WO2012069852A1

WO2012069852A1 - Pharmaceutical compounds as inhibitors of sphingosine kinase

Info

Publication number: WO2012069852A1
Application number: PCT/GB2011/052334
Authority: WO
Inventors: Timothy Harrison; Frank Burkamp; Linda Jordan; Mark Bell; Dominic Janssen; Hugues Miel; Mary Mcfarland
Original assignee: Almac Discovery Limited
Priority date: 2010-11-26
Filing date: 2011-11-25
Publication date: 2012-05-31
Also published as: GB201020161D0

Abstract

The present invention relates to compounds that are useful as inhibitors of the activity of one or more isoforms of sphingosine kinase. Particularly, although not exclusively, the present invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment and/or prevention of cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases.

Description

PHARMACEUTICAL COMPOUNDS AS INHIBITORS OF SPHINGOSINE KINASE

The present invention relates to compounds that are useful as inhibitors of the activity of one or more isoforms of sphingosine kinase. Particularly, although not exclusively, the present invention also relates to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment and/or prevention of cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases. BACKGROUND TO THE INVENTION

The past few years have seen an upsurge of interest in the field of sphingolipids.

Sphingolipids not only represent the major component of the cellular membrane but also serve as a reservoir for important signaling molecules with pleiotropic effects on important cellular processes. Sphingolipid metabolites including ceramide, sphingosine and sphingosine-1 phosphate (S1 P), have emerged as a new class of potent bioactive messengers directly involved in numerous pathological conditions and disorders including cancer, hyperproliferative, inflammatory and immune disorders, angiogenesis, and viral infectious diseases. Consequently, the possibilities of harnessing the sphingolipid metabolic pathways represent a new avenue for the treatment and prevention of a variety of diseases related to undesirable sphingosine kinase (SphK) activity and S1 P homeostasis.

Ceramide results from the hydrolysis of sphingomyelin in response to various stimuli including inflammatory cytokines, chemokines, growth factors and hormones. Ceramide is further hydrolysed by ceramidase to produce sphingosine. Sphingosine in turn is rapidly phosphorylated by sphingosine kinase to produce S1 P.

Cells maintain a tightly-regulated and dynamic balance of distinct sphingolipid metabolites. Evidence demonstrates that ceramide and sphingosine exert antiproliferative effects such as cell growth inhibition, apoptosis induction and/or modulation of senescence. On the contrary, S1 P is a growth promoter and survival factor, acting by up-regulating several anti-apoptotic pathways including PI3K/AKT or nuclear factor-κΒ (NF-KB). Thus, the dynamic balance between intracellular levels of ceramide and/or sphingosine and S1 P, as well as the signaling that control this balance, are critical factors that dictate cell fate (i.e death vs survival). Altering the sphingolipid rheostat thus represents a promising approach to effective therapy.

A complex network of enzymes regulates the balance between the different sphingolipid metabolites in mammalian cells. However, a key enzyme in the sphingolipid metabolic pathway is sphingosine kinase (Sphk), which is responsible for the production of S1 P. Therefore, SphK represents a target for drug discovery and for the development of new therapeutics to treat a wide range of diseases where sphingosine pathway members have been shown to play a role. To date, two isoforms of sphingosine kinase have been identified and characterised, namely sphingosine kinase 1 and sphingosine kinase 2 (herein referred to as SphK1 and SphK2 respectively). Both enzymes phosphorylate sphingosine to produce S1 P. The functions of SphK1 and 2 are at least partly redundant as mice lacking either isoforms maintain nearly normal levels of S1 P and lack severe phenotypes. In contrast, the SphK1 and 2 double knock-out mouse is embryonic lethal due to incomplete maturation of the vascular system and brain. Overexpression of mice SphK1 in NHI-3T3 fibroblasts induces transformation via a Ras-dependant signaling pathway, hence demonstrating the oncogenic function of the enzyme. In humans, sphingosine kinases are ubiquitously expressed in cells with increased expression of SphK1 commonly reported in tumor tissues. SphK may be activated by a variety of proliferative factors including Tumor Necrosis Factor-alpha (TNFoc), protein kinase C (PKC), serum or Platelet-Derived Growth Factors (PDGF). Overexpression of SphK (SphK1 , SphK2) leads to increased S1 P generation. S1 P can then act as an intramolecular messenger and/or extracellular ligand for specific G-protein coupled receptors; namely S1 PR1 , S1 PR2, S1 PR3, S1 PR4, S1 PR5. The intracellular action of S1 P is pro-survival and pro-growth whilst signaling through the S1 P receptors elicits various cellular processes important to tumorigenesis and cancer progression including proliferation, survival, differentiation, transformation and vascularization / angiogenesis. Additional studies also implicate SphK activity (SphK1 , SphK2) in adhesion and migration of cancer cells, properties associated with metastatic potential and advanced state disease. Accordingly, SphK up-regulation correlates in the clinical setting with higher clinical grades and poor patient outcome. Importantly however, down-regulation of SphK (SphK1 , SphK2) by siRNA, inhibition by a dominant-negative SphK mutant or treatment with small molecule inhibitors has demonstrated strong anti-proliferative effects and has been shown to block

tumorigenesis and angiogenesis as well as metastasis in mice xeno- or allograft cancer models. Together these findings highlight the critical role SphK (SphK1 , SphK2) and S1 P signaling plays in the development and progression of cancer. Cancers that can be treated, managed and/or ameliorated include, but are not restricted to, benign, pre- malignant, metastatic and malignant cancers. Such cancers may include, without limitations, solid tumors as well as hematopoietic cancers.

One of the main obstacles involved in cancer therapy is the development of drug resistance. In this regard, numerous studies have reported a correlation between SphK activity and resistance to chemotherapy or irradiation. SphK1 overexpression typically impairs treatment efficacy by decreasing the ceramide / S1 P ratio. Interestingly, down- regulation of SphK (SphK1 , SphK2) by siRNA or pharmacologic inhibition induces ceramide elevation with concomitant loss of S1 P and apoptosis induction hence overcoming the resistance phenotype. Up-regulation of the drug-efflux pumps such as the MDR-associated protein (MRP-1 ) and P-gylcoprotein (Pgp) may represent an alternative mechanism for the development of multi-drug resistance (MDR) phenotypes in cancer. In a recent study performed in brain tumor-derived endothelial cells, overexpression of SphK1 was shown to enhance the expression of the drug-efflux- pumps at the mRNA and protein levels. S1 P was also shown to stimulate the transport activity of Pgp via activation of the S1 P1 and S1 P3 receptors. These findings

demonstrate the important role SphK (SphK1 , SphK2) play in the development and maintenance of MDR. Conseqently, SphK inhibitors alone or in combination therapies could provide a new strategy for the treatment and management of therapeutic-resistant cancers. While maintaining and/or enhancing efficacy of current single agent treatment or combination therapies, combinations with SphK (SphK1 , SphK2) inhibitors may provide a better therapeutic profile by improving efficacy and/or reducing unwanted, adverse effects. Treatments that can be used in combination with SphK (SphK1 , SphK2) inhibitors include, but or not restricted to, chemo- and radiotherapy, cancer vaccines, cytokines, immunotherapeutics (including antibodies or immunomodulators), anti- angiogenic agents, hormone therapies and gene therapies.

Another condition known to promote tumor progression and treatment failure in which the SphK / S1 P pathway is involved is hypoxia. Hypoxia exists in 50-60% of solid tumors. To circumvent periods of insufficient nutrient and oxygen supply, cells evolve

mechanisms to adapt to such conditions in which the hypoxia-inducible factor (HIF-1 oc) is core. Recent studies indicate that the SphK/S1 P pathway is a strong modulator of HIF- 1 a activity under hypoxic conditions. Likewise, HIF-1 a positively regulates the expression of SphK1 under hypoxia. Increased expression and activation of SphK1 and S1 P signaling through the S1 P receptors has been correlated with

vascularization/angiogenesis as well as enhanced survival via activation of the

AKT/GSK33 pathway. Enhanced survival following activation of the p42/44 MAPK signaling as a result of SphK2 activation has also been reported under hypoxia in A549 cells. These findings demonstrate the implication of the SphK / S1 P pathway in mediating hypoxia-related molecular changes that allow cancer cells to adapt and survive hypoxic tumor environments. Interfering with S1 P levels by inhibiting SphK

(SphK1 , SphK2) activity may therefore provide a novel approach to treat hypoxic tumors.

Recent evidence also implicates up-regulation of SphK (SphK1 , SphK2) activity and S1 P production in angiogenesis. Angiogenesis refers to a state in the body whereby various stimuli including growth factors promote the formation of new blood vessels. Excessive angiogenesis is commonly associated with disease progression and/or the production of undesirable effects. For instance, signaling of S1 P through the S1 P1 receptor stimulates NFKB production and promotes the formation of vascular endothelial growth factor (VEGF), COX-2, cytokines and adhesion molecules, all known contributors to

angiogenesis. In addition, SphK regulates the expression of endothelial isoforms of nitric oxide synthase which have also been implicated in modulating angiogenesis. In vivo, treatment of mice with anti-S1 P mAb blocked endothelial cell migration, capillary formation, inhibited VEGF- and FGF-induced blood vessel formation and arrested tumor- associated angiogenesis. The S1 P mAb also prevented the release of pro-angiogenic cytokines (IL-8, IL-6) from tumor cells. Thus inhibiting SphK (SphK1 , SphK2) activity and S1 P production in vascular endothelial cells can lead to reduction of angiogenesis and provide a novel strategy to treat and/or prevent disorders arising from abnormal angiogenesis. Such disorders include, but are not limited to, cancer, hemangiomas, arthritis, psoriasis, atherosclerosis, myocardial angiogenesis, diabetic retinopathy and/or macular degeneration.

Sphk (SphK1 , SphK2) and S1 P are also emerging as important mediators in

inflammatory responses and as regulators of immune cell functions. SphK1 has been shown to be activated by cytokines including tumors necrosis factor-alpha (TNF-alpha) and interleukinl -beta (IL1 -beta). The activation of SphK1 in this pathway has been shown to be, at least in part, required for mediating TNF-alpha and IL1 -beta inflammatory responses in cells, including induction of cyclo-oxygenease 2 (COX2). In addition to their role in inflammatory signaling, SphKs and S1 P have also been implicated in various immune cell functions including mast cell degranulation, migration of neutrophils, maturation and migration of lymphocytes, and T-cell development. Based on the direct involvement of S1 P in regulating specific inflammatory and autoimmune conditions, inhibiting SphK (SphK1 , SphK2) activity and reducing S1 P levels provides a novel approach for preventing, treating, managing, and/or ameliorating inflammation and autoimmune disorders. Sphingosine kinase (SphK1 , SphK2) inhibitors may be used as single agent or administered in conjunction with known immunomodulators or anti- inflammatory agents. Examples of immune disorders include, but are not restricted to ankylosing spondylitis, chronic fatigue immune dysfunction syndrome, Crohn's disease, multiple sclerosis, rheumatoid arthritis, autoimmune hepatitis, polyglandular syndromes, organ transplantation, post-surgical organ failure. Examples of inflammatory diseases include, but are not limited to, inflammatory bowel disease, asthma, allergy, septic shock, inflammatory kidney disease, post-surgical organ failure, organ transplantation, multiple sclerosis, skin inflammation and chronic inflammation as a result of viral or bacteria infections.

In addition to the above, SphK (SphK1 , SphK2) and S1 P are involved in various other pathological states such as diabetes, viral infections including HIV and Hepatitis C as well as diverse hyperproliferative disorders in addition to cancer including, but not limited to, psoriasis which is characterised by local keratinocyte hyperproliferation, mesangial disorders resulting from the abnormal proliferation of mesangial cells in the kidney as well as various vascular disorders such as atherosclerosis and restenosis both characterised by hyperproliferation of vascular smooth muscle cells. Growing evidence implicates SphK (SphK1 , SphK2) activation in the pathogenesis and/or progression of all these disorders. SphK inhibitors are expected to be of use in the prevention, therapy and/or management of these diseases. In spite of the growing interest in the sphingolipid-mediated signaling and the recognised implications thereof in various serious clinical disorders and conditions, as described above, only a few examples of inhibitors of the enzymes of this pathway have been reported. Examples of SphK1 inhibitors are provided in WO 2009/156041 and DE 10 2008/029734. These documents provide specific thiazolo-piperidine compounds. It would be useful if there were compounds available that showed improved activity, differential activity between different types of enzymes, differential activity between the sphingosine isoforms, better stability, greater ease of formulation, and an improved side- effect profile. It is an object of the present invention to address these needs in the art, to address the shortcomings of the prior art compounds, or to at least provide the public with a useful alternative.

SUMMARY OF THE INVENTION

In a first aspect the present invention provides a compound according to formula I

Formula I

wherein:

where RrR₈ are independently hydrogen, lower alkyl, phenyl or benzyl and where X is O, CRR', or NR' where R and R' are independently hydrogen or lower alkyl and where for structures c and d Ri and R₂ may together form an optionally lower alkyl substituted 5 or 6 membered ring and where R₃ is optionally OR" where R" is alkyl or aryl;

X¹ , X², X³, X⁴, X⁵, and X⁶ are independently selected from nitrogen atom or carbon atom optionally substituted with halogen, oxo, cyano, amino, aryl, heteroaryl, optionally substituted lower alkoxyl and optionally substituted lower alkyl,

where if one of X¹ , X², X³, X⁴, X⁵, and X⁶ is an oxo-substituted carbon atom at least one of the others is a nitrogen atom;

wherein not more than three of X¹ , X², X³, X⁴, X⁵, and X⁶ are nitrogen atoms; and wherein Q is a heteroatom-containing alkyl, substituted alkyl, optionally substituted cycloalkyi, optionally substituted aryl, or optionally substituted heterocyclyl containing side chain bound through a heteroatom or directly through a carbon atom; and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

In preferred embodiments where substructure 'a' is present, Ri , R₂, R₅ and R₆ are independently hydrogen, lower alkyl or lower cycloalkyi. More preferably Ri , R₂, R5 and R₆ are each methyl, or and R₂ are both methyl and R₅ and R₆ are both hydrogen, or R₅ and R₆ are both methyl and Ri and R₂ are both hydrogen. In preferred embodiments where substructure 'a' is present R₃ is benzyloxy and R₄ is hydrogen. In preferred embodiments where substructure 'b' is present, Ri , R₂, R₇ and R₈ are independently hydrogen, lower alkyl or lower cycloalkyi. More preferably Ri , R₂, R₇ and R₈ are each methyl, or R₇ and R₈ are both methyl and Ri and R₂ are both hydrogen. In particularly preferred compounds R₇ and R₈ are both methyl. In these preferred embodiments, R₃, R₄, R₅ and R₆ are each hydrogen.

In the preferred embodiments discussed above where substructure 'a' or 'b' is present the preferred gem-dimethyl groups may be joined to form a cyclopropyl group or other lower cycloalkyi group. In preferred embodiments where substructure 'c' or 'd' is present, Ri , R₃, and R₄ are independently hydrogen, lower alkyl or lower cycloalkyi, Ri and R₄ may cooperate to form a lower cycloalkyi group, and R₂ is lower alkyl or lower cycloalkyi; where X is preferably O or NR' where R' is H, lower alkyl or lower cycloalkyi and where R₃ and R₂ may cooperate to form a 5 or 6 membered heterocyclic ring. In preferred embodiments where substructure 'c' or 'd' is present and where X is O or NR', R₂ is a branched lower alkyl group. In other embodiments 'c' or 'd' is present, X is optionally substituted C=C. In other preferred embodiments X is optionally substituted C=C and R₃ and R₄ cooperate to form optionally substituted C=C.

In particularly preferred embodiments

is selected from substructures 'c' and 'd' wherein Ri , R₂, R₃, and R₄ are defined as above.

In one particularly preferred embodiment

is substructure 'c' wherein Ri R₂, R₃, and R₄ are defined as above.

In another particularly preferred embodiment

is substructure 'd' wherein Ri , R₂, R₃, and R₄ are defined as above.

In preferred embodiments the compound is not morpholine-2-carboxylic acid [6-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridin-2-yl]-amide or a compound selected from compounds of formula (I I)

in which, in each case independently of one another:

R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R ⁰, R^{1 1} , R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷ represent H, D (deuterium), A, OR¹⁸, CN, F, CI and NR ⁸R¹⁸ ; wherein R and R², R³ and R⁴, R⁵ and R⁶, R ⁰ and R , R² and R ³, R ⁴ and R⁵, R ⁶ and R⁷ may also in each case together form =0 (carbonyl oxygen);

wherein R⁹ and R\ R and R², R² and R³, R³and R⁴, R⁴ and R⁵, R⁵and R⁶, R⁶ and R⁷, R⁷ and R⁸, R ⁰ and R , R and R², R² and R ³, R ⁴ and R⁵, R⁵ and R ⁶, R ⁶ and R⁷may also in each case together form a cycloalkyl having 3, 4, 5, 6 or 7 C atoms or Het having 3, 4, 5, 6 or 7 ring atoms,

wherein R ⁰ and R ⁹ if Y = CR ⁹, R and R², R³ and R⁹ if Y₂ = CR⁹, R⁴ and R⁹ if Yi = CR¹⁹, R⁵ and R ⁶, R⁷ and R ⁹ if Y₂ = CR¹⁹ may also in each case together form a C=C double bond with the single bond and the C atoms to which they are attached;

R⁸, R ^8' represent H, Dor A;

R⁹, R ^9' represent H, D, A, OR¹⁸, NR⁸R¹⁸, F, CI, Br, CN or Het;

Mi, M₂, M₃, M₄ represent CR¹⁹ or N;

Yi, Y₂ represent CR¹⁹ or N;

V represents C(R⁹)(R^19'), NR⁹ or is absent;

W represents [C(R ⁹)(R^9')]_PZ, CO-[C(R ⁹)(R^9')]_pZ, [C(R ⁹)(R^9')]_PN(R⁹)-Z, CO-N(R¹⁹) [C(R⁹)(R^9')]_pZ, N(R ⁹)-CO-[C(R ⁹)(R^9')]_pZ, CO-0-[C(R ⁹)(R^9')]_pZ, C(0)OR¹⁸, OR¹⁸, H or D;

wherein V, W and Y₂ may also in each case together form a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, in which preferably 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R⁹)(R^19') or N(R ⁹)(R^19'), or form Het having 3, 4, 5, 6 or 7 ring atoms, wherein Het is preferably a saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR ⁸, N0₂, N(R⁹)(R^19'),

NR⁸COOZ, OCONHZ, NR⁸S0₂Z, S0₂N(R⁸)Z, S(0)_mZ, COZ, CHO, COZ, =S, =NH, =NA, Oxy (-0 ) and/or =0 (carbonyl oxygen);

Z represents Het, Ar or A;

A represents unbranched or branched alkyl having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, in which 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R⁹)(R^19') or N(R⁹)(R^19');

and/or in which one or two CH₂ groups can be replaced having O, S, SO, S0₂, CO, COO, NR¹⁸, NR ⁸CO, CONR ⁸, a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, CH=CH groups and/or CH≡CH groups; or a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, in which preferably 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR ⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R ⁹)(R^19') or N(R ⁹)(R^19');

Ar represents phenyl, naphthyl or biphenyl substituted singly, doubly or triply with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR ⁸, N0₂, N(R ⁹)(R^19'), NR ⁸COOZ, OCONHZ, NR ⁸S0₂Z,

S0₂N(R ⁸)Z, S(0)_mZ, COZ, CHO, COZ;

Het represents, in each case independently of one another, a mononuclear, binuclear or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR¹⁸, N0₂, N(R ⁹)(R^19'), NR ⁸COOZ, OCONHZ, NR ⁸S0₂Z,

S0₂N(R ⁸)Z, S(0)_mZ, COZ, CHO, COZ, =S, =NH, =NA, Oxy (-0 ) and/or =0 (carbonyl oxygen);

m is1 , 2 or 3,

n, o are 0, 1 or 2,

p is 0, 1 , 2, 3 or 4

with the proviso compounds of the formula (I) in which

(a) V is absent, and

(b) is W = C(0)-CH₂-Het

are excluded;

In preferred embodiments the compound is not a compound selected from the group: morpholine-2-carboxylic acid [6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)- pyridin-2-yl]-amide

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4- amine

2-(piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyrimidine

1 - (2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4- amine

4-(piperazin-1 -yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine

2- (piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazine 1 -(5-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperazine 1 -(5-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperidin-4-am 3-(4-(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazin-1 - yl)propan-1 -ol.

In one embodiment Q is not a heteroatom-containing optionally substituted aryl.

In certain preferred embodiments one or more of X¹ , X², X³, X⁴, X⁵, and X⁶ is an oxo- substituted carbon atom, methyl substituted carbon atom, or fluorine substituted carbon atom.

In particularly preferred embodiments one or more of X¹, X², X³, X⁴, X⁵, and X⁶ is a carbon atom or nitrogen atom. In particularly preferred embodiments X¹ , X², X³, X⁴, X⁵, and X⁶ are carbon atoms or nitrogen atoms.

Preferably the ring formed by X¹ , X², X³, X⁴, X⁵, and X⁶ is aromatic or doubly unsaturated, more preferably the ring is aromatic.

In preferred embodiments the groups X¹ , X², X³, X⁴, X⁵, and X⁶ are selected so as to form, together with the atoms to which they are bonded, the following ring structures:

where Q is as herein defined and wherein the resulting rings may be additionally substituted in accordance with the selections for groups X¹ , X², X³, X⁴, X⁵, and X⁶. Preferred are the compounds having the above rings with no additional substitution.

In particularly preferred embodiments the groups X¹ , X², X³, X⁴, X⁵, and X⁶ are selected so as to form, together with the atoms to which they are bonded, a pyrimidine ring. Without wishing to be bound by theory, the Inventors have found that surprisingly the presence of a pyrimidine group at this position combines good inhibition activity with improved physical properties of the compounds of the invention, such as their solubility, and that certain compounds having the pyrimidine ring present therefore have good pharmacokinetic properties, and are preferred. In preferred embodiments at least one of the heteroatoms in Q is a nitrogen atom.

In preferred embodiments Q contains at least two heteroatoms, more preferably two nitrogen atoms. In preferred embodiments Q may be selected from:

Where R10- 14 are selected from hydrogen or optionally substituted lower alkyl, or may combine with other R groups in Q to form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl rings which may be aromatic or non-aromatic.

In preferred embodiments R ₀ may, together with a nitrogen atom to which it is bound, form a guanidino group. In other preferred embodiments R ₀ may be a double bonded nitrogen atom and any other R_x moiety bound to the same atom is absent.

In some embodiments one or more aromatic carbon atoms of the benzylamino group may be replaced with N, for example to give those two pyridines shown in the structures above. Where two aromatic carbon atoms are replaced by nitrogen they are preferably arranged to give a pyridazine ring, although pyrimidine and pyrazine arrangements are also available in certain embodiments of the invention. Particulary preferred are compounds of the invention having optionally substituted guanidino or amidino moiety containing Q groups. In particularly preferred embodiments the compounds of the invention have a guanidine or amidino group forming part of the side-chain 'Q' moiety. In certain other embodiments the guanidine or amidino group forming part of the side-chain 'Q' moiety may be optionally substituted, preferably with cyano, OH or OR" where R" is optionally substituted lower alkyl.

In preferred embodiments the moiety Q is selected from the following structures:

or structural isomers thereof, optionally additionally substituted with, for example, hydroxyl, amino, halogen, lower alkyi, lower alkoxy and cyano. Preferred are the compounds having the above Q groups, more preferably with no additional substitution.

The term "alkyi group" refers to an aliphatic group containing at least carbon and hydrogen and containing 1 to 15 carbon atoms, such as 1 to 10 carbon atoms.

Attachment to the alkyi group occurs through a carbon atom.

A "Cn alkyi" group refers to an aliphatic group containing n carbon atoms. For example, a C1 -C10 alkyi group contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

An alkyi group may be straight chained or it may be branched.

An alkyi group may contain no ring structures or it may contain one or more rings.

In preferred embodiments the alkyi group is a lower alkyi group, that is one having between 1 and 6 carbon atoms whether branched or straight chain. For example, a "cycloalkyi" group contains at least one ring. It is understood that attachment to a cycloalkyi group is via a ring of the cycloalkyi group. Each ring may contain 3 to 10 atoms, such as 4 to 8 or 5 to 7 atoms. Each ring may be independently selected to contain just carbon atoms or to contain both carbon atoms and from 1 to 4 heteroatoms selected from O, N and S. For cyclo-heteroalkyl groups (i.e. cycloalkyi groups that contain one or more heteroatoms), attachment to the cycloalkyi group may occur either through a carbon atom or, if one or more heteroatoms are contained in a ring, attachment may also occur through a heteroatom contained in a ring. For example, a cycloalkyi group may be mono-cyclic or bi-cyclic.

Thus, a "C_n cycloalkyi" group contains n carbon atoms. All n carbon atoms may be contained in the ring(s) of the cycloalkyi group or one or more of the carbons may not be contained in the ring(s) and may instead form one or more chains branching from the ring.

If a Cn alkyl group is joined to a separate C_m alkyl group containing m carbon atoms to form, for example, a heterocycle, the two alkyl groups contain a total number of m + n carbon atoms.

An alkyl group may be saturated or unsaturated. Thus, the alkyl group may be an alkenyl group (i.e. contain a carbon-carbon double bond) and / or an alkynyl group (i.e. contain a carbon-carbon triple bond). If the alkyl group is unsaturated, it may contain at least 2 carbon atoms. It is understood that any unsaturated portions of an alkyl group are non-aromatic (aromatic groups fall within the scope of the definition of "aryl'). Any part of the alkyl group may be unsaturated, for example the straight, branched or cyclic portion of an alkyl group may contain a carbon-carbon double bond or a carbon-carbon triple bond. Attachment to an unsaturated alky group may occur through the unsaturated part of the alkyl group or may occur through the unsaturated part of the group.

For example, an unsaturated alkyl group may contain 1 to 4 carbon-carbon double bonds or 1 to 3 carbon-carbon triple bonds or 1 to 4 of a combination of carbon-carbon double bonds and carbon-carbon triple bonds. An alkyl group may be substituted with one or more heteroatoms or it may be

unsubstituted (i.e. not contain any heteroatoms). If more than one hetero-substituent is present, the substituents are independently selected from one another unless they form a part of a particular functional group (e.g. an amide, amidino, or guanidino group).

The heteroatom substituents may in turn be substituted with further carbon-containing groups. In this case, the C_n or C_m prefix that defines the substituted alkyl group refers to the total number of carbons contained in the group, i.e. including the carbon atoms contained in any substituted heteroatomic groups, and the total alkyl group contains 1 to 15 carbon atoms as defined previously.

Accordingly, if the alkyl group is substituted, it may, for example, contain one or more of CN, C0₂H, CONH₂, CONHR, CONR^aR^b, C0₂R, NH₂, NHR, NR^aR^b, OH, OR, SH, SR, F, CI, Br and I, wherein each R, R^a and R^b are independently selected groups (e.g. alkyl / aryl groups) attached to the atom to which the group joins through a carbon atom of each group, including wherein R^a and R^b form a heterocycle that includes the heteroatom to which they are attached. A group containing two C_m-C_n alkyl moieties that form a cycle that includes, for example, the heteroatom to which they are attached may contain from C_2m to C_2n carbon atoms.

Examples of unsubstituted saturated alkyl groups containing no cyclic structures include methyl, ethyl, n-propyl, sec-propyl, n-butyl, sec-butyl, te/t-butyl, pentyl (branched or unbranched), hexyl (branched or unbranched), heptyl (branched or unbranched), octyl (branched or unbranched), nonyl (branched or unbranched), and decyl (branched or unbranched).

Examples of unsubstitued saturated cyclic alkyl groups include cyclopropyl, cylcobutyl, cyclopentyl and cyclohexyl. Examples of unsaturated alkyl groups include ethenyl, propenyl, butenyl, 2-methybutenyl and cyclohexenyl.

The term "aryl group" refers to a group containing at least one ring that is aromatic.

Where an aryl group is stated as being substituted at a particular position, attachment of the position to the aryl group is onto the aromatic ring of the aryl group itself rather than the position being joined to the aryl group through any non-aromatic side-chain of the aryl group. For example, when R is an aryl group in CR , the C is attached to the aromatic part of the aryl group. Each ring may be independently selected to contain only carbon atoms or to contain both carbon atoms and from 1 to 4 heteroatoms selected from O, N and S. For heteroaryl groups (i.e. aryl groups that contain one or more heteroatoms), attachment to the aryl group may occur either through a carbon atom or, if one or more heteroatoms are contained in a ring, attachment may also occur through a heteroatom contained in a ring.

It is noted that the heteroatoms contained in a ring of a heteroaryl group may be substituted, for example forming an /V-oxide.

For example, the aromatic group may be mono-cyclic or bi-cyclic, wherein one or both of the rings of a bi-cyclic system is aromatic.

Examples of aryl groups include acridinyl, phenyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, benzotriazolyl, furanyl, naphthyl, thienyl, thiazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, benzimidazolyl and melaminyl.

It is noted that the term "heterocycle" includes within its scope both cycloalkyl groups containing one or more heteroatoms within the ring system and aryl groups containing one or more heteroatoms within the ring system.

The term "halo" refers to a group selected from chlorine, fluorine, bromine and iodine.

For completeness, it is also noted that certain chemical formulae used herein define delocalized systems. This definition is known in the art as a definition of aromaticity and may indicate the presence of, for example, a mono-, di- or tri-cyclic system that contains (4n+2) electrons where n is an integer. In other words, these systems may display Huckel aromaticity.

Each tautomeric form is intended to fall within the scope of the invention. Where the compound of the invention may have one or more chiral centres, each enantiomer or diastereoisomer is intended to fall within the scope of the invention.

Additionally, where one enantiomer or diasterioisomer has more desirable characteristics than the related molecule(s), the one having desirable characteristics is preferred.

In addition, the compounds of the present invention may be provided as a pro-drug. Prodrugs are transformed, generally in vivo, from one form to the active forms of the drugs described herein. For example, a prodrug may be formed by protecting an amine as a physiological hydrolyzable amide.

In addition, the compounds of the present invention may be provided in the form of their pharmaceutically acceptable salts or as co-crystals. For example, the compounds may be provided having protonated amine groups. The term "pharmaceutically acceptable salt" refers to ionic compounds formed by the addition of an acid to a base. The term refers to such salts that are considered in the art as being suitable for use in contact with a patient, for example in vivo and

pharmaceutically acceptable salts are generally chosen for their non-toxic, non-irritant characteristics.

The term "co-crystal" refers to a multi- component molecular crystal, which may comprise non-ionic interactions.

Pharmaceutically acceptable salts and co-crystals may be prepared by ion exchange chromatography or by reacting the free base or acidic form of a compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in one or more suitable solvents.

Salts known in the art to be generally suitable for use in contact with a patient include salts derived from inorganic and / or organic acids, including the hydrobromide, hydrochloride, sulphate, bisulphate, nitrate, acetate, oxalate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate and tartrate. These may include cations based on the alkali and alkaline earth metals, such as sodium, potassium, calcium and magnesium, as well as ammonium,

tetramethylammonium, tetraethylammonium. Further reference is made to the number of literature sources that survey suitable pharmaceutically acceptable salts, for example the Handbook of pharmaceutical salts published by lUPAC.

In addition, the compounds of the present invention may sometimes exist as zwitterions, which are considered as part of the invention.

The compounds of the present invention are useful in the treatment of medical conditions associated with undesirable SphK activity and S1 P homeostasis and to treat a wide range of diseases where SphK acitivity and S1 P has been shown to play a key role including cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases.

In a further aspect the present invention provides compounds according to the invention for the treatment of a disease or disorder involving associated with SphK activity and S1 P homeostasis. In one preferred embodiment the present invention provides the use of those compounds of the invention having selectivity for Sphkl over Sphk2 for the treatment of a disease or disorder involving or associated with SphK1 activity and S1 P homeostasis. In another preferred embodiment the present invention provides the use of those compounds of the invention having selectivity for Sphk2 over Sphkl for the treatment of a disease or disorder involving or associated with SphK2 activity and S1 P homeostasis.

In particularly preferred embodiments the compounds of the invention are for the treatment of cancers including benign, pre-malignant, metastatic and malignant cancers. The cancers to be treated may include solid tumors as well as hematopoietic cancers. In preferred embodiments the compounds of the invention are for the treatment of solid cancers.

The Inventors have found that surprisingly certain of the compounds developed in the work detailed herein demonstrate an effect not only in inhibiting Sphkl but also a marked inhibition of Sphk2. Such 'dual active' compounds are preferred compounds of the invention and preferred compounds in this regard are detailed below as Examples 39, 41 , 47, 90 and 96. Some compounds of the invention in general show Sphk2 activity and these compounds are also preferred in certain embodiments of the invention. With regard to combination therapy the compounds of the present invention may be administered separately, sequentially, simultaneously, concurrently or may be chronologically staggered with one or more standard therapeutics..

The present invention also provides a pharmaceutical composition suitable for clinical use.

In particular, a pharmaceutical composition may comprise a pharmaceutical carrier and, dispersed therein, a therapeutically effective amount of the compounds of the invention. The composition may be solid or liquid. The pharmaceutical carrier is generally chosen based on the type of administration being used and the pharmaceutical carrier may for example be solid or liquid. The compounds of the invention may be in the same phase or in a different phase than the pharmaceutical carrier.

Pharmaceutical compositions may be formulated according to their particular use and purpose by mixing, for example, excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and / or ointment base. The composition may be suitable for oral, injectable, rectal or topical administration.

For example, the pharmaceutical composition may be administered orally, such as in the form of tablets, coated tablets, hard or soft gelatine capsules, solutions, emulsions, or suspensions. Administration can also be carried out rectally, for example using suppositories, locally or percutaneously, for example using ointments, creams, gels or solution, or parenterally, for example using injectable solutions.

For the preparation of tablets, coated tablets or hard gelatine capsules, the compounds of the present invention may be admixed with pharmaceutically inert, inorganic or organic excipients. Examples of suitable excipients include lactose, mize starch or derivatives thereof, talc or stearic acid or salts thereof. Suitable excipients for use with soft gelatine capsules include, for example, vegetable oils, waxes, fats and semi-solid or liquid polyols. For the preparation of solutions and syrups, excipients include, for example, water, polyols, saccharose, invert sugar and glucose. For injectable solutions, excipients include, for example, water, alcohols, polyols, glycerine and vegetable oil. For suppositories and for local and percutaneous application, excipients include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

The pharmaceutical compositions may also contain preserving agents, solublizing agents, stabilizing agents, wetting agents, emulsifiers, sweeteners, colorants, odorants, buffers, coating agents and / or antioxidants.

For combination therapies, the second drug may be provided in pharmaceutical composition with the present invention or may be provided separately. Thus, a pharmaceutical formulation for oral administration may, for example, be granule, tablet, sugar coated tablet, capsule, pill, suspension or emulsion. For parenteral injection for, for example, intravenous, intramuscular or subcutaneous use, a sterile aqueous solution may be provided that may contain other substances including, for example, salts and / or glucose to make to solution isotonic. The therapeutic agent may also be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.

In certain laboratory and clinical settings it is useful to have selectivity between 2 or more subtypes of a particular target protein. In a situation where, for example, different subtypes of an enzyme are made by a cell in response to different conditions or stimuli, the preferential inhibition of one subtype can leave a pathway involving other subtypes within the cell relatively unaffected by treatment. Given this advantage, although without wishing to be bound by theory, the Inventors consider those compounds of the invention showing selectivity between Sphkl and Sphk2 to be particularly advantageous and therefore preferred. Particularly preferred are those showing a selectivity of

Sphkl /Sphk2 of greater than 10, ie the activity in inhibiting Sphkl is 10-fold greater than the inhibition of Sphk2. Especially preferred are those compounds where the selectivity is much higher than 10, eg 50 or higher. Also preferred are those compounds that demonstrate selectivity for Sphk2 over Sphkl of around 10 times or greater. In another embodiment the present invention provides the use of the preferred compounds having selectivity as described herein for inhibiting Sphkl or Sphk2. In one preferred embodiment these enzymes are inhibited by the use of a compound of the invention having specificity for that subtype such that the other subtype is relatively less inhibited.

