RU2771819C2 - 1,2,4-triazine-3-amine derivatives - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to the field of pharmaceutical chemistry, and it is the use of a compound of the formula A1 (its pharmaceutically acceptable salt) or 6-(2-chloro-6-methylpyridine-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (its pharmaceutically acceptable salt) in the manufacture of a drug for the treatment of cancer mediated by the activity of A1 receptor and/or A2a receptor. In the formula A1, A is Cy^AA or Het^AA; Cy^AA is a 6-element aromatic carbocyclic system, where Cy^AA group has a substituent R^4a at position 3 relatively to the point of attachment to a triazine ring, and, if necessary, has one or more additional substituent R^4a; Het^AA is a 6-element heterocyclic group, which can be aromatic, fully saturated or partially unsaturated, and which contains one or two heteroatoms selected from O and N, while Het^AA group has a substituent R^4b at position 3 relatively to the point of attachment to the triazine ring, and, if necessary, has one or more additional substituent R^4b; B is Cy^BB or Het^BB; Cy^BB is phenyl optionally having one or more substituent R^4c; Het^BB is a 6-element aromatic heterocyclic group that contains one or two N atoms; R^4a-R^4c are as specified in the claims. It is provided that compound A1 is not 5-(2-chlorophenyl)-6-(3,4-dimethoxyphenyl)-[1,2,4]triazine-3-ylamine or 5-(2-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazine-3-ylamine.

EFFECT: use of 1,2,4-triazine-3-amine derivatives in the production of a drug for the treatment of cancer mediated by the activity of A1 receptor and/or A2a receptor.

18 cl, 1 tbl, 7 ex

Description

The field of technology to which the invention belongs

The present invention relates, inter alia, to the use of certain compounds in the treatment of a condition ameliorated by inhibition of the A ₁ receptor or A _2a receptor.

State of the art

Mention or discussion in this specification of a previously published document should not necessarily be construed as an admission that the document is part of the state of the art or is part of the public domain.

Parkinson's disease is a progressive neurodegenerative disease with an approximate prevalence of 0.3% in the general population, rising to 5% in people over 85 years of age. The disease is characterized by tremors, numbness, and slowness of movement, which are caused by the degeneration of dopaminergic neurons in the substantia nigra and the breakdown of dopamine in the striatum.

Due to the aging of the population, the incidence of Parkinson's disease is increasing. However, the most effective pharmacological treatment for this disease is still Levodopa (L-dopa), even fifty years after its discovery as an anti-Parkinsonian agent (Chemical & Engineering News 2005, 83(25)).

L-dopa is a precursor of dopamine and exerts its pharmacological action by increasing dapaminergic conduction (i.e. increasing dopamine levels in the striatum). The physiological effect of L-dopa can also be achieved by the administration of directly acting dopamine agonists such as bromocriptine or pergolide. Although the therapies described above are initially very effective in controlling some of the symptoms of Parkinson's disease, in particular numbness, prolonged use results in a wide range of side effects that can tire the patient (eg, involuntary movements known as dyskinesia).

Other treatments include inhibition of dopamine-metabolizing catechol-o-methyltransferase (COMT) or monoamine oxidase (MAOI) enzymes, or the use of anticholinergics. However, these treatments have low to moderate effects and suffer from a number of harmful side effects.

Adenosine is known as an endogenous modulator of many physiological functions. For example, adenosine has effects on the cardiovascular system and is a potent vasodilator and cardiac depressant, and is known to have cardioprotective properties (see, for example, Norton et al. Am J Physiol. 1999; 276(2 Pt 2), H341- 9; and Auchampach and Bolli Am J Physiol. 1999; 276(3 Pt 2), H1113-6). The action of adenosine on the central nervous system includes sedative, sedative and antiepileptic effects. In addition, adenosine acts on the respiratory system, inducing bronchoconstriction. In the kidney, adenosine has a biphasic effect, causing vasoconstriction at low concentrations and vasodilatory effects at high doses, suggesting that adenosine may be involved in the pathology of certain types of renal failure (Costello-Boerrigter, et al. Med Clin North Am. 2003 Mar; 87(2), 475-91; Gottlieb, Drugs 2001, 61(10), 1387-93). Adenosine also acts as an inhibitor of lipolysis in fat cells (Feoktistov, et al., Pharmacol. Rev. 1997, 49, 381-402) and a platelet antiplatelet agent.

Adenosine acts through a family of G protein-coupled receptors. Biochemical and pharmacological studies, along with advances in molecular biology, have identified at least four subtypes of adenosine receptors, which are classified into adenosine A ₁ , A _2a , A _2b and A ₃ receptors. A ₁ and A ₃ receptors inhibit the action of the enzyme adenylate cyclase, while A _2a and A _2b receptors stimulate the activity of the same enzyme, thereby modulating the level of cyclic adenosine monophosphate in cells.

In the central nervous system, adenosine is a potent endogenous neuromodulator that controls the presynaptic release of many neurotransmitters and thus is involved in the mechanisms of motor function, sleep, anxiety, pain, and psychomotor activity. The main adenosine receptor subtypes in the brain are A ₁ and A _2a . While the A ₁ subtype adenosine receptor is highly distributed throughout the brain, the distribution of the A _2a receptor is more limited, and it has a high distribution density in the striatum (caudate-putamen, nucleus accumbens, olfactory tubercule), where it is localized together with dopamine D2 receptor on striatopallidal output neurons. The discrete distribution of the A _2a receptor in the striatum and its ability to functionally antagonize the D2 receptor has led to the suggestion that A _2a receptor antagonists have potential for the symptomatic treatment of Parkinson's disease (see, for example, Cunha et al., Curr Pharm Des. 2008, 14(15), 1512–1524).

Thus, A _2a antagonists may help with motor dysfunction caused by neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's disease (Tuite P, et al., J. Expert Opin. Investig. Drugs. 2003; 12, 1335-52; Popoli P. et al., J Neurosci 2002; 22, 1967-75; and Dall'Igna, et al., Experimental Neurology, 2007, 241-245). In addition, A _2a antagonists may find use in the treatment of: attention disorders such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD); psychoses; stroke, extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism, and tardive dyskinesia (see Jenner P. J Neurol. 2000; 247 Suppl2: 1143-50), and movement disorders such as restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) (see e.g. WO 02/055083, WO 05/044245, WO 06/132275 and Happe S, et al., Neuropsychobiology. 2003, 48, 82-6) Adenosine A antagonists _2a receptors are described in US 2007037033 as useful in the treatment of amyotrophic lateral sclerosis WO 01/058241 describes the treatment of cirrhosis, fibrosis and fatty liver with adenosine A _2a receptor antagonists WO 06/009698 describes adenosine A _2a receptor antagonists as useful agents for alleviating addictive behavior in humans It has recently been demonstrated that adenosine A _2a receptor antagonists can be used to treat and prevent skin fibrosis in diseases such as sclera derma (Chan et al. Arthritis & Rheumatism, 2006, 54(8), 2632-2642).

In addition, A _2a antagonists may have therapeutic potential as neuroprotective agents (Stone TW. et al., Drag. Dev. Res. 2001, 52, 323-330), in the treatment of sleep disorders (Dunwiddie TV et al., Ann. Rev. . Neurosci. 2001, 24, 31-55) and migraines (Kurokowa et al., 2009. Program No. 714.4/B101. 2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience).

The therapeutic applications for compounds that target A ₁ receptors vary (see, for example, Nature Reviews Drug Discovery 5, 2006, 247-264; Journal of Pharmacology and Experimental Therapeutics 323(2), 2007, 708-719; British Journal of Pharmacology, 155, 2008, 475-486; Journal of the American College of Cardiology 50(16), 2007, 1551-1560; Pharmacology and Therapeutics 123, 2009, 105-116).

Adenosine A ₁ receptors are expressed in the kidney and mediate the effect of adenosine on proximal tubular reabsorption and tubular glomerular response. Therefore, blockade of the A ₁ receptor leads to suppression of proximal tubular sodium reabsorption, which may have a beneficial effect in diseases such as congestive heart failure, chronic renal failure and cirrhosis (Gellai et al., 1998, J Pharmacol Exp Ther 286, 1191-1196; J Am Coll Cardiol, 2007; 50:1551-1560). Compounds under development as adenosine A ₁ receptor antagonists in acute renal failure include rolophyllin from Merck and derenophyllin from Astellas. Adenosine A ₁ receptor antagonists can be used to treat edema (Satoh et al., 2000. Gastroenterol. 119(3):829-36), macular degeneration and cirrhosis.

Although compounds having appreciable biological activity at several adenosine receptor subtypes may have therapeutic potential, they may have undesirable side effects. For example (as described in Gessi S et al. Pharmacol. Ther. 117(1), 2008, 123-140), adenosine A ₃ receptor antagonism causes various effects, such as an increased propensity for tissue damage after ischemia (e.g. CNS , heart, kidney, lung, and eye), increased reperfusion injury, increased neurodegeneration in response to hypoxia, potentially detrimental effects on motor function or pain threshold, immune suppression or immune stimulation.

Several compounds are currently being developed as A _2a receptor antagonists for the treatment of Parkinson's disease. Such compounds include KW6002 (istraddephylline, 8-[(E)-2-(3,4-dimethoxyphenyl)vinyl]-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6- dione) from Kyowa Hakko Kogyo, SCH-420814 (preladenant, 2-(furan-2-yl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]piperazin-1-yl]ethyl]- 7H-pyrazolo[4,3-e][1,2,4]-triazolo[1,5-c]pyrimidine-5-amine) from Schering-Plough/Merck, BIIB014 from Biogen Idec, Lu AA47070 from Lundbeck, ST -1535 from Sigma-Tau Farm Riunite SpA, SYN 115 from Synosia, and ASP 5854 from Astellas.

However, the compounds mentioned above suffer from several disadvantages such as low solubility (KW6002, SCH-420814, BIIB014 and Lu AA47070), photosensitivity (KW6002), low selectivity (Lu AA47070 and ASP 5854), potential toxicity due to the presence of known potential toxicophores (SCH- 420814 and BIIB014) and limited in vivo efficacy (KW6002).

In international patent applications WO 92/02513, WO 00/66568, WO 03/077921, WO 2005/117883, WO 2006/051311, WO 2006/113704 and WO 2009/090431, US patent applications US 2004/01020436, US 2004/01020436 /0229873, US 2007/0135437, European patent application No. 1 400 518 and British Patent No. 1,604,085 describe 1,2,4-triazine compounds with different biological activities. The documents listed above do not suggest or describe 1,2,4-triazine compounds having the substitution pattern required by the present invention, nor that any of the compounds described in the documents listed above can act as A ₁ antagonists or, especially , A _2a receptor.

US Patent No. 4,008,232 and French Patent 2,869,906 describe a number of 1,2,4-triazine compounds for use in the treatment of inflammation and as sunburn agents, respectively. Doig et al., Journal of Chromatography 1991 554(1-2), 181-189 describes a metabolite of the anticonvulsant Lamotrigine. A number of 1,2,4-triazine compounds with anticonvulsant activity are described in Mallikarjuna et al. J Zhejian Univ Sci B 2007 8(7), 526-532. A number of 1,2,4-triazine compounds with antiviral activity are described in Davidson et al. Journal of Pharmaceutical Sciences 67(5), 1978, 737-739. A number of 1,2,4-triazine compounds are described in Eid et al., Indian Journal of Chemistry, Section B 1990 29B(5) 435-439, Zou et al., Chinese Journal of Chemistry 1998 16(1), 58- 64, Lu et al., Youji Huaxue 1992 12(6), 605-607, Lu et al., Organic Preparations and Procedures International 1992 24(3), 358-362 and Konno et al. Heterocycles 19(10), 1982, 1865-8. There is no suggestion or description that any of the compounds listed above can act as A ₁ or especially A _2a receptor antagonists.

Disclosure of invention

The present inventors have surprisingly found that certain 1,2,4-triazine compounds having certain substituents can be used as A ₁ and especially A _2a receptor antagonists.

Thus, in a first aspect of the present invention, a compound of formula I is provided for use in the treatment of a condition or disorder ameliorated by inhibition of A ₁ or especially A _2a receptors, wherein the compound of formula I has the structure

where:

R ¹ is H or C _1-6 alkyl, the last listed group may optionally have one or more substituents representing halogen atoms, OR ^2a or NR ^2b R ^2c ;

L ¹ and L ² independently represent CH=CH, single bond, O, NR ^3a , S(O) _p , CH ₂ or C(O);

R ^2a , R ^2b , R ^2c and R ^3a independently represent H or C _1-6 alkyl, the latter of the listed groups may optionally have one or more substituents representing halogen atoms;

A is Cy ¹ or Het ^A ;

Cy ¹ is a 5-14 membered aromatic, fully saturated or partially unsaturated carbocyclic system containing one, two or three rings, where the Cy ¹ group optionally has one or more R ^4a substituents;

Het ^A is a 5-14 membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, where said heterocyclic group may contain one, two or three cycle, and the specified group Het ^A optionally has one or more substituents R ^4b ;

B is Cy ² or Het ^B ;

Cy ² is a 3-10 membered aromatic, fully saturated or partially unsaturated carbocyclic system containing one or two rings, and said Cy ² group optionally has one or more R ^4c substituents;

Het ^B is a 3-10 membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, where said heterocyclic group may contain one or two rings, and said Het ^B group optionally has one or more R ^4d substituents;

R ^4a - R ^4d are, in each case independently,

(a) a halogen atom,

(b) CN

(c) C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, where the last three groups optionally have one or more substituents selected from halogen atoms, CN nitro, C _1-6 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^5a , S( O) _q R ^5b , S(O) ₂ N(R ^5c )(R ^5d ), N(R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )-B ² -R ⁵ⁱ , aryl and Het ¹ ,

(d) Cy ³ , wherein said Cy ³ group optionally has one or more substituents selected from halogen atoms, nitro groups, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^6a , S(O) _q R ^6b , S(O) ₂ N( R ^6c )(R ^6d ), N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ , aryl and Het ² ,

(e) Het ^a , wherein said Het ^a group optionally has one or more substituents selected from halogen atoms, nitro groups, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^7a , S(O) _q R ^7b , S(O) ₂ N( R ^7c )(R ^7d ), N(R ^7e )S(O) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ , aryl and Het ³ ,

(f) OR ⁸ ,

(g) S(O) _r R ^9a ,

(h) S(O) ₂ N(R ^9b )(R ^9c ),

(i) N(R ^9d )S(O) ₂ R ^9e ,

(j) N(R ^9f )(R ^9g ),

(k) B ⁷ -C(G ¹ )-B ⁸ -R ^9h ,

(l)=O,

(m)=S,

or when two R ^4a , R ^4b , R ^4c or R ^4d groups are attached to the same carbon atom in the non-aromatic portion of the Cy ¹ , Het ^A , Cy ² or Het ^B group, they may form, together with the carbon atom to which they are attached, saturated or unsaturated 3-6-membered ring, which may optionally contain 1-3 heteroatoms selected from O, S and N, and which may optionally have one or more substituents R ⁹ⁱ ;

G ¹ is, in each case independently, O, S or NR ^5j ;

R ⁸ is, in each case independently,

h,

Cy ³ , Het ^a , aryl ^a , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, where the last seven groups optionally have one or more substituents selected from halogen atoms, - CN, C _3-6 cycloalkyl, aryl, Het ⁴ , -C(O)OR ¹⁰ , -C(O)R ¹¹ , -C(O)N(R ^N1 )(R ^N2 ), S(O) _r R ^9aa , S(O) ₂ N(R ^9ba )(R ^9ca ), N(R ^9da )S(O) ₂ R ^9ea and N(R ^9fa )(R ^9ga );

Cy ³ is, at each occurrence independently, a 3-6 membered aromatic, fully saturated or partially unsaturated carbocycle;

Het ^a is, in each occurrence independently, a 3-6 membered heterocyclic ring which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N;

R ¹⁰ and R ¹¹ are independently

(a) H

(b) C _1-6 alkyl optionally having one or more substituents selected from halogen, aryl, -N(R ^N3 )(R ^N4 ) and -OR ^a ,

(c) aryl or

(d) C _3-7 cycloalkyl (which optionally has one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups);

B ¹ - B ⁸ are, independently at each occurrence, a single bond, O, S or N(R ^N3 );

each aryl ^a is independently a C _6-14 carbocyclic aromatic group which may contain one, two or three rings;

each aryl is independently a C _6-14 carbocyclic aromatic group which may contain one, two or three rings and may have one or more substituents selected from

halogen atom,

C _1-6 alkyl which may optionally have one or more substituents selected from halogen atoms -N(R ^N4 )(R ^N5 ) and -OR ^a , and

-OR ^a ;

Het ¹ - Het ⁴ independently represent 4-14-membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, where these heterocyclic groups may contain one, two or three cycles and may have one or more substituents, chosen from

halogen atom,

C _1-6 alkyl which may optionally have one or more substituents selected from halogen atoms -N(R ^N6 )(R ^N7 ) and -OR ^a , and

-OR ^a ;

R ^N1 - R ^N7 independently represent

h,

C _1-6 alkyl or C _3-6 cycloalkyl, where the last two groups optionally have one or more substituents selected from halogen atoms and -OR ^a ;

R ^a is, in each case independently,

(a) H;

(b) C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, C _3-12 cycloalkyl, C _4-12 cycloalkenyl, where the last five groups optionally have one or more substituents selected from halogen atoms, nitro -groups, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl (the last four groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^12a , S(O) _q R ^12b , S(O) ₂ N(R ^12c )(R ^12d ), N(R ^12e )S(O) ₂ R ^12f , N(R ^12g )(R ^12h ), B ⁹ -C(G ² )-B ¹⁰ -R ¹²ⁱ , aryl ¹ and Het ^b , and where said C _3-12 cycloalkyl or C _4-12 cycloalkenyl groups may additionally have a substituent =O,

(c) S(O) _r R ^13a ,

(d) S(O) ₂ N(R ^13b )(R ^13c ) or

(e) C(O)-B ¹¹ -R ^13d ;

R ^5a - R ^5j , R ^6a - R ⁶ⁱ , R ^7a - R ⁷ⁱ , R ^9a - R ⁹ⁱ , R ^9aa - R ^9ga , R ^12a - R ¹²ⁱ and R ^13a - R ^13d are, independently in each case,

(a) H

(b) C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, where these three groups optionally have one or more substituents selected from halogen atoms, nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups ), OR ^5aa , S(O) _q R ^5ab , S(O) ₂ N(R ^5ac )(R ^5ad ), N(R ^5ae )S(O) ₂ R ^5af , N(R ^5ag )(R ^5ah ) , B ¹² -C(G ² )-B ¹³ -R ^5ai , aryl ¹ and Het ^c ;

(c) C _3-10 cycloalkyl or C _4-10 cycloalkenyl (the last two groups optionally have one or more substituents selected from halogen atoms, OH, =O, C _1-6 alkyl and C _1-6 alkoxy groups),

(d) Het ^d ;

G ² is, at each occurrence independently, O, S, or NR ^5aj ;

R ^5aa - R ^5aj are, in each case independently,

(a) H

(b) C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, where these three groups optionally have one or more substituents selected from halogen atoms, nitro group, CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups),

(c) C _3-6 cycloalkyl or C _4-6 cycloalkenyl (the last two groups optionally have one or more substituents selected from halogen atoms, OH, =O, C _1-4 alkyl and C _1-4 alkoxy groups),

(d) Het ^e ,

or R ^5ag and R ^5ah may represent, together with the nitrogen atom to which they are attached, a 3 to 10 membered heterocyclic ring which may be aromatic, fully saturated or partially unsaturated, and which may additionally contain one or more heteroatoms selected of O, S and N, wherein said heterocyclic ring optionally has one or more substituents selected from halogen atoms, CN nitro, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups are optional have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups);

B ⁹ - B ¹³ independently represent a single bond, O, S or N(R ^N8 );

aryl ¹ is, at each occurrence independently, a C _6-10 carbocyclic aromatic group which may contain one or two rings and may have one or more substituents selected from

halogen atom,

C _1-6 alkyl, which may optionally have one or more substituents selected from halogen atoms, -N(R ^N10 )(R ^N11 ) and C _1-6 alkoxy groups (the last substituent listed is optionally substituted one or more halogen atoms), and

C _1-6 alkoxy group (which is optionally substituted with one or more halogen atoms);

R ^N8 , R ^N10 and R ^N11 are independently

h,

C _1-6 alkyl or C _3-6 cycloalkyl, where the last two groups are optionally substituted with one or more halogen atoms;

Het ^b is a 5- or 6-membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, where said heterocyclic group may have one or more substituents, selected from halogen atoms, =O and C _1-6 alkyl;

Het ^c - Het ^e is independently a 3-6 membered heterocyclic ring which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, where the indicated groups are Het ^c - Het ^e optionally have one or more substituents selected from halogen atoms, nitro groups CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, = O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups);

p, q and r are, in each case independently, 0, 1 or 2; and

unless otherwise indicated, alkyl, alkenyl, alkynyl, cycloalkyl, and the alkyl moiety of alkoxy groups may be substituted with one or more halogen atoms.

Reference herein (in any aspect or embodiment of the present invention) to compounds of formula I includes the compounds themselves, as such, tautomers of such compounds, as well as pharmaceutically acceptable salts or solvates, or pharmaceutically functional derivatives of such compounds.

Pharmaceutically acceptable salts worth mentioning include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example by reacting a compound of formula I in the free acid or free base form with one or more equivalents of the appropriate acid or base, optionally in a solvent or medium in which the salt is insoluble, after which time said solvent or medium is removed. according to standard methods (for example, in vacuum, lyophilization or filtration). Salts can also be prepared by exchanging the counterion of a compound of Formula I in salt form with another counterion, for example using a suitable ion exchange resin.

Examples of pharmaceutically acceptable salts include acid addition salts derived from inorganic acids and organic acids, and salts derived from metals such as sodium, magnesium, or preferably potassium and calcium.

Examples of acid addition salts include salts of acetic, 2,2-dichloroacetic, adipic, alginic, arylsulfonic acids (for example, benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1,5-disulfonic and p-toluenesulfonic), ascorbic (for example, L -ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+)-camphoric, camphorsulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamon, citric, cyclamic, dodecylsulfuric, ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D-glucuronic), glutamic (e.g. L- glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (- )-L-apple), malonic, (±)-DL-almond, m metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (eg (+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

Particular examples of salts are salts of inorganic acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids; organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, arysulfonic acids; and metal salts such as sodium, magnesium or, preferably, potassium and calcium.

As indicated above, formula I also covers any solvates of the described compounds and their salts. Preferred solvates are those formed by incorporating into the structure of the solid (eg, crystalline structure) compounds of the present invention the molecules of a non-toxic pharmaceutically acceptable solvent (hereinafter referred to as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethyl sulfoxide. Solvates can be obtained by recrystallization of the compounds of the present invention from a solvent or mixture of solvents containing a solvating solvent. Whether a solvate has formed or not can be determined in each particular case by analyzing the crystals of the compound using well-known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and X-ray diffraction analysis.

Solvates can be stoichiometric and non-stoichiometric solvates. Particularly preferred solvates are hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates.

A more detailed discussion of solvates and methods for their preparation and analysis can be found in Bryn et al., Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710 -3.

The term "pharmaceutically functional derivatives" of compounds of formula I, as used herein, includes ester derivatives and/or derivatives that have or provide the same biological function and/or activity as any corresponding compound of the present invention. Thus, in terms of the present invention, the term also includes prodrugs of the compounds of formula I.

The term “prodrug” of a corresponding compound of formula I includes any compound which, after oral or parenteral administration, is metabolized in vivo to form that compound in experimentally determined amounts and over a specified time (e.g., within a dosing interval between 6 and 24 hours (i.e. . once or four times a day)).

Prodrugs of compounds of formula I can be prepared by modifying the functional groups present on the compound such that the resulting modifications are cleaved in vivo when such a prodrug is administered to a mammal. Modifications are usually obtained by synthesizing the parent compound having a prodrug substituent. Prodrugs include compounds of formula I in which the hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group in the compound of formula I is bonded to any group that can be cleaved off in vivo again to give a free hydroxyl, amino, sulfhydryl, carboxyl or carbonyl group, respectively .

Examples of prodrugs include, but are not limited to, hydroxyl-functional esters and carbamates, carboxyl-functional ester groups, N-acyl derivatives, and N-Mannich bases. General information on prodrugs can be found, for example, in Bundegaard, H. “Design of Prodrugs” p. I-92, Elsevier, New York-Oxford (1985).

Compounds of formula I, as well as pharmaceutically acceptable salts, solvates and pharmaceutically functional derivatives of such compounds, for brevity hereinafter collectively referred to as "compounds of formula I".

The compounds of formula I may contain double bonds and may therefore exist as E (entgegen) and Z (zusammen) geometric isomers on each individual double bond. All such isomers and mixtures thereof are included within the scope of the present invention.

The compounds of formula I may exist as regioisomers and may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the present invention. For example, the following tautomers are included within the scope of the present invention:

Compounds of formula I may contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereomerism. Diastereomers can be separated by standard techniques such as chromatography or fractional crystallization. The various stereoisomers can be isolated by separation of a racemic or other mixture of compounds using well-known methods such as fractional crystallization or HPLC. Alternatively, the desired optical isomers can be obtained by reacting the appropriate optically active starting compounds under conditions that do not exhibit racemization or epimerization (i.e., "chiral pooling" methods), reacting the appropriate starting compound with a "chiral modifier" that can subsequently be removed at appropriate step, derivatization (i.e. separation, including dynamic separation), e.g. with a homochiral acid, followed by separation of the diastereomeric derivatives by conventional methods such as chromatography, or by reaction with a suitable chiral reagent or chiral catalyst, all of these processes are carried out under conditions known qualified professionals. All stereoisomers and mixtures thereof are included within the scope of the present invention.

For the avoidance of doubt, the compounds of formula I may contain these atoms in any isotopic form. In this regard, noteworthy embodiments of the present invention include those in which:

(a) the compound of formula I is not isotopically enriched or labeled on any of the atoms of the compound; and

(b) the compound of formula I is isotopically enriched or labeled at one or more atoms of the compound

The compound for use in the aspect of the present invention described above can be used in a method of medical treatment. Thus, according to other aspects of the present invention, it is described:

(i) the use of a compound of formula I for the manufacture of a medicament for the treatment of a condition or disorder ameliorated by inhibition of the A ₁ or especially A _2a receptor; and

(ii) a method of treating a condition or disorder ameliorated by A ₁ or especially A _2a receptor antagonization, comprising administering an effective amount of a compound of formula I to a patient in need of such treatment.

One of skill in the art will appreciate that the term "disorder or condition ameliorated by inhibition of the A ₁ or especially A _2a receptor" includes: heart failure (such as acute decompensated heart failure and congestive heart failure); renal insufficiency (for example, caused by heart failure); edema; cancer (such as prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, especially breast cancer, bowel cancer, bladder cancer, brain cancer, nervous tissue cancer, melanoma, pineal cancer and especially lung cancer (eg Lewis lung carcinoma)), diabetes; diarrhea macular degeneration (such as macular degeneration caused by angiogenesis (eg angiogenesis in the retina)); or, in particular (for example, for disorders or conditions ameliorated by A _2a receptor inhibition) diseases of the central nervous system such as depression, cognitive impairment, neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; attention disorders (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); movement disorder (such as restless leg syndrome (RLS) and periodic limb movement during sleep (PLMS)); cirrhosis; liver fibrosis; fatty infiltration of the liver; fibrosis of the skin (for example, in diseases such as scleroderma); sleep disorders; stroke; brain damage and neuroinflammation (eg, migraine or other disorder or condition caused by ischemia, stroke, head trauma, or CNS inflammation); the behavior of a person who is prone to drug use.

Thus, other aspects of the present invention relate to the following.

(a) A compound of formula I as described herein for use in the treatment of a condition or disorder selected from heart failure (such as acute decompensated heart failure and congestive heart failure); renal failure (for example, caused by heart failure); edema; cancer (such as prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, especially breast cancer, bowel cancer, bladder cancer, brain cancer, nervous tissue cancer, melanoma, pineal gland cancer and especially lung cancer (eg Lewis lung carcinoma)), diabetes; diarrhea; macular degeneration (such as macular degeneration caused by angiogenesis (eg angiogenesis in the retina)); or, in particular (for example, for disorders or conditions ameliorated by A _2a receptor inhibition) diseases of the central nervous system, such as depression, cognitive impairment, neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; attention disorders (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); movement disorder (such as restless leg syndrome (RLS) and periodic limb movement during sleep (PLMS)); cirrhosis; liver fibrosis; fatty infiltration of the liver; fibrosis of the skin (for example, in diseases such as scleroderma); sleep disorders; stroke; brain damage and neuroinflammation (eg, migraine or other disorder or condition caused by ischemia, stroke, head trauma, or CNS inflammation); the behavior of a person who is prone to drug use.

(b) The use of a compound of formula I described herein for the preparation of a medicament for the treatment of a condition or disorder selected from heart failure (such as acute decompensated heart failure and congestive heart failure); renal failure (for example, caused by heart failure); edema; cancer (such as prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, especially breast cancer, bowel cancer, bladder cancer, brain cancer, nervous tissue cancer, melanoma, pineal gland cancer and especially lung cancer (eg Lewis lung carcinoma)), diabetes; diarrhea; macular degeneration (such as macular degeneration caused by angiogenesis (eg angiogenesis in the retina)); or, in particular (for example, for disorders or conditions ameliorated by A _2a receptor inhibition) diseases of the central nervous system, such as depression, cognitive impairment, neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; attention disorders (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); movement disorder (such as restless leg syndrome (RLS) and periodic limb movement during sleep (PLMS)); cirrhosis; liver fibrosis; fatty infiltration of the liver; fibrosis of the skin (for example, in diseases such as scleroderma); sleep disorders; stroke; brain damage and neuroinflammation (eg, migraine or other disorder or condition caused by ischemia, stroke, head trauma, or CNS inflammation); the behavior of a person who is prone to drug use.

(c) A method of treating a condition or disorder selected from heart failure (such as acute decompensated heart failure and congestive heart failure); renal failure (for example, caused by heart failure); edema; cancer (such as prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, especially breast cancer, bowel cancer, bladder cancer, brain cancer, nervous tissue cancer, melanoma, pineal gland cancer and especially lung cancer (eg Lewis lung carcinoma)), diabetes; diarrhea; macular degeneration (such as macular degeneration caused by angiogenesis (eg angiogenesis in the retina)); or, in particular (for example, for disorders or conditions ameliorated by A _2a receptor inhibition) diseases of the central nervous system, such as depression, cognitive impairment, neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychoses; attention disorders (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); movement disorder (such as restless leg syndrome (RLS) and periodic limb movement during sleep (PLMS)); cirrhosis; liver fibrosis; fatty infiltration of the liver; fibrosis of the skin (for example, in diseases such as scleroderma); sleep disorders; stroke; brain damage and neuroinflammation (eg, migraine or other disorder or condition caused by ischemia, stroke, head trauma, or CNS inflammation); the behavior of a person with a tendency to use drugs, where this method includes the introduction of an effective amount of a compound of formula I described in this text.

Particular variants of disorders or conditions that may be mentioned in relation to the aspects of the present invention described above include drug addictive behavior, ADHD and, in particular, neurodegenerative diseases (e.g., Alzheimer's disease, Huntington's disease, and, in particular, Parkinson's disease). ).

Noteworthy embodiments of the present invention include those in which the compounds of formula I selectively inhibit the A ₁ and A _2a receptor subtypes.

When used herein in relation to the inhibition of A ₁ or A _2a receptors, the terms "selective" and "selectivity" refer to the binding of a compound to an A ₁ or, in particular, to an A _2a receptor, in which the IC ₅₀ value is at least 10 times lower (eg, at least 20, 50, 100, 500, or 1000 times lower) than IC ₅₀ values obtained for binding the same compound to the A ₃ subtype receptor at the same temperature (eg, at room temperature, such like 298K).

Noteworthy embodiments of the present invention include those in which the compounds of formula I are selective inhibitors of the A _2a receptor.

When used herein in relation to inhibition of A _2a receptors, the terms "selective" and "selectivity" refer to the binding of a compound to an A _2a receptor in which the IC ₅₀ value is at least 10 times lower (for example, at least 20, 50, 100, 500, or 1000 times lower) than IC ₅₀ values obtained for the same compound binding to a different adenosine receptor subtype (eg, A _2b subtype receptor, especially A ₁ , or especially A ₃ ) at the same the same temperature (for example, at room temperature, such as 298 K). Selectivity for the A _2a receptor can be observed over one other adenosine receptor subtype, but in some embodiments of the present invention, is observed over two or more (e.g., all other) adenosine receptor subtypes.

Antagonization of the A _2a receptor may have a neuroprotective effect. Thus, according to other aspects of the present invention are described:

(i) a compound of formula I for use as a neuroprotector;

(ii) the use of a compound of formula I for the manufacture of a medicament used as a neuroprotector; and

(iii) a method of reducing brain neuronal damage caused by a neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, or amyotrophic lateral sclerosis), stroke or other brain injury, neurotoxins (e.g., mercury and its compounds, lead and its compounds, organic phosphates and nitrogen mustard), CNS infections (eg, meningitis, encephalitis, poliomyelitis, tuberculosis, toxoplasmosis, neurosyphilis) or drug use (eg, cocaine), said method comprising administering an effective amount of a compound of Formula I to a patient at risk of brain neuronal damage in as a result of a neurodegenerative disease, stroke or other brain injury, exposure to neurotoxins, CNS infections, or drug use.

References in this text to patients at risk of brain neuronal damage from a neurodegenerative disease, stroke, or other brain injury include patients for whom a clinical trial has determined a risk of developing a neurodegenerative disease (e.g., Parkinson's disease, Huntington's disease, Alzheimer's disease, or amyotrophic lateral sclerosis). ) or an above-average stroke (compared to, for example, normal people of the same age).

Antagonization of the A ₁ receptor may affect kidney function. Thus, according to other aspects of the present invention are described:

(i) a compound of formula I for use in reducing/mitigating kidney damage caused by acute renal failure, edema, heart failure, chronic kidney disease and/or cirrhosis;

(ii) the use of a compound of formula I for the manufacture of a medicament that reduces/mitigates kidney damage caused by acute renal failure, edema, heart failure, chronic kidney disease and/or cirrhosis; and

(iii) a method of reducing/mitigating kidney damage caused by acute renal failure, edema, heart failure, chronic kidney disease and/or cirrhosis, wherein said method comprises administering an effective amount of a compound of formula I to a patient at risk for renal impairment caused by acute renal failure , congestive heart failure, chronic kidney disease or cirrhosis.

