using a gradient of MeCN in H2O / MeCN (95 / 5) with FA (20 mM) as mobile phase. In some instances, the compound may be dissolved in a solvent e.g. DMSO and 10 filtered through a syringe filter prior to purification on preparative HPLC. Relevant fractions were collected, combined, and freeze-dried or evaporated to give the purified compound or relevant fractions were collected, combined and concentrated at reduced pressure, the aqueous layer was extracted with DCM or EtOAc, and the organic layer was dried, either over Na2SO4 or by using a phase-separator, and then concentrated at 15 reduced pressure and when needed dried in vacuo, to give the purified compound. Chiral preparative chromatography was carried out using HPLC or SFC on a standard HPLC or SFC instruments, respectively, and using either isocratic or gradient run with mobile phase as described in the experimental section. Yields, where present, are not necessarily the maximum attainable, and when 20 necessary, reactions were repeated if a larger amount of the reaction product was required. Where certain compounds were obtained as an acid-addition salt, for example a mono-hydrochloride salt or a di-hydrochloride salt, the stoichiometry of the salt was based on the number and nature of the basic groups in the compound, the exact stoichiometry of the salt was generally not determined, for example by means of elemental analysis data. 25 In general, the structures of the end-products of the Formula (I) were confirmed by nuclear magnetic resonance (NMR) and / or mass spectral techniques; proton NMR chemical shift values were measured on the delta scale using Bruker Avance III 300, 400, 500 and 600 spectrometers, operating at1H frequencies of 300, 400, 500 and 600 MHz, respectively. The experiments were typically recorded at 25°C. Chemical shifts are given in ppm with the 30 solvent as internal standard. Protons on heteroatoms such as NH and OH protons are only reported when detected in NMR and can therefore be missing. In certain instances, protons 36 201389-PCT01-NP can be masked or partially masked by solvent peaks and will therefore either be missing and not reported or reported as multiplets overlapping with solvent. The following abbreviations have been used (and derivatives thereof, e.g. dd, doublet of doublets, etc.): s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; qn, quintet; p, pentet. It is understood, 5 where the NMR spectra contains residual impurities and / or residual solvent(s), this is not reported unless it partially coincides with peaks of Intermediates and / or Structures of Formula (I), in which case said peaks of Intermediates and / or Structures of Formula (I) are reported as multiplets partially overlapping with said solvent or impurity, and the Integral is omitted. In some cases, the structures of the end-products of the Formula (I) might appear as 10 rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported. In some instances, the structures of the intermediates and / or end-products of Formula (I) might appear as rotamers in a more equal relationship, in such instances the peaks of such rotamers are either reported as multiplets, if the signals of said rotamers are partially overlapping, or as individual peaks, if the signals of said rotamers are well 15 separated. Electrospray mass spectral data were obtained using a Waters Acquity UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported. 20 high resolution electrospray mass spectral data were obtained using a Waters XEVO qToF mass spectrometer or similar equipment, coupled to a Waters Acquity UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported intermediates were not necessarily fully purified but their structures and purity were 25 assessed by TLC, analytical HPLC / UPLC, and / or NMR analysis and / or mass spectrometry; unless stated otherwise compounds containing an asymmetric carbon and / or sulfur atom were not resolved; in general Examples and Intermediate compounds are named using ChemDraw Professional version 22.2.0 from PerkinElmer. ChemDraw Professional version 22.2.0 30 generates the names of chemical structures using the Cahn-Ingold-Prelog (CIP) rules for stereochemistry and follows IUPAC rules as closely as possible when generating chemical 37 201389-PCT01-NP names. Stereoisomers are differentiated from each other by stereodescriptors cited in names and assigned in accordance with the CIP rules. ChemDraw is optionally using labels in the graphical representation of stereocenters such as '&' and 'or' to describe the configuration of the stereochemical centers present in the 5 structure. A number following the '&' and 'or' flag is assigned to each stereocenter present in the structure. The numbers are incremented automatically to indicate that stereocenters may vary independently to each other. In general, for chemical structures of Examples and Intermediates where more than one stereocenter is present and said stereocenters have a fixed relative configuration, the 10 same number is used after the label '&' and 'or' to indicate that said stereocenters forms a group. A third stereocenter present in the same chemical structure, that varies independently to the former stereocenters, is designated with a unique new number following the label '&' and 'or'. In general chemical structures of Examples and Intermediates containing the label '&' 15 at a stereocenter, means the configuration of such Example or Intermediate at that stereocenter is a mixture of both (R) and (S); and a label 'or' means the configuration of such Example or Intermediate at that stereocenter is either (S) or (R). Absolute, unspecified, '&', and 'or' stereocenters can all be present in a single structure. In general for structures of Examples and Intermediates where all of the stereocenters 20 are designated as '&', the structure is named with a “rac-” prefix. The descriptors (RS) and (SR) are used to denote general '&' centers for chemical structures with multiple chiral centers where only some are designated as '&'. In general, for structures of Examples and Intermediates where all of the stereocenters are designated as 'or', the structure is named with a “rel-” prefix. 25 The descriptors (R*) and (S*) are used to denote the general 'or' centers for chemical structures with multiple chiral centers where only some are designated as 'or'. It is to be understood that an Example or Intermediate with a stereocenter labled (R*) or (S*) has an absolute configuration at said stereocenter and while said stereocenter in the compound has been designated as (R*) or (S*), the actual stereochemistry of that particular 30 isomer could be the opposite of the label. For example, while Example 20, the first eluting 38 201389-PCT01-NP isomer from the chiral separation of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide (Intermediate 17) is named “N-(4- (((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide” it could be N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6- 5 (((R)-1-phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((R)-1-Hydroxy-4- methylpentan-2-yl)amino)-6-(((S)-1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide. That is, the actual structure of Example 20, (i.e., the first eluting isomer) could be: . 10 Said Example or Intermediate with one or more stereocenters labled with (R*) or (S*) can also in certain instances be represented by a structure as below; One of skill in the art would also understand that when a numbered example disclosed 15 herein is prepared by chiral separation of diastereomers, such as Example 20 from the chiral separation of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide (Intermediate 17), both diastereomers are disclosed herein. In general, for chemical structures of Examples and Intermediates where a 20 stereocenter present is racemic, no flag is designated to the stereocenter and the bond to said stereocenter is drawn with a straight bond. In general the label “Isomer 1” corresponds to the first eluted isomer, and “Isomer 2” corresponds to the second eluted isomer, on a given chiral HPLC column and eluent, and are 39 201389-PCT01-NP used to distinguish two isomers containing one or more stereocenters with absolute unknown configuration; in addition to the ones mentioned above, the following abbreviations and units have been used: 5 Abbreviations AcOH Acetic acid AIBN Azobisisobutyronitrile AlMe3 Aluminum trimethanide aq aqueous 10 9-BBN 9-borabicyclo[3.3.1]nonane Boc2O di-tert-butyl dicarbonate Brine saturated aqueous sodium chloride solution Calcd calculated d day 15 DAST N,N-diethyl-1,1,1-trifluoro-l4-sulfanamine DCM dichloromethane DEA diethylamine DIPEA N-ethyl-N-isopropyl-propan-2-amine DMA dimethylacetamide 20 DMAP N,N-dimethylpyridin-4-amine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide eq equivalent ESI electrospray ionization 25 Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol FA formic acid (g) gas 30 HPLC high performance liquid chromatography HRMS high resolution mass spectrometry ID inner diameter IPA 2-propyl alcohol IPrOAc isopropyl acetate 35 LCMS liquid chromatography Mass spectrometry MeCN acetonitrile MeMgBr Methylmagnesium bromide MeOH methanol 2-MeTHF 2-methyltetrahydrofuran 40 MS mass spectrometry Ms2O methanesulfonic anhydride MsCl mesyl chloride MTBE methyl tert-butyl ether m / z mass spectrometry peak(s) 45 N2Nitrogen NaOAc sodium acetate 40 201389-PCT01-NP NaOtBu Sodium tert-butoxide NaH sodium hydride NBS N-bromosuccinimide NMR nuclear magnetic resonance 5 on overnight PdCl2(dppf)2 [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3x CHCl3Tris(dibenzylideneacetone)dipalladium(0) (1:1) PE petroleum ether 10 PPh3Triphenylphosphine rt room temperature sat saturated SFC supercritical fluid chromatography TBME tert-butylmethyl ether 15 TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Xantphos (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) 20 X-Phos dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane Units C Celsius g gram 25 h hour(s) L litre M mole per liter mg milligram MHz megaherz 30 min minute(s) mL milliliter mm millimeter mmol millimole(s) mL microlitre 35 µm micrometer nm nanometer ppm parts per million In another aspect there is provided a process for preparing compounds of the formula 40 (I) or a pharmaceutically acceptable salt thereof, which processes comprises Methods a1 to a4 below: Method a1: The compounds of formula (I) in which R1, R2, R3, R4, R5, n, A and p are defined as in formula (I) may be formed by reacting a compound of formula (II) in which R1 and R2are defined as in formula (I), with a compound of formula (III) in which R3, R4, R5, n, 41 201389-PCT01-NP A and p are defined as in formula (I) and LG1 is a suitable leaving group such as chloro, bromo, iodo, triflate (OTf), mesylate (OMs) or tosylate (OTs) (preferentially bromo, chloro or OMs). (II) (III) 5 The reaction is carried out in an inert organic solvent such as DMF, DMSO, 1,4- dioxane, THF or MeCN (preferentially DMF or THF) in the presence of a suitable base (typically 1.1-10 eq) such as DIPEA, TEA, K2CO3, Cs2CO3or NaOAc (preferentially DIPEA). The reaction may be carried out at temperatures ranging typically from 20oC to 140oC for a prolonged time (typically 0.5-72 h) using standard equipment or a single node 10 microwave oven. Formula (III) is typically used in an equimolar amount to formula (II) but can also be used in a slight excess (typically 1.1-2.2 eq). Method a2: The compounds of formula (I) in which R1, R2, R3, R4, R5, n, A and p are defined as in formula (I) may be formed by reacting a compound of formula (IV) in which R2, R3, R4, R5, n, A and p are defined as in formula (I) and LG2is a suitable leaving group 15 such as halo or triflate (OTf) (preferentially chloro) with a compound of formula (V) in which R1 is as defined in formula (I). The reaction is carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH or mixtures thereof in the presence of a suitable base such as DIPEA, TEA or 20 K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically from 20oC to 80oC for a prolonged reaction time (2-48 h) using standard equipment or a single node microwave oven. Formula (V) is normally used in a slight excess (typically 1.2- 3 eq) to formula (IV). 42 201389-PCT01-NP Method a3: The compounds of formula (I) in which R1, R2, R3, R4, R5, n, A and p are defined as in formula (I) may be formed by reacting a compound of formula (VI) in which R1, R3, R4, R5, n, A and p are defined as in formula (I) and LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) with a compound of formula (VII) in 5 which R2 is defined as in formula (I). The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3in combination with a suitable phosphine ligand, typically XPhos or XantPhos in the presence of a base, such as Cs2CO3 or K2CO3, in an inert organic solvent, such as 1,4-dioxane or THF, 10 at temperatures ranging from 25oC to 100oC. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2atmosphere) for a prolonged reaction time (typically 3-24 h). Alternatively, the reaction may also be performed without using a metal catalyst in an inert organic solvent such as DMF in the presence of a base such as K2CO3or Na2CO3at elevated temperatures (e.g.90oC) for a prolonged reaction time (typically overnight). 15 Method a4: The compounds of formula (I) in which R1, R2, R3, R4, R5, n, A and p are defined as in formula (I) may be formed by reacting a compound of formula (VIII) in which R1and R2are defined as in formula (I) and LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) with a compound of formula (IX) in which R3, R4, R5, n, A and p are defined as in formula (I). (V(IX) 20III)The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, MeCN in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3. The reaction may be carried out at temperatures ranging typically from 20oC to 100oC for a prolonged 43 201389-PCT01-NP reaction time using standard equipment or a single node microwave oven. Optionally, the reaction may also be performed in the presence of water. The compounds of formula (II) to (IX) above are commercially available, known in the art or may be prepared by methods analogous to those described in the examples and in the 5 descriptions following below or in a conventional manner known by a person skilled in the art. The compounds of formula (II) in which R1and R2are defined as in formula (I) may be prepared by treating a compound of formula (X) in which R1 and R2 are defined as in formula (I) 10 with an excess TFA in the presence of anisole (typically 1.2 eq) which is used as a scavenger for the benzylic cation formed during the reaction. The reaction is typically carried out at ambient temperature for a prolonged reaction time (typically 2-24 h). The compounds of formula (III) may be prepared from a compound of formula (XI) 15 using any of the methods b1 to b5 below: Method b1: Certain compounds of formula (III) in which R3, R4, R5, n, A and p are defined as in formula (I) and LG1is OMs may be formed by reacting a compound of formula (XI) wherein R3, R4, R5, n, A and p are defined as in formula (I) with MsCl or Ms2O in the presence of a base such as DIPEA, TEA or pyridine. The reaction is performed in an inert 20 organic solvent such as DCM, THF or 1,4-dioxane (preferentially DCM) at ambient temperature for a prolonged reaction time (typically 1-5 h). Method b2: Certain compounds of formula (III) in which R3, R4, R5, n, A and p are defined as in formula (I) and LG1 is chloro or bromo may be formed by reacting a compound of formula (XI) wherein R3, R4, R5, n, A and p are defined as in formula (I) with CCl4(LG1is 44 201389-PCT01-NP chloro) or CBr4 (LG1 is bromo) in the presence of PPh3. The reaction is typically carried out in an inert organic solvent such as DCM at ambient temperature for a prolonged reaction time. Method b3: Certain compounds of formula (III) in which R3, R4, R5, n, A and p are 5 defined as in formula (I) and LG1 is chloro or bromo may also be formed by reacting a compound of formula (XI) wherein R3, R4, R5, n, A and p are defined as in formula (I) with a halogenating agent such as POCl3, PCl3or PCl5(LG1is chloro) or PBr3(LG1is bromo). When POCl3 is used the reaction is typically carried out without an organic solvent at slightly elevated temperatures (typically 60oC) and when PCl3, PCl5or PBr3is used the reaction is 10 typically carried out in an inert organic solvent such as DCM at temperatures ranging from 0oC to ambient temperature and for a prolonged reaction time. Method b4: Certain compounds of formula (III) in which R3 and R4 independently are selected from H, C1-3-alkyl or C1-3haloalkyl, n is 0, and R5, A and p are defined as in formula (I) and LG1 is bromo may be formed by reacting a compound of formula (XI) wherein R3 and 15 R4 independently are selected from H, C1-3-alkyl or C1-3 haloalkyl, n is 0, and R5, A and p are defined as in formula (I) an excess HBr in an inert solvent such as water or AcOH. The reaction is typically performed at ambient temperature for a prolonged reaction time. Optionally, the reaction may be carried out at temperatures ranging from 25oC to 70oC. Method b5: Certain compounds of formula (III) in which R3and R4both are fluoro, n 20 is 1, A, R5and p are defined as in formula (I) and LG1is chloro or bromo may be formed by reacting a compound of formula (XII) in which A, R5 and p are defined as in formula (I) and LG1is chloro or bromo with a deoxofluorinating agent such as DAST or deoxo-fluor reagent (e.g.1,1,1- 25 trifluoro-N,N-bis(2-methoxyethyl)-λ4-sulfanamine) in an inert organic solvent such as DCM at temperatures ranging from ambient temperature to reflux for a prolonged reaction time (typically 12-48 h) 45 201389-PCT01-NP The compounds of formula (IV) in which in which R2, R3, R4, R5, n, A and p are defined as in formula (I) and LG2 is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) may be prepared as illustrated in Scheme TA1. Scheme TA1 5 Step 1: A strong base such as for example NaH is added to a compound of formula (VII), in which R2is defined as in formula (I), dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane at ambient temperature. The mixture is left for about 1 h at ambient temperature before it is added to a solution (typically in the same solvent as above) 10 of a compound of formula (XIII), in which LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro). The mixture is heated, typically to a temperature in the range of 50oC to 70oC for a prolonged reaction time to generate a compound of formula (XIV) in which R2and LG2are defined as above. The reaction is preferentially performed under an inert atmosphere (e.g. an N2atmosphere). 15 Step 2: A strong base such as for example NaH is added to a compound of formula (IX), in which R3, R4, R5, n, A and p are defined as in formula (I), dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane typically at 0oC. The mixture is left for about 1 h at ambient temperature before it is added to a cold solution (e.g.0oC, typically in the same solvent as above) of a compound of formula (XIV) in which R2 and LG2 are 20 defined as above. This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of formula (IV). The compounds of formula (VI), in which R1, R3, R4, R5, n, A and p are defined as in formula (I) and LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), may be prepared by sequentially reacting a compound of formula (IX), in which R3, 25 R4, R5, n, A and p are defined as in formula (I), and a compound of formula (V), in which R1 is defined as in formula (I), with a compound of formula (XIII), in which LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), as illustrated in Scheme TA2 Scheme TA2 46 201389-PCT01-NP A solution of a compound of formula (XIII) and formula (IX) in a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is pre-cooled to about 0oC (ice / bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, 5 preferentially THF is added slowly (typically during 30 min) to the reaction mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h). Optionally, an additional amount of DIPEA is added before addition of a compound of formula (V) in an organic solvent, preferentially THF, and the reaction mixture is stirred at about 0oC for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula 10 (VI). The reaction is preferentially performed under an inert atmosphere (e.g. an N2 atmosphere). The compounds of formula (VIII), in which R1and R2are defined as in formula (I) and LG2 is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), may be prepared by sequentially reacting a compound of formula (V), in which R1, is defined as in 15 formula (I), and a compound of formula (VII), in which R2is defined as in formula (I), with a compound of formula (XIII), in which LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), as illustrated in Scheme TA3. Scheme TA3 (XIII) (V) (VII)(VIII)20 A solution of a compound of formula (V) in a suitable organic solvent, preferentially 2-MeTHF, is added to a solution of a compound of formula (XIII) in an inert organic solvent, preferentially 2-MeTHF, at -35°C to -10°C before an organic base such as DIPEA dissolved in an organic solvent, preferentially 2-MeTHF, is added to the reaction mixture at -35°C to 0°C and the reaction mixture is stirred until finished before any solids are filtered off. The 25 filtrate is added to a compound of formula (VII) in an organic solvent, preferentially DMA, 47 201389-PCT01-NP and an inorganic base, typically K2CO3, and the reaction mixture is stirred at an elevated temperature, typically 70°C to 80°C for a prolonged time, typically 48 h until the reaction is complete, to give the compound of formula (VIII). The compounds of formula (IX) in which R3, R4, R5, n, A and p are defined as in 5 formula (I) may be prepared as illustrated in Scheme TA4. Scheme TA4 Step 1: The compounds of formula (XV) in which R3, R4, R5, n, A and p are defined as in formula (I) may be prepared by reacting a compound of formula (III) in which R3, R4, 10 R5, n, A and p are defined as in formula (I) and LG1is a suitable leaving group such as chloro, bromo, iodo, triflate (OTf), mesylate (OMs) or tosylate (OTs) (preferentially bromo, chloro or OMs) with CH3COSH in the presence of a base such as for example DIPEA, TEA, K2CO3. The reaction is typically carried out in an inert organic solvent such as THF, 2- MeTHF, DMF, MeCN, or EtOH at temperatures typically ranging from ambient temperature 15 to 60oC and for a prolonged reaction time. Step 2: The compounds of formula (IX) defined as above are prepared by hydrolysis of a compound of formula (XV) with a suitable base such as NaOH, KOH, K2CO3in an organic solvent such as MeOH, EtOH, THF or 1,4-dioxane. Optionally, the reaction may also be performed in the presence of water. 20 The compounds of the formula (X) in which R1and R2are defined as in formula (I) may be prepared using the any of the methods c1 to c3 below: Method c1: The compounds of formula (X) in which R1 and R2 are defined as in formula (I) may be formed by reacting a compound of formula (XVI) in which R2is defined as in formula (I) and LG2is a suitable leaving group such as halo or triflate (OTf) 25 (preferentially chloro) with a compound of formula (V) in which R1 is as defined in formula (I). 48 201389-PCT01-NP The reaction is carried out in an inert organic solvent such as 1,4-dioxane, THF, MeOH, EtOH or mixtures thereof in the presence of a suitable base such as DIPEA, TEA or K2CO3 (typically 2-5 eq). The reaction may be carried out at temperatures ranging typically 5 from 20oC to 80oC for a prolonged reaction time (2-48 h) using standard equipment or a single node microwave oven. Formula (V) is normally used in a slight excess (typically 1.2- 3 eq) to formula (XVI). Method c2: The compounds of formula (X) in which R1and R2are defined as in formula (I) may be formed by reacting a compound of formula (XVII) in which R1is defined 10 as in formula (I) and LG2 is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) a with a compound of formula (VII) in which R2 is defined as in formula (I). The reaction may be catalyzed with a suitable palladium reagent, e.g. Pd2(dba)3 in 15 combination with a suitable phosphine ligand, typically XPhos or XantPhos in the presence of a base, such as Cs2CO3or K2CO3, in an inert organic solvent, such as 1,4-dioxane or THF, at temperatures ranging from 25oC to 100oC. The reaction is preferentially conducted under an inert atmosphere (e.g. an N2 atmosphere) for a prolonged reaction time (typically 3-24 h). Alternatively, the reaction may also be performed without using a metal catalyst in an 20 inert organic solvent such as DMF in the presence of a base such as K2CO3 or Na2CO3 at elevated temperatures (e.g.90oC) for a prolonged reaction time (typically overnight). Method c3: The compounds of formula (X) in which R1and R2are defined as in formula (I) may be formed by reacting a compound of formula (VIII) in which R1and R2are 49 201389-PCT01-NP defined as in formula (I) and LG2 is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) with a compound of formula (XVIII). (VIII)(XVIII)The reaction may be carried out in an inert organic solvent such as 1,4-dioxane, THF, 5 MeCN in the presence of a suitable base such as DIPEA, K2CO3 or NaHCO3. The reaction may be carried out at temperatures ranging typically from 20oC to 100oC for a prolonged reaction time using standard equipment or a single node microwave oven. Optionally, the reaction may also be performed with the presence of water. Certain compounds of formula (XI) as defined below may be prepared by the 10 methods d1-d3: Method d1: Certain compounds of formula (XI) in which n is 0, R3is C1-3alkyl or C1-3 haloalkyl, R4 is H and R5, A and p are defined as in formula (I) may be prepared by reacting a compound of formula (XIX) in which R3is C1-3alkyl or C1-3haloalkyl and R5, A and p are defined as in formula (I) with a reducing agent such as NaBH4or NaBH3CN. 15 The reaction is carried out in an inert organic solvent such as MeOH or THF at a temperature typically in the range of 0oC to ambient temperature for a prolonged reaction time (typically 1 to 5h). Method d2: Certain compounds of formula (XI) in which n is 0, R3 and R4 are C1-3 20 alkyl or C1-3 haloalkyl and R5, A and p are defined as in formula (I) may be prepared by reacting a compound of formula (XIX) in which R3is C1-3alkyl or C1-3haloalkyl and R5, A and p are defined as in formula (I) with a nucleophilic reagent containing R4 typically a Grignard reagent (e.g. R4MgX, wherein X is a halogen e.g. chloride, bromine, iodide). 50 201389-PCT01-NP The reaction is carried out in an inert organic solvent such as THF at a temperature typically in the range of 0oC to ambient temperature for a prolonged reaction time. Method d3: Certain compounds of formula (XI) in which n is 0, R3is C1-3alkyl or C1-5 3 haloalkyl, R4 is H and R5, A and p are defined as in formula (I) may be prepared by reacting a compound of formula (XX) in which R5, A and p are defined as in formula (I) with a nucleophilic reagent containing R3typically a Grignard reagent (e.g. R3MgX, wherein X is a halogen e.g. chloride, bromine, iodide). 10 The reaction is carried out in an inert organic solvent such as THF at a temperature in the range of 0oC to ambient temperature for a prolonged reaction time (typically 1 h). The compounds of formula (XVI) in which R2 is defined as in formula (I) and LG2 is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro) may be prepared as illustrated in Scheme TA5. 