The present invention will now be further described. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. EXAMPLES

The present invention will now be described in relation to several examples.

The following exemplary compounds were synthesised according to the methods described. Their IC₅₀ values were then determined as described below and are represented in the following table, in which the compound numbers correspond to the numbers in the examples.

Example

Number IC₅₀ in SphK1 IC₅₀ in SphK2

1 +++ +

2 ++ +

3 ++ +

4 ++ +

5 ++ +

6 ++ +

7 ++ +

8 ++ +

9 ++ +

10 +++ +

1 1 ++ +

12 ++ +

13 ++ + 14 +++ +

15 ++ +

16 +++ +

17 ++ +

18 ++ +

19 + +

20 + +

21 +++ +

22 +++ +

23 + +

24 ++ +

25 ++ +

26 +++ +

27 ++ +

28 + +

29 + +

30 +++ +

31 ++ +

32 ++ +

33 ++ +

34 ++ +

35 ++ +

36 ++ +

37 +++ +

38 +++ +

39 ++ ++

40 ++ +

41 ++ ++

42 ++ +

43 + +

44 ++ +

45 ++ + 46 +++ +

47 ++ ++

48 + +

49 ++ +

50 ++ +

51 ++ +

52 ++ +

53 + n.d.

54 + n.d.

55 + n.d.

56 ++ n.d.

57 ++ n.d.

58 + n.d.

59 + n.d.

60 ++ n.d.

61 + n.d.

62 + n.d.

63 ++ n.d.

64 ++ +

65 ++ +

66 +++ +

67 ++ +

68 ++ +

69 + n.d.

70 + n.d.

71 ++ n.d.

72 ++ n.d.

73 ++ n.d.

74 + n.d.

75 + n.d.

76 + +

77 ++ + 78 ++ n.d.

79 ++ n.d.

80 + n.d.

81 + n.d.

82 + n.d.

83 ++ +

84 ++ +

85 + n.d.

86 + +

87 ++ +

88 ++ +

89 ++ +

90 +++ ++

91 ++ +

92 +++ +

93 +++ n.d.

94 +++ n.d.

95 + +

96 +++ ++

97 +++ n.d.

98 ++ n.d.

99 ++ n.d.

100 + n.d.

101 ++ n.d.

102 ++ n.d.

103 ++ n.d.

104 ++ +

105 ++ +

106 ++ +

107 ++ +

108 ++ + Key

+ Ιΰ₅₀ > 10μΜ

++ 1 μΜ < IC₅₀ < 10μΜ

Abbreviations

AcOH: Acetic acid; nBuLi: n-Butyllithium; BINAP: 2,2'-bis(diphenylphosphino)-1 ,1 '- binaphthyl; COMU: (1 -Cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino- morpholino-carbenium hexafluorophosphate; DBU: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene;

DCM: Dichloromethane; DIPEA: Diisopropylethylamine; DMA: N,N- Dim ethyl acetamide;

DMAP: 4-Dimethylaminopyridine; DME: Dimethyl ether; DMF: /V,/V-Dimethylformamide;

DMSO: Dimethylsulfoxide; EDCI: 1 -Ethyl-3-(3'-dimethylaminopropyl)carbodiimide;

EtOAc: Ethyl acetate; h:Hour: HATU: 0-(7-Azabenzotriazol-1 -yl)-A/,/V,/V',/V- tetramethyluronium hexafluorophosphate; HCI: Hydrochloric acid; HOBt: 1 -

Hydroxybenzotriazole; HPLC: High Pressure Liquid Chromatography; IMS: Industrial methylated spirits: M: Molar; MeOH: Methanol; Min: Minutes; NMP: /V-Methyl-2- pyrrolidone; NMR: Nuclear Magnetic Resonance; Oxyma: Ethyl

(hydroxyimino)cyanoacetate;; RT: Room temperature; SCX: SCX- strong cation exchange; TBAF: Tetra-n-butylammonium fluoride; TEA: Triethylamine; TFA:

Trifluoroacetic acid; THF: Tetrahydrofuran; TMSCI: Trimethylsilyl chloride

General Experimental Conditions

H NMR spectra were recorded at ambient temperature using a Varian Unity Inova (400MHz) spectrometer with a triple resonance 5mm probe, a Bruker Avance DRX (400MHz) with a 5mm inverse detection triple resonance TXI probe, a Bruker Avance (500MHz) spectrometer with a 5mm QNP probe or a Bruker Avance DPX (300MHz) spectrometer with a standard 5mm dual frequency probe. Chemical shifts are expressed in ppm relative to tetramethylsilane.

Preparative HPLC

Method A: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.

Gradient - Time Flow ml/min %A %B

0.00 20.0 50 50

3.00 20 12 88

5.00 20.0 12 88

7.00 20.0 0 100

8.0 20.0 0 100

8.20 20.0 50 50

Detection - MS, UV

MS ionisation method - Multimode (positive and negative ion)

Total experiment time - 10 mins (approx)

Method B: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.

Gradient - Time Flow ml/min %A %B

0.00 20.0 95 5

7.00 20.0 0 100

8.00 20.0 0 100

8.20 20.0 95 5 Detection - MS, UV

MS ionisation method - Multimode (positive and negative ion)

Total experiment time - 10 mins (approx)

Method C: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.

Gradient - Time Flow ml/min %A %B

0.00 60.0 95 5

14.00 60.0 0 100

16.00 60.0 0 100

16.50 60.0 95 5

Detection - MS, UV

MS ionisation method - Multimode (positive and negative ion)

Total experiment time - 18 mins (approx) Method D: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide. Gradient - Time Flow ml/min %A %B

0.00 60.0 68 32

5.00 60.0 59 41

9.00 60.0 59 41

14.00 60.0 0 100

16.00 60.0 0 100

16.50 60.0 68 32

Detection - MS, UV

MS ionisation method - Multimode (positive and negative ion)

Total experiment time - 18 mins (approx)

Method E: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 30 x 100mm column at room temperature. Mobile phase - A) Water 0.1 % ammonium hydroxide B) Acetonitrile/Water 95: 5 with 0.1 % ammonium hydroxide.

Gradient - Time Flow ml/min %A %B

0.00 60.0 61 39

5.00 60.0 34 66

9.00 60.0 34 66

14.00 60.0 0 100

16.00 60.0 0 100

16.50 60.0 61 39

Detection - MS, UV

MS ionisation method - Multimode (positive and negative

Total experiment time - 18 mins (approx) Method H: The system consists of a Agilent Technologies 6120 single quadrupole mass spectrometer linked to a Agilent Technologies 1200 Preparative LC system with Multiple Wavelength detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. Fraction collection is mass-triggered. A purification experiment is performed on each sample submitted using the following conditions: LC Column - Waters XBridge™ Prep C18 5μηι OBD™ 19 x 50mm column at room temperature. Mobile phase - A) Water 0.1 % formic acid B) Acetonitrile/Water 95: 5 with 0.1 % formic acid.

Gradient - Time Flow ml/min %A %B

0.00 20.0 95 5

7.00 20.0 0 100

9.00 20.0 0 100

9.20 20.0 95 5

Detection - MS, UV

MS ionisation method - Multimode (positive and negative ion)

Total experiment time - 10 mins (approx)

High Pressure Liquid Chromatography Mass Spectrometry (LCMS) experiments to determine retention times (R_T) and associated mass ions were performed using one of the following methods.

Method F: The system consists of an Agilent Technologies 6140 single quadrupole mass spectrometer linked to an Agilent Technologies 1290 Infinity LC system with UV diode array detector and autosampler. The spectrometer has a multimode ionization source (electrospray and atmospheric pressure chemical ionizations) operating in positive and negative ion mode. An LCMS experiment is performed on each sample submitted using the following conditions: LC Column - Zorbax Eclipse Plus C18 RRHD 1 .8micron 50 x 2.1 mm maintained at 40^. Mobile phase - A) Water 0.1 % Formic Acid B) Acetonitrile 0.1 % Formic Acid. Gradient - Time Flow ml/min %A %B

0.00 1 .0 95 5

1 .80 1 .0 0 100

2.20 1 .0 0 100

2.21 1 .0 95 5

2.50 1 .0 95 5

Method G/ The system consists of ThermoFinnigan LCQ Advantage Mass Spectrometer with the Surveyor LC system and 200 position autosampler. The spectrometer has an electrospray source operating in positive and negative ion mode. An LC-MS experiment is performed on each sample submitted using the following conditions: LC Column - Luna 3micron Ci₈ 50 x 2 mm; Mobile phase -A) Water 0.1 % Formic Acid B) Acetonitrile 0.1 % Formic Acid

Gradient - Time Flow ml/min %A %B

0.00 0.6 95 5

7.00 0.6 5 95

8.00 0.6 5 95

8.20 0.6 95 5

1 1 .00 0.6 95 5

Split - Ι ΟΟμΙ/min split to the ESI source with inline Surveyor DAD detection.

Detection - MS, UV

MS ionisation method - Electrospray (positive and negative ion)

Total experiment time - 1 1 mins (approx)

Unless quoted otherwise, microwave experiments were carried out using a Biotage Initiator™ Sixty, which uses a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperature from 60-250 °C can be achieved, and pressures of up to 20bar can be reached.

Unless otherwise indicated, the nomenclature of structures was assigned using

ChemDraw Ultra 12.0 (CambridgeSoft). Names highlighted by a superscript asterisk were named using "structure=name" from ChemBioDraw 1 1 (CambridgeSoft). Sphingosine Kinase Assay testing

Sphingosine kinase 1 (SPHK1 ) or 2 (SPHK2) were purchased from Invitrogen (lot number 417324B and 683074A respectively). Unless otherwise indicated, all other reagents were purchased from Sigma. The kinase reaction was performed in white polystyrene 384-well plates in 1 x reaction buffer containing 40 mM Tris (pH 7.5), 20 mM MgCI₂, 0.1 img/mL BSA and 1 mM DTT. SPHK1 (0.26 units) or SPHK2 (0.53 units) (5μΙ) were incubated in the presence or absence of the appropriate concentration of the inhibitor (5μΙ) for 30min at room temperature. Inhibitors were dissolved in a 10 mM DMSO stock solution and serially diluted prior the assay to give a fourteen point half log dose response. The Kinase reaction was then initiated by the addition of Ultrapure ATP (20μΜ) (Promega) and Sphingosine (75μΜ) (Echelon) and allowed to incubate at room temperature for 1 hour (total reaction volume of 15μΙ). Sphingosine kinase inhibition was subsequently determined using the ADP-Glo™ Kinase Assay as described by the manufacturer (Promega). Curve fitting was performed using the GraphPad Prism software and IC₅o values determined using the non-linear regression curve fitting model. IC₅₀ values for the inhibitors of the invention represent the average of at least duplicate experiments.

Example 1 : 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDphenvDpiperazine di(trifluoroacetate)

Step 1: 6-(3-bromophenyl)- 1 , 1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphthalene:

To a solution of 1 ,3-dibromobenzene (0.3 g, 1 .272 mmol) in DMF (10 ml) in a sealable vial was added 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen- 2-yl)-1 ,3,2-dioxaborolane (0.400 g, 1 .272 mmol) and 2M (aq.) sodium carbonate (2.54 ml, 5.09 mmol). Nitrogen was bubbled through the suspension and

[1 ,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) CH₂Cl2 (0.052 g, 0.064 mmol) added. The resulting mixture was heated for 16 hours at 80 °C, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a brown oil, which was used without further purification. LCMS (Method F): R_T = 2.06 min, M+H⁺ = 344.

Step 2: tert-butyl 4-(3-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine- 1 -carboxylate:

To a solution of 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphthalene (215mg, 0.626 mmol) in dioxane (5 ml) in a sealable vial, was added te/t-butyl piperazine-1 -carboxylate (1 17 mg, 0.626 mmol), cesium carbonate (490 mg, 1 .503 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (27.2 mg, 0.047 mmol). Nitrogen was bubbled through the suspension and

tris(dibenzylideneacetone)dipalladium(0) (14.34 mg, 0.016 mmol) added. The resulting mixture was heated for 16 hours at 100 °C, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a yellow oil (52 mg, 18%).

LCMS (Method G): R_T = 9.71 min, M+H⁺ = 449; ¹H NMR (500 MHz, CDCI₃): 7.41 (1 H, d), 7.28 (1 H, d), 7.23-7.25 (2H, m), 7.01 -7.02 (2H, m), 6.82 (1 H, ddd), 3.52 (4H, dd), 3.1 1 (4H, dd), 1 .64 (4H, s), 1 .41 (9H, s), 1 .26 (6H, s), 1 .24 (6H, s).

Step 3: 1 -(3-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine di( trifluoroacetate):

To a solution of te/t-butyl 4-(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine-1 -carboxylate (51 mg, 0.1 1 mmol) in dichloromethane (1 ml_) was added trifluoroacetic acid (1 ml). The yellow solution was stirred at room temperature for 5 minutes before being concentrated in vacuo. The resulting solid was triturated in diethyl ether to give the salt of the title compound as a yellow solid (21 mg, 53%).

LCMS (Method F): R_T = 1 .13 min, M+H⁺ = 349; ¹H NMR (500 MHz, MeOH-d₄): 7.50 (1 H, d), 7.39 (1 H, d), 7.32-7.34 (2H, m), 7.18-7.20 (2H, m), 7.01 (1 H, dd), 3.47-3.49 (4H, m), 3.40-3.43 (4H, m), 1 .78 (4H, s), 1 .35 (6H, s), 1 .33 (6H, s).

Example 2: 1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- yl)piperidin-4-amine di(trifluoroacetate)

Step 1: 1-(2-bromopyridin-4-yl)piperidin-4-amine:

To a solution of 2-chloro-4-iodopyridine (0.5 g, 2.088 mmol) in dioxane (15 ml) in a sealable vial, was added terf-butyl piperidin-4-ylcarbamate (0.418 g, 2.088 mmol), cesium carbonate (1 .633 g, 5.01 mmol) and (9,9-dimethyl-9H-xanthene-4,5- diyl)bis(diphenylphosphine) (0.091 g, 0.157 mmol). Nitrogen was bubbled through the suspension and tris(dibenzylideneacetone)dipalladium(0) (48.1 mg, 0.052 mmol) added. The reaction mixture was heated at 100 °C for 18 h, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a clear oil, which was used without further purification.

LCMS (Method G): R_T = 4.05 min, M+H⁺ = 312. Step 2: tert-butyl (1-(2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-4- yl)piperidin -4 -yl) carbamate:

To a solution of 1 -(2-bromopyridin-4-yl)piperidin-4-amine (325 mg, 1 .042 mmol) in DMF (8 ml) in a sealable vial, was added 4,4, 5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (328 mg, 1 .042 mmol) and 2M (aq.) sodium carbonate (2.085 ml, 4.17 mmol). Nitrogen was bubbled through the suspension and [1 ,1 ' Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) CH₂CI₂ (0.052 g, 0.064 mmol) added. The resulting mixture was heated for 16 hours at 80 °C, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a clear oil (105 mg, 28%).

LCMS (Method F): R_T = 1 .91 min, M+H⁺ = 464; ¹H NMR (500 MHz, CDCI₃): 8.27 (1 H, d), 7.78 (1 H, d), 7.68 (1 H, d), 7.53 (1 H, d), 6.88 (1 H, s), 6.54 (1 H, dd), 4.42 (1 H, s), 3.81 (2H, d), 3.63 (1 H, s), 2.93-2.95 (3H, m), 1 .70 (2H, m), 1 .64 (4H, s) 1 .48 (9H, s). 1 .23 (6H, s). 1 .19 (6H, s).

Step 3: 1-(2-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)pfa 4-amine di(trifluoroacetate): Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), te/t-butyl (1 -(2-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-4-yl)piperidin-4-yl)carbamate (105 mg, 0.23 mmol) was reacted to afford the title compound as a white solid (68 mg, 83%).

LCMS (Method F): R_T = 0.76 min, M+H⁺ = 364; ¹H NMR (500 MHz, MeOH-d₄): 8.16 (1 H, d), 7.77 (1 H, s), 7.60 (2H, s), 7.35 (1 H, d), 7.23 (1 H, dd), 4.49 (2H, d), 3.57-3.60 (1 H, m), 3.33 (2H, d), 2.26 (2H, d), 1 .78 (4H, s), 1 .74 (2H, d), 1 .39 (6H, s), 1 .35 (6H, s).

Example 3: 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- vDpiperazine di(trifluoroacetate)

Step 1: tert-butyl 4-(2-chloropyridin-4-yl)piperazine-1-carboxylate:

To a solution of 2-chloro-4-iodopyridine (500 mg, 2.088 mmol) in toluene (15 ml) in a sealable vial, was added te/t-butyl piperazine-1 -carboxylate (389 mg, 2.088 mmol) and sodium te/t-butoxide (281 mg, 2.92 mmol). Nitrogen was bubbled through the suspension and [1 ,1 ' Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) CH₂CI₂ (0.052 g, 0.064 mmol) added. The resulting mixture was heated for 18 hours at 100 'C, cooled to room temperature, poured onto brine (100 ml), extracted with ethyl acetate, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound as a clear oil, which was used without further purification.

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 298. Step 2: tert-butyl 4-(3-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridin-4- yl)piperazine- 1 -carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 1 -(2-chloropyridin-4-yl)piperidin-4-amine (31 1 mg, 1 .044 mmol) and 4,4,5, 5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 , 3,2- dioxaborolane (328 mg, 1 .044 mmol) were reacted to afford the title compound as a clear oil (256 mg, 55%).

LCMS (Method F): R_T = 1 .82 min, M+H⁺ = 450. Step 3: 1 -(3-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-4- yl) piper azine di( trifluoroacetate) :

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-4-yl)piperazine di(trifluoroacetate), te/t-butyl 4-(3-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)phenyl)piperazine-1 -carboxylate (100 mg, 0.22 mmol) was reacted to afford the title compound as a white solid (64 mg, 83%).

LCMS (Method F): R_T = 0.74 min, M+H⁺ = 350; ¹H NMR (500 MHz, MeOH-d₄): 8.27 (1 H, d), 7.80 (1 H, s), 7.77 (1 H, s), 7.61 (2H, s), 7.43 (1 H, d), 7.28 (1 H, dd), 4.10 (4H, dd), 3.46 (4H, dd), 1 .80 (4H, s), 1 .40 (6H, s), 1 .35 (6H, s).

Example 4: 8-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyridin-4-yl)-2,8- diazaspiro[4.51decane di(trifluoroacetate)

Step 1: tert-butyl 8-(2-chloropyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate:

Following the procedure for te/t-butyl 4-(2-chloropyridin-4-yl)piperazine-1 -carboxylate, 2- chloro-4-iodopyridine (0.15 g, 0.63 mmol) and te/t-butyl 2,8-diazaspiro[4.5]decane-2- carboxylate (151 mg, 0.63 mmol) were reacted to afford the title compound as a yellow oil (162 mg, 77%).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 352.

Step 2: tert-butyl 8-(2-(5A8,8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)pyrid^^ yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, tert-butyl 8-(2-chloropyridin-4-yl)-2,8-diazaspiro[4.5]decane-2- carboxylate (90 mg, 0.256 mmol) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (80 mg, 0.256 mmol) were reacted to afford the title compound as a yellow oil (45 mg, 44%).

LCMS (Method F): R_T = 1 .83 min, M+H⁺ = 504. Step 3: 8-(2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)-2,8- diazaspiro[4.5]decane di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl 8-(2-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (45 mg, 0.09 mmol) was reacted to afford the title compound as a white solid (10 mg, 38%). LCMS (Method F): R_T = 0.82 min, M+H⁺ = 404; ¹H NMR (500 MHz, MeOH-d₄): 8.13 (1 H, d), 7.76 (1 H, s), 7.59 (2H, m), 7.30 (1 H, d), 7.18 (1 H, dd), 3.89-3.93 (2H, m), 3.78-3.82 (2H, m), 3.48 (2H, dd), 3.23 (2H, m), 2.10 (2H, dd), 1 .84-1 .88 (2H, m), 1 .79 (4H, s), 1 .39 (6H, s), 1 .35 (6H, s).

Example 5: 1 -(4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-4- vDphenvDcvclobutanamine di(trifluoroacetate)

Step 1: tert-butyl (1-(4-(2-chloropyridin-4-yl)phenyl)cyclobutyl)carbamate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 2-chloro-4-iodopyridine (0.5 g, 2.01 mmol) and tert-butyl (1 -(4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (780 mg, 2.01 mmol) were reacted to afford the title compound as a brown oil (0.50 mg, 67%).

LCMS (Method F): R_T = 1 .61 min, M+H⁺ = 359.

Step 2: tert-butyl (1-(4-(2-(5,5A8-tetramethyl-5A 7,8-tetrahydronaphthalen-2^

4-yl)phenyl)cyclobutyl)carbamate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, tert-butyl (1 -(4-(2-chloropyridin-4-yl)phenyl)cyclobutyl)carbamate (250 mg, 0.70 mmol) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (219 mg, 0.7 mmol) were reacted to afford the title compound as a clear oil (150 mg, 42%).

LCMS (Method G): R_T = 8.43 min, M+H⁺ = 51 1 . Step 3: 1-(4-(2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-4- yl)phenyl)cyclobutanamine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl (1 -(4-(2-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-4-yl)phenyl)cyclobutyl)carbamate (150 mg, 0.29 mmol) was reacted to afford the title compound as a off-white solid (60 mg, 50%).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 41 1 ; ¹H NMR (500 MHz, MeOH-d₄): 8.82 (1 H, d), 8.49 (1 H, d), 8.18 (1 H, dd), 8.15 (2H, d), 8.02 (1 H, d), 7.76-7.82 (3H, m), 7.66 (1 H, d), 2.83-2.89 (2H, m), 2.70-2.76 (2H, m), 2.28-2.36 (1 H, m), 2.00-2.28 (1 H, m), 1 .81 (4H, s), 1 .42 (6H, s), 1 .37 (6H, s).

Example 6: 2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)-1 ,2,3,6-tetrahvdro-

4.4'-bipyridine di(trifluoroacetate)

Step 1: tert-butyl 2'-chloro-5,6-dihydro-[4,4'-bipyridine]- 1(2H)-carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 2-chloro-4-iodopyridine (0.4 g, 1 .67 mmol) and tert-butyl 4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (0.517 g, 1 .67 mmol) were reacted to afford the title compound as a clear oil (0.35 mg, 71 %).

LCMS (Method G): R_T = 6.62 min, M+H⁺ = 295.

Step 2: tert-butyl 2'-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)-5,6-dihydro- [4,4'-bipyridine]-1(2H)-carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, tert-butyl 2'-chloro-5,6-dihydro-[4,4'-bipyridine]-1 (2H)-carboxylate (245 mg, 0.83 mmol) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (261 mg, 0.83 mmol) were reacted to afford the title compound as a brown oil (181 mg, 49%).

LCMS (Method F): R_T = 1 .87 min, M+H⁺ = 447.

Step 3: 2'-(5_!5A8-tetramethyl-5^ _!8-tetrahydronaphthalen-2-yl)-1_!2,3

bipyridine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), te/t-butyl 2'-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-5,6-dihydro-[4,4'-bipyridine]-1 (2H)-carboxylate (181 mg, 0.40 mmol) was reacted to afford the title compound as a off-white solid (43 mg, 31 %).

LCMS (Method F): R_T = 0.89 min, M+H⁺ = 347; ¹H NMR (500 MHz, MeOH-d₄): 8.74 (1 H, d), 8.22 (1 H, d), 7.96 (1 H, dd), 7.92 (1 H, d), 7.73 (1 H, dd), 7.64 (1 H, d), 6.89 (1 H, s), 4.04 (2H, d), 3.57 (2H, dd), 2.98 (2H, d), 1 .80 (4H, s), 1 .40 (6H, s), 1 .36 (6H, s).

Example 7: 5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)-1 '.2'.3'.6'- tetrahydro-3,4'-bipyridine di(trifluoroacetate)

Step 1: 3-bromo-5-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 3,5-dibromopyridine (1 .0 g, 4.22 mmol) and 4,4,5,5-tetramethyl- 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (1 .327 g, 4.22 mmol) were reacted to afford the title compound as a clear oil (1 .2 g, 83%).

LCMS (Method F): R_T = 1 .94 min, M+H⁺ = 346.

Step 2: tert-butyl 5-(5A8,8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)-^

[3,4'-bipyridine]- 1 '(2'H)-carboxylate:

Following the procedure for for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 3-bromo-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridine (140 mg, 0.41 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (0.126 g, 0.41 mmol) were reacted to afford the title compound as a yellow oil (102 mg, 55%).

LCMS (Method F): R_T = 1 .90 min, M+H⁺ = 447.

Step 3: 5-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro- 3,4'-bipyridine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl 5-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-5',6'-dihydro-[3,4'-bipyridine]-1 '(2'H)-carboxylate (102 mg, 0.22 mmol) was reacted to afford the title compound as a off-white solid (51 mg, 68%). LCMS (Method F): R_T = 0.94 min, M+H⁺ = 347; ¹H NMR (500 MHz, MeOH-d₄): 8.92 (1 H, s), 8.78 (1 H, s), 8.49 (1 H, s), 7.70 (1 H, d), 7.52-7.56 (2H, m), 6.53 (1 H, s), 3.97 (2H, d), 3.55 (2H, dd), 2.95 (2H, d), 1 .78 (4H, s), 1 .40 (6H, s), 1 .35 (6H, s).

Example 8: (4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-2- vDphenvDmethanamine di(trifluoroacetate)

Step 1: tert-butyl 4-(6-(5_!5_!8_!8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrffl^^ yl)benzylcarbamate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridine (56 mg, 0.163 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)benzylcarbamate (54.2 mg, 0.163 mmol) were reacted to afford the title compound as a brown oil (56 mg, 73%).

LCMS (Method F): R_T = 2.01 min, M+H⁺ = 471 .

Step 2: (4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)methanamine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl 4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)benzylcarbamate (56 mg , 0.12 mmol) was reacted to afford the title compound as a white solid (23 mg, 38%).

LCMS (Method F): R_T = 1 .20 min, M+H⁺ = 371 ; ¹H NMR (500 MHz, MeOH-d₄): 8.23 (2H, d), 8.10 (1 H, d), 7.95 (1 H, dd), 7.81 -7.86 (3H, m), 7.61 (2H, d), 7.48 (1 H, d), 4.20 (2H, s), 1 .77 (4H, s), 1 .37 (6H, s), 1 .32 (6H, s).

Example 9: (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-2- vDphenvDmethanamine di(trifluoroacetate)

Step 1: tert-butyl 4-(4-(5_!5_!8_!8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrid^^^ yl)benzylcarbamate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, 2-chloro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridine (77mg, 0.22 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzylcarbamate (74.2 mg, 0.22 mmol) were reacted to afford the title compound as a yellow oil (71 mg, 68%).

LCMS (Method F): R_T = 1 .87 min, M+H⁺ = 471 .

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl 4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)benzylcarbamate (71 mg , 0.15 mmol) was reacted to afford the title compound as a yellow solid (43 mg, 52%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 371 ; ¹H NMR (500 MHz, MeOH-d₄): 8.76 (1 H, d), 8.35 (1 H, s), 8.14 (2H, d), 8.05 (1 H, d), 7.90 (1 H, d), 7.72-7.74 (3H, m), 7.61 (1 H, d), 4.28 (2H, s), 1 .80 (4H, s), 1 .41 (6H, s), 1 .36 (6H, s).

Example 10: 1 -(6-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2- yl)piperidin-4-amine

Step 1: 4,4,5,5-Tetramethyl-2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 , 3, 2-dioxaborolane:

To a solution of 6-bromo-1 ,1 ,4,4-tetramethyl-1 ,2,3,4-tetrahydronaphthalene (3 g, 1 1 .23 mmol) in DMF (45 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (4.28 g, 16.84 mmol) and potassium acetate (3.31 g, 33.7 mmol).

Nitrogen was bubbled through the mixture, and PdCI₂(dppf) CH₂CI₂ (0.917 g, 1 .123 mmol) was added. The mixture was heated at 80 °C for 6 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 10 % EtOAc in cyclohexane) to afford the title compound as a yellow solid (2.49 g, 70 %).

1H NMR (500 MHz, CDCI₃): 7.70-7.69 (1 H, d), 7.51 -7.49 (1 H, dd), 7.25-7.24 (1 H, d), 1 .61 (4H, s), 1 .25 (12H, s), 1 .24 (6H, s), 1 .21 (6H, s).

Step 2: 2-bromo-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:

To a solution of 2,6-dibromopyridine (1 .028 g, 4.34 mmol) in DMF (15 ml) was added 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,3,2- dioxaborolane (1 .5 g, 4.77 mmol) and 2M Na₂C0₃ (aq) (8.68 ml, 17.36 mmol). Nitrogen was bubbled through the mixture for 10 min. PdCI₂(dppf)CH₂CI₂ (0.177 g, 0.217 mmol) was added, and the reaction mixture heated at 80 ^<Ό for 4 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a yellow oil (1 .39 g, 93%).

LCMS (Method F): R_T = 1 .98 min, M+H⁺ = 346. Step 3: 1-(6-(5,5,8,8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyridin

4-amine:

A solution of 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (50 mg, 0.145 mmol) and piperidin-4-amine (0.031 ml, 0.290 mmol) in NMP (0.5 ml) was heated at 200 'Ό in a CEM microwave reactor for 30 min. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH Si0₂, gradient 0 to 100 % EtOAc in cyclohexane) to afford the title compound (15.7 mg, 29%). LCMS (Method F): R_T = 1 .16 min, M+H⁺ = 364; ¹H NMR (500 MHz, MeOH-d₄): 8.12-8.1 1 (1 H, d), 7.59-7.58 (1 H, d), 7.45-7.41 (2H, m), 6.98 (1 H, br s), 6.90-6.89 (1 H, dd), 4.33- 4.31 (2H, m), 3.00-2.90 (3H, m), 1 .96-1 .94 (2H, m), 1 .77 (4H, s), 1 .48-1 .40 (2H, m), 1 .36 (6H, s), 1 .33 (6H, s).

Example 1 1 : 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-2-yl) piperazine

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-bromo-6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine (50 mg, 0.145 mmol) and piperazine (62.5 mg, 0.726 mmol) were reacted to afford the title compound as a yellow gum (7.7 mg, 14 %).

LCMS (Method F): R_T = 1 .14 min, M+H⁺ = 350; ¹H NMR (500 MHz, MeOH-d₄): 7.99 (1 H, d), 7.75-7.72 (1 H, dd), 7.63-7.60 (1 H, dd), 7.40-7.39 (1 H, d), 7.16-7.15 (1 H, d), 6.74-6.72 (1 H, d), 3.64-3.62 (4H, m), 3.00-2.98 (4H, m), 1 .76 (4H, s), 1 .36 (6H, s), 1 .33 (6H, s).

Example 12: 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)-1 '.2'.3'.6'- tetrahvdro-2,4'-bipyridine

Step 1: tert-butyl 6-(5,5^-tetramethyl-5^ ^-tetrahydronaphthalen-2-yl)-5 6'-dihydro- [2,4'-bipyridine]- 1 '(2'H)-carboxylate:

To a solution of 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyridine (75 mg, 0.218 mmol) in DMF (1 ml) was added tert-butyl 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylate (74.1 mg, 0.240 mmol) and 2M Na₂C0₃ (aq) (0.436 ml, 0.871 mmol). Nitrogen was bubbled through the mixture for 10 min. PdCI₂(dppf)CH₂CI₂ (8.9 mg, 10.89 μηιοΙ) was added, and the reaction mixture heated at 90 °C for 72 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 25 % EtOAc in cyclohexane) to afford the title compound as a solid (63 mg, 64 %).

1H NMR (500 MHz, CDCI₃): 7.91 (1 H, s), 7.72-7.70 (1 H, dd), 7.63-7.60 (1 H, dd), 7.50- 7.49 (1 H, d), 7.34-7.32 (1 H, d), 7.23-7.21 (1 H, d), 6.67 (1 H, s), 4.10-4.08 (2H, m), 3.65- 3.55 (2H, m), 2.70-2.65 (2H, m), 1 .65 (4H, s), 1 .43 (9H, s), 1 .29 (6H, s), 1 .24 (6H, s). Step 2: 6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro- 2,4'-bipyridine:

To a solution of tert-butyl 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-5',6'- dihydro-[2,4'-bipyridine]-1 '(2'H)-carboxylate (63 mg, 0.141 mmol) in dioxane (1 ml), was added 4M HCI in dioxane (0.5 ml, 2.00 mmol). The reaction was stirred for 1 h at RT. Et₂0 (approx. 2 ml) was added to the resultant suspension, and the mixture slurried for 15 min. The suspension was filtered, the solid washed with Et₂0 and then dried in vacuo o/n. Further purification was carried out, using preparative HPLC (Method A and B), to afford the title compound as a white solid (9.6 mg, 20 %).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 347; ¹H NMR (500 MHz, MeOH-d₄): 7.94 (1 H, d), 7.69-7.66 (2H, m), 7.58-7.56 (1 H, d), 7.33 (1 H, d), 7.31 (1 H, d), 6.70-6.66 (1 H, m), 3.50-3.48 (2H, m), 3.05-3.03 (2H, t), 2.66-2.61 (2H, m), 1 .65 (4H, s), 1 .26 (6H, s), 1 .22 (6H, s).

Example 13: 1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyridin-2- yl)phenyl)cvclobutanamine dihydrochloride

Step 1: tert-butyl 1-(4-(6-(5,5^^-tetramethyl-5^J^-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutylcarbamate:

To a solution of tert-butyl 1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)

phenyl)cyclobutylcarbamate (178.9 mg, 0.479 mmol) and 2-bromo-6-(5, 5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (150 mg, 0.436 mmol) in DMF (2 ml) was added 2M Na₂C0₃ (aq) (0.44 ml, 1 .743 mmol). Nitrogen was bubbled through the mixture for 5 min. PdCI₂(dppf)CH₂CI₂ (17.8 mg, 0.022 mmol) was added, and the reaction mixture was heated at 80 °C for 18 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound as a white solid (107 mg, 48 %).

LCMS (Method F): R_T = 2.13 min, M+H⁺ = 51 1 .

Step 2: 1-(4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) phenyl)cyclobutanamine hydrochloride:

tert-Butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) phenyl)cyclobutylcarbamate (107 mg, 0.210 mmol) was dissolved in DCM (2 ml) and MeOH (2 ml), and loaded onto a 5 g SCX cartridge. After 5 h at RT, the cartridge was washed with MeOH, and the compound eluted with 7N NH₃ in MeOH. The product containing fractions were concentrated in vacuo and the residue dissolved in DCM

(approx. 1 ml). TFA (approx. 1 ml) was added, and the mixture stirred at RT for 15 min. The mixture was concentrated in vacuo, and DCM was added and subsequently removed in vacuo (three times) to remove TFA. The residue was dissolved in DCM (2 ml) and basified with saturated aq. NaHC0₃. After filtration through a phase separator cartridge, the filtrates were concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH Si0₂, gradient 0 to 100 % EtOAc in cyclohexane). The isolated material was dissolved in 1 ml dioxane and 4M HCI in dioxane (1 .0 ml) was added, then the solvent was concentrated in vacuo and lyophilized o/n to afford the title compound as an off-white solid (24.1 mg, 24 %).