Reference in this text to kidney injury includes, in particular, kidney injury caused by acute renal failure.

References in this text to patients at risk of impaired renal function due to acute renal failure, heart failure, chronic kidney disease, or cirrhosis include patients for whom a clinical study determined an above average risk of developing acute renal failure, heart failure, chronic kidney disease, or cirrhosis ( compared to, for example, normal people of the same age).

For the avoidance of doubt, in the context of the present invention, the term "treatment" includes the therapeutic or palliative treatment of patients in need of such treatment, as well as the prophylactic treatment and/or diagnosis of patients prone to the development of the corresponding disease states.

The terms "patient" and "patients" include mammalian (eg, human) patients.

The term "effective amount" refers to an amount of a compound that has a therapeutic effect on the patient being treated (eg, sufficient to treat or prevent a disease). An action can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows signs of the action or experiences an effect).

The term "halogen", as used herein, includes fluorine, chlorine, bromine, and iodine.

Unless otherwise indicated, the term "carbocyclic" as used herein in connection with Cy ¹ and Cy ² groups includes carbocyclic groups (eg, C _5-6 carbocyclic groups) that are mono-, bi-, or tricyclic, and which may be fully saturated, partially unsaturated or fully aromatic in nature. For example, the Cy ¹ and Cy ² groups may be selected from the group consisting of cyclobutyl, cyclobutenyl, cyclopropyl, cyclopropenyl, especially cyclopentyl, cyclopentenyl, (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, especially cyclohexyl, cyclohexenyl, indanyl, indenyl, naphthalene (eg 1,2,3,4-tetrahydronaphthyl), and especially phenyl). The point of attachment of the carbocyclic group may be any atom of the cyclic system.

Unless otherwise indicated, the term "heterocyclic", when used herein in connection with Het ^A and Het ^B groups, includes heterocyclic groups which may be fully saturated, partially unsaturated, or fully aromatic in nature.

Thus, Het ^A and Het ^B are a 5-14 or 3-10 membered heterocyclic group, respectively, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S, and N , where these heterocyclic groups may contain one, two or three cycles, and the Het ^A or Het ^B group optionally has one or more R ^4b or R ^4d substituents, respectively.

The heterocyclic group (eg Het ^A or Het ^B ) may contain up to 5 heteroatomic ring members selected from O, N and S, and in particular up to 4 heteroatomic ring members. For example, a heterocyclic group may contain 1, 2, or 3 heteroatomic ring members.

In one embodiment, Het ^A and Het ^B may each be a monocyclic, bicyclic, or tricyclic 5-14 or 3-10 membered heterocyclic group, respectively, containing 1, 2, 3, or 4 heteroatomic ring members selected from O, N and S. Within this subset, Het ^A or Het ^B (where appropriate) may be selected from, for example, (i) monocyclic heterocyclic groups having 5-7 ring members containing 1, 2, 3 or 4 heteroatomic cycle members selected from O, N and S; (ii) 6.5-fused bicyclic heterocyclic groups having 9 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; (iii) 6,6-fused bicyclic heterocyclic groups having 9 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; (iv) 6.5.6-fused tricyclic heterocyclic groups having 13 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; (v) 6.6.6-fused tricyclic heterocyclic groups having 14 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; and (vi) bridged bicyclic heterocyclic groups having 7 or 8 ring members containing 1 or 2 heteroatomic ring members selected from O, N and S.

The term "bridged ring systems" refers to ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th ^Edition , Wiley Interscience, pp. 131-133, 1992.

In another embodiment, Het ^A and Het ^B may be the same or different, and each is a monocyclic or bicyclic 5-10 membered heterocyclic group containing 1, 2, 3, or 4 heteroatomic ring members selected from O, N, and S. Within this subset, Het ^A or Het ^B may be selected from, for example, (i) monocyclic heterocyclic groups having 5-7 ring members and containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; (ii) 6.5-fused bicyclic heterocyclic groups having 9 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; (iii) 6,6-fused bicyclic heterocyclic groups having 9 ring members containing 1, 2, 3 or 4 heteroatomic ring members selected from O, N and S; and (vi) bridged bicyclic heterocyclic groups having 7 or 8 ring members containing 1 or 2 heteroatomic ring members selected from O. N and S.

In each of the subsets of compounds described above, when Het ^A is a pyridonyl group, it may be different from a pyridin-2-one group (eg, it may be a pyridin-4-one group).

For example, Het ^A and Het ^B may be selected from the group consisting of the following members: azepinyl, diazepinyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl , furanyl, furazanil, hydantoinyl, imidazolyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiomorpholinyl, thiophenethyl, triazolyl, especially dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), dioxanyl, hexahydropyrimidinyl, isobenzofuranyl, pyranyl , pyrazinyl, pyrazolyl, pyridazinyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, thiazolidinyl, triazinanyl, etc. . The point of attachment of the carbocyclic group may be any atom of the cyclic system.

Thus noteworthy example values for A include indolinonyl, pyridazinonyl, octahydroisoquinolin-(1H)-yl, 2,2,6,6,-tetramethyl-3,6-dihydro-2H-pyran-4-yl, indolinonyl, 6 -oxa-9-azaspiro[4.5]decanyl, octahydroisoquinolin-(1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, pyridazinonyl, or in particular cyclopentyl, cyclopentenyl, dihydrofuranyl (e.g. 2 ,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxolanyl, furanyl, furazanyl, hydantoinyl, imidazolyl, isoxazolyl, isoxazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrrolidinyl, pyrrolidinonyl, pyrazolyl, pyrrolinyl ( e.g. 3-pyrrolinyl), pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetramethylene sulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, triazolyl, or in particular acridinyl, 2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo- [2.2.2]octanyl, azepinyl, benzimidazolyl, benzoisothiazolyl, benzoisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxepinyl, b enzodioxolyl, benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e] pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothriazolyl, carbazolyl, chromanil, chromenyl, cinnolinyl, (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl, cyclohexenyl, decahydroisoquinolinyl, diazepinyl, 2,3- dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl ), 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxolanyl, dioxanyl, hexahydropyrimidinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[2,3-b] thiazolyl, indanyl, indazolyl, indenyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiochromanyl, ketopiperidinyl (e.g., 2-ketopiperidinyl, 3-ketopiperidinyl, or 4-keto piperidinyl), morpholinyl, naphthalinyl (e.g. 1,2,3,4-tetrahydronaphthyl), naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or especially 1,5-naphthyridinyl and 1, 8-naphthyridinyl), 1,2- or 1,3-oxazinanyl, oxazolidinyl, phenazinyl, phenothiazinyl, phenyl, phthalazinyl, piperidinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyridazinyl, pyridinyl (e.g., 2-pyridinyl, 3- pyridinyl, 4-pyridinyl), pyridinonyl (such as 5-1H-pyridin-2-onyl, especially 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2 -onyl, 6-1H-pyridin-2-onyl (where 1-, 3-, 4- and 6- indicate the point of attachment of the 1H-pyridin-2-onyl group to the rest of the molecule), or especially 4-onyl), pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, 4,5,6 ,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinoline yl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrahydropyranyl, tetrahydropyridinyl (e.g. 3,4,5,6 -tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, thieno[5,1-c]pyridinyl, thiochromanyl, thiophenethyl, thiomorpholinyl, triazinanyl, 1,3,4- triazolo[2,3-b]pyrimidinyl or xanthenyl; and the like.

Further noteworthy examples of values for B include 2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, azepinyl, azetidinyl, aziridinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl, benzo[ c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1,3- benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, chromanyl, chromenyl, cinnolinyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclopropyl, cyclopropenyl, decahydroisoquinolinyl, 2,3-dihydrofuranzimidazolyl, diazepinyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, dihydrofuranyl), 2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4,5-dihydro-1H-maleimido , 1,3-dihydro-2,1-benzisoxazolyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, dioxolane yl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl, indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiochromanyl, isoxazolyl, isoxazolidinyl, ketopiperidinyl (for example, 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, naphthalinyl (for example, 1,2,3,4-tetrahydronaphthyl), naphthyridinyl (including 1,6-naphthyridinyl or, especially, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl, piperazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyrrolidinonyl, pyrrolinyl (e.g., 3-pyrrolinyl), pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, quinazolinyl, quinolinyl, quinolisinyl, quinoxalinyl, sulfolanyl, 3-sulfolenyl , tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidine yl, tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo[e]pyrimidine, tetrahydroisoquinolinyl (including 1,2,3,4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetramethylene sulfoxide, tetrazolyl, thiazolidinyl, thiazolyl, thienyl, thieno[5 ,1-c]pyridinyl, thiochromanyl, thiophenethyl, thiomorpholinyl, triazinanyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl or, in particular, benzofuranyl, furanyl, indazolyl, indolyl, pyrazinyl, pyrazolyl, pyridinyl (for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl, pyrrolo[1,5-a]pyridinyl, or phenyl, and the like.

Unless otherwise indicated, the term "aryl" as used herein includes C _6-14 (such as C _6-10 ) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic and have from 6 to 14 carbon atoms per ring and at least one ring is aromatic. The point of attachment of aryl groups can be any atom of the cyclic system. However, when aryl groups are bicyclic or tricyclic, they are attached to the rest of the molecule via an aromatic ring. C _6-14 aryl groups include phenyl, naphthyl and the like such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl. Noteworthy embodiments of the present invention include those in which aryl is phenyl.

Groups Het ¹ - Het ⁴ can be fully saturated, partially saturated, fully aromatic or partially aromatic. Noteworthy examples of Het ¹ - Het ⁴ group values include acridinyl, 1-azabicyclo-[2.2.2]octanyl, azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxepinyl, benzodioxolyl, benzofuranyl, benzodioxanyl, benzodioxolyl benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothriazolyl, carbazolyl, chromanil, chromenyl, cinnolinyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, furanyl, furazanil, hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanil, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiochromanil, isoxazolidine yl, isoxazolyl, maleimido, morpholinyl, naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or especially 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, sulfolanyl, 3-sulfolenyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5, 6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo[e]pyrimidine, tetrahydrofuranyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydropyranyl, 3 ,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8- tetrahydroquinolinyl), thiadiazolyl, thia zolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl, thiochromanil, thiophenethyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, xanthenyl, and the like.

The Het ^a and Het ^c - Het ^e groups can be fully saturated, partially saturated, fully aromatic, or partially aromatic. Noteworthy Het ^a groups include azetidinyl, aziridinyl, dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, maleimido, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl , pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5 ,6-tetrahydropyrimidinyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenethyl, triazolyl, and the like.

Het ^b groups can be fully saturated, partially saturated, fully aromatic, or partially aromatic. Noteworthy Het ^b groups include dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, maleimido, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl , pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl , thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenethyl, triazolyl, and the like.

Substituents in heterocyclic (Het ^A , Het ^B , Het ¹ - Het ⁴ , Het ^a - Het ^e ) groups may, where appropriate, be located at any atom of the cyclic system, including a heteroatom. The point of attachment of heterocyclic (Het ^A , Het ^B , Het ¹ - Het ⁴ , Het ^a - Het ^e ) groups can be any atom of the cyclic system, including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom of any fused carbocyclic ring , which may be present as part of a cyclic system. Heterocyclic (Het ^A , Het ^B , Het ¹ - Het ⁴ , Het ^a - Het ^e ) groups can also be in N- or S-oxidized form.

Noteworthy embodiments of the present invention include those in which L ¹ and L ² independently represent a single bond, O, NR ^3a , S(O) _p , CH ₂ or C(O).

In some embodiments of the present invention, L ¹ and L ² are single bonds, R ¹ is H, and the compound of formula I can be represented by a compound of formula A1,

where A is Cy ^AA or Het ^AA ;

Cy ^AA is a 6-membered aromatic, fully saturated or partially unsaturated carbocyclic system, wherein the Cy ^AA group has an R ^4a substituent in position 3, relative to the point of attachment to the triazine ring, and optionally has one or more additional R ^4a substituents;

Het ^AA is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, wherein the Het ^AA group has in position 3, relative to the point of attachment to the triazine ring, R ^4b substituent, and optionally has one or more additional R ^4b substituents;

B is Cy ^BB or Het ^BB ;

Cy ^BB is phenyl optionally having one or more R ^4c substituents;

Het ^BB is a 6-membered aromatic heterocyclic group which contains one or more N atoms, wherein the Het ^BB group optionally has one or more R ^4d substituents;

R ^4a , R ^4b , R ^4c and R ^4d are as defined above for compounds of formula I.

Noteworthy embodiments of the present invention include those relating to compounds of formula I (or, especially, formula A1), in which A represents Cy ^AA' , Het ^AA' , Het ^AA'' or Het ^AA''' , where:

Cy ^AA' is a 6-membered aromatic, fully saturated or partially unsaturated carbocyclic system, while the Cy ^AA' group has in position 3, relative to the point of attachment to the triazine ring, the R ^4a substituent, and has in position 4, relative to the point of attachment to triazine ring, substituent OR ⁸ , and optionally has one or more additional substituents R ^4a ;

Het ^AA' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, while the Het ^AA' group has in position 3, relative to points of attachment to the triazine ring, substituent R ^4b , and has in position 4, relative to the point of attachment to the triazine ring, substituent OR ⁸ , and optionally has one or more additional substituents R ^4b ;

Het ^AA'' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains in position 4, relative to the point of attachment to the triazine ring, a N atom, and optionally has one or more additional heteroatoms, selected from O, S and N, while the group Het ^AA'' has in position 3, relative to the point of attachment to the triazine ring, substituent R ^4b and optionally has one or more additional substituents R ^4b ; and

Het ^AA''' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, while the group Het ^AA''' has in position 3, relative to the point of attachment to the triazine ring, substituent R ^4b , and substituted in position 4, relative to the point of attachment to the triazine ring, oxo (=O), and optionally has one or more additional substituents R ^4b (for example, Het ^AA''' is 4-pyridon-1-yl optionally having one or more R ^4b substituents).

Other noteworthy embodiments of the present invention include those pertaining to compounds of formula I (or especially formula A1) wherein:

if A is Cy ^AA or Cy ^AA' , then the 6-membered carbocycle additionally has at position 5, relative to the point of attachment to the triazine ring, a R ^4a substituent; or

if A is Het ^AA , Het ^AA' , Het ^AA'' or Het ^AA''' then the 6-membered heterocyclic ring additionally has an R ^4b substituent at position 5, relative to the point of attachment to the triazine ring.

Other noteworthy embodiments of the present invention include those pertaining to compounds of formula I (or especially formula A1) wherein:

(1) Het ^BB is a 6-membered aromatic heterocyclic group containing 3, 2 or especially 1 N atom, wherein the Het ^BB group optionally has one or more R ^4d substituents;

(2) B is Cy ^BB ;

(3) Cy ^BB is phenyl optionally having one or two R ^4c substituents;

(4) Cy ^AA is phenyl having at position 3, relative to the point of attachment to the triazine ring, an R ^4a substituent, and optionally having one or more additional R ^4a substituents;

(5) Het ^AA is a 6-membered aromatic heterocyclic group containing one or more (for example, 3, 2, or especially 1) N atoms, wherein the Het ^AA group is in position 3, relative to the point of attachment to the triazine ring, Deputy R ^4b , and optionally has one or more additional substituents R ^4b ;

(6) B is a pyrimidinyl ring, or especially a phenyl or pyridinyl (eg, pyridin-4-yl) ring, which may optionally have one or more R ^4c or R ^4d substituents;

(7) R ^4c and R ^4d are, in each case independently,

(a) a halogen atom (for example chlorine or especially fluorine),

(b) CN

(c) C _1-6 alkyl optionally having one or more substituents selected from halogen atoms and OR ^5a , or

(d) OR ⁸ ;

(8) A is a Cy ^AA or Het ^AA group which has no substituents in the ortho position relative to the point of attachment to the triazine ring;

(9) R ^4a and R ^4b are, in each case independently,

(a) a halogen atom,

(b) CN

(c) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, where the last three groups optionally have one or more substituents selected from halogen atoms, CN nitro, C _1-4 alkyl (last of the listed groups may optionally have one or more substituents selected from OH, =O, halogen atoms), OR ^5a , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )-B ² -R ⁵ⁱ , aryla and Het ¹ ,

(d) Cy ³ which optionally has one or more substituents selected from halogen atoms, nitro, CN, C _1-4 alkyl (the last of the listed groups may optionally have one or more substituents selected from OH, =O, halogen atoms), OR ^6a , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ , aryl and Het ² ,

(e) Het ^a , which optionally has one or more substituents selected from halogen atoms, nitro, CN, C _1-4 alkyl (the last of the listed groups may optionally have one or more substituents selected from OH, =O, halogen atoms), OR ^7a , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ , aryl and Het ³ ,

(f) OR ⁸ ,

(g) S(O) _r R ^9a ,

(j) N(R ^9f )(R ^9g ),

(k) B ⁷ -C(G ¹ )-B ⁸ -R ^9h ,

(l)=O,

or, when two R ^4a or R ^4b groups are attached to the same carbon atom in the non-aromatic portion of the Cy ¹ , Cy ^AA , Het ^A or Het ^AA group, they may form, together with the carbon atom to which they are attached, a saturated or an unsaturated 3-6 membered ring which may optionally contain 1-3 heteroatoms selected from O, S and N and which may optionally have one or more R ⁹ⁱ substituents;

Other noteworthy embodiments of the present invention include those relating to compounds of formula I (or, especially, formula A1), in which R ^4a - R ^4b represent, in each case independently,

(a) a halogen atom,

(b) CN

(c) C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, where the last three groups optionally have one or more substituents selected from halogen atoms, C _1-4 alkyl and OR ^5a ,

(d) Cy ³ ,

(e) Het ^a ,

(f) OR ⁸ where R ⁸ is H or C _1-4 alkyl optionally substituted with one or more halogen atoms;

(g) S(O) _r R ^9a , where R ^9a is C _1-3 alkyl optionally substituted with one or more halogen atoms;

(h) N(R ^9f )(R ^9g ), where R ^9f and R ^9g independently represent C _1-3 alkyl optionally substituted with one or more halogen atoms;

(i) B ⁷ -C(G ¹ )-B ⁸ -R ^9h where R ^9h is C _1-3 alkyl optionally substituted with one or more halogen atoms;

(j)=O,

or, when two R ^4a or R ^4b groups are attached to the same carbon atom in the non-aromatic part of the Cy ¹ , Cy ^AA , Het ^A or Het ^AA group, they can form, together with the carbon atom to which they are attached, a saturated 3 -6-membered cycle.

Other noteworthy embodiments of the present invention include those pertaining to compounds of formula I (or especially formula A1) in which B is a Cy ^BB or Het ^BB group (e.g. phenyl) which is either unsubstituted or has one or more substituents selected from fluorine, CN, OR ⁸ or C _1-6 alkyl, optionally having one or more substituents selected from halogen atoms and OR ^5a , where R ^5a and R ⁸ correspond to previously defined definitions.

In particular embodiments, B is a Cy ^BB or Het ^BB group (e.g., phenyl) that either has no substituents or has one or more fluorine substituents (e.g., at position 4 relative to the point of attachment to the triazine ring).

In other embodiments of the present invention, R ^4a (or R ^4a and R ^4b ) correspond to the above definitions, except that they are not substituent OR ⁸ in which R ⁸ represents CH ₃ . In such cases, R ^4a (or R ^4a and R ^4b ) may, for example, represent, in each case independently, halogen atoms, OH, N(H)-C(O)-C _1-3 alkyl or C _1-3 alkyl optionally having one or more fluorine substituents.

In some embodiments of the present invention, the compound of formula I can be represented as a compound of formula Ix, Iy or Iz,

,

,

respectively, where:

A' is Cy ^1' or Het ^A' ;

Cy ^1' is a 6-membered aromatic, fully saturated or partially unsaturated carbocyclic system containing one, two or three cycles, while the Cy ^1' group has an OR ⁸ substituent in position 4, relative to the point of attachment to L ¹ , and optionally has one or more additional substituents R ^4a ;

Het ^A' is a 6-membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, where said heterocyclic group may contain one, two or three rings , wherein the Het ^A' group has at position 4, relative to the point of attachment to L ¹ , an OR ⁸ substituent and optionally has one or more additional R ^4b substituents;

(for example, A ^' is phenyl which has at position 4, relative to the point of attachment to L ¹ , an OR ⁸ substituent and optionally has one or more additional R ^4a substituents);

A'' is Het ^A'' ;

Het ^A'' is a 6-membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated, wherein the group contains in position 4, relative to the point of attachment to L ¹ , an N atom, and optionally has one or more additional heteroatoms selected from O, S and N, while the group Het ^A'' optionally has one or more substituents R ^4b ;

(e.g., A'' is a 6-membered aromatic heterocyclic group (e.g., pyridyl) which contains an N atom in position 4, relative to the point of attachment to L ¹ , this heterocyclic group optionally having one or more R ^4b substituents) ;

A''' is Het ^A''' ;

Het ^A''' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, while the Het ^A''' group has in position 4, relative to the point of attachment to L ¹ , oxo (=O) and optionally has one or more additional substituents R ^4b ;

(eg A''' is 4-pyridon-1-yl optionally having one or more R ^4b substituents); and

B, L ¹ , L ² , R ¹ , R ^4a , R ^4b and R ⁸ correspond to the above definitions for compounds of formula I (or A1).

Noteworthy embodiments of the present invention include those relating to compounds of formula I, in which at least one of L ¹ and L ² represents a single bond, and the second may be CH=CH or, especially, a single bond, O, NR ^3a , S(O) _p , CH ₂ or C(O) (for example, at least one of L ¹ and L ² is a single bond, and the second is CH=CH or, especially, C(O) or , in particular a single bond, O, NR ^3a or S(O) _p ).

Thus, in one embodiment of the present invention, L ¹ and L ² are both single bonds.

Noteworthy embodiments of the present invention include those relating to compounds of formula I, where L ¹ represents a single bond, and L ² is selected from CH=CH or, especially, O, NR ^3a , S(O) _p , CH ₂ and C(O) (eg L ¹ is a single bond and L ² is selected from O, CH ₂ or C(O)).

Other noteworthy embodiments of the present invention include those relating to compounds of formula I, where L ² represents a single bond, and L ¹ is selected from CH=CH or, especially, O, NR ^3a , S(O) _p , CH ₂ and C(O) (eg L ² is a single bond and L ¹ is selected from O, CH ₂ or C(O)).

Noteworthy embodiments of the present invention include those pertaining to compounds of formula I, wherein:

(1) R ¹ is H or C _1-3 alkyl, the last listed group may optionally have one or more halogen substituents, OR ^2a or NR ^2b R ^2c

(for example, R ¹ is H or C _1-3 alkyl, the last listed group may optionally have one or more substituents representing halogen atoms or NR ^2b R ^2c or, especially, R ¹ represents H or C _{1- 2} alkyl, the last listed group may optionally have one or more substituents representing halogen atoms or NR ^2b R ^2c );

(2) L ¹ and L ² are independently CH=CH, or especially NR ^3a , S(O) _p , or especially CH ₂ , or especially a single bond, O, or C(O) ;

(3) R ^2a , R ^2b and R ^2c and R ^3a is H or C _1-3 alkyl, the latter of the listed groups may optionally have one or more substituents representing halogen atoms

(e.g. R ^2a is C _1-3 alkyl which optionally has one or more halogen substituents; R ^2b and R ^2c are independently H or methyl, the last listed group may optionally have one or more substituents, representing halogen atoms, and R ^3a represents H or C _1-3 alkyl, the latter of the listed groups may optionally have one or more substituents representing halogen atoms);

(4) Cy ¹ is a 5-13-membered (for example, 5-10 - or, in particular, 6-10-membered) aromatic, fully saturated or partially unsaturated carbocyclic system, including 1-3 (for example, one or two ) rings, wherein the Cy ¹ group optionally has one or more R ^4a substituents;

(5) Het ^A is a 5-13 membered (e.g. 5-10 or especially 6-10 membered) heterocyclic group which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N, where said heterocyclic group may contain 1-3 (eg one or two) rings and said Het ^A group optionally has one or more R ^4b substituents;

(6) Cy ² is a 5-10-membered (for example, 5-9-membered or, especially, 6-9-membered) aromatic, fully saturated or partially unsaturated carbocyclic system containing one or two rings, and said Cy group ² optionally has one or more R ^4c substituents;

(7) Het ^B is a 5-10 membered (e.g. 5-9 membered or especially 6-9 membered) heterocyclic group which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms , selected from O, S and N, where the specified heterocyclic group may contain 1-3 (for example, one or two) rings, and the specified group Het ^B optionally has one or more substituents R ^4d ;

(8) R ^4a - R ^4d are, in each case independently,

halogen atom,

CN,

C _1-6 alkyl (for example, C _2-6 alkyl), C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from halogen atoms, nitro groups, CN, C _{1 -3} alkyl, C _2-3 alkenyl, C _2-3 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-3 alkyl and C _1-3 alkoxy groups) , OR ^5a , S(O) _q R ^5b , S(O) ₂ N(R ^5c )(R ^5d ), N(R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )-B ² -R ⁵ⁱ , aryl and Het ¹ ,

a Cy ³ group which optionally has one or more substituents selected from halogen atoms, a nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^6a , S(O) _q R ^6b , S(O) ₂ N(R ^6c )(R ^6d ), N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ , aryl and Het ² ,

a Het ^a group which optionally has one or more substituents selected from halogen atoms, a nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^7a , S(O) _q R ^7b , S(O) ₂ N(R ^7c )(R ^7d ), N(R ^7e )S(O) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ , aryl and Het ³ ,

^OR8 ,

S(O) _r R ^9a ,

S(O) ₂ N(R ^9b )(R ^9c ),

N(R ^9d )S(O) ₂ R ^9e ,

N(R ^9f )(R ^9g )

B ⁷ -C (G ¹ ) -B ⁸ -R ^9h ,

=O,

=S,

or, when two R ^4a , R ^4b , R ^4c or R ^4d groups are attached to the same carbon atom in the non-aromatic portion of the Cy ¹ , Het ^A , Cy ² or Het ^B group, they can form, together with the carbon atom, to to which they are attached, a saturated or unsaturated 3-6 membered ring which may optionally contain 1-3 heteroatoms selected from O, S and N and which may optionally have one or more R ⁹ⁱ substituents;

(9) G ¹ is, in each case independently, O or S;

(10) R ⁸ is, in each case independently,

h,

Cy ³ , Het ^a , aryl ^a , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, where the last seven groups optionally have one or more substituents selected from halogen atoms - CN, C _3-6 cycloalkyl, aryl, Het ⁴ , -C(O)OR ¹⁰ , -C(O)R ¹¹ and -C(O)N(R ^N1 )(R ^N2 ), S(O) _r R ^9aa , S(O) ₂ N(R ^9ba )(R ^9ca ), N(R ^9da )S(O) ₂ R ^9ea and N(R ^9fa )(R ^9ga );

(11) Cy ³ is, at each occurrence independently, C _3-6 cycloalkyl, C _3-6 cycloalkenyl or phenyl;

(12) Heta is, at each occurrence independently, ^a 4-6 membered heterocyclic ring which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S and N;

(13) R ¹⁰ and R ¹¹ independently represent

h,

C _1-3 alkyl optionally having one or more substituents selected from halogen, aryl, -N(R ^N3 )(R ^N4 ) and -OR ^a ,

phenyl (which may optionally have one or more substituents selected from OH, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups) or

C _3-6 cycloalkyl (which may optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups);

(14) B ¹ - B ⁸ represent, independently in each case, O or, especially, a single bond or N(R ^N3 );

(15) each aryl ^a is independently a C _6-10 carbocyclic aromatic group (eg phenyl) which may contain one or two rings;

(16) each aryl is independently a C _6-10 carbocyclic aromatic group (eg phenyl) which may contain one or two rings and may have one or more substituents selected from

halogen atom,

C _1-6 alkyl which may optionally have one or more substituents selected from halogen atoms -N(R ^N4 )(R ^N5 ) and -OR ^a , and

-OR ^a ;

(17) Het ¹ - Het ⁴ are independently 5-13 membered heterocyclic groups containing one or more heteroatoms selected from O, S and N, wherein said heterocyclic groups may contain one, two or three rings and may have one or more substituents selected from

halogen atom,

C _1-6 alkyl, the last listed group may optionally have one or more substituents selected from halogen atoms -N(R ^N6 )(R ^N7 ) and -OR ^a , and

-OR ^a ;

(18) R ^N1 - R ^N7 are independently

h,

C _1-3 alkyl or C _3-5 cycloalkyl, where the last two groups optionally have one or more substituents selected from halogen atoms and -OR ^a ;

(19) R ^a is, in each case independently,

h,

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, C _4-6 cycloalkenyl (the last five groups optionally have one or more substituents selected from halogen atoms, nitro groups CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^12a , S(O) _q R ^12b , S(O) ₂ N(R ^12c )(R ^12d ), N(R ^12e )S(O) ₂ R ^12f , N( R ^12g )(R ^12h ), B ⁹ -C(G ² )-B ¹⁰ -R ¹²ⁱ , aryl ¹ and Het ^b , while the group C _3-6 cycloalkyl or C _4-6 cycloalkenyl may additionally have a substituent =O) ,

S(O) _r R ^13a ,

S(O) ₂ N(R ^13b )(R ^13c ) or

C(O)-B ¹³ -R ^13d ;

(20) R ^5a - R ^5l , R ^6a - R ⁶ⁱ , R ^7a - R ⁷ⁱ , R ^9a - R ⁹ⁱ , R ^9aa - R ^9ga , R ^12a - R ¹²ⁱ and R ^13a - R ^13d are, independently in each case,

h,

C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from halogen atoms, OH and C _1-4 alkoxy groups),

C _3-6 cycloalkyl or C _4-6 cycloalkenyl (the last two groups optionally have one or more substituents selected from halogen atoms, OH, =O, C _1-6 alkyl and C _1-6 alkoxy groups),

Het ^d ;

(21) G ² is, in each case independently, O or S;

(22) R ^5aa - R ^5aj are, in each case independently,

h,

C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, where these three groups optionally have one or more substituents selected from halogen atoms, nitro group, CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups),

C _3-5 cycloalkyl or C _4-5 cycloalkenyl (the last two groups optionally have one or more substituents selected from halogen atoms, OH, =O, C _1-4 alkyl and C _1-4 alkoxy groups),

Het ^e ;

(23) B ⁹ - B ¹³ independently represent a single bond or N(R ^N8 );

(24) aryl ¹ is, at each occurrence independently, phenyl or naphthyl, which may have one or more substituents selected from

halogen atom,

C _1-3 alkyl, which may optionally have one or more substituents selected from halogen atoms, -N(R ^N10 )(R ^N11 ) and C _1-4 alkoxy groups (the last substituent listed is optionally substituted one or more halogen atoms), and

C _1-4 alkoxy group (which is optionally substituted with one or more halogen atoms);

(25) R ^N8 , R ^N10 and R ^N11 are independently

h,

C _1-3 alkyl or C _3-3 cycloalkyl, where the last two groups are optionally substituted with one or more halogen atoms;

(26) Het ^b is a heterocyclic group selected from the following: dioxanyl, furanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, maleimido, morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolyl, piperazinyl, piperidinyl, pyranyl , pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3 ,4,5,6-tetrahydropyrimidinyl, thiadiazolyl, thiazolidinyl, thiazolyl, thienyl, thiophenethyl, triazolyl, wherein said heterocyclic group may have one or more substituents selected from halogen atoms, =O and C _1-6 alkyl;

(27) Het ^c - Het ^e are independently a 4-6 membered heterocyclic ring which may be aromatic, fully saturated or partially unsaturated and which contains one or more heteroatoms selected from O, S and N, wherein the indicated groups Het ^c - Het ^e optionally have one or more substituents selected from halogen atoms, nitro groups CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl (the last three groups optionally have one or more substituents, selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups).

Noteworthy embodiments of the present invention include those pertaining to compounds of formula I, wherein:

(1) Cy ¹ is a 5-10-membered (e.g. 6-10-membered) aromatic, fully saturated or partially unsaturated carbocyclic system containing one or two rings, said Cy ¹ group optionally having one or more substituents R ^4a ;

(2) Het ^A is a 5-10 membered (e.g. 6-10 membered) heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or more heteroatoms selected from O, S, and N where the specified heterocyclic group may contain one or two cycles and the specified group Het ^A optionally has one or more substituents R ^4b ;

(3) B is a group selected from the following: 2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl, benzo[c]isoxazolidinyl . -dihydrofuranyl, 2,5-dihydrofuranyl), 2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4, 5-dihydro-1H-maleimido, 1,3-dihydro-2,1-benzisoxazolyl 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, dioxolanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1,2 -a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl, indenyl, indolinyl, isobenzofuranyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, isoxazolidinyl, keto piperidinyl (eg 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl (eg piperidin-1-yl or especially piperidine -2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl or piperidin-6-yl), piperazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyrrolidinonyl, pyrrolinyl (e.g. 3- pyrrolinyl), pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5 ,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, tetramethylene sulfoxide, tetrazolyl , thiazolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl, thiophenethyl, triazinanyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, especially benzofuranyl, indazolyl, indolyl, pyrazinyl, pyrazolyl , pyridinyl (for example , 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl, pyrrolo[1,5-a]pyridinyl, and especially phenyl, where B optionally has one or more substituents R ^4c or R ^4d where appropriate (e.g. B is a group selected from the following: benzofuranyl, furanyl, indazolyl, indolyl, pyrazinyl, pyrazolyl, pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl, pyrrolo[1,5 -a]pyridinyl; and phenyl, where B optionally has one or more R ^4c or R ^4d substituents where appropriate.

In some embodiments, implementation of the present invention, B represents phenyl, and the compound of formula I can be represented as a compound of formula Ia,

where s is 0-5 (eg 0-3 or especially 0-2) and R ^4c , A, L ¹ , L ² and R ¹ are as defined above for compounds of formula I.

In some embodiments of the present invention, the compound of formula I can be represented as a compound of formula Ixa, Iya or Iza,

,

,

respectively, where s1, s2 and s3 are independently 0-5 (eg 0-3 or especially 0-2), and A', A'', A''', L ¹ , L ² , R ^4c and R ¹ correspond to the above definitions for compounds of formula I (or A1, or, in particular, Ix, Iy or Iz).