15 Scheme TA5 Method e1: A strong base such as for example NaH is added to a compound of formula (XVIII) dissolved in an inert organic solvent such as THF, 2-MeTHF or 1,4-dioxane typically at 0oC. The mixture is left for about 1 h at ambient temperature before it is added to 20 a cold solution (e.g.0oC, typically in the same solvent as above) of a compound of formula (XIV) in which R2 is defined as in formula (I) and LG2 is a suitable leaving group such as 51 201389-PCT01-NP halo or triflate (OTf) (preferentially chloro). This is then left at ambient temperature for a prolonged reaction time (typically a few hours) to generate a compound of formula (XVI). The compounds of formula (XVII), in which R1is defined as in formula (I) and LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), may be 5 prepared by sequentially reacting a compound of formula (XVIII) and a compound of formula (V), in which R1is defined as in formula (I), with a compound of formula (XIII), in which LG2is a suitable leaving group such as halo or triflate (OTf) (preferentially chloro), as illustrated in Scheme TA6. Scheme TA6 10 Method f1: A solution of a compound of formula (XIII) and formula (XVIII) in a suitable organic solvent such as THF or 2-MeTHF, preferentially THF, is pre-cooled to about 0oC (ice / bath temperature) before an organic base such as DIPEA dissolved in an inert organic solvent, preferentially THF is added slowly (typically during 30 min) to the reaction 15 mixture at 0°C and the reaction mixture is stirred until finished (typically 1 h). Optionally, an additional amount of DIPEA is added before addition of a compound of formula (V) in an inert organic solvent, preferentially THF, and the reaction mixture is stirred at about 0oC for a prolonged reaction time, typically 1-2 h, until the reaction is complete, to give the compound of formula (XVII). The reaction is preferentially performed under an inert atmosphere (e.g. 20 an N2 atmosphere). Where necessary converting the resultant compound of formula (I) into a pharmaceutically acceptable salt thereof, and where desired separating the resultant compound of formula (I) into its individual diastereoisomers or enantiomers such as formula (Ia) or formula (Ib). 25 52 201389-PCT01-NP It is understood that the processes for preparation described above also can be performed starting from any enantiomer, or a racemic mixture, of compounds of formula (II) to formula (XII), formula (XIV) to formula (XVII) and formula (XIX) to formula (XX), to 5 give compounds of formula (I) or any stereoisomer of formula (I) such as formula (Ia) and (Ib). It will also be appreciated that in some of the reactions mentioned herein it may be necessary / desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable, suitable methods for protection are known to those 10 skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see “Protective groups in Organic Chemistry”, edited by J W F McOmie, 1Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4thedition, T.W. Greene & P.G.M Wutz, Wiley-Interscience (2007)). Thus, if reactants include groups such as amino, thiol, carboxy or hydroxy it may be desirable to protect the group in some of 15 the reactions mentioned herein. Suitable protecting groups for hydroxy include trialkyl silyl or diarylalkylsilyl groups (e.g. t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl ethers). Suitable protecting groups for carboxylic acids include (C1-C6)alkyl or benzyl esters. Suitable protecting groups for amino include tert -butyloxycarbonyl, benzyloxycarbonyl, and 9- 20 fluorenylmethoxycrbonyl. Suitable protecting groups for thiols include acetyl and 4-methoxy benzyl groups. The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art. It will be appreciated by those skilled in the art how a compound comprising such a group can be deprotected (see 25 “Protective groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 4rdedition, T.W. Greene & P.G.M Wutz, Wiley-Interscience (2007)). 53 201389-PCT01-NP Persons skilled in the art will appreciate that certain compounds of formula (II) to formula (XII) and formula (XIV) to formula (XX) described above may also be referred to as being “protected derivatives“. Persons skilled in the art will appreciate that in order to obtain compounds of the 5 invention in an alternative, and on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in different order, and / or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and / or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This 10 may negate, or render necessary, the need for protecting groups. Intermediate 1 15 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide Step a) (R)-2-((4-Chloro-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol20 (4-Methoxyphenyl)methanethiol (4.61 g, 29.87 mmol) was added dropwise to 2,4,6- trichloro-1,3,5-triazine (5.51 g, 29.87 mmol) and DIPEA (9.65 g, 74.67 mmol) in THF (200 54 201389-PCT01-NP mL) at 0°C over 30 min under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 30 min and (R)-2-amino-4-methylpentan-1-ol (3.5 g, 29.87 mmol) was added at 0°C over 30 min. The reaction mixture was stirred at 15°C for 2 h, filtered and the filtrate was concentrated and diluted with EtOAc (350 mL). The organic layer was washed twice with 5 water (200 mL), dried over Na2SO4, filtered and evaporated at reduced pressure. The crude residue was purified by straight phase flash chromatography on silica (gradient: 0–30% EtOAc in PE) to give the title compound (16.65 g); MS (ESI) m / z [M+H]+383. Step b) (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4- 10 methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Methanesulfonamide (6.20 g, 65.22 mmol) was added to (R)-2-((4-chloro-6-((4- methoxybenzyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol (16.65 g, 43.48 mmol), Cs2CO3(21.25 g, 65.22 mmol), Pd2(dba)3(0.796 g, 0.87 mmol) and X-phos (1.658 g, 3.48 mmol) in THF (400 mL) under an atmosphere of N2(g). The reaction mixture was stirred at 15 55°C for 12 h. After cooling to rt, the mixture was partitioned between water (500 mL) and MTBE (200 mL). The layers were separated and the organic layer was extracted three times with 0.09 M K2CO3(aq). The combined aqueous layer was acidified with 12 N HCl (aq) and extracted twice with EtOAc (1 L). The combined organic layer was washed with water, dried and evaporated at reduced pressure to give the title compound (18.48 g, 96%); MS (ESI) m / z 20 [M+H]+442. Intermediate 2 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide 25 Anisole (5.43 g, 50.22 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-((4-methoxybenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 55 201389-PCT01-NP Intermediate 1 (18.48 g, 41.85 mmol) in TFA (160 mL) and the reaction mixture was stirred at 20°C for 4 h. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was extracted twice with sat NaHCO3(until slightly basic). The combined aqueous layer was acidified with 12 N HCl to pH 4 and extracted with 5 EtOAc. NaCl was added to the aqueous layer which was extracted three times with EtOAc. The combined organic layer was evaporated at reduced pressure to give the title compound (16.05 g); MS (ESI) m / z [M+H]+322. Intermediate 3 10 6-(2-Bromo-1,1-difluoroethyl)-2,3-dihydrobenzo[b][1,4]dioxine DAST (1.285 mL, 9.72 mmol) was added to a solution of 2-bromo-1-(2,3- dihydrobenzo[b][1,4]dioxin-6-yl)ethan-1-one (500 mg, 1.94 mmol) in DCM (8 mL) in a sealed tube made of polytetrafluoroethylene,. The reaction mixture was stirred at 40°C for 24 15 h. DCM was added and the organic layer was washed with NaHCO3(aq), dried over Na2SO4, filtered and evaporated at reduced pressure to give the title compound (500 mg, 92%) which was used in the next step without further purification.1H NMR (300 MHz, CDCl3) δ 3.73 (t, 2H), 4.29 (s, 4H), 6.86–7.08 (m, 3H). 20 Intermediate 4 2-(2-Bromo-1,1-difluoroethyl)benzo[d]thiazole DAST (1.290 mL, 9.76 mmol) was added to a solution of 1-(benzo[d]thiazol-2-yl)-2- bromoethan-1-one (500 mg, 1.95 mmol) in DCM (8 mL) in a sealed tube made of 25 polytetrafluoroethylene,. The reaction mixture was stirred at 40°C for 24 h. DCM was added and the organic layer was washed with NaHCO3(aq), dried over Na2SO4, filtered and evaporated at reduced pressure to give the title compound (450 mg, 83%) which was used in the next step without further purification.1H NMR (300 MHz, CDCl3) δ 4.22 (t, 2H), 7.49- 7.61 (m, 2H), 7.97 (d, 1H), 8.12 (d, 1H). 56 201389-PCT01-NP Intermediate 5 3-(2-Bromo-1,1-difluoroethyl)pyridine 5 2-Bromo-1-(pyridin-3-yl)ethan-1-one hydrobromide (84 mg, 0.3 mmol) was dissolved in DCM (0.25 mL) and a solution of DAST (0.079 mL, 0.60 mmol) in DCM (0.250 mL) was added. The reaction mixture was stirred at 40°C for 19 h. The reaction mixture was poured on ice and washed with sat NaHCO3. The organic layer was passed through a phase separator and evaporated to give the title compound (21 mg, 31%) which was used in the next step 10 without further purification.1H NMR (500 MHz, DMSO-d6) δ 4.34 (t, 2H), 7.57 (ddd, 1H), 7.99–8.08 (m, 1H), 8.61–8.91 (m, 2H). Intermediate 6 2-(2-Bromo-1,1-difluoroethyl)-3-fluoropyridine 15 2-Bromo-1-(3-fluoropyridin-2-yl)ethan-1-one hydrobromide (90 mg, 0.3 mmol) was dissolved in DCM (0.25 mL) and a solution of DAST (0.079 mL, 0.60 mmol) in DCM (0.250 mL) was added. The reaction mixture was stirred at 40°C for 22 h. DAST (0.040 mL, 0.30 mmol) was added, and the reaction mixture was stirred at 40°C for 4 h. The reaction mixture 20 was poured on ice and washed with sat NaHCO3. The organic layer was passed through a phase separator and evaporated to give the crude title compound (29 mg) which was used in the next step without further purification. Intermediate 7 25 3-(2-Bromo-1,1-difluoroethyl)-2-fluoropyridine 57 201389-PCT01-NP 2-Bromo-1-(2-fluoropyridin-3-yl)ethan-1-one (65 mg, 0.3 mmol) was dissolved in DCM (0.25 mL) and a solution of DAST (0.079 mL, 0.60 mmol) in DCM (0.250 mL) was added. The reaction mixture was stirred at 40°C for 19 h. The reaction mixture was poured on ice and washed with sat NaHCO3. The organic layer was passed through a phase separator 5 and evaporated to give the title compound (21 mg, 29%) which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 4.28 (td, 2H), 7.45–7.64 (m, 1H), 8.18–8.23 (m, 1H), 8.39–8.52 (m, 1H). Intermediate 8 10 1-(2-Bromo-1,1-difluoroethyl)-2-fluorobenzene 2-Bromo-1-(2-fluorophenyl)ethan-1-one (65 mg, 0.3 mmol) was dissolved in DCM (0.25 mL) and a solution of DAST (0.079 mL, 0.60 mmol) in DCM (0.250 mL) was added. The reaction mixture was stirred at 40°C for 22 h. DAST (0.079 mL, 0.60 mmol) was added 15 and the reaction mixture was stirred at 40°C for 4 h. The reaction mixture was poured on ice and washed with sat NaHCO3. The organic layer was passed through a phase separator and evaporated to give the title compound (53 mg, 74%) which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 4.23 (td, 2H), 7.26–7.46 (m, 2H), 7.53–7.68 (m, 2H). 20 Intermediate 9 1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethan-1-ol NaBH4(20.16 mg, 0.53 mmol) was added to a solution of 1- 25 (benzo[c][1,2,5]oxadiazol-4-yl)ethanone (72 mg, 0.44 mmol) in MeOH (2 mL). The reaction mixture was stirred at ambient temperature for 45 min before water and DCM were added. The two phases were separated, and the organic layer was passed through a phase separator. The solvent was evaporated to give (62 mg, 86%) of the title compound which was used 58 201389-PCT01-NP without further purification.1H NMR (500 MHz, CDCl3) δ 1.72 (3H, d), 2.33 (1H, d), 5.38 (1H, p), 7.37–7.47 (2H, m), 7.69–7.78 (1H, m). Intermediate 10 5 1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl methanesulfonate DIPEA (0.073 mL, 0.42 mmol) followed by MsCl (0.044 mL, 0.57 mmol) were added to a solution of 1-(benzo[c][1,2,5]oxadiazol-4-yl)ethanol Intermediate 9 (62 mg, 0.38 mmol) in DCM (1.5 mL). The reaction mixture was stirred at rt for 3.5 h. Water and DCM were 10 added and the two phases separated. The organic layer was passed through a phase separator and concentrated. The crude product was dissolved in DCM (1.5 mL) and DIPEA (0.066 mL, 0.38 mmol) was added followed by MsCl (0.029 mL, 0.38 mmol) and the reaction mixture was stirred at rt for 4 h. Water and DCM were added, and the two phases were separated. The organic layer was passed through a phase separator and concentrated to give (78 mg, 85%) of 15 the crude product which was used without further purification. Intermediate 11 N-(4-((1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 20 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (103 mg, 0.32 mmol) followed by DIPEA (0.14 mL, 0.80 mmol) were added to a solution of 1-(benzo[c][1,2,5]oxadiazol-4-yl)ethyl methanesulfonate Intermediate 10 (78 mg, 0.32 mmol) in DMF (1 mL). The reaction 25 mixture was stirred at rt on. A second batch of Intermediate 2 (0.13 mmol) and 59 201389-PCT01-NP Intermediate 10 (0.13 mmol) was reacted as described above and the reaction mixtures were combined. Water and DCM were added. The two phases were separated, and the organic layer was passed through a phase separator and concentrated. The crude product was purified by preparative SFC, PrepMethod F (gradient: 20–25%) to give the title compound (26 mg, 5 17%). MS (ESI) m / z [M+H]- 468.2. Intermediate 12 tert-Butyl 6-(1-hydroxyethyl)-1H-indazole-1-carboxylate 10 DIPEA (0.042 mL, 0.24 mmol) and a solution of Boc2O (132 mg, 0.60 mmol) in MeCN (0.5 mL) were added to a suspension of 1-(1H-indazol-6-yl)ethanol hydrochloride ((48 mg, 0.24 mmol) in MeCN (1 mL). DMAP (9 mg, 0.07 mmol) was added and within 1 min the mixture had become a clear colorless solution. The reaction mixture was stirred at rt for 30 min and then at 40oC for 3.5 h.1.9 M NaOH (aq) (8 drops) was added and the mixture 15 was stirred at rt for 3 days. Water and DCM were added, and the phases were separated. The organic layer was passed through a phase separator and concentrated. The crude product was purified by preparative HPLC, PrepMethod I, gradient (15-75%) to give the title compound (15 mg, 24%).1H NMR (400 MHz, CD3OD) δ 1.51 (3H, d), 1.73 (9H, s), 5.01 (1H, q), 7.39 (1H, dd), 7.78 (1H, dd), 8.2–8.23 (1H, m), 8.24 (1H, d). 20 Intermediate 13 tert-Butyl 6-(1-((methylsulfonyl)oxy)ethyl)-1H-indazole-1-carboxylate DIPEA (11 µl, 0.06 mmol) followed by MsCl (10 µl, 0.13 mmol) were added to a 25 solution of tert-butyl 6-(1-hydroxyethyl)-1H-indazole-1-carboxylate Intermediate 12 (14 mg, 0.06 mmol) in DCM (0.5 mL) and the reaction mixture was stirred at rt for 1.5 h. Additional DIPEA (10.59 µl, 0.06 mmol) and MsCl (10 µl, 0.13 mmol) were added and the 60 201389-PCT01-NP reaction mixture was stirred for 2.5 h at rt.4 more additions of MsCl (totally 120 uL, 1.56 mmol) were made until the reaction was complete. Water and DCM were added, and the phases were separated. The organic layer was passed through a phase separator and evaporated to give a crude product that was used without further purification. 5 Intermediate 14 tert-Butyl 6-(1-((4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6- (methylsulfonamido)-1,3,5-triazin-2-yl)thio)ethyl)-1H-indazole-1-carboxylate 10 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (15 mg, 0.05 mmol) and DIPEA (0.020 mL, 0.12 mmol) were added to a solution of tert-butyl 6-(1-((methylsulfonyl)oxy)ethyl)-1H-indazole- 1-carboxylate Intermediate 13 (16 mg, 0.05 mmol) in DMF (0.3 mL) and the reaction mixture was stirred at rt for 3 days and then heated to 60oC for 24 h and then left at rt for an 15 additional 3 days. Water and DCM were added. The two phases were separated, and the organic layer was passed through a phase separator and evaporated to give a crude product (containing some DMF) which was used in the next step without further purification. Intermediate 15 20 1-(1-Bromoethyl)-2,3-difluorobenzene HBr (48% in water) (7.15 ml, 63.2 mmol) was added to 1-(2,3-difluorophenyl)ethanol (1.0 g, 6.32 mmol) and the reaction mixture was stirred at rt on. The mixture was partitioned between PE (50 mL) and water (50 mL). The organic layer was separated and dried over 61 201389-PCT01-NP Na2SO4, filtered and evaporated to give the title compound (1.31 g, 94%) as a colorless oil which was used without further purification.1H NMR (400 MHz, CDCl3) δ 2.21 (3H, d), 5.62 (1H, q), 7.2–7.35 (2H, m), 7.42–7.48 (1H, m). 5 Intermediate 16 N-(4-((1-(2,3-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of 1-(1-bromoethyl)-2,3-difluorobenzene Intermediate 15 (40.2 g, 181.910 mmol) in MeCN (100 mL) was added drop-wise to a stirred suspension of (R)-N-(4-((1- hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (83.5 g, 181.9 mmol) and NaOAc (29.8 g, 363.8 mmol) in water (370 mL) and MeCN (270 mL) and the reaction mixture was stirred at rt for 36 h. Water and EtOAc were added and the mixture was concentrated in vacuo. Sat NaHCO3(aq) and IPrOAc were 15 added, and the organic layer was washed with carbonate and concentrated in vacuo. The crude product was purified by straight phase flash chromatography on silica (5% MeOH in DCM) to give the title compound (72.2 g, 88%). MS (ESI) m / z [M+H]+462.2. Intermediate 17 20 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide 62 201389-PCT01-NP DIPEA (50.2 mL, 288.2 mmol) was added in one portion to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (53.8 g, 137.2 mmol) in DMF (550 mL) at rt. (1-Bromoethyl)benzene (19.7 mL, 140.0 mmol) dissolved in DMF (50 mL) was added slowly during 30 min (except for 5 5 mL of the solution which was added after 2.5 h). The reaction mixture was stirred at rt for an additional 2 h (total 4.5 h) after which an additional (1-bromoethyl)benzene (2 g, 10.8 mmol) and the stirring was continued for 1.5 h at rt. Water (1 L) and MTBE (500 mL) was added and the pH was adjusted to approximately 4-5 by the addition of 1 M HCl. The phases were separated, and the aqueous layer was extracted with MTBE (300 mL). The combined organic 10 layers were washed with two portions of water. The solvent was evaporated, and the crude product was purified by straight phase flash chromatography on silica (50-100% MTBE in heptane) to give the title compound (58 g, 99%) as a colourless solid. MS (ESI) m / z [M+H]+426.3. 15 Intermediate 18 N-(4-((1-(2,5-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.072 mL, 0.41 mmol) and a solution of 2-(1-bromoethyl)-1,4-20 difluorobenzene (83 mg, 0.37 mmol) in DMF (1 mL) were added to a solution of (R)-N-(4- ((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (150 mg, 0.37 mmol) in DMF (1 mL) and the reaction mixture was stirred at rt for 20 h. Water and MTBE were added. The two phases were separated, and the organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was 25 purified by straight phase flash chromatography on silica (0-100% EtOAc in heptane) to give the title compound (159 mg, 92%) as a colourless solid. MS (ESI) m / z [M+H]+462.2. Intermediate 19 63 201389-PCT01-NP 1-Phenylpropyl methanesulfonate MsCl (0.078 mL, 1.00 mmol) dissolved in DCM (1.5 mL) was added over 5 min to a solution of 1-phenylpropan-1-ol (0.137 mL, 1.0 mmol) and TEA (0.209 mL, 1.50 mmol) in 5 DCM (3.5 mL) at 0oC and the reaction mixture was stirred for 30 min at 0oC and then at rt for 80 min. DCM (10 mL) and water (2 mL) were added and the organic layer was passed through a phase separator and concentrated to give the title compound (181 mg, 84%) which was used as such the next step.1H NMR (500 MHz, CDCl3) δ 0.94 (3H, t), 1.87 - 2.02 (1H, m), 2.02 - 2.2 (1H, m), 2.64 (3H, s), 5.43 (1H, dd), 7.32 - 7.47 (5H, m). 10 Intermediate 20 N-(4-((1-(2-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 15 1-(1-Chloroethyl)-2-fluorobenzene (49 mg, 0.31 mmol) and DIPEA (0.108 mL, 0.62 mmol) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (100 mg, 0.31 mmol) in DMF (1.5 mL) and the reaction mixture was heated in a microwave reactor at 70°C for 30 min. Water and EtOAc were added and the two phases were separated. The aqueous layer 20 was extracted with EtOAc and the combined organic layers were washed twice with water, dried over MgSO4 and concentrated. The residue was purified by straight phase flash chromatography on silica (heptane / EtOAc, 1 / 2) to give the title compound (55 mg, 40%). MS (ESI) m / z [M+H]+444.1. 25 Intermediate 21 64 201389-PCT01-NP N-(4-((1-(5-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 5 yl)methanesulfonamide Intermediate 2 (55 mg , 170 mmol) dissolved in DMF (436μL) was added to a solution of 2-(1-bromoethyl)-4-chloro-1-fluorobenzene (40 mg, 170 µmol) and DIPEA (32 µl, 187 µmol) in DMF (708 mL). The reaction mixture was stirred at rt for 5 h. Additional DIPEA (32.6 µl, 187µmol) was added. The reaction mixture was concentrated and the crude product was purified by preparative HPLC, PrepMethod N (gradient 5-95%), to 10 give the title compound (74 mg, 91%). MS (ESI) m / z [M+H]+478.1 / 480.1. Intermediate 22 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((2-phenylpropyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide 15 (1-Bromopropan-2-yl)benzene (57 mg, 0.29 mmol) dissolved in DMF (1.2 mL) followed by the addition of DIPEA (0.114 mL, 0.65 mmol) were added to (R)-N-(4-((1- hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (100 mg, 0.26 mmol) and the reaction mixture was stirred at rt for 19 h and 20 then at 60oC for 7 h and then at rt on. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude product was purified by preparative HPLC, 65 201389-PCT01-NP PrepMethod F (gradient 20-25%) to give the title compound (65 mg, 57%). MS (ESI) m / z [M+H]+440.2. Intermediate 23 5 1-(1-Bromoethyl)-2-fluoro-4-methoxybenzene HBr (48% in water) (2 mL, 17.7 mmol) was added to 1-(2-fluoro-4- methoxyphenyl)ethanol (0.251 g, 1.47 mmol). The reaction mixture was stirred at rt on. Water (10 mL) and DCM (10 mL) were added. The two phases were separated, and the 10 organic layer was passed through a phase separator. The solvent was evaporated to give (0.30 g, 87%) of the title compound which was used without further purification. Intermediate 24 N-(4-((1-(2-Fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 15 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (0.412 g, 1.28 mmol) followed by DIPEA (0.559 mL, 3.21 mmol) were added to a solution of 1-(1-bromoethyl)-2-fluoro-4-methoxybenzene 20 Intermediate 23 (0.299 g, 1.28 mmol) in DMF (5 mL). The reaction mixture was stirred at ambient temperature on then at 70°C for 1 h 45 min. Water and DCM were added. The two phases were separated, and the organic layer was passed through a phase separator and concentrated. The crude product was purified by preparative HPLC, PrepMethod M (gradient 15-55%) to give the title compound (0.150 g, 25%). MS (ESI) m / z [M+H]+474.4. 25 66 201389-PCT01-NP Intermediate 25 1-(5-Chloropyrazin-2-yl)ethan-1-ol NaBH4(0.140 g, 3.70 mmol) was added to 1-(5-chloropyrazin-2-yl)ethan-1-one (0.58 5 g, 3.70 mmol) in MeOH (30 mL) at rt and the reaction mixture was stirred for 1 h. The reaction was quenched with sat NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (0.50 g, 85%) as a pale yellow oil. MS (ESI) m / z [M+H]+159.0. 10 Intermediate 26 2-(1-Bromoethyl)-5-chloropyrazine PPh3 (0.675 g, 2.57 mmol) was added to a solution of CBr4 (0.1 mL, 2.57 mmol) and 1-(5-chloropyrazin-2-yl)ethanol Intermediate 25 (0.34 g, 2.14 mmol) in DCM (10 mL) at 15 0°C. The reaction mixture was stirred at rt for 1 h. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE, 1:5) to give the title compound (0.320 g, 67%) as a pale yellow solid.1HNMR (300MHz, CDCl3) δ 2.02 (3H, d), 5.11-5.20 (1H, m), 8.43-8.48 (2H, m). 20 Intermediate 27 N-(4-((1-(5-Chloropyrazin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 67 201389-PCT01-NP DIPEA (373 mg, 2.89 mmol) was added to a solution (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (464 mg, 1.44 mmol) and 2-(1-bromoethyl)-5-chloropyrazine Intermediate 26 (320 mg, 1.44 mmol) in DMF (10 mL) at rt and the reaction mixture was stirred at 30°C for 2 h. The 5 crude product was purified by preparative HPLC, PrepMethod Q, to give the title compound (330 mg, 49%) as a white solid. MS (ESI) m / z [M+H]+462.2. Intermediate 28 5-(1-Bromoethyl)-2-methylpyridine 10 PBr3 (1.38 mL, 14.6 mmol) was added dropwise to a solution of 1-(6-methylpyridin- 3-yl)ethanol (400 mg, 2.92 mmol) in DCM (10 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc (20 mL) 15 and washed sequentially with sat brine (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford crude product which was used in the next step directly without further purification. MS (ESI) m / z [M+H]+200.1 / 202.1. Intermediate 29 20 1-(5-Fluoro-6-methoxypyridin-3-yl)ethan-1-ol NaBH4(179 mg, 4.73 mmol) was added slowly to 1-(5-fluoro-6-methoxypyridin-3- yl)ethan-1-one (800 mg, 4.73 mmol) in MeOH (2 mL) at 0°C. The reaction mixture was stirred at 15°C for 1 h. The mixture was concentrated to dryness and the crude product was 25 dissolved in DCM (150 mL), and washed sequentially with water (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford the title compound (780 mg, 96%) as a yellow oil which was used without further purification. MS (ESI) m / z [M+H]+172. Intermediate 30 68 201389-PCT01-NP 5-(1-Bromoethyl)-3-fluoro-2-methoxypyridine PBr3(1.61 g, 5.96 mmol) was added dropwise to 1-(5-fluoro-6-methoxypyridin-3- yl)ethanol Intermediate 29 (680 mg, 3.97 mmol) in DCM (2 mL) at 15°C and the reaction 5 mixture was stirred at rt for 2 h. The mixture was diluted with DCM (75 mL), and washed sequentially with water (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to afford the title compound (460 mg, 50%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 2.05 (3H, d), 4.05 (3H, s),–5.16 - 5.23 (1H, m), 7.49 (1H, dd), 7.96 (1H d). 10 Intermediate 31 N-(4-((1-(5-Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 15 DIPEA (663 mg, 5.13 mmol) was added dropwise to a solution of 5-(1-bromoethyl)- 3-fluoro-2-methoxypyridine Intermediate 30 (300 mg, 1.28 mmol) and (R)-N-(4-((1- hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (458 mg, 1.28 mmol) in DMF (2 mL) at rt and the reaction mixture was stirred for 2 h. The mixture was evaporated to dryness and redissolved in EtOAc (75 mL) and 20 washed sequentially with water (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC, PrepMethod Q to give the title compound (160 mg, 26%) as a white solid. MS (ESI) m / z [M+H]+475. Intermediate 32 25 1-(6-Chloro-2-fluoropyridin-3-yl)ethan-1-ol 69 201389-PCT01-NP 3 M MeMgBr (6.27 mL, 18.8 mmol) in THF was added portion-wise to 6-chloro-2- fluoronicotinaldehyde (2.0 g, 12.5 mmol) in THF (20 mL) at 0°C over a period of 5 min and under an atmosphere of N2(g). The reaction mixture was stirred at rt for 1 h. The reaction was 5 quenched with sat NH4Cl (1 mL) and the mixture was extracted with EtOAc (3×20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (2.0 g, 91%) as a yellow solid. MS (ESI) m / z [M+H]+176. Intermediate 33 10 3-(1-Bromoethyl)-6-chloro-2-fluoropyridine PBr3(1.39 g, 5.13 mmol) was added dropwise to a solution of 1-(6-chloro-2- fluoropyridin-3-yl)ethanol Intermediate 32 (600 mg, 3.42 mmol) in DCM (10 mL) at 0°. The reaction mixture was stirred at rt for 2 h. The reaction was quenched with water, diluted 15 with DCM (50 mL) and washed sequentially with water (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative TLC (PE:EtOAc, 1:1) to afford the title compound (340 mg, 42%) as a yellow oil. MS (ESI) m / z [M+H]+238.1 / 240.1 20 Intermediate 34 N-(4-((1-(6-chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 70 201389-PCT01-NP DIPEA (737 mg, 5,70 mmol) was added dropwise to a solution of 3-(1-bromoethyl)- 6-chloro-2-fluoropyridine Intermediate 33 (340 mg, 1.43 mmol) and (R)-N-(4-((1-hydroxy- 4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (458 mg, 1.43 mmol) in DMF (5 mL) at rt and the reaction mixture was 5 stirred for 2 h. The mixture was concentrated to dryness and redissolved in EtOAc (75 mL), and washed sequentially with sat brine (2×25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC, PrepMethod Q, to afford the title compound (150 mg, 22%) as a white solid. MS (ESI) m / z [M+H]+479.1. 