LCMS (Method F): R_T = 1 .30 min, M+H⁺ = 41 1 ; ¹H NMR (500 MHz, MeOH-d₄): 8.62-8.59 (1 H, m), 8.23-8.15 (4H, m), 8.00 (1 H, d), 7.86-7.84 (2H, m), 7.79-7.77 (1 H, dd), 7.67-

7.66 (1 H, d), 2.90-2.85 (2H, m), 2.76-2.70 (2H, m), 2.36-2.30 (1 H, m), 2.08-2.02 (1 H, m), 1 .82 (4H, s), 1 .43 (6H, s), 1 .38 (6H, s).

Example 14: 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyridin-2-yl)-2,8- diazaspiro[4.51decane dihvdrochloride

Step 1: tert-butyl 8-(6-(5,5^ etra et y\-5^ etra ydronap t a\en-2-y\)pyridin-2- yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:

To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (62.8 mg, 0.261 mmol) and 2-bromo-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (75 mg, 0.218 mmol) in dioxane (1 ml) was added Xantphos (12.60 mg, 0.022 mmol) and K₃PO₄ (102 mg, 0.479 mmol). Pd₂dba₃ (1 1 .97 mg, 0.013 mmol) was added, and nitrogen was bubbled through the mixture for 5 min. The reaction mixture was heated at 90 °C for 18 h under nitrogen. After cooling to RT, the mixture was filtered through celite and washed with EtOAc. The combined filtrates were concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 25 % EtOAc in cyclohexane) to afford the title compound as a yellow foam (34.2 mg, 31 %).

1H NMR (500 MHz, CDCI₃): 7.86 (1 H, m), 7.67-7.65 (1 H, d), 7.46-7.43 (1 H, m), 7.30-7.29 (1 H, d), 6.98-6.97 (1 H, m), 6.54-6.51 (1 H, m), 3.75-3.60 (2H, m), 3.54-3.41 (2H, m), 3.40-3.32 (2H, m), 3.23 (1 H, s), 3.14 (1 H, s), 1 .72-1 .69 (2H, t), 1 .67-1 .57 (4H, m), 1 .64 (4H, s), 1 .40 (9H, s), 1 .27 (6H, s), 1 .23 (6H, s).

Step 2: 8-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane dihydrochloride:

To a solution of tert-butyl 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (34.2 mg, 0.068 mmol) in dioxane (0.5 ml) was added 4M HCI in dioxane (0.5 ml, 2.000 mmol). The reaction was stirred for 1 h at RT. Et₂0 (approx. 2 ml) was added to the resultant suspension and the mixture slurried for 15 min. The supernatant liquid was removed by pipette. The Et₂0 slurry was repeated twice. The solid residue was dissolved in MeOH (1 ml) / H₂0 (1 ml) and lyophilised o/n to afford the title compound as a yellow solid (20.8 mg, 64%).

LCMS (Method F): R_T = 1 .14 min, M+H⁺ = 404; ¹H NMR (500 MHz, MeOH-d₄): 8.00-7.97 (1 H, m), 7.61 (1 H, d), 7.48-7.47 (1 H, d), 7.42-7.40 (1 H, dd), 7.27-7.25 (1 H, d), 7.07-7.06 (1 H, d). 3.77-3.73 (2H, m), 3.69-3.64 (2H, m), 3.38-3.35 (2H, t), 3.15 (2H, s), 2.00-1 .97 (2H, t), 1 .85-1 .77 (4H, m), 1 .67 (4H, s), 1 .26 (6H, s), 1 .23 (6H, s).

Example 15: 1 -(4-(5,5,8,8-tetramethyl-5,67,8-tetrahvdronaphthalen-2-yl)pyridin-2- yl)piperidin-4-amine

Step 1: 2-chloro-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridine:

To a solution of 2-chloro-4-iodopyridine (1 .385 g, 5.79 mmol) in DMF (20 ml) was added 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,3,2- dioxaborolane (2 g, 6.36 mmol) and 2M Na₂C0₃ (aq) (1 1 .6 ml, 23.14 mmol). Nitrogen was bubbled through the mixture for 5 min. PdCI₂(dppf) CH₂CI₂ (0.236 g, 0.289 mmol) was added and the reaction mixture heated at 60 °C for 2 h under nitrogen. After cooling to RT the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a pale yellow solid (1 .34 g, 77 %).

¹H NMR (500 MHz, CDCI₃): 8.40-8.39 (1 H, d), 7.53-7.51 (2H, m), 7.44-7.40 (2H, m), 7.38-7.36 (1 H, dd), 1 .73 (4H, s), 1 .34 (6H, s), 1 .32 (6H, s).

Step 2: 1-(4-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyridin

4-amine:

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-chloro-4-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine (50 mg, 0.167 mmol) and piperidin-4-amine (0.035 ml, 0.334 mmol) were reacted to afford the title compound as a white solid (30.6 mg, 50 %).

LCMS (Method F): R_T = 0.90 min, M+H⁺ = 364; ¹H NMR (500 MHz, MeOH-d₄): 8.00-7.99 (1 H, d), 7.73-7.72 (1 H, dd), 7.60-7.57 (1 H, dd), 7.40-7.38 (1 H, d), 7.1 1 -7.09 (1 H, d), 6.76-6.74 (1 H, d), 4.48-4.46 (2H, m), 2.99-2.94 (3H, m), 1 .97-1 .94 (2H, m), 1 .76 (4H, s), 1 .50-1 .43 (2H, m), 1 .36 (6H, s), 1 .33 (6H, s).

Example 16: 1 -(4-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2-yl) piperazine

Step 1: 1-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine:

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-chloro-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine (50 mg, 0.167 mmol) and piperazine (28.7 mg, 0.334 mmol) were reacted to afford the title compound as a yellow solid (12.7 mg, 22 %). LCMS (Method F): R_T = 0.98 min, M+H⁺ = 350; ¹H NMR (500 MHz, MeOH-d₄): 8.15-8.14 (1 H, d), 7.60 (s, 1 H), 7.45 (2H, s), 6.99-6.96 (2H, m), 3.60-3.58 (4H, m), 3.03-3.01 (4H, m), 1 .77 (4H, s), 1 .36 (6H, s), 1 .33 (6H, s). Example 17: 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)-1 ',2',3',6'- tetrahvdro-2,4'-bipyridine dihydrochloride

Step 1: tert-butyl 4-(5_!5A8-tetramethyl-5_!6 _!8-tetrahydronaphthalen-2-yl)-5'_!6'-dihydro- [2,4'-bipyridine]- 1 '(2'H)-carboxylate:

Following the procedure for tert-butyl 6-(5,5,8, 8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)-5',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-carboxylate, 2-chloro-4- (5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl)pyridine (75 mg, 0.250 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1 (2H)- carboxylate (85 mg, 0.275 mmol) were reacted to afford the title compound as a solid (54 mg, 48 %).

¹H NMR (500 MHz, CDCI₃): 8.52-8.51 (1 H, d), 7.48-7.46 (2H, m), 7.36-7.31 (2H, m), 7.27-7.26 (1 H, dd), 6.57 (1 H, br s), 4.09 (2H, br m), 3.61 (2H, br m), 2.64 (2H, br m), 1 .66 (4H, s), 1 .43 (9H, s), 1 .28 (6H, s), 1 .26 (6H, s).

Step 2: 4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro- 2, 4 '-bipyridine dihydrochloride:

Following the procedure for 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro-2,4'-bipyridine dihydrochloride, tert-butyl 4-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)-5',6'-dihydro-[2,4'-bipyridine]-1 '(2'H)-carboxylate (54 mg, 0.121 mmol) was reacted to afford the title compound as a white solid (27.4 mg, 59 %).

LCMS (Method F): R_T = 0.99 min, M+H⁺ = 347; ¹H NMR (500 MHz, MeOH-d₄): 8.74-8.73 (1 H, d), 8.37 (1 H, d), 8.29-8.28 (1 H, dd), 7.96 (1 H, d), 7.81 -7.78 (1 H, dd), 7.64-7.62 (1 H, d), 6.93-6.91 (1 H, m), 4.10-4.09 (2H, m), 3.61 (2H, t), 3.08-3.06 (2H, m), 1 .80 (4H, s), 1 .42 (6H, s), 1 .37 (6H, s). Example 18: 1 -(4-(4-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyridin-2- vDphenvDcvclobutanamine dihvdrochloride

Step 1: tert-butyl (1-(4-(4-(5,5A8-tetramethyl-5A7,8-tetrahydronaphthalen-2-y^

2-yl)phenyl)cyclobutyl)carbamate:

Following the procedure for tert-butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutylcarbamate, tert-butyl (1 -(4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (103 mg, 0.275 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (75 mg, 0.250 mmol) were reacted to afford the title compound (104.9 mg, 82 %).

1H NMR (500 MHz, CDCI₃): 8.64-8.63 (1 H, d), 7.95-7.93 (2H, d), 7.82 (1 H, s), 7.54 (1 H, s), 7.49-7.48 (2H, m), 7.38 (2H, s), 7.35-7.34 (1 H, dd), 5.03 (1 H, br s), 2.53-2.50 (4H, m), 2.09-2.03 (1 H, m), 1 .83-1 .78 (1 H, m), 1 .67 (4H, s), 1 .29 (9H, br s), 1 .30 (6H, s), 1 .27 (6H, s).

Step 2: 1-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) phenyl)cyclobutanamine dihydrochloride:

Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl (1 -(4-(4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutyl)carbamate (104.9 mg, 0.205 mmol) was reacted to afford the title compound as an off-white solid (74.1 mg, 81 %).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 41 1 ; ¹H NMR (500 MHz, MeOH-d₄): 8.70-8.69 (1 H, d), 8.45 (1 H, d), 8.20-8.19 (1 H, dd), 8.09-8.07 (2H, m), 7.88 (1 H, d), 7.77-7.75 (2H, m), 7.72-7.70 (1 H, dd), 7.53-7.51 (1 H, d), 2.79-2.73 (2H, m), 2.62-2.58 (2H, m), 2.23- 2.17 (1 H, m), 1 .98-1 .89 (1 H, m), 1 .69 (4H, s), 1 .30 (6H, s), 1 .25 (6H, s).

Example 19: (7S.8aS)-2-(4-(5.5.8.8-tetramethyl-5.6.7.8-tetrahydronaphthalen-2- yl)pyridin-2-yl)octahvdropyrrolo[1 ,2-a1pyrazin-7-ol

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-chloro-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine (50 mg, 0.167 mmol) and (7S,8aS)-tert-butyl 7- hydroxyhexahydropyrrolo[1 ,2-a]pyrazine-2(1 H)-carboxylate (101 mg, 0.417 mmol) were reacted to afford the title compound as an orange solid (21 .8 mg, 32 %).

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 406; ¹H NMR (500 MHz, MeOH-d₄): 8.13-8.12 (1 H, d), 7.60 (1 H, s), 7.44 (2H, s), 6.98 (1 H, s), 6.94-6.92 (1 H, dd), 4.42-4.38 (2H, m), 4.27-4.23 (1 H, m), 3.15-3.04 (3H, m), 2.82-2.77 (1 H, m), 2.45-2.40 (2H, m), 2.34-2.27 (1 H, m), 2.23-2.16 (1 H, m), 1 .77 (4H, s), 1 .36 (6H, s), 1 .33 (6H, s). -(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)-2.4'-bipyridine

Following the procedure for tert-butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutylcarbamate, 2-chloro-4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridine (250 mg, 0.834 mmol) and pyridin-4-ylboronic acid (1 13 mg, 0.917 mmol) were reacted to afford the title compound as an off-white solid (5.5 mg, 2 %).

LCMS (Method F): R_T = 1 .57 min, M+H⁺ = 343; ¹H NMR (500 MHz, CDCI₃): 8.84-8.81 (3H, m), 8.46-8.45 (2H, d), 8.09 (1 H, s), 7.67-7.66 (1 H, d), 7.60-7.59 (1 H, d), 7.50-7.44 (2H, m), 1 .75 (4H, s), 1 .37 (6H, s), 1 .34 (6H, s).

Example 21 : 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-amine dihydrochloride

Step 1: 2-chloro-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidine: To a solution of 2,4-dichloropyrimidine (0.603 g, 4.05 mmol) and 4,4,5, 5-tetramethyl-2- (5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (1 .4 g, 4.45 mmol) in DMF (12 ml) was added 2M Na₂C0₃ (aq) (8.10 ml, 16.20 mmol). Nitrogen was bubbled through the mixture for 5 min. PdCI₂(dppf)CH₂CI₂ (0.331 g, 0.405 mmol) was added, and the reaction mixture was heated at 80 °C for 18 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (596 mg, 49%).

¹H NMR (500 MHz, CDCI₃): 8.62-8.61 (1 H, d), 8.06 (1 H, d), 7.85-7.83 (1 H, m), 7.63-7.62 (1 H, d), 7.47-7.46 (1 H, d), 1 .75 (4H, s), 1 .38 (6H, s), 1 .34 (6H, s).

Step 2: tert-butyl (1-(4-(5,5,8,8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)piperidin-4-yl)carbamate:

Following the procedure for tert-butyl 8-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, tert- butyl piperidin-4-ylcarbamate (59.9 mg, 0.299 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound (55.4 mg, 48 %).

¹H NMR (500 MHz, CDCI₃): 8.26-8.25 (1 H, d), 7.88 (1 H, d), 7.71 -7.69 (1 H, dd), 7.34-7.32 (1 H, d), 6.82-6.81 (1 H, d), 4.72-4.69 (2H, m), 4.40 (1 H, br s), 3.67 (1 H, br s), 3.07-3.01 (2H, m), 2.00-1 .95 (2H, m), 1 .65 (4H, s), 1 .39 (9H, s), 1 .36-1 .29 (2H, m), 1 .27 (6H, s), 1 .24 (6H, s).

Step 3: 1 -(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-amine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl (1 -(4-(5, 5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyr

(55.4 mg, 0.1 19 mmol) was reacted to afford the title compound as an off-white solid (29.1 mg, 56 %).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 365; ¹H NMR (500 MHz, MeOH-d₄): 8.25-8.24 (1 H, d), 8.10 (1 H, d), 7.91 -7.89 (1 H, dd), 7.47-7.45 (1 H, d), 7.43-7.42 (1 H, d), 4.76-4.72 (2H, m), 3.47-3.44 (1 H, m), 3.29-3.23 (2H, m), 2.17-2.14 (2H, m), 1 .68-1 .63 (6H, m), 1 .28 (6H, s), 1 .25 (6H, s).

Example 22: 2-(piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl) pyrimidine dihydrochloride

Step 1: tert-butyl 4-(4-(5,5,8,8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperazine- 1 -carboxylate:

Following the procedure for tert-butyl 8-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, tert- butyl piperazine-1 -carboxylate (55.7 mg, 0.299 mmol) and 2-chloro-4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound (40.5 mg, 36 %).

¹H NMR (500 MHz, CDCI₃): 8.28-8.27 (1 H, d), 7.89-7.88 (1 H, d), 7.71 -7.69 (1 H, dd), 7.34-7.33 (1 H, d), 6.87-6.86 (1 H, d), 3.84-3.82 (4H, m), 3.47-3.45 (4H, m), 1 .65 (4H, s), 1 .43 (9H, s), 1 .27 (6H, s), 1 .24 (6H, s).

Step 2: 2-(piperazin- 1 -yl) -4-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl) pyrimidine dihydrochloride:

Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride tert-butyl 4-(4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazine-1 -carboxylate (40.5 mg, 0.090 mmol) was reacted to afford the title compound as an off-white solid (17.1 mg, 45 %).

LCMS (Method F): R_T = 1 .06 min, M+H⁺ = 351 ; ¹H NMR (500 MHz, MeOH-d₄): 8.45-8.43 (1 H, d), 8.19-8.18 (1 H, d), 8.00-7.98 (1 H, dd), 7.55-7.52 (2H, m), 4.26-4.24 (4H, m), 3.47-3.45 (4H, m), 1 .79 (4H, s), 1 .38 (6H, s), 1 .35 (6H, s).

Example 23: 2-(pyridin-4-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine

To a solution of 2-chloro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine (240 mg, 0.798 mmol) in DMF (5 ml) was added pyridin-4-yl-boronic acid (108 mg, 0.878 mmol) and 2M Na₂C0₃ (aq.) (1 .596 ml, 3.19 mmol). Nitrogen was bubbled through the mixture for 5 min. PdCI₂(dppf)CH₂CI₂ (65.2 mg, 0.080 mmol) was added, and the reaction mixture heated at 80 °C for 18 h. After cooling to RT the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 50 % EtOAc in cyclohexane) to afford the title compound as a colourless oil (83.9 mg, 31 %).

LCMS (Method F): R_T = 1 .70 min, M+H⁺ = 344; ¹H NMR (500 MHz, MeOH-d₄): 8.91 -8.90 (1 H, d), 8.75-8.74 (2H, m), 8.51 -8.49 (2H, m), 8.30-8.29 (1 H, d), 8.06-8.04 (1 H, dd), 7.95-7.94 (1 H, d), 7.55-7.54 (1 H, d), 1 .79 (4H, s), 1 .42 (6H, s), 1 .36 (6H, s).

Example 24: 2-(1 -methyl-1 ,2.3.6-tetrahvdropyridin-4-yl)-4-(5.5.8.8-tetramethyl-5.6.7.8- tetrahvdronaphthalen-2-yl)pyrimidine

To a solution of 2-(pyridin-4-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyrimidine (75 mg, 0.218 mmol) in acetone (1 ml) was added Mel (0.034 ml, 0.546 mmol). After stirring at RT for 18 h further Mel (0.017 ml, 0.273 mmol) was added. After stirring for 6 h at RT the mixture was concentrated in vacuo. The crude mixture was re- suspended in MeOH (1 ml) and NaBH₄ (41 .3 mg, 1 .092 mmol) was added. After stirring at RT for 18 h the mixture was concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, the combined organic extracts were dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 100 % EtOAc in

cyclohexane, increasing to 20% MeOH in EtOAc) to afford the title compound as an off- white solid (55.2 mg, 70%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 362; ¹H NMR (500 MHz, MeOH-d₄): 8.71 -8.70 (1 H, d), 8.22 (1 H, d), 7.96-7.94 (1 H, d), 7.75-7.73 (1 H, d), 7.51 -7.49 (1 H, d), 7.31 -7.29 (1 H, m), 3.33-3.31 (2H, m), 2.90-2.88 (2H, m), 2.83-2.80 (2H, m), 2.48 (3H, s), 1 .78 (4H, s), 1 .38 (6H, s), 1 .35 (6H, s).

Example 25: 1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyrimidin-2- vDphenvDcyclobutanamine dihydrochloride

Step 1: tert-butyl (1-(4-(4-(5,5A8-tetramethyl-5,6 ,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)phenyl)cyclobutyl)carbamate:

Following the procedure for tert-butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutylcarbamate, tert-butyl (1 -(4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)carbamate (102 mg, 0.274 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound (66.1 mg, 52 %).

1H NMR (500 MHz, CDCI₃): 8.73-8.72 (1 H, d), 8.48-8.47 (2H, d), 8.1 1 (1 H, d), 7.88-7.86 (1 H, dd), 7.51 -7.47 (3H, m), 7.41 -7.40 (1 H, d), 5.04 (1 H, br s), 2.58-2.46 (4H, m), 2.10- 2.02 (1 H, m), 1 .86-1 .80 (1 H, m), 1 .68 (4H, s), 1 .36-1 .25 (21 H, m).

Step 2: 1-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)phenyl)cyclobutanamine dihydrochloride:

Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl (1 -(4-(4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)phenyl)cyclobutyl) carbamate (66.1 mg, 0.129 mmol) was reacted to afford the title compound as an off- white solid (47.6 mg, 82 %).

LCMS (Method F): R_T = 1 .18 min, M+H⁺ = 412; ¹H NMR (500 MHz, MeOH-d₄): 8.79-8.78 (1 H, d), 8.54-8.52 (2H, d), 8.23 (1 H, d), 7.99-7.97 (1 H, dd), 7.90-7.89 (1 H, d), 7.65-7.63 (2H, d), 7.47-7.45 (1 H, d), 2.81 -2.75 (2H, m), 2.61 -2.55 (2H, m), 2.23-2.17 (1 H, m), 1 .99- 1 .92 (1 H, m), 1 .69 (4H, s), 1 .31 (6H, s), 1 .26 (6H, s).

Example 26: 8-(4-(5,5,8,8-tetramethyl-5,6J,8-tetrahvdronaphthalen-2-yl)pyrimidin-2-yl)- 2.8-diazaspiro[4.51decane dihydrochloride

Step 1: tert-butyl 8-(4-(5,5,8,8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrimidin yl) -2, 8-diazaspiro[4.5]decane-2-carboxylate:

Following the procedure for tert-butyl 8-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, tert- butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (71 .9 mg, 0.299 mmol) and 2-chloro-4- (5,5,8, 8-tetramethyl-5, 6,7, 8-tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) were reacted to afford the title compound as a yellow oil (45.6 mg, 36 %). ¹H NMR (500 MHz, CDCI₃): 8.27-8.26 (1 H, d), 7.90-7.89 (1 H, d), 7.70-7.68 (1 H, d), 7.34- 7.32 (1 H, d), 6.83-6.80 (1 H, m), 4.07-3.90 (2H, m), 3.80-3.63 (2H, m), 3.42-3.32 (2H, dt), 3.24-3.15 (2H, d), 1 .73-1 .70 (2H, t), 1 .65 (4H, s), 1 .60-1 .50 (4H, m), 1 .40 (9H, s), 1 .27 (6H, s), 1 .24 (6H, s).

Step 2: 8-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)-2,8- diazaspiro[4.5]decane dihydrochloride:

Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 8-(4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane- 2-carboxylate (45.6 mg, 0.090 mmol) was reacted to afford the title compound as a yellow solid (26.5 mg, 61 %).

LCMS (Method F): R_T = 1 .14 min, M+H⁺ = 405; ¹H NMR (500 MHz, MeOH-d₄): 8.21 -8.19 (1 H, d), 8.12 (1 H, d), 7.93-7.91 (1 H, dd), 7.48-7.45 (2H, m), 4.08-3.98 (2H, m), 3.90-3.82 (2H, m), 3.40-3.37 (2H, t), 3.17 (2H, s), 2.03-2.00 (2H, t), 1 .84-1 .80 (4H, m), 1 .68 (4H, s), 1 .27 (6H, s), 1 .25 (6H, s).

Example 27: 2-(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperazin-1 -vDethanol

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-chloro-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidine (75 mg, 0.249 mmol) and 2-(piperazin-1 -yl)ethanol (61 .2 μΙ, 0.499 mmol) were reacted to afford the title compound as an off-white solid (21 .4 mg, 22%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 395; ¹H NMR (500 MHz, MeOH-d₄): 8.24-8.23 (1 H, d), 7.96 (1 H, d), 7.73-7.71 (1 H, dd), 7.34-7.32 (1 H, d), 6.99-6.98 (1 H, d), 3.87-3.83 (4H, m), 3.67-3.65 (2H, t), 2.62-2.54 (6H, m), 1 .65 (4H, s), 1 .24 (6H, s), 1 .21 (6H, s). Example 28: N-(pyridin-4-ylmethyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-

Following the procedure for 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-amine, 2-chloro-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidine (50 mg, 0.166 mmol) and pyridin-4-ylmethanamine (0.034 ml, 0.332 mmol) were reacted to afford the title compound as an orange solid (20.2 mg, 33%).

LCMS (Method F): R_T = 1 .17 min, M+H⁺ = 373; ¹H NMR (500 MHz, MeOH-d₄): 8.47-8.46 (2H, dd), 8.30-8.29 (1 H, d), 7.96 (1 H, br s), 7.73-7.69 (1 H, m), 7.48-7.47 (2H, d), 7.42- 7.40 (1 H, d), 7.14-7.12 (1 H, d), 4.73 (2H, s), 1 .74 (4H, s), 1 .31 (6H, s), 1 .28 (6H, s).

Example 29: 2-(Dyridin-3-yl)-4-(5.5.8.8-tetramethyl-5.6.7.8-tetrahvdronaDhthalen-2- vDpyrimidine

Step 1: 2-(pyridin-3-yl)4-(5A8,8-tetramethyl-5A7,8-tetrahydronapM

pyrimidine:

Following the procedure for tert-butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutylcarbamate, 2-chloro-4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (200 mg, 0.665 mmol), and pyridin-3-yl-boronic acid (90 mg, 0.731 mmol) were reacted to afford the title compound as an off-white solid (84.4 mg, 37%).

LCMS (Method F): R_T = 1 .78 min, M+H⁺ = 344; ¹H NMR (500 MHz, CDCI₃): 9.82 (1 H, d), 9.01 -9.00 (1 H, d), 8.85-8.83 (1 H, d), 8.77-8.75 (1 H, dd), 8.16 (1 H, d), 7.95-7.93 (1 H, dd), 7.67-7.66 (1 H, d), 7.62-7.60 (1 H, dd), 7.50-7.49 (1 H, d), 1 .75 (4H), 1 .39 (6H, s), 1 .34 (6H, s).

Example 30: 1 -(2-(5,5,8,8-tetramethyl-5,67,8-tetrahvdronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride

Step 1: tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate:

To a solution of 2,4-dichloropyrimidine (250 mg, 1 .678 mmol) and tert-butyl piperidin-4- ylcarbamate (370 mg, 1 .846 mmol) in DMF (2.5 ml) was added Et₃N (0.351 ml, 2.52 mmol) at RT. After stirring at RT for 18 h the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant solid was slurried in Et₂0, filtered and dried under vacuum to afford the title compound as a white solid (272 mg, 52%).

¹H NMR (500 MHz, CDCI₃): 8.06-8.04 (1 H, d), 6.43-6.42 (1 H, d), 4.55-4.20 (3H, br m), 3.85-3.70 (1 H, br m), 3.12-3.05 (2H, dt), 2.12-2.02 (2H, m), 1 .48 (9H, s), 1 .43-1 .35 (2H, ddd).

Step 2: tert-butyl (1-(2-(5,5A8-tetramethyl-5A 7,8-tetrahydronaphthalen-2-yl)pyr^ 4-yl)piperidin-4-yl)carbamate:

Following the procedure for 2-bromo-6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine, tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4- yl)carbamate (100 mg, 0.320 mmol) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (1 1 1 mg, 0.352 mmol) were reacted to afford the title compound as a white foam (81 .3 mg, 55%).

1H NMR (500 MHz, CDCI₃): 8.25-8.23 (2H, m), 8.02-8.00 (1 H, dd), 7.32-7.30 (1 H, d), 6.34-6.33 (1 H, d), 4.42-4.34 (3H, m), 3.69 (1 H, br s), 3.05-2.99 (2H, m), 2.01 -1 .99 (2H, m), 1 .64 (4H, s), 1 .35-1 .31 (2H, dd), 1 .29 (6H, s), 1 .24 (6H, s). Step 3: 1 -(2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride:

Following the procedure for 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)- 1 \2',3',6'-tetrahydro-2,4'-bipyridine hydrochloride, tert-butyl (1 -(2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4-yl)carbamate (81 mg, 0.174 mmol) was reacted to afford the title compound as a white solid (32.6 mg, 43 %).

LCMS (Method F): R_T = 0.75 min, M+H⁺ = 365; ¹H NMR (500 MHz, MeOH-d₄): 8.25-8.24 (1 H, d), 8.17 (1 H, d), 7.99-7.97 (1 H, dd), 7.64-7.63 (1 H, d), 7.19-7.17 (1 H, d), 5.41 (1 H, br s), 4.45 (1 H, br s), 3.65-3.60 (1 H, m), 3.55-3.35 (2H, br m), 2.31 -2.29 (2H, d), 1 .80 (4H, s), 1 .79-1 .70 (2H, m), 1 .40 (6H, s), 1 .36 (6H, s).

Example 31 : 4-(piperazin-1 -yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine dihydrochloride

Step 1: tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine- 1-carboxylate:

Following the procedure for tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate, 2,4-dichloropyrimidine (250 mg, 1 .678 mmol) and tert-butyl piperazine-1 -carboxylate (344 mg, 1 .846 mmol) were reacted to afford the title compound as a white solid

(169 mg, 34%).

¹H NMR (500 MHz, CDCI₃): 8.10-8.09 (1 H, d), 6.42-6.41 (1 H, d), 3.72-3.64 (4H, m), 3.58- 3.53 (4H, m), 1 .51 (9H, s).

Step 2: tert-butyl (1-(2-(5,5^-tetramethyl-5^ ^-tetrahydronaphthalen-2-yl)pyr^ 4-yl)piperidin-4-yl)carbamate:

Following the procedure for 2-bromo-6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridine, tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1 - carboxylate (100 mg, 0.335 mmol) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (1 16 mg, 0.368 mmol) were reacted to afford the title compound as a colourless oil (90.5 mg, 60%). ¹H NMR (500 MHz, CDCI₃): 8.38-8.37 (1 H, d), 8.35 (1 H, d), 8.12-8.10 (1 H, dd), 7.42-7.40 (1 H, d), 6.42-6.41 (1 H, d), 3.78-3.74 (4H, br m), 3.60-3.58 (4H, m), 1 .74 (4H, s), 1 .39 (6H, s), 1 .33 (6H, s). Step 3: 4-(piperazin- 1 -yl)-2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine dihydrochloride:

Following the procedure for 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)- 1 ',2',3',6'-tetrahydro-2,4'-bipyridine dihydrochloride, tert-butyl 4-(2-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperazine-1 -carboxylate (90 mg, 0.200 mmol) was reacted to afford the title compound as a white solid (32.6 mg, 54%).

LCMS (Method F): R_T = 0.71 min, M+H⁺ = 351 ; ¹H NMR (500 MHz, MeOH-d₄): 8.25-8.24 (1 H, d), 8.09 (1 H, d), 7.92-7.90 (1 H, dd), 7.54-7.52 (1 H, d), 7.13-7.1 1 (1 H, d), 4.24 (4H, br s), 3.41 -3.39 (4H, t), 1 .70 (4H, s), 1 .30 (6H, s), 1 .26 (6H, s). Example 32: 1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine

dihydrochloride

Step 1: Methyl 4-bromo-2-isopropoxybenzoate:

To a solution of methyl 4-bromo-2-hydroxybenzoate (3 g, 12.98 mmol) in DMF (15 ml) was added K₂C0₃ (2.153 g, 15.58 mmol), Kl (0.022 g, 0.130 mmol) and 2-iodopropane (1 .95 ml, 19.48 mmol). After stirring at 70 °C for 18 h, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo to afford the title compound as a brown liquid (3.0 g, 85%).

¹H NMR (500 MHz, CDCI₃): 7.57-7.56 (1 H, d), 7.05 (1 H, d), 7.03-7.01 (1 H, dd), 4.53-4.46 (1 H, sept), 3.79 (3H, s), 1 .32-1 .30 (6H, d).

Step 2: 2-(4-Bromo-2-isopropoxyphenyl)propan-2-ol: To a solution of methylmagnesium chloride (3M in THF, 4.88 ml, 14.65 mmol) in THF (4 ml) was slowly added a solution of methyl 4-bromo-2-isopropoxybenzoate (1 g, 3.66 mmol) in THF (4 ml). After stirring at 60 °C for 7 h, the mixture was added to 2N HCI (10 ml) and then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgS0₄) and concentrated in vacuo to afford the title compound as a brown oil (1 .0 g, 100%).

1H NMR (500 MHz, CDCI₃): 7.19-7.18 (1 H, d), 7.05-7.02 (2H, m), 4.72-4.65 (1 H, sept), 1 .58 (6H, s), 1 .43-1 .42 (6H, d). Step 3: tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3-isopropoxyphenyl)pyridin-2- yl)piperazine- 1 -carboxylate:

To a solution of 2-(4-bromo-2-isopropoxyphenyl)propan-2-ol (250 mg, 0.915 mmol) in DMF (3 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (349 mg, 1 .373 mmol) and potassium acetate (269 mg, 2.75 mmol)). Nitrogen was bubbled through the mixture for 10 min and PdCI₂(dppf)CH₂CI₂ (74.7 mg, 0.092 mmol) was added. Nitrogen was bubbled for a further 5 min, and then the mixture was heated at 80 °C for 6 h. After cooling to RT, tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1 - carboxylate (209 mg, 0.610 mmol), PdCI₂(dppf)CH₂CI₂ (74.7 mg, 0.092 mmol) and 2M Na₂C0₃ (aq) (1 .830 ml, 3.66 mmol) were added. After stirring at 80 °C for 18 h the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound as an off- white solid (129 mg, 46%).

1H NMR (500 MHz, CDCI₃): 7.55 (1 H, d), 7.51 -7.47 (1 H, dd), 7.41 -7.39 (1 H, dd), 7.29- 7.27 (1 H, d), 7.03-7.01 (1 H, d), 6.55-6.53 (1 H, d), 4.81 -4.76 (1 H, sept), 3.57-3.48 (8H, m), 1 .56 (6H, s), 1 .43 (9H, s), 1 .41 -1 .40 (6H, d).

Step 4: 1-(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: To a solution of tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3-isopropoxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (0.1 g, 0.219 mmol) in DCM (1 ml) at 0 °C, was added triethylsilane (0.1 15 ml, 0.720 mmol) and borontrifluoride diethyletherate (0.088 ml, 0.713 mmol). The mixture was stirred for 18 h, gradually warming to RT, then quenched with sat. aq. NaHC0₃ (1 ml). The two layers were separated and the aqueous layer was extracted with DCM. The combined organic extracts were washed with water, filtered through a phase separator cartridge and concentrated in vacuo. The residue was dissolved in 4M HCI in dioxane (2 ml). The reaction was stirred for 5 min at RT. Et₂0 (approx. 2 ml) was added to the resultant suspension, and the mixture slurried for 15 min. The supernatant liquid was removed by pipette. The Et₂0 slurry was repeated twice and the residue was dissolved in MeOH (1 ml) / H₂0 (1 ml) and lyophilized o/n to afford the title compound as a yellow solid (72.6 mg, 80%).

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 340; ¹H NMR (500 MHz, MeOH-d₄): 8.02-7.99 (1 H, dd), 7.31 -7.20 (5H, m), 4.72-4.66 (1 H, sept), 3.94-3.92 (4H, m), 3.40-3.36 (4H, m), 3.33-3.25 (1 H, sept), 1 .29-1 .28 (6H, d), 1 .15-1 .13 (6H, d).

Example 33: 1 -(6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

dihvdrochloride

Step 1: Methyl 5-bromo-2-isopropoxybenzoate:

Following the procedure for methyl 4-bromo-2-isopropoxybenzoate, methyl 5-bromo-2- hydroxybenzoate (3 g, 12.98 mmol)) was reacted to afford the title compound as a colourless liquid (3.14 g, 89%).

1H NMR (500 MHz, CDCI₃): 7.80-7.79 (1 H, d), 7.44-7.42 (1 H, dd), 6.80-6.78 (1 H, d), 4.51 -4.43 (1 H, sept), 3.81 (3H, s), 1 .30-1 .28 (6H, d).

Step 2: 2-(5-bromo-2-isopropoxyphenyl)propan-2-ol:

Following the procedure for 2-(4-Bromo-2-isopropoxyphenyl)propan-2-ol, methyl 5- bromo-2-isopropoxybenzoate (1 g, 3.66 mmol)) was reacted to afford the title compound as a yellow oil (0.93 g, 93%).