Noteworthy embodiments of the present invention include those pertaining to compounds of formula I (or A1 or especially Ix, Iy Iz, Ixa, Iya and Iza, or especially Ia) wherein:

(1) R^one represents H, CH₃, CF₃, CH₂F,CHF₂, CH₂CH₃, CH₂CF₃, (CH₂)₂OCH₃, (CH₂)₂OCF₃, (CH₂)₃OCH₃, (CH₂)₃OCF₃, (CH₂)₂NH₂, (CH₂)₂NH(CH₃), (CH₂)₂N(CH₃)₂, (CH₂)₃NH₂, (CH₂)₃NH(CH₃) or (CH₂)₃N(CH₃)₂;

(2) L ¹ is S, NH, CH=CH, or especially CH ₂ , a single bond, O or C(O) (for example, L ¹ is S, NH, CH=CH, a single bond, O or C(O) or especially a single bond, O or C(O), or especially L ¹ is a single bond);

(3) L ² is CH ₂ , a single bond, O or C(O) (eg L ² is a single bond or O, or especially L ² is a single bond);

(4) R ^2a , R ^2b , R ^2c and R ^3a are independently H, CH ₃ , CF ₃ , CH ₂ F, CHF ₂ , CH ₂ CH ₃ or CH ₂ CF ₃

(for example, R ^2a is CH ₃ , CF ₃ , CH ₂ F, CHF ₂ , CH ₂ CH ₃ or CH ₂ CF ₃ and R ^2b , R ^2c and R ^3a are independently H, CH ₃ , CF ₃ , CH ₂ F, CHF ₂ , CH ₂ CH ₃ or CH ₂ CF ₃ );

(5) A is a group selected from the following: 2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl, 6-oxa-9-azaspiro[4.5]decanyl, octahydroisoquinolin- (1H)-yl, hexahydropyrrolo[1,2-a]pyrazin-(1H)-yl, pyridazinonyl or especially cyclopentyl, dihydrofuranyl (e.g. 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5- dihydro-1H-maleimido, dioxanyl, furazanyl, hydantoinyl, imidazolyl, isoxazolyl, isoxazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl, pyrrolidinonyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetramethylene sulfoxide, tetrazolyl , thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, triazolyl, especially 2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzofurazanyl, benzo[c] isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzopyrazolyl, benzo [e]pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, carbazolyl, chromanil, chromenyl, cinnolinyl, (1Z,2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl, cyclopentenyl, decahydroisoquinolinyl, 2,3 -dihydrobenzimidazolyl, 1,3-dihydrobenzo-[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 2,3-dihydropyrrolo[2 ,3-b]pyridinyl, dioxolanyl, hexahydropyrimidinyl, imidazo[2,3-b]thiazolyl, indanyl, indazolyl, indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isothiochromanyl, ketopiperidinyl (e.g., 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or especially 1,5-naphthyridinyl and 1,8-naphthyridinyl), 1,2- or 1,3- oxazinanil, oxazolidinyl, phenazinyl, phenothiazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, quinazolinil, quinolisinyl, quinoxalinyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine, tetrahydroisoquinolinyl (including 1,2,3,4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrahydropyranyl, tetrahydropyridinyl (e.g. 3,4,5,6 -tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, thieno[5,1-c]pyridinyl, thiochromanyl, thiophenethyl, triazinanyl, 1,3,4-triazolo[ 2,3-b]pyrimidinyl, especially benzoxazolyl, benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl, isoquinolinyl, morpholinyl, naphthalene (e.g. 1-naphthalenyl, 2-naphthalenyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl, pyrimidinyl, pyrrolidinyl pyrrolo[1,5-a]pyridinyl, pyrazinyl, pyridinonyl (such as 1- 1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl, 6-1H -pyridin-2-onyl, or especially 4-pyridinonyl), quinolinyl, especially phenyl and pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), where the listed ring systems optionally have one or more substituents R ^4a or R ^4b where appropriate;

(6) R ^4a - R ^4d are, in each case independently,

halogen atom,

CN,

C _1-6 alkyl (which may optionally have one or more substituents selected from halogen atoms, CN nitro groups, C _1-3 alkyl (the latter of the listed groups may optionally have one or more substituents representing are substituents selected from OH, =O, halogen atoms, C _1-3 alkyl and C _1-3 alkoxy groups), OR ^5a , S(O) _q R ^5b , S(O) ₂ N(R ^5c )( R ^5d ), N(R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ) and B ¹ -C(G ¹ )-B ² -R ⁵ⁱ ),

Cy ³ , where Cy ³ is a group selected from the following: cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl and, in particular, cyclopropyl, while the Cy ³ group optionally has one or more substituents selected from halogen atoms, nitro groups, CN, C _1-3 alkyl (which optionally has one or more substituents selected from OH, =O, halogen atoms, C _1-3 alkyl and C _1-3 alkoxy groups), OR ^6a , S(O) _q R ^6b , S(O) ₂ N(R ^6c )(R ^6d ), N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C (G ¹ )-B ⁴ -R ⁶ⁱ and aryl,

Het ^a where Het ^a is a group selected from the following: azetidinyl, dihydrofuranyl (eg 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), dihydropyranyl (eg 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4,5-dihydro-1H-maleimido, dioxanyl, dioxolanyl, furanyl, furazanil, hexahydropyrimidinyl, hydantoinyl, imidazolyl, isothiazolyl, isoxazolidinyl, isoxazolyl, morpholinyl, 1,2- or 1,3-oxazinanyl, oxazolidinyl, oxazolyl, piperidinyl, piperazinyl , pyranyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl, pyrrolidinyl, pyrrolidinonyl, 3-sulfolenyl, sulfolanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl (e.g. 3,4,5,6- tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, tetramethylene sulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, thiophenethyl, triazolyl and triazinanyl, wherein the Het ^a group optionally has one or more batches substituents selected from halogen atoms, nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms , C _1-3 alkyl and C _1-3 alkoxy groups), OR ^7a , S(O) _q R ^7b , S(O) ₂ N(R ^7c )(R ^7d ), N(R ^7e )S(O ) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ and aryl,

^OR8 ,

S(O) _r R ^9a ,

S(O) ₂ N(R ^9b )(R ^9c ),

N(R ^9d )S(O) ₂ R ^9e ,

N(R ^9f )(R ^9g )

B ⁷ -C (O) -B ⁸ -R ^9h ,

B ⁷ -C (G ¹ ) -B ⁸ -R ^9h ,

=O,

or, when two R ^4a , R ^4b , R ^4c or R ^4d groups are attached to the same carbon atom in the non-aromatic portion of the Cy ¹ , Het ^A , Cy ² or Het ^B group, they may form together with the carbon atom to which they are attached, a saturated or unsaturated 3-6 membered ring (e.g. dioxolanyl or 1,4-dioxanyl) which may optionally contain 1-3 heteroatoms selected from O, S and N and which may optionally have one or more substituents ^R9i ;

(7) G ¹ is, in each case independently, O;

(8) R ⁸ is, in each case independently,

h,

C _1-6 alkyl, which may optionally have one or more substituents selected from halogen atoms, -CN, C _3-6 cycloalkyl, aryl, Het ⁴ , -C(O)OR ¹⁰ , -C( O)R ¹¹ and -C(O)N(R ^N1 )(R ^N2 )

(for example, R ⁸ is, in each case independently, H or C _1-3 alkyl, optionally substituted with fluorine atoms (for example, CH ₂ F, CHF ₂ , CH ₂ CH ₃ , CH ₂ CF ₃ , or, in particular , CH ₃ or CF ₃ );

(9) each aryl is independently a phenyl group and optionally has one or more substituents selected from

halogen atom,

C _1-3 alkyl which may optionally have one or more substituents selected from halogen atoms -N(R ^N4 )(R ^N5 ) and -OR ^a , and

-OR ^a ;

(10) R ^a is in each case independently,

h,

C _1-3 alkyl (which may optionally have one or more substituents selected from halogen, OH, and C _1-4 alkoxy groups) or

C _3-6 cycloalkyl (which may optionally have one or more substituents selected from halogen, OH, ═O, C _1-6 alkyl, and C _1-4 alkoxy groups).

In some other embodiments of the present invention, B is phenyl and L ² is a single bond, and the compound of formula I can be represented as a compound of formula Ib,

where R ^4c , A and L ¹ correspond to the above definitions for compounds of formula I (or A1 or, especially, Ia), and t is 0-5 (for example, 0-3, or, in particular, 0-2).

In some embodiments of the present invention, the compound of formula I can be represented as a compound of formula Ixb, Iyb or Izb,

,

,

respectively, where t1, t2 and t3 are independently 0-5 (eg 0-3 or especially 0-2) and A', A'', A''', R ^4c and L ¹ correspond to the above definitions for compounds of formula I (or A1 or especially Ix, Iy, Iz, Ia, Ixa, Iya or Iza).

In some embodiments of the present invention, the compounds of formula I (or A1 or especially Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, or especially Ia or Ib) are compounds in which:

(1) L ¹ is S, NH, CH=CH, or especially a single bond or O (eg L ¹ is a single bond);

(2) A is a group selected from the following: furanyl, pyrrolidinyl, pyrazolyl, oxazolyl, especially benzoxazolyl, benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, cyclohexenyl, decahydroisoquinolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl, isoquinolinyl, morpholinyl, naphthalinyl (e.g. 1-naphthalinyl, 2-naphthalinyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl, pyrimidinyl, pyrrolo[1,5-a ]pyridinyl, pyrazinyl, pyridinonyl (such as 1-1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or , especially 4-pyridinonyl), quinolinyl, especially phenyl and pyridinyl (for example, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), while the group A optionally has one or more substituents R ^4a or R ^4b where it is necessary;

(3) R ^4a and R ^4b are, in each case independently,

a halogen atom (for example, iodine or, in particular, chlorine, bromine or fluorine),

CN,

C _1-6 alkyl, (which may optionally have one or more substituents selected from aryl or especially halogen and OR ^5a ),

Cy ³ where Cy ³ is a group selected from the following: cyclobutyl, cyclopentyl, cyclohexyl phenyl and, in particular, cyclopropyl, while the Cy ³ group optionally has one or more substituents in the form of halogen atoms, nitro groups CN, C _{1 -3} alkyl (which optionally has one or more substituents selected from OH, =O, halogen atoms, C _1-3 alkyl and C _1-3 alkoxy groups), OR ^6a , S(O) _q R ^6b , S( O) ₂ N(R ^6c )(R ^6d ), N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ and arila,

Het ^a , where Het ^a is a group selected from the following: azetidine and, in particular, dioxanyl and dioxolanyl, while the Het ^a group optionally has one or more substituents selected from halogen atoms, nitro groups, CN, C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-3 alkyl and C _1-3 alkoxy groups), OR ^7a , S(O) _q R ^7b , S(O) ₂ N(R ^7c )(R ^7d ), N(R ^7e )S(O) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ and aryl,

^OR8 ,

S(O) _r R ^9a ,

N(R ^9f )(R ^9g )

B ⁷ -C (G ¹ ) -B ⁸ -R ^9h ,

=O,

or, when two R ^4a or R ^4b groups are attached to the same carbon atom in the non-aromatic part of the Cy ¹ or Het ^A group, they can form, together with the carbon atom to which they are attached, a saturated or unsaturated 5-membered ring (for example , dioxolanyl), which optionally contains one or two heteroatoms selected from O and N, and which may optionally have one or more R ⁹ⁱ substituents,

(for example, R ^4a or R ^4b is, in each case independently, CH ₂ F or, especially, iodine, butyl, CH(CH ₃ )OH, OCH ₂ CH ₂ CH ₃ , NH(CH ₃ ), NHC(O )O-tert-butyl, morpholino, phenyl or, in particular, bromine, pyrazolyl, imidazolyl, benzyl, or, especially, chlorine, fluorine, CN, ethyl, methyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH, OCH (CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH, CH ₂ OCH ₃ , N(CH ₃ ) ₂ , cyclopropyl, dioxolanyl, SCH ₃ , SCH ₃ , C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)NH ₂ , C(O)NHCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NHCH ₂ CH ₃ , S(O)CH ₃ , S(O) ₂ CH ₃ , S(O) ₂ CH ₂ CH ₃ , NHC(O)CH ₃ , NHS(O) ₂ CH ₃ , =O, or when two R ^4a or R ^4b groups are attached to the same carbon atom in the non-aromatic part of the Cy ¹ or Het ^A group, they can form dioxolanyl which optionally contains one or two heteroatoms selected from O and N and which may optionally have one or more substituents ^R9i ;

(4) R ^4c or R ^4d are, in each case independently,

halogen atom

CN,

C _1-3 alkyl (which may optionally have one or more substituents selected from halogen and OR ^5a ),

^OR8 ,

N(R ^9f )(R ^9g ) or

B ⁷ -C(G ¹ ) -B ⁸ -R ^9h

(for example, R ^4c or R ^4d is, in each case independently, CH ₂ OCH ₃ , or, in particular, bromine, imidazolyl, S(O) ₂ CH ₃ , =O or, in particular, chlorine, fluorine, CN , methyl, ethyl, n-propyl, isopropyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , OH, OCH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , N(CH ₃ ) ₂ , CH ₂ OH, CH ₂ OCH ₃ , CH ₂ CN, C(O)CH ₃ , C(O)CH ₂ CH ₃ , NHC(O)CH ₃ ).

In some embodiments of the present invention, a compound of formula Ixb, Iyb or Izb can be represented as a compound of formula Ixb1, Iyb1 or Izb1,

,

,

respectively, where u1, u2 and u3 are independently 0-4 (eg 0-3 or especially 1 or 2) and L ¹ , R ^4a , R ^4b , R ^4c , R ⁸ t1, t2 and t3 correspond to the above definitions for compounds of formula I (or A1 or especially Ix, Iy, Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb or Izb) (for example, L ¹ is a bond, and R ^4a , R ^4b , R ^4c and R ⁸ are as defined above for compounds of formula I (or A1 or especially Ix, Iy, Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb or Izb)).

In some other embodiments of the present invention, the compound of formula Ib, Ixb, Iyb, Izb, Ixb1, Iyb1 or Izb1 (for example, the compound of formula Iyb1) is a compound in which:

(1) t, t1, t2 or t3 is 3 or especially 2, 1 or 0; and

(2) a phenyl group substituted with substituents (R ^4c ) _t , (R ^4c ) _t1 , (R ^4c ) _t2 or (R ^4c ) _t3 has no substituents in the ortho positions relative to the point of attachment to the 1,2,4-triazine group .

In some other embodiments of the present invention, B is unsubstituted phenyl and L ² is a single bond, and the compound of formula I can be represented as a compound of formula Ic,

where A and L ¹ correspond to the above definitions for compounds of formula I (or A1 or, especially, Ia or Ib).

Noteworthy embodiments of the present invention include those wherein the compounds of formula I (or A1 or especially Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, or especially Ia , Ib or Ic) are compounds in which:

(1) L ¹ is a bond or O (eg, L ¹ is a single bond);

(2) A is furanyl, imidazolyl, ketopiperidinyl (for example, 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), pyrazinyl, pyrrolidinyl, pyrrolidinonyl, especially cyclohexenyl, pyridinonyl (such as 1-1H-pyridin-2-onyl , 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or especially 4-pyridinonyl), or especially morpholinyl, piperidinyl, phenyl or pyridinyl (eg 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), wherein the A group optionally has one or more R ^4a or R ^4b substituents where appropriate;

(3) R ^4a or R ^4b is, in each occurrence independently, CH ₂ F, cyclopropyl, N(Me) ₂ , Br, ═O, azetidine, or especially chlorine, fluoro, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ (for example, R ^4a or R ^4b is, in each case independently, chlorine, fluorine, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ ).

Other noteworthy embodiments of the present invention relate to compounds of formula I (or A1 or especially Ia, Ib or especially Ic), in which:

(1) L ¹ is a single bond;

(2) A is a non-aromatic, 6-membered Het ^A ring containing at least one N atom, wherein the Het ^A group optionally has one or more R ^4b substituents, where the Het ^A ring is attached to the rest of the molecule via an N atom.

These embodiments include those in which L ¹ is a single bond, A is piperidinyl or morpholinyl optionally having one or more R ^4b substituents, R ¹ is H, L ² is a single bond, and B is phenyl, optionally having one or more R ^4c substituents).

Other noteworthy embodiments of the present invention relate to compounds of formula I (or A1 or especially Ia, Ib or especially Ic), in which:

(1) L ¹ is O;

(2) A is a 6-membered Cy ¹ group optionally having one or more R ^4a substituents.

These embodiments include those in which L ¹ is O, A is pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, or especially phenyl optionally having one or more R ^4a substituents, R ¹ is H, L ² is single bond, and B is phenyl optionally having one or more R ^4c substituents.

In some other embodiments of the present invention, B is phenyl and L ¹ and L ² are a single bond, and the compound of formula I can be represented as a compound of formula Iyc,

,

,

where v1 is 0-4 (eg 0-3 or especially 1 or 2), w1 is independently 0-5 (eg 0-3 or especially 0-2), and R ^4b and R ^4c correspond to the above definitions for compounds of formula I (or A1 or especially Iy, Ia, Iya, Ib, Iyb, Iyb1 or Ic).

Noteworthy embodiments of the present invention relate to compounds of formula Iyc, in which:

(1) R ^4b is, in each occurrence independently, NMe ₂ , Br, azetidin-1-yl, CH ₂ F or especially chlorine, fluorine, ethyl, methyl, cyclopropyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ or OCH ₃ ;

(2) R ^4c is, in each occurrence independently, CN, chlorine, fluorine, ethyl, methyl, CH ₂ OCH ₃ , CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ ;

(3) v1 is 0-4;

(4) w1 is 0-3.

Other noteworthy embodiments of the present invention relate to compounds of formula Iyc, in which:

(1) R ^4b is, in each occurrence independently, NMe ₂ , Br, azetidin-1-yl, CH ₂ F, CHF ₂ or especially cyclopropyl, OCH ₃ or especially chlorine, methyl or CF ₃ ;

(2) R ^4c is, at each occurrence independently, CN, chlorine, fluorine, CH ₂ OCH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F or OCHF ₂ ;

(3) v1 is 1 or 2;

(4) w1 is 0-3 (eg 3 or especially 2, 1 or 0);

(5) substituent(s) R ^4b is attached(s) to positions of the 3- and/or 5-pyridyl group, relative to the point of attachment to the 1,2,4-triazine group;

(6) the phenyl ring is unsubstituted or has 1-3 R ^4c substituents attached at the meta and/or para positions relative to the point of attachment to the 1,2,4-triazine group.

Other noteworthy embodiments of the present invention relate to compounds of formula Iyc, in which:

(1) R ^4b is, in each occurrence independently, NMe ₂ , Br, azetidin-1-yl, CH ₂ F, CHF ₂ or especially cyclopropyl, OCH ₃ or especially chlorine, methyl or CF ₃ ;

(2) R ^4c is, at each occurrence independently, CN, chlorine, fluorine, CH ₂ OCH ₃ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F or OCHF ₂ ;

(3) v1 is 1 or 2;

(4) w1 is 0-3 (eg 3 or especially 2, 1 or 0);

(5) substituent(s) R ^4b is attached(s) to positions of the 3- and/or 5-pyridyl group, relative to the point of attachment to the 1,2,4-triazine group; and

(6) the phenyl ring is unsubstituted or has 1-3 R ^4c substituents attached at the meta and/or para positions relative to the point of attachment to the 1,2,4-triazine group.

Other noteworthy embodiments of the present invention relate to compounds of formula Iyc, in which:

(1) v1 is 1 and R ^4b is attached to the positions of the 3-pyridyl group, relative to the point of attachment to the 1,2,4-triazine group;

(2) v1 is 2 and R ^4b substituents are attached to the 3- and 5-pyridyl positions relative to the point of attachment to the 1,2,4-triazine group.

Noteworthy compounds of formula I (or Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1 and Iyc, or especially Ia, Ib or Ic) include compounds in which when A ', A'', A''' or, especially, A is a substituted 6-membered Cy ¹ or Het ^A group (or Cy ^1' , Het ^A' , Het ^A'' or Het ^A''' ), the substituent(s) are in ortho or especially meta or para position(s) relative to the point of attachment to the rest of the molecule (for example, when A is a substituted 6-membered Cy ¹ or Het ^A group, then at least one substituent is in the meta or para positions and optionally a substituent in the ortho position of A or, in particular, at least one substituent is in the meta or para position and there are no substituents in the ortho position of A relative to the point attachment to the rest of the molecule). In particular embodiments, a 6-membered group Cy ¹ , Cy ^1' , Het ^A , Het ^A' , Het ^A'' or Het ^A''' has:

- the absence of substituents in the ortho positions;

a substituent at one or both of the meta positions; and, if necessary, for Cy ¹ , Cy ^1' or Het ^A

- Deputy in para-position.

For example, in a particular embodiment of the present invention, a compound of formula I (or A1 or especially Ix, Iy Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Ic or Iyc) may be represented as a compound of formula Ixd, Iyd or Izd,

,

,

respectively, where:

rr1 is 0-3 (eg 1 or especially 0);

rr2 and rr3 are independently 0-2 (eg 1 or especially 0);

ss and tt are, independently in each case, 0 or 1, provided that ss and tt cannot both be 0;

R ^4a' has the same meanings as R ^4a ;

R ^4b' has the same meanings as R ^4b ; and

B, L ¹ , L ² , R ^4a and R ^4b correspond to the above definitions for compounds of formula I (or A1 or, especially, Ix, Iy Iz, Ia, Ixa, Iya, Iza, Ib, Ixb, Iyb, Izb, Ixb1 , Iyb1, Izb1, Ic or Iyc).

Noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which R ^4a , R ^4a' , R ^4b and R ^4b' independently represent cyclopropyl, iodine, bromine, chlorine, fluorine, ethyl, methyl, d ₃ - methyl, iso-propyl, -C≡CH, phenyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CF ₂ CF ₃ , CN, = O, OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CF ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ , CH(CH ₃ )OH, C(CH ₃ ) ₃ OH , CH ₂ CH ₂ OH, NH ₂ , N(CH ₃ ) ₂ , N(H)CH ₂ CH ₃ , N(H)C(O)CH ₃ , C(O)CH ₃ , C(O)N( CH ₃ ) ₂ , S(O) ₂ CH ₃ , S(O)CH ₃ , SCH ₃ , S(O) ₂ CF ₃ , azetidine, morpholine or dioxolane (e.g. OH, chlorine, fluorine, bromine, ethyl, methyl , d ₃ -methyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CF ₂ CF ₃ , or N(H)C(O)CH ₃ ).

Noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which R ^4a , R ^4a' , R ^4b and R ^4b' are, in each case independently,

(a) a halogen atom,

(b) CN

(c) C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, where the last three groups optionally have one or more substituents selected from halogen atoms, nitro groups CN, OR ^5a , S(O) _q R ^5b , S(O) ₂ N(R ^5c )(R ^5d ), N(R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )- B ² -R ⁵ⁱ and Het ¹ (for example, one or more substituents selected from the nitro group CN, OR ^5a , S(O) _q R ^5b , S(O) ₂ N(R ^5c )(R ^5d ), N (R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )-B ² -R ⁵ⁱ and Het ¹ ),

(d) Cy ³ which optionally has one or more substituents selected from the nitro group CN, OR ^6a , S(O) _q R ^6b , S(O) ₂ N(R ^6c )(R ^6d ), N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ and Het ² ,

(e) Het ^a , which optionally has one or more substituents selected from halogen atoms, nitro groups, CN, OR ^7a , S(O) _q R ^7b , S(O) ₂ N(R ^7c )(R ^7d ) , N(R ^7e )S(O) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ and Het ³ ,

(f) OR ⁸ ,

(g) S(O) _r R ^9a ,

(h) S(O) ₂ N(R ^9b )(R ^9c ),

(i) N(R ^9d )S(O) ₂ R ^9e ,

(j) N(R ^9f )(R ^9g ) or

(k) B ⁷ -C(G ¹ )-B ⁸ -R ^9h ,

where R ^5a - R ⁵ⁱ , R ^6a - R ⁶ⁱ , R ^7a - R ⁷ⁱ , R ⁸ , R ^9a - R ^9h , Cy ³ , Het ¹ - Het ³ , Het ^a , B ¹ - B ⁸ , G ¹ , q and r correspond to the definitions given above.

Noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which:

(1) R ^4a and R ^4b are, at each occurrence independently, OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ , NH ₂ , NHCH(CH ₃ ) ₂ , NHCH ₃ , NHCH ₂ CH ₃ , NHCH ₂ CH ₃ , NH (CH (CH ₃ ) ₂ ) ₂ , NH(CH ₃ ) ₂ , NH(CH ₂ CH ₃ ) ₂ or NH(CH ₂ CH ₃ ) ₂ );

(2) the sum of ss and tt is 1;

(3) rr1, rr2 and rr3 are 0;

(4) L ¹ and L ² are both single bonds.

Other noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which:

(1) R ^4a and R ^4b are, in each case independently, CH ₂ F or, especially, cyclopropyl, chlorine, fluorine, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH , OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ ;

(2) ss and tt are both 1;

(3) rr1 is equal to 1 or, especially, 0;

(4) rr2 and rr3 are equal to 0;

(5) when present, R ^4a' is attached at position 4 to L ¹ and is cyclopropyl, chlorine, fluorine, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ ;

(6) L ¹ and L ² are both single bonds.

Other noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which:

(1) R ^4a and R ^4b are, in each case independently, CH ₂ F or, especially, cyclopropyl, chlorine, fluorine, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ , OH , OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CH ₃ , OCH ₂ CF ₃ , OCH ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ (eg chlorine, fluorine, ethyl, methyl, CF ₃ , CHF ₂ , CH ₂ CF ₃ , CF ₂ CF ₃ );

(2) ss and tt are both 1;

(3) rr1, rr2 and rr3 are 0; and

(4) L ¹ and L ² are both single bonds.

Noteworthy embodiments of the present invention relate to compounds of formulas Ixd, Iyd and Izd, in which R ^4a , R ^4a' , R ^4b and R ^4b' correspond to the previously given definitions, and these compounds are compounds of formula A1 (i.e. where L ¹ and L ² are both single bonds and B is Cy ^BB or Het ^BB as described above In such embodiments of the present invention, R ^4a , R ^4a' , R ^4b and R ^4b' are independently cyclopropyl, iodo, bromine , chlorine, fluorine, ethyl, methyl, d ₃ -methyl, iso-propyl, -C≡CH, phenyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CF ₂ CF ₃ , CN, = O, OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , OCH ₂ F, OCHF ₂ , OCH ₂ CF ₃ , OCF ₃ , (CH ₂ ) ₃ OH, CH ₂ OH or CH ₂ OCH ₃ , CH( CH ₃ )OH, C(CH ₃ ) ₃ OH, CH ₂ CH ₂ OH, NH ₂ , N(CH ₃ ) ₂ , N(H)CH ₂ CH ₃ , N(H)C(O)CH ₃ , C (O)CH ₃ , C(O)N(CH ₃ ) ₂ , S(O) ₂ CH ₃ , S(O)CH ₃ , SCH ₃ , S(O) ₂ CF ₃ , azetidine, morpholine or dioxolane (for example , OH, chlorine, fluorine, bromine, ethyl, methyl, d ₃ - methyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CF ₂ CF ₃ or N(H)C(O)CH ₃ ).

Other worthy mention of the compounds of formula I include compounds from the examples described below. Thus, noteworthy embodiments of the present invention include those in which the compound of formula I is a compound selected from the following list:

(i) 5,6-diphenyl-1,2,4-triazine-3-amine; or especially

(ii) 6-(2-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(iii) 6-(3-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(iv) 6-(4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(v) 6-(5-chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(vi) 6-(3-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(vii) 6-(4-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(viii) 5-phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine;

(ix) 6-(2-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(x) 6-(furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xi) 6-phenoxy-5-phenyl-1,2,4-triazine-3-amine;

(xii) 6-(morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xiii) 6-(3-methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xiv) 6-(4,4-difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xv) 6-(3-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xvi) 6-(4-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xvii) 6-(2-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xviii) 6-(4-methoxyphenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xix) 6-(3-chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine;

(xx) 5-phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazine-3-amine;

(xxi) 6-(2,6-dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xxii) 5-phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazine-3-amine;

(xxiii) 6-(3-chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine;

(xxiv) 5-phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazine-3-amine;

(xxv) 6-(3,5-difluorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xxvi) 5-phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazine-3-amine;

(xxvii) 6-[3-fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazine-3-amine;

(xxviii) 6-(3,5-dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xxix) 6-(5-chloropyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xxx) 6-(3-chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xxxi) 6-(3-fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xxxii) 6-[4-fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazine-3-amine;

(xxxiii) 5-phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazine-3-amine;

(xxxiv) 6-(3-chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine;

(xxxv) 6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xxxvi) 6-(3-aminophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xxxvii) 6-(3-chlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xxxviii) 6-(3,3-dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xxxix) 6-(3-bromophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xl) 6-(3,5-dichlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xli) 5-phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine;

(xlii) 6-(1H-indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xliii) 6-(3,5-difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(xliv) 6-(octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xlv) 6-(3,4-dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xlvi) 6-(3-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xlvii) 6-(1,3-benzodioxol-5-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xlviii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile;

(xlix) 6-(3,5-dimethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(l) 6-(3,5-dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(li) 6-(3,4-dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lii) 6-[3-(dimethylamino)phenyl]-5-phenyl-1,2,4-triazine-3-amine;

(liii) N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide;

(liv) N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide;

(lv) 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lvi) 6-(1-benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine;

(lvii) 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazine-3-amine;

(lviii) 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine;

(lix) 6-(3,5-bis(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lx) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenol;

(lxi) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylphenol;

(lxii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol;

(lxiii) 6-(2-chloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(lxiv) 6-(3-(methylsulfonyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxv) 6-(3,5-dichloro-4-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxvi) 6-(4-methoxy-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxvii) 6-(3-chloro-5-(dimethylamino)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxviii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)benzonitrile;

(lxix) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(lxx) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxi) 6-(3-chloro-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxii) 6-(3-(methylthio)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxiii) 6-(3-methoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxiv) 6-(3-ethoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxv) 6-(3-t-butyl-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxvi) 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(lxxvii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorobenzonitrile;

(lxxviii) 6-(3-ethylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxix) 6-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(lxxx) 6-(3-methyl-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxxi) 6-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;

(lxxxii) 5-phenyl-6-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-triazine-3-amine;

(lxxxiii) 6-(3-(methoxymethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxxiv) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one;

(lxxxv) 6-(3-methyl-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxxvi) 6-(2-methoxypyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(lxxxvii) 1-(3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl)ethanone;

(lxxxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzamide;

(lxxxix) 6-(4-fluoro-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xc) 6-(4-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xci) 6-(3-bromo-5-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine;

(xcii) 6-(naphthalene-2-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xiii) 5-phenyl-6-m-tolyl-1,2,4-triazine-3-amine;

(xciv) 5-phenyl-6-(pyridin-4-yl)-1,2,4-triazin-3-amine;

(xcv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenol;

(xcvi) 6-(2,6-dimethoxypyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(xcvii) 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(xcviii) 5-phenyl-6-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-triazin-3-amine;

(xcix) 6-(2-cyclopropylpyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(c) 5-phenyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1,2,4-triazin-3-amine;

(ci) 6-(5-chloro-2-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(cii) 6-(2,6-dichloropyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(ciii) 6-(3-bromo-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(civ) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chloro-6-methoxyphenol;

(cv) 6-(3,5-dichloro-4-ethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(cvi) 6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine;

(cvii) 4-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine;

(cix) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine;

(cx) 4-(3-amino-5-(4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxi) 6-(3-chloro-5-propoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(cxii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine;

(cxiii) 6-(2-chloropyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(cxiv) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(cxv) 4-(3-amino-5-(4-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxvi) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-chlorophenyl)-1,2,4-triazine-3-amine;

(cxvii) 5-(4-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;

(cxviii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-chlorophenyl)-1,2,4-triazin-3-amine;

(cxix) 4-(3-amino-5-(3-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxx) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chlorophenyl)-1,2,4-triazine-3-amine;

(cxxi) 5-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;

(cxxii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-chlorophenyl)-1,2,4-triazin-3-amine;

(cxxiii) 4-(3-amino-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazin-5-yl)benzonitrile;

(cxxiv) 4-(3-amino-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;

(cxxv) 4-(3-amino-5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxxvi) 5-(3-chloro-5-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine;

(cxxvii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine;

(cxxviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine;

(cxxix) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;

(cxxx) 4-(3-amino-5-(3,5-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxxxi) 4-(3-amino-5-(3-chloro-4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxxxii) 5-(3-chloro-4-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine;

(cxxxiii) 5-(3-chloro-4-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;

(cxxxiv) 5-(3-chloro-4-fluorophenyl)-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazine-3-amine;

(cxxxv) 4-(3-amino-5-(3,4-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(cxxxvi) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;

(cxxxvii) 6-(2-chloropyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine;

(cxxxviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine;

(cxxxix) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine;

(cxl) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;

(cxli) 6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(cxlii) 6-(3-chloro-5-methylphenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine;

(cxliii) 6-(6-fluoropyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine;

(cxliv) 6-(3,5-dimethylisoxazol-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(cxlv) 6-(3,5-diisopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(cxlvi) 6-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(cxlvii) N-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(trifluoromethyl)phenyl)acetamide;

(cxlviii) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-fluorobenzonitrile;

(cxlix) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-N,N-dimethylbenzamide;

(cl) 6-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(cli) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one;

(clii) 6-(3-(morpholin-4-yl)phenyl)-5-phenyl-1,2,4-triazin-3-amine;

(cliii) 6-(1-benzyl-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(cliv) 6-(2-methoxypyrimidin-5-yl)-5-phenyl-1,2,4-triazine-3-amine;

(clv) 6-(6-methoxypyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine;

(clvi) 6-(3-(methylsulfinyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(clvii) 4-(3-amino-6-(2-chloropyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;

(clviii) 4-(3-amino-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(clix) 6-(2-chloropyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;

(clx) 6(E)-5-phenyl-6-styryl-1,2,4-triazine-3-amine;

(clxi) 6-(3-amino-5-phenyl-1,2,4-triazin-6-yl)indolin-2-one;

(clxii) tert-butyl 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate;