10 Intermediate 35 1-(5-Fluoropyridin-2-yl)ethyl methanesulfonate DIPEA (0.217 mL, 1.25 mmol) and MsCl (0.096 mL, 1.25 mmol) were added to a solution of 1-(5-fluoropyridin-2-yl)ethanol (160 mg, 1.13 mmol) in DCM (3 mL) and the 15 reaction mixture was stirred at rt for 3 h. Water was added and the two phases were separated and the organic layer was filtered through a short silica plug (eluted with DCM:EtOAc, 5:1) to yield the title compound (161 mg, 65%).1H NMR (400 MHz, CDCl3) δ 1.75 (3H, d), 2.96 (3H, s), 5.80 (1H, q), 7.39–7.53 (2H, m), 8.45 (1H, d). 20 Intermediate 36 5-(1-Chloroethyl)-2-methoxypyridine DIPEA (0.888 mL, 5.10 mmol) was added to a solution of 1-(6-methoxypyridin-3- yl)ethanol (710 mg, 4.64 mmol) in DCM (10 mL) followed by a dropwise addition of MsCl 25 (0.394 mL, 5.10 mmol). The reaction mixture was stirred at rt for 2.5 h before water was added. The two phases were separated, and the organic layer was filtered through a short pad of silica (eluted with DCM) to yield the title compound (798 mg, 100 %) as a colorless oil. 71 201389-PCT01-NP 1H NMR (500 MHz, CDCl3) δ 1.84 (3H, d), 3.94 (3H, s), 5.09 (1H, q), 6.76 (1H, dt), 7.68 (1H, ddd), 8.15 (1H, dt). Intermediate 37 5 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(6-methoxypyridin-3- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.072 mL, 0.41 mmol) and a solution of 5-(1-chloroethyl)-2- methoxypyridine Intermediate 36 (86 mg, 0.50 mmol) in DMF (1 mL) were added to a10 solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (150 mg, 0.37 mmol) in DMF (1 mL) and the reaction mixture was stirred at ambient temperature for 19 h. Water and MTBE were added. The two phases were separated, and the organic layer was purified using an ion exchange SCX-2 column. The column was washed with DCM, EtOAc and MeOH. and the product was 15 eluted with NH3 / MeOH to give the title compound (91 mg, 52%) as a solid. MS (ESI) m / z [M+H]+457.3. Intermediate 38 1-(2-Fluoro-6-methoxypyridin-3-yl)ethan-1-ol 20 NaBH4 (0.029 mL, 0.83 mmol) was added 1-(2-fluoro-6-methoxypyridin-3- yl)ethanone (128 mg, 0.76 mmol) dissolved in MeOH (1.5 mL) and the reaction mixture was stirred at rt for 1.5 h. Water and DCM were added, the two phases were separated and the aqueous phase was extracted with DCM. The combined organic layers were dried over 25 Na2SO4, filtered and concentrated to give the crude title compound was used in the next step without purification assuming full conversion. 72 201389-PCT01-NP Intermediate 39 3-(1-Chloroethyl)-2-fluoro-6-methoxypyridine 5 DIPEA (0.159 mL, 0.91 mmol) and MsCl (0.065 mL, 0.84 mmol) were added to a solution of 1-(2-fluoro-6-methoxypyridin-3-yl)ethanol Intermediate 38 (0.130 g, 0.76 mmol) in DCM (3 mL). The reaction mixture was stirred at ambient temperature for 3 h. Water (3 mL) was added and the two phases were separated. The aqueous layer was extracted with DCM (1 mL). The combined organic layer was washed with water (3 mL) and concentrated 10 to give the crude title compound which was used in the next step without further purification assuming quantitative yield.1H NMR (400 MHz, CDCl3) δ 1.82 (3H, d), 3.92 (3H, s), 5.28– 5.32 (1H, m), 6.57–6.68 (1H, m), 7.76–7.88 (1H, m). Intermediate 40 15 5-(1-Chloroethyl)-2-methylpyrimidine 1-(2-Methylpyrimidin-5-yl)ethanol (250 mg, 1.81 mmol) was added to POCl3 (1 mL, 10.73 mmol) at rt and the reaction mixture was stirred at 60°C for 1 h. The mixture was concentrated to dryness and the residue was azeotroped with toluene two times to afford the 20 title compound (300 mg, 106%) which was used in the next step directly without further purification. MS (ESI) m / z [M+H]+157. Intermediate 41 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(2-methylpyrimidin-5- 25 yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 73 201389-PCT01-NP DIPEA (1.30 mL, 7.47 mmol) was added to 5-(1-chloroethyl)-2-methylpyrimidine Intermediate 40 (300 mg, 1.92 mmol) and (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (600 mg, 1.87 5 mmol) in DMF (20 mL) at 0°C under an atmosphere of N2(g), and the reaction mixture was stirred at 70°C for 15 h. The mixture was diluted with EtOAc (20 mL), and washed sequentially with sat brine (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was first purified by preparative TLC (MeOH:DCM, 1:20) and then by preparative HPLC, PrepMethod D (gradient 5-65%) to afford the title compound 10 (160 mg, 19%) of as a white solid. MS (ESI) m / z [M+H]+442. Intermediate 42 5-(1-Bromoethyl)-2-cyclopropylpyrimidine 15 PBr3(0.42 mL, 4.45 mmol) was added dropwise to 1-(2-cyclopropylpyrimidin-5- yl)ethanol (730 mg, 4.45 mmol) in DCM (15 mL) at 0°C over a period of 3 min and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 40 min. The reaction was quenched with water (25 mL), extracted with EtOAc (2×100 mL), and the combined organic layer was dried over Na2SO4, filtered and concentrated to afford the title compound (400 mg, 20 40%) as a brown oil. MS (ESI) m / z [M+H]+226.9 / 228.9. Intermediate 43 N-(4-((1-(2-Cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 74 201389-PCT01-NP DIPEA (1.54 mL, 8.81 mmol) was added to 5-(1-bromoethyl)-2- cyclopropylpyrimidine Intermediate 42 (400 mg, 1.76 mmol), and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 5 2 (566 mg, 1.76 mmol) in DMF (8 mL) at rt, under an atmosphere of N2(g), and the reaction mixture was stirred for 3 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod D (gradient 10-45%) to give the title compound (140 mg, 17%) as a white solid. MS (ESI) m / z [M+H]+468.4. 10 Intermediate 44 N-(4-((1-(5-Chloropyrimidin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (152 mg, 1.17 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- 15 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (189 mg, 0.59 mmol) and 2-(1-bromoethyl)-5-chloropyrimidine Intermediate 45 (130 mg, 0.59 mmol) in DMF (5 mL) at rt and the reaction mixture was stirred at 30°C for 1 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod R,to afford the title compound (120 mg, 44%) as a white solid. MS (ESI) m / z 20 [M+H]+462.3. Intermediate 45 2-(1-Bromoethyl)-5-chloropyrimidine 75 201389-PCT01-NP PPh3(0.198 g, 0.76 mmol) was added to CBr4(0.1 mL, 0.76 mmol) and 1-(5- chloropyrimidin-2-yl)ethanol (0.10 g, 0.63 mmol) in DCM (5 mL) at rt and the reaction mixture was stirred for 1 h. The solvent was removed under reduced pressure. The crude 5 product was combined with a second batch made in the same way (0.44 mmol scale) before purification. The residue was purified by preparative TLC (EtOAc:PE, 1:5) to afford the title compound (0.130 g, 55%) as a pale yellow oil.1HNMR (300 MHz, CDCl3): δ 2.07-2.11 (3H, d), 5.24-5.31(1H, m), 8.70 (2H, s). 10 Intermediate 46 N-(4,6-Dichloro-1,3,5-triazin-2-yl)methanesulfonamide NaH (60% in oil, 2.08 g, 52.06 mmol) was washed twice with heptane under an atmosphere of N2(g).2-MeTHF (40 mL) was added followed by methanesulfonamide (4.13 15 g, 43.38 mmol). The reaction mixture was stirred at ambient temperature for 1 h and then added to a solution of 2,4,6-trichloro-1,3,5-triazine (8.0 g, 43.38 mmol) in 2-MeTHF (40 mL). The reaction mixture was heated at 70oC for 6 h and then at 50oC on. The mixture was poured over ice. The pH was adjusted to approximately 4 by the addition of 1 M HCl. EtOAc was added, and the two phases were separated. The aqueous phase was extracted with EtOAc 20 (×3) and the combined organic layer was dried over MgSO4, filtered and concentrated. The residue was re-solidified from MTBE to give the title compound (4.61 g, 44%) as a colourless solid. MS (ESI) m / z [M+H]+242.9. Intermediate 47 25 N-(4-Chloro-6-((1-(2,4-difluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide 76 201389-PCT01-NP NaH (2.369 g, 98.74 mmol) was added to a solution of 1-(2,4-difluorophenyl)ethane- 1-thiol (5.73 g, 32.91 mmol) in THF (30 mL) at 0°C and the reaction mixture was stirred at rt for 1 h. The mixture was added dropwise to a solution of N-(4,6-dichloro-1,3,5-triazin-2- 5 yl)methanesulfonamide Intermediate 46 (8.00 g, 32.91 mmol) in THF (150 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by straight phase flash chromatography on silica (0–10% DCM in MeOH) to give the title compound (4.00 g, 32%) 10 as a white solid. MS (ESI) m / z [M+H]+381. Intermediate 48 N-(4-((1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4-dimethylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 15 K2CO3 (218 mg, 1.58 mmol) was added to a solution of N-(4-chloro-6-((1-(2,4- difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 47 (300 mg, 0.79 mmol) and (R)-2-amino-4,4-dimethylpentan-1-ol (180 mg, 0.95 mmol) in 1,4-dioxane (10 mL) and the reaction mixture was stirred at 80°C for 2 h. The mixture was evaporated to 20 dryness. The residue was redissolved in DMF and filtered through diatomite. The filtrate was concentrated, and the crude product was purified by preparative HPLC, PrepMethod A (gradient: 20–60%) to give the title compound (220 mg, 59%) as a white solid. MS (ESI) m / z [M+H]+476. 25 Intermediate 49 77 201389-PCT01-NP N-(4-((1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3-dimethylbutan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide K2CO3(218 mg, 1.58 mmol) was added to a solution of N-(4-chloro-6-((1-(2,4- 5 difluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 47 (300 mg, 0.79 mmol) and (R)-2-amino-3,3-dimethylbutan-1-ol (185 mg, 1.58 mmol) in dioxane (20 mL). The reaction mixture was stirred at 80oC for 2 h. The solvent was removed under reduced pressure and the crude product was purified by preparative HPLC, PrepMethod B, to give the title compound (200 mg, 55%) as a white solid. MS (ESI) m / z [M+H]+462. 10 Intermediate 50 (2R)-2-((4-Chloro-6-((1-phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4- dimethylpentan-1-ol 15 1-Phenylethanethiol (492 mg, 3.56 mmol)) was added to a solution of 2,4,6-trichloro- 1,3,5-triazine (657 mg, 3.56 mmol) in dry THF (20 mL), and the mixture was cooled on an ice-bath under an atmosphere of N2(g). A solution of DIPEA (0.933 mL, 5.34 mmol) in THF (10 mL) was added dropwise over 30 min and the reaction mixture was stirred at 0oC for 1 h. DIPEA (0.933 mL, 5.34 mmol) was added followed by a dropwise addition over 20 min of a 20 solution of (R)-2-amino-4-methylpentan-1-ol (418 mg, 3.56 mmol) in THF (10 mL). The reaction mixture was stirred at 0oC for 1.5 h. The mixture was allowed to attain rt and then concentrated at reduced pressure. The residue was purified by preparative TLC (MeCN:H2O, 78 201389-PCT01-NP 9:1) to give the title compound (1.0 g, 77%) as a yellow oil which solidified upon standing; MS (ESI) m / z [M+H]+367.1. Intermediate 51 5 1-(2-Bromo-1,1-difluoroethyl)-2,4-difluorobenzene 2-Bromo-1-(2,4-difluorophenyl)ethan-1-one (71 mg, 0.3 mmol) was dissolved in DCM (0.25 mL) and DAST (0.079 mL, 0.60 mmol) in DCM (0.250 mL) was added. The reaction mixture was stirred at 40°C for 22 h. DAST (0.079 mL, 0.60 mmol) was added, and 10 the reaction mixture was stirred at 40°C for 4 h. The mixture was poured on ice and washed with sat NaHCO3. The organic phase was passed through a phase separator and concentrated to give the title compound (53 mg, 69%) which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6) δ 4.23 (td, 2H), 7.22–7.34 (m, 1H), 7.49 (tdd, 1H), 7.68 (td, 1H). 15 Intermediate 52 5-(1-Bromoethyl)-2,4-dimethyloxazole 48% HBr (aq, 1.15 mL, 21.2 mmol) was added to 1-(2,4-dimethyloxazol-5-yl)ethanol 20 Chemistry A European Journal (2006), 12(22), 5806-5814 (300mg, 2.13 mmol) and the reaction mixture was stirred for 3 h. Water and MTBE was added and the phases were separated. The aqueous layer was extracted with MTBE and the combined organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (193 mg, 44%) as an oil.1H NMR (500 MHz, CDCl3, 25°C) δ 2.03 (3H, d), 2.43 (3H, s), 5.08 (1H, q). 25 Intermediate 53 (R)-2-((4-Chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol 79 201389-PCT01-NP A solution of (2,3-difluorophenyl)methanethiol (1.1 g, 6.87 mmol) in dry THF (10 mL) was added dropwise to 2,4,6-trichloro-1,3,5-triazine (1.266 g, 6.87 mmol) and DIPEA (1.794 ml, 10.30 mmol) in dry THF (30 mL) at 0°C under an atmosphere of N2(g). The 5 reaction mixture was stirred at 0°C for 1 h. DIPEA (1.794 ml, 10.30 mmol) followed by (R)- 2-amino-4-methylpentan-1-ol (0.805 g, 6.87 mmol) in dry THF (10 mL) were added dropwise. The reaction mixture was stirred at 0°C for 1.5 h and then concentrated. The crude residue was purified by straight phase flash chromatography on silica (gradient: 5–100% EtOAc in heptane) followed by straight phase flash chromatography on silica (gradient: 1– 10 8% MeOH in DCM) to give the title compound (1.59 g, 60%); MS (ESI) m / z [M+H]+389. Intermediate 54 N-(4-Chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 15 3.5 M K2CO3 (aq, 0.389 mL, 6.44 mmol) was added to a solution of N-(4,6-dichloro- 1,3,5-triazin-2-yl)methanesulfonamide Intermediate 46 (447 mg, 1.84 mmol) in THF (15 mL) and the reaction mixture was stirred at rt for a few min. S-(2,3-Difluorobenzyl) ethanethioate (27 mg, 0.13 mmol) was added and the reaction mixture was heated under an atmosphere of N2(g) at 45°C for 4 h, and then stirred at rt for 4 days. The mixture was concentrated and the 20 residue was dissolved in DMSO, filtered and purified by preparative HPLC, PrepMethod M (gradient: 20–85%) to give the title compound (312 mg, 46%). MS (ESI) m / z [M+H]+366.8. Intermediate 55 N-(4-((1-(3-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 80 201389-PCT01-NP (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (0.132 g, 0.33 mmol) followed by DIPEA (0.143 mL, 0.82 mmol) were added to a solution of 1-(1-bromoethyl)-3-chloro-2-fluorobenzene 5 (0.078 g, 0.33 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature overnight. Water (1.5 mL) and DCM (2.5 mL) were added to the mixture. The two phases were separated, and the organic layer was passed through a phase separator and concentrated. The crude residue was purified by preparative SFC, PrepMethod F (gradient: 20–25%), to give the title compound (0.107 g, 68%). MS (ESI) m / z [M+H]+478.12 / 480.11. 10 Intermediate 56 N-(4-((1-(2,6-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 15 yl)methanesulfonamide Intermediate 2 (0.091 g, 0.23 mmol) followed by DIPEA (0.099 mL, 0.57 mmol) were added to a solution of 2-(1-bromoethyl)-1,3-difluorobenzene (0.050 g, 0.23 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature overnight. Water (1.5 mL) and DCM (2.5 mL) were added to the mixture and the two phases were separated. The organic layer was passed through a phase separator and concentrated. 20 The residue was purified by preparative SFC, PrepMethod F (gradient: 20–25%) to give the title compound (0.069 g, 66%). MS (ESI) m / z [M+H]+462.14. Intermediate 57 81 201389-PCT01-NP N-(4-((1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 5 yl)methanesulfonamide Intermediate 2 (0.089 g, 0.22 mmol) followed by DIPEA (0.097 mL, 0.55 mmol) were added to a solution of 1-(1-bromoethyl)-2,4-difluorobenzene (0.049 g, 0.22 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature overnight. Water (1.5 mL) and DCM (2.5 mL) were added, and the two phases were separated. The organic layer was passed through a phase separator and concentrated. The 10 residue was purified by preparative SFC, PrepMethodF (gradient: 15–20%) to give the title compound (0.068 g, 667%). MS (ESI) m / z [M+H]+462.14. Intermediate 58 N-(4-((1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 15 DIPEA (0.086 mL, 0.49 mmol) and 4-(1-bromoethyl)-1-chloro-2-fluorobenzene (106 mg, 0.45 mmol) were added to a solution of (R)-N-(4-((1-ydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (180 mg, 0.45 mmol) in DMF (3 mL). The reaction mixture was stirred at ambient temperature over the 20 weekend. Water and MTBE were added, and the two phases were separated. The organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by normal phase flash column chromatography on silica (gradient: 0–100% EtOAc 82 201389-PCT01-NP in DCM) to yield the title compound (136 mg, 64%) as a colourless solid. MS (ESI) m / z [M- H]- 476.2. Intermediate 59 N-(4-((1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 5 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.086 mL, 0.49 mmol) and 1-(1-bromoethyl)-4-chloro-2-fluorobenzene (106 mg, 0.45 mmol) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (180 mg, 0.45 10 mmol) in DMF (3 mL). The reaction mixture was stirred at ambient temperature for 19 h. Water and MTBE were added, and the two phases were separated. The organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by normal phase flash column chromatography on silica (0–100% EtOAc in DCM) to yield the title compound (195 mg, 91%) as a colourless solid. MS (ESI) m / z [M-H]- 476.3. 15 Intermediate 60 N-(4-((1-(2-Chlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- 20 triazin-2-yl)methanesulfonamide Intermediate 2 (96 mg, 0.30 mmol) in DMF (1 mL) was added to a solution of 1-(1-bromoethyl)-2-chlorobenzene (65.9 mg, 0,3 mmol) in DMF (0.55 83 201389-PCT01-NP mL). DIPEA (105 µL, 0.60 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was diluted with DMSO (1 mL) and purified by preparative HPLC, PrepMethod V (gradient: 5–95%) to give the title compound (97 mg, 70%). MS (ESI) m / z [M+H]+416.13. 5 Intermediate 61 N-(4-((1-(2,4-Dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- 10 triazin-2-yl)methanesulfonamide Intermediate 2 (96 mg, 0.30 mmol) in DMF (1 mL) was added to a solution of 1-(1-bromoethyl)-2,4-dichlorobenzene (76 mg, 0.3 mmol) in DMF (0.44 mL). DIPEA (105 µl, 0.60 mmol) was added and the reaction mixture was stirred at rt over the weekend. The mixture was concentrated in vacuo, dissolved in 1mL DMSO and purified by preparative HPLC, PrepMethod X (gradient: 5–95%) to give the title compound 15 (100 mg, 67%). MS (ESI) m / z [M+H]+494.09. Intermediate 62 N-(4-((1-(5-Chloropyridin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 20 1-(5-Chloropyridin-2-yl)ethyl methanesulfonate WO2016188828 (70 mg, 0.30 mmol) and DIPEA (0.103 mL, 0.59 mmol) was added to a solution of (R)-N-(4-((1-hydroxy-4- 84 201389-PCT01-NP methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (95 mg, 0.30 mmol) in DMF (1.5 mL). The reaction mixture was heated in a microwave reactor at 70°C for 30 min. Water and EtOAc were added to the mixture and the two phases were separated. The aqueous layer was extracted with EtOAc and the combined organic 5 layers were washed twice with water, dried over MgSO4, filtered and concentrated. The residue was purified by normal phase column chromatography on silica (heptane:EtOAc, 1:2) to give the title compound (59 mg, 43%). MS (ESI) m / z [M+H]+451.1. Intermediate 63 4-(1-Bromoethyl)-2-methoxypyridine 10 CBr4 (812 mg, 2.45 mmol) was added to a solution of 1-(2-methoxypyridin-4- yl)ethan-1-ol (250 mg, 1.63 mmol) and PPh3(642 mg, 2.45 mmol) in DCM (8 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at 0oCfor 1 h. The mixture was concentrated and the residue was purified by preparative TLC (PE:EtOAc, 5:1) to give 15 the title compound (250 mg, 71%) as a yellow oil.1HNMR (300 MHz, DMSO-d6) δ 1.93 (d, 3H), 3.86 (s, 3H), 5.40-5.34 (m, 1H), 6.90 (d, 1H), 7.11-7.08 (m, 1H), 8.16 (d, 1H). Intermediate 64 4-(1-Bromoethyl)-2-methylpyridine 20 CBr4 (725 mg, 2.19 mmol) was added to a solution of 1-(2-methylpyridin-4- yl)ethanol (200 mg, 1.46 mmol) and PPh3(574 mg, 2.19 mmol) in DCM (8 mL) at 0°C under an atmosphere of N2(g). The reaction mixture was stirred at 0oC for 1 h. The mixture was concentrated and the residue was purified by preparative TLC (PE:EtOAc, 3:1) to give the title compound (250 mg, 86%) as a yellow oil.1HNMR (300 MHz, DMSO-d6) δ 1.94 (d, 3H), 25 2.47 (s, 3H), 5.41-5.34 (m, 1H), 7.29-7.27 (m, 1H), 7.35 (s, 1H), 8.43 (d, 1H). Intermediate 65 85 201389-PCT01-NP 1-(5-Methylpyrimidin-2-yl)ethan-1-ol NaBH4 (0.306 g, 8.08 mmol) was added to a solution of 1-(5-methylpyrimidin-2- yl)ethanone (1 g, 7.34 mmol) in THF (10 mL) at 0°C under an atmosphere of N2(g) The 5 reaction mixture was stirred at rt for 3 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (700 mg, 69%) as a yellow oil. MS (ESI) m / z [M+H]+139. Intermediate 66 10 2-(1-Bromoethyl)-5-methylpyrimidine PBr3 (2.048 mL, 21.71 mmol) was added dropwise to a solution of 1-(5- methylpyrimidin-2-yl)ethan-1-ol Intermediate 65 (600 mg, 4.34 mmol) in DCM (10 mL) at 0°C over a period of 5 min and under an atmosphere of N2(g). The reaction mixture was 15 stirred at rt for 3 h. The reaction was quenched with water (10 mL) and extracted with DCM (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (275 mg, 31%) as a brown oil. MS (ESI) m / z [M+H]+201. Intermediate 67 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(5-methylpyrimidin-2- 20 yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 86 201389-PCT01-NP DIPEA (0.478 mL, 2.74 mmol) was added to a solution of 2-(1-bromoethyl)-5- methylpyrimidine Intermediate 66 (275 mg, 1.37 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (440 mg, 1.37 mmol) in DMF (6 mL) at 0°C under an atmosphere of N2(g). The reaction 5 mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (3×10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (200 mg, 33%). MS (ESI) m / z [M+H]+442. Intermediate 68 2-(1-Bromoethyl)-1,3,4-trifluorobenzene10 HBr in AcOH (33%, w / w, 5 mL) was added to 1-(2,3,6-trifluorophenyl)ethan-1-ol (580 mg, 3.29 mmol) at 15°C . The reaction mixture was stirred at 50°C for 1 h. The mixture was diluted with EtOAc (75 mL) and washed sequentially with water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the title 15 compound (400 mg, 51%). Intermediate 69 5-(1-Bromoethyl)-2-chloro-3-fluoropyridine PBr3 (0.110 mL, 1.17 mmol) was added dropwise to a solution of 1-(6-chloro-5- 20 fluoropyridin-3-yl)ethanol (410 mg, 2.34 mmol) in DCM (0.5 mL) at 0°C and under an atmosphere of N2(g). The reaction mixture was stirred at 0°C for 1 h. The mixture was concentrated. The residue was purified by preparative TLC (PE:EtOAc, 5:1) to give the title compound (270 mg, 48%) as a pale yellow oil.1HNMR (300 MHz, CDCl3): δ 2.05 (3H, d), 5.17 (1H, q), 7.61 (1H, dd), 8.25 (1H, d). 25 Intermediate 70 87 201389-PCT01-NP N-(4-((1-(6-Chloro-5-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.326 mL, 1.87 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan- 5 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (300 mg, 0.93 mmol) and 5-(1-bromoethyl)-2-chloro-3-fluoropyridine Intermediate 69 (223 mg, 0.93 mmol) in DMF (0.5 mL) at 20°C. The reaction mixture was stirred at 30°C for 1 h. The mixture was concentrated. The crude product was purified by preparative HPLC, PrepMethod T (gradient: 40–52%) to give the title compound (80 mg, 18%) as a colourless gum. MS 10 (ESI) m / z [M+H]+479. Intermediate 71 N-(4-((1-(4-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide 15 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (0.139 g, 0.34 mmol) followed by DIPEA (0.150 mL, 0.86 mmol) were added to a solution of 1-(1-bromoethyl)-4-fluorobenzene (0.070 g, 0.34 mmol) in DMF (1 mL). The reaction mixture was stirred at ambient temperature overnight. Water (1.5 mL) and DCM (2.5 mL) were added. The two phases were separated, and the 20 organic layer was passed through a phase separator and concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient: 15–20%) to give the title compound (67 mg, 44%). MS (ESI) m / z [M+H]+444.16. 88 201389-PCT01-NP Intermediate 72 N-(4-((1-(4-(Difluoromethoxy)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 5 1-(1-Bromoethyl)-4-(difluoromethoxy)benzene (305 mg, 1.21 mmol) was added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (300 mg, 0.93 mmol) and DIPEA (0.326 mL, 1.87 mmol) in DMF (10 mL). The reaction mixture was stirred at rt for 2 h. The mixture was concentrated. The crude product was purified by preparative HPLC, PrepMethod D (gradient: 10 15–70%) to give the title compound (170 mg, 37.1 %) as a brown gum. MS (ESI) m / z [M+H]+492. Intermediate 73 1-(1-Bromoethyl)-2-(difluoromethyl)benzene 15 1-(2-(Difluoromethyl)phenyl)ethanol (455 mg, 2.64 mmol) was dissolved in HBr (aq, 48%, w / w, 3 mL, 62.29 mmol) and the reaction mixture was stirred at ambient temperature for 2.5 h. Water and MTBE were added and the phases were separated. The organic layer was washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica (DCM:heptane, 2:1) to give the title compound (419 mg, 20 67%) as a colorless oil.1HNMR (500 MHz, CDCl3) δ 7.76 (1H, dd), 7.52 (2H, ddt), 7.39 (1H, tt), 6.79–7.04 (1H, m), 5.56 (1H, q), 2.08 (3H, d). Intermediate 74 89 201389-PCT01-NP 1-(2-Bromopyridin-4-yl)ethyl methanesulfonate DIPEA (0.314 mL, 1.80 mmol) and MsCl (0.128 mL, 1.65 mmol) were added to a 5 solution of 1-(2-bromopyridin-4-yl)ethanol (0.303 g, 1.5 mmol) in DCM (3 mL). The reaction mixture was stirred at rt for 3 h. Water (3 mL) was added. The two phases were separated, and the aqueous layer was extracted with DCM (1 mL). The combined organic layer was washed with water (3 mL), concentrated, and the crude title compound which was used in the next step without further purification.1HNMR (400 MHz, CDCl3) δ 8.43 (1H, d), 10 7.50 (1H, s), 7.25 (1H, d), 5.65 (1H, q), 2.99 (3H, s), 1.70 (2H, d). Intermediate 75 1-(4-(Chloromethyl)phenyl)cyclopropane-1-carboxamide SOCl2(23.5 g, 197 mmol) was added to a solution of 1-(4- 15 (hydroxymethyl)phenyl)cyclopropane-1-carboxamide (19 g, 99.4 mmol) in DCM (300 mL) and the mixture was stirred at rt for 6 h. The solvent was removed under reduced pressure, and the residue was washed with a mixture of PE and EtOAc (1:1, 100 mL). The solid was collected and dried in vacuo to give the title compound (17 g, 80% yield) as a solid. MS (ESI) m / z [M+H]+210.2.1HNMR (400 MHz, CDCl3) δ 7.45-7.38 (4H, m,), 5.66 (1H, s), 5.31 (1H, 20 s), 4.58 (2H, s), 1.63-1.64 (2H, m), 1.10-1.07 (2H, m). Intermediate 76 (R)-N-(1-(3-(Hydroxymethyl)phenyl)ethyl)acetamide 90 201389-PCT01-NP LiAlH4 (9 g, 237 mmol) was added portionwise at 0oC to a solution of methyl (R)-3- (1-acetamidoethyl)benzoate (35 g, 158 mmol) in THF (400 mL). The reaction mixture was stirred at 0oC for 2 h. The reaction was quenched by the sequential addition of H2O (9 mL), NaOH (aq, 15%, 9 mL) and H2O (18 mL). The mixture was filtered, and the filtrate was 5 concentrated under reduced pressure. The residue was re-crystallized from DCM to give the title compound (27 g, 89%) as white solid. MS (ESI) m / z [M+H]+194.0. Intermediate 77 (R)-N-(1-(3-(Chloromethyl)phenyl)ethyl)acetamide 10 SOCl2 (42.4 g, 350 mmol) was added dropwise at rt to a suspension of (R)-N-(1-(3- (hydroxymethyl)phenyl)ethyl)acetamide Intermediate 76 (23 g, 119 mmol) in DCM (400 mL). The reaction mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the crude product was dissolved in EtOAc (500 mL). The organic layer was washed with brine (3×300 mL), dried over MgSO4, filtered, and concentrated to give the title compound 15 (24 g, 95%). MS (ESI) m / z [M+H]+211.9.1HNMR (300 MHz, DMSO-d6) δ 8.30-8.27 (1H, d), 7.30-7.21 (4H, m), 4.90-4.80 (1H, m), 4.70 (2H, s), 1.79 (3H, s), 1.29-1.21 (3H, d). Intermediate 78 (S)-N-(1-(3-(Chloromethyl)phenyl)ethyl)acetamide 20 The title compound was prepared in two steps from methyl (S)-3-(1- acetamidoethyl)benzoate as described for Intermediate 77 to give the title compound (24 g, 95%) as brown solid. MS (ESI) m / z [M+H]+211.9.1HNMR (400 MHz, CDCl3) δ 11.17(1H, s), 7.39-7.26 (5H, m), 5.12-5.05 (1H, m), 4.56 (2H, s), 2.49 (3H, s), 1.63-1.51 (3H, m). Intermediate 79 25 Methyl 2,3-dihydrobenzo[d]isothiazole-5-carboxylate 1,1-dioxide 91 201389-PCT01-NP A solution of 5-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (33 g, 133 mmol), PdCl2(dppf)2 (4.0 g, 5.5 mmol) and TEA in DMF(150 mL) and MeOH (250 mL) was stirred under an atmosphere of CO(g) (3.8 bar) at 80oC for 15 h. The mixture was concentrated to 5 dryness. Water (100 mL) and MeOH (100 mL) were added to the residue, and the resulting precipitate was filtered to give the title compound (27.9 g, 93%). MS (ESI) m / z [M+H]+227.8.1HNMR (400 MHz, DMSO-d6) δ 8.13 (1H, s), 8.09-8.04 (2H, m), 7.96-7.94 (1H, d), 4.47 (2H, s), 3.89 (3H, m). Intermediate 80 10 2,3-Dihydrobenzo[d]isothiazole-5-carboxylic acid 1,1-dioxide LiOH H2O (15.5 g, 369.66 mmol) was added under an atmosphere of N2(g) at 0oC to a well stirred suspension of methyl 2,3-dihydrobenzo[d]isothiazole-5-carboxylate 1,1-dioxide Intermediate 79 (65 g, 328 mmol) in THF (400 mL) and H2O (400 mL). After the addition, 15 the reaction mixture was warmed to 15oC and stirred for 18 h. The mixture was washed with EtOAc (200 mL), and the aqueous phase was acidified to pH=3 with 3 M HCl (aq). The precipitate was collected by filtration to give the title compound (28.00 g, 99%) as white solid. MS (ESI) m / z [M+H]+213.8.1HNMR (400 MHz, DMSO-d6) δ 13.5 (1H, br), 8.10-8.01 (3H, m), 7.93-7.91 (1H, d), 4.46-4.45 (2H, d). 