¹H NMR (500 MHz, CDCI₃): 7.43-7.42 (1 H, d), 7.31 -7.27 (1 H, dd), 6.78-6.76 (1 H, d), 4.71 -4.64 (1 H, sept), 1 .58 (6H, s), 1 .41 -1 .40 (6H, d). Step 3: tert-butyl 4-(6-(3-(2-hydroxypropan-2-yl)-4-isopropoxyphenyl)pyridin-2- yl)piperazine- 1 -carboxylate: Following the procedure for tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate, 2-(5-bromo-2- isopropoxyphenyl)propan-2-ol (250 mg, 0.915 mmol) was reacted to afford the title compound as an off-white foam (139 mg, 50%).

1H NMR (500 MHz, CDCI₃): 7.92-7.91 (1 H, d), 7.79-7.77 (1 H, dd), 7.49-7.46 (1 H, dd), 7.00-6.99 (1 H, d), 6.90-6.89 (1 H, d), 6.51 -6.49 (1 H, d), 4.74-4.68 (1 H, sept), 3.57-3.50 (8H, m), 1 .60 (6H, s), 1 .42 (9H, s), 1 .38-1 .37 (6H, d).

Step 4: 1-(6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride, tert-butyl 4-(6-(3-(2-hydroxypropan-2-yl)-4-isopropoxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (0.1 1 g, 0.241 mmol) was reacted to afford the title compound as a yellow solid (78 mg, 78%).

LCMS (Method F): R_T = 0.98 min, M+H⁺ = 340; ¹H NMR (500 MHz, MeOH-d₄): 8.20-8.17 (1 H, dd), 7.69-7.68 (2H, m), 7.37-7.34 (2H, m), 7.18-7.16 (1 H, d), 4.84-4.77 (1 H, sept), 4.07-4.04 (4H, t), 3.52-3.50 (4H, t), 3.44-3.35 (1 H, sept), 1 .42-1 .41 (6H, d), 1 .31 -1 .30 (6H, d). Example 34: 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6 ,7,8-tetrahydronaphthalen-2- vDpyrazine dihydrochloride

Step 1: tert-butyl 4-(6-chloropyrazin-2-yl)piperazine-1 -carboxylate;

A solution of 2,6 dichloropyrazine (1 .0 g, 6.71 mmol), tert-butyl 4-(6-chloropyrazin-2- yl)piperazine-1 -carboxylate (1 .25 g, 6.71 mmol) and triethylamine (0.68 g, 6.71 mmol) in acetonitrile (10 ml) was heated in a microwave vial at 120 °C for 2 h. The solution was then diluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated in vacuo to afford the title compound (1 .86 g, 93%).

¹H NMR (500 MHz, CDCI₃): 7.98 (s, 1 H), 7.83 (s, 1 H), 3.61 (m, 4H), 3.56 (s, 4H), 1 .48 (s, 9H). Step 2: tert-butyl 4-(6-(5,5 -tetramethyl-5 frtetrahydronaphthalen-2-yl)pyrazin-2- yl)piperazine- 1 -carboxylate:

A solution of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)-1 ,3,2-dioxaborolane (0.4 g, 1 .27 mmol), tert-butyl 4-(6-chloropyrazin-2-yl)piperazine- 1 -carboxylate (0.19 g, 0.636 mmol), 2N sodium carbonate (2 ml) and

PdCI₂(dppf) CH₂CI₂ (0.037 g, 0.045 mmol) was heated at 140 °C under microwave irradiation for 2h. After cooling to room temperature, the solution was diluted with DCM and filtered through a phase separator cartridge. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography using a Biotage SP4 instrument to afford the title compound (0.18 g, 64%).

¹H NMR (500 MHz, CDCI₃): 8.35 (s, 1 H), 8.07 (s, 1 H), 7.93 (s, 1 H), 7.75 (d, 1 H), 7.43 (d, 1 H), 3.69 (m, 4H), 3.62 (m, 4H), 1 .74 (s, 4H), 1 .52 (s, 9H), 1 .37 (s, 6H), 1 .33 (s, 6H). Step 3 : 2-(piperazin-1-yl)-6-(5_!5A8-tetramethyl-5^ ,8-tetrahydronaphthalen-2- yl)pyrazine dihydrochloride:

Te -butyl 4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperazine-1 -carboxylate (0.15 g, 0.33 mmol) was added to a solution of 4N HCI in dioxane (2 ml). The resulting solution was heated at 40 °C for 30 min then cooled to room temperature. The resulting precipitate was filtered and dried at ambient to give the title compound (0.1 18 g, 84%).

LCMS (Method F): R_T = 1 .06 min, M+H⁺ = 361 ; ¹H NMR (500 MHz, DMSO-d₆): 9.57 (s, 2H), 8.56 (s, 1 H), 8.37 (s, 1 H), 7.99 (s, 1 H), 7.81 (d, 1 H), 7.45 (s, 1 H), 3.95 (s, 4H), 3.2 (s, 4H), 1 .68 (s, 4H), 1 .32 (s, 6H), 1 .27 (s, 6H).

Example 35: 1 -(5-(5,5,8,8-tetramethyl-5,6 ,7,8-tetrahvdronaphthalen-2-yl)pyridin-3- vDpiperazine trihvdrochloride

Step 1: tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1 -carboxylate: A solution of 3,5-dibromopyridine (0.6 g, 2.53 mmol), tert-butyl piperazine-1 -carboxylate (0.71 g, 3.8 mmol), Pd₂dba₃ (0.07 g, 0.076 mmol), cesium carbonate (0.82 g, 2.53 mmol) and xantphos (0.132 g, 0.228 mmol) in dioxane (10 ml) was heated at 1 15 °C for 15 h. The solution was cooled to room temperature and concentrated in vacuo. The residue was redissolved in DCM and water. The organic layer was filtered through a phase separator cartridge. The filtrate was concentrated in vacuo. The resulting residue was purified by chromatography using a Biotage SP4 instrument to afford the title compound (0.44 g, 51 %).

¹H NMR (500 MHz, CDCI₃): 8.21 (s, 1 H), 8.15 (s, 1 H), 7.30 (s, 1 H), 3.59 (m, 4H), 3.19 (m, 4H), 1 .49 (s, 9H).

Step 2: tert-butyl 4-(5-(5,5^ etra et y\-5^ etra ydronap t a\en-2-y\)pyridin-3- yl)piperazine- 1 -carboxylate:

Following the procedure for tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate, tert-butyl 4-(5- bromopyridin-3-yl)piperazine-1 -carboxylate (0.2 g, 0.58 mmol) was reacted to give the title compound (0.15 g, 57%).

¹H NMR (500 MHz, CDCI₃): 8.34 (s, 1 H), 8.27 (s, 1 H), 7.47 (s, 1 H), 7.40 (s, 1 H), 7.31 (m, 2H), 3.62 (m, 4H), 3.22 (m, 4H), 1 .69 (s, 4H), 1 .43 (s, 9H), 1 ,34 (s, 6H). 1 .32 (s, 6H).

Step 3 : ^-(5-(5,5β etra et y\-5β etra ydronap t a\en-2-y\)pyridin-3- yl)piperazine trihydrochloride:

Following the procedure for 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrazine dihydrochloride, tert-butyl 4-(5-(5,5,8,8-tetramethyl- 5, 6,7,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperazine-1 -carboxylate (0.15 g, 0.33 mmol) was reacted to give the title compound (0.107 g, 76%).

LCMS (Method F): R_T = 0.94 min, M+H⁺ = 350; ¹H NMR (500 MHz, DMSO-d₆): 9.73 (s, 2H), 8.57 (s, 1 H), 8.47 (s, 1 H), 8.16 (s, 1 H), 7.76 (s, 1 H), 7.60 (d, 1 H), 7.50 (s, 1 H), 3.81 (m, 4H), 3.39 (m, 4H), 1 .68 (s, 4H), 1 .34 (s, 6H), 1 .32 (s, 6H).

Example 36: 1 -(5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-3- yl)piperidin-4-amine trihydrochloride

Step 1: tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate:

Following the procedure for tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1 -carboxylate,

3,5-dibromopyridine (0.6 g, 2.53 mmol) was reacted to give the title compound (0.44 g,

49%).

¹H NMR (500 MHz, CDCI₃): 8.20 (s, 1 H), 8.09 (s, 1 H), 7.28 (s, 1 H), 4.50 (br s, 1 H), 3.63 (m, 3H), 2.92 (m, 2H), 2.07 (m, 2H), 1 .52 (m, 2H), 1 .46 (s, 9H).

Step 2 : tert-butyl 1-(5-(5 -tetramethyl-5fi -tetrahydronaphthalen-2-yl)pyrM^ yl)piperidin-4-ylcarbamate:

Following the procedure for tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate, tert-butyl 1-(5- bromopyridin-3-yl)piperidin-4-ylcarbamate (0.2 g, 0.56 mmol) was reacted to give the title compound (0.125 g, 48%).

¹H NMR (500 MHz, CDCI₃): 8.29 (s, 1 H), 8.26 (s, 1 H), 7.47 (s, 1 H), 7.40 (s, 1 H), 7.31 (m, 2H), 4.50 (br s, 1 H), 3.70 (m, 3H), 2.95 (m, 2H), 2.10 (m, 2H), 1 ,73 (s, 4H), 1 .54 (m, 2H), 1 .43 (s, 9H), 1 ,34 (s, 6H). 1 .32 (s, 6H).

Step 3 : 1-(5-(5 -tetramethyl-5fi -tetrahydronaphthalen-2-yl)pyrti^^^

yl)piperidin-4-amine trihydrochloride:

Following the procedure for 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrazine dihydrochloride, tert-butyl 1 -(5-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (0.10 g, 0.216 mmol) was reacted to give the title compound (0.082 g, 88%).

LCMS (Method F): R_T = 0.78 min, M+H⁺ = 364; ¹H NMR (500 MHz, DMSO-d₆): 8.48 (s, 1 H), 8.42 (s, 1 H), 8.37 (s, 2H), 8.1 1 (s, 1 H), 7.73 (s, 1 H), 7.59 (d, 1 H), 7.50 (d, 1 H), 4.13 (m, 2H), 3.40 (m, 1 H), 3.07 (m, 2H), 2.06 (m, 2H), 1 .71 (s, 4H), 1 .70 (m, 2H), 1 .33 (s, 6H), 1 .28 (s, 6H).

Example 37 : 4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine dihydrochloride

Step 1: tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine- 1-carboxylate:

A solution of 4,6-dichloropyrimidine (0.5 g, 3.36 mmol), tert-butyl piperazine-1 - carboxylate (0.69 g, 3.69 mmol) and triethylamine (0.34 g, 3.36 mmol) in acetonitrile (10ml) was heated in a microwave vial at 120 °C for 2 h. The solution was then diluted with ethyl acetate, washed with a saturated solution of ammonium chloride, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (0.82 g, 91 %).

1H NMR (500 MHz, CDCI₃): 8.39 (s, 1 H), 6.50 (s, 1 H), 3.65 (m, 4H), 3.52 (m, 4H), 1 .48 (s, 9H).

Step 2: tert-butyl 4-(6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperazine- 1 -carboxylate:

Following the procedure for tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate, tert-butyl 4-(6- chloropyrimidin-4-yl)piperazine-1 -carboxylate (0.19 g, 0.63 mmol) was reacted to give the title compound (0.20 g, 72%).

¹H NMR (500 MHz, CDCI₃): 8.62 (s, 1 H), 7.87 (s, 1 H), 7.58 (d, 1 H), 7.32 (d, 1 H), 6.75 (s, 1 H), 3.64 (m, 4H), 3.49 (m, 4H), 1 .64, (s, 4H), 1 .43 (s, 9H), 1 ,28 (s, 6H), 1 .26 (s, 6H).

Step 3 : 4-(piperazin-1-yl)-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine dihydrochloride:

Following the procedure for 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrazine dihydrochloride, tert-butyl 4-(6-(5,5,8,8-tetramethyl- 5^ ^-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate (0.10 g, 0.222 mmol) was reacted to give the title compound (0.086 g, 92%).

LCMS (Method F): R_T = 0.86 min, M+H⁺ = 351 ; ¹H NMR (500 MHz, DMSO-d₆): 9.86 (s, 2H), 8.84 (s, 1 H), 8.47 (s, 1 H), 8.06 (s, 1 H), 7.87 (d, 1 H), 7.58 (d, 1 H), 7.50 (s, 1 H), 4.22 (m, 4H), 3.27 (m, 4H), 1 .69 (s, 4H), 1 .35 (s, 6H), 1 .29 (s, 6H). Example 38: 1 -(6-(5,5,8,8-tetramethyl-5,6 J,8-tetrahvdronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride

Step 1: tert-butyl 1-(6-chloropyrimidin-4-yl)piperidin-4-ylcarbamate:

Following the procedure for tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1 -carboxylate,

4,6-dichloropyrimidine (0.5 g, 3.36 mmol) was reacted to give the title compound (0.97 g,

93%).

¹H NMR (500 MHz, CDCI₃): 8.36 (s, 1 H), 6.52 (s, 1 H), 4.54 (br s , 1 H), 4.30 (br s, 2H), 3.75 (br s, 1 H), 3.04 (m, 2H), 2.05 (m, 2H), 1 .48 (s, 9H), 1 .39 (m, 2H).

Step 2: tert-butyl 1-(6-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-ylcarbamate:

Following the procedure for tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate, tert-butyl (1 -(6- chloropyrimidin-4-yl)piperidin-4-yl)carbamate (0.2 g, 0.63 mmol) was reacted to give the title compound (0.19 g, 64%).

¹H NMR (500 MHz, CDCI₃): 8.70 (s, 1 H), 7.96 (s, 1 H), 7.67 (d, 1 H), 7.41 (d, 1 H), 6.86 (s, 1 H), 4.40-4.50 (m, 3H), 3.75 (br s, 1 H), 3.1 1 (m, 2H), 2.10 (m, 2H) 1 .68, (s, 4H), 1 .43 (s, 9H), 1 .39 (M, 1 H), 1 ,30 (s, 6H), 1 .28 (s, 6H).

Step 3 : 1-(6-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyrimidin-4- yl)piperidin-4-amine dihydrochloride:

Following the procedure for 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrazine dihydrochloride tert-butyl 1 -(6-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4-ylcarbamate (0.1 10 g, 0.237mmol) was reacted to give the title compound (0.082 g, 79%).

LCMS (Method F): R_T = 0.86 min, M+H⁺ = 351 ; ¹H NMR (500 MHz, DMSO-d₆): 8.78 (s, 1 H), 8.58 (s, 2H), 8.47 (s, 1 H), 8.05 (s, 1 H), 7.87 (d, 1 H), 7.58 (d, 1 H), 7.47 (s, 1 H), 4.70 (br s, 2H), 3.3-3.7 (m, 4H), 2.15 (m, 2H), 1 .69 (s, 4H), 1 .68 (m, 1 H), 1 .35 (s, 6H), 1 .29 (s, 6H), 1 .27 (m, 1 H). Example 39: 1 -(6-(5,5,8,8-tetramethyl-5,6 ,7,8-tetrahvdronaphthalen-2-yl)pyrazin-2- yl)piperidin-4-amine trihydrochloride

Step 1: tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate:

Following the procedure for tert-butyl 1 -(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate,

2,6-dichloropyrazine (1 g, 6.71 mmol) was reacted to give the title compound (1 .91 g,

91 %).

¹H NMR (500 MHz, CDCI₃): 8.0 (s, 1 H), 7.80 (s, 1 H), 4.53 (brs, 1 H), 4.25 (m, 2H), 3.70 (m, 1 H), 3.07 (m, 2H), 2.09 (m, 2H), 1 .42 (s, 9H), 1 .40 (m, 2H).

Step 2: tert-butyl 1-(6-(5^^-tetramethyl-5^ ^-tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperidin -4 -ylcarbamate

Following the procedure for tert-butyl 4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperazine-1 -carboxylate, tert-butyl 1 -(6- chloropyrazin-2-yl)piperidin-4-ylcarbamate (0.15g, 0.48mmol) was reacted to give the title compound (0.15 g, 71 %).

¹H NMR (500 MHz, CDCI₃): 8.20 (s, 1 H), 7.96 (s, 1 H), 7.80 (s, 1 H), 7.62 (d, 1 H), 7.31 (d, 1 H), 4.66 (brs, 1 H), 4.25 (m, 1 H), 4.15 (m, 1 H), 3.65 (m, 1 H), 2.98 (m, 2H), 1 .97 (m, 2H), 1 .42 (s, 9H), 1 .40 (m, 2H).

Step 3 : 1-(6-(5^^-tetramethyl-5^ ^-tetrahydronaphthalen-2-yl)pyrazin-2- yl)piperidin-4-amine dihydrochloride:

Following the procedure for 2-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrazine dihydrochloride tert-butyl 1 -(6-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.120 g, 0.258mmol) was reacted to give the title compound (0.092 g, 81 %).

LCMS (Method F): R_T = 1 .03 min, M+H⁺ = 365; ¹H NMR (500 MHz, DMSO-d₆): 8.52 (s, 1 H), 8.47 (s, 2H), 8.47 (s, 1 H), 8.38 (s, 1 H), 8.01 (s, 1 H), 7.84 (d, 1 H), 7.45 (d, 1 H), 4.51 (m, 2H), 3.36 (m, 1 H), 3.15 (m, 2H), 2.09 (m, 2H), 1 .62 (s, 4H), 1 .60-1 .65 (m, 2H), 1 .30 (s, 6H), 1 .26 (s, 6H).

Example 40: 1 -(2-methoxyethyl)-4-(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen- 2-yl)pyridin-2-yl)piperazine dihydrochloride

To a solution of 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazine (200 mg, 0.57 mmol) in ethanol (5 ml) and triethylamine (0.24 ml, 1 .72 mmol) in a sealable microwave vial was added 1 -chloro-2-methoxyethane (0.081 g, 0.86 mmol). The resulting mixture was heated for 2 hours at 160 °C, cooled to room temperature, concentrated in vacuo and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH, Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a yellow oil. The oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being concentrated in vacuo. The residue was triturated with diethyl ether to give the target compound as a yellow solid (121 mg, 52%).

LCMS (Method F): R_T = 1 .21 min, M+H⁺ = 408; ¹H NMR (500 MHz, MeOH-d₄): 7.91 -7.92 (2H, m), 7.70 (1 H, dd), 7.49 (1 H, d), 7.32 (1 H, d), 7.1 1 (1 H, d), 4.54-4.56 (2H, m), 3.77- 3.84 (4H, m), 3.55-3.59 (2H, m), 3.47 (3H, s), 3.31 -3.35 (4H, m), 1 .78 (4H, s), 1 .35 (6H, s), 1 .33 (6H, s). Example 41 : 3-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)propan-1 -ol

3-(4-(6-(5,5,8,8-tetramethyl-5fi ,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)pfa yl)propan-1-ol:

To a solution of 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazine (200 mg, 0.57 mmol) in ethanol (5 ml) and triethylamine (0.24 ml, 1 .72 mmol) in a sealable microwave vial was added 3-bromopropan-1 -ol (0.1 19 g, 0.858 mmol). The resulting mixture was heated for 2 hours at 160 °C, cooled to room temperature, concentrated in vacuo and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH, Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a yellow solid (1 16 mg, 50%).

LCMS (Method F): R_T = 1 .13 min, M+H⁺ 408; ¹ H NMR (500 MHz, CDCI₃): 7.92 (1 H, d), 7.72 (1 H, d), 7.53 (1 H, dd), 7.36 (1 H, d), 7.08 (1 H, d), 6.57 (1 H, d), 5.1 1 (1 H, bs) 3.84 (2H, dd), 3.64-3.66 (4H, m), 2.67-2.69 (6H, m), 1 .78 (2H, dd), 1 .71 (4H, s), 1 .34 (6H, s), 1 .30 (6H, s).

Example 42: A/,A/-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2- yl)pyridin-2-yl)piperazin-1 -yl)acetamide

N, N-dimethyl-2-(4-(6-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin- 1 -yl)acetamide:

To a solution of 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazine (200 mg, 0.57 mmol) in ethanol (5 ml) and triethylamine (0.24 ml, 1 .72 mmol) in a sealable microwave vial was added 2-chloro-/V,/V-dimethylacetamide (0.104 g, 0.858 mmol). The resulting mixture was heated for 2 hours at 160 'Ό, cooled to room temperature, concentrated in vacuo and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH, Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as an off white solid (135 mg, 54%).

LCMS (Method F): R_T = 1 .17 min, M+H⁺ = 435; ¹H NMR (500 MHz, CDCI₃): 7.93 (1 H, d), 7.72 (1 H, dd), 7.53 (1 H, dd), 7.36 (1 H, d), 7.06 (1 H, d), 6.57 (1 H, d), 3.67 (4H, dd), 3.23 (2H, s), 3.10 (3H, s), 2.97 (3H, s), 2.67 (4H, dd), 1 .71 (4H, s), 1 .34 (6H, s), 1 .30 (6H, s).

Example 43: (rac)-1 -methoxy-3-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen- 2-yl)pyridin-2-yl)piperazin-1 -yl)propan-2-ol dihvdrochloride

To a solution of 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazine (100 mg, 0.29 mmol) in ethanol (3 ml) in a sealable microwave vial was added (rac)-2-(methoxymethyl)oxirane (0.039 ml, 0.429 mmol). The resulting mixture was heated for 1 hours at 120 'Ό, cooled to room temperature, concentrated in vacuo and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and

concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH, Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a yellow oil. The oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being

concentrated in vacuo. The residue was triturated with diethyl ether to give the target compound as an off white solid (72 mg, 58%).

LCMS (Method F): R_T = 1 .15 min, M+H⁺ = 438; ¹H NMR (500 MHz, MeOH-d₄): 7.92 (1 H, d), 7.91 (1 H, d), 7.70 (1 H, dd), 7.49 (1 H, d), 7.32 (1 H, d), 7.1 1 (1 H, d), 4.52 (2H, dd), 4.25-4.31 (1 H, m), 3.81 -3.94 (2H, m), 3.66-3.70 (4H, m), 3.42 (3H, s), 3.31 -3.35 (4H, m), 1 .78 (4H, s), 1 .37 (6H, s), 1 .34 (6H, s).

Example 44: A/.A/-dimethyl-2-(4-(6-(5.5.8.8-tetramethyl-5.6.7.8-tetrahvdronaphthalen-2- yl)pyridin-2-yl)piperazin-1 -vDethanamine trihydrochloride

To a solution of /V,/V-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen- 2-yl)pyridin-2-yl)piperazin-1 -yl)acetamide (63 mg, 0.15 mmol) in THF (1 ml) was added lithium aluminiumhydride (0.435 ml, 0.435 mmol). The resulting mixture was heated for 2 hours at 80 °C, cooled to room temperature and quenched by dropwise addition of 40% aq. KOH. The resulting suspension was heated at 80 °C for 30 min. and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH, Si0₂, gradient 0 to 50 % ethyl acetate in cyclohexane) to afford the title compound as a clear oil. The oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being concentrated in vacuo. The residue was triturated with diethyl ether to give the target compound as a yellow solid (24 mg, 34%).

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 421 ; ¹H NMR (500 MHz, MeOH-d₄): 8.03 (1 H, dd), 7.85 (1 H, d), 7.65 (1 H, dd), 7.55 (1 H, d), 7.32 (1 H, d), 7.25 (1 H, d), 3.69-3.75 (4H, m), 3.60-3.66 (2H, m), 3.48-3.54 (2H, m), 3.31 -3.35 (4H, m), 3.04 (6H, s), 1 .78 (4H, s), 1 .38 (6H, s), 1 .35 (6H, s).

Example 45: 3-hvdroxy-2-(hvdroxymethyl)-2-methyl-1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahvdronaphthalen-2-yl)pyridin-2-yl)piperazin-1 -yl)propan-1 -one hydrochloride

To a solution of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (0.032 g, 0.238 mmol) in DMF (2 ml) was added COMU (0.102 g, 0.238 mmol) and Oxyma (0.034 g, 0.238 mmol). The resulting solution was stirred at room temperature for 10 minutes. 1 - (6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazine (63 mg, 0.15 mmol) and DIPEA (0.083 ml, 0.477 mmol) were added, the resulting solution was stirred at room temperature for 16 hours and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 50 % ethyl acetate in

cyclohexane) to afford the title compound as a clear oil. The oil was dissolved in dioxane and 4M HCI in dioxane was added. The solution was stirred at room temperature for 5 min. before being concentrated in vacuo. The residue was triturated with diethyl ether to give the target compound as a yellow solid (43 mg, 38%).

LCMS (Method F): R_T = 1 .62 min, M+H⁺ = 466; ¹H NMR (500 MHz, MeOH-d₄): 7.99 (1 H, dd), 7.76 (1 H, dd), 7.62 (1 H, dd), 7.40 (1 H, d), 7.18 (1 H, d), 6.75 (1 H, d), 3.84-3.86 (4H, m), 3.76 (4H, s), 3.21 -3.23 (4H, m), 1 .74 (4H, s), 1 .35 (6H, s), 1 .31 (6H, s) 1 .25 (3H, s).

Example 46: 4-(piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine di(trifluoroacetate)

Step 1: tert-butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine- 1-carboxylate:

To a solution of te/t-butyl 4-hydroxypiperidine-1 -carboxylate (0.675 g, 3.36 mmol) in THF (15 ml) was added potassium te/t-butoxide (0.414 g, 3.69 mmol). The resulting solution was stirred at room temperature for 10 min., cooled to 0 'Ό and 2,4-dichloropyrimidine (0.5 g, 3.36 mmol) in THF (15 ml) was added. The resulting solution was stirred at room temperature for 16 hours and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give a 1 :1 mixture of te/t-butyl 4-((4- chloropyrimidin-2-yl)oxy)piperidine-1 -carboxylate and te/t-butyl 4-((2-chloropyrimidin-4- yl)oxy)piperidine-1 -carboxylate as a yellow oil which was used without further purification (884 mg, 84%).

Step 2: tert-butyl 4-((2-(5_!5A8-tetramethyl-5^ _!8-tetrahydronaphthalen-2-yl)pyrim 4-yl)oxy)piperidine- 1 -carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, a mixture of te/t-butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine-1 - carboxylate and te/t-butyl 4-((4-chloropyrimidin-2-yl)oxy)piperidine-1 -carboxylate (0.44 g, 1 .40 mmol) and 4,4,5, 5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen- 2-yl)-1 ,3,2-dioxaborolane (0.44 g, 1 .40 mmol) were reacted to afford the title compound as a clear oil (0.22 g, 34%).

LCMS (Method F): R_T = 2.07 min, M+H⁺ = 466.

Step 3: 4-(piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine, te/t-butyl 4-((2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-4-yl)oxy)piperidine-1 -carboxylate (100 mg , 0.23 mmol) was reacted to afford the title compound as a white solid (67 mg, 78%).

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 366; ¹H NMR (500 MHz, MeOH-d₄): 8.57 (1 H, d), 8.37 (1 H, d), 8.1 1 (1 H, dd), 7.45 (1 H, d), 6.80 (1 H, d), 5.62-5.66 (1 H, m), 3.45-3.52 (2H, m), 3.45-3.52 (2H, m), 2.35-2.37 (2H, m), 2.21 -2.23 (2H, m), 1 .78 (4H, s), 1 .37 (6H, s), 1 .34 (6H, s). Example 47: 2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine di(trifluoroacetate)

Step 1: tert-butyl 4-((4-chloropyrimidin-2-yl)oxy)piperidine- 1 -carboxylate:

To a solution of tert-butyl 4-hydroxypiperidine-1 -carboxylate (0.675 g, 3.36 mmol) in THF (15 ml) was added potassium tert-butoxide (0.414 g, 3.69 mmol). The resulting solution was stirred at room temperature for 10 minutes then cooled to 0 °C and 2,4- dichloropyrimidine (0.5 g, 3.36 mmol) in THF (15 ml) added. The resulting solution was stirred at room temperature for 16 hours and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give a 1 :1 mixture of tert-butyl 4-((4-chloropyrimidin-2-yl)oxy)piperidine-1 -carboxylate and tert-butyl 4-((2- chloropyrimidin-4-yl)oxy)piperidine-1 -carboxylate as a yellow oil which was used without further purification (884 mg, 84%). Step 2: tert-butyl 4-((4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)oxy)piperidine- 1 -carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, a mixture of tert-butyl 4-((2-chloropyrimidin-4-yl)oxy)piperidine-1 - carboxylate and tert-butyl 4-((4-chloropyrimidin-2-yl)oxy)piperidine-1 -carboxylate (0.44 g, 1 .40 mmol) and 4,4,5, 5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen- 2-yl)-1 ,3,2-dioxaborolane (0.44 g, 1 .40 mmol) were reacted to afford the title compound as a clear oil (0.27 g, 44%).

LCMS (Method F): R_T = 1 .99 min, M+H⁺ = 466. Step 3: 2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), tert-butyl 4-((4-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)oxy)piperidine-1 -carboxylate (100 mg , 0.23 mmol) was reacted to afford the title compound as a white solid (67 mg, 69%). LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 366; ¹H NMR (500 MHz, MeOH-d₄): 8.48 (1 H, d), 8.02 (1 H, d), 7.77 (1 H, d), 7.50 (1 H, d), 7.39 (1 H, d), 5.36-5.40 (1 H, m), 3.34-3.40 (2H, m), 3.18-3.21 (2H, m), 2.18-2.22 (2H, m), 2.09-2.12 (2H, m), 1 .66 (4H, s), 1 .26 (6H, s), 1 .22 (6H, s).

Example 48: 2-methyl-4-(piperazin-1 -yl)-6-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahvdronaphthalen-2-yl)pyrimidine di(trifluoroacetate)

Step 1: tert-butyl 4-(6-chloro-2-methylpyrimidin-4-yl)piperazine-1-carboxylate:

To a solution of 4,6-dichloro-2-methylpyrimidine (1 g, 6.13 mmol) in THF (50ml) was added DBU (0.93 ml, 6.13 mmol) and te/t-butyl piperazine-1 -carboxylate (1 .257 g, 6.75 mmol). The resulting solution was stirred at 70 °C for 16 hours and poured into water (100 ml). The product was extracted with ethyl acetate, the combined organic phases were dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a brown oil which was used without further purification (1 .7 g, 80%).

LCMS (Method F): R_T = 1 .30 min, M+H⁺ = 313.

Step 2: tert-butyl 4-(2-methyl-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidin-4-yl)piperazine- 1 -carboxylate:

Following the procedure for 6-(3-bromophenyl)-1 ,1 ,4,4-tetramethyl-1 ,2,3,4- tetrahydronaphthalene, tert-butyl 4-(6-chloro-2-methylpyrimidin-4-yl)piperazine-1 - carboxylate (0.15 g, 0.48 mmol) and 4,4, 5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)-1 ,3,2-dioxaborolane (0.15 g, 0.48 mmol) were reacted to afford the title compound as a clear oil (0.12 g, 54%).

LCMS (Method F): R_T = 1 .33 min, M+H⁺ = 465.

Step 3: 2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate): Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate), te/t-butyl 4-(2-methyl-6-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperazine-1 -carboxylate (120 mg , 0.26 mmol) was reacted to afford the title compound as a white solid (82 mg, 87%).

LCMS (Method F): R_T = 0.76 min, M+H⁺ = 365; ¹H NMR (500 MHz, MeOH-d₄): 7.75 (1 H, d), 7.48-7.53 (2H, m), 7.13 (1 H, s), 4.17-4.20 (4H, m), 3.33 (4H, dd), 2.61 (3H, s), 1 .67 (4H, s), 1 .27 (6H, s), 1 .23 (6H, s).

Example 49: 1 -(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: 4-bromo-2-isopropylphenol:

To a solution of 2-isopropylphenol (5 ml, 37.2 mmol) in DCM (30 ml) was added bromine (1 .914 ml, 37.2 mmol) slowly during 15 min. The solution was stirred for 1 h and then concentrated in vacuo. The product was obtained as a red-brown liquid (8.29 g) and was used without further purification.

¹H NMR (500 MHz, CDCI₃): 7.31 (1 H, d), 7.19-7.17 (1 H, dd), 6.66-6.64 (1 H, d), 4.72 (1 H, br s), 3.23-3.15 (1 H, sept), 1 .27-1 .26 (6H, d).

Step 2: tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:

Following the procedure for tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate, 4-bromo-2-isopropylphenol (1 .5 g, 6.97 mmol) and tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1 -carboxylate (1 .592 g, 4.65 mmol) were reacted to afford the title compound as a yellow solid (983 mg, 53 %). LCMS (Method F): R_T = 1 .56 min, M+H⁺ = 398.

Step 3: tert-butyl 4-(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate: Following the procedure for Methyl 4-bromo-2-isopropoxybenzoate, tert-butyl 4-(6-(4- hydroxy-3-isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (150 mg, 0.377 mmol) and 1 -bromo-2-methylpropane (0.062 ml, 0.566 mmol) were reacted to afford the title compound as a yellow solid (37.7 mg, 22%).

1H NMR (500 MHz, CDCI₃): 7.86-7.85 (1 H, d), 7.80-7.78 (1 H, dd), 7.54-7.51 (1 H, dd), 7.08-7.07 (1 H, d), 6.88-6.86 (1 H, d), 6.54-6.53 (1 H, d), 3.79-3.78 (2H, d), 3.65-3.55 (8H, m), 3.41 -3.36 (1 H, sept), 2.17-2.10 (1 H, sept), 1 .49 (9H, s), 1 .29-1 .28 (6H, d), 1 .08-1 .06

(6H, d).

Step 4: 1-(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(4-isobutoxy-3- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (37.7 mg, 0.083 mmol) was reacted to afford the title compound as a yellow solid (20.9 mg, 59%).

LCMS (Method F): R_T = 1 .08 min, M+H⁺ = 354; ¹H NMR (500 MHz, MeOH-d₄): 8.03-7.99 (1 H, dd), 7.76-7.72 (2H, m), 7.34-7.32 (1 H, d), 7.17-7.15 (1 H, d), 7.10-7.08 (1 H, d), 4.01 - 3.99 (4H, m), 3.89-3.88 (2H, d), 3.48-3.46 (4H, m), 3.46-3.40 (1 H, sept), 2.20-2.13 (1 H, sept), 1 .33-1 .31 (6H, d), 1 .13-1 .12 (6H, d).

Step 1: 4-bromo-2-(tert-butyl)phenol:

To a solution of 2-(tert-butyl)phenol (5 ml, 32.6 mmol) in DCM (30 ml) was added bromine (1 .67 ml; 32.6 mmol) slowly during 15 min. The solution was stirred for 1 h and then concentrated in vacuo. The product was obtained as a red-brown liquid (8.40 g) which was used without further purification. ¹H NMR (500 MHz, CDCI₃): 7.35 (1 H, d), 7.17-7.15 (1 H, dd), 6.55-6.54 (1 H, d), 4.77 (1 H, br s), 1 .38 (9H, s).

Step 2: tert-butyl 4-(6-(3-(tert-butyl)-4-hydroxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(4-(2-hydroxypropan-2-yl)-3- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate, 4-bromo-2-(tert-butyl)phenol (1 .5 g, 6.55 mmol) and tert-butyl 4-(6-bromopyridin-2-yl)piperazine-1 -carboxylate (1 .494 g, 4.37 mmol) were reacted to afford the title compound as a yellow solid (658 mg, 37%). LCMS (Method F): R_T = 1 .66 min, M+H⁺ = 412.

Step 3: tert-butyl 4-(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for Methyl 4-bromo-2-isopropoxybenzoate, tert-butyl 4-(6-(3- (tert-butyl)-4-hydroxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (150 mg, 0.364 mmol) and 2-iodopropane (0.055 ml, 0.547 mmol) were reacted to afford the title compound as a yellow oil (60.0 mg, 36%).