(clxiii) 6-(3-methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazine-3-amine;

(clxiv) 6-(3-ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazine-3-amine;

(clxv) 6-(2,6-dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(clxvi) 6-(2-ethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine;

(clxvii) 5-phenyl-6-(6-oxa-9-azaspiro[4.5]decan-9-yl)-1,2,4-triazin-3-amine;

(clxviii) 6-(2,2-diethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine;

(clxix) 6-(2,2-dimethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine;

(clxx) (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-methylpiperidin-3-yl)methanol;

(clxxi) 6-(3-(methoxymethyl)piperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine;

(clxxii) 1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanol;

(clxxiii) (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)methanol;

(clxxiv) 1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanone;

(clxxv) 6-(octahydroisoquinolin-2(1H)-yl)-5-phenyl-1,2,4-triazin-3-amine;

(clxxvi) N6-(4-methyl-1,3-thiazol-2-yl)-5-phenyl-1,2,4-triazin-3,6-diamine;

(clxxvii) 5-phenyl-6-[4-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine;

(clxxviii) 5-phenyl-6-(3-phenylpiperidin-1-yl)-1,2,4-triazin-3-amine;

(clxxix) (4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)methanol;

(clxxx) 5-phenyl-6-(3-(propoxymethyl)pyrrolidin-1-yl)-1,2,4-triazin-3-amine;

(clxxxi) 2-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)propan-2-ol;

(clxxxii) 6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-phenyl-1,2,4-triazin-3-amine;

(clxxxiii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-ethylpiperidin-3-ol;

(clxxxiv) 2-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)ethanol;

(clxxxv) 6-(3,5-dimethylphenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(clxxxvi) 6-(3-chloro-5-methoxyphenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(clxxxvii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-4(1H)-one;

(clxxxviii) 6-(4-methylphenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(clxxxix) 6-(4-chlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(cxc) 6-(3,4-difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(cxci) 6-[(6-methoxypyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;

(cxcii) 6-[(2-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;

(cxciii) 6-[(6-chloropyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;

(cxciv) 4-[(3-amino-5-phenyl-1,2,4-triazin-6-yl)oxy]benzonitrile;

(cxcv) 6-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-5-phenyl-1,2,4-triazin-3-amine;

(cxcvi) 6-[(1-methyl-1H-benzimidazol-5-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;

(cxcvii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridazin-4(1H)-one;

(cxcviii) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dichloropyridin-4(1H)-one;

(cxcix) 6-(2,4-difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(cc) 5-phenyl-6-(pyridin-3-yloxy)-1,2,4-triazine-3-amine;

(cci) 6-[(4-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine;

(ccii) 5-phenyl-6-(p-tolylthio)-1,2,4-triazine-3-amine;

(cciii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol;

(cciv) 6-(3-chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(ccv) 6-(3-chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine;

(ccvi) 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine;

(ccvii) 6-(6-(methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine;

(ccviii) 5-(3-chloro-5-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;

(ccix) 6-(2-chloropyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine;

(ccx) 4-(3-amino-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile;

(ccxi) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine;

(ccxii) 6-(2-chloropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine;

(ccxiii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine;

(ccxiv) 5-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2-chlorophenol;

(ccxv) 4-[3-amino-6-(3-chloro-4-hydroxyphenyl)-1,2,4-triazin-5-yl]benzonitrile;

(ccxvi) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol;

(ccxvii) 5-(3-chloro-5-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxviii) 5-(3,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxix) 5-(3,4-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxx) 5-(3-chloro-4-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxxi) 5-(4-(difluoromethoxy)phenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxxii) 6-(2,6-dimethylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;

(ccxxiii) 5-(4-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxxiv) 4-(3-amino-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile;

(ccxxv) 5-(3-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxxvi) 6-(2,6-dimethylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine;

(ccxxvii) 4-(3-amino-6-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,2,4-triazin-5-yl)benzonitrile;

(ccxxviii) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol;

(cxxxix) 6-(6-chloropyridin-2-yl)-5-phenyl-1,2,4-triazine-3-amine;

(ccxxx) 6-(4-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine;

(ccxxxi) 5-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine;

(ccxxxii) 5-phenyl-6-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine;

(ccxxxiii) 6-(6-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazine-3-amine;

(ccxxxiv) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyrazin-2-ol;

(ccxxxv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol;

(ccxxxvi) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol;

(ccxxxvii) 6-(3-methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine;

(ccxxxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol;

(ccxxxix) 5-(3-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine;

(ccxl) 6-(2,4-dichlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine;

(ccxli) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine;

(ccxlii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine;

(ccxliii) 6-[2-(ethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(ccxliv) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;

(ccxlv) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(ccxlvi) 6-{2-[ethyl(methyl)amino]-6-methylpyridin-4-yl}-5-phenyl-1,2,4-triazin-3-amine;

(ccxlvii) 6-[2-(dimethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(ccxlviii) 1-[6-(2,6-d6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(ccxlix) 6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(ccl) 5-(4-fluorophenyl)-6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(ccli) 6-(2,6-dimethylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;

(cclii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;

(ccliii) 6-(2,6-dimethylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazine-3-amine;

(ccliv) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazine-3-amine;

(cclv) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclvi) 6-[2-chloro-6-(difluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclvii) 6-[2-chloro-6-(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclviii) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(cclix) 6-[2,6-bis(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclx) 6-[2-(fluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxi) 6-(2-chloro-6-methylpyridin-4-yl)-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine;

(cclxii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;

(cclxiii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine;

(cclxiv) 6-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxv) 6-[2-ethyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxvi) 6-(2-cyclopropyl-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(cclxvii) 5-(2-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxviii) 5-(3-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxix) 5-(4-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxx) 5-(2,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxxi) 5-(3,4-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxxii) 5-(3,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine;

(cclxxiii) 6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine;

(cclxxiv) 6-[2-methyl-6-(morpholin-4-yl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxxv) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-ethylphenyl)-1,2,4-triazin-3-amine;

(cclxxvi) 5-(2,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine;

(cclxxvii) 6-(2,6-dimethylpyridin-4-yl)-5-(4-methylphenyl)-1,2,4-triazin-3-amine;

(cclxxviii) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine;

(cclxxix) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine;

(cclxxx) 6-(3,5-dichlorophenyl)-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;

(cclxxxi) 6-(3-chloro-5-methylphenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine;

(cclxxxii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxxxiii) 6-[2,6-bis(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxxxiv) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;

(cclxxxv) 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxxxvi) 6-(3,5-dimethylphenyl)-5-(pyridin-2-yl)-1,2,4-triazin-3-amine;

(cclxxxvii) 6-[2-(dimethylamino)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(cclxxxviii) 6-(2-bromo-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(cclxxxix) 6-(2,6-dimethyl-1-oxypyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine;

(ccxc) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-6-methylpyridine-2-carbonitrile;

(ccxci) 6-(3,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazin-3-amine;

(ccxcii) 6-(3-chloro-5-methylphenyl)-5-(pyridin-3-yl)-1,2,4-triazine-3-amine;

(ccxciii) 6-(3,5-dichlorophenyl)-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine;

(ccxciv) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine;

(ccxcv) 6-[2-bromo-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(ccxcvi) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1,2,4-triazin-3-amine;

(ccxcvii) 6-(3-chloro-5-methylphenyl)-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine;

(ccxcviii) N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide;

(ccxcix) N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide;

(ccc) 6-(2-methyl-6-d3-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine;

(ccci) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one;

(cccii) 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine;

(ccciii) 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; and

(ccciv) 6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine.

Compounds deserving special mention include compounds (iii), (v), (vi), (xiii), (xix) - (xxi), (xxiii) - (xxv), (xxvii) - (xxxi), (xxxiv ), (xxxv), (xxxviii), (xxxix), (xli), (xlv), (xlvi), (xlviii) – (lv), (lvii) – (lxxxvii), (lxxxix) – (xci), (xciii), (xcvi) - (cxlii), (cxlv) - (cxlix), (cli), (clii), (clvi) - (clix) - (clxxiv), (clxxviii), (clxxix), (clxxxi ), (clxxxiii), (clxxxiv), (clxxxvii), (cxcvii), (cxcviii), (cciii) - (ccv), (ccviii) - (ccxxxiii), (ccxxxv) - (ccxxxix), and (ccxli) – (ccciv) described above.

Other specific compounds deserving special mention include compounds (iii), (v), (vi), (xiii), (xix) - (xxi), (xxiii) - (xxv), (xxvii) - (xxxi), (xxxiv), (xxxv), (xxxviii), (xxxix), (xli), (xlv), (xlvi), (xlviii) - (lv), (lvii) - (lxxxvii), (lxxxix) - (xci ), (xciii), (xcvi) - (cxlii), (cxlv) - (cxlix), (cli), (clii), (clvi) - (clix), (clxiii) - (clxxiv), (clxxviii), (clxxix), (clxxxi), (clxxxiii), (clxxxiv), (clxxxvii), (cxcvii), (cxcviii), (cciii) - (ccv), (ccviii) - (ccxxxiii), (ccxxxv) - (ccxxxix ) and (ccxli) - (ccciv) described above.

Other specific compounds deserving special mention include compounds (xxviii), (lix), (lxi), (lxiii), (lxxi), (lxxvi), (lxxxv), (lxxxvi), (xci), (xcvii), (xcviii), (xcix), (cii), (cviii), (cix), (cxii), (cxiv), (cxvi), (cxvii), (cxx), (cxxi), (cxxviii), (cxxxiii ), (cxli), (cxlii), (clxxxvii), (ccxvi), (ccxviii), (ccxxii), (ccxxiii), (ccxxvii), (ccxxx), (ccxxxvi), (ccxxxviii), (ccxxxix), (ccxlv), (ccxlix), (ccl), (cclii), (cclv), (cclvi), (cclvii), (cclx), (cclxii), (cclxiii), (cclxvi), (cclxvii), (cclxviii ), (cclxix), (cclxxii), (cclxxxii), (cclxxxv), (cclxxxviii), (ccxcv), (ccxcix), and (cccii) described above.

Other specific compounds that deserve special mention include compounds (lxi), (cxiv), (ccl), (cclv) - (cclvii), (cclx), (cclxxxv), (cclxxxviii) and (ccxcix) described above.

Other compounds that may be mentioned include:

- compounds (ii) - (ccxl) described above (for example, compounds (ii) - (lxvii) described above); and

- compounds (lxxvi), (cix), (xcvii), (cxiv), (cxli), (ccxvii), (ccxviii), (ccxxii), (ccxxiii) and (ccxxv) described above.

For the avoidance of confusion, reference in this text to compounds of formula I includes, where the context permits, any compounds of formula I, A1, Ia, Ib or Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd, or Izd (or, in some embodiments, compounds of formula I, Ia, Ib, or Ic). In addition, reference to any compounds of formula I, A1, Ia, Ib or Ic includes such compounds as such, tautomers of such compounds, as well as pharmaceutically acceptable salts and solvates or pharmaceutically functional derivatives of such compounds.

Some compounds described in this text may be new. Thus, another aspect of the present invention relates to a compound of formula I (or A1, Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in some embodiments, Formula I, A1, Ia, Ib, or Ic)), or a pharmaceutically acceptable salt and solvate or pharmaceutically functional derivative thereof, as described above, provided that the compound is not:

(a) 5,6-diphenyl-[1,2,4]triazin-3-ylamine;

(b) 5-(2-chlorophenyl)-6-(3,4-dimethoxyphenyl)-[1,2,4]triazin-3-ylamine;

(c) 5,6-di-p-tolyl-[1,2,4]triazin-3-ylamine;

(d) 5-(4-dimethylaminophenyl)-6-phenyl-[1,2,4]triazin-3-ylamine;

(e) 6-(4-dimethylaminophenyl)-5-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamine;

(f) 5-(2-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazin-3-ylamine;

(g) N*5*-(2,4-dichlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(h) N*5*-(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(i) N*5*-(4-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(j) 6-phenyl-N*5*-p-tolyl-[1,2,4]triazine-3,5-diamine;

(k) N*5*-(4-methoxyphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(l) 2-[5,6-bis-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;

(m) 1-[5-(4-dimethylaminophenyl)-6-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]butan-2-ol;

(n) 2-[5-(4-dimethylaminophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;

(o) 2-[6-(4-fluorophenyl)-5-(4-propoxyphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;

(p) 1-[5-(4-dimethylaminophenyl)-6-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamino]butan-2-ol;

(q) 2-[5-(4-dimethylaminophenyl)-6-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-ethanol;

(r) 1-[6-(4-ethoxyphenyl)-5-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]butan-2-ol;

(s) 1-[5,6-bis-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]-propan-2-ol;

(t) 1-[5,6-bis-(4-methanesulfinylphenyl)-[1,2,4]triazin-3-ylamino]butan-2-ol;

(u) 2-[5-(4-dimethylaminophenyl)-6-(4-fluorophenyl)-[1,2,4]triazin-3-ylamino]-ethanol;

(v) 6-benzyl-5-piperidin-1-yl-[1,2,4]triazin-3-ylamine;

(w) 6-benzyl-N*5*-phenyl-[1,2,4]triazine-3,5-diamine;

(x) 5-benzyl-6-phenyl-[1,2,4]triazin-3-ylamine;

(y) N*5*-(2,4-dichlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(z) 6-phenyl-N*5*-o-tolyl-[1,2,4]triazine-3,5-diamine;

(aa) N*5*-(4-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(bb) N*5*-(3-chloro-4-fluorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(cc) N*5*-(2-bromophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(dd) N*5*-(2-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(ee) N*5*-(4-iodophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(ff) N*5*-(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(gg) N*5*-(4-fluorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(hh) N*5*-(4-chlorophenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(ii) N*5*-(4-methoxyphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(jj) N*5*-(4-methylphenyl)-6-phenyl-[1,2,4]triazine-3,5-diamine;

(kk) 6,N*5*-diphenyl-[1,2,4]triazine-3,5-diamine;

(ll) (2S,3S,4S,5R,6R)-6-[3-amino-6-(2,3-dichlorophenyl)-[1,2,4]triazin-5-ylamino]-3,4, 5-trihydroxytetrahydropyran-2-carboxylic acid;

(mm) (5,6-diphenyl-[1,2,4]triazin-3-yl)-methylamine;

(nn) (5,6-difuran-2-yl-[1,2,4]triazin-3-yl)-methylamine;

(oo) 5,6-bis-(4-methoxyphenyl)-[1,2,4]triazin-3-ylamine;

(pp) butyl-(5,6-diphenyl-[1,2,4]triazin3-yl)-amine;

(qq) N*4*-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N*1*,N*1*-diethylpentan-1,4 -diamine;

(rr) N'-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N,N-dibutylpropan-1,3-diamine;

(ss) N'-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-yl]-N,N-diethylpropan-1,3-diamine;

(tt) 3-[5,6-bis-(4-chlorophenyl)-[1,2,4]triazin-3-ylamino]-propan-1-ol;

(uu) N,N-dibutyl-N'-(5,6-diphenyl-[1,2,4]triazin-3-yl)-propan-1,3-diamine;

(vv) N'-(5,6-diphenyl-[1,2,4]triazin-3-yl)-N,N-diethylpropan-1,3-diamine; and

(ww) 3-(5,6-diphenyl-[1,2,4]triazin-3-ylamino)-propan-1-ol.

In this aspect of the present invention, the compound may be a compound of formula I (or A1 or especially Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc , Ixd, Iyd, or Izd (or, in some embodiments, Formula I, Ia, Ib, or Ic)), or a pharmaceutically acceptable salt thereof and a solvate or pharmaceutically functional derivative as described above, provided that the compound is not:

(a) 2-(5,6-diphenyl-[1,2,4]triazin-3-ylamino)-ethan-1-ol;

(b) 3-amino-5,6-bis(2-chlorophenyl)-1,2,4-triazine; and

(c) 3-amino-5,6-bis(furan-2-yl)-1,2,4-triazine.

Similarly, other compounds of formula I may be new. In this regard, other aspects of the present invention relate to compounds of formula I (or Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in some embodiments, formulas I, Ia, Ib or Ic)) as described above, where,

(i) if L ¹ is a bond or CH ₂ , L ² is a bond, CH ₂ or NH, B is unsubstituted phenyl, and A is phenyl, then A has one or more R ^4a substituents;

(ii) if L^one represents a bond, L² is a bond or NH, B is phenyl monosubstituted with a CH substituent₃, OCH₃, N(CH₃)₂or Cl at para, Cl at ortho, or disubstituted with Cl at ortho and para, and A is phenyl, then A has one or more R substituents^4a provided that A is not monosubstituted with substituents CH₃, OCH₃, N(CH₃)₂ or Cl in the para position;

(iii) if L ¹ is a bond, L ² is a bond, R ¹ is -CH ₂ CH ₂ OH, -CH ₂ CH(OH)CH ₃ or -CH ₂ CH(OH)CH ₂ CH ₃ , A is phenyl substituted in the para position by the substituent OR ⁷ , N(CH ₃ ) ₂ , F or S(O)CH ₃ , and B is phenyl, then B is not substituted in the para position of the phenyl ring by substituents OR ⁷ , N (CH ₃ ) ₂ , F or S(O)CH ₃ ;

(iv) if L ¹ is CH ₂ , L ² is a bond, B is an unsubstituted piperidinyl attached to the rest of the molecule through the nitrogen atom of the piperidinyl group, and A is phenyl, then A has one or more R ^4a substituents;

(v) if L ¹ is a bond, L ² is NH, B is phenyl optionally having one or more substituents selected from halogen atoms, CH ₃ and OCH ₃ , and A is phenyl, then A has one or more substituents R ^4a ;

(vi) if L ¹ is a bond, L ² is NH, and A is 2,3-dichlorophenyl, then B is not 3,4,5-trihydroxytetrahydropyran-2-carboxylic acid;

(vii) if L ¹ is a bond, L ² is a bond, B is unsubstituted furanyl, and A is furanyl, then A has one or more R ^4a substituents;

(viii) if A is a phenyl ring having R ^4a substituents at both meta positions and no substituents at the para position relative to the point of attachment of A to the rest of the molecule, then B may be unsubstituted phenyl.

Other compounds of formula I may be new. In this regard, other aspects of the present invention relate to compounds of formula I (or A1 or especially Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd, or Izd (or, in some embodiments, formulas I, Ia, Ib, or Ic)) as described above, where if L ¹ is a bond or CH ₂ , L ² is a bond or NH, then at least one of A and B is not phenyl.

Other compounds of formula I may be new. Thus, in another aspect of the present invention, a compound of formula I is described, which is a compound of formula I, in which:

(1) R ¹ is H;

(2) L^one is CH₂, NR^3a, S(O)_p or, especially, a single bond, O, or C(O);

(3) L ² is CH ₂ , S(O) _p , or especially a single bond, O, or C(O);

(4) A is a group selected from the following: cyclopentyl, dihydrofuranyl (e.g., 2,3-dihydrofuranyl, 2,5-dihydrofuranyl), 4,5-dihydro-1H-maleimido, dioxanyl, furazanyl, hydantoinyl, imidazolyl, isoxazolyl , isoxazolidinyl, isothiazolyl, oxadiazolyl, oxazolyl, pyrazolyl, pyrrolinyl (e.g. 3-pyrrolinyl), pyrrolyl, pyrrolidinonyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetramethylene sulfoxide, tetrazolyl, thiadiazolyl, thiazolyl, thiazolidinyl, thienyl, triazolyl, especially 2- azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzofuranyl, benzofurazanyl, benzo[c]isoxazolidinyl, benzomorpholinyl, 2,1,3-benzoxadiazolyl, benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolidinyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, carbazolyl, chromanil, chromenyl, cinnolinyl, (1Z, 2Z,4Z,6Z,8Z)-cyclodecapentaenyl, cyclohexyl, cyclopentenyl, decahydroisoquinolinyl, 2,3-dihydrobenzimidazolyl, 1,3-dihydrobenzo[c]furanyl, 1,3-dihydro-2,1-benzisoxazolyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxolanyl, hexahydropyrimidinyl, imidazo[2,3-b]thiazolyl, indanyl, indazolyl, indenyl, indolinyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isothiochromanyl, ketopiperidinyl (e.g., 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), naphtho[1,2-b]furanyl, naphthyridinyl (including 1,6-naphthyridinyl or especially 1,5-naphthyridinyl and 1,8-naphthyridinyl), 1, 2- or 1,3-oxazinanyl, oxazolidinyl, phenazinyl, phenothiazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2 ,3-c]pyridinyl, quinazolinyl, quinolizinyl, quinoxalinyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, 5,6,7,8-tetrahydrobenzo-[e]pyrimidine, tetrahydroisoquinolinyl ( including 1,2,3,4-those trahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrahydropyranyl, tetrahydropyridinyl (e.g. 3,4,5,6 -tetrahydropyridinyl), 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, thieno[5,1-c]pyridinyl, thiochromanyl, thiophenethyl, triazinanyl, 1,3,4-triazolo[ 2,3-b]pyrimidinyl, especially benzoxazolyl, benzodioxolyl, 2,3-dihydrobenzo[b]furanyl, cyclohexyl, furanyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, indolyl, isoquinolinyl, morpholinyl, naphthalinyl (e.g. 1-naphthalinyl, 2-naphthalinyl, 1,2,3,4-tetrahydronaphthyl), piperidinyl, pyrimidinyl, pyrrolidinyl pyrrolo[1,5-a]pyridinyl, pyrazinyl, pyridinonyl (such as 1- 1H-pyridin-2-onyl, 3-1H-pyridin-2-onyl, 4-1H-pyridin-2-onyl, 6-1H-pyridin-2-onyl, or especially 4-pyridinonyl), quinolinyl, in pyridinyl features (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), which optionally have one or more substituents R ^4a or R ^4b where appropriate, and phenyl substituted with one or more substituents R ^4a ;

(5) B is piperidine, or especially phenyl substituted with one or more R ^4c substituents;

(6) R ^4c is, in each case independently,

Cl or especially Br, F, I,

CN,

C _2-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, where the last three groups optionally have one or more substituents selected from halogen atoms, CN nitro, C _1-6 alkyl, C _2-6 alkenyl , C _2-6 alkynyl (the last three groups optionally have one or more substituents selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^5a , S(O) _q R ^5b , S(O) ₂ N(R ^5c )(R ^5d ), N(R ^5e )S(O) ₂ R ^5f , N(R ^5g )(R ^5h ), B ¹ -C(G ¹ )- B ² -R ⁵ⁱ , aryl and Het ¹ ,

Cy ³ which optionally has one or more substituents selected from halogen atoms, nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents, selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^6a , S(O) _q R ^6b , S(O) ₂ N(R ^6c )(R ^6d ) , N(R ^6e )S(O) ₂ R ^6f , N(R ^6g )(R ^6h ), B ³ -C(G ¹ )-B ⁴ -R ⁶ⁱ , aryl and Het ² ,

Het ^a , which optionally has one or more substituents selected from halogen atoms, nitro group, CN, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl (the last three groups optionally have one or more substituents, selected from OH, =O, halogen atoms, C _1-4 alkyl and C _1-4 alkoxy groups), OR ^7a , S(O) _q R ^7b , S(O) ₂ N(R ^7c )(R ^7d ) , N(R ^7e )S(O) ₂ R ^7f , N(R ^7g )(R ^7h ), B ⁵ -C(G ¹ )-B ⁶ -R ⁷ⁱ , aryl and Het ³ ,

^OR8 ,

a methoxy group located in the meta or ortho position relative to the point of attachment of B to the rest of the molecule;

S(O) _r R ^9a ,

S(O) ₂ N(R ^9b )(R ^9c ),

N(R ^9d )S(O) ₂ R ^9e ,

N(R ^9f )(R ^9g )

B ⁷ -C (G ¹ ) -B ⁸ -R ^9h ,

=O,

=S,

or, when two R ^4c groups are attached to the same carbon atom in the non-aromatic part of the Cy ¹ , Het ^A , Cy ² or Het ^B group, they can form, together with the carbon atom to which they are attached, a saturated or unsaturated 3- A 6-membered ring which may optionally contain 1-3 heteroatoms selected from O, S and N and which may optionally have one or more R ⁹ⁱ substituents;

(7) R ⁸ is, in each case independently,

h,

Cy ³ , Het ^a , aryl ^a , C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, where the last seven groups optionally have one or more substituents selected from halogen atoms, - CN, C _3-6 cycloalkyl, aryl, Het ⁴ , -C(O)OR ¹⁰ , -C(O)R ¹¹ , -C(O)N(R ^N1 )(R ^N2 ), S(O) _r R ^9aa , S(O) ₂ N(R ^9ba )(R ^9ca ), N(R ^9da )S(O) ₂ R ^9ea and N(R ^9fa )(R ^9ga ).

Other embodiments of the present invention include those in which L ¹ is a single bond, O, NH, S, SO ₂ or C(O), and L ² is a single bond (for example, L ¹ is a single bond or O, and L ² is a single bond.)

Also, other compounds of formula I may be new. Thus, in another aspect of the present invention, a compound of formula I is described, referring to compounds of formula I, in which:

(1) L ¹ is a single bond, O, NR ^3a , S(O) _p or C(O);

(2) L ² is a single bond, O, S(O) _p , NR ^3a , CH ₂ or C(O);

(3) B is a group selected from the following: 2-azabicyclo[4.1.0]heptanyl, 1-azabicyclo-[2.2.2]octanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodioxanyl, benzodioxolyl, benzofurazanyl, benzo[c]isoxazolidinyl . -dihydrofuranyl, 2,5-dihydrofuranyl), 2,3-dihydrobenzo[b]furanyl, 1,3-dihydrobenzo-[c]furanyl, dihydropyranyl (e.g. 3,4-dihydropyranyl, 3,6-dihydropyranyl), 4, 5-dihydro-1H-maleimido, 1,3-dihydro-2,1-benzisoxazolyl, 2,3-dihydropyrrolo[2,3-b]pyridinyl, dioxanyl, dioxolanyl, furazanyl, hexahydropyrimidinyl, hydantoinyl, imidazolyl, imidazo[1, 2-a]pyridinyl, imidazo[2,3-b]thiazolyl, indanyl, indenyl, indolinyl, isobenzofuranyl, isoindolinyl, isoindolyl, isothiazolyl, isoxazolyl, isoxazolidinyl, ket opiperidinyl (eg 2-ketopiperidinyl, 3-ketopiperidinyl or 4-ketopiperidinyl), morpholinyl, oxadiazolyl, 1,2- or 1,3-oxazinanil, oxazolidinyl, oxazolyl, piperidinyl (eg piperidin-1-yl or especially piperidine -2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl or piperidin-6-yl), piperazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyridazinyl, pyrrolidinonyl, pyrrolinyl (e.g. 3- pyrrolinyl), pyrrolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[5,1-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, sulfolanyl, 3-sulfolenyl, tetrahydrofuranyl, tetrahydropyranyl, 3,4,5 ,6-tetrahydropyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 3,4,5,6-tetrahydropyrimidinyl, tetrahydrothiophenyl, 4,5,6,7-tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzopyrazolyl, tetramethylene sulfoxide, tetrazolyl , thiazolidinyl, thiazolyl, thienyl, thieno[5,1-c]pyridinyl, thiophenethyl, triazinanyl, triazolyl, 1,3,4-triazolo[2,3-b]pyrimidinyl, especially benzofuranyl, indazolyl, indolyl, pyrazinyl, pyrazolyl , pyridinyl (for example p, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridinonyl, pyrimidinyl and pyrrolo[1,5-a]pyridinyl, where B optionally has one or more R ^4c or R ^4d substituents when appropriate.

The present invention encompasses embodiments wherein, for a compound of formula A1 or especially I, Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd , Iyd, or Izd (or, in some embodiments, formulas I, Ia, Ib, or Ic) A, B, L ¹ , L ² , and R ¹ are selected from any mutually compatible combination of any of the values for these substituents listed above with respect to to compounds of formulas A1 or especially I, Ia, Ib, Ic, Ix, Iy Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or, in some embodiments, formula I, Ia, Ib or Ic).

According to the present invention, the compounds of formula I (eg, formula A1) can be administered separately (ie as monotherapy, such as monotherapy of a condition or disorder ameliorated by inhibition of the A ₁ receptor or, especially, A _2a ). However, in alternative embodiments of the present invention, compounds of formula I (e.g., formula A1) may be administered in combination with another therapeutic agent (e.g., another therapeutic agent for the treatment of a condition or disorder ameliorated by inhibition of the A ₁ receptor or, especially, A _2a .

Thus, other aspects of the present invention relate to the following options:

(a) A compound of formula I (eg formula A1) as described herein and another therapeutic agent for use in the treatment of a condition or disorder ameliorated by inhibition of an A ₁ or especially A _2a receptor.

In this aspect of the present invention, the compound of formula I described in the present text, you can enter sequentially, simultaneously or concomitantly with another therapeutic agent.

(b) A compound of formula I (e.g., formula A1) as described herein for use in the treatment of a condition or disorder ameliorated by inhibition of an A ₁ or especially A _2a receptor, wherein the compound of formula I is administered sequentially, simultaneously, or concomitantly with another therapeutic agent.

(c) The use of a compound of formula I (eg formula A1) described herein and another therapeutic agent for the preparation of a medicament for the treatment of a condition or disorder ameliorated by inhibition of an A ₁ or especially A _2a receptor, wherein the compound of formula I is administered sequentially, simultaneously or concomitantly with another therapeutic agent.

(d) The use of a compound of formula I (eg formula A1) described herein for the preparation of a medicament for the treatment of a condition or disorder ameliorated by inhibition of an A ₁ or especially A _2a receptor, wherein said drug is administered in combination with another therapeutic agent.

(e) A method of treating a disorder or condition ameliorated by antagonization of an A ₁ or especially A _2a receptor, which comprises administering an effective amount of a compound of formula I (eg, formula A1) described herein and another therapeutic agent to a patient in need of such treatment.

(f) Combination medicinal product containing

(A) a compound of formula I (e.g., formula A1) as described herein, and

(B) another therapeutic agent,

where each of the components (A) and (B) is part of the finished product in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

(g) A combination drug as described in (f) above for the treatment of a condition or disorder ameliorated by inhibition of the A ₁ or, especially, A _2a receptor.

(h) The use of the combination medicinal product described in point (f) above for the manufacture of a medicament intended for the treatment of a condition or disorder ameliorated by inhibition of the A ₁ or especially A _2a receptor.

(i) A method of treating a condition or disorder ameliorated by A ₁ or especially A _2a receptor antagonization, comprising administering an effective amount of the combination drug described in (f) above.

As used herein, the term “other therapeutic agent” refers to one or more (e.g., one) therapeutic agents (e.g., one therapeutic agent) that are known to be useful (e.g., known to be effective) for the treatment of: insufficiency (such as decompensated heart failure and congestive heart failure); renal failure (for example, caused by heart failure); edema; cancer (such as prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, especially breast cancer, bowel cancer, bladder cancer, brain cancer, nervous tissue cancer, melanoma, pineal gland cancer and especially Lewis lung carcinoma), diabetes; diarrhea; macular degeneration (such as macular degeneration caused by angiogenesis (eg angiogenesis in the retina)); or, in particular, diseases of the central nervous system such as depression, cognitive impairment, neurodegenerative disease (such as Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis) and psychosis; attention disorders (such as attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD)); extrapyramidal syndrome (eg, dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia); movement disorder (such as restless leg syndrome (RLS) and periodic limb movement during sleep (PLMS)); cirrhosis; liver fibrosis; fatty infiltration of the liver; fibrosis of the skin (for example, in diseases such as scleroderma); sleep disorders; stroke; and the behavior of a person with a propensity to use drugs. In noteworthy particular embodiments of the present invention, one or more of the other therapeutic agents used do not exert their therapeutic effect by binding to an adenosine receptor (eg, an A _2a receptor).

Noteworthy particular variants of other therapeutic agents include, for example, levodopa (l-DOPA), dopamine agonists (for example, pramipexole, ropinirole, or rotigotine), monoamine oxidase B inhibitors (for example, selegiline or rasagiline), catechol O-methyl transferase inhibitors (for example, entacapone or tolcapone), amantadine, acetylcholinesterase inhibitors (eg donepezil, rivastigmine or galantamine), and glutamate release inhibitors (eg memantine).

As used herein, the term "administered sequentially, simultaneously, or concomitantly" includes:

administration of separate pharmaceutical compositions (one containing a compound of formula I and one or more others containing one or more other therapeutic agents); and

the introduction of a single pharmaceutical composition containing the compound of formula I and other therapeutic agent(s).

The combination drug described above provides for the administration of component (A) in combination with component (B), and thus may take the form of either separate formulations, where at least one of the formulations contains component (A) and at least one of the formulations contains component (B), or may take the form of a combined composition (ie, a single composition containing component (A) and component (B)).

Thus it is also described:

(I) a pharmaceutical composition comprising a compound of formula I (e.g., formula A1) described herein and another therapeutic agent, in admixture with a pharmaceutically acceptable adjuvant, diluent, or carrier (such preparation is hereinafter referred to as a "combination drug" ); and

(II) a set of parts, including components:

(i) a pharmaceutical composition comprising a compound of formula I (eg formula A1) described herein in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and

(ii) a pharmaceutical composition containing another therapeutic agent in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier,

where components (i) and (ii) are each available in a form suitable for administration with the other.

Component (i) of the set of parts is component (A) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Similarly, component (ii) is component (B) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

The compounds of formula I (e.g. formula A1) can be administered by any suitable route, but in particular they can be administered orally, intravenously, intramuscularly, dermally, subcutaneously, transmucosally (for example, sublingually or buccally), rectally, transdermally, nasally, through the lungs ( for example, via the trachea or via the bronchi), topically, by any other route of parenteral administration, in the form of a pharmaceutical formulation containing the compound in a pharmaceutically acceptable dosage form. Routes of administration worthy of special mention include oral, intravenous, dermal, subcutaneous, nasal, intramuscular and intraperitoneal administration.

Compounds of Formula I (eg Formula A1) are generally administered as a pharmaceutical composition in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier which may be selected according to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may not have harmful side effects or toxicity under the conditions of use. Suitable pharmaceutical formulations can be found, for example, in Remington The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995). In the case of parenteral administration, a parenterally acceptable pyrogen-free aqueous solution having the desired pH, isotonicity and stability can be used. Suitable solutions are well known to those skilled in the art, and numerous methods are described in the literature. A summary of drug administration methods can also be found, for example, in Langer, Science (1990) 249, 1527.