20 Intermediate 81 5-(Hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide BH3.S(CH3)2 (94 mL, 1.0 mol) was added dropwise at 0℃ and under an atmosphere of N2(g) to a solution of 2,3-dihydrobenzo[d]isothiazole-5-carboxylic acid 1,1-dioxide 92 201389-PCT01-NP Intermediate 80 (40 g, 187 mmol) in THF (500 mL). The reaction mixture was stirred at 25oC for 10 h. The mixture was cooled to 0℃ and MeOH (100 mL) was added. The mixture was concentrated at reduced pressure to give the title compound (32 g, 86%). MS (ESI) m / z [M+H]+199.9. 5 Intermediate 82 5-(Chloromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide SOCl2 (10.75 g, 90.4 mmol) was added dropwise over 10 min at 0℃ to a suspension of 5- (hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide Intermediate 81 (15 g, 75.3 10 mmol) in DCM (200 mL). The reaction mixture was stirred at 25℃ for 10 h The mixture was washed with sat NaHCO3 (aq, 2×200 mL) and brine (2×200 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the title compound (13 g, 79%). MS (ESI) m / z [M+H]+218.1HNMR (400 MHz CDCl3) δ 8.30-8.27(1H, d), 7.30-7.21 (4H, m), 4.90-4.80 (1H, m), 4.70 (2H, s), 1.79 (3H, s), 1.29-1.21 (3H, d). 15 Intermediate 83 6-(Chloromethyl)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one The title compound was prepared from 6-bromo-2-methyl-1,4-dihydroisoquinolin- 3(2H)-one in analogy with the description for Intermediate 87. 20 Intermediate 84 Methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate 7-Bromo-2-methyl-1,4-dihydroisoquinolin-3(2H)-one (145 g, 0.60mol) and DIPEA (170 mL, 5.3 mmol) was stirred in MeOH (350 mL). Pd(dppf)2Cl2(30 g) was added to the 93 201389-PCT01-NP solution and the reaction mixture was stirred under an atmosphere of CO(g) (50 bar) at 110℃ for 17 h. The mixture was cooled to 20℃ and concentrated. The crude product was purified by column chromatography (gradient: 20–33% of EtOAc in PE) to give the title compound (99.5 g, 75%) as yellow solid. MS (ESI) m / z [M+H]+220.0. 5 Intermediate 85 2-Methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid A solution of LiOH (62.94 g, 1.5 mol) in H2O (120mL) was added to a solution of methyl 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Intermediate 84 (110 10 g, 0.5 mol) in THF (400 mL) and MeOH (200 mL). The reaction mixture was stirred at 25oC for 12 h. The mixture was acidified to pH 4-5 and filtered to give the title compound (90 g, 85%) as a yellow solid. MS (ESI) m / z [M+H]+205.9. Intermediate 86 7-(Hydroxymethyl)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one 15 Isobutyl chloroformate (2.4 g, 17.3 mmol) and 4-methylmorpholine (1.8 g, 17.3 mmol) was added to a solution of 2-methyl-3-oxo-1,2,3,4-tetrahydroisoquinoline-7- carboxylic acid Intermediate 85 (3 g, 14.4 mmol) in THF (60 mL) at 0oC and the reaction mixture was stirred at 0oC for 1 h. LiBH4 (1.3 g, 57.6 mmol) was added and the reaction 20 mixture was stired at 25oC for 3 h. The mixture was concentrated and the residue was diluted with H2O (20 mL) and the aqueous layer was extracted with DCM (2×90mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica (PE:EtOAc, 2:1) to give the title compound (1.79 g, 65%) as yellow solid. MS (ESI) m / z [M+H]+192.0. 25 Intermediate 87 7-(Chloromethyl)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one 94 201389-PCT01-NP SOCl2 (6.20 g, 26.05 mmol) was added dropwise at 0℃ to a solution of 7- (hydroxymethyl)-2-methyl-1,4-dihydroisoquinolin-3(2H)-one Intermediate 86 (8.25 g, 43 mmol) in DCM (500 mL). The reaction mixture was stirred at 0oC for 30 min. K2CO3(7.19 g, 5 52.1 mmol) was added and the reaction mixture was stirred at 25oC for 3 h. The mixture was filtered. The filtrate was collected, washed with water (200 mL) and concentrated in vacuo. The crude product was re-crystallized from PE:EtOAc (10:1) to give the title compound (4.7 g, 86%) as a light yellow solid. MS (ESI) m / z [M+H]+210.1.1HNMR (400 MHz, CDCl3): 7.22-7.19 (1H, m); 7.14 (1H, s,); 7.10-7.08(1H, d); 4.51 (2H, s); 4.43 (2H, s), 3.55 (2H, s), 10 3.04 (3H, s). Intermediate 88 5-(Bromomethyl)-N-methylpyrazine-2-carboxamide 15 A mixture of N,5-dimethylpyrazine-2-carboxamide (120 g, 795 mmol), NBS (244 g, 1907 mmol) and AIBN (26.1 g, 159 mmol) in CCl4 (5 L) was stirred at 800C overnight. The mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography on silica (9–20% EtOAc in PE). The compound containing fractions were collected and concentrated and the solid was washed with EtOAc to give the title 20 compound (145 g, 82%) as yellow solid.1HNMR (400 MHz, CDCl3) δ 9.33(1H, s), 8.63(1H, s), 7.75 (1H, s), 4.60 (2H, s), 3.06-3.03 (3H, m). Intermediate 89 Methyl 2,3-dihydrobenzo[d]isothiazole-6-carboxylate 1,1-dioxide 95 201389-PCT01-NP Pd(dppf)Cl2 (15 g, 0.021 mol) and TEA (143.2 mL, 1.03 mol) were added to a solution of 6-bromo-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (90 g, 362.73 mmol) in DMF:MeOH (1:1, 900 mL). The mixture was evacuated and backfilled with CO(g) 3 times, and then stirred under an atmosphere of CO(g) (3.4 bar) at 80oC for 24 h. The mixture was 5 filtered and the filtrate was concentrated under reduce pressure. The crude product was purified by column chromatography on silica (PE:EtOAc, 3:1) to give the title compound (72 g, 87%) as brown solid.1H NMR (400 MHz, DMSO-d6) δ 8.20-8.22 (2H, m), 8.02 (1H, s), 7.70-7.75 (1H, m), 4.48-4.52 (2H, m), 3.89 (3H, s) Intermediate 90 10 6-(Hydroxymethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide A solution of methyl 2,3-dihydrobenzo[d]isothiazole-6-carboxylate 1,1-dioxide Intermediate 89 (60 g, 264 mmol) in THF (500 mL) was added dropwise to a mixture of LiAlH4(20 g, 528 mmol) in THF (1000 mL) at -10oC. After complete addition, the mixture 15 was stirred at rt for 3 h. The reaction was quenched with water and the mixture was filtered. The filtrate was concentrated under reduce pressure. The crude product was purified by chromatography on silica (DCM:MeOH, 20:1) to give the title compound (41.2 g, 78%) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.81 (1H, s), 7.69 (1H, s), 7.60 (1H, d), 7.50 (1H, d), 5.47 (1H, t), 4.59 (2H, m), 4.38 (2H, s). 20 Intermediate 91 6-(Chloromethyl)-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide SOCl2(43.23 g, 4 eq) was added dropwise at 0oC to a solution of 6-(hydroxymethyl)- 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide Intermediate 90 (18.1 g, 90.85 mmol) in CHCl325 (500 mL). The reaction mixture was stirred and warmed up to 50℃ for 3 h. The mixture was concentrated under reduce pressure to give the title compound (19.2 g, 97%) as brown solid. 96 201389-PCT01-NP MS (ESI) m / z [M+H]+217.9.1H NMR (400 MHz, DMSO-d6) δ 7.90 (2H, s), 7.74(1H, dd), 7.58(1H, d), 4.89 (2H, s), 4.41 (2H, d) Intermediate 92 6-(Bromomethyl)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide 5 A solution of PBr3 (52.0 g, 190.0 mmol) in THF (100 mL) was added dropwise at 0oC to a solution of 6-(hydroxymethyl)-1,3-dihydrobenzo[c]isothiazole 2,2-dioxide (35.0 g, 175.0 mmol) in THF (400 mL). The reaction mixture was stirred at rt for 4 h. Ice water (500 mL) was added at 0oC. The mixture was extracted with EtOAc (3×500 mL). The combined 10 organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica (PE:EtOAc, 2:1) to afford the crude product as a colorless oil, which was washed with MTBE (50 mL) to give the title compound (18.5 g, 40%) as a white solid. MS (ESI) m / z [M+H]+261.9.1HNMR (400 MHz, DMSO-d6) δ 10.61 (1H, s), 7.25-7.27 (1H, m), 7.04-7.06 (1H, m), 6.90 (1H, s), 4.69 (2H, s), 4.54 15 (2H, s). Synthesis of Example CX3CR1 Modulators: Example 1 (R)-N-(4-((2-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,2-difluoroethyl)thio)-6-((1- 20 hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- triazin-2-yl)methanesulfonamide, Intermediate 2 (200 mg, 0.62 mmol), 6-(2-bromo-1,1- difluoroethyl)-2,3-dihydrobenzo[b][1,4]dioxine, Intermediate 3 (347 mg, 1.24 mmol) and 25 DIPEA (0.435 mL, 2.49 mmol) in DMF (8 mL) was stirred at 100°C on. The solvent was 97 201389-PCT01-NP removed under reduced pressure and the residue was first purified by preparative TLC (DCM:MeOH, 10:1) then by preparative HPLC, PrepMethod C, (gradient: 35–70%) to give the title compound (60 mg, 18%); HRMS (ESI) m / z [M+H]+calcd for C20H28F2N5O5S2: 520.1494, found: 520.1484;1H NMR (400 MHz, DMSO-d6) δ 0.84–0.91 (m, 6H), 1.29–1.43 5 (m, 2H), 1.54–1.61 (m, 1H), 3.27–3.40 (m, partly overlapping with solvent), 3.97–4.16 (m, 3H), 4.24–4.35 (s, 4H), 4.40–4.80 (m, 1H), 6.92–6.98 (d, 1H), 7.00–7.13 (m, 2H), 7.79–8.19 (m, 1H), 11.21–11.45 (m, 1H). Example 2 10 (R)-N-(4-((2-(Benzo[d]thiazol-2-yl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- triazin-2-yl)methanesulfonamide, Intermediate 2 (300 mg, 0.93 mmol), 2-(2-bromo-1,1- 15 difluoroethyl)benzo[d]thiazole Intermediate 4 (260 mg, 0.93 mmol) and DIPEA (0.652 mL, 3.73 mmol) in DMF (8 mL) was stirred at 100°C on. The solvent was removed under reduced pressure and the residue was first purified by preparative TLC (DCM:MeOH, 10:1) then by preparative HPLC, PrepMethod C, (gradient: 32–65%) to give the title compound (30 mg, 6%); HRMS (ESI) m / z [M+H]+calcd for C19H25F2N6O3S3: 519.1112, found: 519.1132;1H 20 NMR (300 MHz, DMSO-d6) δ 0.83-0.85 (m, 6H), 1.24-1.56 (m, 3H), 3.27-3.40 (m, partly overlapping with solvent), 3.92-4.15 (m, 1H), 4.37-4.59 (m, 2H), 4.69 (s, 1H), 7.60-7.70 (m, 2H), 7.86 (t, 1H), 8.16 (t, 1H), 8.27 (d, 1H), 11.29 (d, 1H). Example 3 25 (R)-N-(4-((2-(3-Bromophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 98 201389-PCT01-NP 2-Bromo-1-(3-bromophenyl)ethan-1-one (83 mg, 0.30 mmol) was dissolved in DCM 5 (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added and the reaction mixture was stirred at 40°C for 24 h. DCM (2 mL) and sat NaHCO3 (2 mL) were added and the reaction mixture was stirred vigorously. The organic layer was passed through a phase separator and concentrated to give a crude product which was used in the next step without further 10 purification;1H NMR (400 MHz, DMSO-d6) δ 4.27 (t, 2H), 7.4–7.53 (m, 1H), 7.62 (ddd, 1H), 7.72–7.84 (m, 2H). Step b) (R)-N-(4-((2-(3-Bromophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4-methylpentan- 15 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of 1-bromo-3-(2-bromo-1,1-difluoroethyl)benzene Example 3 Step a) (63 mg, 0.21 mmol) in DMF (0.8 mL) followed by DIPEA (0.091 mL, 0.52 mmol), were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol). The reaction mixture was 20 heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The two layers were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod E, (gradient: 20–25%) to give the title compound (23 mg, 20%). HRMS (ESI) m / z [M+H]+calcd for C18H25BrF2N5O3S2: 540.0544, found: 540.0552;1H NMR (600 25 MHz, DMSO-d6) δ 0.75-0.96 (m, 6H), 1.25-1.46 (m, 2H), 1.5-1.63 (m, 1H), 3.15-3.61 (m, 99 201389-PCT01-NP partly overlapping with solvent), 3.94-4.26 (m, 3H), 4.63-4.8 (m, 1H), 7.47 (q, 1H), 7.63 (dd, 1H), 7.68-7.91 (m, 3H), 11.25 (d, 1H). Example 4 5 (R)-N-(4-((2-(4-Cyanophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 4-(2-Bromoacetyl)benzonitrile (67 mg, 0.30 mmol) was dissolved in DCM (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added, and the reaction mixture was stirred at 40°C for 24 h. DCM (2 mL) and sat NaHCO3 (2 mL) were added and the reaction mixture was stirred vigorously. The organic phase was passed through a phase separator and concentrated 15 to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.29 (t, 2H), 7.75–7.86 (m, 2H), 8.02 (d, 2H). Step b) (R)-N-(4-((2-(4-Cyanophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 20 4-(2-Bromo-1,1-difluoroethyl)benzonitrile Example 4 Step a) (51 mg, 0.21 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol). DIPEA (0.091 mL, 0.52 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The 25 two layers were separated and the organic layer passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod 100 201389-PCT01-NP E, (gradient: 20–25%) to give the title compound (30 mg, 30%). HRMS (ESI) m / z [M+H]+calcd for C19H25F2N6O3S2: 487.1392, found: 487.1400;1H NMR (600 MHz, DMSO-d6) δ 0.77–0.94 (m, 6H), 1.26–1.45 (m, 2H), 1.49–1.63 (m, 1H), 3.11–3.66 (m, partly overlapping with solvent), 3.93–4.08 (m, 1H), 4.07–4.23 (m, 2H), 4.65–4.81 (m, 1H), 7.81 (t, 3H), 7.97 5 (dd, 2H), 11.25 (s, 1H). Example 5 (R)-N-(4-((2,2-Difluoro-2-(3-nitrophenyl)ethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 2-Bromo-1-(3-nitrophenyl)ethan-1-one (73 mg, 0.30 mmol) was dissolved in DCM (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 15 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added, and the reaction mixture was stirred at 40°C for 24 h. DCM (2 mL) and sat NaHCO3 (2 mL) were added and the reaction mixture was stirred vigorously. The organic layer was passed through a phase separator and concentrated to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.36 (t, 2H), 7.85 (dd, 1H), 8.02–8.12 (m, 20 1H), 8.34–8.47 (m, 2H). Step b) (R)-N-(4-((2,2-Difluoro-2-(3-nitrophenyl)ethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 1-(2-Bromo-1,1-difluoroethyl)-3-nitrobenzene Example 5 Step a) (56 mg, 0.2125 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 101 201389-PCT01-NP mmol). DIPEA (0.091 mL, 0.52 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The two layer were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod 5 E, (gradient: 20–25%) to give the title compound (29 mg, 28%). HRMS (ESI) m / z [M+H]+calcd for C18H25F2N6O5S2: 507.1290, found: 507.1302;1H NMR (600 MHz, DMSO-d6) δ 0.74–0.96 (m, 6H), 1.26–1.43 (m, 2H), 1.49–1.61 (m, 1H), 3.15–3.62 (m, partly overlapping with solvent), 3.92–4.08 (m, 1H), 4.14–4.29 (m, 2H), 4.63–4.77 (m, 1H), 7.72–7.88 (m, 2H), 8.04–8.15 (m, 1H), 8.32–8.43 (m, 2H), 11.24 (s, 1H). 10 Example 6 (R)-N-(4-((2,2-Difluoro-2-(4-fluorophenyl)ethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 15 1-(2-Bromo-1,1-difluoroethyl)-4-fluorobenzene (34 mg, 0.14 mmol) dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto- 1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (50 mg, 0.13 mmol). DIPEA (0.057 mL, 0.33 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 2 h. Water (2 mL) and DCM (2 mL) were added. The layers were separated, and 20 the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod G, (gradient: 15–20%) to give the title compound (20 mg, 32%). HRMS (ESI) m / z [M+H]+calcd for C18H25F3N5O3S2: 480.1346, found: 480.1356;1H NMR (600 MHz, DMSO-d6) δ 0.78–0.92 (m, 6H), 1.26–1.44 (m, 2H), 1.49–1.64 (m, 1H), 3.19–3.48 (m, partly overlapping with solvent), 3.94–4.18 (m, 25 3H), 4.73 (dt, 1H), 7.26–7.36 (m, 2H), 7.62–7.7 (m, 2H), 7.80 (t, 1H), 11.24 (s, 1H). Example 7 (R)-N-(4-((2,2-Difluoro-2-phenylethyl)thio)-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 102 201389-PCT01-NP (2-Bromo-1,1-difluoroethyl)benzene (32 mg, 0.14 mmol) dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide, Intermediate 2 (50 mg, 0.13 mmol). DIPEA (0.057 mL, 0.33 mmol) 5 was added and the reaction mixture was stirred at rt for 20 h and then heated in a microwave reactor at 140°C for 1 h. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod G, (gradient: 20–25%) to give the title compound (18 mg, 29%). HRMS (ESI) m / z [M+H]+calcd for 10 C18H26F2N5O3S2: 462.1440, found: 462.1428;1H NMR (600 MHz, DMSO-d6) δ 0.8–0.92 (m, 6H), 1.27–1.44 (m, 2H), 1.52–1.63 (m, 1H), 3.23–3.52 (m, partly overlapping with solvent), 3.94–4.21 (m, 3H), 4.65–4.78 (m, 1H), 7.45–7.55 (m, 3H), 7.57–7.64 (m, 2H), 7.78 (s, 1H), 11.24 (s, 1H). 15 Example 8 (R)-N-(4-((2,2-Difluoro-2-(pyridin-3-yl)ethyl)thio)-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 3-(2-Bromo-1,1-difluoroethyl)pyridine, Intermediate 5 (18 mg, 0.08 mmol) 20 dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (31 mg, 0.08 mmol). DIPEA (0.036 mL, 0.2 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The solvent was 25 evaporated, and the crude residue was purified by preparative SFC, PrepMethod G, (gradient: 103 201389-PCT01-NP 15–20%) to give the title compound (1 mg, 3%). HRMS (ESI) m / z [M+H]+calcd for C17H25F2N6O3S2: 463.1392, found: 463.1380. Example 9 5 (R)-N-(4-((2,2-Difluoro-2-(3-fluoropyridin-2-yl)ethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of 2-(2-bromo-1,1-difluoroethyl)-3-fluoropyridine, Intermediate 6 (26 mg, 0.11 mmol) in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- 10 yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (41 mg, 0.11 mmol). DIPEA (0.047 mL, 0.27 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod 15 G, (gradient: 20–25%) to give the title compound (2 mg, 3%). HRMS (ESI) m / z [M+H]+calcd for C17H24F3N6O3S2: 481.1298, found: 481.1280. Example 10 (R)-N-(4-((2,2-Difluoro-2-(2-fluoropyridin-3-yl)ethyl)thio)-6-((1-hydroxy-4- 20 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 3-(2-Bromo-1,1-difluoroethyl)-2-fluoropyridine, Intermediate 7 (17 mg, 0.07 mmol) dissolved in DMF (0.6 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 104 201389-PCT01-NP 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (27 mg, 0.07 mmol). DIPEA (0.030 mL, 0.17 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The 5 solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod G, (gradient: 15–20%) to give the title compound (2 mg, 6%). HRMS (ESI) m / z [M+H]+calcd for C17H24F3N6O3S2: 481.1298, found: 481.1284;1H NMR (600 MHz, DMSO-d6) δ 0.78–0.92 (m, 6H), 1.26–1.45 (m, 2H), 1.5–1.65 (m, 1H), 3.15–3.48 (m, partly overlapping with solvent), 3.93–4.11 (m, 1H), 4.1–4.3 (m, 2H), 4.65–4.73 (m, 1H), 7.45–7.55 (m, 1H), 10 8.13–8.22 (m, 1H), 8.40 (dd, 1H), 11.23 (s, 1H). Example 11 (R)-N-(4-((2,2-Difluoro-2-(2-fluorophenyl)ethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide15 1-(2-Bromo-1,1-difluoroethyl)-2-fluorobenzene, Intermediate 8 (50 mg, 0.21 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol). DIPEA (0.091 mL, 0.52 mmol) was added and the reaction mixture was heated in a 20 microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (10 mg, 10%). HRMS (ESI) m / z [M+H]+calcd for C18H25F3N5O3S2: 480.1346, found: 480.1342;1H NMR (600 MHz, 25 DMSO-d6) δ 0.77–0.93 (m, 6H), 1.25–1.45 (m, 2H), 1.51–1.63 (m, 1H), 3.17–3.48 (m, partly overlapping with solvent), 3.96–4.1 (m, 1H), 4.1–4.25 (m, 2H), 4.65–4.74 (m, 1H), 7.28–7.41 (m, 2H), 7.55–7.65 (m, 2H), 7.77 (d, 1H), 11.23 (s, 1H). 105 201389-PCT01-NP Example 12 (R)-N-(4-((2-(3-Cyanophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 5 3-(2-Bromoacetyl)benzonitrile (67 mg, 0.30 mmol) was dissolved in DCM (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added, and the reaction mixture was stirred at 40°C 10 for 24 h. DCM (2 mL) and sat NaHCO3(2 mL) were added and the reaction mixture was stirred vigorously. The organic layer was passed through a phase separator and concentrated to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.29 (t, 2H), 7.75 (t, 1H), 7.94 (d, 1H), 8.03 (d, 1H), 8.10 (s, 1H). 15 Step b) (R)-N-(4-((2-(3-Cyanophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 3-(2-Bromo-1,1-difluoroethyl)benzonitrile Example 12 Step a) (51 mg, 0.21 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol) 20 followed by DIPEA (0.091 mL, 0.52 mmol). The reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 ml) and DCM (2 ml) were added. The two phases were separated and the organic phase passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod E, (gradient: 20–25%) to give the title compound (26 mg, 25%). HRMS (ESI) m / z [M+H]+calcd for 25 C19H25F2N6O3S2: 487.1392, found: 487.1402;1H NMR (600 MHz, DMSO-d6) δ 0.75–0.94 (m, 6H), 1.25–1.45 (m, 2H), 1.48–1.64 (m, 1H), 3.15–3.62 (m, partly overlapping with 106 201389-PCT01-NP solvent), 3.93–4.08 (m, 1H), 4.09–4.25 (m, 2H), 4.64–4.79 (m, 1H), 7.67–7.75 (m, 1H), 7.76–7.89 (m, 1H), 7.91–8.06 (m, 2H), 8.08 (d, 1H), 11.27 (s, 1H). Example 13 5 (R)-N-(4-((2-(3-Chlorophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 2-Bromo-1-(3-chlorophenyl)ethan-1-one (70 mg, 0.30 mmol) was dissolved in DCM (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added, and the reaction mixture was stirred at 40°C for 24 h. DCM (2 mL) and sat NaHCO3(2 mL) were added and the reaction mixture was stirred vigorously. The organic layer was passed through a phase separator and 15 concentrated to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.27 (t, 2H), 7.53–7.65 (m, 3H), 7.67 (t, 1H). Step b) (R)-N-(4-((2-(3-Chlorophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 20 1-(2-Bromo-1,1-difluoroethyl)-3-chlorobenzene Example 13 Step a) (53 mg, 0.21 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol). DIPEA (0.091 mL, 0.52 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The 25 layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod 107 201389-PCT01-NP E, (gradient: 20–25%) to give the title compound (22 mg, 21%). HRMS (ESI) m / z [M+H]+calcd for C18H25ClF2N5O3S2: 496.1050, found: 496.1076;1H NMR (600 MHz, DMSO-d6) δ 0.77–0.92 (m, 6H), 1.25–1.45 (m, 2H), 1.51–1.63 (m, 1H), 3.18–3.51 (m, partly overlapping with solvent), 3.95–4.23 (m, 3H), 4.63–4.78 (m, 1H), 7.5–7.63 (m, 3H), 7.66 (d, 1H), 7.75– 5 7.9 (m, 1H), 11.27 (s, 1H). Example 14 (R)-N-(4-((2,2-Difluoro-2-(pyridin-4-yl)ethyl)thio)-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 2-Bromo-1-(pyridin-4-yl)ethan-1-one hydrobromide (84 mg, 0.30 mmol) was dissolved in DCM (0.5 mL) and DAST (0.079 mL, 0.60 mmol) was added. The reaction mixture was stirred at 40°C for 18 h. DAST (0.079 mL, 0.60 mmol) was added and the 15 reaction mixture was stirred at 40°C for 24 h. DCM (2 mL) and sat NaHCO3 (2 mL) were added and the reaction mixture was stirred vigorously. The organic layer was passed through a phase separator and concentrated to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.29 (t, 2H), 7.61 (d, 2H), 8.74–8.81 (m, 2H). 20 Step b) (R)-N-(4-((2,2-Difluoro-2-(pyridin-4-yl)ethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 4-(2-Bromo-1,1-difluoroethyl)pyridine Example 14 Step a) (46 mg, 0.21 mmol) dissolved in DMF (0.8 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)- 25 6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol). DIPEA (0.091 mL, 0.52 mmol) was added and the reaction mixture was heated in a 108 201389-PCT01-NP microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod E, (gradient: 15–20%) to give the title compound (3 mg, 3%). HRMS (ESI) m / z [M+H]+5 calcd for C17H25F2N6O3S2: 463.1392, found: 463.1382. Example 15 (R)-N-(4-((2-(2,3-Difluorophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 2-Bromo-1-(2,3-difluorophenyl)ethan-1-one (94 mg, 0.40 mmol) was dissolved in DCM (0.7 mL) and DAST (0.106 mL, 0.80 mmol) was added. The reaction mixture was 15 stirred at 40°C for 22 h. DCM and sat NaHCO3were added, and the layers were separated. The organic layer was passed through a phase separator and concentrated to give a crude product which was used in the next step without further purification.1H NMR (400 MHz, DMSO-d6) δ 4.27 (td, 2H), 7.32–7.51 (m, 2H), 7.6–7.82 (m, 1H). 20 Step b) (R)-N-(4-((2-(2,3-difluorophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 1-(2-Bromo-1,1-difluoroethyl)-2,3-difluorobenzene Example 15 Step a) (103 mg, 0.4 mmol) dissolved in DMF (1 mL) was added to (R)-N-(4-((1-hydroxy-4-methylpentan-2- yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (122 mg, 0.32 25 mmol). DIPEA (0.174 mL, 1.00 mmol) was added and the reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The 109 201389-PCT01-NP layers were separated and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative SFC, PrepMethod F, (gradient: 20–25%) to give the title compound (30 mg, 15%). HRMS (ESI) m / z [M+H]+calcd for C18H24F4N5O3S2: 498.1252, found: 498.1246.1H NMR (600 MHz, DMSO-d6) δ 5 0.78–0.92 (m, 6H), 1.26–1.44 (m, 2H), 1.51–1.62 (m, 1H), 3.19–3.48 (m, partly overlapping with solvent), 3.94–4.1 (m, 1H), 4.1–4.29 (m, 2H), 4.63–4.76 (m, 1H), 7.3–7.38 (m, 1H), 7.39–7.45 (m, 1H), 7.58–7.68 (m, 1H), 7.69–7.86 (m, 1H), 11.24 (s, 1H). Example 16 10 N-(4-(((R*)-1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 15 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(Benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 11 (30 mg, 0.06 mmol) were separated by preparative chiral SFC on a CHIRALPAK AD 20 SFC column (50×220 mm,5µm), eluted with 25% IPA / DEA (100 / 0.5) in CO2 at 120 bar with a flow rate of 80 mL / min and detection at 290 nm to give the second eluting compound (Isomer 2). The product containing fractions were collected, evaporated and dissolved in DCM and washed with 1M citric acid followed by water. The organic layer was passed through phase separator and concentrated to give (10 mg, 31%) of N-(4-(((R*)-1-25 (benzo[c][1,2,5]oxadiazol-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 Example 16. HRMS (ESI) m / z [M+H]+calcd for C18H26N7O4S2: 468.1482, found: 468.1484.1H NMR (400 MHz, CD3OD, mixture of two rotamers about 1 / 1) δ 0.88 – 0.99 (6H, m), 1.26 – 1.55 (2H, m), 1.55 – 1.74 (1H, m, 110 201389-PCT01-NP 1H), 1.85 and 1.90 (3H, d, rotamers), 3.30-3.34 (3H, m, overlapping with the solvent), 3.19 – 3.41 and 3.48 – 3.61 (2H, m, rotamers), 4.04 – 4.25 (1H, rotamers), 5.51 – 5.62 (1H, m), 7.4 – 7.51 (1H, m), 7.64 (1H, dd), 7.78 (1H, d). 