¹H NMR (500 MHz, CDCI₃): 7.98-7.97 (1 H, d), 7.79-7.77 (1 H, dd), 7.54-7.51 (1 H, dd), 7.07-7.05 (1 H, d), 6.91 -6.89 (1 H, d), 6.54-6.52 (1 H, d), 4.73-4.69 (1 H, sept), 3.65-3.55 (8H, m), 1 .49 (9H, s), 1 .44 (9H, s), 1 .41 -1 .39 (6H, d).

Step 4: 1-(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(3-(tert-butyl)-4- isopropoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (60 mg, 0.132 mmol) was reacted to afford the title compound as a yellow solid (35.6 mg, 63%).

LCMS (Method F): R_T = 1 .10 min, M+H⁺ = 354; ¹H NMR (500 MHz, MeOH-d₄D): 8.03- 8.00 91 H, dd), 7.81 (1 H, d), 7.75-7.72 (1 H, dd), 7.33-7.32 (1 H, d), 7.17-7.16 (1 H, d), 7.14-7.13 (1 H, d), 4.00-3.98 (4H, m), 3.48-3.45 (4H, m), 1 .47 (9H, s), 1 .45-1 .44 (6H, d).

Example 51 ): 1 -(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine

dihydrochloride

Step 1: tert-butyl 4-(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for Methyl 4-bromo-2-isopropoxybenzoate, tert-butyl 4-(6-(3- (tert-butyl)-4-hydroxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (120 mg, 0.292 mmol) and 1 -bromo-2-methylpropane (0.048 ml, 0.437 mmol) were reacted to afford the title compound as a colourless oil (43.6 mg, 32%).

¹H NMR (500 MHz, CDCI₃): 7.99 (1 H, d), 7.79-7.77 (1 H, dd), 7.54-7.51 (1 H, dd), 7.07- 7.06 (1 H, d), 6.91 -6.90 (1 H, d), 6.54-6.53 (1 H, d), 3.82-3.81 (2H, d), 3.65-3.55 (8H, m), 2.22-2.16 (1 H, sept), 1 .49 (9H, s), 1 .45 (9H, s), 1 .1 1 -1 .10 (6H, d).

Step 2: 1-(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine dihydrochloride: Following the procedure for 8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)-2,8-diazaspiro[4.5]decane dihydrochloride, tert-butyl 4-(6-(3-(tert-butyl)-4- isobutoxyphenyl)pyridin-2-yl)piperazine-1 -carboxylate (43.6 mg, 0.093 mmol) was reacted to afford the title compound as a yellow solid (25.0 mg, 61 %).

LCMS (Method F): R_T = 1 .13 min, M+H⁺ = 368; ¹H NMR (500 MHz, MeOH-d₄): 8.1 1 -8.07 (1 H, dd), 7.78 (1 H, d), 7.75-7.72 (1 H, dd), 7.35-7.34 (1 H, d), 7.26-7.24 (1 H, d), 7.17-7.16 (1 H, d), 4.03-4.01 (4H, m), 3.94-3.92 (2H, d), 3.50-3.48 (4H, m), 2.25-2.20 (1 H, sept), 1 .50 (9H, s), 1 .17-1 .15 (6H, d).

Example 52): 1 -(6-(2-(benzyloxy)-1 .1 ,3,3-tetramethyl-2,3-dihvdro-1 H-inden-5-yl)pyridin-

2-yl)piperidin-4-amine dihydrochloride

Step 1: 1 , 1 ,3,3-tetramethyl- 1H-inden-2(3H)-one:

Into a 3-necked round-bottomed flask equipped with a reflux condenser, mechanical stirrer, thermometer and dropping funnel was added DMSO (210 ml) and potassium hydroxide (1 12 g, 2 moles). The resulting suspension was heated at 50-55 ° . A solution of inden-2(3H)-one (13.2 g, 0.1 mol) and methyl iodide (50 ml, 0.8 mol) was added by portions so as to keep the temperature between 50 and 60 °C (the heating was stopped after the first portion and cooling was applied when the temperature exceeded 60 °C. Once the addition was completed, the resulting suspension was stirred for another 1 h. The excess methyl iodide was then distilled off. The suspension was then poured onto ice-water (500 ml) and extracted with hexane (2 times 150 ml). The combined hexane extracts were concentrated in vacuo to afford the title compound as a brown oil (8.5 g, 45.1 %).

¹H NMR (500 MHz, CDCI₃): 7.14-7.08 (m, 4H), 1 .17 (s, 12H). Step 2: 5-bromo- 1, 1 ,3,3-tetramethyl-1 H-inden-2(3H)-one:

To a solution of aluminium chloride (23.90 g, 179 mmol) in dichloroethane (100 ml) was added a solution of 1 ,1 ,3,3-tetramethyl-1 H-inden-2(3H)-one (15 g, 71 .7 mmol) in dichloroethane (50 ml). A solution of bromine (3.69 ml, 71 .7 mmol) in dichloroethane (30 ml) was added over 30 min. The resulting solution was stirred at room temperature overnight. It was then poured onto ice and extracted with DCM. The DCM layer was washed with a 20% aqueous sodium thiosulfate solution then filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to afford the title compound (17g, 89%), contaminated with appr. 10% of 4,5-dibromo-1 ,1 ,3,3-tetramethyl-1 H-inden-2(3H)-one. This material was used without further purification.

H NMR (500 MHz, CDCI₃): 7.33 (d, 1 H), 7.31 (s, 1 H), 7.06 (s, dH), 1 .16 (s, 12H).

Step 3: 5-bromo- 1, 1,3,3-tetramethyl-2,3-dihydro-1H-inden-2-ol:

To a cold stirred solution of 5-bromo-1 ,1 ,3,3-tetramethyl-1 H-inden-2(3H)-one (7 g, 26.2 mmol) in THF/Methanol (7/3, 50 ml) was added sodium borohydride in small portions (2.97 g, 79 mmol). The solution was stirred at 0 ^ for 1 h then room temperature over 72h. It was quenched with a 1 N aqueous NaOH solution then extracted with ethyl acetate, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the title compound (4.9 g, 69.5%). H NMR (500 MHz, CDCI₃): 7.32 (d, 1 H), 7.26 (s, 1 H), 7.01 (d, 1 H), 3.80 (d, 1 H), 2.08 (d, 1 H), 1 .33 (s, 6H), 1 .17 (s, 3H), 1 .16 (s, 3H).

Step 4: 2-(benzyloxy)-5-bromo- 1 , 1 ,3,3-tetramethyl-2,3-dihydro- 1 H-indene:

To a solution of sodium hydride (60% in mineral oil, 0.30 g, 7.58 mmol) in dry THF (15ml) at 0 °C was added a solution of 5-bromo-1 ,1 ,3,3-tetramethyl-2,3-dihydro-1 H-inden-2-ol (1 .2 g, 4.46 mmol) in dry THF (5 ml). The resulting solution was stirred for 30 min at 0 'Ό. Benzyl bromide (0.91 g, 5.35 mmol) was added and the solution was stirred at room temperature overnight. It was quenched with ice water, diluted with DCM and filtered through a phase separator cartridge. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography using a Biotage SP4 instrument to afford the title compound (0.97 g, 61 %).

¹H NMR (500 MHz, CDCI₃): 7.4-7.2 (m, 7H), 6.99 (d, 1 H), 4.77 (s, 2H), 3.66 (s, 1 H), 1 .36 (s, 3H), 1 .35 (s, 3H), 1 .24 (s, 3H), 1 .22 (s, 3H).

Step 5: 2-(2-(benzyloxy)- 1, 1 ,3,3-tetramethyl-2,3-dihydro-1 H-inden-5-yl)-4,4,5,5- tetramethyl- 1,3,2-dioxaborolane:

Nitrogen was bubbled through a suspension of 2-(benzyloxy)-5-bromo-1 ,1 ,3,3- tetramethyl-2,3-dihydro-1 H-indene (1 .1 g, 3.06 mmol), PdCI₂(dppf) CH₂CI₂ (0.250 g, 0.306 mmol), potassium acetate (0.9 g, 9.18 mmol) and 4,4,4',4', 5,5,5', 5'-octamethyl- 2,2'-bi(1 ,3,2-dioxaborolane) (1 .166 g, 4.59 mmol) in DMF (10 ml) for 10 minutes. The mixture was heated at 100 'Ό for 15h. After cooling to room temperature the solution was diluted with water (3 ml) and DCM (15 ml). The mixture was filtered through a phase separator cartridge and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using a Biotage SP4 instrument to afford the title compound (0.43 g, 35%).

¹H NMR (500 MHz, CDCI₃): 7-7.7.0 (m, 8H), 4.78 (d, 2H), 3.67 (d, 1 H), 1 .4-1 .2 (m, 24H).

Step 6: tert-butyl 1-(6-(2-(benzyloxy)-1 , 1,3,3-tetramethyl-2,3-dihydro- 1H-inden-5- yl)pyridin-2-yl)piperidin-4-ylcarbamate:

Nitrogen was bubbled through a solution of 2-(2-(benzyloxy)-1 ,1 ,3,3-tetramethyl-2,3- dihydro-1 H-inden-5-yl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.148 g, 0.365 mmol) , tert-butyl 1 -(6-bromopyridin-2-yl)piperidin-4-ylcarbamate (0.100 g, 0.281 mmol)

PdCI₂(dppf) CH₂CI₂ (0.018 g, 0.022 mmol) and 2N aqueous sodium carbonate (0.291 mL, 0.561 mmol) in dioxane (1 .2 ml) for 10 min and subsequently heated at 90 °C for 15h. After cooling to room temperature, the reaction mixture was diluted with DCM/water and filtered through a phase separator cartridge. The filtrate was concentrated in vacuo and the residue purified by flash chromatography using a Biotage SP4 instrument to afford the title compound (0.039 g, 25%).

LCMS (Method F): R_T = 2.06 min, M+H⁺ = 350; ¹H NMR (500 MHz, CDCI₃): 7.84 (d, 1 H), 7.70 (s, 1 H), 7.50 (t, 1 H), 7.40 (2, 2H), 7.38 (d, 2H), 7.30 (t, 1 H), 7.19 (d, 1 H), 7.05 (d, 1 H), 6.58 (d, 1 H), 4.80 (s, 2H), 4.49 (brs, 1 H), 4.31 (m, 2H), 3.71 (m, 2H), 3.02 (m, 2H), 2.02 (m, 2H), 1 .70 (m, 1 H), 1 .45 (s, 9H), 1 .39 (s, 3H), 1 .29 (s, 3H), 1 .27 (s, 3H).

Step 7 : 1-(6-(2-(benzyloxy)-1, 1 ,3 etramethyl-2,3-dihydro-1H-inden-5-yl)pyridin-2- yl)piperidin-4-amine

1 -(6-(2-(benzyloxy)-1 ,1 ,3,3-tetramethyl-2,3- dihydro-1 H-inden-5-yl)pyridin-2-yl)piperidin-4-ylcarbamate (50 mg, 0.09 mmol) was added to a 4N HCI solution in dioxane (2ml_, 8mmol). The resulting solution was stirrred at 50 °C for 15 min then concentrated in vacuo to afford the title compound (48 mg, 100%).

LCMS (Method F): R_T = 1 .28 min, M+H⁺ = 456; ¹H NMR (500 MHz, CDCI₃): 8.77 (brs, 3H), 7-7.8 (m, 1 1 H), 4.75 (s, 2H), 4.4 (m, 2H), 3.4 (m, 2H), 2.5 (m, 2H), 2.15 (m, 2H), 1 .41 (s, 3H), 1 .35 (s, 3H), 1 .30 (s, 3H), 1 .25 (s, 3H).

Step 1 : 4-bromo-2-(tert-butyl)- 1-isopropoxybenzene:

A solution of 4-bromo-2-(tert-butyl)phenol (10 g, 43.6 mmol) in DMF (50 ml) was cooled to 0 °C. NaH (60 % in mineral oil, 3.49 g, 87 mmol) was added slowly. After 30 min, 2- iodopropane (13.07 ml, 131 mmol) was added. Further DMF (40 ml) was added to mobilise the mixture, and it was stirred at RT for 18h. The mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo to afford the title compound as a yellow liquid (12.35 g, >100%). Used without further purification.

¹H NMR (500 MHz, CDCI₃): 7.35-7.34 (1 H, d), 7.24-7.22 (1 H, dd), 6.71 -6.69 (1 H, d), 4.63-4.58 (1 H, sept), 1 .38-1 .37 (6H, d), 1 .36 (9H, s).

Step 2: 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane: To a solution of 4-bromo-2-(tert-butyl)-1 -isopropoxybenzene (1 1 .8 g, 43.5 mmol) in DMF (150 ml) was added 4,4,4',4', 5,5, 5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (16.57 g, 65.3 mmol) and potassium acetate (12.81 g, 131 mmol). Nitrogen was bubbled through the mixture, and PdCI₂(dppf)CH₂CI₂ (1 .777 g, 2.176 mmol)) was added. The mixture was heated at 80 °C for 18 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a yellow solid (7.60 g, 55%). ¹H NMR (500 MHz, CDCI₃): 7.72 (1 H, d), 7.64-7.62 (1 H, dd), 6.85-6.83 (1 H, d), 4.72-4.68 (1 H, sept), 1 .40 (9H, s), 1 .37-1 .36 (6H, d), 1 .32 (12H, s). Step 3: 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine:

To a solution of 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (7.604 g, 23.89 mmol) and 2,4-dichloropyrimidine (2.97 g, 19.91 mmol) in dioxane (80 ml), was added 2M aq Na₂C0₃ (39.8 ml, 80 mmol). Nitrogen was bubbled through the mixture, and PdCI₂(dppf)CH₂CI₂ (0.813 g, 0.996 mmol) was added. Nitrogen was bubbled through the mixture for a further 5 min. The mixture was heated at 90 °C for 18 h under nitrogen. After cooling to RT, the mixture was concentrated in vacuo. The residue was partitioned between DCM and water, filtered through a phase separator cartridge and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a yellow solid (2.19 g, 36 %).

LCMS (Method F): R_T = 1 .80 min, M+H⁺ = 305.

Step 4: 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin- 1 -yl)ethanol: To a solution of 2-(piperazin-1 -yl)ethanol (42.7mg, 0.328 mmol) in THF (0.5 ml), in a sealable vial, was added DIPEA (0.086 ml, 0.492 mmol). A solution of 4-(3-(tert-butyl)-4- isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) in THF (0.500 ml) was added and the vial was sealed. After heating to 70 'Ό o/n the mixture was partitioned between DCM and water, filtered through a phase separator cartridge and loaded onto a 2 g SCX cartridge. The cartridge was washed with MeOH, and then the desired compound was eluted with 7N NH₃ in MeOH. The product containing fractions were concentrated in vacuo to afford the title compound as an orange gum (62 mg, 95%).

LCMS (Method F): R_T = 1 .13 min, M+H⁺ = 399; ¹H NMR (500 MHz, MeOH-d₄): 8.31 -8.30 (1 H, d), 8.03 (1 H, d), 7.86-7.84 (1 H, dd), 6.92-6.90 (1 H, d), 6.90-6.89 (1 H, d), 4.75-4.70 (1 H, sept), 3.96-3.93 (4H, m), 3.69-3.66 (2H, t), 2.62-2.60 (6H, m), 1 .43 (9H, s), 1 .42- 1 .40 (6H, d).

Example 54: cis-A/_l-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)cvclohexane-1 ,4- diamine

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, cis-cyclohexane-1 ,4-diamine (37.5 mg, 0.328 mmol) and 4-(3- (tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (50 mg, 81 %).

LCMS (Method F): R_T = 1 .06 min, M+H⁺ = 383; ¹H NMR (500 MHz, MeOH-d₄): 8.26-8.25 (1 H, d), 8.04-8.01 (1 H, m), 7.81 -7.80 (1 H, d), 6.92-6.90 (1 H, d), 6.89-6.88 (1 H, d), 5.19 (1 H, br s), 4.74-4.71 (1 H, sept), 4.1 1 (1 H, br s), 2.91 (1 H, br s), 1 .90-1 .85 (2H, m), 1 .79- 1 .73 (4H, m), 1 .43 (9H, s), 1 .41 -1 .40 (6H, d).

Example 55: 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-2-one

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, piperazin-2-one trifluoroacetate (70.3 mg, 0.328 mmol) and 4- (3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (55 mg, 92 %).

LCMS (Method F): R_T = 1 .51 min, M+H⁺ = 369; ¹H NMR (500 MHz, MeOH-d₄): 8.34-8.33 (1 H, d), 8.02-8.01 (1 H, d), 7.91 -7.89 (1 H, dd), 6.98-6.97 (1 H, d), 6.93-6.91 (1 H, d), 6.14 (1 H, br s), 4.76-4.71 (1 H, sept), 4.56 (2H, s), 4.16-4.14 (2H, t), 3.53-3.50 (2H, m), 1 .43 (9H, s), 1 .42-1 .41 (6H, d).

Example 56: (fi)-4-(3-(tert-butvn-4-isopropoxyphenyl)-2-(3-methylpiperazin-1 - vDpyrimidine

To a solution of (R)-tert-butyl 2-methylpiperazine-1 -carboxylate (82 mg, 0.328 mmol) in THF (0.5 ml), in a sealable vial, was added DIPEA (0.086 ml, 0.492 mmol). A solution of 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) in THF (0.5 ml) was added and the vial was sealed. After heating to 70 'Ό o/n the mixture was partitioned between DCM and water and filtered through a phase separator cartridge. HCI in dioxane (4M, 1 .0 ml, 4 mmol) was added and the mixture stirred for 1 h. The reaction was neutralized with sat. aq. NaHC0₃, filtered through a phase separator cartridge and loaded onto a 2 g SCX cartridge. The cartridge was washed with MeOH, and then the desired compound was eluted with 7N NH₃ in MeOH. The product containing fractions were concentrated in vacuo to afford the title compound as an orange gum (47 mg, 78 %).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 369; ¹H NMR (500 MHz, MeOH-d₄): 8.33-8.32 (1 H, d), 8.06 (1 H, d), 7.89-7.87 (1 H, dd), 6.95-6.93 (1 H, d), 6.90-6.89 (1 H, d), 6.14 (1 H, br s), 4.80-4.72 (3H, m), 3.15-3.13 (1 H, br d), 3.05-2.90 (3H, m), 2.66-2.62 (1 H, br t), 1 .46 (9H, s), 1 .44-1 .43 (6H, d), 1 .19-1 .18 (3H, d).

Example 57: 7-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-1 ,7- diazaspiro[3.51nonane

Following the procedure for (R)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3- methylpiperazin-1 -yl)pyrimidine, tert-butyl 1 ,7-diazaspiro[3.5]nonane-1 -carboxylate (93 mg, 0.328 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (42 mg, 64%).

LCMS (Method F): R_T = 1 .10 min, M+H⁺ = 395; ¹H NMR (500 MHz, MeOH-d₄): 8.34-8.33 (1 H, d), 8.07 (1 H, d), 7.90-7.88 (1 H, dd), 6.94-6.93 (1 H, d), 6.90-6.89 (1 H, d), 5.62 (1 H, br s), 4.77-4.72 (1 H, sept), 4.32 (2H, br s), 4.07-4.04 (2H, t), 2.87-2.84 (2H, t), 2.27-2.19 (5H, m), 1 .46 (9H, s), 1 .44-1 .43 (6H, d).

Example 58: 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-4-methyl-1 A- diazepane

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, 1 -methyl-1 ,4-diazepane (46.8 mg, 0.410 mmol) and 4-(3-(tert- butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (55 mg, 88%).

LCMS (Method F): R_T = 1 .13 min, M+H⁺ = 383; ¹H NMR (500 MHz, MeOH-d₄): 8.33-8.32 (1 H, d), 8.10 (1 H, d), 7.89-7.87 (1 H, dd), 6.94-6.92 (1 H, d), 6.88-6.87 (1 H, d), 4.77-4.72 (1 H, sept), 4.05 (2H, br s), 3.94 (2H, br s), 2.77-2.75 (2H, m), 2.63-2.60 (2H, m), 2.41 (3H, s), 2.09-2.04 (2H, m), 1 .46 (9H, s), 1 .44-1 .43 (6H, d). Example 59: (1 -(4-(3-(tert-butvn-4-isopropoxyphenyl)pyrimidin-2-vnazetidin-3- vDmethan amine

Following the procedure for (R)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3-methyl- piperazin-1 -yl)pyrimidine, tert-butyl (azetidin-3-ylmethyl)carbamate (92 mg, 0.492 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum ( 39.7 mg, 68% ).

LCMS (Method F): R_T = 0.98 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.33-8.32 (1 H, d), 8.08 (1 H, d), 7.88-7.86 (1 H, dd), 6.94-6.92 (2H, m), 4.77-4.72 (1 H, sept), 4.33- 4.29 (2H, t), 3.93-3.90 (2H, m), 3.05-3.03 (2H, d), 2.82-2.74 (1 H, m), 1 .45 (9H, s), 1 .44- 1 .43 (6H, d). Example 60: 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 - vDethanamine

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, 2-(piperazin-1 -yl)ethanamine (63.6 mg, 0.492 mmol) and 4-(3- (tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (52.4 mg, 80%).

LCMS (Method F): R_T = 1 .02 min, M+H⁺ = 398; ¹H NMR (500 MHz, MeOH-d₄): 8.33-8.32 (1 H, d), 8.05 (1 H, d), 7.88-7.86 (1 H, dd), 6.94-6.92 (1 H, d), 6.90-6.89 (1 H, d), 4.76-4.72 (1 H, sept), 3.96-3.94 (4H, m), 2.88-2.86 (2H, t), 2.60-2.48 (6H, m), 1 .45 (9H, s), 1 .44- 1 .42 (6H, s).

Example 61 : 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 -yl)-A/.A/- dimethylethan amine

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, /V,/V-dimethyl-2-(piperazin-1 -yl)ethanamine

(77 mg, 0.492 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (57.9 mg, 83%).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 426; ¹H NMR (500 MHz, MeOH-d₄): 8.33-8.32 (1 H, d), 8.05 (1 H, d), 7.88-7.86 (1 H, dd), 6.94-6.92 (1 H, d), 6.90-6.89 (1 H, d), 4.77-4.72 (1 H, sept), 3.97-3.95 (4H, m), 2.61 -2.51 (8H, m), 2.30 (6H, m), 1 .45 (9H, s), 1 .44-1 .43 (6H, s). Example 62: (rac)-1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyrrolidin-3- amine

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, (rac)-pyrrolidin-3-amine (42.4 mg, 0.492 mmol) and 4-(3-(tert- butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) were reacted to afford the title compound as an orange gum (50.4 mg, 86%).

LCMS (Method F): R_T = 1 .02 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.34-8.32 (1 H, d), 8.1 1 (1 H, d), 7.90-7.87 (1 H, dd), 6.94-6.92 (1 H, d), 6.90-6.89 (1 H, d), 4.77-4.72 (1 H, sept), 3.95-3.85 (2H, br d), 3.77-3.73 (2H, m), 3.45-3.40 (1 H, br s), 2.28-2.21 (1 H, m), 1 .88-1 .82 (1 H, m), 1 .46 (9H, s), 1 .44-1 .43 (6H, d).

Example 63: (4-amino-1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4- vDmethanol

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, ethyl 4-((tert-butoxycarbonyl)amino)piperidine-4-carboxylate (179 mg, 0.656 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (100 mg, 0.328 mmol) were reacted to afford crude ethyl 4-((tert-butoxycarbonyl)amino)-1 -(4- (3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carboxylate (200 mg, >100%). This material was dissolved in THF (2 ml) and LiAIH₄ (35.1 mg, 0.925 mmol) was added. After stirring at RT for 18 h, 40% aq KOH (0.3 ml) was added slowly, and the mixture stirred at RT for 15 min. The resultant suspension was filtered through celite, washed with EtOAc, and the combined filtrates concentrated in vacuo. The resultant residue was dissolved in dioxane (1 ml) and HCI (4M in dioxane, 2 ml, 8.00 mmol) was added. After stirring at RT for 2 h DCM (2 ml) was added, and the reaction was neutralized with sat. aq. NaHC0₃, filtered through phase separator cartridge and loaded onto a 2 g SCX cartridge. The cartridge was washed with MeOH, and the desired compound was eluted with 7N NH₃ in MeOH. The product containing frations were concentrated in vacuo. Further purification was carried out, using preparative HPLC (Methods C & D) to afford the title compound as a white solid (0.9 mg, 0.6%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 399; ¹H NMR (500 MHz, MeOH-d₄): 8.35-8.34 (1 H, d), 8.08-8.07 (1 H, d), 7.91 -7.89 (1 H, dd), 6.96-6.95 (1 H, d), 6.91 -6.90 (1 H, d), 4.79- 4.74 (1 H, sept), 4.32-4.29 (2H, m), 3.75-3.69 (4H, m), 1 .75-1 .71 (4H, m), 1 .47 (9H, s), 1 .46-1 .44 (6H, d). Example 64: 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 -vDpyrimidine

dihvdrochloride

Step 1 2-(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: Following the procedure for 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane, 4-bromo-1 -isopropoxy-2-isopropylbenzene (1 .67 g, 6.49 mmol) was reacted to afford the title compound (686 mg, 35%).

¹H NMR (500 MHz, CDCI₃): 7.64 (1 H, s), 7.62-7.60 (1 H, d), 6.84-6.82 (1 H, d), 4.62-4.58 (1 H, sept), 3.32-3.28 (1 H, sept), 1 .35-1 .33 (6H, d), 1 .33 (12H, s), 1 .23-1 .22 (6H, d).

Step 2: 2-chloro-4-(4-isopropoxy-3-isopropylphenyl)pyrimidine:

Following the procedure for 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine, 2-

(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (300 mg, 0.986 mmol) and 2,4-dichloropyrimidine (122 mg, 0.822 mmol) were reacted to afford the title compound as a yellow oil (59 mg, 25%).

¹H NMR (500 MHz, CDCI₃): 8.54-8.52 (1 H, d), 7.93-7.91 (2H, m), 7.57-7.56 (1 H, d), 6.94- 6.92 (1 H, dd), 4.69-4.66 (1 H, sept), 3.36-3.33 (1 H, sept), 1 .38-1 .37 (6H, d), 1 .29-1 .28 (6H, d).

Step 3: tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2-yl)piperazine-1- carboxylate:

To a solution of tert-butyl piperazine-1 -carboxylate (37.7 mg, 0.203 mmol) and 2-chloro- 4-(4-isopropoxy-3-isopropylphenyl)pyrimidine (58.9 mg, 0.203 mmol) in dioxane, was added Xantphos (1 1 .72 mg, 0.020 mmol) and potassium phosphate (95 mg, 0.446 mmol). Nitrogen was bubbled through the mixture, and Pd₂dba₃ (1 1 .13 mg, 0.012 mmol) was added. The mixture was heated at 80 °C for 18 h under nitrogen. The mixture was cooled to RT and filtered through celite (washing with EtOAc). The combined filtrates were concentrated in vacuo and the resultant residue was subjected to flash

chromatography (Si0₂, gradient 0 to 15 % EtOAc in cyclohexane) to afford the title compound as an orange oil (56 mg, 63%).

¹H NMR (500 MHz, CDCI₃): 8.32-8.31 (1 H, d), 7.89-7.85 (2H, m), 6.92-6.90 (2H, m), 4.66-4.62 (1 H, sept), 3.91 -3.89 (4H, m), 3.54-3.52 (4H, m), 3.37-3.33 (1 H, sept), 1 .52 (9H, s), 1 .37-1 .36 (6H, d), 1 .24-1 .23 (6H, d).

Step 4: 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin- 1-yl)pyrimidine dihydrochloride: To a solution of tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2-yl)piperazine- 1 -carboxylate (56.3 mg, 0.128 mmol) in dioxane (0.5 ml) was added HCI (4M in dioxane, 1 ml, 4.00 mmol). The mixture was stirred at room temperature for 1 h, and then further HCI (4M in dioxane, 0.5 ml, 2.00 mmol) was added. After 1 h at room temperature the mixture was concentrated in vacuo .The resultant solid was slurried in Et₂0, then lyophilized o/n to afford the title compound as a white solid (19 mg, 36%).

LCMS (Method F): R_T = 1 .02 min, M+H⁺ = 341 ; ¹H NMR (500 MHz, MeOH-d₄): 8.26-8.24 (1 H, d), 7.98-7.96 (2H, m), 7.31 -7.30 (1 H, d), 6.99-6.97 (1 H, d), 4.70-4.65 (1 H, sept), 4.12-4.10 (4H, t), 3.32-3.30 (4H, t), 3.29-3.22 (1 H, sept), 1 .29-1 .28 (6H, d), 1 .18-1 .17 (6H, d).

Step 1: tert-butyl 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2- yl)piperazine-1 -carboxylate, tert-butyl piperazine-1 -carboxylate (29.1 mg, 0.156 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (47.7 mg, 0.156 mmol) were reacted to afford the title compound as a yellow oil (39 mg, 55%).

¹H NMR (500 MHz, CDCI₃): 8.32-8.31 (1 H, d), 8.02 (1 H, d), 7.87-7.85 (1 H, dd), 6.92-6.90 (2H, m), 4.65-4.60 (1 H, sept), 3.90-3.88 (4H, m), 3.54-3.52 (4H, m), 1 .50 (9H, s), 1 .43 (9H, s), 1 .42-1 .41 (6H, d). Step 2: 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(piperazin- 1 -yl)pyrimidine dihydrochloride: Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin- 2-yl)piperazine-1 -carboxylate (39.4 mg, 0.087 mmol) was reacted to afford the title compound as a white solid (16 mg, 44%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.25-8.24 (1 H, d), 8.07-8.06 (1 H, d), 7.98-7.96 (1 H, dd), 7.30-7.28 (1 H, d), 7.01 -6.99 (1 H, d), 4.78- 4.73 (1 H, sept), 4.1 1 -4.09 (4H, t), 3.32-3.30 (4H, t), 1 .35 (9H, s), 1 .33-1 .32 (6H, s).

Example 66: 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-amine dihydrochloride

Following the procedure for tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)pyrimidin-2- yl)piperazine-1 -carboxylate, tert-butyl piperidin-4-ylcarbamate (31 .3 mg, 0.156 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (47.7 mg, 0.156 mmol) were reacted to afford the title compound as an orange oil (38 mg, 55%).

1H NMR (500 MHz, CDCI₃): 8.30-8.29 (1 H, d), 8.02 (1 H, d), 7.86-7.84 (1 H, dd), 6.92-6.90 (1 H, d), 6.87-6.86 (1 H, d), 4.76-4.72 93H, m), 4.48 (1 H, br s), 3.72 (1 H, br s), 3.15-3.10 (2H, m), 2.04-2.02 (2H, m), 1 .56-1 .52 (2H, m), 1 .46 (9H, s), 1 .41 -1 .40 (9H, s), 1 .39-1 .38 (6H, d).

Step 2: 1-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperidin-4-amine (38.3 mg, 0.104 mmol) was reacted to afford the title compound as a white solid (19 mg, 42%).

LCMS (Method F): R_T = 1 .21 min, M+H⁺ = 369; ¹H NMR (500 MHz, MeOH-d₄): 8.15-8.14 (2H, m), 8.07-8.05 (1 H, dd), 7.42-7.41 (1 H, d), 7.07-7.05 (1 H, d), 4.82-4.76 (1 H, sept), 4.76-4.65 (2H, br m), 3.51 -3.46 (1 H, m), 3.33-3.28 (2H, dt), 2.20-2.14 (2H, m), 1 .73-1 .65 (2H, ddd), 1 .36 (9H, s), 1 .35-1 .34 (6H, d).

Example 67: 1 -(4-(3-(tert-butyl)-4-(cvclopentyloxy)phenyl)pyrimidin-2-yl)piperidin-4-amine dihydrochloride

Step 1: 4-bromo-2-(tert-butyl)- 1-(cyclopentyloxy)benzene:

Following the procedure for 4-bromo-2-(tert-butyl)-1 -isopropoxybenzene, 4-bromo-2- (tert-butyl)phenol (10 g, 43.6 mmol) and bromocyclopentane (14.04 ml, 131 mmol) were reacted to afford to afford the title compound as a yellow liquid (16.06 g). Used without further purification.

¹H NMR (500 MHz, CDCI₃): 7.34-7.33 (1 H, d), 7.24-7.23 (1 H, dd), 6.71 -6.69 (1 H, d), 4.43-4.40 (1 H, m), 2.09-2.07 (2H, m), 1 .91 -1 .89 (2H, m), 1 .83-1 .80 (2H, m), 1 .67-1 .64 (2H, m), 1 .34 (9H, s).

Step 2: 2-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-4,4,5,5-tetramethyl- 1,3,2- dioxaborolane:

Following the procedure for 2-(3-(tert-butyl)-4-isopropoxyphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane, 4-bromo-2-(tert-butyl)-1 -(cyclopentyloxy)benzene (12.9 g, 43.4 mmol) was reacted to afford the title compound as a yellow oil (3.96 g, 26%).

Used without further purification.

Step 3: 4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-2-chloropyrimidine:

Following the procedure for 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine, 2- (3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (3.8 g, 1 1 .06 mmol) and 2,4-dichloropyrimidine (1 .373 g, 9.21 mmol) were reacted to afford the title compound as an orange semi-solid (750 mg, 25%).

H NMR (500 MHz, CDCI₃): 8.53-8.52 (1 H, d), 8.01 -8.01 (1 H, d), 7.55-7.52 (2H, m), 6.95- 6.93 (1 H, d), 4.93-4.91 (1 H, m), 1 .98-1 .95 (4H, m), 1 .86-1 .82 (2H, m), 1 .71 -1 .68 (2H, m), 1 .42 (9H, s).

Step 4: 1-(4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)pyrimidin-2-yl)piperidin-4-am dihydrochloride:

To a solution of tert-butyl piperidin-4-ylcarbamate (76 mg, 0.378 mmol) in THF (0.5 ml), in a sealable vial, was added DIPEA (0.086 ml, 0.492 mmol). A solution of 4-(3-(tert- butyl)-4-(cyclopentyloxy)phenyl)-2-chloropyrimidine (50 mg, 0.151 mmol) in THF (0.500 ml) was added, and the vial was sealed. After heating to 70 °C o/n the mixture was partitioned between DCM and water, filtered through phase separator cartridge and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane). The isolated material was dissolved in dioxane (0.5 ml), and HCI (4M in dioxane, 1 ml) was added. After stirring for 2h at room temperature, the mixture was concentrated in vacuo .The resultant solid was slurried in Et₂0 and then lyophilized o/n to afford the title compound as a pale yellow solid (47 mg, 67 %).

LCMS (Method F): R_T = 1 .32 min, M+H⁺ = 395; ¹H NMR (500 MHz, MeOH-d₄): 8.15-8.13 (1 H, d), 8.13-8.12 (1 H, d), 8.06-8.04 (1 H, dd), 7.40-7.39 (1 H, d), 7.05-7.03 (1 H, d), 4.96- 4.94 (1 H, sept), 4.71 -4.65 (2H, br m), 3.50-3.44 (1 H, m), 3.32-3.27 (2H, dt), 2.18-2.13 (2H, m), 1 .97-1 .92 (2H, m), 1 .87-1 .82 (2H, m), 1 .77-1 .63 (6H, m), 1 .34 (9H, s).

Example 68: 1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride

Step 1: tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate:

To a solution of 2,4-dichloropyrimidine (250 mg, 1 .678 mmol) and tert-butyl piperidin-4- ylcarbamate (370 mg, 1 .846 mmol) in DMF (2.5 ml) was added triethylamine (0.351 ml, 2.52 mmol). After stirring at RT for 18h the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant solid was slurried in Et₂0, filtered and dried in vacuo to afford the title compound as a white solid (272 mg, 52%)

1H NMR (500 MHz, CDCI₃): 8.06-8.04 (1 H, d), 6.43-6.42 (1 H, d), 4.70-4.20 (3H, br m), 3.75 (1 H, br s), 3.1 1 -3.06 (2H, dt), 2.10-2.07 (2H, m), 1 .41 (9H, s), 1 .41 -1 .38 (2H, m).