In other instances, the preparation of suitable formulations may be routinely performed by a skilled person using standard techniques and/or in accordance with standard and/or accepted pharmaceutical practice.

The amount of a compound of Formula I (eg Formula A1) in any pharmaceutical composition used in accordance with the present invention will depend on various factors such as the severity of the condition being treated, the particular patient being treated, and the compound(s) used. In any event, the amount of a compound of formula I in a formulation can be routinely determined by the skilled artisan.

For example, a solid composition for oral administration, such as a tablet or capsule, may contain 1-99% (w/w) of the active ingredient; 0-99% (w/w) diluent or filler; 0-20% (w/w) baking powder; 0-5% (w/w) lubricant; 0-5% (w/w) flow improver; 0-50% (w/w) granulation aid or binder, 0-5% (w/w) antioxidant; and 0-5% (w/w) pigment. Controlled release tablets may further contain 0-90% (w/w) of a release control polymer.

A parenteral formulation (such as an injection solution or suspension, or an infusion solution) may contain 1-50% (w/w) of the active ingredient; and from 50% (w/w) to 99% (w/w) of a liquid or semi-liquid carrier (eg a solvent such as water); and 0-20% (w/w) of one or more other excipients such as buffers, antioxidants, suspension stabilizers, tonicity controls, and preservatives.

Depending on the disorder and the patient being treated, as well as the route of administration, the compounds of formula I (eg, formula A1) can be administered in varying therapeutically effective dosages to a patient in need of such treatment.

However, the dosage administered to a mammal, in particular a human, in the context of the present invention should be sufficient to elicit a therapeutic response in the mammal within a reasonable period of time. The skilled artisan will appreciate that the selection of the precise dosage and composition, as well as the most appropriate dosage regimen, is also influenced by, among other things, the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental clarity of the recipient, as well as the efficacy of the particular compounds, age, condition, body weight, sex and response of the patient being treated, and the stage/severity of the disease.

Administration may be continuous or intermittent (eg, bolus injection). The dosage may also be determined by the time and frequency of administration. In the case of oral or parenteral administration, the dosage may vary from about 0.01 mg to about 1000 mg of a compound of formula I (eg, formula A1) per day.

In any case, the physician or other qualified person is able to routinely determine the necessary dosage, which will be most suitable for a particular patient. The dosages described above are examples for the average case; of course, there may be individual cases where higher or lower dosages are required, and such cases are within the scope of the present invention.

As indicated above, compounds of formula A1 or especially Ix, Iy, Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or especially formula I, Ia, Ib or Ic) can selectively bind to A ₁ or especially A _2a receptors and can therefore be used as diagnostic agents to determine the presence and/or location (in vivo or in vitro) of adenosine A ₁ receptors or, especially, A _2a .

Thus, in another aspect of the present invention, a method (for example, in vivo or, especially, ex vivo method) is described for determining the presence and/or location of A _2a adenosine receptors in a tissue sample, this method includes contacting the tissue sample with a compound of formula A1 or, especially, Ix, Iy, Iz, Ixa, Iya, Iza, Ixb, Iyb, Izb, Ixb1, Iyb1, Izb1, Iyc, Ixd, Iyd or Izd (or especially formulas I, Ia, Ib or Ic) and subsequent detection (with using the imaging method) to localize the compound of formula I in the sample.

Imaging techniques worth mentioning include spectroscopic detection techniques (e.g. fluorescence detection, magnetic resonance imaging, etc.) or when a compound of formula I is isotopically labeled or enriched with a radioactive isotope (such as ³ H, ¹¹ C, ³⁵ S, ¹⁸ F , or ¹²⁵ I), methods for detecting radioactivity (for example, alpha, beta, or gamma detection by standard autoradiography methods, luminescent or scintillation methods known to those skilled in the art, or positron emission tomography (this method can be used, for example, when the compound of formula I is isotopically labeled or enriched with ¹¹ C, or especially ¹⁸ F)).

The aspects of the present invention described herein (for example, the compounds, combinations, methods and uses mentioned above) may have the advantage that, in the treatment of the conditions described herein, they are more convenient for the physician and / or patient, more effective, less toxic, more selective, broader spectrum of activity, more potent, fewer side effects, or may have other beneficial pharmacological properties than similar compounds, combinations, methods (treatments), or uses known in the art for treatment specified states.

In this regard, noteworthy side effects include those caused by A ₃ receptor antagonization (such as increased proneness to tissue damage after ischemia (eg, CNS, heart, kidney, lungs, and eye), increased reperfusion injury, increased neurodegeneration in response to hypoxia, potentially detrimental effects on motor function or pain threshold, immune suppression or immune stimulation).

Compounds of Formula I may be known and/or commercially available. Other compounds of Formula I (eg, not available from commercial sources) may be prepared according to procedures well known to those skilled in the art, such as those described hereinafter.

In another aspect of the present invention, a method for preparing a compound of formula I is described, which includes:

(ia) for compounds of formula I in which R ¹ is CH ₂ -R ^1a where R ^1a is C _1-5 alkyl optionally substituted with one or more halogen atoms, the reaction of a compound of formula I in which R ¹ is H, with a compound of formula IIa,

where R ^1a is H or C _1-5 alkyl, optionally having one or more substituents in the form of halogen atoms, followed by reduction of the resulting imine with a suitable reducing agent (for example, LiBH ₄ , NaBH ₄ , NaBH(OAc) ₃ , LiAlH ₄ ) , under conditions well known to those skilled in the art, for example under conditions where the two steps may be carried out with or without separation or purification of the reaction mixture.

(ib) for compounds of formula I in which R ¹ is C _1-6 alkyl optionally having one or more halogen substituents, OR ^2a or NR ^2b R ^2c , the reaction of a compound of formula I in which R ¹ is H, with a compound of formula IIb,

L ^xaa -R ^1x IIb

where L ^xaa is a suitable leaving group (such as chlorine, bromine, or preferably iodine) and R ^1x is C _1-6 alkyl optionally having one or more halogen substituents, OR ^2a or NR ^2b R ^2c under conditions known to those skilled in the art, e.g., in the presence of a suitable base (such as Hunig's base, triethylamine, pyridine), in a suitable solvent (e.g., pyridine, triethylamine, dichloromethane, tetrahydrofuran), and at a suitable temperature (e.g., at temperature from room temperature to about 180°C);

(ii) for compounds of formula I in which L ¹ represents a single bond,

(a) reaction of a compound of formula III,

where L ^x1a represents a metal halide (eg zinc halide (eg -ZnCl) or magnesium halide (eg -MgBr)), -Sn(R ^x1 ) ₃ , an organoboronic acid (eg an alkyl cyclotriboroxane derivative, or especially - B(OH) ₂ or -B(OR ^x1 ) ₂ ), or an organosilane (eg -Si(OEt) ₃ ), where each R ^x1 is independently a C _1-6 alkyl group, or in the case of -B( OR ^x1 ) ₂ , two R ^x1 groups can be connected to form a 4-6 membered cyclic group (such as a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl group), and L ² , B, and R ¹ are as defined above, with a compound of formula IV,

A—X ^1a IV

where X ^1a is a suitable leaving group (such as chlorine, bromine, or preferably iodine) and A is as defined above, under conditions known to those skilled in the art, such as in the presence of a suitable metal catalyst (or salt or a complex such as Cu, Cu(OAc) ₂ , CuI (or CuI/diamine complex), copper tris(triphenylphosphine) bromide, Pd(OAc) ₂ , Pd ₂ (dba) ₃ or NiCl ₂ ) and an optional additive (such as Ph ₃ P, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, xanthphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), NaI or a suitable crown ether such as 18- crown-6-benzene), in the presence of a suitable base (such as NaH, Et ₃ N, pyridine, N,N'-dimethylethylenediamine, triethanolamine, N-methyldiethanolamine, N,N-diisopropylethanolamine, triisopropanolamine, Na ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuONa or t-BuOK or mixtures thereof, optionally in the presence of 4Å molecular sieves), in a suitable solvent (eg dichloromethane , dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, propionitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, diethyl ether, or mixtures thereof) and at a suitable temperature (for example, at a temperature from room temperature up to about 180°C);

(b) reacting a compound of formula V,

where X ^1b is a suitable leaving group (such as chlorine, bromine, or preferably iodine) and L ² , B, and R ¹ are as defined above, with a compound of formula VI,

A—L ^x1b VI

where L ^x1b represents a metal halide (eg zinc halide (eg -ZnCl) or magnesium halide (eg -MgBr)), -Sn(R ^x1 ) ₃ , an organoboronic acid (eg an alkyl-cyclotriboroxane derivative or especially - B(OH) ₂ or -B(OR ^x1 ) ₂ ), or an organosilane (eg, -Si(OEt) ₃ ), where each R ^x1 is as defined above and A is as defined above, under conditions known to those skilled in the art in this area, for example in those described above for the method at stage (ii)(a);

(iii) for compounds of formula I in which L ¹ is -NR ^3a -,

(a) reaction of a compound of formula VII,

where X ^2a is a suitable leaving group (such as chlorine, bromine, iodine or a sulfonate group (eg -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe)), and L ² , B, and R ¹ are as defined above, with a compound of formula VIII,

A—NHR ^3a VIII

where A and R ^3a correspond to the above definitions, under conditions known to those skilled in the art, for example in the presence of a suitable base (such as NaH, Et ₃ N, pyridine, N,N'-dimethylethylenediamine, Na ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuONa or t-BuOK or mixtures thereof, optionally in the presence of 4Å molecular sieves), optionally in the presence of a suitable solvent (eg dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof) and at a suitable temperature (eg, room temperature to about 180° C.);

(b) reacting a compound of formula IX,

where R ^3a , L ² , B, and R ¹ are as defined above, with a compound of formula X,

A—X ^2b X

where X ^2b represents a suitable leaving group (such as chlorine, bromine, iodine or a sulfonate group (eg -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe)), and A is Cy ¹ or Het ^A as defined above, except that the Cy ¹ or Het ^A group contains a fully saturated carbon atom attached to X ^2b under conditions known to those skilled in the art, such as those described above. for the method in step (iii)(a);

(c) reacting a compound of formula IX described above with a compound of formula XI,

A—L ^x2a XI

where L ^x2a represents a suitable leaving group (such as chlorine, bromine, iodine, or a sulfonate group (for example, -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe), - B(OH) ₂ or -B(OR ^x1 ) ₂ where each R ^x1 is as defined above and A is Cy ¹ or Het ^A as defined above, except that the Cy ¹ or Het ^A group contains an aromatic ring attached to L ^x2a through a carbon atom, under conditions known to those skilled in the art, for example in the presence of a suitable metal catalyst (or salt or complex thereof, such as Cu, Cu(OAc) ₂ , CuI (or CuI/diamine complex ), copper tris(triphenylphosphine) bromide, in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, or mixtures thereof) , and at a suitable temperature (for example, at temperatures e from room temperature to about 180° C.), for example as described in Quach et al. Org. Lett., 2003, 5, 4397-4400 or Wolfe et al. 2004. Org. synth.; Coll. Vol. 10:423;

(d) reaction of a compound of formula XII,

where L ^x2b represents a suitable leaving group (such as chlorine, bromine, iodine, or a sulfonate group (for example, -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe), - B(OH) ₂ or -B(OR ^x1 ) ₂ where each R ^x1 is as defined above and L ² , B, and R ¹ are as defined above, with a compound of formula VIII as described above, under conditions known to those skilled in the art in this area, for example in those described above for the method at stage (iii)(c);

(iv) for compounds of formula I in which L ¹ is -O- or -S-,

(a) reacting a compound of formula VII as described above with a compound of formula XIII,

A—Q ^a —H XIII

where Q ^a is O or S and A is as defined above, under conditions known to those skilled in the art, e.g. base (such as, for example, cesium carbonate, sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene , sodium hydroxide, N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6, 6-tetramethylpiperidine or mixtures thereof), or alternatively in the presence of a suitable coupling agent (such as a dialkyl azodicarboxylate, eg diethyl azodicarboxylate) together with a trialkyl or triarylphosphine (eg PPh ₃ )), and a suitable a solvent (eg dimethyl sulfoxide, tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine);

(b) reaction of a compound of formula XIV,

where Q ^b represents O or S, and L ² , B and R ¹ correspond to the above definitions, with the compound of formula X described above, under conditions known to those skilled in the art, for example, as described above for the method in stage (iv) (a);

(v) for compounds of formula I in which L ¹ is -O- and A is Cy ¹ or Het ^A as described above, except that the Cy ¹ or Het ^A group is directly attached to the rest of the molecule through the entire a saturated carbon atom, the reaction of a compound of formula XIII wherein Q ^a is O and A is as defined above with a compound of formula XIV where Q ^b is O and L ² , B and R ¹ are as defined above, in conditions known to those skilled in the art, e.g., the reaction can be carried out at a suitable temperature (e.g., room temperature to about 180° C.), in the presence of a suitable coupling agent (such as a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate) together with a trialkyl or triarylphosphine ( e.g. PPh ₃ )), and a suitable solvent (e.g. tetrahydrofuran, dimethyl sulfoxide, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoro pmethylbenzene, dioxane or triethylamine);

(vi) for compounds of formula I, in which L ¹ represents -S(O)- or -S(O) ₂ -, oxidation of the compound of formula I, in which L ¹ represents -S-, in the presence of a suitable oxidizing agent, ( such as, for example, meta-chloroperoxybenzoic acid, KMnO ₄ , t-butylammonium periodate and/or potassium peroxymonosulfate (eg Oxone®)). For selective oxidation to give compounds of formula I in which L ¹ is -S(O)- or -S(O) ₂ -, the skilled artisan will appreciate that increased selectivity can be achieved by adjusting the reaction time (and number of oxidant equivalents) or using certain oxidizing agents. For example, to prepare compounds of formula I, in which L ¹ represents -S(O)-, the best oxidizing agent is preferably t-butylammonium periodate (and one equivalent or a slight excess of this reagent is preferably used). Such a reaction can be carried out in the presence of a suitable solvent such as dichloromethane and, if necessary, in the presence of a catalyst such as 5,10,15,20-tetraphenyl-21H,23H-porphine iron(III) chloride, under an inert atmosphere. To obtain compounds I, in which L ¹ represents -S(O) ₂ -, the oxidizing agent is preferably potassium peroxymonosulfate (eg Oxone®), and the reaction can preferably be carried out in the presence of a suitable solvent such as tetrahydrofuran;

(vii) for compounds of formula I in which L ² is a single bond,

(a) reaction of a compound of formula XV,

where L ^x3a represents a metal halide (eg zinc halide (eg -ZnCl) or magnesium halide (eg -MgBr)), -Sn(R ^x1 ) ₃ , an organoboronic acid (eg an alkyl cyclotriboroxane derivative, or especially - B(OH) ₂ or -B(OR ^x1 ) ₂ ), or an organosilane (eg, -Si(EtO) ₃ ), where each R ^x1 is as defined above and L ¹ , A, and R ¹ are as defined above , with a compound of formula XVI,

B-X ^3a XVI

where X ^3a is a suitable leaving group such as chlorine, bromine, or preferably iodine, and B is as defined above, under conditions known to those skilled in the art, such as those described above for the process in step (ii)( a);

(b) reacting a compound of formula XVII,

where X ^3b is a suitable leaving group such as chlorine, bromine, or preferably iodine, and L ¹ , A, and R ¹ are as defined above, with a compound of formula XVIII,

B—L ^x3b XVIII

where L ^x3b is a metal halide (eg zinc halide (eg -ZnCl) or magnesium halide (eg -MgBr)), -Sn(R ^x1 ) ₃ , organoboronic acid (eg alkyl cyclotriboroxane derivative or especially -B(OH) ₂ or -B(OR ^x1 ) ₂ ), or an organosilane (eg -Si(EtO) ₃ ), where each R ^x1 is as defined above and B is as defined above, under conditions known to those skilled in the art. specialists in this field, for example in those described above for the method at stage (ii)(a);

(viii) for compounds of formula I in which L ² is -NR ^3a -,

(a) reaction of a compound of formula XIX,

where X ^4a is a suitable leaving group (such as chlorine, bromine, iodine or a sulfonate group (eg -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe)), and L ¹ , A, and R ¹ are as defined above, with a compound of formula XX,

B—NHR ^3a XX

where B and R ^3a correspond to the above definitions, under conditions known to those skilled in the art, for example as described above for the method in step (iii)(a);

(b) reaction of a compound of formula XXI,

where R ^3a , L ¹ , A, and R ¹ correspond to the above definitions, with the compound of formula XXII,

B-X ^4b XXII

where X ^4b represents a suitable leaving group (such as chlorine, bromine, iodine, or a sulfonate group (eg, -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe)), and B is Cy ² or Het ^B as described above, except that the Cy ² or Het ^B group contains a fully saturated carbon atom attached to X ^4b under conditions known to those skilled in the art, such as those described above. for the method in step (iii)(a);

(c) reacting a compound of formula XXI described above with a compound of formula XXIII,

B—L ^x4a XXIII

where L ^x4a is a suitable leaving group, -B(OH) ₂ or -B(OR ^x1 ) ₂ where each R ^x1 is as defined above and B is as defined above, except that Cy ² or Het ^B contains an aromatic ring attached to L ^x4a through a carbon atom, under conditions known to those skilled in the art, for example as described above for the process in step (iii)(c);

(d) reaction of a compound of formula XXIV,

where L ^x4b is -B(OH) ₂ or -B(OR ^x1 ) ₂ where each R ^x1 is as defined above and L ¹ , A, and R ¹ are as defined above, with a compound of formula XX as described above, under conditions known to those skilled in the art, such as those described above for the process in step (iii)(c);

(ix) for compounds of formula I in which L ² is -O- or -S-,

(a) reacting a compound of formula XIX described above with a compound of formula XXV,

B—Q ^c —H XXV

where Q ^c represents O or S, and B corresponds to the above definition, under conditions known to those skilled in the art, for example, as described above for the method in stage (iv)(a);

(b) reaction of a compound of formula XXVI,

where Q ^d represents O or S, and L ¹ , A and R ¹ correspond to the above definitions, with the compound of formula XXII described above, under conditions known to those skilled in the art, for example, as described above for the method in stage (iv) (a);

(x) for compounds of formula I in which L ² is -O- and B is Cy ² or Het ^B as described above, except that the Cy ² or Het ^B group is directly attached to the rest of the molecule through the entire a saturated carbon atom, the reaction of a compound of formula XXV in which Q ^c is O and B is as defined above with a compound of formula XXVI in which Q ^d is O and L ¹ , A and R ¹ are as defined above, under conditions known to those skilled in the art, e.g., the reaction can be carried out at a suitable temperature (e.g., room temperature to about 180° C.), in the presence of a suitable coupling agent (such as a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate) together with a trialkyl or triarylphosphine (eg PPh ₃ )), and a suitable solvent (such as, for example, tetrahydrofuran, dimethyl sulfoxide, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimeth ilformamide, trifluoromethylbenzene, dioxane or triethylamine);

(xi) for compounds of formula I, in which L ² represents -S(O)- or -S(O) ₂ -, the oxidation of the compound of formula I, in which L ² represents -S-, where A, L ¹ , B, and R ¹ correspond to the above definitions, in the presence of a suitable oxidizing agent, under conditions known to those skilled in the art, for example, as described above for the method in step (vi);

(xii) for compounds of formula I in which L ¹ and/or L ² is N(R ^3x ), where R ^3x has the same meanings as R ^3a described above, except that R ^3x is not H, the reaction of the corresponding compound of formula I, in which L ¹ and/or L ² represents NH, with a compound of formula XXVII,

X ^5a -R ^3x XXVII

where X ^5a represents a suitable leaving group, such as described above for X ^2a or -Sn(R ^x1 ) ₃ where R ^3x and each R ^x1 correspond to the above definitions, under conditions known to those skilled in the art, for example in the case when X ^5a is a leaving group (such as iodo, bromine, chlorine, or a sulfonate group), the reaction can be carried out at a suitable temperature (eg, room temperature to about 180° C.), optionally in the presence of a suitable base (such as, for example, , sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N -(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine or mixtures thereof) and suitable its solvent (eg tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, trifluoromethylbenzene, dioxane or triethylamine). When X ^5a is -B(OH) ₂ or -Sn(alkyl) ₃ , the reaction can be carried out in the presence of a suitable catalytic system, (for example, a metal (or a salt or complex thereof) such as CuI (or a CuI/ diamine), Cu, Cu(OAc) ₂ , copper tris(triphenylphosphine) bromide, Pd/C, PdCl ₂ , Pd(OAc) ₂ , Pd(Ph ₃ P) ₂ Cl ₂ , Pd(Ph ₃ P) ₄ , Pd ₂ (dba) ₃ or NiCl ₂ and a ligand such as t-Bu ₃ P, (C ₆ H ₁₁ ) ₃ P, Ph ₃ P, AsPh ₃ , P(o-Tol) ₃ , 1,2-bis(diphenylphosphino )ethane, 2,2'-bis(di-tert-butylphosphino)-1,1'-biphenyl, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, 1,1'-bis(diphenylphosphinoferrocene) , 1,3-bis(diphenylphosphino)-propane, xanthos or mixtures thereof), together with a suitable base (such as Na ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , NaOH, KOH, K ₂ CO ₃ , CsF , Et ₃ N, (i-Pr) ₂ NEt, t-BuONa or t-BuOK, NaH, Et ₃ N, pyridine, N,N'-dimethylethylenediamine, (or mixtures thereof, if necessary in the presence of 4 Å molecular sieves) ) in a suitable solvent (such as dioxane, toluene, ethanol, isopropanol, ethylene glycol , dimethylformamide, ethylene glycol dimethyl ether, water, dimethyl sulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or mixtures thereof);

(xiii) reaction of a compound of formula XXVIII,

where X ⁶ represents a suitable leaving group (such as chlorine, bromine, iodine, sulfonate group (for example, -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe), sulfonic a group (for example, -S(O) ₂ CH ₃ , -S(O) ₂ CF ₃ or -S(O) ₂ -PhMe) or -OR ^4x where R ^4x represents an aryl or heteroaryl group), and A, B, L ¹ and L ² are as defined above, with a compound of formula XXIX,

R ¹ NH ₂ XXIX

where R ¹ corresponds to the above definition, under conditions known to those skilled in the art, for example as described above for the method in step (iii)(a);

(xiv) for compounds of formula I, the reaction of a compound of formula XXX,

where R ^x2 is a suitable leaving group (for example, a tosyl, mesylate group, or an electron withdrawing aryl or heteroaryl group (such as pentafluorophenyl)), and A, B, L ¹ and L ² are as defined above, or a protected derivative thereof, with the compound formula XXIX, where R ¹ corresponds to the definition given above, under conditions known to a qualified person in this field, for example, the reaction can be carried out at room temperature or higher (for example, up to 40-180ºC), in a suitable solvent such as dioxane, ethanol, isopropanol, dimethylformamide, acetonitrile, tetrahydrofuran or mixtures thereof;

(xv) for compounds of formula I in which L ¹ and L ² are both single bonds, the reaction of a compound of formula XXXI,

where A and B are as defined above, with a compound of formula XXXII,

where R ¹ corresponds to the above definition, under conditions known to those skilled in the art, such as those described in WO 92/02513;

(xvi) for compounds of formula I in which L ¹ is a single bond and A is a nitrogen-containing group Het ^A attached via a nitrogen atom in the cyclic system, reaction of a compound of formula VII described above with a compound of formula XXXIII,

Het ^A1 —H XXXIII

where Het ^A1 has the same meanings as Het ^A described above, except that Het ^A1 is a nitrogen-containing heterocycle attached to the H-atom depicted for the compound of formula XXXIII through the nitrogen atom in the heterocycle, under conditions known those skilled in the art, such as those described above for the method in step (iii)(a);

(xvii) for compounds of formula I in which L ² is a single bond and B is a nitrogen-containing group Het ^B attached via a nitrogen atom in the ring system, reaction of a compound of formula XIX described above with a compound of formula XXXIV,

Het ^B2 -H XXXIV

where Het ^B2 has the same meanings as Het ^B described above, except that Het ^B2 is a nitrogen-containing heterocycle attached to the H-atom depicted for the compound of formula XXXIV through the nitrogen atom in the heterocycle, under conditions known those skilled in the art, such as those described above for the method in step (iii)(a);

(xviii) for compounds of formula I in which L ¹ is a single bond and A is a phenyl group optionally having one or more R ^4a substituents, the reaction of a compound of formula XXXV,

where X ⁷ represents a suitable leaving group (such as chlorine, bromine, iodine, sulfonate group (for example, -OS(O) ₂ CF ₃ , -OS(O) ₂ CH ₃ or -OS(O) ₂ PhMe), and L ² , B and R ^4a are as defined above, with a compound of formula XXXVI,

where R ¹ corresponds to the above definition, under conditions known to those skilled in the art, such as those described in WO 00/66568;

(xix) for compounds of formula I in which L ¹ is -CH=CH-, reaction of a compound of formula V described above with a compound of formula XXXVII,

A-CH=CH-L ^x5a XXXVII

where L ^x5a is a metal halide (eg zinc halide (eg -ZnCl) or magnesium halide (eg -MgBr)), -Sn(R ^x1 ) ₃ , -B(OH) ₂ , -B(OR ^x1 ) ₂ , or an organosilane (eg, -Si(OEt) ₃ ), where each R ^x1 corresponds to the above definition, and A corresponds to the above definition, under conditions known to those skilled in the art, for example, as described above for the method in step (ii )(a); and

(xx) for compounds of formula I in which one of R ^4a - R ^4d is -OH, the reaction of a compound of formula I in which one of R ^4a - R ^4d is -OR ^4y where R ^4y is C _{1- 6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, which optionally have one or more substituents selected from halogen, C _1-4 alkyl and aryl, with a suitable dealkylating agent (such as tribromide boron, 2-(diethylamino)ethanethiol or hydrogen halide (e.g. HBr)), under conditions known to those skilled in the art, e.g. in a suitable solvent (such as e.g. dichloromethane, dimethylformamide, dioxane, toluene, ethanol, isopropanol, dimethyl sulfoxide , acetonitrile, dimethylacetamide, tetrahydrofuran, or mixtures thereof, or an ionic liquid (eg, [bmim][BF ₄ ])), and at a suitable temperature (eg, room temperature to about 180°C), for example, as described in references I. Ryu et al., J. Am. Chem. Soc., 2002, 124, 12946-12947; J. Magano et al., J. Org. Chem., 2006, 71, 7103-7105; or SK Boovanahalli et al., J. Org. Chem., 2004, 69, 3340-3344.

Compounds of formula XXVIII where X ⁶ is OR ^4x can be prepared by reacting a compound of formula XXXVIII,

where A, B, L ¹ and L ² correspond to the above definitions, with the compound of formula XXXIXa,

R ^4x —OH XXXIXa

where R ^4x corresponds to the definition given above, under conditions known to those skilled in the art, for example as described in FR 2,485,531.

Compounds of formula XXVIII wherein L ¹ is a single bond and X ⁶ is a sulfonic group (eg -S(O) ₂ CH ₃ , -S(O) ₂ CF ₃ or -S(O) ₂ -PhMe), can be prepared by reacting a compound of formula XXXIXb,

where L ^1aa is a halogen atom (such as chlorine, bromine, or preferably iodine), X ⁶ is a sulfone group, and A, B and L ² are as defined above, with a compound of formula VI as described above, under conditions known to those skilled in the art, such as those described above for the method in step (ii)(a)).

Compounds of formula XXVIII wherein L ² is a single bond and X ⁶ is a sulfonic group (eg -S(O) ₂ CH ₃ , -S(O) ₂ CF ₃ or -S(O) ₂ -PhMe), can be prepared by reacting a compound of formula XXXIXc,

where L ^2aa is a halogen atom (such as chlorine, bromine, or preferably iodine), X ⁶ is a sulfonic group, and A, B and L ¹ are as defined above, with the compound of formula XVIII described above, under conditions known to those skilled in the art, such as those described above for the method in step (ii)(a)).

Other intermediates (e.g., intermediate XXVIII) containing a 1,2,4-triazine core in a similar manner to compounds of formula I can be prepared by reacting a compound of formula XXXI described above with a compound of formula XL,

where R ^7x represents the corresponding C _1-6 alkyl or aryl group, under conditions known to those skilled in the art, for example as described in WO 92/02513, followed, if necessary, by oxidation of the sulfur atom to the desired oxidation state.

Compounds of formula VI in which L ^x1b is B(OH) ₂ can be prepared by reacting a compound of formula XLI,

A-H XLI

where A is as defined above, with a boronic acid derivative (such as bis(pinacolato)diborone, trimethylborate), under conditions known to those skilled in the art, e.g. in the presence of a suitable metal catalyst (or salt or complex thereof, such as [Ir (COD)(OMe)] ₂ , [Rh(COD)(OMe)] ₂ , [Rh(COD)Cl] ₂ , Cu, Cu(OAc) ₂ , CuI (or CuI/diamine complex), copper tris(triphenylphosphine )bromide, Pd(OAc) ₂ or Pd ₂ (dba) ₃ ) and an optional additive (such as 4,4'-di-tert-butyl-2,2'-bipyridine(dtbpy), Ph ₃ P, 2.2 '-bis(diphenylphosphino)-1,1'-binaphthyl, xanthphos, NaI or a suitable crown ether such as 18-crown-6-benzene) in the presence of a suitable base (such as NaH, Et ₃ N, pyridine, N ,N'-dimethylethylenediamine, triethanolamine, N-methyldiethanolamine, N,N-diisopropylethanolamine, triisopropanolamine, Na ₂ CO ₃ , K ₂ CO ₃ , K ₃ PO ₄ , Cs ₂ CO ₃ , t-BuONa or t-BuOK or mixtures thereof , optionally in the presence of 4Å molecular sieves), in a suitable solvent (such as, for example, dichloromethane, dimethylformamide, dioxane, toluene, ethanol, isopropanol, dimethyl sulfoxide, acetonitrile, dimethylacetamide, tetrahydrofuran, or mixtures thereof, or an ionic liquid (for example, [bmim][BF ₄ ])) and at a suitable temperature ( for example, at room temperature to about 180°C), for example, as described in JM Murphy, CC Tzschucke, JF Hartwig, Org. Lett., 2007, 9, 757-760.

Compounds of formulas IIa, IIb, III, IV, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXIX, XXX, XXXI, XXXII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIXa, XXXIXb, XXXIXc, XL, and XLI are commercially available, known in the literature, or can be prepared by analogy with the processes described in this text ( or with the processes described in the references cited in this text), or by well-known synthetic methods in accordance with standard methods, from available starting materials using the necessary reagents and reaction conditions.

Substituents such as R ^3a , R ^4a , R ^4b , R ^4c and R ^4d in the final compounds of formula I (or their precursors and other related intermediates) can be modified one or more times, after or during the processes described above, using methods well known to those skilled in the art. Examples of such methods include palladium-catalyzed cross-coupling or especially substitution reactions, reduction (eg reduction of a carbonyl bond in the presence of suitable and if necessary chemoselective reducing agents such as LiBH ₄ or NaBH ₄ ), oxidation, alkylation, acylation , hydrolysis, esterification and ether formation. Precursor groups can be converted to another group or to the groups described for Formula I at any time during the reaction chain.

The compounds of the present invention can be isolated from reaction mixtures by conventional methods (eg, recrystallization, column chromatography, preparative HPLC, etc.).

In the processes described above and below, the functional groups of intermediates may require protection with protective groups.

Protection and deprotection of functional groups can be carried out before or after the reactions in the above schemes.

Protecting groups can be removed in accordance with techniques well known to those skilled in the art and as described below. For example, the protected compounds/intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques.

The particular chemistry of the process will dictate the need and type of protecting groups, as well as the sequence in which the synthesis is carried out.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by JWF ^McOmie , Plenum Press (1973) and "Protective Groups in Organic Synthesis", 3rd edition, TW Greene & PGM Wutz, Wiley-Interscience (1999) .

As used herein, the term "functional group" means, in the case of unprotected functional groups, a hydroxy group, a thiol group, an amine functional group, a carboxyl group, and, in the case of protected functional groups, a lower alkoxy group, N-, O- , S-acetyl, an ester of a carboxylic acid.

Some of the intermediates mentioned above are new. In another aspect of the present invention, there is described: (a) a compound of formula XXVIII, or a protected derivative thereof, wherein X ⁶ is SO ₂ R ^x6 , where R ^x6 is C _1-12 alkyl optionally having one or more atomic substituents halogen (eg fluorine), or R ^x6 is phenyl optionally having one or more substituents selected from C _1-6 alkyl (eg methyl), nitro and halogen (eg bromine); (b) a compound of formula XXXIXb or a protected derivative thereof; and (c) a compound of formula XXXIXc or a protected derivative thereof.

Biological testing

All cell lines mentioned below were purchased from the European Collection of Cell Cultures (ECACC: http://www.hpacultures.org.uk/collections/ecacc.jsp).

Test A

HEK293-hA _2a [ ³ H]-ZM241385 / CHO-hA ₁ [ ³ H]DPCPX binding assay

Compounds tested

All test compounds were in the form of stock solutions at a concentration of 10 mm in 100% DMSO.

Binding inhibition assays were performed using 2.5 μg of membranes derived from HEK293 cells transiently transfected with the human adenosine A _2a receptor or 10 μg of membranes derived from CHO cells stably transfected with the human adenosine A ₁ receptor. The membranes were incubated in 50 mM Tris-HCl (HEK293-hA _2a ; pH 7.4) or 20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ (CHO-hA ₁ ; pH 7.4) in the presence of various concentrations of test compounds and 1 nM [ ³ H]ZM241385 (HEK293-hA _2a ) or [ ³ H]DPCPX (CHO-hA ₁ ) at 25°C for 1 hour. The test was then stopped by rapid filtration on Unifilter GF/B plates using a TomTec cell collector, followed by a 5 x 0.5 ml rinse with bidistilled water. Non-specific binding was determined in the presence of 1 μM CGS15943 (HEK293-hA _2a ) or 1 μM DPCPX (CHO-hA ₁ ). Bound radioactivity was determined by a liquid scintillation activity measurement (trilux ^Microbeta® Counter) and inhibition curves were analyzed using a 4-parameter logistic equation. IC ₅₀ values were converted to K _i values by the Cheng-Prusoff equation using the K _D value obtained from the binding site saturation study.