5 Example 17 N-(4-((1-(1H-Indazol-6-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide TFA (0.05 ml, 0.67 mmol) was added to a solution of tert-butyl 6-(1-((4-(((R)-1-10 hydroxy-4-methylpentan-2-yl)amino)-6-(methylsulfonamido)-1,3,5-triazin-2-yl)thio)ethyl)- 1H-indazole-1-carboxylate Intermediate 14 (28. mg, 0.05 mmol) in DCM (0.45 mL) and the reaction mixture was stirred at rt for 1.5 h. Additional TFA (0.1 ml, 1.35 mmol) was added and the stirring was continued for 72 h. DCM and sat NaHCO3 (aq) were added and the mixture was stirred for 1.5 h. The organic layer was passed through a phase separator and 15 concentrated. DCM and sat NaHCO3 (aq) were added together with a few drops of MeOH. The mixture was stirred at 40°C for 2 h. DCM and water were added, and the layers were separated. The aqueous layer was freeze-dried and the crude product was purified by preparative HPLC, PrepMethod I, gradient (5-55%) to give (1.7 mg, 7%) of the title compound. HRMS (ESI) m / z [M+H]+calcd for C19H28N7O3S2: 466.1690, found: 466.1696. 201H NMR (400 MHz, CD3OD) δ 0.69 – 1.05 (6H, m), 1.28 – 1.87 (6H, m), 3.22 – 3.37 (3H, m), 3.5 – 3.64 (2H, m), 4.07 – 4.35 (1H, m), 5.13 – 5.32 (1H, m), 7.22 – 7.29 (1H, m), 7.62 (1H, s), 7.69 – 7.76 (1H, m), 7.99 (1H, s). Example 18 25 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2,3,4- trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-(2,3,4- trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 111 201389-PCT01-NP N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((S)-1-(2,3,4- trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.679 mL, 3.89 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan- 5 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (250 mg, 0.78 mmol), and 1-(1-bromoethyl)-2,3,4-trifluorobenzene (186 mg, 0.78 mmol) in DMF (5 mL) at 15°C under an atmosphere of N2(g). The reaction mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The crude product was purified and isolated by chiral preparative HPLC on a Chiralpak IA column (20×250 mm, 5µm), using 15% IPA in 10 hexane as eluent, with a flow rate of 20 mL / min and detection at 254 / 220 nm to give the second eluting compound N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1- (2,3,4-trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2, Example 18, (80 mg, 21%) as a white solid. HRMS (ESI) m / z [M+H]+ calcd for C18H25F3N5O3S2: 480.1346, found: 480.1338.1H NMR (400MHz, DMSO, mixture of rotamers about 1 / 1) δ 15 0.76-0.90 (6H, m), 1.26-1.65 (3H, m), 1.65 and 1.70 (3H, d, rotamers), 3.2-3.3 (m, 2H), 3.38 (3H, s), 3.94-4.10 (1H, m), 4.46-4.75 (1H, m), 5.20 (1H, q), 7.25-7.35 (1H, m), 7.40-7.55 (m, 1H), 7.80 (1H, t), 11.32 (1H, d), Example 19 20 N-(4-(((R*)-1-(2,3-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-(2,3-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2,3-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 25 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 112 201389-PCT01-NP The diastereomers of N-(4-((1-(2,3-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 16 (61 g, 132 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column (50×250 5 mm, 5µm), eluted with 20% MeOH / DEA (100 / 0.5) in CO2 (120 bar) with a flow rate of 130 mL / min and detection at 230 nm to give the second eluting compound N-(4-(((R*)-1-(2,3- difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 2, Example 19 (29.9 g, 42%). HRMS (ESI) m / z [M+H]+ calcd for C18H26F2N5O3S2: 462.1440, found: 462.1440.1H NMR (400 MHz, CD3OD) δ 0.89– 10 0.99 (6H, m), 1.35–1.57 (2H, m), 1.61–1.77 (4H, m), 3.30-3.34 (3H, m, overlapping with the solvent), 3.38–3.62 (2H, m), 4.15–4.28 (1H, m), 5.3–5.41 (1H, m), 7.07–7.22 (2H, m), 7.28– 7.39 (1H, m). Example 20 15 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-phenylethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-phenylethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((S)-1-phenylethyl)thio)-1,3,5- 20 triazin-2-yl)methanesulfonamide 113 201389-PCT01-NP The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 17 (57.9 g, 136 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column (50×230 mm, 5µm), eluted with 35% MeOH / DEA (100 / 0.5) in CO2 (100 bar) at a flow rate of 160 5 mL / min and detection at 290 nm to give the first eluting compound N-(4-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-6-(((R*)-1-phenylethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 1) containing TEA from the eluent. The compound was dissolved in DCM and washed two times with 1 M citric acid solution and once with water. The solvent was evaporated and the residue was co-evaporated twice with EtOH to give (19,310 g, 33%) of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-phenylethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 Example 20 as a colourless solid. HRMS (ESI) m / z [M+H]+calcd for C18H28N5O3S2: 426.1628, found: 426.1624.1H NMR (600 MHz, CD3OD, mixture of rotemers about 1 / 1) δ 0.9–1.03 (6H, m), 1.37–1.54 (2H, m), 1.65–1.72 (1H, m), 1.71–1.74 (3H, m), 3.30-3.34 (3H, m, overlapping with the solvent), 3.45–3.61 (2H, 15 m), 4.16–4.29 (1H, m), 5.04–5.12 (1H, m), 7.2–7.26 (1H, m), 7.31 (2H, q), 7.41–7.45 (2H, m). Example 21 N-(4-(((R*)-1-(2,5-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 20 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-(2,5-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2,5-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 25 The diastereomers of N-(4-((1-(2,5-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 18 (73 mg, 114 201389-PCT01-NP 0.16 mmol) were separated by preparative chiral SFC on a Chiralcel OJ SFC column (50×230 mm, 5µm), eluted with 10% EtOH / DEA (100 / 0.5) in CO2 (90 bar) at a flow rate of 120 mL / min and detection at 260 nm to give the second eluting compound N-(4-(((R*)-1-(2,5- difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- 5 yl)methanesulfonamide, Isomer 2 Example 21 (35 mg, 41%). HRMS (ESI) m / z [M+H]+calcd for C18H26F2N5O3S2: 462.1440, found: 462.1444.1H NMR (500 MHz, CDCl3, mixture of two rotamers) δ 0.73–0.99 (6H, m), 1.31–1.63 (3H, m), 1.66 (3H, d), 3.15 (3H, s), 3.48– 3.59 (1H, m), 3.64–3.78 (1H, m), 3.98–4.15 (1H, m), 5.1–5.27 (1H, m), 6.84–6.93 (1H, m), 6.93–7 (1H, m), 7.13–7.23 (1H, m). 10 Example 22 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylpropyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide 15 1-Phenylpropyl methanesulfonate Intermediate 19 (90 mg, 0.42 mmol) dissolved in DMF (0.6 mL) followed by DIPEA (0.14 mL, 0.78 mmol) were added to a solution of (R)-N- (4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (100 mg, 0.31 mmol) in DMF (0.6 mL). The reaction mixture was stirred at rt on. Water (2 mL) and DCM (6 mL) were added and the mixture was 20 shaken vigorously. The layers were separated using a phase separator. The solvent was evaporated in vacuo to give the crude product (129 mg) as a clear oil. The crude product was purified by preparative SFC, PrepMethod F (gradient: 20–25%) to give the title compound (60 mg, 44%). HRMS (ESI) m / z [M+H]+calcd for C19H30N5O3S2: 440.1784, found: 440.1762.1H NMR (600 MHz, DMSO-d6, mixture of diastereomers / rotamers) δ 0.82–0.91 25 (9H, m), 1.25–1.47 (2H, m), 1.52–1.64 (1H, m), 1.9–2.02 (1H, m), 2.09 (1H, dp), 3.26–3.46 (3H + 2H, overlapping with the solvent), 3.96–4.17 (1H, m), 4.71–4.83 (1H, m), 7.22–7.29 (1H, m), 7.29–7.36 (2H, m), 7.36–7.44 (2H, m). 115 201389-PCT01-NP Example 23 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((2-methyl-1- phenylpropyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 5 DIPEA (0.095 mL, 0.55 mmol) and (1-bromo-2-methylpropyl)benzene (106 mg, 0.50 mmol) dissolved in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (200 mg, 0.50 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and then heated to 60°C for 1 h 35 min. Water and MTBE were added. The layers were separated 10 and the organic layer was washed with water and brine and then concentrated. The residue was purified by straight phase flash chromatography on silica (DCM / MeOH 20 / 1) to give (152 mg, 57%) of the title compound as a colourless solid. HRMS (ESI) m / z [M+H]+calcd for C20H32N5O3S2: 454.1940, found: 454.1924.1H NMR (400 MHz, DMSO-d6) δ 0.78–0.93 (9H, m), 0.97–1.08 (3H, m), 1.25–1.47 (2H, m), 1.49–1.7 (1H, m), 2.09–2.31 (1H, m), 3.25– 15 3.47 (5H, m, overlapping with the solvent), 3.94–4.16 (1H, m), 4.6–4.76 (1H, m), 4.76–4.87 (1H, m), 7.17–7.26 (1H, m), 7.27–7.44 (4H, m), 7.68 (1H, s). Example 24 N-(4-(((R*)-1-(2-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 20 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(2-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 116 201389-PCT01-NP The diastereomers of N-(4-((1-(2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 20 (34 mg, 0.08 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column 5 (20×230 mm, 5µm), eluted with 30% EtOH in CO2(120 bar) at a flow rate of 70 mL / min and detection at 254 nm to give the first eluting compound N-(4-(((R*)-1-(2- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 1, Example 24 (14 mg, 41%). HRMS (ESI) m / z [M+H]+calcd for C18H27FN5O3S2: 444.1534, found: 444.1530.1H NMR (500 MHz, CD3OD, mixture 10 of rotamers) δ 0.88 – 1 (6H, m), 1.35 – 1.54 (2H, m), 1.63 – 1.77 (4H, m), 3.24 – 3.39 (3H, m, overlapping with the solvent), 3.39 – 3.61 (2H, m), 4.16 – 4.3 (1H, m), 5.34 (1H, q), 7.04 – 7.18 (2H, m), 7.24 – 7.32 (1H, m), 7.47 – 7.57 (1H, m). Example 25 15 N-(4-(((R*)-1-(5-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(5-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 20 N-(4-(((S)-1-(5-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 117 201389-PCT01-NP The diastereomers of N-(4-((1-(5-chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 21 (63mg, 0.13 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column (20×250 mm, 5µm), eluted with 30% EtOH in CO2 (120 bar) at a flow rate of 70 5 mL / min and detection at 254 nm to give the first eluting compound N-(4-(((R*)-1-(5-Chloro- 2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 1, Example 25 (22 mg, 36%). HRMS (ESI) m / z [M+H]+calcd for C18H26ClFN5O3S2: 478.1144, found: 478.1128.1H NMR (500 MHz, CD3OD, mixture of rotamers) δ 0.87 – 0.98 (6H, m), 1.33 – 1.53 (2H, m), 1.61 – 1.74 (4H, m), 3.26 – 10 3.35 (3H, m, overlapping with the solvent), 3.36 – 3.64 (2H, m), 4.15 – 4.25 (1H, m), 5.22 – 5.31 (1H, m), 7.04 – 7.13 (1H, m), 7.23 – 7.29 (1H, m), 7.51 – 7.57 (1H, m). Example 26 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-2-phenylpropyl)thio)- 15 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-2-phenylpropyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((S)-2-phenylpropyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide 20 The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((2- phenylpropyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 22 (70 mg, 0.16 mmol) were separated by preparative chiral SFC on a Chiralcel OJ SFC column (50×230 mm, 5µm), eluted with 30% EtOH / TEA (100 / 0.5) in CO2 (120 bar) at a flow rate of 15025 mL / min and detection at 230 nm to give the first eluting compound N-(4-(((R)-1-Hydroxy-4- methylpentan-2-yl)amino)-6-(((R*)-2-phenylpropyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 1) containing residual TEA from the eluent. The compound was dissolved in DCM and washed with 1 M citric acid solution. The organic layer was 118 201389-PCT01-NP passed through a phase separator and concentrated to give (26 mg, 37%) of N-(4-(((R)-1- Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-2-phenylpropyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 1, Example 26. HRMS (ESI) m / z [M+H]+calcd for C19H30N5O3S2: 440.1784, found: 440.1760.1H NMR (400 MHz, CD3OD, mixture of 5 rotamers) δ 0.88–0.98 (6H, m), 1.35–1.53 (5H, m), 1.59–1.76 (1H, m), 3.02–3.18 (1H, m), 3.29–3.32 (3H, m, overlapping with the solvent peak), 3.33–3.45 (2H, m), 3.47–3.61 (2H, m), 4.15–4.3 (1H, m), 7.14–7.22 (1H, m), 7.23–7.31 (4H, m). Example 27 10 N-(4-(((R*)-1-(2-Fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(2-Fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2-Fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- 15 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(2-fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 24 (148 mg, 0.31 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC 20 column (50×230 mm, 5µm), eluted with 35% EtOH / TEA (100 / 0.5) in CO2(100 bar) at a flow rate of 160 mL / min and detection at 280 nm to give the first eluting compound N-(4- (((R*)-1-(2-fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1, containing residual TEA. The compound was dissolved in DCM and washed once with 1 M citric acid solution and once 25 with water. The organic layer was passed through a phase separator and concentrated to give (78 mg, 53 %) of N-(4-(((R*)-1-(2-fluoro-4-methoxyphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1, Example 27. 119 201389-PCT01-NP HRMS (ESI) m / z [M+H]+calcd for C19H29FN5O4S2: 474.1640, found: 474.1642.1H NMR (400 MHz, CD3OD) δ 0.85 – 1.03 (6H, m), 1.35 – 1.58 (2H, m), 1.6 – 1.79 (4H, m), 3.25 – 3.42 (3H, m, overlapping with the solvent), 3.43 – 3.67 (2H, m), 3.78 (3H, s), 4.16 – 4.33 (1H, m), 5.21 – 5.35 (1H, m), 6.61 – 6.79 (2H, m), 7.32 – 7.46 (1H, m). 5 Example 28 N-(4-(((R*)-1-(5-Chloropyrazin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(5-Chloropyrazin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 10 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(5-Chloropyrazin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(5-chloropyrazin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 15 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 27 (330 mg, 0.72 mmol) were separated by preparative chiral-HPLC on a Chiralpak IA column (20×250 mm, 5µm), using 5% EtOH in TBME as eluant, with a flow rate of 18 mL / min and detection at 254 / 220 nm to give the first eluting compound N-(4-(((R*)-1-(5-chloropyrazin-2- yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- 20 yl)methanesulfonamide, Isomer 1, Example 28 (58 mg, 17%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C16H25ClNO3S2: 462.1144, found: 462.1144.1HNMR (400MHz, CD3OD): δ 0.87-0.93 (6H, m), 1.33-1.51 (2H, m), 1.60-1.70 (4H, m), 3.05 (3H, s), 3.29- 3.56(2H, m), 4.13-4.19(1H, m), 5.17-5.24(1H, m), 8.56-8.64(2H, m). 25 Example 29 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(5-methylpyrazin-2- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 120 201389-PCT01-NP A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 2 (300 mg, 0.93 mmol) in DMF (10 mL) was added dropwise to a stirred solution of 2-(1-bromoethyl)-5-methylpyrazine (188 mg, 0.93 5 mmol) and DIPEA (1.20 g, 9.33 mmol) in DMF (10 mL) at rt and the resulting mixture was stirred for 4 h. The reaction mixture was concentrated, diluted with DCM (100 mL), and washed sequentially with sat brine (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC, PrepMethod O, to give the title compound (130 mg, 32%) as an off-white solid. HRMS (ESI) m / z [M+H]+10 calcd for C17H28N7O3S2: 442.1690, found: 442.1700.1H NMR (400 MHz, DMSO-d6, diastereomeric mixture) δ 0.76–0.91 (6H, m), 1.28–1.46 (2H, m), 1.49–1.63 (1H, m), 1.64– 1.71 (3H, m), 2.47 (1.5 H, s, diastereomer) and 2.48 (1.5H, s, diastereomer), 3.26–3.43 (5H, m, overlapping with the water peak), 3.87–4.15 (1H, m), 4.72 (1H, t), 5.06–5.19 (1H, m), 7.49–7.97 (1H, m), 8.51 (1H, t), 8.69 (0.5H, t, rotamer) and 8.77 (0.5H, dd, diastereomer), 15 11.24 (1H, s). Example 30 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(6-methylpyridin-3- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 20 DIPEA (0,.54 mL, 2.60 mmol) was added to a solution of 5-(1-bromoethyl)-2- methylpyridine Intermediate 28 (260 mg, 1.30 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (418 mg, 1.30 mmol) in DMF (6 mL) at 0°C under an atmosphere of N2(g). The resulting 121 201389-PCT01-NP mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with sat brine (3×5 mL) The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod P, to give the title compound (40 mg, 7%) as a white solid. HRMS (ESI) m / z [M+H]+calcd 5 for C18H29N6O3S2: 441.1738, found: 441.1742.1H NMR (400 MHz, DMSO-d6, mixture of diastereomers) δ 0.77–0.91 (6H, m), 1.21–1.48 (2H, m), 1.5–1.63 (1H, m), 1.62–1.7 (3H, m), 2.41–2.46 (3H, m), 3.35 (5H, m, ovelapping with the water peak), 3.84–4.21 (1H, m), 4.73 (1H, s), 4.91–5.03 (1H, m), 7.17–7.26 (1H, m), 7.65–7.82 (2H, m), 8.55 (0.5H, t, diastereomer) and 8.60 (0.5H, t, diastereomer), 11.29 (1H, s). 10 Example 31 -1-(5-Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(5-Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 15 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(5-Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(5-fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1- 20 hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 31 (160 mg, 0.34 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column (50×250 mm, 5µm), using 50% MeOH / DEA (100 / 0.2) in CO2 as eluant, with a flow rate of 160 mL and detection at 254 nm to give the first eluting compound N-(4-(((R*)-1-(5- Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 25 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 Example 31 (50 mg, 31%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C18H28FN6O4S2: 475.1592, found: 475.1602.1H NMR (400 MHz, DMSO-d6, mixture of rotamers about 1 / 1) δ 0.81–0.91 (6H, m), 1.21–1.47 (2H, m), 1.51–1.64 (1H, m), 1.68 (3H, d), 3.25–3.4 (5H, m, overlapping with the water signal), 3.92 (1.5H, s, rotamer) and 3.93 (1.5H, s, rotamer), 3.95–4.16 (1H, m), 4.5–4.8 (1H, m), 122 201389-PCT01-NP 4.85–5.11 (1H, m), 7.66–7.82 (1H, m), 7.82–7.92 (1H, m), 8.14 (0.5H, d, rotamer) and 8.20 (1H, d, rotamer), 11.23 (1H, s). Example 32 5 N-(4-(((R*)-1-(6-Chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-(6-Chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(6-Chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 10 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(6-chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 34 (128 mg, 0.27 mmol) were separated by preparative chiral SFC on a Chiralpak AD SFC 15 column (20×250 mm, 5µm), eluted with 25% IPA / TEA (100 / 0.5) in CO2 (120 bar) with a flow rate of 80 mL / min and detection at 260 nm to give the second eluting compound N-(4- (((R*)-1-(6-chloro-2-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2, containing some residual TEA. The compound was dissolved in DCM (30 mL) and washed once with 1 M citric acid 20 solution (5 mL) and once with water (5 mL). The organic layer was passed through a phase separator and concentrated to give (57 mg, 44%) of N-(4-(((R*)-1-(6-chloro-2-fluoropyridin- 3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 2, Example 32. HRMS (ESI) m / z [M+H]+calcd for C17H25ClFN6O3S2: 479.1096, found: 479.1054.1H NMR (400 MHz, CDCl3, mixture of 25 rotamers) δ 0.76 – 1.01 (6H, m), 1.34 – 1.51 (2H, m), 1.5-1.7 (1H, m), 1.65 (3H, d), 3.32 (3H, s), 3.38 – 3.53 (2H, m), 4.07 – 4.31 (1H, m), 5.11 (1H, q), 7.12 – 7.25 (2H, m, Ar-H and NH), 7.82 – 8.03 (1H, m). Example 33 123 201389-PCT01-NP N-(4-((1-(5-Fluoropyridin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.062 mL, 0.36 mmol) and a solution of 1-(5-fluoropyridin-2-yl)ethyl 5 methanesulfonate Intermediate 35 (71 mg, 0.32 mmol) in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (130 mg, 0.32 mmol) in DMF (2 mL). The reaction mixture was stirred at ambient temperature on. Additional 1-(5-fluoropyridin-2-yl)ethyl methanesulfonate Intermediate 35 (20 mg, 0.09 mmol) was added and the reaction mixture 10 was heated to 50°C for 4 h. Water and MTBE were added and the layers were separated. The aqueous layer was extracted with MTBE and the combined organic layers were washed with water, dried over MgSO4and concentrated. The residue was purified by straight phase flash chromatography on silica (0–100% EtOAc in DCM) to give the title compound (105 mg, 73%). HRMS (ESI) m / z [M+H]+calcd for C17H26FN6O3S2: 445.1486, found: 445.1486.1H 15 NMR (400 MHz, CD3OD, mixture of diastereomers) δ 0.82–0.98 (6H, m), 1.33–1.53 (2H, m), 1.63–1.75 (4H, m), 3.33 (3H, d, isomers), 3.42–3.6 (2H, m), 4.14–4.28 (1H, m), 5.12– 5.25 (1H, m), 7.5–7.72 (2H, m), 8.34–8.49 (1H, m). Example 34 20 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(6-methoxypyridin-3- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-(6-methoxypyridin-3- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((S)-1-(6-methoxypyridin-3- 25 yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 124 201389-PCT01-NP The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-(6- methoxypyridin-3-yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 37 (64 mg, 0.14 mmol) were separated by preparative chiral SFC on a Chiralpak AD SFC column 5 (20×250 mm, 5µm), eluted with 30% IPA / TEA (100 / 0.5) in CO2(120 bar) with a flow rate of 65 mL / min and detection at 230 nm to give the second eluting compound N-(4-(((R)-1- Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(6-methoxypyridin-3-yl)ethyl)thio)-1,3,5- triazin-2-yl)methanesulfonamide, Isomer 2, containing some residual TEA. The compound was dissolved in DCM (5 mL) and washed once with 1 M citric acid solution (1 mL). The 10 organic layer was passed through a phase separator and concentrated to give (21 mg, 44%) of N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(6-methoxypyridin-3- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2, Example 34. HRMS (ESI) m / z [M+H]+calcd for C18H29N6O4S2: 457.1686, found: 457.1682.1H NMR (500 MHz, CD3OD) δ 0.86 – 0.98 (m, 6H), 1.34 – 1.53 (m, 2H), 1.61 – 1.73 (m, 4H), 3.27 – 3.34 (m, 15 3H), 3.41 – 3.6 (m, 2H), 3.87 (d, 3H), 4.13 – 4.28 (m, 1H), 4.99 – 5.08 (m, 1H), 6.76 (dd, 1H), 7.77 (dt, 1H), 8.20 (dd, 1H). Example 35 N-(4-((1-(2-Fluoro-6-methoxypyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 20 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of DIPEA (0.157 mL, 0.90 mmol) and 3-(1-chloroethyl)-2-fluoro-6- methoxypyridine Intermediate 39 (187 mg, 0.98 mmol) in DMF (1.5 mL) was added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 125 201389-PCT01-NP yl)methanesulfonamide Intermediate 2 (0.241 g, 0.75 mmol) in DMF (2 mL) and the reaction mixture was heated to 80°C for 6 h. Water and DCM were added and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with water and concentrated. The crude product was purified by preparative HPLC, 5 PrepMethod R (gradient 5-95%), to give the title compound (118 mg, 33%). HRMS (ESI) m / z [M+H]+calcd for C18H28FN6O4S2: 475.1592, found: 475.1608.1H NMR (600 MHz, DMSO, mixture of diastereomers about 1 / 1) δ 0.75–0.92 (6H, m), 1.26–1.37 (1H, m), 1.37– 1.45 (1H, m), 1.51–1.62 (1H, m), 1.64–1.71 (3H, m), 3.33 (5H , m, hidden by the solvent peak), 3.79–3.83 (3H,s), 3.98–4.1 (1H, m), 4.65–4.76 (1H, m, OH), 5.04–5.11 (1H, m), 6.7– 10 6.77 (1H, m), 7.98–8.1 (1H, m). Example 36 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2-methylpyrimidin-5- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 15 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-(2-methylpyrimidin-5- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((S)-1-(2-methylpyrimidin-5- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 20 The diastereomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-(2- methylpyrimidin-5-yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 41 (160 mg, 0.36 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC column (50×250 mm, 5µm), eluted with 40% MeOH / DEA (100 / 0.2) in CO2(120 bar) with a flow rate of 150 mL / min and detection at 254 nm to give the first eluting compound N-(4-25 (((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2-methylpyrimidin-5- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1, Example 36 (66 mg, 41%) as a white solid. HRMS (ESI) m / z [M+H]+ calcd for C17H28N7O3S2: 442.1690, found: 442.1660. 1H NMR (400 MHz, DMSO-d6, mixture of rotamers about 1 / 1) δ 0.75–0.94 (6H, m), 1.22– 1.47 (2H, m), 1.5–1.64 (1H, m), 1.69 (3H, d), 2.59 (3H, apparent d, rotamers), 3.22–3.39 (5H, 126 201389-PCT01-NP m, overlapping with the water), 3.88–4.05 (1H, m), 4.71 (1H, t), 4.92 (1H, dq), 7.64 (1H, s), 8.83 (1H, s), 8.88 (1H, s), 11.32 (1H, s). Example 37 5 N-(4-(((R*)-1-(2-Cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 N-(4-(((R)-1-(2-Cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2-Cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 10 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide The diastereomers of N-(4-((1-(2-cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 43 (140 mg, 0.30 mmol) were separated by preparative chiral SFC on a Chiralpak IC SFC 15 column (50×250 mm, 5µm), eluted with 40% MeOH in CO2 (120 bar) with a flow rate of 150 mL / min and detection at 220 nm to give the first eluting compound N-(4-(((R*)-1-(2- cyclopropylpyrimidin-5-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide, Isomer 1, Example 37 (85 mg, 61%) as a white solid. HRMS (ESI) m / z [M+H]+ calcd for C19H30N7O3S2: 468.1846, found: 468.1888.1H NMR 20 (300 MHz, DMSO-d6): δ 0.80-0.87 (6H, m), 0.97-1.03 (4H, m), 1.31-1.44 (3H, m), 1.56 (1H, brs), 1.68 (3H, d), 2.15 (1H, apparent brs), 3.25-3.36 (4H, m), 4.00 (1H, apparnt brs), 4.69 (1H, t, OH), 4.85-4.93 (1H, m), 7.67-7.75 (1H, m, NH), 8.76 (1H, s), 8.81 (1H, s), 11.18 (1H, brs, NH). 25 Example 38 N-(4-(((R*)-1-(5-Chloropyrimidin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(5-Chloropyrimidin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 127 201389-PCT01-NP N-(4-(((S)-1-(5-Chloropyrimidin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) The diastereomers of N-(4-((1-(5-chloropyrimidin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy- 5 4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 44 (120 mg, 0.12 mmol) were separated by preparative chiral-HPLC on a Chiralpak IA column, (10 x 250 mm, 5mM) eluted with 30% EtOH in hexane, at a flow rate of 20 mL / min and detection at 254 / 220 nm to give the first eluting compound N-(4-(((R*)-1-(5-chloropyrimidin-2- yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- 10 yl)methanesulfonamide, Isomer 1, Example 38 (33 mg, 28%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C16H25ClN7O3S2: 462.1144, found: 462.1186.1HNMR (400MHz, CD3OD, mixture of rotamers): δ 0.93-0.99 (6H, m), 1.38-1.53 (2H, m), 1.68-1.77 (4H, m), 3.33-3.36 (4H, m), 3.43-3.49 (1H, m), 3.50-3.60(1H, m), 4.18-4.26(1H, m), 5.26-5.34(1H, m), 8.79(2H, s). 