Step 2: tert-butyl (1-(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4- yl) carbarn ate:

Following the procedure for 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine, 2- (3-isopropoxy-4-isopropylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (60 mg, 0.197 mmol) and tert-butyl (1 -(2-chloropyrimidin-4-yl)piperidin-4-yl)carbamate (51 .4 mg, 0.164 mmol) were reacted to afford to afford the title compound as a yellow oil (39.3 mg, 52%). ¹H NMR (500 MHz, CDCI₃): 8.24-8.23 (1 H, d), 7.88-.784 (2H, m), 7.22-7.21 (1 H, d), 6.35- 6.37 (1 H, m), 4.73 (1 H, br s), 4.56-4.58 (1 H, sept), 4.50-4.70 (3H, br m), 3.72-3.69 (1 H, br s), 3.31 -3.28 (2H, m), 3.10-3.00 (2H, m), 2.05-2.00 (2H, m), 1 .39 (9H, s), 1 .34-1 .32 (6H, d), 1 .27 (9H, s), 1 .20-1 .19 (6H, d).

Step 3: 1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl (1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin- 4-yl)piperidin-4-yl)carbamate (39.3 mg, 0.086 mmol) was reacted to afford the title compound as a tan solid (15.5 mg, 41 %).

LCMS (Method F): R_T = 0.70 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.25-8.24 (1 H, d), 7.78-7.76 (1 H, dd), 7.72 (1 H, d), 7.49-7.48 (1 H, d), 7.1 19-7.18 (1 H, d), 4.86-4.80 (1 H, sept), 4.85-4.80 (2H, br m), 3.66-3.60 (2H, m), 3.55-3.35 (2H, br m), 3.45-3.40 (1 H, sept), 2.31 -2.29 (2H, br d), 1 .80-1 .70 (2H, br m), 1 .43-1 .42 (6H, d), 1 .28-1 .27 (6H, d).

Step 1: tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:

To a solution of 5-bromo-2-isopropylphenol (1 .5 g, 6.97 mmol) in DMF (20 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (2.66 g, 10.46 mmol) and potassium acetate (2.053 g, 20.92 mmol). Nitrogen was bubbled through the mixture, and PdCI₂(dppf)CH₂CI₂ (0.570 g, 0.697 mmol) was added. The mixture was heated at 80 °C for 18 h under nitrogen. After cooling to RT, tert-butyl 4-(6-bromopyridin- 2-yl)piperazine-1 -carboxylate (1 .592 g, 4.65 mmol), PdCI₂(dppf)CH₂CI₂ (0.570 g, 0.697 mmol) and Na₂C0₃ (2M aq) (13.95 ml, 27.9 mmol) were added. The mixture was heated at 80 °C for 5 h under nitrogen. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound as a brown oil (1 .0 g, 54%).

LCMS (Method F): R_T = 1 .66 min, M+H⁺ = 398.

Step 2: tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1- carboxylate:

To a solution of tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1 - carboxylate (120 mg, 0.302 mmol) in DMF (1 .5 ml) was added K₂C0₃ (50.1 mg, 0.362 mmol) and 1 -bromo-2-methylpropane (0.049 ml, 0.453 mmol). The resultant suspension was stirred at 70 °C for 18 h. Further K₂C0₃ (50.1 mg, 0.362 mmol) and 1 -bromo-2- methylpropane (0.049 ml, 0.453 mmol) were added, and heating continued for 72 h. After cooling to RT, the mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water, dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a yellow oil (58.7 mg, 43%).

¹H NMR (500 MHz, CDCI₃): 7.50-7.49 (1 H, t), 7.43-7.42 (1 H, dd), 7.40-7.39 (1 H, d), 7.20- 7.18 (1 H, m), 7.04-7.02 (1 H, d), 6.54-6.52 (1 H, d), 3.78-3.77 (2H, d), 3.58-3.52 (8H, m), 3.35-3.30 (1 H, sept), 2.10-2.05 (1 H, sept), 1 .43 (9H, s), 1 .19-1 .17 (6H, d), 1 .03-1 .02 (6H, d).

Step 3: 1-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2-yl)piperazinedihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (58.7 mg, 0.129 mmol) was reacted to afford the title compound as a yellow solid (39.7 mg, 72%).

LCMS (Method F): R_T = 1 .16 min, M+H⁺ = 354; ¹H NMR (500 MHz, MeOH-d₄): 8.01 -7.97 (1 H, dd), 7.47-7.43 (2H, m), 7.39-7.36 (2H, dd), 7.19-7.17 (1 H, d), 4.01 -3.99 (4H, t), 3.92-3.90 (2H, d), 3.47-3.40 (5H, m), 2.21 -2.15 (1 H, sept), 1 .29-1 .28 (6H, d), 1 .14-1 .12 (6H, d).

Example 70: 1 -(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and 1 -bromopropane (0.041 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (64.4 mg, 48%).

LCMS (Method F): R_T = 2.03 min, M+H⁺ = 440.

Step 2: 1-(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride tert-butyl 4-(6-(4-isopropyl-3-propoxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (64.4 mg, 0.147 mmol) was reacted to afford the title compound as a yellow solid (43.6 mg, 72%).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 340; ¹H NMR (500 MHz, MeOH-d₄): 7.90-7.87 (1 H, dd), 7.50-7.49 (2H, m), 7.35-7.33 (2H, d), 7.08-7.06 (1 H, d), 4.10-4.07 (2H, t), 3.98- 3.96 (4H, t), 3.44-3.37 (5H, m), 1 .94-1 .87 (2H, m), 1 .28-1 .27 (6H, d), 1 .15-1 .12 (3H, t).

Example 71 : 1 -(6-(3-(cvclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(3-(cyclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and bromocyclopentane (0.049 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (62.8 mg, 45%). LCMS (Method F): R_T = 2.10 min, M+H⁺ = 466.

Step 2: 1-(6-(3-(cyclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(3-(cyclopentyloxy)-4- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (62.8 mg, 0.135 mmol) was reacted to afford the title compound as a yellow solid (35.7 mg, 60%).

LCMS (Method F): R_T = 1 .14 min, M+H⁺ = 366; ¹H NMR (500 MHz, MeOH-d₄): 8.08-8.02 (1 H, br m), 7.42-7.35 (4H, m), 7.27-7.22 (1 H, br m), 5.04-5.02 (1 H, br m), 4.03-4.01 (4H, t), 3.48-3.46 (4H, t), 3.37-3.32 (1 H, sept), 2.05-1 .70 (8H, m), 1 .26-1 .25 (6H, d).

Example 72: 1 -(6-(4-isopropyl-3-(prop-1 -en-2-yl)phenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(4-isopropyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyridin-2- yl)piperazine- 1 -carboxylate:

To a solution of tert-butyl 4-(6-(3-hydroxy-4-isopropylphenyl)pyridin-2-yl)piperazine-1 - carboxylate (220 mg, 0.553 mmol) in DCM (3 ml) at 0 °C, was added triflic anhydride (0.1 12 ml, 0.664 mmol) and pyridine (0.063 ml, 0.775 mmol). The reaction mixture was stirred for 30 min and quenched with aq NaHC0₃. The mixture was passed through a phase separator cartridge and the organic fraction was concentrated in vacuo to afford the title compound as a brown gum (302 mg). This material was used without further purification.

LCMS (Method F): R_T = 1 .98 min, M+H⁺ = 530. Step 2: tert-butyl 4-(6-(4-isopropyl-3-(prop-1-en-2-yl)phenyl)pyridin-2-yl)piperazine- 1- carboxylate:

To a solution of tert-butyl 4-(6-(4-isopropyl-3-(((trifluoromethyl)sulfonyl)oxy)phenyl)- pyridin-2-yl)piperazine-1 -carboxylate (290 mg, 0.548 mmol) in toluene (2.5 ml) and water (1 ml) was added potassium isopropenyltrifluoroborate (105 mg, 0.712 mmol) and Cs₂C0₃ (357 mg, 1 .095 mmol)). Nitrogen was bubbled through the mixture and

Pd(PPh₃)₄ (31 .6 mg, 0.027 mmol) was added. The mixture was heated at 100 °C for 15 h under nitrogen. After cooling to RT the organic layer was decanted, filtered through a phase separator cartridge and the organic fraction was concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound as a yellow oil (1 14.9 mg, 50 %). LCMS (Method F): R_T = 2.00 min, M+H⁺ = 422.

Step 3: 1-(6-(4-isopropyl-3-(prop-1-en-2-yl)phenyl)pyridin-2-yl)piperazine

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(4-isopropyl-3-(prop-1 -en-2- yl)phenyl)pyridin-2-yl)piperazine-1 -carboxylate (30 mg, 0.071 mmol) was reacted to afford the title compound as a yellow solid (23.4 mg, 83%).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 322; ¹H NMR (500 MHz, MeOH-d₄): 7.87-7.84 (2H, m), 7.67-7.66 (1 H, d), 7.47-7.46 (1 H, d), 7.33-7.32 (1 H, d), 7.06-7.05 (1 H, d), 5.29- 5.28 (1 H, m), 4.89-4.87 (1 H, m), 3.98-3.96 (4H, t), 3.43-3.41 (4H, t), 3.28-3.22 (1 H, sept), 2.1 1 (3H, s), 1 .28-1 .27 (6H, d).

Example 73: 1 -(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine- 1 -carboxylate:

A solution of tert-butyl 4-(6-(4-isopropyl-3-(prop-1 -en-2-yl)phenyl)pyridin-2-yl)piperazine- 1 -carboxylate (80 mg, 0.190 mmol) in Ethanol (4 ml) was hydrogenated using an H-cube (Pd/C, full H₂, RT, 1 ml/min). The resultant solution was passed through the H-cube twice more (full H₂, 50°C, 1 ml/min), and then concentrated in vacuo Xo afford the title compound as a yellow oil (61 .1 mg, 76%).

LCMS (Method F): R_T = 2.01 min, M+H⁺ = 424. Step 2: 1-(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(3,4-diisopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (60 mg, 0.142 mmol) was reacted to afford the title compound as a yellow solid (42.0 mg, 75%).

LCMS (Method F): R_T = 1 .06 min, M+H⁺ = 324; ¹H NMR (500 MHz, MeOH-d₄): 8.17-8.13 (1 H, dd), 7.74 (1 H, d), 7.68-7.66 (1 H, dd), 7.53-7.51 (1 H, d), 7.37-7.34 (2H, m), 4.06- 4.04 (4H, t), 3.51 -3.49 (4H, t), 3.45-3.39 (2H, 2 x sept), 1 .35-1 .34 (6H, d), 1 .32-1 .31 (6H, d). Example 74: 1 -(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and 1 -bromopropane (0.041 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (62.6 mg, 47%).

LCMS (Method F): R_T = 2.00 min, M+H⁺ = 440. Step 2: 1-(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (62 mg, 0.141 mmol) was reacted to afford the title compound as a yellow solid (50.9 mg, 88%).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 340; ¹H NMR (500 MHz, MeOH-d₄): 8.07-8.04 (1 H, dd), 7.73-7.71 (2H, m), 7.35-7.33 (1 H, d), 7.22-7.20 (1 H, d), 7.12-7.10 (1 H, d), 4.09- 4.07 (2H, t), 4.02-4.00 (4H, t), 3.49-3.47 (4H, t), 3.45-3.39 (1 H, sept), 1 .94-1 .87 (2H, m), 1 .32-1 .31 (6H, d), 1 .15-1 .12 (3H, t).

Example 75: 1 -(6-(4-(cvclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(4-(cyclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and bromocyclopentane (0.049 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (56.0 mg, 40%). LCMS (Method F): R_T = 2.07 min, M+H⁺ = 466.

Step 2: 1-(6-(4-(cyclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(4-(cyclopentyloxy)-3- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (56 mg, 0.120 mmol) was reacted to afford the title compound as a yellow solid (47.1 mg, 89%). LCMS (Method F): R_T = 1 .17 min, M+H⁺ = 366; ¹H NMR (500 MHz, MeOH-d₄): 8.10-8.07 (1 H, dd), 7.71 -7.68 (2H, m), 7.35-7.34 (1 H, d), 7.25-7.23 (1 H, d), 7.13-7.1 1 (1 H, d), 5.02- 4.97 (1 H, br m), 4.03-4.01 (4H, t), 3.49-3.47 (4H, t), 3.36-3.33 (1 H, sept), 2.05-1 .72 (8H, m), 1 .30-1 .29 (6H, d).

Example 76: (rac)-1 -(6-(3-isopropyl-4-((1 .1 ,1 -trifluoropropan-2-yl)oxy)phenyl)pyridin-2- vDpiperazine dihydrochloride

Step 1: (rac)-tert-butyl 4-(6-(3-isopropyl-4-((1 , 1, 1-trifluoropropan-2-yl)oxy)phenyl)pyridin- 2-yl)piperazine- 1 -carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and (rac)-1 ,1 , 1 -trif luoropropan-2-yl trifluoromethanesulfonate (360 mg, 0.453 mmol) were reacted to afford the title compound as a yellow oil (28.7 mg, 19%).

LCMS (Method F): R_T = 1 .93 min, M+H⁺ = 494.

Step 2 (rac)-1 -(6-(3-isopropyl-4-((1 , 1, 1-trifluoropropan-2-yl)oxy)phenyl)pyridin-2- yl)piperazine dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, (rac)-tert-butyl 4-(6-(3-isopropyl-4-((1 ,1 ,1 -trifluoropropan-2- yl)oxy)phenyl)pyridin-2-yl)piperazine-1 -carboxylate (28.7 mg, 0.058 mmol) was reacted to afford the title compound as a yellow solid (18.3 mg, 68%).

LCMS (Method F): R_T = 1 .09 min, M+H⁺ = 394; ¹H NMR (500 MHz, MeOH-d₄): 8.05-8.02 (1 H, dd), 7.81 -7.80 (1 H, d), 7.77-7.75 (1 H, dd), 7.35-7.33 (1 H, d), 7.25-7.23 (1 H, d), 7.22-7.21 (1 H, d), 5.19-5.14 (1 H, sept), 4.03-4.01 (4H, t), 3.48-3.46 (4H, t), 3.43-3.38 (1 H, sept), 1 .57-1 .55 (3H, d), 1 .32-1 .31 (6H, d). Example 77: (rac)-1 -(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: (rac)-tert-butyl 4-(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine- 1- carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, (rac)-tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and 2-iodobutane (0.052 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (39.9 mg, 29%).

LCMS (Method F): R_T = 2.03 min, M+H⁺ = 454.

Step 2: (rac)-1-(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, (rac)-tert-butyl 4-(6-(4-(sec-butoxy)-3- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (39.9 mg, 0.088 mmol) was reacted to afford the title compound as a yellow solid (23.1 mg, 62%).

LCMS (Method F): R_T = 1 .12 min, M+H⁺ = 354; ¹H NMR (500 MHz, MeOH-d₄): 7.88-7.84 (1 H, dd), 7.64 (1 H, d), 7.62-7.60 (1 H, dd), 7.21 -7.19 (1 H, d), 7.02-7.00 (1 H, d), 6.98-6.96 (1 H, d), 4.46-4.40 (1 H, m), 3.89-3.86 (4H, t), 3.35-3.33 (4H, t), 3.33-3.25 (1 H, sept), 1 .74-1 .58 (2H, m), 1 .23-1 .22 (3H, d), 1 .19-1 .17 (6H, dd), 0.95-0.92 (3H, t). Example 78: 4-(3-(tert-butyl)-4-(cvclopentyloxy)phenyl)-2-(piperazin-1 -yl) pyrimidine dihydrochloride

Following the procedure for 1 -(4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)pyrimidin-2- yl)piperidin-4-amine dihydrochloride, 4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-2- chloropyrimidine (50 mg, 0.151 mmol) and piperazine (32.5mg, 0.378 mmol) were reacted to afford the title compound as a pale yellow solid (36 mg, 53%).

LCMS (Method F): R_T = 1 .22 min, M+H⁺ = 381 ; ¹H NMR (500 MHz, MeOH-d₄): 8.35-8.34 (1 H, d), 8.25-8.24 (1 H, d), 8.21 -8.19 (1 H, dd), 7.61 -7.60 (1 H, d), 7.17-7.15 (1 H, d), 5.09- 5.05 (1 H, m), 4.29-4.27 (4H, t), 3.52-3.50 (4H, t), 2.12-1 .73 (8H, m), 1 .46 (9H, s).

Example 79: (1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4- vDmethan amine

Following the procedure for (R)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3- methylpiperazin-1 -yl)pyrimidine, 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) and tert-butyl (piperidin-4-ylmethyl)carbamate (70.3 mg, 0.328 mmol) were reacted to afford the title compound as a yellow gum (63 mg, 95%).

LCMS (Method F): R_T = 0.97 min, M+H⁺ = 383; ¹H NMR (500 MHz, CDCI₃): 8.30-8.29 (1 H, d), 8.04-8.03 (1 H, d), 7.86-7.84 (1 H, dd), 6.92-6.90 (1 H, d), 6.84-6.83 (1 H, d), 6.94- 6.91 (2H, br d), 4.74-4.70 (1 H, sept), 2.95-2.88 (2H, m), 2.63-2.62 (2H, d), 1 .88-1 .82 (2H, m), 1 .66-1 .56 (1 H, m), 1 .48-1 .47 (2H, d), 1 .43 (9H, s), 1 .41 -1 .40 (6H, d), 1 .27-1 .19 (2H, m). Example 80: 2-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-2,8- diazaspiro[4.51decane

Following the procedure for (fi)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3- methylpiperazin-1 -yl)pyrimidine, 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) and tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (79 mg, 0.328 mmol) were reacted to afford the title compound as a yellow gum (3.2 mg, 5%). LCMS (Method F): R_T = 1 .03 min, M+H⁺ = 409; ¹H NMR (500 MHz, CDCI₃): 8.23-8.22 (1 H, d), 7.99-7.96 (1 H, m), 7.83-7.75 (1 H, m), 6.86-6.78 (2H, m), 4.67-4.63 (1 H, m), 3.97-3.52 (6H, m), 3.1 1 -3.07 (2H, m), 3.01 -2.96 (2H, m), 2.73-2.57 (1 H, m), 2.04-2.02 (1 H, m), 1 .88-1 .85 (1 H, t), 1 .78-1 .76 (2H, t), 1 .36 (9H, s), 1 .34-1 .33 (6H, d). Example 81 : 1 -(6-(3-isopropyl-4-(2.2.2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(3-isopropyl-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazin 1-carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and 1 ,1 ,1 -trifluoro-2-iodoethane (0.045 ml, 0.453 mmol) were reacted to afford the title compound as a yellow oil (44.9 mg, 31 %). - I l l -

LCMS (Method F): R_T = 1 .89 min, M+H⁺ = 480.

Step 2: 1-(6-(3-isopropyl-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazin

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(3-isopropyl-4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)piperazine-1 -carboxylate (44.9 mg, 0.094 mmol) was reacted to afford the title compound as a yellow solid (28.7 mg, 68%).

LCMS (Method F): R_T = 1 .01 min, M+H⁺ = 380; ¹H NMR (500 MHz, MeOH-d₄): 8.08-8.04 (1 H, dd), 7.81 -7.76 (2H, m), 7.35-7.34 (1 H, d), 7.25-7.23 (1 H, d), 7.19-7.18 (1 H, d), 4.71 - 4.58 (2H, q), 4.04-4.00 (4H, m), 3.49-3.45 (4H, m), 3.45-3.40 (1 H, sept), 1 .33-1 .32 (6H, d).

Example 82: 1 -(6-(3-(tert-butyl)-4-(2.2.2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(3-(ten-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2- yl)piperazine- 1 -carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(3-(tert-butyl)-4-hydroxyphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.292 mmol) and 1 ,1 ,1 -trifluoro-2-iodoethane (0.043 ml, 0.437 mmol) were reacted to afford the title compound as a yellow oil (51 .2 mg, 36%).

LCMS (Method F): R_T = 1 .93 min, M+H⁺ = 494.

Step 2: 1 -(6-(3-(ten-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyrid^

dihydrochloride: Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(3-(tert-butyl)-4-(2,2,2- trifluoroethoxy)phenyl)pyridin-2-yl)piperazine-1 -carboxylate (51 .2 mg, 0.104 mmol) was reacted to afford the title compound as a yellow solid (37.1 mg, 77%).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 394; ¹H NMR (500 MHz, MeOH-d₄): 8.03-8.01 (1 H, dd), 7.89 (1 H, d), 7.89-7.81 (1 H, dd), 7.34-7.32 (1 H, d), 7.20-7.15 (2H, m), 4.71 - 4.67 (2H, q), 4.03-3.99 (4H, m), 3.48-3.45 (4H, m), 1 .48 (9H, s).

Example 83: 1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride

Step 1: tert-butyl (1-(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4- yl) carbarn ate:

To a solution of 2-(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (60 mg, 0.197 mmol) in dioxane (1 ml) was added tert-butyl (1 -(2- chloropyrimidin-4-yl)piperidin-4-yl)carbamate (51 .4 mg, 0.164 mmol) and 2M aq Na₂C0₃ (0.329 ml, 0.657 mmol). Nitrogen was bubbled through the mixture, and

PdCI₂(dppf) CH₂CI₂ (13.42 mg, 0.016 mmol) was added. The mixture was heated to 150 ° for 30 min. under microwave conditions. After cooling to RT, the reaction mixture was partitioned between DCM and water. The organic phase was dried, using a phase separator cartridge, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 40 % EtOAc in cyclohexane) to afford the title compound as a yellow oil (28.9 mg, 39%).

LCMS (Method F): R_T = 1 .23 min, M+H⁺ = 455.

Step 2: 1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-ami

dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl (1 -(2-(4-isopropoxy-3-isopropylphenyl)py 4-yl)piperidin-4-yl)carbamate (28.9 mg, 0.064 mmol) was reacted to afford the title compound as an off-white solid (1 1 .3 mg, 77%).

LCMS (Method F): R_T = 0.69 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.08-8.06 (1 H, d), 7.99-7.97 (1 H, dd), 7.94 (1 H, d), 7.08-7.06 (1 H, d), 7.00-6.98 (1 H, d), 4.72-4.70 (1 H, m), 3.53-3.48 (1 H, m), 3.30-3.20 (5H, m), 2.18-2.16 (2H, br d), 1 .64-1 .61 (2H, m), 1 .31 -1 .30 (6H, d), 1 .19-1 .18 (6H, d).

Example 84: 1 -(6-(4-(cvclopropylmethoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride

Step 1: tert-butyl 4-(6-(4-(cyclopropylmethoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine- 1-carboxylate:

Following the procedure for tert-butyl 4-(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate, tert-butyl 4-(6-(4-hydroxy-3-isopropylphenyl)pyridin-2- yl)piperazine-1 -carboxylate (120 mg, 0.302 mmol) and (bromomethyl)cyclopropane (0.059 ml, 0.604 mmol) were reacted to afford the title compound as a pink oil (61 .4 mg, 45%).

LCMS (Method F): R_T = 1 .97 min, M+H⁺ = 452.

Step 2: 1-(6-(4-(cyclopropylmethoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine dihydrochloride:

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(6-(4-(cyclopropylmethoxy)-3- isopropylphenyl)pyridin-2-yl)piperazine-1 -carboxylate (61 .4 mg, 0.136 mmol) was reacted to afford the title compound as a yellow solid (38.3 mg, 66%).

LCMS (Method F): R_T = 1 .03 min, M+H⁺ = 352; ¹H NMR (500 MHz, MeOH-d₄): 7.80-7.77 (1 H, dd), 7.67 (1 H, d), 7.64-7.62 (1 H, dd), 7.18-7.17 (1 H, d), 6.94-6.90 (2H, m), 3.86- 3.83 (6H, m), 3.33-3.29 (5H, m), 1 .26-1 .22 (1 H, m), 1 .20-1 .19 (6H, d), 0.57-0.53 (2H, m), 0.31 -0.29 (2H, m). Example 85: 1 -(6-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride

Step 1: tert-butyl 1-(6-chloropyrimidin-4-yl)piperidin-4-ylcarbamate:

To a solution of 4,6-dichloropyrimidine (0.5 g, 3.36 mmol) in acetonitrile (10 ml) was added tert-butyl piperidin-4-ylcarbamate (0.74 g, 3.69 mmol) and triethylamine (0.47 ml, 3.36 mmol). The mixture was heated at 120 °C for 2 h under microwave conditions, and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with aq. ammonium chloride, dried (MgS0₄) and concentrated in vacuo to afford the title compound as a white solid (0.98 g, 93%).

1H NMR (500 MHz, CDCI₃): 8.00 (1 H, s), 7.80 (1 H, s), 4.53 (1 H, br s), 4.27-4.24 (2H, d), 3.75 (1 H, br s), 3.10-3.04 (2H, m), 2.09-2.07 (2H, m), 1 .47 (9H, s), 1 .44-1 .39 (2H, m).

Step 2: tert-butyl (1-(6-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4- yl) carbarn ate:

Following the procedure for tert-butyl (1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4- yl)piperidin-4-yl)carbamate, 2-(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (75 mg, 0.247 mmol) and tert-butyl (1 -(6-chloropyrimidin-4- yl)piperidin-4-yl)carbamate (64.3 mg, 0.205 mmol) were reacted to afford the title compound as a yellow oil (81 .0 mg, 87%).

LCMS (Method F): R_T = 1 .22 min, M+H⁺ = 455.

Step 3: 1-(6-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine dihydrochloride

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl (1 -(6-(4-isopropoxy-3-isopropylphenyl)pyrimidin- 4-yl)piperidin-4-yl)carbamate (81 .0 mg, 0.178 mmol) was reacted to afford the title compound as a yellow solid (53.8 mg, 70%).

LCMS (Method F): R_T = 0.70 min, M+H⁺ = 355; ¹H NMR (500 MHz, MeOH-d₄): 8.56 (1 H, s), 7.67-7.64 (2H, m), 7.23 (1 H, s), 7.08-7.06 (1 H, d), 4.72-4.68 (1 H, m), 3.50-3.47 (1 H, m), 3.29-3.20 (5H, m), 2.16-2.14 (2H, br d), 1 .63-1 .60 (2H, m), 1 .30-1 .29 (6H, d), 1 .18- 1 .17 (6H, d).

Example 86: 2-(4-isopropoxy-3-isopropylphenyl)-4-(piperazin-1 -yl)-1 ,3,5-triazine dihydrochloride

Step 1: tert-butyl 4-(4-chloro- 1 ,3,5-triazin-2-yl)piperazine- 1 -carboxylate:

To a solution of 2,4-dichloro-1 ,3,5-triazine (200 mg, 1 .334 mmol) in acetonitrile (2 ml) at 0 °C was added Et₃N (0.279 ml, 2.000 mmol) and tert-butyl piperazine-1 -carboxylate (248 mg, 1 .334 mmol). The mixture was warmed to RT and stirred for 2 h. The mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 100% EtOAc in cyclohexane) to afford the title compound as a white solid (227 mg, 37%).

¹H NMR (500 MHz, CDCI₃): 8.39 (1 H, s), 3.90-3.86 (4H, m), 3.54-3.52 (4H, m), 1 .51 (9H, s).

Step 2: tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)-1 ,3,5-triazin-2-yl)piperazine-1 - carboxylate:

Following the procedure for tert-butyl (1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4- yl)piperidin-4-yl)carbamate, 2-(4-isopropoxy-3-isopropylphenyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (50 mg, 0.164 mmol) and tert-butyl 4-(4-chloro-1 ,3,5-triazin-2- yl)piperazine-1 -carboxylate (41 .1 mg, 0.137 mmol) were reacted to afford the title compound as an off-white solid (5.4 mg, 9%).

LCMS (Method F): R_T = 1 .91 min, M+H⁺ = 442. Step 3: 2-(4-isopropoxy-3-isopropylphenyl)-4-(piperazin- 1-yl)- 1 ,3,5-triazine

dihydrochloride

Following the procedure for 4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 - yl)pyrimidine dihydrochloride, tert-butyl 4-(4-(4-isopropoxy-3-isopropylphenyl)-1 ,3,5- triazin-2-yl)piperazine-1 -carboxylate (6 mg, 0.014 mmol) was reacted to afford the title compound as a white solid (5.8 mg, >100%).

LCMS (Method F): R_T = 1 .03 min, M+H⁺ = 342; ¹H NMR (500 MHz, MeOH-d₄): 8.80 (1 H, s), 8.24-8.22 (1 H, dd), 8.18-8.17 (1 H, d), 7.18-7.16 (1 H, d), 4.84-4.81 (1 H, sept), 4.45- 4.35 (4H, m), 3.50-3.40 (4H, m), 3.45-3.39 (1 H, sept), 1 .41 -1 .40 (6H, d), 1 .25-1 .24 (6H, d).

Example 87: (rac)-(1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyrrolidin-3- vDmethan amine

Following the procedure for (/^:?)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3- methylpiperazin-1 -yl)pyrimidine, 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) and (rac)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate (82 mg, 0.410 mmol) were reacted to afford the crude title compound. Further purification was carried out, using preparative HPLC (Methods C & D) to afford the title compound as a white solid (3.4 mg, 5.7%).

LCMS (Method F): R_T = 0.93 min, M+H⁺ = 369; ¹H NMR (500 MHz, CDCI₃): 8.33-8.32 (1 H, d), 8.08 (1 H, br s), 7.91 -7.89 (1 H,dd), 6.94-6.92 (1 H, d), 6.89-6.88 (1 H, d), 4.76- 4.74 (1 H, sept), 3.95-3.80 (2H, br m), 3.70-3.60 (1 H, br m), 3.45-3.35 (1 H, br m), 2.88- 2.85 (2H, m), 2.50-2.40 (1 H, m), 2.25-2.15 (1 H, m), 1 .80-1 .70 (1 H, m), 1 .46 (9H, s), 1 .44- 1 .43 (6H, d). Example 88: 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-4-phenylpiperidin-4- amine

Step 1: 1-(4-(3-(tei1-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-ol:

Following the procedure for 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)piperazin-1 -yl)ethanol, 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (500 mg, 1 .640 mmol) and piperidin-4-ol (332 mg, 3.28 mmol) were reacted to afford the title compound as a yellow oil (714 mg, >100%) which was used without further purification. LCMS (Method F): R_T = 1 .51 min, M+H⁺ = 370.

Step 2: 1-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperid

To a solution of 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-ol (606 mg, 1 .640 mmol) and Et₃N (0.571 ml, 4.10 mmol) in DMSO (10 ml), was added sulfur trioxide pyridine complex (1 .149 g, 7.22 mmol). The reaction mixture was stirred at RT for 18 h. Further Et₃N (0.571 ml, 4.10 mmol) and sulfur trioxide pyridine complex (1 149 mg, 7.22 mmol) were added and the reaction was stirred at RT for a further 18 h. The reaction mixture was partitioned between EtOAc and water. The organic extracts were washed with water (6 times), dried (MgS0₄), and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 50% EtOAc in cyclohexane) to afford the title compound as a yellow oil (100 mg, 17 %).

1H NMR (500 MHz, CDCI₃): 8.39-8.38 (1 H, d), 8.07 (1 H, s), 7.92-7.90 (1 H, dd), 7.01 -7.00 (1 H, d), 6.96-6.95 (1 H, d), 4.80-4.70 (1 H, sept), 4.27-4.24 (4H, m), 2.58-2.56 (4H, m), 1 .46 (9H, s), 1 .45-1 .44 (6H, d).

Step 3: N-( 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin

methylpropane-2-sulfinamide:

To a solution of 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-one (100 mg, 0.272 mmol) and 2-methylpropane-2-sulfinamide (36.3 mg, 0.299 mmol) in DCE (2 ml), was added Ti(OEt)₄ (0.068 ml, 0.299 mmol). The reaction mixture was heated to 85 °C for 18 h. The reaction mixture was diluted with DCM, and sat. aq.

NaHC0₃ solution was added. This mixture was stirred at room temperature for 5 min. and the resulting mixture was filtered through celite, the layers separated using a phase separator and the organic filtrates concentrated in vacuo to afford the title compound as a yellow oil (1 18 mg, 92%). Used without further purification.

LCMS (Method F): R_T = 1 .76 min, M+H⁺ = 471 .

Step 4: 1-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin^

To a solution of Phenylmagnesiumbromide, 1 M in THF (0.351 ml, 0.351 mmol) in THF (1 ml) at 0 °C, was slowly added a solution of N-(1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)- pyrimidin-2-yl)piperidin-4-ylidene)-2-methylpropane-2-sulfinamide (55 mg, 0.1 17 mmol) in THF (1 .0 ml). The reaction mixture was warmed to RT, and stirred at RT for 18 h. The mixture was partitioned between DCM and sat. aq. NaHC0₃, and filtered through a phase separator cartridge. 4M HCI in dioxane (~1 .5ml) was added to the organic filtrate, and the solution stirred for 1 .5 h. The mixture was neutralized with sat. aq. NaHC0₃, extracted into DCM, and filtered through a phase separator cartridge. The organic filtrate was concentrated in vacuo. Purification was carried out, using preparative HPLC

(Methods C & D), to afford the title compound as a white solid (3.5 mg, 6.7%).

LCMS (Method F): R_T = 1 .82 min, M+H⁺ = 446; ¹H NMR (500 MHz, CDCI₃): 8.28-8.27 (1 H, d), 8.01 -8.00 (1 H, d), 7.84-7.82 (1 H, dd), 7.49-7.47 (2H, dd), 7.34-7.31 (1 H, t), 7.20- 7.19 (1 H, m), 6.88-6.86 (1 H, d), 6.83-6.82 (1 H, d), 4.70-4.67 (1 H, sept), 4.51 -4.48 (2H, m), 3.64-3.59 (2H, dt), 2.18-2.12 (2H, dt), 1 .77-1 .74 (2H, m), 1 .39 (9H, s), 1 .37-1 .36 (6H, d). Example 89: 4-(piperidin-4-yloxy)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- vDpyrimidine di(trifluoroacetate)

Step 1: 4-chloro-6-(piperidin-4-yloxy)pyrimidine: Following the procedure for te/t-butyl 4- ((4-chloropyrimidin-2-yl)oxy)piperidine-1 -carboxylate, 4,6-dichloropyrimidine (1 .0 g , 6.71 mmol) and tert-butyl 4-hydroxypiperidine-1 -carboxylate (1 .35 g, 6.71 mmol) were reacted to afford the title compound as a white solid (1 .67 g, 80%).

¹H NMR (500 MHz, CDCI₃): 8.55 (1 H, s), 7.75 (1 H, s), 5.29-5.33 (1 H, m), 3.73-3.77 (2H, m), 1 .94-2.00 (2H, m), 1 .70-1 .76 (2H, m), 1 .47 (9H, s).

Step 2: tert-butyl 4-((6-(5,5,8,8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrimidin- 4-yl)oxy)piperidine-1-carboxylate: Following the procedure for tert-butyl 4-((4-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)oxy)piperidine-1 - carboxylate, 4-chloro-6-(piperidin-4-yloxy)pyrimidine (0.1 g, 0.39 mmol) and 4,4,5,5- tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,3,2- dioxaborolane (0.1 g, 0.39 mmol) were reacted to afford the title compound as a clear oil (0.6 g, 40%).

LCMS (Method F): R_T = 2.06 min, M+H⁺ = 466.

Step 3: 4-(piperidin-4-yloxy)-6-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidine di(trifluoroacetate):

Following the procedure for 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)phenyl)piperazine di(trifluoroacetate , tert-butyl 4-((6-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-4-yl)oxy)piperidine-1 -carboxylate (60 mg , 0.13 mmol) was reacted to afford the title compound as a white solid (23 mg, 48%).