Test B

Catalepsy reversal study

The dopamine D ₂ receptor antagonist, haloperidol, causes parkinsonism in humans and induces motor effects such as catalepsy in rats. There is good evidence that adenosine A _2A receptor antagonists reverse haloperidol-induced motor effects in preclinical studies. Suggested mechanisms for these effects include the hypothesis that A _2A receptor antagonism modulates D ₂ receptor sensitivity such that D ₂ receptors exhibit increased sensitivity to striatal dopamine in the presence of an A _2A receptor antagonist. In the present study, the ability of novel A _2A receptor antagonists to reverse haloperidol-induced catalepsy in rats was determined.

Catalepsy was monitored individually in Sprague-Dawley rats (Charles River, UK; 200-250 g; n = 8 per group) by carefully placing each paw in turn on a large rubber stopper. One point was awarded for each paw that remained in the starting position for 15 seconds, giving each rat a maximum score of 4 points. Haloperidol (0.82 mg/kg, ip; time to test 150 min) induces marked cataleptic behavior in rats (mean score 3.1). The effect of selected compounds of the present invention (2-10 mg/kg or 0.3-3 mg/kg, po; time to test 120 min) on catalepsy was determined by administering said compounds to rats previously treated with haloperidol as described above.

Details of a similar test can be found, for example, in Hodgson et al., J. Pharmacol. Exp. Ther. 330, 2009, 294-303.

Implementation of the invention

Examples

If no route is given, the corresponding intermediate is commercially available (eg from Sigma Aldrich or Manchester Organics Ltd).

General Methods

Commercial reagents were used without further purification. Room temperature is 20-27 ^° C. Melting points, where indicated, are uncorrected. ¹ H-NMR spectra were recorded on a Bruker instrument at an operating frequency of 400 MHz. Chemical shift values are given in parts per million, i.e. are given as δ values. The following abbreviations are used to describe the multiplicity of NMR signals: c = singlet, br. = broadened, d = doublet, t = triplet, q = quartet, fifth. = quintet, r = heptet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet. The spin-spin coupling constants are given as J values in Hertz. NMR and mass spectroscopy results corrected for background peaks. The description of the chromatography refers to silica gel column chromatography with a particle size of 60-120 mesh, which was carried out under nitrogen pressure (flash chromatography). TLC for monitoring reactions is a TLC using the specified mobile phase and silica gel F254 manufactured by Merck as the stationary phase. Reactions under microwave irradiation were carried out in a Biotage Initiator reactor.

HPLC purity was measured under the following conditions:

Instrument: Waters Alliance 2695. Column: Sunfire C-18, 250 x 4.6 mm, 5 µm or equivalent. Gradient [time (min)/% solvent B in A]: 0.00/10, 9.00/90, 11.00/100, 20.00/100, 20.01/10, 25.00/10 (solvent A = 0.1% formic acid in water; solvent B = 0.1% formic acid in acetonitrile). 1 ml/min; the detection wavelength is indicated for each compound in the detailed description of the experimental part.

Mass spectroscopy was performed on a Shimadzu LCMS-2010 EV instrument, using the electrospray method, as indicated for each compound in the detailed description of the experimental section.

LCMS experiments were performed according to methods A-C, as indicated for each compound in the detailed description of the experimental section, using the following conditions:

LCMS method A: Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1 x 20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0 x 30 mm. Gradient [time(min)/solvent D in C (%)]: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 (solvent C = 1.58 g ammonium formate in 2.5 L water + 2.7 ml ammonia solution, solvent D = 2.5 l acetonitrile + 132 ml (5%) solvent C + 2.7 ml ammonia solution). The volume of the injected sample is 5 µl; UV detection: 230-400 nm; column temperature 45 ^° C.

LCMS method B: Instrument: Waters Semi-Prep LCMS with ZQ MS. Column: Agilent Prep-C18 Scalar, 5 µm, 4.6 x 50 mm. Detector wavelength: 254 nm and 215 nm. Gradient [time(min)/solvent B to A (%), flow rate]: 0.00/5 (2.5 ml/min), 0.10/5 (2.5 ml/min), 5.0/95 (2.5 ml/min), 5.50 /95 (2.5 ml/min), 5.60/95 (3.5 ml/min), 6.60/95 (3.5 ml/min), 6.75/5 (3.5 ml/min) 6.90/5 (3.5 ml/min), 7.00/ 5 (2.5 ml/min), (solvent A: water 0.1% NH ₄ OH; solvent B: MeOH with 0.1% NH ₄ OH).

LCMS method C: Instruments: Waters Alliance 2795, Waters 2996 PDA detector, Micromass ZQ. Column: Waters X-Bridge C-18, 2.5 micron, 2.1 x 20 mm or Phenomenex Gemini-NX C-18, 3 micron, 2.0 x 30 mm. Gradient [time(min/solvent D in C (%)]: 0.00/2, 0.10/2, 8.40/95, 9.40/95, 9.50/2, 10.00/2 (solvent C = 1.58 g ammonium formate in 2.5 l water + 2.7 ml ammonia solution, solvent D = 2.5 L acetonitrile + 132 ml (5%) solvent C + 2.7 ml ammonia solution) Injection volume 5 µl, UV detector: 230-400 nm, column temperature 45 ^o C, 1.5 ml/min.

Preparative HPLC was usually performed on instrument A or B using the acid method (acetonitrile and water gradients, each containing 0.1% formic acid) or the basic method (methanol and water gradients, each containing 0.1% NH ₄ OH).

Conditions for instrument A: Waters delta 600 HPLC. Column: X-bridge C-18, 250 x 19 mm, 5 µm or equivalent. Flow rate: 19 ml/min.

Appliance B: Gilson HPLC. Column: Agilent Zorbax Extend Cartridge, 5 µm, 21.2 x 100 mm. Guard column: Agilent Prep-C18 Guard Cartridge, 10 µm. Flow rate: 28 ml/min.

Synthesis 1

Method for obtaining methyl hydrazine carbimidothioate

Methyl hydrazinecarbimidothioate was obtained by dropping methyl iodide (2.80 g, 19.8 mmol) into a solution of thiosemicarbazide (1.80 g, 19.75 mmol) in ethanol (50 ml). The resulting mixture was refluxed for 2.5 h monitored by TLC (methanol/DCM, 1:9). The reaction mixture was then evaporated in vacuo and the crude product (1.80 g, 90%) was used in the next step without further purification.

Mass spectroscopy: (ESI +ve) 106 [MH] ⁺

Standard Procedure for the Preparation of Arylglyoxal Derivatives Using Example (i) 4-Fluorophenylglyoxal

Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 ml) and water (3 ml), and the resulting mixture was heated to 55°C until the complete dissolution of selenium dioxide. The reaction mixture was then refluxed for 5-6 hours. At the end of the reaction (TLC), the mixture was filtered and the filtrate was evaporated in vacuo to give a viscous oil. Water (50 ml) was added and the resulting mixture was stirred for 12 h after which the solid was filtered off, washed with water (25 ml) and dried in vacuo to give 4-fluorophenylglyoxal (6.60 g, 85%).

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 7.18 (m, 2H), 8.11 (d, 2H), no signal from the CHO aldehyde group.

(ii) (3-Chloro-5-fluorophenyl)(oxo)acetaldehyde

(3-Chloro-5-fluorophenyl)(oxo)acetaldehyde (27 g, 84%) was obtained from 3-chloro-5-fluoroacetophenone (30.0 g, 174.4 mmol) and selenium dioxide (21.28 g, 191.8 mmol) according to the standard method used in Synthesis 1.

(iii) (3,5-Difluorophenyl)(oxo)acetaldehyde

(3,5-Difluorophenyl)(oxo)acetaldehyde (28 g, 84%) was obtained from 3,5-difluoroacetophenone (30.0 g, 192.3 mmol) and selenium dioxide (23.55 g, 214.0 mmol) according to the standard procedure used in Synthesis 1 .

(iv) 4-(Methoxymethyl)phenylglyoxal

Step 1: Preparation of 4-(Methoxymethyl)benzonitrile

4-(Hydroxymethyl)benzonitrile (6.0 g, 45.09 mmol) was dissolved in THF (60 ml), cooled to -5°C to -10°C, and sodium hydride (2.16 g, 90.19 mmol) was added. The resulting mixture was stirred for 30 minutes, then methyl iodide (9.6 g, 67.65 mmol) was added at room temperature over 2 hours. At the end of the reaction (TLC; ethyl acetate/hexane, 5:5), the reaction mixture was poured into water (50 ml) and extracted ethyl acetate (3 × 25 ml). The separated organic layers were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude product was purified by gradient flash chromatography using 5% ethyl acetate in hexane as eluent to give 4-(methoxymethyl)benzonitrile (6.7 g, 90%).

HPLC purity: 99.20% (232 nm).

Mass spectroscopy: (ESI +ve) 148.0 [M+H] ⁺ .

Step 2: Preparation of 1-[4-(methoxymethyl)phenyl]ethanone

4-(Methoxymethyl)benzonitrile (6.0 g, 40.82 mmol) was dissolved in THF/diethyl ether (1:1, 60 ml) and the resulting solution was cooled to -10°C. A 3M solution of methylmagnesium iodide (13.57 g, 81.63 mmol) was added and the resulting mixture was stirred at the same temperature for 5 h. After completion of the reaction (TLC; toluene/methanol, 97:3), the reaction mixture was poured into acidified water (50 mL; pH 3-4) and extracted with ethyl acetate (3 x 50 ml). The separated organic layers were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude product was purified by gradient flash chromatography using 8% ethyl acetate in hexane as eluent to give the title compound (3.7 g, 55%).

Mass spectroscopy: (ESI +ve) 165.0 [M+H] ⁺ .

Step 3: Preparation of 4-(methoxymethyl)phenylglyoxal

Selenium dioxide (3.53 g, 31.84 mmol) was dissolved in 1,4-dioxane (50 mL) and water (0.5 mL). The solution was heated to 40°C and 1-(4-(methoxymethyl)phenyl)ethanone (3.9 g, 26.53 mmol) was added; the resulting mixture was refluxed for 6 h and monitored by TLC (chloroform/methanol, 95:5). At the end of the reaction, the mixture was filtered through celite and evaporated in vacuo. The resulting crude product was purified by column chromatography using up to 15% ethyl acetate in hexane as eluent to give the desired glyoxal (4.0 g, 85%).

Mass spectroscopy: (ESI +ve) 179.0[MH] ⁺

(v) 2-Pyrimidinglyoxal

Step 1: Preparation of 1-(pyrimidin-2-yl)ethanone

A solution of 2-cyanopyrimidine (10.0 g, 95.2 mmol) in THF (100 ml) was cooled to -5 ^° C. and a 3M solution of methylmagnesium bromide in THF (38.0 ml, 98.4 mmol) was added. The reaction mixture was stirred at 0 ^o C two hours until complete conversion according to TLC (chloroform/methanol, 9:1). The reaction mixture was poured into water; the pH was adjusted to 5-6 and the aqueous layer was extracted with ethyl acetate (3 x 150 ml). The combined aqueous layers were evaporated under reduced pressure and the resulting crude product was purified by column chromatography using chloroform as eluent to give the title compound (6.5 g, 48%).

HPLC purity: 97.2% (223 nm).

Mass spectroscopy: (ESI +ve) 123.1 [M+H] ⁺

Stage 2: Obtaining 2-pyrimidinglyoxal

A solution of selenium dioxide (15 g, 135 mmol) in ethanol (150 ml) was stirred at 50°C until a clear solution was obtained. Added 1-(pyrimidin-2-yl)ethanone (10 g, 82.0 mmol) to the resulting mixture, which was stirred for 6 hours at 78ºC, monitored by TLC. The resulting crude mixture was used in the next step without further purification.

Mass spectroscopy: (ESI +ve) 137.1 [M+H] ⁺ _.

TLC R _f : 0.3 (chloroform/methanol, 9:1)

(vi) 2-Pyridylglyoxal

2-Pyridylglyoxal (8.0 g, crude) was prepared from selenium dioxide (15 g, 135 mmol) and 2-acetylpyridine (10 g, 82 mmol) according to the standard procedure used in Synthesis 1.

TLC R _f : 0.1 (ethyl acetate)

Mass spectroscopy: (ESI +ve) 136.1 [M+H] ⁺ _.

(vii) 3-Pyridylglyoxal

3-Pyridylglyoxal (5.0 g, crude) was obtained from selenium dioxide (6.82 g, 61.4 mmol) and 3-acetylpyridine (5.0 g, 41.0 mmol) according to the standard procedure used in Synthesis 1.

Mass spectroscopy: (ESI +ve) 136.1 [M+H] ⁺ _.

TLC R _f : 0.1 (ethyl acetate)

Phenylglyoxal monohydrate is commercially available from Sigma Aldrich. 2,4-difluorophenylglyoxal and 3-methoxyphenylglyoxal are commercially available from Manchester Organics Ltd.

Synthesis 2

General procedure for the preparation of 5-aryl-1,2,4-triazine-3-amine derivatives from arylglyoxal derivatives

Stage 1: Sodium bicarbonate (3.32 g, 39.5 mmol) and methyl hydrazinecarbimidothioate (19.7 mmol) were successively added to a solution of the arylglyoxal derivative (19.7 mmol) in ethanol (50 ml), and the resulting mixture was refluxed for 3 h. After completion of the reaction (TLC), the mixture was evaporated in vacuo, poured into water (50 ml) and extracted with dichloromethane or ethyl acetate (2 x 25 ml). The combined organic extracts were then dried over Na ₂ SO ₄ , evaporated in vacuo, and purified by gradient flash chromatography to give intermediate A, a 3-(methylsulfanyl)-5-aryl-1,2,4-triazine derivative.

Step 2: m-CPBA (7.44 g, 43.3 mmol) was added to a solution of intermediate A (14.4 mmol) in DCM (50 ml) at -20 to -15ºC, and the resulting mixture was stirred at this temperature until the end of the reaction according to TLC (usually 8 hours). The reaction mixture was then quenched with saturated aqueous NaHCO ₃ (100 ml) and was extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product, intermediate B, a 3-(methylsulfonyl)-5-aryl-1,2,4-triazine derivative, was purified by gradient flash chromatography.

Stage 3: A 0.5 M solution of ammonia in THF (100 ml, 500 mmol) was cooled to -33°C and iron nitrate (5.50 g, 13.6 mmol) was added over 10 minutes. Then a solution of intermediate B (13.6 mmol) in THF (15 ml) was added dropwise, and the resulting mixture was stirred for 4 hours with monitoring by TLC (methanol/DCM, 1:9). At the end of the reaction, the mixture was poured into water (150 ml) and extracted with dichloromethane or ethyl acetate (2 x 50 ml). The combined organic extracts were then dried over Na ₂ SO ₄ , evaporated in vacuo and 4N was added. aqueous solution of HCl (40-50 ml) for 10 minutes. The aqueous phase was then extracted with ethyl acetate (150 ml), neutralized with an aqueous solution of K ₂ CO ₃ (90-100 ml), and re-extracted with ethyl acetate (100 ml). All organic extracts were combined, dried over Na ₂ SO ₄ and evaporated in vacuo to give intermediate C, a 5-aryl-1,2,4-triazine-3-amine derivative.

(i) 5-Phenyl-1,2,4-triazine-3-amine

Stage 1: 3-(Methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 73%) was obtained from methylhydrazinecarbimidothioate (2.07 g, 19.7 mmol) and phenylglyoxal monohydrate (2.89 g, 19.7 mmol) according to the general method described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 204 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 2.73 (s, 3H), 7.53-7.60 (m, 3H), 8.14-8.17 (m, 2H), 9.38 (s, 1H).

Stage 2: 3-(Methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 96%) was obtained from 3-(methylsulfanyl)-5-phenyl-1,2,4-triazine (2.93 g, 14.4 mmol) and m-CPBA (7.44 g, 43.3 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 236.9 [M+H] ⁺

Stage 3: 5-Phenyl-1,2,4-triazine-3-amine (1.70 g, 73%) was obtained from 3-(methylsulfonyl)-5-phenyl-1,2,4-triazine (3.20 g, 13.6 mmol ) and 0.5 M ammonia in THF (100 ml, 500 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 172.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 7.30 (broad s, 2H), 7.53-7.60 (m, 3H), 8.19-8.21 (dd, 2H), 9.20 (s, 1H).

(ii) 5-(2,4-Difluorophenyl)-1,2,4-triazine-3-amine

Stage 1: 3-(Methylsulfanyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.00 g, 78%) was obtained from methylhydrazinecarbimidothioate (0.63 g, 6.0 mmol) and 2,4-difluorophenylglyoxal monohydrate (1.00 g, 6.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 239.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 2.69 (s, 3H), 6.96-7.02 (m, 1H), 7.06-7.11 (m, 1H), 8.27-8.33 (m, 1H), 9.46 (s , 1H).

Stage 2: 3-(Methylsulfonyl)-5-(2,4-difluorophenyl)-1,2,4-triazine (1.1 g, 97%) was obtained from 3-(methylsulfanyl)-5-(2,4-difluorophenyl) -1,2,4-triazine (1.00 g, 4.17 mmol) and m-CPBA (2.16 g, 4.17 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 271.9 [M+H] ⁺

Step 3: 5-(2,4-Difluorophenyl)-1,2,4-triazine-3-amine (0.45 g, 53%) was obtained from 3-(methylsulfonyl)-5-(2,4-difluorophenyl)-1 ,2,4-triazine (1.10 g, 4.05 mmol) and 0.5 M ammonia in THF (50 ml, 25 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 208.9 [M+H] ⁺

(iii) 5-(3-Methoxyphenyl)-1,2,4-triazine-3-amine

Stage 1: 3-(Methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.01 g, 79%) was obtained from methylhydrazinecarbimidothioate (0.58 g, 5.50 mmol) and 3-methoxyphenylglyoxal monohydrate (1.00 g, 5.50 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 233.9 [M+H] ⁺

Stage 2: 3-(Methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4-triazine (0.90 g, 79%) was obtained from 3-(methylsulfanyl)-5-(3-methoxyphenyl)-1,2 ,4-triazine (1.00 g, 4.20 mmol) and m-CPBA (2.30 g, 12.8 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 265.9 [M+H] ⁺

Step 3: 5-(3-Methoxyphenyl)-1,2,4-triazine-3-amine (0.31 g, 45%) was obtained from 3-(methylsulfonyl)-5-(3-methoxyphenyl)-1,2,4 -triazine (0.90 g, 3.39 mmol) and 0.5 M ammonia in THF (50 ml, 25.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 202.9 [M+H] ⁺

(iv) 5-(4-fluorophenyl)-1,2,4-triazine-3-amine

Stage 1: 3-(Methylsulfanyl)-5-(4-fluorophenyl)-1,2,4-triazine (6.00 g, 69%) was obtained from methylhydrazinecarbimidothioate (4.51 g, 43.0 mmol) and 4-fluorophenylglyoxal monohydrate (6.60 g, 43.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 221.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 2.73 (s, 3H), 7.24 (d, 2H), 8.18 (d, 2H), 9.34 (s, 1H).

Stage 2: 3-(Methylsulfonyl)-5-(4-fluorophenyl)-1,2,4-triazine (5.00 g, 72%) was obtained from 3-(methylsulfanyl)-5-(4-fluorophenyl)-1,2 ,4-triazine (6.00 g, 27.0 mmol) and m-CPBA (12.4 g, 81.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 253.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.55 (s, 3H), 7.34 (d, 2H), 8.33 (d, 2H), 9.82 (s, 1H).

Stage 3: 5-(4-Fluorophenyl)-1,2,4-triazine-3-amine (2.80 g, 74%) was obtained from 3-(methylsulfonyl)-5-(4-fluorophenyl)-1,2,4 -triazine (5.00 g, 19.7 mmol) and 0.5 M ammonia in THF (100 ml, 50.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 191.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 6.79 (s, 2H), 7.40 (m, 2H), 8.23 (m, 2H), 9.21 (s, 1H).

(v) 5-[4-(Methoxymethyl)phenyl]-1,2,4-triazine-3-amine

Stage 1: 5-[4-(Methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (4.0 g, 72%) was obtained from methylhydrazinecarbimidothioate (7.33 g, 31.46 mmol) and 4-(methoxymethyl) phenylglyoxal (4 g, 22.47 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 248.0 [MH] ⁺

Stage 2: 5-[4-(Methoxymethyl)phenyl]-3-(methylsulfonyl)-1,2,4-triazine (3.5 g, 83%) was obtained from 5-[4-(methoxymethyl)phenyl]-3-( methylsulfanyl)-1,2,4-triazine (3.75 g, 15.2 mmol) and m-CPBA (7.92 g, 45.6 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 279.9 [MH] ⁺

Step 3: 5-[4-(Methoxymethyl)phenyl]-1,2,4-triazine-3-amine (2.2 g, 85%) was obtained from 5-[4-(methoxymethyl)phenyl]-3-(methylsulfonyl) -1,2,4-triazine (3.40 g, 12.2 mmol) in THF (35 ml) and NH ₃ gas was passed through for 30 minutes, similar to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 217.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 3.32 (s, 3H), 4.48 (s, 2H), 7.22 (s, 2H), 7.47 (d, 2H), 8.14 (d, 2H), 9.2 (s , 1H).

(vi) 5-(3-Chloro-5-fluorophenyl)-1,2,4-triazine-3-amine

Stage 1: 3-(Methylsulfanyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 38.4%) was obtained from methylhydrazinecarbimidothioate (25.5 g, 243 mmol) and 2-(3 -chloro-5-fluorophenyl)-2-oxoacetaldehyde (30 g, 162 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 255.9 [MH] ⁺

Stage 2: 3-(Methylsulfonyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine (16 g, 88%) was obtained from 3-(methylsulfanyl)-5-(3-chloro- 5-fluorophenyl)-1,2,4-triazine (16 g, 62.7 mmol) and m-CPBA (16.18 g, 94.11 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 287.9 [MH] ⁺

Step 3: 5-(3-Chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (1.70 g, 73%) was obtained from 3-(methylsulfonyl)-5-(3-chloro-5- fluorophenyl)-1,2,4-triazine (16.0 g, 55.5 mmol) and ammonia gas according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 224.9 [MH] ⁺

(vii) 5-(3,5-Difluorophenyl)-1,2,4-triazine-3-amine

Stage-1: 3-(Methylsulfanyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (28 g, 80.0%) was obtained from methylhydrazinecarbimidothioate (20.68 g, 197.4 mmol) and 2-(3, 5-difluorophenyl)-2-oxoacetaldehyde (25 g, 147.0 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 240.0 [MH] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 2.74 (s, 3H), 7.02-7.07 (m, 1H), 7.69 (d, 2H), 9.32 (s, 1H).

Stage 2: 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1,2,4-triazine (31 g, 97.7%) was obtained from 3-(methylsulfonyl)-5-(3-chloro-5- fluorophenyl)-1,2,4-triazine (28.0 g, 117.0 mmol) and m-chloroperbenzoic acid (40 g, 234 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 271.9 [MH] ⁺

Stage 3: 5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (18 g, 74%) was obtained from 3-(methylsulfonyl)-5-(3,5-difluorophenyl)-1 ,2,4-triazine (31.0 g, 115.0 mmol) and ammonia gas according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 209.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 7.37 (broad s, 2H), 7.4 (m, 3H), 9.29 (s, 1H).

(viii) 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine

Stage 1: 3-(Methylsulfanyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, 67%) was obtained from methylhydrazinecarbimidothioate (4.8 g, 44.1 mmol) and 2-pyrimidine glyoxal (5.0 g , 37 mmol) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ES+I +ve) 206.0 [M+H] ⁺ _.

Stage 2: 3-(Methylsulfonyl)-5-(pyrimidin-2-yl)-1,2,4-triazine (5.0 g, crude) was obtained from 3-(methylsulfanyl)-5-(pyrimidin-2-yl)- 1,2,4-triazine (5.0 g, 24.3 mmol) and m-CPBA (10.5 g, 58.0 mmol) according to the general procedure described for Synthesis 2, without chromatographic purification.

Mass spectroscopy: (ESI +ve) 237.0 [M+H] ⁺ _.

TLC R _f : 0.5 (chloroform/methanol, 9:1)

Stage 3: 5-(Pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 23%) was obtained from 3-(methylsulfonyl)-5-(pyrimidin-2-yl)-1 ,2,4-triazine (5.0 g, crude) and 0.5M ammonia in THF (20 ml) according to the general procedure described for Synthesis 2.

Mass spectroscopy: (ESI +ve) 175 [M+H] ⁺ _.

The following triazine intermediates were obtained from arylglyoxal derivatives in one step by condensation with aminoguanidine:

(ix) 5-(Pyridin-2-yl)-1,2,4-triazine-3-amine (1.5 g, 8% over 2 steps) was prepared from a crude sample of 2-pyridylglyoxal (8.0 g) and aminoguanidine bicarbonate (6.0 d, 44 mmol). The reagents were boiled in EtOH (100 ml) for 4 hours. The reaction mixture was then cooled, evaporated under reduced pressure and purified by gradient flash chromatography (using 0-30% ethyl acetate/hexane as eluent). The resulting sample contained a mixture of isomers and was used without further purification.

HPLC purity: 35%, (265 nm)

Mass spectroscopy: (ESI +ve) 174 [M+H] ⁺ _.

(x) 5-(Pyridin-3-yl)-1,2,4-triazin-3-amine (1.5 g, 16% over 2 steps) was prepared from a crude sample of 3-pyridylglyoxal (10.0 g) and aminoguanidine bicarbonate (3.0 d, 22 mmol). The reagents were boiled in EtOH (100 ml) for 4 hours. The reaction mixture was then cooled, evaporated under reduced pressure and purified by gradient flash chromatography (using 0-30% ethyl acetate/hexane as eluent).

Mass spectroscopy: (ESI +ve) 174 [M+H] ⁺ _.

TLC R _f = 0.2 (ethyl acetate).

The following 3-amino-5-aryl-1,2,4-triazine compounds are commercially available from UkrOrgSynth:

5-[4-(difluoromethoxy)phenyl]-1,2,4-triazine-3-amine;

5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine;

5-(3-chlorophenyl)-1,2,4-triazine-3-amine;

5-(4-chlorophenyl)-1,2,4-triazine-3-amine;

5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine;

5-(3-fluorophenyl)-1,2,4-triazine-3-amine;

4-(3-amino-1,2,4-triazin-5-yl)benzonitrile;

5-(4-ethylphenyl)-1,2,4-triazine-3-amine;

5-(4-methylphenyl)-1,2,4-triazine-3-amine;

5-(2-fluorophenyl)-1,2,4-triazine-3-amine;

5-(4-methoxyphenyl)-1,2,4-triazine-3-amine and

5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine.

Synthesis 3

General procedure for halogenation of 5-aryl-1,2,4-triazine-3-amine derivatives

Method 1

A solution of intermediate C, 5-aryl-1,2,4-triazine-3-amine derivative (8.70 mmol), in DMF (15 mL) was cooled to –25°C, and a solution of N-chlorosuccinimide or N-bromosuccinimide ( 26.6 mmol) in DMF (10 ml). The reaction mixture was stirred overnight and monitored by TLC (methanol/DCM, 1:9). At the end of the reaction, the mixture was poured into a saturated bicarbonate solution (50 ml) and extracted with diethyl ether (25 x 3 ml). The organic phases were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude product was purified by gradient flash chromatography using mixtures of ethyl acetate and hexane (e.g. 10% ethyl acetate in hexane) as eluent to give the title compound, intermediate D.

Method 2

A solution of intermediate C, 5-aryl-1,2,4-triazine-3-amine derivative (8.70 mmol), in DMF (15 mL) was cooled to –25°C, and a solution of N-chlorosuccinimide or N-bromosuccinimide ( 26.6 mmol) in DMF (10 ml). The reaction mixture was stirred at room temperature and monitored by TLC or LCMS. After completion of the reaction, the mixture was poured into a saturated bicarbonate solution (50 ml) and extracted with an organic solvent such as diethyl ether or ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude product was purified by gradient flash chromatography using mixtures of ethyl acetate and hexane or methanol and DCM as eluent to give the title compound, intermediate D.

(i) 6-Bromo-5-phenyl-1,2,4-triazine-3-amine

6-Bromo-5-phenyl-1,2,4-triazine-3-amine (1.40 g, 64%) was obtained from 5-phenyl-1,2,4-triazine-3-amine (1.50 g, 8.70 mmol) and N-bromosuccinimide (4.50 g, 26.6 mmol) according to the general procedure described for Synthesis 3.

Mass spectroscopy: (ESI +ve) 251.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.49 (s, 2H), 7.49-7.58 (m, 3H), 7.82-7.85 (m, 2H).

(ii) 6-Chloro-5-phenyl-1,2,4-triazine-3-amine

6-Chloro-5-phenyl-1,2,4-triazine-3-amine (0.38 g, 65%) was obtained from 5-phenyl-1,2,4-triazine-3-amine (0.50 g, 1.99 mmol) and N-chlorosuccinimide (0.50 g, 3.7 mmol) according to the general procedure described for Synthesis 3.

Mass spectroscopy: (ESI +ve) 207.9 [M+H] ⁺

(iii) 6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine

6-Bromo-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine (0.13 g, 21%) was obtained from 5-(2,4-difluorophenyl)-1,2,4- triazine-3-amine (0.45 g, 2.1 mmol) and N-bromosuccinimide (0.49 g, 2.80 mmol) according to the general procedure described for Synthesis 3.

Mass spectroscopy: (ESI +ve) 286.8 [M+H] ⁺

(iv) 6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine

6-Bromo-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine (0.18 g, 42%) was obtained from 5-(3-methoxyphenyl)-1,2,4-triazine-3- amine (0.31 g, 1.50 mmol) and N-bromosuccinimide (0.35 g, 1.99 mmol) according to the general procedure described for Synthesis 3.

Mass spectroscopy: (ESI +ve) 280.9 [M+H] ⁺

(v) 6-Bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine

6-Bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (1.95 g, 49%) was obtained from 5-(4-fluorophenyl)-1,2,4-triazine-3- amine (2.8 g, 14.00 mmol) and N-bromosuccinimide (7.87 g, 44.00 mmol) according to the general procedure described for Synthesis 3.

Mass spectroscopy: (ESI +ve) 268.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.43 (s, 2H), 7.19 (d, 2H), 7.87 (d, 2H).