15 Example 39 N-(4-(((R*)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4- dimethylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4-dimethylpentan- 20 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4-dimethylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) 128 201389-PCT01-NP The diastereomers of N-(4-((1-(2,4-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4- dimethylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 48 (220 mg, 0.46 mmol) were separated by preparative chiral HPLC on a Chiralpak IC SFC column (50×250 mm, 5µm), eluted with 40% MeOH in CO2, at a flow rate of 150 mL / min and 5 detected at 220 nm to give the first eluting compound N-(4-(((R*)-1-(2,4- difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4,4-dimethylpentan-2-yl)amino)-1,3,5-triazin- 2-yl)methanesulfonamide, Isomer 1, Example 39 (95 mg, 43%) as a white solid; HRMS (ESI) m / z [M+H]+calcd for C19H28F2N5O3S2: 476.1596, found: 476.1598 1H NMR (300 MHz, DMSO-d6) δ 0.80–0.95 (m, 9 H), 1.43 (t, 2 H), 1.70 (t, 3 H), 10 3.05–3.40 (m, 4 H), 4.00–4.20 (m, 1 H), 4.73 (t, 1 H), 5.19 (q, 1 H), 6.95–7.15 (m, 1 H), 7.19 - 7.31 (m, 1 H), 7.56 - 7.74 (m, 2 H), 11.25 (s, 1 H). Example 40 N-(4-(((R*)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3-dimethylbutan- 15 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3-dimethylbutan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide N-(4-(((S)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3-dimethylbutan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) 20 The diastereomers of N-(4-((1-(2,4-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3- dimethylbutan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 49 (200 mg, 0.43 mmol) were separated by preparative chiral SFC on Chiralpak IC column (50×250 25 mm, 5 um) eluted with 50% EtOH in CO2, at a flow rate of 150 mL / min and detected at 220 nm. The first eluted compound was collected to give N-(4-(((R*)-1-(2,4- difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-3,3-dimethylbutan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide, Isomer 1, Example 40 (95 mg, 48%) as white solid. HRMS (ESI) m / z [M+H]+calcd for C18H26F2N5O3S2: 462.1440, found: 462.1444. 129 201389-PCT01-NP 1H NMR (400 MHz, DMSO-d6) δ 0.80–095 (m, 9H), 1.60–1.80 (m, 3H), 3.36–3.45 (m, 3H), 3.60–3.69 (m, 1H), 3.80–3.96 (m, 1H), 4.40–4.55 (m, 1H), 5.10–5.30 (m, 1H), 7.00– 7.15 (m, 1H), 7.21–7.31 (m, 1H), 7.62–7.71 (m, 2H), 11.19 (s, 1H). 5 Example 41 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)ethanesulfonamide Pd2(dba)3 x CHCl3 (21 mg, 0.02 mmol), Xantphos (23.7 mg, 0.04 mmol) and Cs2CO310 (200 mg, 0.61 mmol) were added sequentially to a solution of (2R)-2-((4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4-dimethylpentan-1-ol Intermediate 50 (150 mg, 0.41 mmol) and ethanesulfonamide (89 mg, 0.82 mmol) in 1,4-dioxane (8 mL). The reaction vessel was sealed, and the mixture was heated at 100°C for 3 h. The reaction mixture was diluted with EtOAc (50 mL), and washed with H2O (50 mL), and sat NaCl (2×50 mL). 15 The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod C (gradient: 30–70%) to give the title compound (114 mg, 63%) as a yellow solid. HRMS (ESI) m / z [M+H]+calcd for C19H30N5O3S2: 440.1784, found: 440.1778;1H NMR (300 MHz, CDCl3) δ 0.87–0.94 (m, 6H), 1.29–1.75 (m, 9H), 3.46–3.74(m, 4H), 4.10–4.35 (m, 1H), 4.93–4.97(m, 1H), 7.22–7.42 (m, partly 20 overlapping with solvent). Example 42 2,2,2-Trifluoro-N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)ethane-1-sulfonamide 130 201389-PCT01-NP Pd2(dba)3 x CHCl3 (21 mg, 0.02 mmol), XPhos (20 mg, 0.04 mmol) and Cs2CO3 (200 mg, 0.61 mmol) were added sequentially to a solution of (2R)-2-((4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4-dimethylpentan-1-ol Intermediate 50 (150 5 mg, 0.41 mmol) and 2,2,2-trifluoroethanesulfonamide (133 mg, 0.82 mmol) in THF (8 mL). The reaction vessel was sealed, and the mixture was heated at 70°C on. The reaction mixture was diluted with EtOAc (50 mL), and washed with H2O (50 mL), and sat NaCl (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC , PrepMethod C, (gradient: 20–75%) to give the title 10 compound (180 mg, 89%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C19H27F3N5O3S2: 494.1502, found: 494.1502;1H NMR (300 MHz, CDCl3) δ 0.89–0.95 (m, 6H), 1.34–1.77 (m, 6H), 3.45–3.72 (m, 2H), 4.13–4.28 (m, 3H), 4.90–4.96 (m, 1H), 7.26– 7.43 (m, partly overlapping with solvent), 8.25 (t, 1H). 15 Example 43 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)-1,3,5- triazin-2-yl)propane-2-sulfonamide Pd2(dba)3x CHCl3(21 mg, 0.02 mmol), Xantphos (24 mg, 0.04 mmol) and Cs2CO320 (200 mg, 0.61 mmol) were added sequentially to a solution of (2R)-2-((4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4-dimethylpentan-1-ol Intermediate 50 (150 mg, 0.41 mmol) and propane-2-sulfonamide (101 mg, 0.82 mmol) in 1,4-dioxane (8 mL). The reaction vessel was sealed, and the mixture was heated at 100°C for 3 h. The reaction 131 201389-PCT01-NP mixture was diluted with EtOAc (50 mL), and washed with H2O (50 mL), and sat NaCl (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod C, (gradient: 30–70%) to give the title compound (150 mg, 81%) as a yellow solid. HRMS (ESI) m / z [M+H]+calcd for 5 C20H32N5O3S2: 454.1940, found: 454.1932;1H NMR (300 MHz, CDCl3) δ 0.87–0.94 (m, 6H), 1.33–1.76(m, 12H), 3.49–3.85 (m, 2H), 3.90–4.30 (m, 2H), 4.93–4.97 (m, 1H), 7.00– 7.45 (m, partly overlapping with solvent). Example 44 10 3-Fluoro-N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)- 1,3,5-triazin-2-yl)propane-1-sulfonamide Pd2(dba)3 x CHCl3 (31 mg, 0.03 mmol), Xantphos (39 mg, 0.07 mmol) and Cs2CO3 (333 mg, 1.02 mmol) were added sequentially to a solution of (2R)-2-((4-chloro-6-((1- 15 phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4-dimethylpentan-1-ol Intermediate 50 (250 mg, 0.68 mmol) and 3-fluoropropane-1-sulfonamide (192 mg, 1.36 mmol) in 1,4-dioxane (12 mL). The reaction vessel was sealed, and the mixture was heated under an atmosphere of N2(g) at 100°C for 3 h. The reaction mixture was diluted with EtOAc, and washed with H2O, and sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude 20 product was purified by preparative HPLC, PrepMethod D (gradient: 45–55%), give the title compound (176 mg, 55%) as a yellow solid. HRMS (ESI) m / z [M+H]+calcd for C20H31FN5O3S2: 472.1846, found: 472.1822;1H NMR (300 MHz, CDCl3) δ 0.88–0.94 (m, 6H), 1.23–1.77 (m, 7H), 2.13–2.35 (m, 2H), 3.40–3.72 (m, 4H), 4.20 (s, 1H), 4.35–4.50 (m, 1H), 4.55–4.70 (m, 1H), 4.90– 5.00 (m, 1H), 7.25–7.43 (m, partly overlapping with solvent), 25 7.55–7.65 (m, 1H). Example 45 3,3,3-Trifluoro-N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)propane-1-sulfonamide 132 201389-PCT01-NP Pd2(dba)3 x CHCl3 (27 mg, 0.03 mmol), Xantphos (25 mg, 0.05 mmol) and Cs2CO3 (280 mg, 0.78 mmol) were added sequentially to a solution of (2R)-2-((4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4,4-dimethylpentan-1-ol Intermediate 50 (200 5 mg, 0.52 mmol) and 3,3,3-trifluoropropane-1-sulfonamide (139 mg, 0.78 mmol) in 1,4- dioxane (12 mL). The reaction vessel was sealed, and the mixture was heated under an atmosphere of N2(g) at 100°C for 3 h. The reaction mixture was diluted with EtOAc, and washed with H2O, and sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod C, to give 10 the title compound (52 mg, 20%) as a yellow solid. HRMS (ESI) m / z [M+H]+calcd for C20H29F3N5O3S2: 508.1658, found: 508.1666;1H NMR (300 MHz, CDCl3) δ 0.92–0.99 (m, 6H), 1.30–1.69 (m, 8H), 2.62–2.74 (m, 2H), 3.61–3.77 (m, 4H), 4.23–4.30 (m, 1H), 4.94– 4.98 (m, 1H), 7.30–7.45 (m, partly overlapping with solvent), 8.13 (1H, s). 15 Example 46 (R)-N-(4-((2,2-Difluoro-2-(3-fluorophenyl)ethyl)thio)-6-((1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 20 yl)methanesulfonamide, Intermediate 2 (80 mg, 0.21 mmol) followed by DIPEA (0.091 mL, 0.52 mmol) were added to 1-(2-bromo-1,1-difluoroethyl)-3-fluorobenzene (50 mg, 0.21 mmol) dissolved in DMF (0.8 mL). The reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic phase passed through a phase separator. The solvent was 133 201389-PCT01-NP evaporated, and the crude residue was purified by preparative SFC, PrepMethod K, (gradient: 15–20%) to give the title compound (15 mg, 14%). HRMS (ESI) m / z [M+H]+calcd for C18H25F3N5O3S2: 480.1346, found: 480.1332.1H NMR (600 MHz, DMSO-d6) δ 0.78–0.92 (m, 6H), 1.26–1.44 (m, 2H), 1.51–1.62 (m, 1H), 3.19–3.48 (m, partly overlapping with 5 solvent), 0.70–1.00 (m, 6H), 1.25–1.45 (m, 2H), 1.49–1.64 (m, 1H), 2.93–3.79 (m, partly overlapping with solvent), 3.93–4.25 (m, 3H), 4.62–4.8 (m, 1H), 7.3–7.61 (m, 4H), 7.72–7.92 (m, 1H), 11.26 (s, 1H). Example 47 10 (R)-N-(4-((2-(2,4-Difluorophenyl)-2,2-difluoroethyl)thio)-6-((1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide, Intermediate 2 (74 mg, 0.19 mmol) followed by DIPEA (0.084 mL, 15 0.48 mmol) were added to 1-(2-bromo-1,1-difluoroethyl)-2,4-difluorobenzene, Intermediate 51 (50 mg, 0.19 mmol) dissolved in DMF (0.8 mL). The reaction mixture was heated in a microwave reactor at 140°C for 30 min. Water (2 mL) and DCM (2 mL) were added. The layers were separated and the organic layer passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative HPLC, PrepMethod H, 20 (gradient: 5–95%) to give the title compound (12 mg, 12%). HRMS (ESI) m / z [M+H]+calcd for C18H24F4N5O3S2: 498.1252, found: 498.1254.1H NMR (600 MHz, DMSO-d6) δ 0.78– 0.92 (m, 6H), 1.25–1.45 (m, 2H), 1.50–1.63 (m, 1H), 3.35–3.46 (m, partly overlapping with solvent), 3.96–4.09 (m, 1H), 4.09–4.22 (m, 2H), 4.64–4.75 (m, 1H), 7.16–7.26 (m, 1H), 7.37–7.48 (m, 1H), 7.59–7.75 (m, 2H), 11.23 (s, 1H). 25 Examples 48-56 General Synthesis Scheme 1 134 201389-PCT01-NP Intermediate 2 Intermediate A Example 48 - 56 Scheme General Preparation Method A A solution of Intermediate A (1.1-1.2 eq) in DMF (0.6 mL) followed by DIPEA (2.6 5 eq) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 2 (50 mg, 0.14 mmol, 1 eq). The reaction mixture was stirred at rt for 20 h – 4 days. Equal amounts of water and DCM were added, and the layers were separated. The organic layer was passed through a phase separator. The eluant was concentrated and the crude product of Example 48 was purified by preparative SFC, 10 PrepMethod F (gradient: 25–30%) to give the final product. The crude product of Example 49 was purified by preparative HPLC, PrepMethod J (gradient: 5–95%) to give the final product. The crude products of Examples 50 – 53 were purified by preparative HPLC, PrepMethod H (gradient: 5–95%) to give the final products. The crude products of Examples 54 – 56 were purified by preparative SFC, PrepMethod E (gradient: 15–30%) to give the final 15 products. Table 1: The Examples included in Table 1 were synthesized and purified as described in General Preparation Method A using appropriate Intermediate A as described in the table. 20 The Intermediates A are commercially available if not otherwise stated. 135 201389-PCT01-NP 136 201389-PCT01-NP 137 201389-PCT01-NP Example 57 (R)-N-(4-((2,3-Difluorobenzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 5 A mixture of methanesulfonamide (78 mg, 0.82 mmol), Cs2CO3 (113 mg, 0.82 mmol), (R)-2-((4-chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)amino)-4- methylpentan-1-ol, Intermediate 53 (160 mg, 0.41 mmol), Pd2(dba)3 (40 mg, 0.04 mmol) and X-phos (40 mg, 0.08 mmol) in THF (5 mL) was stirred at 70°C for 14.5 h under an 10 atmosphere of N2(g). After cooling to rt AcOH (50 µL) was added and the mixture was concentrated. The residue was suspended in DMSO (4 mL), filtered through a pad of silica and purified by preparative HPLC, PrepMethod L, (gradient: 5–95%) to give the title compound (40 mg, 22%). HRMS (ESI) m / z [M+H]+calcd for C17H24F2N5O3S2: 448.1282, found: 448.1308.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers 1:1) δ 0.91–0.76 15 (m, 6H), 1.45–1.25 (m, 2H), 1.63–1.51 (m, 1H), 3.35–3.22 (m, partly overlapping with solvent), 4.12–3.96 (m, 1H, rotamers), 4.48–4.34 (m, 2H), 4.79–4.61 (m, 1H), 7.19–7.10 (m, 1H), 7.36–7.29 (m, 1H), 7.40 and 7.49 (t, 1H, rotamers), 7.70 (s, 1H), 11.24 (s, 1H). Example 58 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((5-methylpyrazin-2- 20 yl)methyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 138 201389-PCT01-NP 2-(Chloromethyl)-5-methylpyrazine (22 mg, 0.12 mmol) followed by DIPEA (0.043 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (40 mg, 0.12 mmol) in 5 DMF (1 mL). The reaction mixture was heated in a microwave reactor at 110°C for 1 h, filtered and purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (38 mg, 71%). HRMS (ESI) m / z [M+H]+calcd for C16H26N7O3S2: 428.1532, found: 428.1552.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) δ 0.75– 0.91 (m, 6H), 1.24–1.44 (m, 2H), 1.50–1.65 (m, 1H), 2.46 (m, 3H, rotamers), 3.34–3.38 (m, 10 partly overlapping with solvent), 3.35–4.05 (m, 1H), 4.32–4.51 (m, 2H), 4.62–4.78 (m, 1H), 7.71 and 7.82 (s, 1H, rotamers), 8.47 (m, 1H, rotamers), 8.66 and 8.76 (s, 1H, rotamers), 11.23 (s, 1H). Example 59 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((2-methylthiazol-4- 15 yl)methyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 4-(Chloromethyl)-2-methylthiazole (18 mg, 0.12 mmol) followed by DIPEA (0.043 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (40 mg, 0.12 mmol) in 20 DMF (1 mL). The reaction mixture was heated in a microwave reactor at 110°C for 1 h, filtered and purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (38 mg, 71%). HRMS (ESI) m / z [M+H]+calcd for C15H25N6O3S3: 433.1144, 139 201389-PCT01-NP found: 433.1162.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) δ 0.77– 0.95 (m, 6H), 1.27–1.48 (m, 2H), 1.56–1.65 (m, 1H), 2.61 (s, 3H), 3.3–3.41 (m, partly overlapping with solvent), 4.05 (m, 1H, rotamers), 4.33–4.44 (m, 2H), 4.65–4.78 (m, 1H), 7.42 and 7.51 (s, 1H, rotamers), 7.60–7.90 (m, 1H, rotamers), 11.18 (s, 1H). 5 Example 60 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((5-methylisoxazol-4- yl)methyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide 4-(Chloromethyl)-5-methylisoxazole (16 mg, 0.12 mmol) followed by DIPEA (0.04310 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (40 mg, 0.12 mmol) in DMF (1 mL). The reaction mixture was heated in a microwave reactor at 70°C for 30 min, filtered and purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (5 mg, 10%). HRMS (ESI) m / z [M+H]+calcd for C15H25N6O4S2: 417.1372, found: 15 417.1380.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers 2:1) δ 0.8–0.9 (m, 6H), 1.25–1.46 (m, 2H), 1.56–1.63 (m, 1H), 2.40–2.41 (m, 3H, rotamers), 3.26–3.44 (m, partly overlapping with solvent), 3.95–4.18 (m, 3H), 4.66–4.78 (m, 1H), 7.75 (s, 1H), 8.56 and 8.64 (s, 1H, rotamers), 11.20 (s, 1H). Example 61 20 (R)-N-(4-(((5-Cyclopropyloxazol-2-yl)methyl)thio)-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 140 201389-PCT01-NP 2-(Chloromethyl)-5-cyclopropyloxazole (20 mg, 0.12 mmol) followed by DIPEA (0.043 mL, 0.25 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (40 mg, 0.12 mmol) in 5 DMF (1 mL). The reaction mixture was heated in a microwave reactor at 70°C for 30 min, filtered and purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (12 mg, 23%). HRMS (ESI) m / z [M+H]+calcd for C17H27N6O4S2: 443.1530, found: 443.1532.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers about 1:1) δ 0.61– 0.7 (m, 2H), 0.81–0.92 (m, 8H), 1.27–1.34 (m, 1H), 1.36–1.43 (m, 1H), 1.52–1.62 (m, 1H),10 1.87–1.96 (m, 1H), 3.28–3.40 (m, partly overlapping with solvent), 3.99–4.12 (m, 1H), 4.36– 4.51 (m, 2H), 4.68 (t, 1H), 6.73 and 6.76 (d, 1H, rotamers), 7.66–7.85 (m, 1H, rotamers), 11.22 (s, 1H). Example 62 (R)-N-(4-((Benzo[c][1,2,5]oxadiazol-4-ylmethyl)thio)-6-((1-hydroxy-4-methylpentan- 15 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 4-(Bromomethyl)benzo[c][1,2,5]oxadiazole (31 mg, 0.14 mmol) followed by DIPEA (0.057 mL, 0.33 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (50 mg, 0.13 mmol) in 20 DMF (0.6 mL). The reaction mixture was stirred at rt for 20 h. Water (2 mL) and DCM (2 mL) were added. The layers were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by 141 201389-PCT01-NP preparative SFC, PrepMethod G, (gradient: 20–25%) to give the title compound (44 mg, 74%). HRMS (ESI) m / z [M+H]+calcd for C17H24N7O4S2: 454.1326, found: 454.1332.1H NMR (600 MHz, DMSO-d6, mixture of two rotamers 1:1) δ 0.67–0.92 (m, 6H), 1.19–1.63 (m, 3H), 3.17–3.49 (m, partly overlapping with solvent), 3.91–4.06 (m, 1H), 4.63–4.75 (m, 5 3H), 7.52–7.56 (m, 1H, rotamers), 7.67–7.86 (m, 2H, rotamers), 7.93 and 7.95 (d, 1H, rotamers), 11.23 (s, 1H). Example 63 (R)-N-(4-((4-Cyano-3-fluorophenethyl)thio)-6-((1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 10 4-(2-Bromoethyl)-2-fluorobenzonitrile (33 mg, 0.14 mmol) followed by DIPEA (0.057 mL, 0.33 mmol) were added to (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6- mercapto-1,3,5-triazin-2-yl)methanesulfonamide, Intermediate 2 (50 mg, 0.13 mmol) in DMF (0.6 mL). The reaction mixture was stirred at rt for 21 h. Water (2 mL) and DCM (2 15 mL) were added. The layers were separated, and the organic layer was passed through a phase separator. The solvent was evaporated, and the crude residue was purified by preparative HPLC, PrepMethod H, (gradient: 5–95%) to give the title compound (50 mg, 81%). HRMS (ESI) m / z [M+H]+calcd for C19H26FN6O3S2: 469.1486, found: 469.1480.1H NMR (600 MHz, DMSO-d6) δ 0.77–0.92 (m, 6H), 1.26–1.45 (m, 2H), 1.52–1.64 (m, 1H),20 3.04–3.14 (m, 2H), 3.15–3.6 (m, partly overlapping with solvent), 3.97–4.12 (m, 1H), 4.59– 4.82 (m, 1H), 7.32–7.40 (m, 1H), 7.47–7.55 (m, 1H), 7.68 (s, 1H), 7.83–7.90 (m, 1H), 11.18 (s, 1H). Example 64 (R)-N-(4-((2,3-Difluorobenzyl)thio)-6-((4-fluoro-1-hydroxy-4-methylpentan-2- 25 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 142 201389-PCT01-NP MeOH (1.0 mL), DIPEA (0.085 mL, 0.49 mmol) and (R)-2-amino-4-fluoro-4- methylpentan-1-ol (40.6 mg, 0.30 mmol) were added to a solution of N-(4-chloro-6-((2,3- difluorobenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 54 (37 mg, 0.1 5 mmol). The reaction mixture was stirred under an atmosphere of N2(g) at rt on. A solution of N-(4-chloro-6-((2,3-difluorobenzyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 54 (11 mg, 0.03 mmol) and DIPEA (0.026 mL, 0.15 mmol) were added and the reaction mixture was stirred at rt on. The reaction mixture was concentrated, and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC, PrepMethod H 10 (gradient: 5–95%) to give the title compound (1.8 mg, 4%). HRMS (ESI) m / z [M+H]+calcd for C17H23F3N5O3S2: 466.1188, found: 466.1214. Examples 65–74 General Synthesis Scheme 2 Intermediate 2 Intermediate B Example 65 - 74 Scheme 15 Table 2: Examples 65–72 were synthesized and purified in analogy with the description for Example 3, and Examples 73–74 were synthesized and purified in analogy with the description for Example 1. The examples were synthesized from Intermediate 2 and the appropriate Intermediate B. The Intermediates B are commercially available or may be prepared in analogy with previous descriptions. 143 201389-PCT01-NP 144 201389-PCT01-NP Example 75–101 were prepared from Intermediate 2, unless otherwise, stated in analogy with the description for previously described Examples. Example 75 5 N-(4-((1-(2-(Difluoromethyl)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide 145 201389-PCT01-NP DIPEA (0.083 mL, 0.48 mmol) followed by a solution of 1-(1-bromoethyl)-2- (difluoromethyl)benzene Intermediate 73 (102 mg, 0.44 mmol) in DMF (1 mL) was added to a solution of (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin- 2-yl)methanesulfonamide Intermediate 2 (175 mg, 0.44 mmol) in DMF (1 mL). The 5 reaction mixture was stirred at ambient temperature for 20 h. Water and MTBE were added to the mixture. The two phases were separated, and the organic layer was washed with water, dried over MgSO4, filtered and concentrated to give the title compound (199 mg, 96%) as a colourless solid. HRMS (ESI) m / z [M+H]+calcd for C19H28F2N5O3S2: 476.1596, found: 476.1592. 10 Example 76 N-(4-((1-(2-Fluoro-5-methylphenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide A solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- 15 triazin-2-yl)methanesulfonamide Intermediate 2 (19.3 mg,0.060 mmol) dissolved in DMF (153µL) was added to a solution of 2-(1-bromoethyl)-1-fluoro-4-methylbenzene (13.02 mg, 0.060 mmol) and DIPEA (11.5μL, 0.066 mmol) in DMF (250 µL). The reaction mixture was stirred at rt for 5h. DIPEA (11.5μL, 0.066 mmol) was added and the reaction mixture was stirred at rt overnight. The mixture was concentrated in vacuo and the residue was dissolved 20 in DMSO (1 mL) and stirred at rt for 30 min, and then purified by preparative HPLC, PrepMethod V (gradient: 5–95%) to give the title compound (5.1 mg, 19%). HRMS (ESI) m / z [M+H]+calcd for C19H29FN5O3S2: 458.1690, found: 458.1702.1H NMR (600 MHz, DMSO-d6) δ 0.81 – 0.9 (6H, m), 1.28 – 1.45 (2H, m), 1.53 – 1.63 (1H, m), 1.65–1.74 (3H, m), 2.28 (3H, d), 3.26 – 3.45 (m, partly overlapping with solvent), 3.98 – 4.13 (1H, m), 4.66 25 – 4.75 (1H, m), 5.15 – 5.23 (1H, m), 7.03 – 7.14 (2H, m), 7.31 – 7.39 (1H, m), 7.69 (1H, br s), 11.19 (1H, br s). 146 201389-PCT01-NP Example 77 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylethyl)thio)-1,3,5-triazin-2- yl)propane-1-sulfonamide 5 Pd2dba3 ×CHCl3 (21.1 mg, 0.02 mmol) and Xantphos (23.6 mg, 0.04 mmol) and Cs2CO3 (199 mg, 0.61 mmol) were added to a solution of (2R)-2-((4-chloro-6-((1- phenylethyl)thio)-1,3,5-triazin-2-yl)amino)-4-methylpentan-1-ol Intermediate 50 (150 mg, 0.41 mmol) and propane-1-sulfonamide (100 mg, 0.82 mmol) in 1,4-dioxane (8 mL) and the reaction mixture was degassed with N2(g) for 5 min and then heated to 100°C for 3 h. The 10 mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and sat NaCl (2×50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC, PrepMethod C (gradient 20-70%) to afford the title compound (70 mg, 38%) as a yellow solid. HRMS (ESI) m / z [M+H]+calcd for C20H32N5O3S2: 454.1940, found: 454.1896.1H NMR (300 MHz, CDCl3): δ 0.87-0.93 (6H, 15 m), 0.98-1.05 (3H, m), 1.25-1.54 (2H, m), 1.55-1.86 (6H, m), 3.41-3.74 (4H, m), 4.22 (1H, d), 4.94-4.98 (1H, m), 7.24-7.42 (6H, m). Example 78 N-(4-(((R*)-1-(3-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 20 (N-(4-(((R)-1-(3-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(3-Chloro-2- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide) 147 201389-PCT01-NP The diastereomers of N-(4-((1-(3-chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 55 (95 mg, 0.20 mmol) were separated by preparative chiral SFC on a Chiralpak AD column 5 (5µm, 250×30 mm ID) eluted with 30% IPA / DEA (100 / 0.5) in CO2at 120 bar and 40oC, and at a flow rate of 140 mL / min and detection at 240 nm. The second eluted compound was collected to give the title compound N-(4-(((R*)-1-(3-Chloro-2-fluorophenyl)ethyl)thio)-6- (((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) (55 mg, 50%). HRMS (ESI) m / z [M+H]+calcd for C18H26ClFN5O3S2: 478.1144, found: 10 478.1144.1H NMR (500 MHz, CDCl3) δ 8.70 (1H, s), 7.40 (1H, td), 7.24–7.31 (1H, m), 7.05 (1H, t), 5.27 (1H, q), 3.99–4.22 (1H, m), 3.47–3.69 (2H, m), 3.14 (3H, s), 1.58–1.72 (4H, m), 1.50 (1H, ddd), 1.24–1.41 (partly overlapping with solvent, m), 0.81–0.96 (6H, m). Example 79 N-(4-(((R*)-1-(2,6-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 15 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(2,6-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(2,6- Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide)20 148 201389-PCT01-NP The diastereomers of N-(4-((1-(2,6-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 56 (60mg, 0.13 mmol) were separated by preparative chiral SFC on a Chiralpak IC column (5µm, 250×30 mm ID) eluted with 20% EtOH / DEA (100 / 0.5) in CO2 at 90 bar and 30oC, and at a 5 flow rate of 130 mL / min and detection at 260 nm. The first eluted compound was collected to give the title compound N-(4-(((R*)-1-(2,6-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) (25 mg, 36%). HRMS (ESI) m / z [M+H]+calcd for C18H26F2N5O3S2: 462.1440, found: 462.1420.1H NMR (500 MHz, CDCl3) δ 7.14–7.24 (1H, m), 6.82–6.9 (2H, m), 5.44–5.65 (1H, m), 4.0–4.4 (1H, 10 m), 3.49–3.78 (2H, m), 3.04 (3H, d), 1.45–1.83 (4H, m), 1.21–1.44 (overlapping with solvent, m), 0.87–0.99 (6H, m). Example 80 N-(4-(((R*)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 15 (N-(4-(((R)-1-(2,4-Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(2,4- Difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide) 20 The diastereomers of N-(4-((1-(2,4-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 57 (64 mg, 0.14 mmol) were separated by preparative chiral SFC on a Chiralpak AD column (5µm, 250×30 mm ID) eluted with 20% IPA / DEA (100 / 0.5) in CO2at 120 bar and 40oC, and at a flow rate of 110 mL / min and detected at 240 nm. The second eluted compound was collected25 to give the title compound N-(4-(((R*)-1-(2,4-difluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy- 4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) (24 mg, 32%). HRMS (ESI) m / z [M+H]+calcd for C18H26F2N5O3S2: 462.1440, found: 462.1430.1H 149 201389-PCT01-NP NMR (500 MHz, CDCl3) δ 0.83–0.96 (6H, m), 1.25–1.41 (overlapping with solvent, m), 1.43–1.75 (3H, m), 3.04 (3H, q), 3.48–3.72 (2H, m), 3.98–4.29 (1H, m), 5.06–5.34 (1H, m), 6.73–6.88 (2H, m), 7.00 (1H, s), 7.39–7.49 (1H, m). Example 81 5 N-(4-(((R*)-1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 (N-(4-(((R)-1-(4-Chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(4-Chloro-3- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- 10 yl)methanesulfonamide) The diastereomers of N-(4-((1-(4-chloro-3-fluorophenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 58 (114mg, 0.24 mmol) were separated by preparative chiral SFC on a Chiralpak AD column 15 (5 µm, 250×30 mm ID) eluted with 20% IPA / DEA (100 / 0.5) in CO2 at 120 bar and 40oC, and at a flow rate of 120 mL / min and detection at 230 nm. The second eluted compound was collected to give the title compound N-(4-(((R*)-1-(4-chloro-3-fluorophenyl)ethyl)thio)-6- (((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) (61 mg, 54%). HRMS (ESI) m / z [M+H]+calcd for C18H26ClFN5O3S2: 478.1144, found: 20 478.1132.1H NMR (500 MHz, CD3OD) δ 0.87–0.97 (6H, m), 1.35–1.51 (2H, m), 1.67 (4H, d), 3.16 (3H, d), 3.37–3.6 (2H, m), 4.18 (1H, dq), 5.09 (1H, p), 7.28 (1H, d), 7.31–7.43 (2H, m). Example 82 N-(4-(((R*)-1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 25 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 150 201389-PCT01-NP (N-(4-(((R)-1-(4-Chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(4-Chloro-2- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide) 5 The diastereomers of N-(4-((1-(4-chloro-2-fluorophenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 59 (171 mg, 0.36 mmol) were separated by preparative chiral SFC on a Chiralpak AD column (5 µm, 250×30 mm ID) eluted with 20% IPA / DEA (100 / 0.5) in CO2 at 120 bar and 10 40oC, and at a flow rate of 120 mL / min and detection at 230 nm. The second eluted compound was collected to give the title compound N-(4-(((R*)-1-(4-chloro-2- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 2) (58 mg, 34%). HRMS (ESI) m / z [M+H]+calcd for C18H26ClFN5O3S2: 478.1144, found: 478.1160.1H NMR (500 MHz, CDCl3) δ 1.20 (6H, dd), 15 1.62–1.8 (1H, m), 1.88–2.03 (4H, m), 3.45 (3H, d), 3.63–3.85 (2H, m), 4.46 (1H, dq), 5.57 (1H, q), 7.38–7.47 (2H, m), 7.76–7.84 (1H, m). Example 83 N-(4-(((R*)-1-(2-Chlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)a 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 20 (N-(4-(((R)-1-(2-Chlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(2-Chlorophenyl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) 151 201389-PCT01-NP The diastereomers of N-(4-((1-(2-chlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 60 (87 mg, 0.19mol) were separated by preparative chiral SFC on a Chiralpak AD column (5µm, 250×20 5 mm ID) eluted with 20% IPA in CO2 at 120 bar and 30oC, and at a flow rate of 70 mL / min and detection at 254 nm. The second eluted compound was collected to give the title compound N-(4-(((R*)-1-(2-chlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) (29 mg, 34%). HRMS (ESI) m / z [M+H]+calcd for C18H27ClN5O3S2: 460.1238, found: 460.1222.1H NMR (500 MHz, 10 CD3OD) δ 0.78 - 0.96 (m, 6H), 1.28 - 1.53 (m, 2H), 1.56 - 1.78 (m, 4H), 3.25 - 3.37 (m, overlapping with solvent), 3.48 - 3.63 (m, 2H), 4.14 - 4.24 (m, 1H), 5.42 - 5.52 (m, 1H), 7.19 - 7.26 (m, 1H), 7.26 - 7.32 (m, 1H), 7.35 - 7.4 (m, 1H), 7.55 (ddd, 1H). Example 84 N-(4-(((R*)-1-(2,4-Dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 15 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(2,4-Dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(2,4- Dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide) 20 152 201389-PCT01-NP The diastereomers of N-(4-((1-(2,4-dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 61 (89 mg, 0.18 mol) were separated by preparative chiral SFC on a Chiralpak IC column (5µm, 250×20 mm ID) eluted with 30% EtOH in CO2 at 120 bar and 30oC, and at a flow rate of 70 mL / min 5 and detection at 254 nm. The first eluted compound was collected to give the title compound N-(4-(((R*)-1-(2,4-dichlorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) (32 mg, 35%). HRMS (ESI) m / z [M+H]+calcd for C18H26Cl2N5O3S2: 494.0848, found: 494.0854.1H NMR (500 MHz, CD3OD) δ 0.89 – 1 (m, 6H), 1.33 – 1.57 (m, 2H), 1.62 – 1.78 (m, 4H), 3.28 – 3.41 (m, 10 overlapping with solvent), 3.42 – 3.65 (m, 2H), 4.16 – 4.27 (m, 1H), 5.4 – 5.49 (m, 1H), 7.31 – 7.36 (m, 1H), 7.45 – 7.51 (m, 1H), 7.59 (dd, 1H). Example 85 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-phenylbutyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide 15 DIPEA (0.080 mL, 0.46 mmol) and a solution of (1-chlorobutyl)benzene (70 mg, 0.42 mmol) in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (167 mg, 0.42 mmol) in DMF (2 mL). The reaction mixture was heated at 60°C for 19 h. (1- 20 Chlorobutyl)benzene (38 mg, 0.22 mmol) was added and the reaction mixture was heated in a microwave reactor at 100°C for 30 min. Water and MTBE was added and the two phases were separated. The organic layer was washed with water, concentrated and the residue was purified by normal phase flash column chromatography on silica (DCM, then DCM:MeOH, 10:1) to give the title compound (101 mg, 54%) as a solid. HRMS (ESI) m / z [M+H]+calcd 25 for C20H32N5O3S2: 454.1940, found: 454.1934.1H NMR (400 MHz, DMSO-d6) δ 0.80–0.92 (9H, m), 1.05–2.21 (6H, m), 3.32–3.46 (overlapping with solvent, m), 3.89–4.21 (1H, m), 4.64–4.77 (1H, m), 4.83–4.93 (1H, m), 7.16–7.55 (5H, m). 