LCMS (Method F): R_T = 1 .1 1 min, M+H⁺ = 366; ¹H NMR (500 MHz, MeOH-d₄): 8.66 (1 H, s), 7.95 (1 H, d), 7.67 (1 H, d), 7.38 (1 H, d), 7.19 (1 H, s), 5.40-5.43 (1 H, m), 3.33-3.38 (2H, m), 3.16-3.19 (2H, m), 2.14-2.16 (2H, m), 2.01 -2.04 (2H, m), 1 .65 (4H, s), 1 .25 (6H, s), 1 .22 (6H, s).

Example 90: 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- vDbenzimidamide

Step 1: 4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)benzonitrile:

Following the procedure for tert-butyl 1 -(4-(6-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)phenyl)cyclobutylcarbamate, (4- cyanophenyl)boronic acid (0.49 g, 3.32 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (1 .0 g, 3.32 mmol) were reacted to afford the title compound (766 mg, 63%).

LCMS (Method F): R_T = 1 .97 min, M+H⁺ = 368. Step 2: 4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)benzimidamide:

A solution of LHMDS (1 .09 ml, 1 .09 mmol) in diethyl ether (3 ml) under a nitrogen atmosphere was cooled to 0 'Ό and 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphthalen-2-yl)pyrimidin-2-yl)benzonitrile (0.2 g, 0.54 mmol) in diethyl ether (3 ml) added dropwise. The solution was warmed to RT over 2 hours and left to stir for 16 hours. The solution was added to 100 ml 1 M HCI (aq) then washed with diethylether (2x 100 ml). The aqueous layer was basified to pH 12 with Na₂C0₃ (aq) and extracted with EtOAc (2x 100 ml), dried (MgS0₄) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (KP-NH Si0₂, gradient 0 to 10% MeOH in EtOAc) to afford the title compound as an off white solid (125 mg, 65%).

LCMS (Method F): R_T = 1 .31 min, M+H⁺ = 385; ¹H NMR (500 MHz, MeOH-d₄): 8.87 (1 H, d), 8.62-8.64 (2H, d), 8.31 (1 H, d), 8.04-8.06 (1 H, dd), 7.91 -7.92 (2H, d), 7.85-7.83 (1 H, d), 7.57-7.55 (1 H, d), 1 .80 (4H, s), 1 .42 (6H, s), 1 .37 (6H, s). Example 91 : 1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperazin-1 -vDethanimine dihydrochloride

A solution of 2-(piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine (0.1 g, 0.285 mmol) and ethyl acetimidate hydrochloride (0.035 g, 0.285 mmol) in DMF (3 ml) was stirred at room temperature for 3 days. The solution was then concentrated in vacuo and the residue purified by flash chromatography. The resulting product was treated with HCI (4N in dioxane, 1 ml). The resulting precipitate was filtered and dried at ambient temperature to afford the title compound as a white solid (53 mg, 43%).

LCMS (Method F): R_T = 1 .32 min, M+H⁺ = 392; ¹H NMR (500 MHz, DMSO-d₆): 9.59 (s, 1 H), 8.95 (s, 1 H), 8.48 (d, 1 H), 8.09 (s, 1 H), 7.89 (d, 1 H), 7.48 (d, 1 H), 7.36 (d, 1 H), 4.00 (m, 4H), 3.78 (m, 4H), 2.37 (s, 3H), 1 .77 (s, 4H), 1 .32 (s, 6H), 1 .28 (s, 6H).

Example 92 : 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperazine-1 -carboximidamide dihydrochloride

Step 1 : tert-butyl (4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)piperazin- 1 -yl)methanediylidenedicarbamate:

A solution of 2-(piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine (0.60 g, 1 .79 mmol), 1 ,3-bis(te/?-butoxycarbonyl)-2-methyl-2- thiopseudourea (0.54 g, 1 .88 mmol), mercury chloride (0.51 g, 1 .97 mmol) and triethylamine (0.596 ml, 4.28 mmol) in DMF (5 ml) was stirred at room temperature overnight. The solution was diluted with ethylacetate (30 ml) and the mercury sulfide precipitate was filtered through a phase separator cartridge. The filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound as a colourless oil (0.55 g, 51 %).

LCMS (Method F): R_T = 1 .99 min, M+H⁺ = 593; ¹H NMR (500 MHz, CDCI₃): 10.23 (s, 1 H), 8.35 (d, 1 H), 7.96 (s, 1 H), 7.76 (d, 1 H), 7.40 (d, 1 H), 6.94 (d, 1 H), 4.00 (m, 4H), 3.71 (m, 4H), 2.37 (s, 3H), 1 .72 (s, 4H), 1 .51 , (s, 9H), 1 .49 (s, 9H), 1 .31 (s, 6H), 1 .26 (s, 6H).

Step 2 : 4-(4-(5_!5A8-tetramethyl-5^ ,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperazine-1 -carboximidamide dihydrochloride: A solution of tert-butyl (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperazin-1 -yl)methanediylidenedicarbamate (80 mg, 0.135 mmol) and HCI (4N in dioxane 1 ml) was stirred at 65 °C for 30 min then concentrated in vacuo. The resulting residue was triturated in diethyl ether. The solvent was decanted and the resulting solid was dried at ambient temperature to afford the title compound (50 mg, 80%).

LCMS (Method F): R_T = 1 .08 min, M+H⁺ = 393; ¹H NMR (500 MHz, DMSO-d₆): 8.46 (d, 1 H), 8.09 (s, 1 H), 7.90 (m, 1 H), 7.78 (s, 4H) 7.49 (d, 1 H), 7.40 (d, 1 H), 4.02 (m, 4H), 3.71 (m, 4H), 1 .68 (s, 4H),1 .31 (s, 6H), 1 .27 (s, 6H).

Example 93 : 1 -(1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaDhthalen-2-yl)Dyridin-2- yl)piperidin-4-yl)quanidine dihydrochloride

Step 1 : tert-butyl (tert-butoxycarbonylamino)(1-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-ylam

Following the procedure for tert-butyl (4-(4-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin-1 -yl)methanediylidenedicarbamate, 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine dihydrochloride (1 g, 2.29 mmol) and 1 ,3-bis(te/?-butoxycarbonyl)-2-methyl-2- thiopseudourea (0.73 g, 2.52 mmol) were reacted to afford the title compound as an off- white solid (1 .15 g, 83%).

LCMS (Method F): R_T = 2.23 min, M+H⁺ = 606; ¹H NMR (500 MHz, CDCI₃): 1 1 .56 (s, 1 H), 8.41 (d, 1 H), 7.96 (s, 1 H), 7.75 (d, 1 H), 7.54 (m, 1 H), 7.40 (d, 1 H), 7.06 (d, 1 H), 6,62 (d, 1 H), 4.31 (m, 1 H), 4.29 (m, 2H), 3.22 (m, 2H), 2.1 1 (m, 2H), 1 .72 (s, 4H), 1 ,60 (m, 2H), 1 .51 , (s, 9H), 1 .49 (s, 9H), 1 .31 (s, 6H), 1 .26 (s, 6H).

Step 2 : 1-(1-(6-(5 -tetramethyl-5fi -tetrahydronaphthalen-2-yl)pyridin-2- yl)piperidin-4-yl)guanidine dihydrochloride: Following the procedure for 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperazine-1 -carboximidamide dihydrochloride, tert-butyl (tert- butoxycarbonylamino)(1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyridin-2-yl)piperidin-4-ylamino)methylenecarbamate (0.2 g, 0.33 mmol) was reacted to afford the title compound as a white solid (0.13 g, 82%).

LCMS (Method F): R_T = 1 .30 min, M+H⁺ = 406; ¹H NMR (500 MHz, DMSO-d₆): 8.22 (brs, 2H), 7.85 (s, 1 H), 7.76 (brs, 1 H), 7.63 (d, 1 1-1) 7.45 (d, 1 H), 7.16 (d, 1 H), 7.04 (brs, 1 H), 6.3-5.5 (brs, 2H), 4.26 (m, 2H), 3.80 (m, 1 H), 3.21 (m, 2H), 1 .96 (m, 2H), 1 .68 (s, 4H), 1 .51 (m, 2H) 1 .31 (s, 6H), 1 .27 (s, 6H).

Example 94 : 1 -(1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-yl)quanidine dihydrochloride

Step 1: tert-butyl (tert-butoxycarbonylamino)(1-(4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4-ylam

Following the procedure for tert-butyl (4-(4-(5,5, 8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin-1 -yl)methanediylidenedicarbamate 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4- amine dihydrochloride (0.6 g, 1 .37 mmol) and 1 ,3-bis(te/?-butoxycarbonyl)-2-methyl-2- thiopseudourea (0.44 g, 1 .51 mmol) were reacted to afford the title compound as an off- white solid (0.68 g, 82%).

LCMS (Method F): R_T = 2.42 min, M+H⁺ = 607; ¹H NMR (500 MHz, CDCI₃): 1 1 .56 (s, 1 H), 8.42 (d, 1 H), 8.35 (d, 1 H), 7.98 (s, 1 H), 7.78 (d, 1 H), 7.42 (d, 1 H), 6,91 (d, 1 H), 4.71 (m, 2H), 4.40 (m, 1 H), 3.31 (m, 2H), 2.1 1 (m, 2H), 1 .74 (s, 4H), 1 ,55 (s, 9H), 1 .50, (s, 9H), 1 .50 (m, 2H), 1 .37 (s, 6H), 1 .33 (s, 6H).

Step 2:_ 1-(1-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperidin-4-yl)guanidine dihydrochloride:

Following the procedure for 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperazine-1 -carboximidamide dihydrochloride, tert-butyl (tert- butoxycarbonylamino)(1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperidin-4-ylamino)methylenecarbamate (0.16 g, 0.26 mmol) was reacted to afford the title compound as a white solid (0.13 g, 98%).

LCMS (Method F): R_T = 1 .33 min, M+H⁺ = 407; ¹H NMR (500 MHz, DMSO-d₆): 8.41 (d, 1 H), 8.1 1 (d, 1 H), 8.07 (s, 1 H), 7.90 (d, 1 H) 7.50 (d, 1 H), 7.36 (d, 1 H), 7.04 (brs, 1 H), 6.0-5.5 (brs, 2H), 4.60 (m, 2H), 3.80 (m, 1 H), 3.21 (m, 2H), 1 .96 (m, 2H), 1 .46 (s, 4H), 1 .48 (m, 2H) 1 .31 (s, 6H), 1 .28 (s, 6H).

Example 95 : N'-cvano-4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahvdronaphthalen-2- yl)pyrimidin-2-yl)piperazine-1 -carboximidamide

Step 1 : phenyl N-cyano-4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperazine- 1 -carbimidate:

A solution of 2-(piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine (0.24 g, 0.68 mmol), diphenyl cyanocarbonimidate (0.16 g, 0.68 mmol) and triethylamine (0.095 ml, 0.68 mmol) in acetonitrile (5 ml) was heated at 50 °C overnight then concentrated in vacuo. The crude product was used in the next step without further purification.

LCMS (Method F): R_T = 1 .87 min, M+H⁺ = 495.

Step 2 : N'-cyano-4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-yl)piperazine- 1 -carboximidamide:

A solution of phenyl A/-cyano-4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)piperazine-1 -carbimidate (0.25 g, 0.5 mmol) and ammonia (7N in methanol, 10 ml) was heated in a sealed flask at 1 10 °C for 5h. The resulting precipitate was filtered and dried at ambient temperature.

LCMS (Method F): R_T = 2.23 min, M+H⁺ = 418 ; ¹H NMR (500 MHz, DMSO-d₆): 8.42 (d, 1 H), 8.02 (s, 1 H), 7.85 (d, 1 H), 7.45 (d, 1 H), 7.22 (m, 3H), 4.00 (m, 4H), 3.85 (m, 4H), 3.59 (m, 4H), 1 .68 (s, 4H), 1 .31 , (s, 6H), 1 .27 (s, 6H). Example 96 : 4-(4-(3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1 - carboximidamide dihydrochloride

Step 1 : 2-(tert-butyl)-4-(2-chloropyrimidin-4-yl)phenol:

A solution of 4-bromo-2-(tert-butyl)phenol (6.5 g, 28 mmol), potassium acetate (8.35 g, 85 mmol), 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane (7.2 g, 28.4 mmol) and PdCI₂(dppf)-CH₂CI₂adduct (1 .57 g, 2.84 mmol) in dioxane (100 ml) was heated at 100 °C overnight. An aqueous solution of sodium carbonate (2N, 42.6 ml, 42.5 mmol), PdCI₂(dppf)-CH₂CI₂adduct (1 .57g, 2.84 mmol) and 2,4-dichloropyrimidine (4.2 g, 28.4 mmol) were then added. The resulting solution was heated at 100 °C for 4h. The organic phase was then decanted, dried over MgS0₄ and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (2.38 g, 32%).

1H NMR (500 MHz, DMSO-d₆): 10.3 (s, 1 H), 8.65 (d, 1 H), 8.01 (s, 1 H), 7.97 (d, 1 H), 7.90 (d, 1 H), 6.95 (d, 1 H), 1 .40 (s, 9H).

Step 2 : tert-butyl 4-(4-(3-(tert-butyl)-4-hydroxyphenyl)pyrimidin-2-yl)piperazine- 1- carboxylate:

A solution of 2-(tert-butyl)-4-(2-chloropyrimidin-4-yl)phenol (1 g, 3.81 mmol), tert-butyl piperazine-1 -carboxylate (1 .06 g, 5.71 mmol) and triethylamine (0.796 ml, 5.71 mmol) in

THF (6 ml) was heated at 140 °C for 25 min under microwave irradiation. The solution was diluted with ethyl acetate and water and the organic phase was decanted, dried over

MgS0₄, filtered and concentrated in vacuo. The residue was purified by flash

chromatography to afford the title compound (1 .35 g, 86%).

LCMS (Method F): R_T = 1 .65 min, M+H⁺ = 413; ¹H NMR (500 MHz, DMSO-d₆): 9.90 (s,

1 H), 8.33 (d, 1 H), 7.98 (s, 1 H), 7.82 (d, 1 H), 7.08 (d, 1 H), 6.98 (d, 1 H), 1 .44 (s, 9H), 1 .40

(s, 9H).

Step 3 : tert-butyl 4-(4-(3-(tert-butyl)-4-(((trifluoromethyl)sulfonyl)oxy)phenyl)pyrimidi yl)piperazine- 1 -carboxylate: A solution of tert-butyl 4-(4-(3-(tert-butyl)-4-hydroxyphenyl)pyrimidin-2-yl)piperazine-1 - carboxylate (1 .35 g, 3.27 mmol), triflic anhydride (1 .016 g, 3.60 mmol) and triethylamine (0.68 ml, 3.91 mmol) in DCM (20 ml) and THF (20 ml) was stirred at RT overnight. The solution was concentrated in vacuo and the residue was purified by flash

chromatography to afford the title compound (1 .26 g, 71 %).

LCMS (Method F): R_T = 1 .65 min, M+ = 489 (544 -tBu); ¹H NMR (500 MHz, CDCI₃): 8.40 (d, 1 H), 8.18 (s, 1 H), 7.92 (d, 1 H), 7.47 (d, 1 H), 6.93 (d, 1 H), 3.91 (m, 4H), 3.54 (m, 4H), 1 .50 (s, 9H), 1 .49 (s, 9H). Step 4 : tert-butyl 4-(4-(3-(tert-butyl)-4-(prop- 1 -en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1 - carboxylate:

A solution of tert-butyl 4-(4-(3-(tert-butyl)-4-(((trifluoromethyl)sulfonyl)oxy)phenyl) pyrimidin-2-yl)piperazine-1 -carboxylate (1 g, 183 mmol), isopropenyl trifluoroborate (0. 4g, 2.75 mmol), tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.018 mmol) and cesium carbonate (1 .1 9g, 3.67 mmol) in water (5 ml) and toluene (20 ml) was heated at 95 °C overnight. The mixture was diluted with ethyl acetate and water and the organic phase was decanted, dried over MgS0₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography to afford the title compound (0.5 g, 62.4 %).

LCMS (Method F): R_T = 1 .65 min, M+H⁺ = 437 ; ¹H NMR (500 MHz, CDCI₃): 8.36 (d, 1 H), 8.14 (s, 1 H), 7.77 (d, 1 H), 7.09 (d, 1 H), 6.93 (d, 1 H), 5.23 (m, 1 H), 4.90 (m, 1 H), 3.91 (m, 4H), 3.54 (m, 4H), 2.04 (s, 3H), 1 .50 (s, 9H), 1 .49 (s, 9H).

Step 5 : 4-(3-(tert-butyl)-4-(prop-1-en-2-yl)phenyl)-2-(piperazin- 1-yl)pyrimidine

dihydrochloride:

A solution of tert-butyl 4-(4-(3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)pyrimidin-2- yl)piperazine-1 -carboxylate (0.3 g, 0.68 mmol) and HCI (4N in dioxane, 3 ml) was heated at 50 °C for 30 min then concentrated in vacuo to afford the title compound (0.3 g, 100%).

LCMS (Method F): R_T = 1 .07 min, M+H⁺ = 337.

Step 6 : tert-butyl (((tert-butoxycarbonyl)amino)(4-(4-(3-(tert-butyl)-4-(prop-1-en-2- yl)phenyl)pyrimidin-2-yl)piperazin- 1-yl)methylene)carbamate:

Following the procedure for tert-butyl (4-(4-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin-1 yl)methanediylidenedicarbamate, 4- (3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)-2-(piperazin-1 -yl)pyrimidine dihydrochloride (0.28 g, 0.068 mmol) was reacted to afford the title compound (0.2 g, 50%).

LCMS (Method F): R_T = 2.01 min, M+H⁺ = 580 ; ¹H NMR (500 MHz, CDCI₃): 10.21 (s, 1 H), 8.36 (d, 1 H), 8.14 (s, 1 H), 7.77 (d, 1 H), 7.08 (d, 1 H), 6.95 (d, 1 H), 5.23 (m, 1 H), 4.90 (m, 1 H), 4.01 (m, 4H), 3.71 (m, 4H), 2.10 (s, 3H), 1 .50 (s, 9H), 1 .49 (s, 9H).

Step 7 : 4-(4-(3-(tert-butyl)-4-(prop-1-en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1- carboximidamide dihydrochloride:

A solution of tert-butyl (((tert-butoxycarbonyl)amino)(4-(4-(3-(tert-butyl)-4-(prop-1 -en-2- yl)phenyl)pyrimidin-2-yl)piperazin-1 -yl)methylene)carbamate (0.2 g, 0.68 mmol) and HCI (4N in dioxane, 3 ml) was heated at 60 °C for 30 min then concentrated in vacuo to afford the title compound (0.15 g, 100%).

LCMS (Method F): R_T = 1 .14 min, M+H⁺ = 379. ¹H NMR (500 MHz, DMSO-d6): 8.50 (d, 1 H), 8.20 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 3H), 7.20 (d, 1 H), 7.10 (d, 1 H), 5.23 (m, 1 H), 4.85 (m, 1 H), 3.95 (m, 4H), 3.62 (m, 4H), 2.10 (s, 3H), 1 .40 (s, 9H).

Example 97: 2-(fer/-butyl)-A/-cvclopentyl-4-(4-(piperazin-1 -yl)pyrimidin-2-yl)aniline trihydrochloride

Step 1: 2-(tert-butyl)-N-cyclopentylaniline:

To a solution of 2-(tert-butyl)aniline (1 .567 ml, 10.05 mmol) in 1 ,2-Dichloroethane (15 ml) was added cyclopentanone (1 .78 ml, 20.1 mmol), sodium triacetoxyborohydride (5.33 g, 25.1 mmol) and acetic acid (1 .726 ml, 30.2 mmol). The reaction mixture was heated in a microwave at 140 'Ό for 10 min. After cooling to RT the mixture was redissolved in CH₂CI₂. The mixture was washed with water and brine. The organic layer was dried over Na₂S0₄, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound (1 .89 g, 87 %). LCMS (Method F): R_T = 1 .84 min, M+H⁺ = 218. Step 2: 4-bromo-2-(tert-butyl)-N-cyclopentylaniline:

To a solution of 2-(te/t-butyl)-/V-cyclopentylaniline (3.78 g, 17.39 mmol) in THF (30 ml) was added tetra- /V-butylammonium tribromide (8.39 g, 17.39 mmol) at O 'C. The reaction mixture was then stirred at RT for 10 min. Water was added to the reaction and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated in vacuo to afford the title compound (4.9 g, 95 %) which was used without further purification.

LCMS (Method F): R_T = 1 .94 min, M+H⁺ = 296/298.

Step 3: 2-(tert-butyl)-N-cyclopentyl-4-(4^,5,5-tetramethyl- 1,3,2-dioxab

To a solution of 4-bromo-2-(te/?-butyl)-/V-cyclopentylaniline (0.9 g, 3.04 mmol) in DMF (7 ml) was added 4,4,4',4', 5,5,5', 5'-ocfamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (0.771 g, 3.04 mmol) and KOAc (0.894 g, 9.1 1 mmol). Nitrogen was bubbled through the mixture for 10 min and then PdCI₂(dppf)-CH₂CI₂ (0.248 g, 0.304 mmol) was added. The mixture was heated for 16 h at 80 °C under nitrogen. After cooling to RT the reaction mixture was diluted with EtOAc. The mixture was washed with brine. The organic layer was dried over Na₂S0₄, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si0₂, gradient 0 to 20 % EtOAc in cyclohexane) to afford the title compound (389 mg, 37 %).

LCMS (Method F): R_T = 1 .96 min, M+H⁺ = 344.

Step 4: tert-butyl 4-(4-(3-(tert-butyl)-4-(cyclopentylamino)phenyl)pyrimidin-2- yl)piperazine- 1 -carboxylate:

To a solution of 2-(ie -butyl)-/V-cyclopentyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)aniline (390 mg, 1 .136 mmol) in DMF (2 ml) was added a mixture of terf-butyl 4-(2- chloropyrimidin-4-yl)piperazine-1 -carboxylate and terf-butyl 4-(4-chloropyrimidin-2- yl)piperazine-1 -carboxylate (339 mg, 1 .136 mmol) and 2M aq. Na₂C0₃ (1 .136 ml, 2.272 mmol). The reaction mixture was degassed by bubbling nitrogen through the mixture for 10 min and then PdCI₂(dppf)-CH₂CI₂ (93 mg, 0.1 14 mmol) was added. The mixture was heated for 16 h at 80 °C under nitrogen. After cooling to RT the reaction mixture was diluted with EtOAc. The mixture was washed with brine. The organic layer was dried with Na₂S0₄, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound (89 mg, 16%).

LCMS (Method F): R_T = 2.02 min, M+H⁺ = 480; H-NMR (500 MHz, CDCI₃): 8.26 (1 H, d), 8.03 (1 H, d), 7.82 (1 H, dd), 6.88 (1 H, d), 6.73 (1 H, d), 4.25 (1 H, d), 3.96-3.93 (1 H, m), 3.90-3.88 (4H, m), 3.54-3.52 (4H, m), 2.10-2.04 (2H, m), 1 .77-1 .67 (4H, m), 1 .57-1 .55 (2H, m), 1 .50 (9H, s), 1 .45 (9H, s).

Step 5: 2-(tert-butyl)-N-cyclopentyl-4-(4-(piperazin- 1-yl)pyrimidin-2-yl)ani

trihydrochloride:

To a solution of te/t-butyl 4-(2-(3-(ie -butyl)-4-(cyclopentylamino)phenyl)pyrimidin-4- yl)piperazine-1 -carboxylate (50mg, 0.104 mmol) in CH₂CI₂ (1 ml) was added HCI (4M in dioxane, 1 ml, 4.00 mmol). The reaction mixture was then stirred at RT for 4h. The solvents were removed and the resulting solid was dried in vacuo to afford the title compound (41 mg, 95%).

LCMS (Method F): R_T = 1 .17 min, M+H⁺ = 380; ¹H NMR (500Mhz, MeOH-d₄): 8.20 (1 H, d), 8.17 (1 H, d), 8.13 (1 H, dd), 7.52 (1 H, d), 6.91 (1 H, d), 4.36-4.34 (1 H, m), 4.28-4.26 (4H, m), 4.09-4.05 (1 H, m), 3.52-3.50 (4H, m), 2.17-2.10 (2H, m), 1 .82-1 .72 (4H, m), 1 .70-1 .63 (2H, m), 1 .47 (9H, s).

Example 98: 2-(fer/-butyl)-A/-cvclopentyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline trihydrochloride

Step 1: tert-butyl 4-(2-(3-(tert-butyl)-4-(cyclopentylamino)phenyl)pyrimidin-4- yl)piperazine- 1 -carboxylate:

To a solution of 2-(ie -butyl)-/V-cyclopentyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)aniline (390 mg, 1 .136 mmol) in DMF (2 ml) was added a mixture of terf-butyl 4-(2- chloropyrimidin-4-yl)piperazine-1 -carboxylate and terf-butyl 4-(4-chloropyrimidin-2- yl)piperazine-1 -carboxylate (339 mg, 1 .136 mmol) and 2M aq. Na₂C0₃ (1 .136 ml, 2.272 mmol). Nitrogen was bubbled through the mixture for 10 min and then PdCI₂(dppf)- CH₂CI₂ (93 mg, 0.1 14 mmol) was added. The mixture was heated for 16 h at 80 °C under nitrogen. After cooling to RT the reaction mixture was diluted with EtOAc. The mixture was washed with brine. The organic layer was dried with Na₂S0₄, filtered and concentrated in vacuo. The resultant crude was subjected to flash chromatography (Si0₂, gradient 0 to 30 % EtOAc in cyclohexane) to afford the title compound (59 mg, 1 1 %).

LCMS (Method F): R_T = 1 .62 min, M+H⁺ = 480; H-NMR (500 MHz, CDCI₃): 8.32 (1 H, d), 8.28 (1 H, d), 8.14 (1 H, dd), 6.72 (1 H, d), 6.29 (1 H, d), 4.19 (1 H, d), 3.99-3.93 (1 H, m), 3.74-3.70 (4H, m), 3.58-3.53 (4H, m), 2.09-2.01 (2H, m), 1 .77-1 .64 (4H, m), 1 .59-1 .54 (2H, m), 1 .49 (9H, s), 1 .46 (9H, s).

Step 2: 2-(tert-butyl)-N-cyclopentyl-4-(2-(piperazin- 1-yl)pyrimidi

trihydrochloride:

To a solution of te/t-butyl 4-(2-(3-(ie -butyl)-4-(cyclopentylamino)phenyl)pyrimidin-4- yl)piperazine-1 -carboxylate (50mg, 0.104 mmol) in CH₂CI₂ (1 ml) was added HCI (4M in dioxane, 1 ml, 4.00 mmol). The reaction mixture was then stirred at RT for 4h. The solvents were removed and the resulting solid was dried in vacuo to afford the title compound (36 mg, 91 %).

LCMS (Method F): R_T = 0.94 min, M+H⁺ = 380; ¹H NMR (500Mhz, MeOH-d₄): 8.19 (1 H, d), 8.08 (1 H, d), 8.05 (1 H, d), 7.05 (1 H, d), 6.88 (1 H, d), 4.49 (2H, bs), 4.13 (2H, bs), 4.07-4.02 (1 H, m), 3.47 (4H, bs), 2.15-2.10 (2H, m), 1 .83-1 .71 (4H, m), 1 .65-1 .60 (2H, m), 1 .47 (9H, s).

Example 99: 5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolinimidamide dihvdrochloride

Step 1: 5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolinonitrile:

To a solution of 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)picolinonitrile (91 mg, 0.394 mmol) and 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) in dioxane (2 ml) was charged Na₂C0₃ (1 M aq), (1 ml, 1 mmol). Nitrogen was bubbled through the mixture, and Pd(PPh₃)₄ (19 mg, 0.016 mmol) was added. The mixture was heated to 120 'Ό for 20 min under microwave conditions. After cooling to RT the reaction mixture was partitioned between DCM and water, filtered through a phase separator cartridge and concentrated in vacuo. The remaining residue was purified by flash chromatography (Si0₂, 5-30%, EtOAc in cyclohexane) to give the title compound (64 mg, 52%) as an off white solid.

LCMS (Method F): R_T = 1 .87 min, M+H⁺ = 373.

Step 2: 5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolini

dihydrochloride:

To a solution of 5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolinonitrile (30 mg, 0.081 mmol) in methanol (1 ml) was charged sodium methoxide (0.870 mg, 0.016 mmol) the mixture was heated under microwave conditions for 10 min at 100 °C.

Ammonium chloride (4.31 mg, 0.081 mmol) was then charged to the reaction and the mixture heated under microwave conditions for a further 12 min at 80 °C. After cooling to RT the mixture was partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgS0₄) filtered and concentrated in vacuo. The resultant residue was loaded onto a 2 g SCX cartridge. The cartridge was washed with MeOH, and then the desired compound was eluted with 7N NH₃ in MeOH. The product containing fractions were concentrated in vacuo and the hydrochloride salt of the product was prepared by dissolving this material in dioxane (2 ml) and adding to this a solution of HCI in dioxane (4M, 0.1 ml). The solvent was removed in vacuo and the material was dissolved in water (1 ml) and lyophilized to afford the desired product (15 mg, 40 %) as a white solid.

LCMS (Method F): R_T = 1 .22 min, M+H⁺ = 390; ¹H NMR (500 MHz, MeOH-d₄): 9.79 (1 H, d), 9.01 (1 H, dd), 8.77 (1 H, d), 8.22-8.24 (2H, m), 8.05 (1 H, dd), 7.80 (1 H, d), 7.04 (1 H, d), 4.75 (1 H, m), 1 .40 (9H, s), 1 .34 (6H, d). Example 100: (5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyridin-2- vDmethanamine dihydrochloride

Using the H-Cube and Raney Nickel as catalyst, a solution of 2.0M ammonia in methanol was flushed through the system at 1 ml/min for 5 min at 80 'Ό and 50 bar with a constant flow of hydrogen. The flow was stopped and a solution of 5-(4-(3-(tert-butyl)- 4-isopropoxyphenyl)pyrimidin-2-yl)picolinonitrile (50 mg, 0.134 mmol) in 100 ml of 2.0M ammonia in methanol was then pumped through the system at a flow rate of 1 .0 ml/min. The solvent was removed in vacuo and the residue purified by flash chromatography (Si0₂, 5-30%, EtOAc in cyclohexane). The hydrochloride salt of the product was prepared by dissolving this material in dioxane (1 ml) and adding to this a solution of HCI in dioxane (4M, 0.1 ml). The solvent was then removed in vacuo and the material was dissolved in water (1 ml) and lyophilized to afford the desired product (13 mg, 21 %) as a green solid.

LCMS (Method F): R_T = 1 .19 min, M+H⁺ = 377; ¹H NMR (500 MHz, MeOH-d₄): 9.60

(1 H,d), 8.78 (1 H, dd), 8.72 (1 H, d), 8.23 (1 H, d), 8.04 (1 H, dd), 7.77 (1 H, d), 7.53 (1 H, d),

7.03 (1 H, d), 4.77 (1 H, m), 4.30 (2H, s), 1 .39 (9H, s), 1 .34 (6H, d).

Example 101 : 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 - carboximidamide hydrochloride

Step 1: tert-butyl (((tert-butoxycarbonyl)imino)(4-(4-(3-(tert-butyl)-4- isopropoxyphenyl)pyrimidin-2-yl)piperazin- 1-yl)methyl)carbamate:

To 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(piperazin-1 -yl)pyrimidine hydrochloride (188 mg, 0.440 mmol), 1 ,3-bis(te/t-butoxycarbonyl)-2-methyl-2-thiopseudourea (128 mg, 0.440 mmol) and triethylamine (0.245 ml, 1 .759 mmol) in DMF (1 .5 ml) was charged mercury(ll) chloride (1 19 mg, 0.440 mmol). The reaction was then stirred at RT under a nitrogen atmosphere overnight. The reaction was diluted with EtOAc and water and the layers separated. The organic layer was washed three times with water, dried (MgS04), filtered and concentrated in vacuo. The crude material was purified by flash

chromatography (S1O2, 0-20% ethyl acetate and cyclohexane) to afford the title compound (100 mg, 38%) as a colourless gum.

LCMS (Method F): R_T = 1 .98 min M+H⁺ = 597.

Step 2: 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine- 1 - carboximidamide hydrochloride:

To a solution of tert-butyl (((tert-butoxycarbonyl)imino)(4-(4-(3-(tert-butyl)-4- isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 -yl)methyl)carbamate (50 mg, 0.084 mmol) in dioxane (1 ml) was charged HCI (4M in dioxane, 1 ml). The reaction was then stirred at RT overnight. The solvent was removed in vacuo, and the material slurried in Et20, dissolved in water (1 ml) and lyophilized to afford the title compound (20 mg, 60 %) as a white solid.

LCMS (Method F): R_T = 1 .19 min, M+H⁺ = 397; ¹H NMR (500 MHz, MeOH-d₄): 8.3

(1 H,d), 8.26 (1 H, d), 8.17 (1 H, dd), 7.53 (1 H, d), 7.46 (1 H, s), 7.17 (1 H, d), 4.91 (1 H, m),

4.15 (4H, m), 3.83 (4H, m), 1 .47 (9H, s), 1 .46 (6H, d).

Example 102: 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 - carboximidamide hydrochloride

To a solution of tert-butyl 5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (100 mg, 0.446 mmol) in dichloromethane (5 ml) was charged trifluoroacetic acid (1 .5 ml, 19.47 mmol) and the reaction was stirred at RT for 2 h. The reaction was concentrated in vacuo, the resulting oil was dissolved in DMF (1 .5 ml) and 4-(3-(tert-butyl)-4- isopropoxyphenyl)-2-chloropyrimidine (100 mg, 0.328 mmol) and DIPEA (0.229 ml, 1 .312 mmol) were added. The mixture was heated at 120°C under microwave conditions for 80 min. After cooling the reaction mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted once more with ethyl acetate and the organic extracts were combined, washed four times with water/brine

1 :1 , dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Si0₂, 0-10%, MeOH in DCM) to afford the title compound (8 mg, 6%) as a colourless gum.

LCMS (Method F): R_T = 1 .53 min, M+H⁺ = 393; ¹H NMR (500 MHz, MeOH-d₄): 8.50 (1 H,s), 8.41 (1 H, d), 8.16 (1 H, d), 7.98 (1 H, dd), 7.19 (1 H, d), 7.06 (1 H, d), 5.27 (2H, s), 4.83 (1 H, m), 4.42 (2H, t), 4.29 (2H, t), 1 .48 (9H, s), 1 .43 (6H, d).

Example 103: 2-(4-(1 H-imidazol-2-yl)DiDeridin-1 -yl)-4-(3-(tert-butyl)-4- isopropoxyphenvDpyrimidine

To a solution of 4-(1 H-imidazol-2-yl)piperidine (49.6 mg, 0.328 mmol) and 4-(3-(tert- butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (50 mg, 0.164 mmol) in DMF (2 ml) was charged DIPEA (0.086 ml, 0.492 mmol). The reaction was heated at 120 °C under microwave conditions for 40 min. The reaction mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted once more with ethyl acetate and the organic extracts were combined, washed four times with water/brine 1 :1 , dried (MgS04), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Si0₂, 0-10%, MeOH in DCM) to afford the title compound (50 mg, 73%) as a white solid.