The following intermediates were also prepared following the general procedure described for Synthesis 3:

No. Product (output) Derived from LCMS NMR (vi) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (1.71 g, 44%) 5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (2.8 g, 13.45 mmol) Mass spectroscopy: m/z 287, 289 (M+H) ⁺ (ES ⁺ ); 285, 287 (MH) ^- (ES ^- ), at 4.07 min, 100% (method B). (400 MHz, DMSO) δ: 7.58 – 7.66 (m, 3H), 7.77 – 7.98 (m, 2H). (viii) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (1.27 g, 44.9%) 5-(3-fluorophenyl)-1,2,4-triazine-3-amine (2.00 g, 10.52 mmol) Mass spectroscopy: m/z (Br) 269.6/271.7 (M+H) ⁺ (ES ⁺ ); 267.9/269.9 (MH)- (ES-), at 3.85 min, 100% (method B). (400 MHz, DMSO) δ: 7.38 – 7.47 (m, 1H), 7.51 – 7.70 (m, 5H). (viii) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (1.1 g, 40%) 5-(3-chlorophenyl)-1,2,4-triazine-3-amine (2.00 g, 9.68 mmol) Mass spectroscopy: m/z (Br, Cl) 285.7/287.7/289.7 (M+H) ⁺ (ES ⁺ ); 283.9/285.9/288.0 (MH)- (ES-), at 4.32 min, 100% (method B). (400 MHz, DMSO) δ: 7.52 – 7.66 (m, 4H), 7.69 – 7.73 (m, 1H), 7.79 (t, J 1.7 Hz, 1H). (ix) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (605 mg, 21%) 4-(3-amino-1,2,4-triazin-5-yl)benzonitrile (2.00 g, 10.14 mmol) Mass spectroscopy: m/z (Br) 276.6/278.6 (M+H) ⁺ (ES ⁺ ); 274.9/276.9 (MH)- (ES-), at 3.42 min, 98.6% (method B). (400 MHz, DMSO) δ: 7.66 (s, 2H), 7.86 – 7.94 (m, 2H), 7.99 – 8.06 (m, 2H). (x) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (890 mg, 32%) 5-(4-chlorophenyl)-1,2,4-triazine-3-amine (2.00 g, 9.68 mmol) Mass spectroscopy: m/z (Br, Cl) 285.0/287.0/289.0 (M+H) ⁺ (ES ⁺ ); 283.2/285.2/287.2 (MH)- (ES-), at 4.32 min, 98.0% (method B). (400 MHz, DMSO) δ: 7.58 (s, 2H), 7.60–7.65 (m, 2H), 7.74–7.81 (m, 2H). (xi) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (1.32 g, 50%) 5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (2 g, 8.40 mmol) Mass spectroscopy: m/z 317, 319 (M+H) ⁺ (ES ⁺ ); 315-, 317 (MH) ^- (ES ^- ), at 3.98 min, 100% pure, method B. (400 MHz, DMSO) δ: 7.30 – 7.36 (m, 2H), 7.39 (t, 2JHF 72 Hz, 1H), 7.57 (s, 2H), 7.81 – 7.87 (m, 2H). (xi) 6-bromo-5-[4-(methoxymethyl)phenyl]-1,2,4-triazine-3-amine (1.3 g, 43%) 5-[4-(methoxymethyl)phenyl]-1,2,4-triazine-3-amine (2.2 g, 15.2 mmol) HPLC purity: 98.35% (242 nm); Mass spectroscopy: (ESI +ve) 295.0 [M+H] ⁺ . (400 MHz, DMSO) δ: 3.33 (s, 3H), 4.48 (s, 2H), 7.44 (d, 2H), 7.54 (broad s, 2H), 7.72 (d, 2H). (xiii) 6-bromo-5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (1.12 g, 36%) 5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (2.2 g, 9.79 mmol) Mass spectroscopy: m/z 303, 305 (M+H) ⁺ (ES ⁺ ); 301, 303 (MH) ^- (ES ^- ), at 4.35 min, 100% pure, method B. (400 MHz, DMSO) δ: 7.54 – 7.70 (m, 3H), 7.80 (ddd, J 8.6, 4.7, 2.2 Hz, 1H), 7.99 (dd, J 7.2, 2.2 Hz, 1H). (xiv) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (8.0 g, 38%) 5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (16.0 g, 55.55 mmol) HPLC purity: 99.01% (247 nm); Mass spectroscopy: (ESI +ve) 304.0 [M+H] ⁺ . (400 MHz, CDCl ₃ ) δ: 5.53 (broad s, 2H), 7.27 (m, 1H), 7.48 (m, 1H), 7.64 (m, 1H). (xv) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (6.0 g, 24%) 5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (18.0 g, 62.0 mmol) HPLC purity: 97.88% (247 nm); Mass spectroscopy: (ESI +ve) 286.8 [M+H] ⁺ . (400 MHz, CDCl ₃ ) δ: 7.48 (m, 3H), 7.62 (s, 2H). (xvi) 6-bromo-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.90 g, 64%) 5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (1.0 g, 5.75 mmol) and N -bromosuccinimide (1.53 g, 8.60 mmol) HPLC purity: 99.08%
Mass spectroscopy: (ESI +ve) 253. [M+H] ⁺ _. (400 MHz, DMSO) δ: 7.73 (t, 1H), 7.79 (s, 2H), 9.04 (d, 2H) (xviii) 6-bromo-5-(pyridin-2-yl)-1,2,4-triazine-3-amine (0.18 g, 41%) 5-(pyridin-2-yl)-1,2,4-triazin-3-amine (0.30 g, 1.73 mmol) and N -bromosuccinimide (0.46 g, 2.60 mmol) Mass spectroscopy: (ESI +ve) 253. [M+H] ⁺ _.
TLC R _f : 0.6 (ethyl acetate) (xiii) 6-bromo-5-(pyridin-3-yl)-1,2,4-triazine-3-amine (0.19 g, 33%) 5-(pyridin-3-yl)-1,2,4-triazin-3-amine (0.4 g, 2.3 mmol) and N -bromosuccinimide (0.61 g, 3.4 mmol) TLC R _f : 0.6 (ethyl acetate)
Mass spectroscopy: (ESI +ve) 253. [M+H] ⁺ _. (xix) 6-bromo-5-(4-methylphenyl)-1,2,4-triazine-3-amine (450 mg, 34%) 5-(4-methylphenyl)-1,2,4-triazine-3-amine (930 mg, 5.0 mmol) and N -bromosuccinimide (2.67 g, 15.0 mmol) Mass spectroscopy: m/z 265.0/267.0 (M+H) ⁺ (ESI+) at 3.0 min, >95% (method C). (400 MHz, DMSO) δ: 3.35 (s, 3H), 7.41 (m, 2H), 7.74 (m, 2H) (NH ₂ not visible). (xx) 6-bromo-5-(4-ethylphenyl)-1,2,4-triazine-3-amine (500 mg, crude; used without chromatographic purification) 5-(4-ethylphenyl)-1,2,4-triazine-3-amine (930 mg, 5.0 mmol) and N -bromosuccinimide (2.67 g, 15.0 mmol) Mass spectroscopy: m/z 279.0/281.0 (M+H) ⁺ (ESI+) at 3.48 min, 90% (method C).
TLC R _f : 0.11 (MeOH/DCM, 3:97) (xxi) 6-bromo-5-(2-fluorophenyl)-1,2,4-triazine-3-amine (700 mg, 20%) 5-(2-fluorophenyl)-1,2,4-triazine-3-amine (2.5 g, 13.2 mmol) and N -bromosuccinimide (7.05 g, 39.6 mmol) TLC R _f : 0.4 (EtOAc:isohexane 1:1) (400 MHz, DMSO)
δ: 7.32-7.42 (m, 2H), 7.54-7.67 (m, 4H) (xxi) 6-bromo-5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine (800mg, 27%) 5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine (2.5 g, 10.4 mmol) and N -bromosuccinimide (7.05 g, 39.6 mmol) Mass spectroscopy: m/z 288.9 ( ⁸¹ Br) (M+H) ⁺ (ES ⁺ ), at 1.29 min, 100% (method A) (400 MHz, DMSO)
δ: 7.43-7.86 (m, 5H) (xiii) 6-bromo-5-(4-methoxyphenyl)-1,2,4-triazine-3-amine (600mg, 17%) 5-(4-methoxyphenyl)-1,2,4-triazine-3-amine (2.5 g, 12.4 mmol) and N -bromosuccinimide (7.05 g, 39.6 mmol) TLC R _f : 0.4 (EtOAc:isohexane 1:1) (400 MHz, DMSO)
δ: 3.83 (s, 3H), 7.08 (d, J 9.0, 2H), 7.47-7.54 (broad s, 2H), 7.80 (d, J 9.0, 2H)

Synthesis 4

4a: General procedure for S _N Ar substitution of 2-chloropyridine derivatives with amines

The 2-chloropyridine derivative (1 equivalent) and the amine (typically 5 equivalents) were dissolved in MeCN and sealed in a microwave vial. The reaction mixture was heated under microwave conditions (typically 160-180 ^° C.) for up to 1 hour while monitoring the progress of the reaction by LCMS. If necessary, more amine was added and the procedure was repeated. At the end of the reaction, the mixture was evaporated under reduced pressure and purified by flash chromatography using ethyl acetate/hexane as eluent, or by preparative HPLC.

The following intermediates were prepared using the general procedure described for Synthesis 4a:

No. Product (output) Derived from LC/MS NMR (i) 2-ethyl(methyl)amino-6-methylpyridine (534mg, 45%) 2-chloro-6-methylpyridine (0.87 ml, 7.84 mmol) and ethylmethylamine (3.37 ml, 39.2 mmol) Mass spectroscopy: m/z 151 (M+H) ⁺ (ES+) at 1.56 min, 95% (method A)
TLC R _f : 0.55 (EtOAc/isohexane, 1:20) (ii) 2-dimethylamino-6-methylpyridine (93 mg, 21%). 2-chloro-6-methylpyridine (0.35 ml, 3.20 mmol) and dimethylamine (2.0 M solution in THF, 8.0 ml, 16.0 mmol) Mass spectroscopy: m/z 137 (M+H) ⁺ (ES) ⁺ at 1.37 min (method A)
TLC R _f : 0.38 (Et ₂ O/isohexane, 1:20) (iii) 2-(azetidin-1-yl)-6-(trifluoromethyl)pyridine (807 mg, 72%) 2-chloro-6-trifluoromethylpyridine (1.00 g, 5.51 mmol) and azetidine (1.57 g, 1.86 ml, 27.5 mmol) Mass spectroscopy: m/z (ES ⁺ ) 223.0 (M+H) ⁺ at 1.68 min, 90% (method A) (400 MHz, CDCl ₃ ) δ: 2.41 (quint, J7.5, 2H), 4.08 (t, J7.5, 4H), 6.36 – 6.39 (m, 1H), 6.89 – 6.91 (m, 1H), 7.49 – 7.53 (m, 1H). (iv) 4-(6-methylpyridin-2-yl)morpholine (693 mg, 50%) 2-chloro-6-methylpyridine (1.00 g, 0.87 ml, 7.84 mmol) and morpholine (3.41 g, 3.45 ml, 39.2 mmol) Mass spectroscopy: m/z (ES ⁺ ) 179.0 (M+H) ⁺ at 1.26 min, 90% (method A). (400 MHz, CDCl ₃ ) δ: 2.41 (s, 3H), 3.48 – 3.50 (m, 4H), 3.81 – 3.84 (m, 4H), 6.42 – 6.44 (m, 1H), 6.53 – 6.55 (m, 1H ), 7.38–7.42 (m, 1H).

4b: Preparation of other pyridine derivatives

(i) Preparation of 2,6-d ₆ -dimethylpyridine

A solution of methyl-d ₃ -magnesium iodide (9.60 ml, 1 M solution in diethyl ether, 9.60 mmol) was added dropwise over 10 min to a solution of 2,6-dibromopyridine (947 mg, 4.00 mmol) and iron(III) acetylacetonate (141 mg, 0.40 mmol) in THF (30 ml) and NMP (3 ml) under N ₂ atmosphere. After stirring at room temperature for 40 minutes, 1M HCl aqueous solution (10 ml) was added and the mixture was stirred for 5 minutes. Diethyl ether (20 ml) was added and the phases were separated. The organic phase was extracted with water (2 x 10 ml) and the combined aqueous phases were made basic by adding 1M aqueous NaOH solution (15 ml). The aqueous phase was extracted with dichloromethane (3 x 25 ml) and the combined organic phases were evaporated in vacuo. Purification by gradient flash chromatography (SiO ₂ , 5-20% EtOAc in isohexane) gave the title compound as a colorless oil (430 mg, 95%).

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 6.95 (d, J 7.8, 2H), 7.45 (t, J = 7.8, 1H).

TLC R _f : 0.30 (EtOAc/isohexane, 1:4)

(ii) Preparation of 2-d ₃ -methyl-6-(trifluoromethyl)pyridine

A mixture of 2-chloro-6-(trifluoromethyl)pyridine (2.69 g, 14.8 mmol) and iron(III) acetylacetonate (523 mg, 1.48 mmol) in THF (100 ml) and NMP (10 ml) was stirred at 0°C under N ₂ 5 minutes. A solution of methyl-d ₃ -magnesium iodide (18.0 ml, 1M solution in diethyl ether, 18.0 mmol) was added dropwise over 10 minutes, and the reaction mixture was stirred under N ₂ at 0 ºC for 5 minutes, then at room temperature for 75 minutes. A 1M HCl aqueous solution (50 ml) was added and the reaction mixture was stirred for 5 minutes, after which diethyl ether (50 ml) was added and the phases were separated. The organic phase was washed with 0.5M aqueous HCl (50 ml) and water (50 ml), and the combined aqueous phases were extracted with diethyl ether (2 x 50 ml). The combined organic phases were evaporated to a volume of about 25 ml, short distillation (bp 28-30° C. at 35 mbar) gave a clear oil to which DCM (5 ml) and H ₂ O (5 ml) were added. The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 5 ml); the combined organic phases were evaporated in vacuo to give the title compound (639 mg, 26%) as a clear oil.

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 7.34 (d, J 7.8, 1H), 7.49 (d, J 7.8, 1H), 7.75 (t, J 7.8, 1H).

Boiling point: 28-30ºC at 35 mbar.

(iii) Preparation of 2-cyclopropyl-6-(trifluoromethyl)pyridine

2-Chloro-6-trifluoromethylpyridine (451 mg, 2.5 mmol), potassium cyclopropyl trifluoroborate salt (373 mg, 2.52 mmol), palladium acetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg, 0.075 mmol), and cesium carbonate (2.4 g, 7.5 mmol) was suspended in a mixture of toluene and water (10:1, 10 ml). After purging the reaction vessel with nitrogen for 5 minutes, the reaction mixture vial was sealed and then heated at 100 ^° C. for 18 hours. After cooling, the mixture was partitioned between DCM (15 ml) and water (15 ml). The separated aqueous phase was extracted with dichloromethane (2 x 15 ml), the combined organic phases were passed through a phase separator and evaporated in vacuo to give a yellow oil which was used without further purification (423 mg, crude).

LCMS: main peak at 1.77 min; poor ionization (method A).

TLC R _f : 0.6 (EtOAc/hexane, 1:9).

(iv) Preparation of 2-ethyl-6-(trifluoromethyl)pyridine

2-Chloro-6-trifluoromethylpyridine (451 mg, 2.5 mmol), potassium ethyltrifluoroborate salt (374 mg, 2.75 mmol), palladium acetate (11 mg, 0.05 mmol), di(1-adamantyl)-n-butylphosphine (27 mg, 0.075 mmol) and cesium carbonate (2.4 g, 7.5 mmol) were suspended in a mixture of toluene and water (10:1, 10 ml). After purging the reaction vessel with nitrogen for 5 minutes, the reaction mixture vial was sealed and then heated at 100 ^° C. for 18 hours. After cooling, the mixture was partitioned between DCM (15 ml) and water (15 ml). The separated aqueous phase was extracted with dichloromethane (2 x 15 ml), the combined organic phases were passed through a phase separator and evaporated in vacuo to give a yellow oil which was used without further purification (460 mg, crude).

LCMS: main peak at 1.53 min; poor ionization (method A)

TLC R _f : 0.55 (EtOAc/hexane, 1:9).

(v) Preparation of 2-ethylamino-6-methylpyridine

A mixture of 2-amino-6-methylpyridine (1.00 g, 9.25 mmol) and acetaldehyde (0.52 ml, 9.34 mmol) was stirred in anhydrous methyl alcohol for 1 hour at room temperature under a nitrogen atmosphere. Then, sodium triacetoxyborohydride (7.84 g, 37.0 mmol) and five drops of acetic acid were added to the mixture, after which it was stirred for another 4 h. The reaction mixture was evaporated in a vacuum. The residue was partitioned between water and DCM and the separated aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over MgSO ₄ , filtered and evaporated in vacuo to give a mobile oil which was purified by flash chromatography using 2% MeOH/DCM as eluent to give 2-ethylamino-6-methylpyridine (636 mg, 51%) .

LCMS: 137.0 [M+H] ⁺ (ES+) at 1.17 min, 100% (method A).

Synthesis 5

General procedure for the preparation of 2-fluoromethylpyridine derivatives

(Diethylamino)sulfur trifluoride (1.0 ml, 7.7 mmol) was added dropwise to a solution of 2-pyridinylmethanol derivative (7.0 mmol) in DCM (30 ml, anhydrous) under nitrogen atmosphere while cooling in an acetone/CO ₂ bath to -20 ^° C The resulting solution was allowed to warm to room temperature and then stirred until complete conversion by TLC. The reaction mixture was quenched with ice and basified to pH 8-10 with solid sodium bicarbonate. The layers were separated and the organic phase was washed successively with water and saturated sodium chloride solution, after which it was dried (MgSO ₄ ), evaporated in vacuo and purified by gradient flash chromatography to give the 2-fluoromethylpyridine derivative.

The following intermediates were prepared using the general procedure described for Synthesis 5:

No. Product (output) Derived from LCMS/TLC NMR (i) 2-(fluoromethyl)-6-methylpyridine (850 mg, 84%) 6-methyl-2-pyridine methanol (1.0 g, 8.1 mmol) TLC R _f : 0.9 (EtOAc/isohexane 1:9) (400 MHz, DMSO)
δ: 2.48 (s, 3H), 5.43 (d, J 47.2 2H), 7.23 (d, J 7.8, 1H), 7.29 (d, J 7.8, 1H), 7.76 (t, J 7.8, 1H) (ii) 2-chloro-6-(fluoromethyl)pyridine (200 mg, 17%) (6-chloro-2-pyridinyl)methanol (1.0 g, 7.0 mmol) TLC R _f : 0.9 (EtOAc/isohexane 1:9) (400 MHz, DMSO)
δ: 5.51 (d, J 46.7 Hz, 2H), 7.55 (d, J 7.78, 1H), 7.57 (d, J 7.78, 1H), 8.00 (t, J 7.78, 1H) (iii) 2,6-bis-(fluoromethyl)pyridine (850 mg, 41%) 2,6-bis(hydroxymethyl)pyridine (2.0 g, 14.4 mmol) TLC R _f : 0.9 (EtOAc/isohexane 1:9) (400 MHz, DMSO)
δ: 5.50 (d, J 46.6, 2H), (d, J 7.78, 2H), 7.98 (t, J 7.78, 1H)

Synthesis 6

General procedure for the preparation of 2-difluoromethylpyridine derivatives

(Diethylamino)sulfur trifluoride (2.4 ml, 18.3 mmol) was added dropwise to a solution of 2-pyridinecarboxaldehyde derivative (8.3 mmol) in DCM (30 ml, anhydrous) under nitrogen atmosphere while cooling in an acetone/CO ₂ bath to -20 ^° C The resulting solution was allowed to warm to room temperature and then stirred until complete conversion by TLC. The reaction mixture was quenched with ice and basified to pH 8-10 with solid sodium bicarbonate. The layers were separated and the organic phase was washed successively with water and saturated sodium chloride solution, after which it was dried (MgSO ₄ ), evaporated in vacuo and purified by gradient flash chromatography to give the 2-fluoromethylpyridine derivative.

The following intermediates were prepared using the general procedure described for Synthesis 6:

No. Product (output) Derived from LCMS/TLC NMR (i) 2-chloro-6-(difluoromethyl)pyridine (1.1 g, 86%) 6-chloro-2-pyridinecarboxaldehyde (1.0 g, 7.07 mmol) TLC R _f : 0.9 (EtOAc/isohexane 1:9) (400 MHz, DMSO), δ: 4.69 (s, 1H), 7.50 (m, 2H), 7.91 (m, 1H) (ii) 2-(difluoromethyl)-6-methylpyridine (410 mg, 35%) 6-methyl-2-pyridinecarboxaldehyde (1.0 g, 8.26 mmol) TLC R _f : 0.9 (EtOAc/isohexane 1:9) (400 MHz, DMSO), δ: 2.53 (3H, s) 6.90 (d, J 55.2, 1H), 7.47 (m, 2H), 7.89 (m, 1H)

Synthesis 7

General procedure for 4-borylation of 2,6-disubstituted pyridine derivatives

Methoxy(cyclooctadiene)rhodium(I) dimer (0.05 mole equivalents of Rh), 4,4'-di-tert-butyl-2,2'-bipyridine (dtbpy) (0.05 mole equivalents), and bis(pinacolato)diborone (2 molar equivalent) were placed in a flask thoroughly purged with nitrogen. The flask was purged one more time, after which hexane was added by syringe (final pyridine concentration approximately 0.5 mM). The resulting mixture was heated to 50 ^o C for 10 minutes until a dark red color of the solution. Then a pyridine derivative (1 mole equivalent) was added via syringe and heating was continued for another 6 hours. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure. The resulting evaporation residue was purified by column chromatography using ethyl acetate/hexane as eluent to give the title compound.

The compounds listed below were prepared according to the general procedure described for Synthesis 7 by reacting the indicated starting materials for 6 hours at 50 ^° C, unless otherwise indicated:

No. Product (output) Derived from LCMS/TLC NMR (i) 2,6-d ₆ -dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.56 g, crude) was used without chromatographic purification bis(pinacolato)diborone (1.93 g, 7.60 mmol) and 2,6-d ₆ -dimethylpyridine (430 mg, 3.80 mmol) were heated at 70 ^° C. for 105 minutes by standard procedure. Mass spectroscopy: m/z 240.1 [M+H] ⁺ (ESI +ve) at 0.1 min, 100% (method A). (ii) 2-d ₃ -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (716 mg, 32%) 2-d ₃ -methyl-6-(trifluoromethyl)pyridine (639 mg, 3.89 mmol) and bis(pinacolato)diborone (1.98 g, 7.80 mmol) were heated at 70ºC for 3.5 hours according to the standard procedure. Mass spectroscopy: m/z: 291.1 [M+H] ⁺ (ESI +ve) at 0.15 min, 100% (method A) (400 MHz, CDCl ₃ ) δ: 1.37 (s, 12H), 7.70 (s, 1H), 7.82 (s, 1H). (iii) 2-ethylamino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (crude sample, used without chromatographic purification) bis(pinacolato)diborone (776 mg, 3.06 mmol) and 2-ethylamino-6-methylpyridine (277 mg, 2.04 mmol) were heated to 55 ^° C. for 6 hours by standard procedure. Mass spectroscopy: m/z 263.2 [M+H] ⁺ (ESI+) at 0.10 min, (method A). 2-ethyl(methyl)amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (2.04 g, crude) was used without chromatographic purification. bis(pinacolato)diborone (1.81 g, 7.11 mmol) and 2-ethyl(methyl)amino-6-methylpyridine (534 mg, 3.55 mmol) were heated at 65°C for 3 hours according to the standard procedure. Mass spectroscopy: m/z 277 (M+H) ⁺ (ES) ⁺ at 1.11 min, (method A). 2-dimethylamino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (414 mg, crude) was used without chromatographic purification. 2-dimethylamino-6-methylpyridine (93 mg, 0.68 mmol) and bis(pinacolato)diborone (348 mg, 1.37 mmol) were heated at 70°C for 2 hours according to the standard procedure. No ionization in LCMS, main peak at 0.8 min (method A). 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (46.9 g, 94%) 2-methyl-6-chloro pyridine (25 g, 195.9 mmol) and bis(pinacolato)diborone (32.3 g, 127 mmol) according to the standard procedure. HPLC purity: 99.33% (282 nm)
Mass spectroscopy: (ESI +ve) 254.1 [M+H] ⁺ _. (400 MHz, DMSO) δ: 1.30 (s, 12 H), 2.50 (s, 3H), 7.35 (s, 1H), 7.44 (s, 1H). 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 30%) 2,6-dimethylpyridine (1.5 g, 13.9 mmol) and bis(pinacolato)diborone (1.9 g, 7.69 mmol) according to the standard method. HPLC purity: 93.33% (268 nm)
Mass spectroscopy: (ESI +ve) 234.1 [M+H] ⁺ _. (400 MHz, DMSO) δ: 1.27 (s, 12 H), 2.48 (s, 6H), 7.20 (s, 2H). 2-(trifluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (5.9 g, 83%) 2-trifluoromethyl-6-methyl pyridine (4.0 g, 24.8 mmol) and bis(pinacolato)diborone (4.09 g, 16.1 mmol) according to the standard procedure. HPLC purity: 95.65% (210 nm)
Mass spectroscopy: (ESI +ve) 287.8 [M+H] ⁺ _. (400 MHz, DMSO) δ: 1.31 (s, 12 H), 2.51 (s, 3H), 7.70 (s, 1H), 7.76 (s, 1H). 2-dimethylamino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.98 g, 53%) N,N -dimethylpyridin-2-amine (0.9 g, 7.4 mmol) and bis(pinacolato)diborone (1.12 g, 4.4 mmol) according to the standard procedure. Mass spectroscopy: (ESI +ve) 248.9 [M] ⁺ ).
TLC R _f : 0.10 (5:5 ethyl acetate/hexane) 2-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (0.70 g, 81%) 2-methyl-6-bromo pyridine (0.50 g, 2.90 mmol) and bis(pinacolato)diborone (0.48 g, 1.8 mmol) according to the standard method. Mass spectroscopy: (ESI +ve) 299.7 [M+H] ⁺
TLC R _f : 0.15 (5:5 ethyl acetate/hexane) 2-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (0.70 g, 70%) 2-methyl-6-cyanopyridine (0.5 g, 4.2 mmol) and bis(pinacolato)diborone (0.69 g, 2.7 mmol), Mass spectroscopy: (ESI +ve) 244.9 [M+H] ⁺
TLC R _f : 0.15 (5:5 ethyl acetate/hexane) 1-oxo-2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.8 g, 90%) 2,6-dimethyl pyridine- N -oxide (1.0 g, 8.12 mmol) and bis(pinacolato)diborone (1.34 g, 5.27 mmol) Mass spectroscopy: (ESI +ve) 249.9 [M] ⁺
TLC R _f : 0.12 (5:5 ethyl acetate/hexane) 2-bromo-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-trifluoromethylpyridine (0.5 g, 64%) 2-trifluoromethyl-6-bromopyridine (0.5 g, 2.20 mmol) and bis(pinacolato)diborone (0.36 g, 1.4 mmol) according to the standard procedure. Mass spectroscopy: (ESI +ve) 352.9 [M] ⁺ ).
TLC R _f : 0.18 (5:5 ethyl acetate/hexane) 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(difluoromethyl)pyridine (310 mg, 13%) 2-chloro-6-(difluoromethyl)pyridine (1.4 g, 8.56 mmol) and bis(pinacolato)diborone (10.1 g, 42.8 mmol) were heated at 60°C for 2 hours according to the standard procedure. TLC R _f : band from baseline to 0.3 (EtOAc/isohexane, 1:9) (400 MHz, DMSO)
δ: 1.33 (s, 12H), 7.03 (t, J 54.5, 1H), 7.75 (s, 1H), 7.80 (s, 1H) 2-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (1.1 g, 26%) 2-(fluoromethyl)-6-methylpyridine (2.1 g, 16.8 mmol) and bis(pinacolato)diborone (8.5 g, 33.6 mmol) were heated at 60ºC for 48 hours according to the standard procedure. Mass spectroscopy: (ESI +ve) 252.1 [M+H] ⁺ at 0.13 min, (method A). (400 MHz, DMSO)
δ: 1.32 (s, 12H), 2.55 (s, 3H), 5.45 (d, J 47.2, 2H), 7.45 (s, 1H), 7.47 (s, 1H) 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(fluoromethyl)pyridine (450mg, 24%) 2-chloro-6-(fluoromethyl)pyridine (1.0 g, 6.9 mmol) and bis(pinacolato)diborone (3.5 g, 13.8 mmol) were heated at 60ºC for 2 hours according to the standard procedure. TLC R _f : band from baseline to 0.3 (EtOAc/isohexane, 1:9) (400 MHz, DMSO)
δ: 1.33 (s, 12H), 5.50(d, J 46.7, 2H), 7.57 (s, 1H), 7.65 (s, 1H) 2,6-bis-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridine (1.6 g, 88%) 2,6-bis-fluoromethylpyridine (1.2 g, 6.8 mmol) and bis(pinacolato)diborone (3.5 g, 13.6 mmol) were heated at 65°C for 2 hours according to the standard procedure. TLC R _f : band from baseline to 0.3 (EtOAc/isohexane, 1:9) (400 MHz, DMSO)
δ: 1.22 (s, 12H), 5.50 (d, J 46.7, 4H), 7.51 (s, 2H) 2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (500 mg, 22%) 2-(difluoromethyl)-6-methylpyridine (1.2 g, 8.4 mmol) and bis(pinacolato)diborone (4.3 g, 16.8 mmol) were heated at 60°C for 2 hours according to the standard procedure. TLC R _f : band from baseline to 0.3 (EtOAc/isohexane, 1:9) (400 MHz, DMSO)
δ: 1.32 (s, 12H), 2.55 (s, 3H), 6.94 (t, J 55, 1H), 7.61 (s, 1H), 7.63 (s, 1H) 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (551 mg, 73%) 2-ethyl-6-(trifluoromethyl)pyridine (440 mg, 2.50 mmol) and bis(pinacolato)diborone (1.27 g, 5.00 mmol) according to the standard procedure. Mass spectroscopy: m/z 302.1 (M+H) ⁺ (ES+); at 0.93 min (method A). (400 MHz, DMSO) δ: 1.25 (t, 3H, J 8.0), 1.33 (s, 12H), 2.88 (q, 2H, J 8.0), 7.74 (s, 1H), 7.77 (s, 1H). 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (473 mg, 67%) 2-cyclopropyl-6-(trifluoromethyl)pyridine (423 mg, 2.25 mmol) and bis(pinacolato)diborone (1.14 g, 4.50 mmol) according to the standard procedure. Mass spectroscopy: m/z 314.1 (M+H) ⁺ (ES+); at 1.02 min (method A). (400 MHz, DMSO) δ: 0.92 – 0.97 (m, 2H), 1.02 – 1.08 (m, 2H), 1.33 (s, 12H), 2.29 – 2.36 (m, 1H), 7.63 (s, 1H), 7.79 (s, 1H). 2-(azetidin-1-yl)-6-trifluoromethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (68%) 2-(azetidin-1-yl)-6-(trifluoromethyl)pyridine (807 mg, 3.99 mmol) and bis(pinacolato)diborone (2.03 g, 7.98 mmol) were heated at 70ºC for 2.0 hours according to the standard procedure. Mass spectroscopy: m/z 329.0 (M+H) ⁺ (ES ⁺ ), at 1.00 min, 98% (method A). (400 MHz, CDCl₃) δ: 1.31 (s, 12H), 2.35 (quint, J 7.5, 2H), 4.03 (t, J 7.5 Hz, 4H), 6.74 (s, 1H), 7.06 (s, 1H). 2-methyl-6-(morpholin-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.09 g, 92%) 4-(6-methylpyridin-2-yl)morpholine (693 mg, 3.89 mmol) and bis(pinacolato)diborone (1.97 g, 7.78 mmol) were heated at 70ºC for 4.0 hours according to the standard procedure Mass spectroscopy: m/z 305.0 (M+H) ⁺ (ES ⁺ ), at 2.02 min, ~80% (method A).
TLC R _f : 0.3 (DCM/MeOH, 1:9 (5% NH ₃ )) 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-trifluoromethylpyridine (2.6 g, 68%). bis(pinacolato)diborone (1.99 g, 7.9 mmol) and 2-trifluoromethyl-6-chloropyridine (2.2 g, 12.1 mmol) HPLC purity: 95.87% (273 nm)
Mass spectroscopy: (ESI +ve) 308.1 [M+H] ⁺ _. (400 MHz, DMSO) δ: 1.31 (s, 12 H), 7.88 (s, 1H), 7.89 (s, 1H).

Example 1

General procedure for the preparation of 5,6-biaryl-3-amino-1,2,4-triazines

Arylboronic acid (0.92 mmol) and K ₂ CO ₃ ( 0.23 g, 1.67 mmol). The resulting mixture was diluted with water (1.0 mL), degassed, tetrakis(triphenylphosphine)palladium (0.05 g, 0.04 mmol) was added and stirred at 150°C for 2.25 h with TLC monitoring (hexane/ethyl acetate, 5:5). At the end of the reaction, the mixture was diluted with water (30 ml) and extracted with ethyl acetate (3 x 20 ml); the combined organic extracts were then dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude product, product A, was purified by gradient flash chromatography or preparative HPLC.

(i) 5,6-diphenyl-1,2,4-triazine-3-amine

5,6-Diphenyl-1,2,4-triazine-3-amine (86.0 mg, 42%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.21 g, 0.8 mmol) and phenylboronic acid (0.11 g, 0.92 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.6% (261 nm)

Mass spectroscopy: (ESI +ve) 249.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.49 (s, 2H), 7.30-7.37 (m, 5H), 7.40-7.43 (m, 3H,) 7.45-7.46 (m, 1H), 7.47-7.51 (m, 1H).

(ii) 6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (106 mg, 47%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.8 mmol) and 3-methoxyphenylboronic acid (0.137 g, 0.90 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.58% (223 nm)

Mass spectroscopy: (ESI +ve) 278.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.72 (s, 3H), 5.47 (s, 2H), 6.88-6.94 (m, 2H), 7.03 (m, 1H), 7.20 (t, 1H), 7.33 (m, 2H), 7.40 (m, 1H), 7.44 (m, 2H).

(iii) 6-(4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(4-Fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine (99 mg, 46%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.80 mmol) and 4-fluorophenylboronic acid (0.112 g, 0.80 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.93% (261 nm)

Mass spectroscopy: (ESI +ve) 267.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.49 (s, 2H), 6.99 (m, 2H), 7.31-7.37 (m, 2H), 7.37-7.46 (m, 5H).

(iv) 6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(5-Chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (57 mg, 22%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.21 g, 0.80 mmol) and 5-chloro-2-methoxyphenylboronic acid (0.15 g, 0.80 mmol) according to the general procedure described in Example 1.

HPLC purity: 98.73% (229 nm)

Mass spectroscopy: (ESI +ve) 312.9 [M] ⁺ ,

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.16 (s, 3H), 5.46 (s, 2H), 6.62 (d, 1H), 7.26-7.33 (m, 3H), 7.37 (m, 1H), 7.44 (m, 2H), 7.66 (d, 1H).

(v) 6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(2-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (103 mg, 45%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.80 mmol) and 2-chlorophenylboronic acid (0.125 g, 0.80 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.27% (245 nm)

Mass spectroscopy: (ESI +ve) 282.9 [M] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.62 (s, 2H), 7.26-7.32 (m, 2H), 7.33-7.36 (m, 4H) 7.43-7.45 (m, 2H), 7.52 (m, 1H).

(vi) 6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (110 mg, 49%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.80 mmol) and 3-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure described in Example 1.

HPLC purity: 93.7% (261 nm)

Mass spectroscopy: (ESI +ve) 282.9 [M] ^+.

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.50 (s, 2H), 7.18-7.26 (m, 2H), 7.30-7.36 (m, 3H) 7.42-7.47 (m, 3H), 7.53 (s, 1H).

(vii) 6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(4-Chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (125 mg, 56%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.80 mmol) and 4-chlorophenylboronic acid (0.12 g, 0.80 mmol) according to the general procedure described in Example 1.

HPLC purity: 97.7% (264 nm)

Mass spectroscopy: (ESI +ve) 282.9 [M] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.46 (s, 2H), 7.28-7.33 (m, 2H), 7.35-7.38 (m, 5H) 7.42-7.46 (m, 2H).

(viii) 6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine (100 mg, 35%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.3 g, 1.19 mmol) and 2-furanboronic acid (0.16 g, 1.428 mmol) according to the general procedure described in Example 1.

HPLC purity: 95.03% (290 nm)

Mass spectroscopy: (ESI +ve) 239.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.58 (s, 2H), 6.43 (m, 1H), 6.55 (m, 1H) 7.40-7.47 (m, 3H), 7.47-7.59 (m, 3H) .

(ix) 5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazine-3-amine

5-Phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazine-3-amine (120 mg, 31%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine -3-amine (0.30 g, 1.19 mmol) and 3-trifluoromethylphenylboronic acid (0.25 g, 1.30 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.4% (262 nm)

Mass spectroscopy: (ESI +ve) 316.9 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.42 (m, 2H), 7.51 (s, 2H) 7.56 (m, 1H), 7.63 (m, 3H).

(x) 6-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazine-3-amine

6-[3-Fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazine-3-amine (149 mg, 37%) was obtained from 6-bromo-5-phenyl-1,2 ,4-triazine-3-amine (0.30 g, 1.19 mmol) and 3-fluoro-5-(trifluoromethyl)phenylboronic acid (0.27 g, 1.30 mmol) according to the general procedure described in Example 1.

HPLC purity: 94.3% (265 nm)

Mass spectroscopy: (ESI +ve) 335.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 7.36 (m, 4H), 7.45 (m, 3H), 7.61 (s, 2H) 7.64 (d, 1H).

(xi) 5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazine-3-amine

5-Phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazine-3-amine (131 mg, 37%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.30 g, 1.19 mmol) and 3,4,5-trifluorophenylboronic acid (0.23 g, 1.30 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.6% (262 nm)

Mass spectroscopy: (ESI +ve) 303.0 [M+H] ⁺ , (ESI -ve) 301.2 [MH] ^-

¹ H NMR: (400 MHz, DMSO) δ: 7.24 (t, 2H), 7.38 (m, 4H), 7.44 (m, 1H), 7.56 (s, 2H).