153 201389-PCT01-NP Example 86 N-(4-(((R*)-1-(5-Chloropyridin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(5-Chloropyridin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- 5 yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(5-Chloropyridin-2- yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide) The diastereomers of N-(4-((1-(5-chloropyridin-2-yl)ethyl)thio)-6-(((R)-1-hydroxy-4- 10 methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 62 (36 mg, 0.08 mol) were separated by preparative chiral SFC on a Chiralcel OJ column (5µm, 250×30 mm ID) eluted with 15% EtOH / DEA (100 / 0.5) in CO2at 120 bar and 40oC, and at a flow rate of 80 mL / min and detection at 230 nm. The first eluted compound was collected to give the title compound containing DEA from the eluent. The compound was dissolved in DCM and 15 washed with 1 M citric acid solution. The organic layer was passed through a phase separator and concentrated to give the title compound N-(4-(((R*)-1-(5-chloropyridin-2-yl)ethyl)thio)- 6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) (14 mg, 38%). HRMS (ESI) m / z [M+H]+calcd for C17H26ClN6O3S2: 461.1190, found: 461.1180.1HNMR (500 MHz, CD3OD) δ 0.86 – 1.00 (m, 6H), 1.35 – 1.53 (m, 2H), 20 1.60 – 1.78 (m, 4H), 3.29 – 3.34 (m, overlapping with solvent), 3.35–3.6 (2H, m), 4.13 – 4.27 (m, 1H), 5.17 (q, 1H), 7.60 (ddd, 1H), 7.79 (ddd, 1H), 8.47 (ddd, 1H). Example 87 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((3,3,3-trifluoro-1-phenylpropyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide 154 201389-PCT01-NP DIPEA (0.074 mL, 0.42 mmol) and a solution of (1-bromo-3,3,3- trifluoropropyl)benzene (98 mg, 0.39 mmol) in DMF (0.5 mL) were added to a solution of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- 5 yl)methanesulfonamide Intermediate 2 (155 mg, 0.39 mmol) in DMF (2 mL). The reaction mixture was stirred at ambient temperature for 30 min and then heated to 100°C for 1 h. Water and MTBE were added, and the two phases were separated. The organic layer was washed with water and brine, and then concentrated. The residue was purified by normal phase column chromatography on silica (DCM:MeOH, 20:1) to yield the title compound as a 10 colourless solid (57 mg, 36%). MS (ESI) m / z [M+H]+494.3. HRMS (ESI) m / z [M+H]+calcd for C19H27F3N5O3S2: 494.1502, found: 494.1510.1H NMR (400 MHz, CD3OD) δ 0.90–1.01 (6H, m), 1.35–1.57 (2H, m), 1.68 (1H, dd), 3.29–3.37 (overlapping with solvent, m), 3.55 (2H, tt), 4.1–4.37 (1H, m), 5.20 (1H, ddd), 7.24–7.49 (5H, m). Example 88 15 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(2-methoxypyridin-4-yl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide A mixture of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5- triazin-2-yl)methanesulfonamide Intermediate 2 (298 mg, 0.93 mmol), 4-(1-bromoethyl)-2- 20 methoxypyridine Intermediate 63 (200 mg, 0.93 mmol) and DIPEA (0.323 mL, 1.85 mmol) in DMF (10 mL) was stirred at rt for 5 h. The mixture was concentrated. The residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (200 mg, 47%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C18H29N6O4S2: 457.1686, found: 155 201389-PCT01-NP 457.1686.1H NMR (300MHz, DMSO-d6) δ 0.89-0.73 (m, 6H), 1.24-1.48 (m, 2H), 1.48-1.68 (m, 4H), 3.21-3.43 (m, overlapping with solvent), 3.83 (s, 3H), 3.88-4.09 (m, 1H), 4.63-4.74 (m, 1H), 4.87-4.98 (m, 1H), 6.89 (d, 1H), 7.06-7.13 (m, 1H), 7.68- 7.84 (m, 1H). 5 Example 89 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(2-methylpyridin-4-yl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide A mixture of (R)-N-(4-((1-hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-10 triazin-2-yl)methanesulfonamide Intermediate 2 (321 mg, 1.00 mmol), 4-(1-bromoethyl)-2- methylpyridine Intermediate 64 (200 mg, 1.00 mmol), and DIPEA (0.349 mL, 2.00 mmol) in DMF (8 mL) was stirred at rt for 5 h. The mixture was concentrated and the residue was purified by preparative TLC (DCM:MeOH, 10:1) to give the title compound (200 mg, 44%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C18H29N6O3S2: 441.1738, found: 15 441.1730.1H NMR (300MHz, DMSO-d6) δ 0.66-0.88 (m, 6H) 1.25-1.70 (m, 6H), 2.55 (s, 3H), 3.21-3.47 (m, overlapping with solvent), 3.88-4.16 (m, 1H), 4.63-4.75 (m, 1H), 4.84- 4.97 (m, 1H), 7.25-7.45 (m, 1H), 7.68-7.48 (m, 1H). Example 90 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(5-methylpyrimidin-2- 20 yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 (N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-(5-methylpyrimidin-2- yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((R)-1-Hydroxy-4- methylpentan-2-yl)amino)-6-(((S)-1-(5-methylpyrimidin-2-yl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide) 156 201389-PCT01-NP The diastereoisomers of N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-(5- methylpyrimidin-2-yl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 67 (200 mg, 0.45 mmol) were separated by preparative HPLC, PrepMethod P (using 5 decreasingly polar mixtures of 1% NH4CO3 aq) in MeCN as eluant). The desired compound were collected and concentrated to give the title compound N-(4-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-6-(((R*)-1-(5-methylpyrimidin-2-yl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 2) (35 mg, 17%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C17H28N7O3S2: 442.1690, found: 442.1706.1H NMR (400 MHz, DMSO-d6): δ 0.88- 10 0.85 (m,6H), 1.5-1.25 (m,2H), 1.6 (s,1H), 1.70-1.67 (t,3H), 2.25 (s,3H), 3.19-3.13 (d,2H), 3.31 (s,3H), 4.2-3.8 (d,1H), 4.65 (s,1H), 5.22-5.14 (m,1H), 8.62 (s,2H). Example 91 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-((1-(5-methylpyridin-2-yl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide 15 DIPEA (0.314 mL, 1.80 mmol) was added to 2-(1-bromoethyl)-5-methylpyridine ACS Catalysis (2023), 13(23), 15633-15640 (180 mg, 0.90 mmol) and (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (289 mg, 0.90 mmol) in DMF (10 mL) at 0°C under an atmosphere of N2(g). The reaction 20 mixture was stirred at rt for 3 h. The mixture was diluted with EtOAc (20 mL) and washed with brine (3×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by preparative HPLC, PrepMethod P using decreasingly 157 201389-PCT01-NP polar mixture of the mobile phase, to give the title compound (200 mg, 50%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C18H29N6O3S2: 441.1738, found: 441.1742.1H NMR (400 MHz, DMSO-d6): δ 0.80-0.95 (m, 6H), 1.20-1.48 (m, 2H), 1.50-1.65 (s, 1H), 1.65-1.75 (d, 3H), 2.20- 2.40 (s, 3H), 3.30-3.50 (m, 4H), 3.90-4.30 (d, 1H), 4.30-4.90 (s, 1H), 5.0-5.20 5 (m, 1H), 7.30-7.50 (m, 1H), 7.50-7.80 (m, 2H), 8.36 (s, 1H). Example 92 N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2,3,6- trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R)-1-(2,3,6-10 trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((R)-1-Hydroxy- 4-methylpentan-2-yl)amino)-6-(((S)-1-(2,3,6-trifluorophenyl)ethyl)thio)-1,3,5-triazin-2- yl)methanesulfonamide) Step a) N-(4-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-((1-(2,3,6- 15 trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.679 mL, 3.89 mmol) was added to (R)-N-(4-((1-hydroxy-4-methylpentan- 2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (250 mg, 0.78 mmol), and 2-(1-bromoethyl)-1,3,4-trifluorobenzene Intermediate 68 (186 mg, 0.78 20 mmol) in DMF (5 mL) at 15°C under an atmosphere of N2(g). The reaction mixture was stirred at 25°C for 2 h. The mixture was concentrated to give crude title compound. 158 201389-PCT01-NP Step b) N-(4-(((R)-1-Hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2,3,6- trifluorophenyl)ethyl)thio)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 The diastereomers of the crude step a) product were separated by preparative chiral HPLC on a ChiralPak IC column (5 µm, 250×20 mm ID), eluted with 15% EtOH in hexane. 5 The first eluted compound was collected and concentrated to give the title compound N-(4- (((R)-1-hydroxy-4-methylpentan-2-yl)amino)-6-(((R*)-1-(2,3,6-trifluorophenyl)ethyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) (53.0 mg, 14%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C18H25F3N5O3S2: 480.1346, found: 480.1382.1H NMR (400MHz, DMSO-d6) δ 0.85-0.92 (m, 6H), 1.30-1.65 (m, 3H), 1.72 (d, 3H), 3.35-3.45 (m, 10 5H), 3.98-4.15 (m, 1H), 4.70 (t, 1H), 5.46-5.52 (m, 1H), 7.15-7.25 (m, 1H), 7.42-7.52 (m, 1H), 7.70-7.85 (m, 1H), 11.30 (br, 1H). Example 93 N-(4-(((R*)-1-(6-Chloro-5-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 2 15 (N-(4-(((R)-1-(6-Chloro-5-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(6-Chloro-5- fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide)20 The diastereoisomers of N-(4-((1-(6-chloro-5-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1- hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 70 (80 mg, 0.17 mmol) were separated by preparative chiral HPLC on a Chiralpak IA column (5 µm, 250×20 mm ID), eluted with 20% IPA in hexane (0.1% TFA). The second eluted 25 compound was collected to give the title compound as a TFA salt. The isomer was further purified by preparative HPLC, PrepMethod S (gradient 30–70%) to give the title compound 159 201389-PCT01-NP N-(4-(((R*)-1-(6-chloro-5-fluoropyridin-3-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan- 2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 2) (20.0 mg, 25%) as a white solid. HRMS (ESI) m / z [M+H]+calcd for C17H25ClFN6O3S2: 479.1096, found: 479.1086.1H NMR (300 MHz, DMSO-d6): δ 0.83-0.89 (6H, m), 1.24-1.69 (6H, m), 3.24-3.36 (5H, m), 5 3.96-4.03 (1H, m), 5.00 (1H, q), 8.15 (1H, dd), 8.50 (1H, d). Example 94 N-(4-((1-(2-Bromopyridin-4-yl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide 10 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2- yl)methanesulfonamide Intermediate 2 (0.241 g, 0.75 mmol) was dissolved in DMF (2 mL) and DIPEA (0.157 mL, 0.90 mmol) was added followed by a solution of 1-(2-bromopyridin- 4-yl)ethyl methanesulfonate Intermediate 74 (210 mg, 0.75 mmol) in DMF (1.5 mL). The reaction mixture was heated at 80°C for 6 h. Water and DCM were added and the two phases 15 were separated. The aqueous layer was extracted with DCM. The combined organic layer was washed with water and concentrated. The residue was purified by preparative HPLC, PrepMethod U (gradient: 25–30%) to give the title compound (153 mg, 43%). HRMS (ESI) m / z [M+H]+calcd for C17H26BrN6O3S2: 505.0686, found: 505.0674.1H NMR (600 MHz, DMSO-d6): δ 0.8–0.89 (6H, m), 1.22–1.45 (2H, m), 1.47–1.71 (3H, m), 3.84–4.05 (1H, m), 20 4.62–4.76 (1H, m), 4.88–4.99 (1H, m), 7.52–7.64 (1H, m), 7.68–7.86 (2H, m), 8.28–8.36 (1H, m), 11.22 (1H, s). Example 95 N-(4-((1-(2-Bromophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide 160 201389-PCT01-NP 1-(2-Bromophenyl)ethan-1-ol (101 mg, 0.5 mmol) was dissolved in DCM (2 mL). 5 Methanesulfonyl chloride (0.043 ml, 0.55 mmol) and DIPEA (0.105 ml, 0.60 mmol) were added. The reaction mixture was stirred at rt for 5 h. Water (3 mL) and DCM (6 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The mixture was concentrated and used in the next step without further purification assuming full conversion. 10 Step b) N-(4-((1-(2-Bromophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide DIPEA (0.105 mL, 0.60 mmol) was added to a solution of (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (0.161 g, 0.50 mmol) in DMF (1 mL). The mixture was added to a solution of 1-(2- 15 bromophenyl)ethyl methanesulfonate Example 95 Step a) (139 mg, 0.5 mmol) in DMF (1 mL). The reaction mixture was stirred at 80°C for 6 h. Water (3 mL) and DCM (6 mL) were added, and the two phases were separated. The aqueous layer was extracted with DCM (1 mL). The combined organic layer was concentrated, and the residue was purified by preparative HPLC, PrepMethod J (gradient: 5-95%) to give the title compound (103 mg, 20 41%). HRMS (ESI) m / z [M+H]+calcd for C18H27BrN5O3S2: 504.0734, found: 504.0748.1H NMR (600 MHz, DMSO-d6) 7.73 (1H, br s), 7.63–7.67 (1H, m), 7.61 (1H, td), 7.38–7.45 (1H, m), 7.21–7.28 (1H, m), 5.27–5.42 (1H, m), 4.58–4.73 (1H, m), 3.98–4.17 (1H, m), 3.22– 3.44 (m, partly overlapping with solvent), 1.66–1.8 (3H, m), 1.53–1.64 (1H, m), 1.27–1.5 (2H, m), 0.78–0.91 (6H, m). 25 Example 96 161 201389-PCT01-NP N-(4-(((R*)-1-(4-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 (N-(4-(((R)-1-(4-Fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)- 1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(4-Fluorophenyl)ethyl)thio)-6-(((R)-1- 5 hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide) The diastereoisomers of N-(4-((1-(4-fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 71 (59 mg, 0.13 mmol) were separated by chiral SFC on a Chiralcel OJ column (5µm, 250×30 mm ID), 10 eluted with 40% MeOH in CO2 at 120 bar and at rt, and at a flow rate of 80 mL / min. The first eluted compound was collected to give the title compound N-(4-(((R*)-1-(4- fluorophenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin-2- yl)methanesulfonamide (Isomer 1) (23 mg, 39%). HRMS (ESI) m / z [M+H]+calcd for C18H27FN5O3S2: 444.1534, found: 444.1536.1H NMR (500 MHz, CD3OD) δ 0.82 – 1.04 (m, 15 6H), 1.34 – 1.55 (m, 2H), 1.6 – 1.8 (m, 4H), 3.24 – 3.40 (m, 3H), 3.41 – 3.65 (m, 2H), 4.14 – 4.32 (m, 1H), 5.01 – 5.14 (m, 1H), 6.95 – 7.12 (m, 2H), 7.37 – 7.56 (m, 2H). Example 97 N-(4-(((R*)-1-(4-(Difluoromethoxy)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide, Isomer 1 20 (N-(4-(((R)-1-(4-(Difluoromethoxy)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2- yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide or N-(4-(((S)-1-(4- (Difluoromethoxy)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide) 162 201389-PCT01-NP The diastereoisomers of Intermediate 72 (170 mg, 0.35 mmol) were separated by chiral SFC on a CHIRALPAK IC column (5µm, 250×50 mm ID) eluted with 40% EtOH in CO2, at a flow rate of 170 mL / min. The first eluted compound was collected to give the title 5 compound N-(4-(((R*)-1-(4-(difluoromethoxy)phenyl)ethyl)thio)-6-(((R)-1-hydroxy-4- methylpentan-2-yl)amino)-1,3,5-triazin-2-yl)methanesulfonamide (Isomer 1) (65 mg, 38%). HRMS (ESI) m / z [M+H]+calcd for C19H28F2N5O4S2: 492.1546, found: 492.1542.1H NMR (400 MHz, CD3OD) δ 0.95-0.99 (m, 6H), 1.42-1.52 (m, 2H), 1.65-1.79 (m, 4H), 3.49-3.58 (m, 2H), 4.18-4.29 (m, 1H), 5.09-5.12 (m, 1H), 6.80 (t, 1H), 7.11 (t, 2H), 7.50-7.53 (m, 2H). 10 Example 98 (R)-N-(4-((2-(Difluoromethyl)benzyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5- triazin-2-yl)methanesulfonamide DIPEA (0.043 mL, 0.25 mmol) and 1-(bromomethyl)-2-(difluoromethyl)benzene15 (0.018 mL, 0.12 mmol) was added to a solution of (R)-N-(4-(1-hydroxy-4-methylpentan-2- ylamino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (0.04 g, 0.12 mmol) in DMF (1 mL). The reaction mixture was stirred at 110°C for 1 h. The reaction was cooled, water (100 µL) was added and the mixture was purified by preparative HPLC, PrepMethod L (gradient: 30–80%) to give the title compound (31 mg, 54%). HRMS (ESI) 20 m / z [M+H]+calcd for C18H26F2N5O3S2: 462.1440, found: 462.1436.1H NMR (600 MHz, DMSO-d6) δ 0.73–0.97 (6H, m), 1.29–1.46 (2H, m), 1.52–1.67 (1H, m), 3.98–4.18 (1H, m), 163 201389-PCT01-NP 4.47–4.58 (2H, m), 4.73 (1H, t), 7.44 (1H, t), 7.16–7.41 (1H, m), 7.51 (1H, t), 7.59 (1H, d), 7.64–7.72 (1H, m), 7.72–7.88 (1H, m), 11.24 (1H, s). Example 99 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-methoxyphenethyl)thio)-1,3,5- 5 triazin-2-yl)methanesulfonamide A solution of 1-(2-chloroethyl)-4-methoxybenzene (24.53 mg, 0.14 mmol) in DMF (0.6 mL) followed by of DIPEA (0.057 mL, 0.33 mmol) was added to (R)-N-(4-((1-hydroxy- 4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide 10 Intermediate 2 (50 mg, 0.13 mmol). The reaction mixture was stirred at rt for 21 h and then heated in a microwave reactor at 140oC for 30 min. DCM (2 mL) and water (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator and concentrated. The residue was purified by preparative HPLC, PrepMethod H (gradient 0–50%) to give the title compound (47 mg, 79%). HRMS (ESI) m / z [M+H]+calcd 15 for C19H30N5O4S2: 456.1734, found: 456.1726.1H NMR (600 MHz, DMSO-d6) δ 0.82–0.89 (6H, m), 1.27–1.44 (2H, m), 1.52-1.63 (1H, m), 2.88 (2H, ddd), 3.15–3.26 (2H, m), 3.72 (3H, d), 3.97–4.17 (1H, m), 4.64–4.78 (1H, m), 6.82–6.88 (2H, m), 7.17–7.24 (2H, m), 7.65 (1H, s), 11.15 (1H, s). Example 100 20 (R)-N-(4-((4-Acetylphenethyl)thio)-6-((1-hydroxy-4-methylpentan-2-yl)amino)-1,3,5-triazin- 2-yl)methanesulfonamide 164 201389-PCT01-NP A solution of 1-(4-(2-chloroethyl)phenyl)ethanone (26 mg, 0.14 mmol) in DMF (0.6 mL) followed by DIPEA (0.057 mL, 0.33 mmol) were added to (R)-N-(4-((1-hydroxy-4- methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (50 mg, 0.13 mmol). The reaction mixture was stirred at rt for 21 h.1-(4-(2- 5 Chloroethyl)phenyl)ethanone (26 mg, 0.14 mmol) was added and the reaction mixture was heated in a microwave reactor at 140oC for 30 min. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a phase separator. The mixture was concentrated, and the residue was purified by preparative HPLC, PrepMethod H (gradient: 0–50%) to give the title compound (43 mg, 70%). HRMS (ESI) m / z10 [M+H]+calcd for C20H30N5O4S2: 468.1734, found: 468.1734,1H NMR (600 MHz, DMSO- d6) δ 0.85 (6H, ddd), 1.27–1.43 (2H, m), 1.51-1.63 (1H, m), 2.56 (3H, s), 3.01–3.09 (2H, m), 3.25-3.49 (partly overlapping with solvent, d), 3.97–4.15 (1H, m), 4.65–4.78 (1H, m), 7.45 (2H, dd), 7.90 (2H, dd). Example 101 15 (R)-N-(4-((1-Hydroxy-4-methylpentan-2-yl)amino)-6-((4-(2-methylthiazol-4-yl)benzyl)thio)- 1,3,5-triazin-2-yl)methanesulfonamide A solution of 4-(4-(bromomethyl)phenyl)-2-methylthiazole (38 mg, 0.14 mmol) in DMF (0.6 mL) followed by DIPEA (0.054 ml, 0.31 mmol) were added to (R)-N-(4-((1- 20 hydroxy-4-methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (50 mg, 0.12 mmol) The reaction mixture was stirred at rt for 20 h.4-(4- (Bromomethyl)phenyl)-2-methylthiazole (38 mg, 0.14 mmol) was added and the reaction mixture was heated in a microwave reactor at 140oC for 30 min. Water (2 mL) and DCM (2 mL) were added. The two phases were separated, and the organic layer was passed through a 25 phase separator. The mixture was concentrated, and the residue was purified by preparative HPLC, PrepMethod H (gradient: 25–30%) to give the title compound (11 mg, 17%). HRMS 165 201389-PCT01-NP (ESI) m / z [M+H]+calcd for C21H29N6O3S3: 509.1458, found: 509.1458.1H NMR (600 MHz, DMSO-d6) δ 0.78 – 0.93 (m, 6H), 1.28 – 1.46 (m, 2H), 1.53 – 1.65 (m, 1H), 2.70 (s, 3H), 3.25 – 3.42 (m, overlapping with solvent), 3.96 – 4.16 (m, 1H), 4.37 (d, 2H), 7.49 (dd, 2H), 7.82 – 7.91 (m, 3H). 5 Examples 102–131 General Synthesis Scheme 3 Intermediate 2 Intermediate A Example 102-131 X=Cl, Br and nand p are as defined in Formula 1 Scheme 3=0 or 1, A, R3, R4, R5General Preparation Method C Intermediate A (0.2 mmol, 1.1 eq) was added to a solution of (R)-N-(4-((1-hydroxy-4- 10 methylpentan-2-yl)amino)-6-mercapto-1,3,5-triazin-2-yl)methanesulfonamide Intermediate 2 (0.20 mmol, 1.0 eq) and DIPEA (0.44 mmol, 2.2 eq) in THF (2 mL) and the reaction mixture was shaken at 50oC on. The mixture was concentrated, and the crude product was purified by preparative TLC to afford the compounds in Example 102-131 below. 166 201389-PCT01-NP Table 3: The Examples included in Table 3 were synthesized and purified as described in General Preparation Method C using appropriate Intermediate A. The Intermediates A are commercially available or can be prepared in analogy with previous descriptions, or can be prepared as described in the intermediate section. 5 Ex. HRM NoStructure NameS (ESI) m / z [M+H]+ Y (mg) A*1 167 201389-PCT01-NP (R)-N-(4-((1-Hydroxy-4- methylpentan calcd for OH -2-yl)amino)- H 168 201389-PCT01-NP yl)thio)methyl)phenyl)carba mate 5 169 201389-PCT01-NP (R)-2-(4-(((4-((1-Hydroxy- 4-methylpentan-2- H calcd for 2) 7 8 170 201389-PCT01-NP (R)-N-(4-(((1,1-Dioxido- 2,3- OH calcd for 2 3 7 171 201389-PCT01-NP (R)-5-(((4-((1-Hydroxy-4- OH methylpentan-2-yl)amino)- calcd for 8 1 2 ) lit ref WO2024025907 3)lit ref ChemistrySelect (2017), 2(33), 10804-10808 172 201389-PCT01-NP Pharmacological Activity: Materials Adherent CHO-K1 cells stably expressing hCX3CR1 (ES-137-C) were purchased from PerkinElmer. The RPMI-8226 cell line (CCL-155) was purchased from A.T.C.C. The CHO-K1 CX3CR1 β-arrestin cell line (93-0290C2) was from DiscoveRx. hWB was collected from healthy volunteers. The work was performed in accordance with the Declaration of Helsinki (2013) of the World Medical Association and has been approved by the relevant ethical committee. AZD8797 (CAS911715-90-7) was synthesized as described previously (J. Med. Chem (2013), 56(8), 3177-3190; J, Labelled Comp. and Radiopharmaceuticals, (2012), 55(10), 387-392). [3H]AZD8797 (50 Ci / mmol, 52.932 μM) was labelled in-house,125I-CX3CL1 (2200 C / mmol) and [35S]GTPγ S (guanosine 5’- [γ-thio]triphosphate) (1250 Ci / mmol) were purchased from PerkinElmer, CX3CL1 (8.5 kDa, soluble chemokine domain, unless otherwise stated, was the ligand used) was from Peprotech and recombinant His-tagged full-length human CX3CL1 (365-FR-025 / CF) was from R&D Systems. Pertussis toxin (PTX), polyethyleneimine (PEI), GTPγ S, GDP and gelatin type A were purchased from Sigma Aldrich. Vena8 Fluoro+ Biochips for cell adhesion assays were purchased from Cellix.3,3’- dihexyloxacarbocyanine iodide (DiOC6) was from Molecular Probes and Hoechst 33342 was from Invitrogen. HEPES, Roswell Park Memorial Institute 1640 (RPMI 1640) medium, Ham’s F12 (Nutrient mixture F-12 Ham) medium, Dulbecco’s modified eagle medium (DMEM), geneticin, phosphate-buffered saline 200898-US-PSP 14 (PBS), Hanks’ balanced salt solution (HBSS) and Opti-MEM were purchased from Gibco (Life Technologies). Abbreviations and units used: A.T.C.C. American Type Culture Collection; distributes reference microorganisms / cell lines for R&D BSA Bovine serum albumin derived from cows and used as a protein concentration standard in lab and protein supplement in in vitro assays. CHO-K1 an immortalized cell line isolated from the ovary of an adult, female Chinese hamster 173 201389-PCT01-NP Ci Curie = 3.7mmol-1 x 1010atoms that decay / second; Ci / mmol = amount radiolabeled mass in a sample DiOC6 Dihexyloxacarbocyanine iodide DMEM Dulbecco’s modified eagle medium (cell medium) FBS Fetal bovine serum GDP Guanosine diphosphate GTP Guanosine-5'-triphosphate HBSS Hanks’ balanced salt solution HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid); zwitterionic sulfonic acid buffering agent Hoechst 33342 a fluorescent stain for labeling DNA in fluorescence microscopy kDa Kilodalton Opti-MEM™ Reduced-Serum Medium; contains insulin, transferrin, hypoxanthine, thymidine, and trace elements PBS Phosphate-buffered saline 200898-US-PSP 14 PEI Polyethyleneimine PTX Pertussis toxin RPMI 1640 Roswell Park Memorial Institute 1640 cell medium WGA coated PVT Wheat germ agglutinin PEI-coated SPA beads for proximity-based radiometric scintillation assays hCX3CR1 [3H]-AZD8797 competitive binding assay (filter) CHO-hCX3CR1 membranes (9 μg per well) together with 2 nM [3H]-AZD8797 and different concentrations of competitor compound were incubated in 25 mM HEPES (pH 7.4), 10 mM MgCl2, 1mM CaCl2 and 0.5% BSA in a Corning polystyrene flat-bottom 96-well plate. The plate was incubated for 2 h at room temperature before free radioligand was separated from bound by vacuum filtration on to a Multiscreen HTS + HiFlow FB (Millipore) filter plate, using a Biomek 174 201389-PCT01-NP FX (Beckman Coulter). The filter plate was washed in ice-cold 25 mM HEPES (pH 7.4), 5 mM MgCl2, 1 mM CaCl2 and 500 mM NaCl and dried at 50ºC for 1 h. Scintillation cocktail, Optiphase Supermix (PerkinElmer) was added to each well and the radioactivity was measured using a MicroBeta Trilux reader (PerkinElmer). The DMSO concentration was held constant at 1%. The results from this assay are shown below in . hCX3CR1 [125I]-CX3CL1 displacement binding (SPA) CHO-hCX3CR1 membranes (3 μg per well) together with 75 pM [125I]-CX3CL1 (Perkin Elmer) and different concentrations of competitor compound were incubated together with 400 µg / well WGA coated PVT SPA beads (Perkin Elmer) in 50 mM HEPES (pH 7.4), 10 mM MgCl2, 1mM EDTA and 0.1% Gelatin in a Greiner polystyrene flat-bottom 384-well plate. The plate was incubated for 20 h at room temperature before the radioactivity was measured using a MicroBeta Trilux reader (PerkinElmer). The DMSO concentration was held constant at 1%. Results are shown below in . Table 4: Binding Data 175 201389-PCT01-NP Filter SPA Cmpd Binding Binding StructureMean Mean 176 201389-PCT01-NP 177 201389-PCT01-NP 178 201389-PCT01-NP 179 201389-PCT01-NP 180 201389-PCT01-NP 201389-PCT01-NP 201389-PCT01-NP 183 201389-PCT01-NP 184 201389-PCT01-NP 185 201389-PCT01-NP 186 201389-PCT01-NP 201389-PCT01-NP 188 201389-PCT01-NP 189 201389-PCT01-NP 190 201389-PCT01-NP 191 201389-PCT01-NP F 192 201389-PCT01-NP 193 201389-PCT01-NP 201389-PCT01-NP 201389-PCT01-NP 196 201389-PCT01-NP 197 201389-PCT01-NP 198 201389-PCT01-NP 201389-PCT01-NP 200 201389-PCT01-NP 201 201389-PCT01-NP 202 201389-PCT01-NP 201389-PCT01-NP 201389-PCT01-NP 201389-PCT01-NP 206 201389-PCT01-NP 207 201389-PCT01-NP 208