LCMS (Method F): R_T = 1 .17 min, M+H⁺ = 420; ¹H NMR (500 MHz, MeOH-d₄): 8.29 (1 H, d), 8.13 (1 H, d), 7.94 (1 H, dd), 7.03-7.06 (2H, m), 6.93 (2H, s), 4.95 (2H, m), 4.82 (1 H, m), 3.07-3.14 (3H, m), 2.03-2.08 (2H, m), 1 .78-1 .87 (2H, m), 1 .46 (9H, s), 1 .43 (6H, d).

Example 104: 2-(tert-butyl)-N-isopropyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline

Step 1 : 2-(tert-butyl)-N-isopropylaniline:

To a solution of 2-(tert-butyl)aniline (1 .045 ml, 6.70 mmol) in 1 ,2-Dichloroethane (10 ml) was added propan-2-one ( 0.541 ml, 7.37 mmol), followed by sodium

triacetoxyborohydride ( 2.27 g, 10.72 mmol) and acetic acid ( 0.422 ml, 7.37 mmol). This mixture was heated to 60 °C overnight under a nitrogen atmosphere. After cooling to RT the reaction mixture was partitioned between DCM and water. The organic phase was dried (phase separator cartridge) and concentrated in vacuo to afford the desired product (1 .53 g, 100%) as an orange oil.

¹ H NMR (500 MHz, CDCI₃): 7.26 (1 H, dd), 7.14 (1 H, m), 6.68-6.72 (2H, m), 3.76 (1 H, m), 1 .46 (9H, s), 1 .29 (6H, d).

Step 2: 4-bromo-2-(tert-butyl)-N-isopropylaniline:

To a solution of 2-(te/?-butyl)-/V-isopropylaniline (1 .282 g, 6.70 mmol) in THF (20 ml) was added tetra-n-butylammonium tribromide (3.23 g, 6.70 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 10 min, quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried (MgS0₄) and concentrated in vacuo to afford a brown solid.

LC-MS (Method F) R_T =1 .82min, M+H+=270/272.

Step 3: 2-(tert-butyl)-N-isopropyl-4-(4^,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline: To a solution of 4-bromo-2-(te/t-butyl)-/V-isopropylaniline (1 .69 g, 6.25 mmol) in DMF (12 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1 .588 g, 6.25 mmol) and potassium acetate (1 .841 g, 18.76 mmol). The reaction mixture was degassed by bubbling nitrogen through for 10 min, PdCI₂(dppf)-CH₂CI₂ adduct (0.51 1 g, 0.625 mmol) was added. The mixture was heated to 80 °C for 16 h. After cooling the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed twice with water, followed by brine, dried (MgS0₄), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 8 % EtOAc in cyclohexane) to afford the title compound as an orange gum (1 .00 g, 50 %).

LC-MS (Method F) R_T =1 .87min, M+H+=318.

Step 4: 2-(tert-butyl)-4-(2-chloropyrimidin-4-yl)-N-isopropylaniline:

To a solution of 2,4-dichloropyrimidine (0.939 g, 6.30 mmol) and 2-(tert-butyl)-N- isopropyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (1 g, 3.15 mmol) in dioxane (30 ml) was charged a solution of sodium carbonate (1 .002 g, 9.46 mmol) in water (10 ml). The reaction was then degassed by bubbling nitrogen through for 10 min, Palladium-tetrakis(triphenylphosphine) (0.182 g, 0.158 mmol) was added and the reaction heated at 90 'Ό under a nitrogen atmosphere overnight. The reaction was diluted with water and EtOAc and the layers separated. The aqueous was extracted twice more with ethyl acetate and the organic layers were combined, dried (MgS04) filtered and concentrated in vacuo. The crude material was purified by flash (S1O2, 0-

15% ethylacetate in cyclohexane) to afford the desired product (557 mg, 58%) as an orange solid.

LC-MS (Method F) R_T =1 .71 min, M+H+=304.

Step 5: tert-butyl 4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2-yl)piperazine- 1-carboxylate:

To a solution of tert-butyl piperazine-1 -carboxylate (245 mg, 1 .317 mmol) and 2-(tert- butyl)-4-(2-chloropyrimidin-4-yl)-N-isopropylaniline (200 mg, 0.658 mmol) in DMF (2 ml) was charged DIPEA (0.345 ml, 1 .975 mmol). The mixture was heated to 120 °C for 20 min under microwave conditions. After cooling to RT the reaction mixture was partitioned between DCM and water. The organic phase was dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 14 % EtOAc in cyclohexane) to afford the title compound as a yellow oil (212 mg, 71 %).

LCMS (Method F): R_T = 1 .88 min, M+H⁺ = 454. Step 6: 2-(tert-butyl)-N-isopropyl-4-(2-(piperazin- 1 -yl)pyrimidin-4-yl)aniline:

To a solution of tert-butyl 4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- yl)piperazine-1 -carboxylate (200 mg, 0.441 mmol) in DCM (2 ml) was charged 4M HCI in dioxane (6 ml, 24.00 mmol). The reaction was stirred at RT overnight. The solvent was removed in vacuo and the residue was partitioned between aq. NaHC03 solution and DCM. The organic phase was dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was purified using preparative HPLC (Method E) to afford the title compound (72 mg, 46%) as a colourless gum.

LCMS (Method F): R_T = 1 .06 min, M+H⁺ = 354; ¹H NMR (400 MHz, MeOH-d₄): 8.22 (1 H, d), 8.10 (1 H, d), 7.86 (1 H, dd), 7.00 (1 H, d), 6.78 (1 H, d), 3.82-3.88 (5H, m), 2.92 (4H, t), 1 .48 (9H, s), 1 .32 (6H, d).

Example 105: (rac)-2-amino-2-(4-(4-(5,5,8,8-tetramethyl-5,6 ,7,8-tetrahvdronaphthalen-2- yl)pyrimidin-2-yl)phenyl)ethanol ditrifluoroacetate

Step 1: (rac)-tert-butyl (1 -(4-chlorophenyl)-2-hydroxyethyl)carbamate:

To a solution of (rac)-2-amino-2-(4-chlorophenyl)ethanol (2 g, 1 1 .65 mmol) (prepared as described WO2009/47563 A1 ) in THF (20 ml) was added Boc anhydride (2.84 ml, 12.24 mmol) followed by triethylamine (2.436 ml, 17.48 mmol) . The reaction mixture was then stirred at RT and maintained at this temperature overnight. The reaction mixture was concentrated in vacuo, diluted with EtOAc and 1 N HCI and extracted. The organic extracts were then washed with brine, dried (Na2S04) and concentrated in vacuo affording the title compound as a sticky solid (2.8 g, 88%). ¹H NMR (500 MHz, CDCI₃): 7.34 (2H, m), 7.27 (1 H, d), 5.35 (1 H, m), 4.75 (1 H, m), 3.75- 3.90 (2H, m), 1 .44 (9H, s).

Step 2: (rac)-tert-butyl (2-hydroxy-1-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)phenyl)ethyl)carbamate:

To a solution of (rac)-tert-butyl (1 -(4-chlorophenyl)-2-hydroxyethyl)carbamate (1 .7 g, 6.26 mmol) in THF (25 ml) was added bis(pinacolato)diboron (1 .747 g, 6.88 mmol), 1 ,3-di- isopropylimidazoliumchloride (0.160 g, 0.375 mmol) and potassium acetate (1 .535 g, 15.64 mmol). Nitrogen was bubbled through the reaction mixture for 10 min before the addition of palladium(ll)acetate (0.042 g, 0.188 mmol). The reaction mixture was then heated at 80 °C for 2 h. The reaction mixture was cooled to room temperature, concentrated, diluted with EtOAc and water and extracted with EtOAc. The organic extracts were then washed with brine, dried (Na₂S0₄), filtered and concentrated in vacuo. The resultant residue was purified by flash chromatography (0 to 50% EtOAc in cyclohexane), affording the title compound as a gummy solid (1 .13 g, 50%).

LCMS (Method F): R_T = 1 .32 min, (M-Boc) + H⁺ = 264.

Step 3: (rac)- tert-butyl (2-hydroxy- 1-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)phenyl)ethyl)carbamate:

To a solution of (rac)-tert-butyl (2-hydroxy-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)carbamate (145 mg, 0.399 mmol) and 2-chloro-4-(5,5,8,8-tetramethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine (100 mg, 0.332 mmol) in dioxane (1 ml) was charged 1 M aq. sodium carbonate (1 ml, 1 .00 mmol). Nitrogen was bubbled through the reaction mixture for 10 min before the addition of

tetrakis(triphenylphosphine)palladium(0) (19.21 mg, 0.017 mmol). The reaction was sealed and heated under microwave conditions (Biotage initiator) at 120 'Ό for 40 min. The reaction was diluted with water and DCM, the layers separated using a phase separator cartridge and the organic layer concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 45% EtOAc in cyclohexane) to afford the title compound as an orange gum (82 mg, 49%).

LC-MS (Method F) R_T = 1 .82 min, M+H+ = 502.

Step 4: (rac)-2-amino-2-(4-(4-(5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphthalen-2- yl)pyrimidin-2-yl)phenyl)ethanol ditrifluoroacetate: To a solution of (rac)-tert-butyl (2-hydroxy-1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyrimidin-2-yl)phenyl)ethyl)carbamate (40 mg, 0.080 mmol) in DCM (2 ml) was charged TFA (1 ml, 12.98 mmol) the reaction was then stirred at RT for 10 min. The reaction was concentrated in vacuo to afford the desired product (41 mg, 100%) as an off-white solid.

LC-MS (Method F) R_T =1 .15 min, M+H+=402; ¹H NMR (500 MHz, MeOH-d₄): 8.86 (1 H, d), 8.63 (2H, d), 8.30 (1 H, d), 8.05 (1 H, dd), 7.87 (1 H, d), 7.64 (2H, d), 7.55 (1 H, d), 4.48 (1 H, m), 3.88-4.01 (2H, m), 1 .80 (4H, s), 1 .42 (6H, s), 1 .37 (6H, s). Example 106: (rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- vDphenvDethanol ditrifluoroacetate

Step 1: (rac)-tert-butyl ( 1-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)phenyl)- 2-hydroxyethyl)carbamate:

To a solution of (rac)-tert-butyl (2-hydroxy-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)carbamate (143 mg, 0.394 mmol) and 4-(3-(tert-butyl)-4- isopropoxyphenyl)-2-chloropyrimidine (100 mg, 0.328 mmol) in dioxane (1 ml) was charged 1 M sodium carbonate (1 ml, 1 .000 mmol). Nitrogen was bubbled through the reaction mixture for 10 min before the addition of

tetrakis(triphenylphosphine)palladium(0) (18.96 mg, 0.016 mmol). The reaction was sealed and heated under microwave conditions (CEM) at 120 'C for 40 min. The reaction was diluted with water and DCM, the layers were separated using a phase separator cartridge and the organic layer was then concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 45% EtOAc in cyclohexane) to afford the title compound as a colourless gum (40 mg, 24%).

LC-MS (Method F) R_T = 1 .80 min, M+H+ = 506. Step 2: (rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)phenyl)ethanol ditrifluoroacetate:

To a solution of (rac)-tert-butyl (1 -(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2- yl)phenyl)-2-hydroxyethyl)carbamate (40 mg, 0.079 mmol) in DCM was charged TFA (1 ml, 12.98 mmol) the reaction was then stirred at RT for 10 min. The reaction was concentrated in vacuo to afford the desired product as a yellow solid (40 mg, 97%).

LC-MS (Method F) R_T = 1 .12 min, M+H+ = 406; ¹H NMR (500 MHz, MeOH-d₄): 8.79 (1 H, d), 8.61 (2H, d), 8.34 (1 H, d), 8.13 (1 H, dd), 7.81 (1 H, d), 7.63 (2H, d), 7.13 (1 H, d), 4.90 (1 H, m) 4.47-4.49 (1 H, m), 3.88-4.01 (2H, m), 1 .51 (9H, s), 1 .45 (6H, d).

Example 107: (rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- vDphenvDethanol:

Step 1: (rac)-tert-butyl (1-(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- yl) phenyl) -2-hydroxyethyl) carbamate:

To a solution of 2-(tert-butyl)-4-(2-chloropyrimidin-4-yl)-/V-isopropylaniline (100 mg, 0.329 mmol) and (rac)-tert-butyl (2-hydroxy-1 -(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)ethyl)carbamate (143 mg, 0.395 mmol) in dioxane (1 ml) was charged 1 M aq. sodium carbonate (1 ml, 1 .000 mmol). Nitrogen was bubbled through the reaction mixture for 10 min before the addition of tetrakis(triphenylphosphine)palladium(0) (19.02 mg, 0.016 mmol). The reaction was sealed and heated under microwave conditions (CEM) at 120 °C for 60 min. The reaction was diluted with water and DCM and the layers separated using a phase separator cartridge, the organic layer was then concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si0₂, gradient 0 to 45 % EtOAc in cyclohexane) to afford the title compound as an orange gum (65 mg, 39%).

LC-MS (Method F) R_T = 1 .72 min, M+H+ = 505. Step 2: (rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- yl)phenyl)ethanol:

To a solution of (rac)-tert-butyl (1 -(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin- 2-yl)phenyl)-2-hydroxyethyl)carbamate (65 mg, 0.129 mmol) in DCM (2 ml) was charged TFA (1 ml, 12.98 mmol) the reaction was then stirred at RT for 10 min. The reaction was concentrated in vacuo and the residue basified using aq. NaHC03 and extracted with

DCM. The layers were separated (phase separator cartridge) and the organic layer concentrated in vacuo. The crude material was purified by flash chromatography (KP-NH 50-100% EtOAc in cyclohexane) followed by preparative HPLC (Method H) to afford the desired product (5 mg, 10%) as a colourless gum.

LC-MS (Method F) R_T = 1 .10 min, M+H+ = 405; ¹H NMR (500 MHz, MeOH-d₄): 8.67 (1 H, d), 8.54 (2H, d), 8.24 (1 H, d), 7.98 (1 H, dd), 7.46-7.47 (3H, m), 6.77 (1 H, d), 4.06-4.24 (2H, m) 4.76-4.87 (2H, m), 3.59-3.63 (1 H, m), 1 .51 (9H, s), 1 .32 (6H, d).

Example 108: 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4- carboximidamide:

Step 1: 1-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carbonitri A solution of 4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-chloropyrimidine (200 mg, 0.656 mmol), piperidine-4-carbonitrile (0.148 ml, 1 .312 mmol) and DIPEA (0.344 ml, 1 .968 mmol) in DMF (3 ml) was heated under microwave conditions (CEM) at 120 °C for 20 min. The reaction mixture was diluted with water and EtOAc and the layers were separated. The aqueous layer was extracted once more with EtOAc and the organic extracts were combined, washed four times with water/brine 1 :1 , dried (MgS04), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography

(Si0₂, gradient 0 to 10% EtOAc in cyclohexane) to afford the title compound (166 mg, LC-MS R_T = 1 .85 min, M+H⁺ = 379.

Step 2: 1-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4- carboximidamide:

To a suspension of ammonium chloride (72.1 mg, 1 .347 mmol) in toluene (1 ml) at 0 'Ό was charged a solution of trimethylaluminum (0.674 ml, 1 .347 mmol) 2.0 M in toluene over 5 min. The mixture was then stirred at RT for 25 min. A solution of 1 -(4-(3-(tert- butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carbonitrile (170 mg, 0.449 mmol) in toluene (1 ml) was then charged to the reaction and this heated at 80 °C for 18 h under an atmosphere of nitrogen. The reaction was then cooled to 0 'Ό and quenched by the careful addition of dry methanol. After stirring for 20 min at 0 °C the white precipitate was filtered off through celite and the filter cake washed with methanol. The filtrate was then concentrated in vacuo to yield 220 mg of a waxy solid. 70 mg of this crude material was loaded onto a 2 g SCX-2 cartridge. The cartridge was washed with MeOH, and then the desired compound was eluted with 4M NH₃ in MeOH to afford the title compound (14 mg, 25%) as an off white solid.

LC-MS (Method F) R_T = 1 .14 min, M+H+ = 396; ¹H NMR (500 MHz, DMSO-d₆): 8.34 (1 H, d), 8.03 (1 H, d), 7.92 (1 H, dd), 7.07-7.09 (2H, m), 6.71 (2H, brs), 4.78-4.87 (3H, m), 2.90 (2H, m) 2.35-2.40 (1 H, m), 1 .81 -1 .83 (2H, m), 1 .51 -1 .59 (2H, m), 1 .41 (9H, s), 1 .35-1 .36 (6H, d).

Claims

What we claims is:

1 . A compound according to formula I

Formula I

wherein:

where if one of X¹ , X², X³, X⁴, X⁵, and X⁶ is an oxo-substituted carbon atom at least one of the others is a nitrogen atom; wherein not more than three of X¹, X², X³, X⁴, X⁵, and X⁶are nitrogen atoms; and wherein Q is a heteroatom containing alkyl, substituted alkyl, optionally substituted cycloalkyi, optionally substituted aryl, or optionally substituted heterocyclyl containing side chain bound through a heteroatom or directly through a carbon atom; and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

2. The compound of claim 1 wherein the compound is not morpholine-2-carboxylic acid [6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pyridin-2-yl]-amide or a compound selected from compounds of formula (II)

in which, in each case independently of one another:

R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R ⁰, R¹¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷ represent H, D

(deuterium), A, OR¹⁸, CN, F, CI and NR ⁸R¹⁸ ;

wherein R and R², R³ and R⁴, R⁵ and R⁶, R ⁰ and R¹¹, R ² and R ³, R ⁴ and R ⁵, R ⁶ and R ⁷ may also in each case together form =0 (carbonyl oxygen);

wherein R⁹ and R¹, R and R², R² and R³, R³ and R⁴, R⁴ and R⁵, R⁵ and R⁶, R⁶ and R⁷, R⁷ and R⁸, R ⁰ and R¹¹, R and R ², R ² and R ³, R ⁴ and R ⁵, R ⁵ and R ⁶, R ⁶ and R ⁷ may also in each case together form a cycloalkyi having 3, 4, 5, 6 or 7 C atoms or Het having 3, 4, 5, 6 or 7 ring atoms,

wherein R ⁰ and R ⁹ if = CR ⁹, R and R ², R ³ and R ⁹ if Y₂ = CR ⁹, R ⁴ and R ⁹ if Yi = CR¹⁹, R ⁵ and R ⁶, R ⁷ and R ⁹ if Y₂ = CR¹⁹ may also in each case together form a C=C double bond with the single bond and the C atoms to which they are attached;

R ⁸, R ^8' represent H, Dor A;

R ⁹, R ^9' represent H, D, A, OR¹⁸, NR ⁸R¹⁸, F, CI, Br, CN or Het; Mi, M₂, M₃, M₄ represent CR ⁹ or N;

Yi, Y₂ represent CR¹⁹ or N;

V represents C(R ⁹)(R^19'), NR ⁹ or is absent;

W represents [C(R ⁹)(R ^9')]_PZ, CO-[C(R ⁹)(R ^9')]_pZ, [C(R ⁹)(R ^9')]_PN(R ⁹)-Z, CO-N(R¹⁹) [C(R ⁹)(R ^9')]_pZ, N(R ⁹)-CO-[C(R ⁹)(R ^9')]_pZ, CO-0-[C(R ⁹)(R ^9')]_pZ, C(0)OR¹⁸, OR¹⁸, H or D;

wherein V, W and Y₂ may also in each case together form a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, in which preferably 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR ⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R ⁹)(R^19') or N(R ⁹)(R^19'), or form Het having 3, 4, 5, 6 or 7 ring atoms, wherein Het is preferably a saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR ⁸, N0₂, N(R ⁹)(R^19'), NR ⁸COOZ, OCONHZ, NR ⁸S0₂Z, S0₂N(R ⁸)Z, S(0)_mZ, COZ, CHO, COZ, =S, =NH, =NA, Oxy (-0 ) and/or =0 (carbonyl oxygen);

Z represents Het, Ar or A;

A represents unbranched or branched alkyl having 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms, in which 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR ⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R ⁹)(R^19') or N(R ⁹)(R^19');

and/or in which one or two CH₂ groups can be replaced having O, S, SO, S0₂,

CO, COO, NR¹⁸, NR ⁸CO, CONR ⁸, a cycloalkyl having 3, 4, 5, 6 or 7 C atoms,

CH=CH groups and/or CH≡CH groups;

or a cycloalkyl having 3, 4, 5, 6 or 7 C atoms, in which preferably 1 , 2, 3, 4, 5, 6 or 7 H atoms can be replaced with F, CI, Br, CN and/or OH, OR¹⁹, OC(0)R¹⁹, NR ⁹C(0)OZ, C(0)OR¹⁹, C(0)N(R ⁹)(R^19') or N(R ⁹)(R^19');

Ar represents phenyl, naphthyl or biphenyl substituted singly, doubly or triply with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR¹⁸, N0₂, N(R ⁹)(R^19'), NR ⁸COOZ, OCONHZ, NR ⁸S0₂Z, S0₂N(R ⁸)Z, S(0)_mZ, COZ, CHO, COZ;

Het represents, in each case independently of one another, a mononuclear, binuclear or trinuclear saturated, unsaturated or aromatic heterocycle having 1 to 4 N, O and/or S atoms which can be unsubstituted or singly, doubly or triply substituted with Hal, F, CI, Br, CN, A, OR¹⁸, W, SR¹⁸, N0₂, N(R ⁹)(R^19'), NR ⁸COOZ, OCONHZ, NR ⁸S0₂Z, S0₂N(R ⁸)Z, S(0)_mZ, COZ, CHO, COZ, =S, =NH, =NA, Oxy (-0 ) and/or =0 (carbonyl oxygen); m is1 , 2 or 3,

n, o are 0, 1 or 2,

p is 0, 1 , 2, 3 or 4

with the proviso compounds of the formula (I) in which

(a) V is absent, and

(b) is W = C(0)-CH₂-Het

are excluded;

The compound of claim 1 wherein

4 The compound of any preceding claims wherein R ₀ together with a nitrogen atom to which it is bound, forms a guanidino group. 5 The compound of any one of claims 1 to 3 wherein R₁₀ is a double bonded

nitrogen atom and any other R_x moiety bound to the same atom is absent.

6. The compound of any one of claims 1 to 3 having a guanidine or amidino group forming part of the side-chain 'Q' moiety

7. The compound of any preceding claim wherein one or more of X¹ , X², X³, X⁴, X⁵, and X⁶ is an oxo-substituted carbon atom, methyl substituted carbon atom, or fluorine substituted carbon atom. 8. The compound of any preceding claim wherein one or more of X¹ , X², X³, X⁴, X⁵, and X⁶ is a carbon atom or nitrogen atom.

9. The compound of any one of claims 1 to 6 wherein X¹ , X², X³, X⁴, X⁵, and X⁶ are carbon atoms or nitrogen atoms.

10 The compound of any preceding claim wherein the ring formed by X¹ , X², X³, X⁴, X⁵, and X⁶ is aromatic or doubly unsaturated.

1 1 . The compound of claim 10 wherein the ring is aromatic.

12 The compound of any one of claims 1 to 6 wherein the groups X¹ , X², X³, X⁴, X⁵, and X⁶ are selected so as to form, together with the atoms to which they are bonded, the following ring structures:

where Q is as herein defined and wherein the resulting rings may be additionally substituted in accordance with the selections for groups X¹ , X², X³, X⁴, X⁵, and X⁶.

13. The compound of claim 12 wherein the compounds have the rings shown with no additional substitution.

14 The compound of any preceding claim wherein at least one of the heteroatoms in Q is a nitrogen atom. The compound of claim 14 wherein Q contains at least two heteroatoms,. The compound of claim 15 wherein Q contains at least two nitrogen atoms. The compound of claim 14 wherein Q is selected from:

where R10- 14 are selected from hydrogen or optionally substituted lower alkyl, or may combine with other R groups in Q to form optionally substituted cycloalkyi or optionally substituted heterocycloalkyl rings.

18. The compound of any one of claims 1 to 14 wherein the moiety Q is selected from the following structures:

5

10

15

or structural isomers thereof, optionally additionally substituted with, for example, hydroxyl, amino, halogen, lower alkyl, lower alkoxy and cyano.

19. The compound according to claim 18 wherein the compounds have the Q groups shown with no additional substitution.

20. The compound of claim 1 being:

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)piperidin-4-amine

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

8-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)-2,8- diazaspiro[4.5]decane

1 -(4-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-4- yl)phenyl)cyclobutanamine

2'-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ,2,3,6-tetrahydro-4,4'- bipyridine

5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-3,4'- bipyridine

(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)methanamine

(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)methanamine

1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-2,4'- bipyridine

1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutanamine

8-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)-2,8- diazaspiro[4.5]decane

1 -(4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine 1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-2,4'- bipyridine

1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutanamine

(7S,8aS)-2-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)octahydropyrrolo[1 ,2-a]pyrazin-7-ol

4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,4'-bipyridine

1 - (4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4- amine

2- (piperazin-1 -yl)-4-(5,5,8_!8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyrimidine 2-(pyridin-4-yl)-4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidine 2-(1 -methyl-1 ,2,3, 6-tetrahydropyridin-4-yl)-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidine

1 - (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)phenyl)cyclobutanamine

8-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)-2,8- diazaspiro[4.5]decane

2- (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin yl)ethanol

N-(pyridin-4-ylmethyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimi 2-amine

2-(pyridin-3-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin amine

4-(piperazin-1 -yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine 1 - (6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

2- (piperazin-1 -yl)-6-(5,5,8_!8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazine 1 -(5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperazine 1 -(5-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperidin-4-amine 4-(piperazin-1 -yl)-6-(5,5 _!8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4- amine

1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazin-2-yl)piperidin-4- amine

1 -(2-methoxyethyl)-4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazine

3- (4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazin-1 - yl)propan-1 -ol

N,N-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)acetamide

1 - methoxy-3-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)propan-2-ol

N,N-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)ethanamine

3- hydroxy-2-(hydroxymethyl)-2-methyl-1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazin-1 -yl)propan-1 -one

4- (piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine

2- (piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 2-methyl-4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine

1 -(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine; or

1 -(6-(2-(benzyloxy)-1 ,1 ,3,3-tetramethyl-2,3-dihydro-1 H-inden-5-yl)pyridin-2-yl)piperidin-4- amine;

and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

21 The compound of claim 1 being: 1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

1 -(2-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)piperidin-4-amine

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

5- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-3,4'- bipyridine

1 -(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl) piperazine

6- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-2,4'- bipyridine

4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,4'-bipyridine

1 -(4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin amine 2-(piperazin-1 -yl)-4-(5,5,8_!8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyrimidine 2-(pyridin-4-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 2-(1 -methyl-1 ,2,3, 6-tetrahydropyridin-4-yl)-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidine

2- (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin-1 - yl)ethanol

N-(pyridin-4-ylmethyl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin- 2-amine

2-(pyridin-3-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine

1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4- amine

4-(piperazin-1 -yl)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine

1 - (6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

2- (piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrazine 1 -(5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperazine 1 -(5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-3-yl)piperidin-4-amine 4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4- amine

1 -methoxy-3-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)propan-2-ol N,N-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)ethanamine

4- (piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 2-methyl-4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2- yl)pyrimidine

1 -(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine; or

1 - (6-(2-(benzyloxy)-1 ,1 ,3,3-tetramethyl-2,3-dihydro-1 H-inden-5-yl)pyridin-2-yl)piperidin-4- amine;

2- (4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 -yl)ethanol cis-N1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)cyclohexane-1 ,4-diamine 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-2-one

(R)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3-methylpiperazin-1 -yl)pyrimidine

7-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-1 ,7-diazaspiro[3.5]nonane

1 - (4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-4-methyl-1 ,4-diazepane

(1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)azetidin-3-yl)methanamine

2- (4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 -yl)ethanamine 2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazin-1 -yl)-N,N- dimethylethan amine

(rac)-1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyrrolidin-3-amine

(4-amino-1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)metha

4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 -yl)pyrimidine

4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(piperazin-1 -yl)pyrimidine

1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-amine

1 -(4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)pyrimidin-2-yl)piperidin-4-amine

1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

1 -(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(cyclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(4-isopropyl-3-(prop-1 -en-2-yl)phenyl)pyridin-2-yl)piperazine 1 -(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine

1 - (6-(4-(cyclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

(rac)-1 -(6-(3-isopropyl-4-(( 1 ,1 ,1 -trif luoropropan-2-yl)oxy)phenyl)pyridin-2-yl)piperazine (rac)-1 -(6-(4-(sec-butoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-2-(piperazin-1 -yl) pyrimidine

(1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-yl)methanamine

2- (4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-2,8-diazaspiro[4.5]decane 1 -(6-(3-isopropyl-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine

1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

1 -(6-(4-(cyclopropylmethoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

1 - (6-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

2- (4-isopropoxy-3-isopropylphenyl)-4-(piperazin-1 -yl)-1 ,3,5-triazine

(rac)-(1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyrrolidin-3-yl)methanamine 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)-4-phenylpiperidin-4-amine 4-(piperidin-4-yloxy)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)benzimidamide 1 -(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazin-1 - yl)ethanimine

4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazine-1 - carboximidamide

1 -(1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4- yl)guanidine

1 - (1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4- yl)guanidine

N'-cyano-4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)piperazine-1 -carboximidamide

4- (4-(3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide

2- (tert-butyl)-N-cyclopentyl-4-(4-(piperazin-1 -yl)pyrimidin-2-yl)aniline

2-(tert-butyl)-N-cyclopentyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline

5- (4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolinimidamide

(5-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)pyridin-2-yl)methanamine

4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide 4- (4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide 2-(4-(1 H-imidazol-2-yl)piperidin-1 -yl)-4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidine 2-(tert-butyl)-N-isopropyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline

(rac)-2-amino-2-(4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2- yl)phenyl)ethanol

(rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)phenyl)ethanol

(rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- yl)phenyl)ethanol

1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carboximidamide and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

22. The compound of claim 1 or 2 being:

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

1 -(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)piperidin-4-amine 8-(2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-4-yl)-2,8- diazaspiro[4.5]decane

1 -(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2-yl)piperidin-4-amine 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1 ',2',3',6'-tetrahydro-2,4'- bipyridine

1 - (4-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)phenyl)cyclobutanamine

4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,4'-bipyridine

2- (pyridin-4-yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 2-(1 -methyl-1 ,2,3, 6-tetrahydropyridin-4-yl)-4-(5,5,8,8-tetramethyl-5, 6,7,8- tetrahydronaphthalen-2-yl)pyrimidine

1 -(6-(3-isopropoxy-4-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(4-isopropoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-4-yl)piperidin-4- amine

1 -methoxy-3-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)propan-2-ol

N,N-dimethyl-2-(4-(6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyridin-2- yl)piperazin-1 -yl)ethanamine 3- hydroxy-2-(hydroxymethyl)-2-methyl-1 -(4-(6-(5,5,8,8-tetramethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pyridin-2-yl)piperazin-1 -yl)propan-1 -one

1 -(6-(4-isobutoxy-3-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isopropoxyphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(tert-butyl)-4-isobutoxyphenyl)pyridin-2-yl)piperazine; or

(R)-4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(3-methylpiperazin-1 -yl)pyrimidine

4-(4-isopropoxy-3-isopropylphenyl)-2-(piperazin-1 -yl)pyrimidine

4-(3-(tert-butyl)-4-isopropoxyphenyl)-2-(piperazin-1 -yl)pyrimidine

1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-amine

1 -(4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)pyrimidin-2-yl)piperidin-4-amine

1 -(2-(3-isopropoxy-4-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

1 -(6-(3-isobutoxy-4-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(4-isopropyl-3-propoxyphenyl)pyridin-2-yl)piperazine

1 -(6-(3-(cyclopentyloxy)-4-isopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(4-isopropyl-3-(prop-1 -en-2-yl)phenyl)pyridin-2-yl)piperazine

1 -(6-(3,4-diisopropylphenyl)pyridin-2-yl)piperazine

1 -(6-(3-isopropyl-4-propoxyphenyl)pyridin-2-yl)piperazine 1 - (6-(4-(cyclopentyloxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

4-(3-(tert-butyl)-4-(cyclopentyloxy)phenyl)-2-(piperazin-1 -yl) pyrimidine

1 -(6-(3-(tert-butyl)-4-(2,2,2-trifluoroethoxy)phenyl)pyridin-2-yl)piperazine

1 -(2-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

1 -(6-(4-(cyclopropylmethoxy)-3-isopropylphenyl)pyridin-2-yl)piperazine

1 - (6-(4-isopropoxy-3-isopropylphenyl)pyrimidin-4-yl)piperidin-4-amine

2- (4-isopropoxy-3-isopropylphenyl)-4-(piperazin-1 -yl)-1 ,3,5-triazine

2- (tert-butyl)-N-cyclopentyl-4-(4-(piperazin-1 -yl)pyrimidin-2-yl)aniline

2-(tert-butyl)-N-cyclopentyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline

5- (4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)picolinimidamide

4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide 4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide 2-(4-(1 H-imidazol-2-yl)piperidin-1 -yl)-4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidine 2-(tert-butyl)-N-isopropyl-4-(2-(piperazin-1 -yl)pyrimidin-4-yl)aniline

(rac)-2-amino-2-(4-(4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin yl)phenyl)ethanol

(rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)phenyl)ethanol (rac)-2-amino-2-(4-(4-(3-(tert-butyl)-4-(isopropylamino)phenyl)pyrimidin-2- yl)phenyl)ethanol

1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidine-4-carboximidamide and pharmaceutically acceptable salts, stereoisomers and tautomers thereof. 23. The compound of any preceding claim for use in therapy.

24. A pharmaceutical composition comprising a compound of any one of claims 1 to 22 and one or more pharmaceutically acceptable excipients. 25. A pharmaceutical composition comprising a compound of any one of claims 1 to 22, one or more other therapeutically active agents and one or more pharmacuetically acceptable excipients

26 The compound of any one of claims 1 to 22 having selectivity for Sphkl over Sphk2 for the treatment of a disease or disorder involving or associated with SphK1 activity and S1 P homeostasis or having selectivity for Sphk2 over Sphkl for the treatment of a disease or disorder involving or associated with SphK2 activity and S1 P homeostasis. 27 The compound of claim 26 being selected from the group:

1 -(3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)phenyl)piperazine

1 - (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperidin-4- amine

2- (piperazin-1 -yl)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl) pyrimidine 8-(4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)-2,8- diazaspiro[4.5]decane

4-(piperazin-1 -yl)-6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(6-(5,5,8,8-tetramethyl-5,67,8-tetrahydronap

amine

4-(piperidin-4-yloxy)-2-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidine 1 -(4-(3-(tert-butyl)-4-isopropoxyphenyl)pyrimidin-2-yl)piperidin-4-amine

4-(4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)benzimidami 4-(4-(5,5,8,8-tetramethyl-5,67,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)piperazine-1 - carboximidamide

4-(4-(3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

28. The compound of any one of claims 1 to 22 having an inhibitory activity on Sphkl and Sphk2 for the treatment of a disease or disorder involving or associated with SphK1 and/or Sphk2 activity and S1 P homeostasis. 29. The compound of claim 28 being selected from the group:

2-(piperidin-4-yloxy)-4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidine

4- (4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)pyrimidin-2-yl)benzimidamide 4-(4-(3-(tert-butyl)-4-(prop-1 -en-2-yl)phenyl)pyrimidin-2-yl)piperazine-1 -carboximidamide and pharmaceutically acceptable salts, stereoisomers and tautomers thereof. 30. The compound of any one of claims 1 to 22, and 26 to 29 for the treatment and/or prevention of conditions selected from cancers, hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases.

31 . A method of treating or preventing a condition selected from cancers,

hyperproliferative, inflammatory, angiogenic, immune and viral infectious diseases comprising administering a compound of any one of claims 1 to 22, and 26 to 29 to a patient in need thereof.