Claims

201389-PCT01-NP CLAIMS What is claimed:

1. A compound of Formula (I) R1OH (I) whereinR1 is a C3-6 branched alkyl or C3-6 branched haloalkyl; R2 is a C1-3 alkyl or C1-3 haloalkyl; n is 0 or 1; R3 and R4 are, independently, selected from H, halo, C1-3 alkyl, and C1-3 haloalkyl; A is phenyl, monocyclic heteroaryl, bicyclic aryl, or bicyclic heteroaryl; p is 0, 1, 2, 3, or 4; each R5is independently selected from halo, hydroxy, oxo, C1-3alkyl, C1-3haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkoxy-C1-3alkyl, C1-3 hydroxyalkyl, -NO2, - (CH2)qCN, -C(O)NR6R7, -NS(O)R6R7, NR6C(O)R7, -NR6R7,-NR6C(O)OR7, - (CH2)qC(O)NR6R7, -(CH2)qNR6C(O)R7, -C(O)NR6COR7,-(CH2)qR8, -C(O)R8, -C(O)OR9,-OC(O)R9, C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl, wherein the C3-6cycloalkyl or 4-6 member heterocyclyl can be optionally substituted with 1 to 3 substituents selected from hydroxy, oxy, halo, -C(O)NR6R7, and -C(O)OR9; the 4-6 member heteroaryl can be optionally substituted with 1 to 3 halo substituents; the C1-4alkoxy can be optionally substituted with a 4-6 member heterocyclyl; 210201389-PCT01-NP the C3-6 cycloalkyl, 4-6 member heteroaryl, 4-6 member heterocyclyl, and phenyl can be optionally substituted with -CH3; each R6and R7are, independently, selected from H, -C1-3alkyl, and -C1-3alkoxy each q is, independently, 0, 1, 2, or 3; each R8 is, independently, a C1-5 alkyl or a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy; and each R9is, independently, a C1-5alkyl; or a pharmaceutically acceptable salt or tautomer thereof.

2. The compound of claim 1, having the structure of Formula (Ia): R1a).

3. The compR1b).

4. The compound of any one of claims 1 to 3, wherein A is phenyl.

5. The compound of any one of claims 1 to 3, wherein A is a monocyclic heteroaryl. 211201389-PCT01-NP 6. The compound of claim 5, wherein A is a monocyclic N-heteroaryl.

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

8. The compound of any one of claims 5 to 7, wherein the 6-member monocyclic heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine or triazine.

9. The compound of any one of claims 1 to 3, wherein A is a 5-member monocyclic heteroaryl.

10. The compound of claim 9, wherein the 5-member monocyclic heteroaryl is a monocyclic- N-heteroaryl.

11. The compound of claim 10, wherein the 5-member monocyclic heteroaryl is pyrrole, pyrazole, or imidazole.

12. The compound of any one of claims 1 to 3, wherein A is a bicyclic aryl.

13. The compound of claim 12, wherein the bicyclic aryl comprises two 6-membered rings.

14. The compound of claim 12, wherein the bicyclic aryl is a naphthalene or isoindene.

15. The compound of any one of claims 1 to 3, wherein A is a bicyclic heteroaryl.

16. The compound of claim 15, wherein the bicyclic heteroaryl is benzodioxanyl, benzothioazolyl, benzodioxazolyl, indazolyl, indoxazinyl, indolyl, benzodihydrofuranyl, benzofuranyl, benzodihydropyrone, benzoxazolyl, indolizinyl, benzothiazolyl, benzoxazinyl, benzodihydrothiophenyl, quinolinyl, phthalazinyl, purinyl, indazolyl, indolyl, naphthyridinyl, pteridinyl, 17. The compound of any one of claims 1 to 16, wherein p is at least 1.

18. The compound of any one of claims 1 to 17, wherein p is 1, 2, 3, or 4.

19. The compound of any one of claims 1 to 16, wherein p is 0. 212201389-PCT01-NP 20. The compound of any one of claims 4 to 8, wherein p is 1, 2, 3, or 4 and at least one R5 is para to the ring atom bound to the R3-R4- substituted carbon.

21. The compound of any one of claims 4 to 8, wherein p is 1, 2, 3, or 4 and at least R5is ortho to the ring atom bound to the R3-R4- substituted carbon.

22. The compound of any one of claims 4 to 8, wherein p is 1, 2, 3, or 4 and at least one R5 is meta to the ring atom bound to the R3-R4- substituted carbon.

23. The compound of any one of claims 1 to 18 and 20 to 22, wherein p is 1, 2, 3 or 4 and at least one R5 is halo.

24. The compound of claim 23, wherein p is 1, 2, 3 or 4 and at least one R5is F.

25. The compound of claim 24, wherein p is 2, 3, or 4 and at least two R5are F.

26. The compound of claim 25, wherein p is 3 or 4 and at least three R5 are F.

27. The compound of any one of claims 1 to 18 and 20 to 26, wherein p is 1, 2, 3 or 4 and at least one R5is Cl.

28. The compound of claim 27, wherein p is 2, 3 or 4 and at least two R5 are Cl.

29. The compound of any one of claims 1 to 18 and 20 to 28, wherein p is 1, 2, 3 or 4 and at least one R5is oxo.

30. The compound of any one of claims 1 to 18 and 20 to 29, wherein p is 1, 2, 3 or 4 and at least one R5 is a C1-C3 alkyl.

31. The compound of claim 30, wherein p is 1, 2, 3 or 4 and at least one R5is methyl or ethyl.

32. The compound of any one of claims 1 to 18 and 20 to 31, wherein p is 1, 2, 3 or 4 and at least one R5is a C1-C3haloalkyl.

33. The compound of claim 32, wherein the C1-C3haloalkyl is fluoromethyl, fluoroethyl, difluoroethyl, fluoropropyl or difluoropropyl. 213201389-PCT01-NP 34. The compound of any one of claims 1 to 18 and 20 to 33, wherein p is 1, 2, 3 or 4 and at least one R5 is a C1-4 alkoxy.

35. The compound of claim 34, wherein p is 1, 2, 3 or 4 and at least one R5is -OCH3.

36. The compound of claim 35, wherein p is 1, 2, 3 or 4 and at least one R5 is -OCH2CH3.

37. The compound of any one of claims 1 to 18 and 20 to 36, wherein p is 1, 2, 3 or 4 and at least one R5is a C1-4haloalkoxy.

38. The compound of any one of claims 1 to 18 and 20 to 37, wherein p is 1, 2, 3 or 4 and at least one R5 is a C1-4 alkoxy- C1-3 alkyl.

39. The compound of claim 38, wherein the C1-4alkoxy- C1-3alkyl is ethoxyalkyl or methoxyalkyl.

40. The compound of claim 39, wherein the ethoxyalkyl is ethoxymethyl or ethoxyethyl.

41. The compound of claim 40, wherein the methoxyalkyl is methoxymethyl or methoxyethyl.

42. The compound of any one of claims 1 to 18 and 20 to 41, wherein p is 1, 2, 3 or 4 and at least one R5 is a hydroxy or a C1-C3 hydroxyalkyl.

43. The compound of claim 42, wherein the C1-C3hydroxyalkyl is hydroxymethyl or hydroxyethyl.

44. The compound of any one of claims 1 to 25, wherein p is 1, 2, 3 or 4 and at least one R5 is -(CH2)qCN, -C(O)NR6R7, or -NS(O)R6R7.

45. The compound of claim 44, wherein R6is H and R7is C1-3alkyl.

46. The compound of claim 44, wherein both R6 and R7 are C1-3 alkyl.

47. The compound of claim 44, wherein both R6and R7are H.

48. The compound of any one of claims 1 to 18 and 20 to 47, wherein p is 1, 2, 3 or 4 and at 214201389-PCT01-NP least one R5 is NR6C(O)R7, -NR6R7, -NR6C(O)OR7, -(CH2)qC(O)NR6R7, - (CH2)qNR6C(O)R7, -C(O)NR6COR7.

49. The compound of claim 48, wherein R6is H and R7is C1-3alkyl.

50. The compound of claim 48, wherein both R6 and R7 are C1-3 alkyl.

51. The compound of claim 48, wherein both R6 and R7 are H.

52. The compound of any one of claims 1 to 18 and 20 to 51, wherein p is 1, 2, 3 or 4 and at least one R5is -(CH2)qR8, or -C(O)R8.

53. The compound of claim 52, wherein R8 is a C1-5 alkyl.

54. The compound of any one of claims 1 to 18 and 20 to 53, wherein p is 1, 2, 3 or 4 and at least one R5is -CR6NR7C(O)R8, 55. The compound of claim 54, wherein R6 is methyl or ethyl, R7 is H, and R8 is ethyl or methyl.

56. The compound of claim 54, wherein R8is methyl, ethyl, or propyl.

57. The compound of claim 54, wherein R8 is a 4-6 member heterocyclyl, wherein the heterocyclyl is optionally substituted with an oxy.

58. The compound of any one of claims 1 to 57, wherein one of R3or R4is C1-3alkyl.

59. The compound of claim 58, wherein the C1-3alkyl is methyl or ethyl.

60. The compound of any one of claims 1 to 57, wherein one of R3 or R4 is H.

61. The compound of claim 60, wherein R4is H.

62. The compound of any one of claims 1 to 61, wherein one of R3or R4is halo.

63. The compound of any one of claims 1 to 62, wherein R1 is a C3-6 branched alkyl.

64. The compound of claim 63, wherein R1is a C4branched alkyl. 215201389-PCT01-NP 65. The compound of claim 64, wherein R1 is -CH2CH(CH3)2.

66. The compound of any one of claims 1 to 65, wherein R2 is a C1-3 alkyl.

67. The compound of claim 66, wherein R2is methyl.

68. The compound of any one of claims 1 to 67, wherein n is 0.

69. The compound of any one of claims 1 to 67, wherein n is 1.

70. The compound of claim 1, selected from any of the compounds in Error! Reference source not found. and pharmaceutically acceptable salts thereof.

71. The compound of claim 1, selected from the following compounds: 3 4216201389-PCT01-NP 9 10217201389-PCT01-NP 19 20218201389-PCT01-NP 33 36219201389-PCT01-NP 80 8372. The compound of claim 1, selected from one of the following compounds: 6 7201389-PCT01-NP 21 47 F221201389-PCT01-NP and pharmaceutically acceptable salts thereof.

73. A pharmaceutical composition comprising a compound of any one of claims 1 to 72 and a pharmaceutically acceptable excipient.

74. A compound of any one of claims 1 to 72 or a pharmaceutical composition of claim 73, for use in the treatment of cardiovascular disease.

75. The compound or composition of claim 74 wherein the cardiovascular disease is non- ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction.

76. 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 or composition of any one of claims 1 to 73.

77. The method of claim 76 wherein the cardiovascular disease is non-ischemic dilated cardiomyopathy, heart failure, cardiovascular disease associated with autoimmune conditions, cardiovascular disease associated with chronic inflammatory diseases, heart failure with reduced ejection fraction, heart failure with mildly reduced ejection fraction, or heart failure with preserved ejection fraction. 222

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