(xii) 6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Difluorophenyl)-5-phenyl-1,2,4-triazine-3-amine (160 mg, 47%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.30 g, 1.19 mmol) and 3,5-difluorophenylboronic acid (0.20 g, 1.30 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.3% (262 nm)

Mass spectroscopy: (ESI +ve) 284.9[M+H] ⁺ , (ESI -ve) 283.1 [MH] ^-

¹ H NMR: (400 MHz, DMSO) δ: 6.99 (d, 2H), 7.12 (t, 1H), 7.40 (m, 5H) 7.56 (s, 2H).

(xiii) 6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (130 mg, 34%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.30 g, 1.19 mmol) and 3,5-dichlorophenylboronic acid (0.42 g, 2.19 mmol) according to the general procedure described in Example 1.

HPLC purity: 90% (245 nm)

Mass spectroscopy: (ESI +ve) 316.9 [M+H] ⁺ , (ESI -ve) 315.1 [MH] ^-

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.55 (s, 2H), 7.33 (m, 3H), 7.38 (m, 2H) 7.49 (m, 3H).

(xiv) 6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(5-Chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.30 g, 1.19 mmol) and 5-chloropyridin-3-ylboronic acid (0.20 g, 1.30 mmol) according to the general procedure described in Example 1.

HPLC purity: 98.9% (262 nm)

Mass spectroscopy: (ESI +ve) 283.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 7.38 (m, 4H), 7.45 (m, 1H), 7.61 (s, 2H), 7.87 (t, 1H), 8.35 (d, 1H), 8.55 (d , 1H).

(xv) 6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine (140 mg, 29%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.40 g, 1.59 mmol) and 3-chloro-4-fluorophenylboronic acid (0.33 g, 1.91 mmol) according to the general procedure described in Example 1.

HPLC purity: 93.7% (261 nm)

Mass spectroscopy: (ESI +ve) 300.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.49 (s, 2H), 7.04 (t, 1H), 7.18 (m, 1H), 7.37 (m, 2H), 7.45 (m, 3H), 7.60 ( dd, 1H).

(xvi) 6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (36 mg, 9%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.30 g, 1.19 mmol) and 3-chloro-5-methoxyphenylboronic acid (0.27 g, 1.43 mmol) according to the general procedure described in Example 1.

HPLC purity: 99% (254 nm)

Mass spectroscopy: (ESI +ve) 312.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 3.63 (s, 3H), 6.78 (m, 1H), 6.94 (m, 2H), 7.34-7.45 (m, 5H), 7.49 (broad s, 2H) .

(xvii) 6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (193 mg, 32%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.50 g, 1.99 mmol) and 3-fluoro-5-methoxyphenylboronic acid (0.37 g, 2.19 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.6% (263 nm)

Mass spectroscopy: (ESI +ve) 296.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.69 (s, 3H), 5.56 (s, 2H), 6.59 (d, 1H) 6.70 (d, 1H), 6.78 (s, 1H), 7.35 (m , 2H), 7.45 (m, 3H).

(xviii) 6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(1H-Indol-6-yl)-5-phenyl-1,2,4-triazin-3-amine (107 mg, 23%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.4 g, 1.59 mmol) and indole-6-boronic acid (0.256 g, 1.59 mmol) according to the general procedure described in Example 1.

HPLC purity: 97.75% (222 nm)

Mass spectroscopy: (ESI +ve) 288.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 6.38 (m, 1H), 6.89 (dd, 1H), 7.26-7.40 (m, 3H), 7.42-7.62 (m, 5H), 11.12 (s, 1H) .

(xix) 6-(3-Bromophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Bromophenyl)-5-phenyl-1,2,4-triazine-3-amine (218 mg, 52%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.4 g, 1.59 mmol) and 3-bromophenylboronic acid (0.32 g, 1.59 mmol) according to the general procedure described in Example 1.

HPLC purity: 95.65% (262 nm)

Mass spectroscopy: (ESI +ve) 326.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.61 (s, 2H), 7.15 (t, 1H), 7.24 (m, 1H), 7.35 (m, 2H), 7.47 (m, 4H), 7.69 ( t, 1H).

(xx) 6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,4-Dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (52 mg, 54%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (75 mg, 0.299 mmol) and 3,4-dichlorophenylboronic acid (65.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.2% (254 nm)

Mass spectroscopy: (ESI +ve) 317.1/319.1/321.1 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 7.24 (dd, 1H), 7.35-7.47 (m, 5H), 7.53 (broad s, 2H), 7.57 (m, 1H), 7.63 (d, 1H).

(xxi) 6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine (49 mg, 62%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (75 mg, 0.299 mmol) and 3-fluorophenylboronic acid (48.1 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 267.1 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 7.10-7.20 (m, 3H), 7.31-7.44 (m, 6H), 7.45 (broad s, 2H).

(xxii) 6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(1,3-Benzodioxol-5-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 62%) was obtained from 6-bromo-5-phenyl-1,2, 4-triazin-3-amine (75 mg, 0.299 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (57.0 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: 293.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 6.05 (s, 2H), 6.52 (dd, 1H), 6.83 (m, 1H), 6.87 (m, 1H), 7.32 (broad s, 2H) , 7.35-7.43 (m, 5H).

(xxiii) 3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile (20 mg, 25%) was obtained from 6-bromo-5-phenyl-1,2,4-triazin-3 -amine (75 mg, 0.299 mmol) and 3-cyanophenylboronic acid (50.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 96.0% (254 nm)

Mass spectroscopy: (ESI +ve) 274.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 7.30-7.35 (m, 4H), 7.52 (m, 1H), 7.52 (m, 1H), 7.54 (broad s, 2H), 7.63 (m, 1H), 7.82 (m, 2H).

(xxiv) 6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Dimethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (55 mg, 60%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (75 mg, 0.299 mmol) and 3,5-dimethoxyphenylboronic acid (62.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 309.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 3.70 (s, 6H), 6.54 (m, 3H), 7.42-7.54 (m, 7H).

(xxv) 6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine (54 mg, 65%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (75 mg, 0.299 mmol) and 3,5-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 277.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 2.06 (s, 6H), 6.82 (m, 3H), 7.18-7.27 (m, 7H).

(xxvi) 6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,4-Dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine (55 mg, 67%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (75 mg, 0.299 mmol) and 3,4-dimethylphenylboronic acid (51.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 277.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 2.15 (s, 3H), 2.17 (s, 3H), 6.88 (m, 1H), 7.02 (m, 1H), 7.23 (m, 1H), 7.32 (broad s, 2H), 7.34 (m, 2H), 7.87–7.42 (m, 3H).

(xxvii) 6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazine-3-amine

6-[3-(Dimethylamino)phenyl]-5-phenyl-1,2,4-triazine-3-amine (53 mg, 60%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine -3-amine (75 mg, 0.299 mmol) and 3-(dimethylamino)phenylboronic acid (56.7 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 98.3% (254 nm)

Mass spectroscopy: (ESI +ve) 292.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 2.77 (s, 6H), 6.58 (m, 1H), 6.67 (m, 2H), 7.09 (m, 1H), 7.32 (broad s, 2H) , 7.34 (m, 2H), 7.40 (m, 3H).

(xxviii) N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide

N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide (59 mg, 62%) was obtained from 6-bromo-5-phenyl-1,2, 4-triazine-3-amine (75 mg, 0.299 mmol) and 3-acetamidophenylboronic acid (61.5 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 306.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 1.95 (s, 3H), 6.70 (m, 1H), 7.07 (m, 1H), 7.25-7.35 (m, 6H), 7.52 (m, 2H) , 7.64 (m, 1H), 9.89 (s, 1H).

(xxix) N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide

N-[3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide (42 mg, 41%) was obtained from 6-bromo-5-phenyl-1,2, 4-triazine-3-amine (75 mg, 0.299 mmol) and N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (102 mg, 0.344 mmol) according to the general procedure described in Example 1.

HPLC purity: 100% (254 nm)

Mass spectroscopy: (ESI +ve) 342.2 (M+H) ⁺

¹ H NMR: (400 MHz, d6-DMSO) δ: 2.79 (s, 3H), 7.02 (m, 1H), 7.36 (m, 1H), 7.26 (m, 2H), 7.35-7.48 (m, 7H) , 9.78 (s, 1H).

(xxx) 6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine

6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine (23 mg, 15%) was obtained from 6-bromo-5-(2,4-difluorophenyl )-1,2,4-triazine-3-amine (0.13 g, 0.40 mmol) and 3-chlorophenylboronic acid (0.07g, 0.40 mmol) according to the general procedure described in Example 1.

HPLC purity: 98.7% (260 nm).

Mass spectroscopy: (ESI +ve) 318.9 [M+H] ⁺ , 317.1 [MH] ^- .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.64 (s, 2H), 6.75 (m, 1H), 7.01 (m, 1H), 7.20 (m, 2H), 7.32 (m, 1H), 7.48 ( s, 1H), 7.54 (m, 1H).

(xxxi) 6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine

6-(3-Chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine (18 mg, 9%) was obtained from 6-bromo-5-(3-methoxyphenyl)-1, 2,4-triazine-3-amine (0.18 g, 0.60 mmol) and 3-chlorophenylboronic acid (0.10 g, 0.60 mmol) according to the general procedure described in Example 1.

HPLC purity: 88% (258 nm)

Mass spectroscopy: (ESI +ve) 313.0 [M+H] ⁺ , 311.1 [MH] ^- .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.72 (s, 3H), 6.53 (s, 2H), 7.04 (m, 3H), 7.23-7.30 (m, 3H), 7.37 (d, 1H), 7.49 (s, 1H).

(xxxii) 6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine

6-(3-Chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (65.0 mg, 19%) was obtained from 6-bromo-5-(4-fluorophenyl)-1, 2,4-triazine-3-amine (0.30 g, 1.11 mmol) and 3-chlorophenylboronic acid (0.19 g, 1.23 mmol) according to the general procedure described in Example 1.

HPLC purity: 98% (261 nm)

Mass spectroscopy: (ESI +ve) 300.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.47 (s, 2H), 7.03 (m, 2H), 7.19-7.26 (m, 3H), 7.33 (m, 1H), 7.47 (m, 2H), 7.53 (m, 1H).

(xxxiii) 6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(2-Methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (108 mg, 48%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.21 g, 0.80 mmol) and 2-methoxyphenylboronic acid (0.137 g, 0.90 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.28% (223 nm)

Mass spectroscopy: (ESI +ve) 278.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.20 (s, 3H), 5.49 (s, 2H), 6.70 (t, 1H) 7.10 (m, 2H), 7.26 (m, 1H), 7.32-7.39 (m, 2H), 7.43 (m, 2H), 7.64 (dd, 1H).

(xxxiv) 6-(3-Trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (170 mg, 25%) was prepared from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenylboronic acid (0.44 g, 2.13 mmol) according to the general procedure described in Example 1.

HPLC purity: 99% (262 nm)

Mass spectroscopy: (ESI +ve) 332.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl3) δ: 5.46 (s, 2H), 7.19 (m, 1H), 7.25 (m, 1H) 7.36 (m, 3H), 7.43 (t, 4H).

(xxxv) 6-(1-Benzofuran-5-yl)-5-phenyl-1,2,4-triazine-3-amine

6-(1-Benzofuran-5-yl)-5-phenyl-1,2,4-triazin-3-amine (225 mg, 47%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.50 g, 1.99 mmol) and benzofuran-5 boronic acid (0.32 g, 1.99 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.61% (245 nm)

Mass spectroscopy: (ESI +ve) 288.9 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 6.92 (m, 1H), 7.20 (m, 1H), 7.27 (m, 2H), 7.36 (m, 5H), 7.52 (d, 1H), 7.66 (d , 1H), 7.98 (d, 1H).

(xxxvi) 5-Phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazine-3-amine

5-Phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazin-3-amine (110 mg, 33%) was obtained from 6-bromo-5-phenyl-1,2 ,4-triazine-3-amine (0.3 g, 1.19 mmol) and 3-isopropyl-phenylboronic acid (0.215 g, 1.31 mmol) according to the general procedure described in Example 1.

HPLC purity: 99.78% (262 nm)

Mass spectroscopy: (ESI +ve) 291.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 1.09 (d, 6H), 2.79 (m, 1H), 5.48 (broad s, 2H), 7.19 (m, 2H), 7.31 (m, 4H), 7.44 (m, 3H).

(xxxvii) 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine

6-(3,5-Dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (0.11 g, 17.6%) was obtained from 6-bromo-5-(4-fluorophenyl)- 1,2,4-triazine-3-amine (0.5 g, 1.18 mmol) and 3,5-dichloro-phenylboronic acid (0.47 mg, 2.4 mmol) according to the general procedure described in Example 1.

HPLC purity: 97.46% (225 nm)

Mass spectroscopy: (ESI +ve) 334.9 [M] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 7.24 (m, 2H), 7.34 (m, 2H), 7.45 (m, 2H), 7.58 (m, 3H).

(xxxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol

4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol (0.450 g, 18%) was obtained from 6-bromo-5-phenyl -1,2,4-triazine-3-amine (1.9 g, 7.52 mmol) and 3-isopropoxy-4-hydroxyphenylboronic acid pinacol ester (2.5 g, 9.02 mmol) according to the general procedure described in Example 1.

HPLC purity: 94.14% (290 nm)

Mass spectroscopy: (ESI +ve) 323.1 [M+H] ⁺ (ESI -ve) 321.1 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 1.04 (d, 6H), 4.20 (m, 1H), 6.68 (m, 1H), 6.70 (m, 1H), 6.84 (m, 1H), 7.26 (broad s, 2H), 7.32–7.44 (m, 5H), 9.01 (s, 1H).

The compounds shown in the table below were prepared according to the general procedure described for Example 1 by reacting the respective starting compounds at 140° C. for 1 hour.

No. Product (output) Derived from LCMS NMR (xxxix) 6-(3,5-bis(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (50.2 mg, 0.131 mmol, 36.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3,5-bis(trifluoromethyl)phenylboronic acid (106 mg, 0.412 mmol) Mass spectroscopy: m/z 385.3 (M+H) ⁺ (ES ⁺ ); 383.5 (MH)- (ES-), at 4.89 min, 100% (method B). (400 MHz, DMSO) δ: 7.35 – 7.43 (m, 4H), 7.44 – 7.50 (m, 1H), 7.68 (s, 2H), 7.94 (s, 2H), 8.06 (s, 1H). (xl) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenol (42.5 mg, 0.139 mmol, 38.7%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and -methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenol (103 mg, 0.412 mmol) Mass spectroscopy: m/z 295.2 (M+H) ⁺ (ES ⁺ ); 293.4 (MH)- (ES-), at 2.70 min, 96.0% (method B). (400 MHz, DMSO) δ: 3.55 (s, 3H), 6.65 – 6.76 (m, 2H), 6.85 (d, J 1.8, 1H), 7.28 (s, 2H), 7.33 – 7.45 (m, 5H), 9.18 (s, 1H). (xli) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylphenol (41.3 mg, 0.141 mmol, 39.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenol (102 mg, 0.412 mmol) Mass spectroscopy: m/z 293.2 (M+H) ⁺ (ES ⁺ ); 291.4 (MH)- (ES-), at 3.57 min, 100% (method B). (400 MHz, DMSO) δ: 2.06 (s, 6H), 6.87 (s, 2H), 7.31 – 7.64 (m, 7H), 8.46 (s, 1H). (xlii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol (26.8 mg, 0.085 mmol, 23.78%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-chloro-4-hydroxyphenylboronic acid (64.9 mg, 0.376 mmol) Mass spectroscopy: m/z (Cl) 299.2/301.2 (M+H) ⁺ (ES ⁺ ); 297.4/299.4 (MH)- (ES-), at 2.15 min, 97.1% (method B). (400 MHz, DMSO) δ: 6.87 (d, J 8.4, 1H), 7.03 (dd, J 8.4, 2.2, 1H), 7.31 (d, J 2.2, 1H), 7.33 – 7.47 (m, 7H), 10.38 (s, 1H). (xiii) 6-(2-chloropyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine (22.5 mg, 0.079 mmol, 22.12%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-chloropyridin-4-ylboronic acid (59.2 mg, 0.376 mmol) Mass spectroscopy: m/z (Cl) 284.1/286.1 (M+H) ⁺ (ES ⁺ ); 282.3/284.3 (MH)- (ES-), at 3.55 min, 100% (method B). (400 MHz, DMSO) δ: 7.28 (dd, J 5.2, 1.5, 1H), 7.38 – 7.53 (m, 6H), 7.74 (s, 2H), 8.33 (dd, J 5.2, 0.6, 1H). (xliv) 6-(3-(methylsulfonyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (78.8 mg, 0.241 mmol, 67.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(methylsulfonyl)phenylboronic acid (82 mg, 0.412 mmol) Mass spectroscopy: m/z 327.2 (M+H) ⁺ (ES ⁺ ); 325.4 (MH)- (ES-), at 3.12 min, 100% (method B). (400 MHz, DMSO) δ: 3.10 (s, 3H), 7.33–7.48 (m, 5H), 7.50–7.68 (m, 4H), 7.83–7.91 (m, 2H). (xlv) 6-(3,5-dichloro-4-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (52 mg, 0.147 mmol, 41.1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3,5-dichloro-4-methoxyphenylboronic acid (83 mg, 0.376 mmol) Mass spectroscopy: m/z (2Cl) 347.2/349.2/351.2 (M+H) ⁺ (ES ⁺ ); 345.3/347.3/349.4 (MH)- (ES-), at 4.57 min, 91.0% (method B). (400 MHz, DMSO) δ: 3.83 (s, 3H), 7.37 – 7.50 (m, 7H), 7.55 (s, 2H). (xlvi) 6-(4-methoxy-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (53.4 mg, 0.154 mmol, 51.6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (75 mg, 0.299 mmol) and 4-methoxy-3-(trifluoromethyl)phenylboronic acid (76 mg, 0.344 mmol) Mass spectroscopy: m/z 347.2 (M+H) ⁺ (ES ⁺ ); 345.4 (MH)- (ES-), at 4.25 min, 100% (method B). (400 MHz, DMSO) δ: 3.88 (s, 3H), 7.21 (d, J 8.6, 1H), 7.33 – 7.50 (m, 7H), 7.51 – 7.59 (m, 2H). (xlvii) 6-(3-chloro-5-(dimethylamino)phenyl)-5-phenyl-1,2,4-triazine-3-amine (68.3 mg, 0.204 mmol, 57.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-chloro-N,N-dimethyl-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)aniline (106 mg, 0.376 mmol) Mass spectroscopy: m/z (Cl) 326.3/328.2 (M+H) ⁺ (ES ⁺ ); 324.4/326.4 (MH)- (ES-), at 4.53 min, 100% (method B). (400 MHz, DMSO) δ: 2.75 (s, 6H), 6.47–6.53 (m, 1H), 6.61–6.68 (m, 2H), 7.30–7.54 (m, 7H). (xlviii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)benzonitrile (47.5 mg, 0.137 mmol, 38.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5-(trifluoromethyl)benzonitrile (122 mg, 0.412 mmol) Mass spectroscopy: m/z 342.9 (M+H) ⁺ (ES ⁺ ); 341.0 (MH)- (ES-), at 4.25 min, 98.4% (method B). (400 MHz, DMSO) δ: 7.36 – 7.42 (m, 4H), 7.43 – 7.51 (m, 1H), 7.69 (s, 2H), 7.90 (s, 1H), 8.09 (s, 1H), 8.31 (s , 1H). (xlix) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (72.4 mg, 0.233 mmol, 65.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzonitrile (106 mg, 0.412 mmol) Mass spectroscopy: m/z 302.2 (M+H) ⁺ (ES ⁺ ); 300.4 (MH)-(ES-), at 4.14 min, 100% (method B). (400 MHz, DMSO) δ: 2.37 (s, 6H), 7.22 (s, 2H), 7.35 – 7.42 (m, 4H), 7.43 – 7.49 (m, 1H), 7.57 (s, 2H). (l) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (42.5 mg, 0.117 mmol, 32.6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (115 mg, 0.376 mmol) Mass spectroscopy: m/z 351.9 (M+H) ⁺ (ES ⁺ ); 350.0 (MH)- (ES-), at 4.80 min, 96.4% (method B). (400 MHz, DMSO) δ: 7.35 – 7.43 (m, 4H), 7.44 – 7.49 (m, 1H), 7.55 (s, 1H), 7.63 (s, 2H), 7.72 (s, 1H), 7.82 (s , 1H). (li) 6-(3-chloro-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine (65.1 mg, 0.219 mmol, 61.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-chloro-5-methylphenylboronic acid (64.1 mg, 0.376 mmol) Mass spectroscopy: m/z (Cl) 297.1/299.3 (M+H) ⁺ (ES ⁺ ); 295.3/297.3 (MH)- (ES-), at 4.55 min, 100% (method B). (400 MHz, DMSO) δ: 2.24 (s, 3H), 7.07–7.12 (m, 1H), 7.13–7.17 (m, 1H), 7.21–7.25 (m, 1H), 7.33–7.57 (m, 7H) . (lii) 6-(3-(methylthio)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (66 mg, 0.181 mmol, 50.5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(methylthio)-5-(trifluoromethyl)phenylboronic acid (97 mg, 0.412 mmol) Mass spectroscopy: m/z 363.2 (M+H) ⁺ (ES ⁺ ); 361.4 (MH)- (ES-), at 4.75 min, 99.4% (method B). (400 MHz, DMSO) δ: 2.33 (s, 3H), 7.35–7.43 (m, 6H), 7.43–7.47 (m, 1H), 7.57 (s, 2H), 7.49 (s, 1H). (iii) 6-(3-methoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (62.9 mg, 0.179 mmol, 49.9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-methoxy-5-(trifluoromethyl)phenylboronic acid (91 mg, 0.412 mmol) Mass spectroscopy: m/z 347.2 (M+H) ⁺ (ES ⁺ ); 345.4 (MH)- (ES-), at 4.52 min, 99.5% (method B). (400 MHz, DMSO) δ: 3.71 (s, 3H), 7.14–7.22 (m, 3H), 7.35–7.42 (m, 4H), 7.42–7.47 (m, 1H), 7.55 (s, 2H). (liv) 6-(3-ethoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (76.4 mg, 0.211 mmol, 58.8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-ethoxy-5-(trifluoromethyl)phenylboronic acid (96 mg, 0.412 mmol) Mass spectroscopy: m/z 361.2 (M+H) ⁺ (ES ⁺ ); 359.5 (MH)- (ES-), at 4.74 min, 99.4% (method B). (400 MHz, DMSO) δ: 1.23 (t, J 7.0, 3H), 3.97 (q, J 7.0, 2H), 7.12 – 7.15 (m, 1H), 7.15 – 7.17 (m, 1H), 7.18 – 7.21 ( m, 1H), 7.34–7.48 (m, 5H), 7.54 (s, 2H). (lv) 6-(3-tert-butyl-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine (80 mg, 0.249 mmol, 69.5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-tert-butyl-5-methylphenylboronic acid (79 mg, 0.412 mmol) Mass spectroscopy: m/z 319.5 (M+H) ⁺ (ES ⁺ ); 317.5 (MH)- (ES-), at 4.99 min, 99.1% (method B). (400 MHz, DMSO) δ: 1.03 (s, 9H), 2.31 (s, 3H), 6.80 – 6.85 (m, 1H), 7.11 – 7.15 (m, 1H), 7.24 – 7.28 (m, 1H), 7.30 – 7.44 (m, 7H). (lvi) 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (52.5 mg, 0.170 mmol, 47.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (100 mg, 0.394 mmol) Mass spectroscopy: m/z (Cl) 298.1/300.1 (M+H) ⁺ (ES ⁺ ); 296.3/298.3 (MH)- (ES-), at 3.73 min, 99.6% (method B). (400 MHz, DMSO) δ: 2.39 (s, 3H), 7.08 – 7.13 (m, 1H), 7.24 – 7.30 (m, 1H), 7.39 – 7.45 (m, 4H), 7.46 – 7.53 (m, 1H) , 7.71 (s, 2H). (lvii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorobenzonitrile (29 mg, 0.092 mmol, 25.7%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-chloro-4-cyanophenylboronic acid (71.5 mg, 0.394 mmol) Mass spectroscopy: m/z (Cl) 308.1/310.1 (M+H) ⁺ (ES ⁺ ); 306.3/308.3 (MH)- (ES-), at 4.02 min, 97.9% (method B). (400 MHz, DMSO) δ: 7.36 – 7.44 (m, 5H), 7.44 – 7.50 (m, 1H), 7.69 (s, 2H), 7.73 (d, J 1.3, 1H), 7.91 (d, J 8.2, 1H). (lviii) 6-(3-ethylphenyl)-5-phenyl-1,2,4-triazine-3-amine (70 mg, 0.252 mmol, 70.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-ethylphenylboronic acid (61.8 mg, 0.412 mmol) Mass spectroscopy: m/z 277.2 (M+H) ⁺ (ES ⁺ ); 275.4 (MH)- (ES-), at 4.49 min, 99.5% (method B). (400 MHz, DMSO) δ: 1.03 (t, J 7.6, 3H), 2.51 (q, J 7.6, 2H), 7.12 – 7.18 (m, 3H), 7.20 – 7.26 (m, 1H), 7.31 – 7.45 ( m, 7H). (lix) 6-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (61.6 mg, 0.176 mmol, 49.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (125 mg, 0.412 mmol) Mass spectroscopy: m/z 348.2 (M+H) ⁺ (ES ⁺ ); 346.4 (MH)- (ES-), at 4.47 min, 99.4% (method B). (400 MHz, DMSO) δ: 3.86 (s, 3H), 7.00 – 7.04 (m, 1H), 7.34 (d, J 1.1, 1H), 7.38 – 7.46 (m, 4H), 7.46 – 7.52 (m, 1H ), 7.75 (s, 2H). (lx) 6-(3-methyl-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine (41 mg, 0.116 mmol, 32.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4,4,5,5-tetramethyl-2-(3-methyl-5-(trifluoromethoxy)phenyl )-1,3,2-dioxaborolane (125 mg, 0.412 mmol) Mass spectroscopy: m/z 347.2 (M+H) ⁺ (ES ⁺ ); 345.4 (MH)- (ES-), at 4.72 min, 97.7% (method B). (400 MHz, DMSO) δ: 2.32 (s, 3H), 6.85 – 6.91 (m, 1H), 7.12 – 7.18 (m, 1H), 7.32 – 7.41 (m, 5H), 7.41 – 7.47 (m, 1H) , 7.51 (s, 2H). (lxi) 6-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (76 mg, 0.194 mmol, 54.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenylboronic acid (108 mg, 0.412 mmol) Mass spectroscopy: m/z 389.3 (M+H) ⁺ (ES ⁺ ); 387.5 (MH)- (ES-), at 4.32 min, 95.3% (method B). (400 MHz, DMSO) δ: 3.92 (s, 4H), 5.81 (s, 1H), 7.34 – 7.41 (m, 4H), 7.41 – 7.48 (m, 1H), 7.57 (s, 2H), 7.60 (s , 1H), 7.68 (s, 1H), 7.73 (s, 1H). (lxii) 5-phenyl-6-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-triazine-3-amine (86 mg, 0.246 mmol, 68.6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(2,2,2-trifluoroethoxy)phenylboronic acid (91 mg, 0.412 mmol) Mass spectroscopy: m/z 347.2 (M+H) ⁺ (ES ⁺ ); 345.4 (MH)- (ES-), at 4.30 min, 99.0% (method B). (400 MHz, DMSO) δ: 4.69 (q, J 8.9, 2H), 6.87 – 6.93 (m, 1H), 7.02 (ddd, J 8.3, 2.7, 0.8, 1H), 7.07 – 7.12 (m, 1H), 7.25 (t, J 8.0, 1H), 7.31–7.52 (m, 7H). (lxiii) 6-(3-(methoxymethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (76 mg, 0.256 mmol, 71.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(methoxymethyl)phenylboronic acid (68.4 mg, 0.412 mmol) Mass spectroscopy: m/z 293.0 (M+H) ⁺ (ES ⁺ ); 291.3 (MH)- (ES-), at 3.85 min, 98.5% (method B). (400 MHz, DMSO) δ: 3.16 (s, 3H), 4.35 (s, 2H), 7.16 – 7.22 (m, 1H), 7.25 – 7.30 (m, 2H), 7.30 – 7.37 (m, 3H), 7.36 – 7.49 (m, 5H). (lxiv) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one (50 mg, 0.177 mmol, 49.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2(1H)-one (97 mg, 0.412 mmol) Mass spectroscopy: m/z 280.0 (M+H) ⁺ (ES ⁺ ); 278.2 (MH)- (ES-), at 2.73 min, 98.6% (method B). (400 MHz, DMSO) δ: 3.44 (s, 3H), 6.23 (d, J 9.4, 1H), 7.03 (dd, J 9.4, 2.6, 1H), 7.33 – 7.50 (m, 5H), 7.51 – 7.57 ( m, 2H), 7.97 (d, J 2.5, 1H). (lxv) 6-(3-methyl-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (79 mg, 0.239 mmol, 66.6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-methyl-5-(trifluoromethyl)phenylboronic acid (84 mg, 0.412 mmol) Mass spectroscopy: m/z 331.1 (M+H) ⁺ (ES ⁺ ); 329.3 (MH)- (ES-), at 4.62 min, 99.8% (method B). (400 MHz, DMSO) δ: 2.33 (s, 3H), 7.32 (s, 1H), 7.34 – 7.41 (m, 4H), 7.41 – 7.47 (m, 1H), 7.48 – 7.60 (m, 4H). (lxvi) 6-(2-methoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 39%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (97 mg, 0.412 mmol) Mass spectroscopy: m/z 280.1 (M+H) ⁺ (ES ⁺ ); 278.4 (MH)- (ES-), at 3.60 min, 99.4% (method B). (400 MHz, DMSO) δ: 3.81 (s, 3H), 6.75 (dd, J 1.4, 0.7, 1H), 6.88 (dd, J 5.3, 1.5, 1H), 7.34 – 7.51 (m, 5H), 7.61 ( s, 2H), 8.08 (dd, J 5.3, 0.7, 1H). (lxviii) 1-(3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl)ethanone (71 mg, 0.243 mmol, 67.8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-acetylphenylboronic acid (67.6 mg, 0.412 mmol) Mass spectroscopy: m/z 291.1 (M+H) ⁺ (ES ⁺ ); 289.3 (MH)- (ES-), at 3.62 min, 99.4% (method B). (400 MHz, DMSO) δ: 2.46 (s, 3H), 7.32 – 7.52 (m, 8H), 7.52 – 7.57 (m, 1H), 7.87 – 7.93 (m, 1H), 7.93 – 7.98 (m, 1H) . (lxviii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzamide (73 mg, 0.243 mmol, 67.7%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4-carbamoylphenylboronic acid (68.0 mg, 0.412 mmol) Mass spectroscopy: m/z 292.2 (M+H) ⁺ (ES ⁺ ); 290.4 (MH)- (ES-), at 2.93 min, 96.9% (method B). (400 MHz, DMSO) δ: 7.31 – 7.46 (m, 8H), 7.48 (s, 2H), 7.81 (d, J 8.5, 2H), 7.98 (s, 1H). (lxix) 6-(4-fluoro-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (83 mg, 0.244 mmol, 68.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(4-fluoro-3-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (120 mg, 0.412 mmol) Mass spectroscopy: m/z 335.2 (M+H) ⁺ (ES ⁺ ); 333.4 (MH)- (ES-), at 4.42 min, 98.2% (method B). (400 MHz, DMSO) δ: 7.32 – 7.51 (m, 6H), 7.55 (s, 2H), 7.63 – 7.68 (m, 1H), 7.70 (dd, J 7.0, 2.1, 1H). (lxx) 6-(4-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine (72 mg, 0.257 mmol, 71.7%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4-fluoro-3-methylphenylboronic acid (63.5 mg, 0.412 mmol) Mass spectroscopy: m/z 281.1 (M+H) ⁺ (ES ⁺ ); 279.3 (MH)- (ES-), at 4.32 min, 100% (method B). (400 MHz, DMSO) δ: 2.19 (s, 3H), 7.00–7.09 (m, 2H), 7.32–7.46 (m, 8H). (lxxi) 6-(3-bromo-5-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine (30 mg, 0.083 mmol, 23.14%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3-bromo-5-chlorophenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (116 mg, 0.366 mmol) Mass spectroscopy: m/z (Br) 361.2/363.1/365.1 (M+H) ⁺ (ES ⁺ ); 359.3/361.3/363.3 (MH)- (ES-), at 5.07 min, 100% (method B). (400 MHz, DMSO) δ: 7.36 – 7.38 (m, 1H), 7.39 – 7.44 (m, 4H), 7.44 – 7.50 (m, 2H), 7.59 (s, 2H), 7.69 (t, J 1.9, 1H ). (lxxxii) 6-(naphthalene-2-yl)-5-phenyl-1,2,4-triazin-3-amine (83 mg, 0.278 mmol, 77%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and naphthalene-2-ylboronic acid (70.9 mg, 0.412 mmol) Mass spectroscopy: m/z 299.2 (M+H) ⁺ (ES ⁺ ), at 4.67 min, 99.8% (method B). (400 MHz, DMSO) δ: 7.28 – 7.36 (m, 3H), 7.37 – 7.48 (m, 5H), 7.48 – 7.56 (m, 2H), 7.81 (d, J 8.7, 1H), 7.83 – 7.92 (m , 2H), 8.02 (s, 1H). (lxiii) 5-phenyl-6-m-tolyl-1,2,4-triazine-3-amine (73.4 mg, 0.278 mmol, 78%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and m-tolylboronic acid (56.0 mg, 0.412 mmol) Mass spectroscopy: m/z 263.2 (M+H) ⁺ (ES ⁺ ); 261.3 (MH)- (ES-), at 4.43 min, 99.4% (method B). (400 MHz, DMSO) δ: 2.26 (s, 3H), 6.97–7.02 (m, 1H), 7.11–7.20 (m, 2H), 7.26 (s, 1H), 7.30–7.45 (m, 7H). (lxxiv) 5-phenyl-6-(pyridin-4-yl)-1,2,4-triazine-3-amine (16 mg, 0.064 mmol, 17.78%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and pyridin-4-ylboronic acid (50.7 mg, 0.412 mmol) Mass spectroscopy: m/z 250.2 (M+H) ⁺ (ES ⁺ ); 248.3 (MH)- (ES-), at 3.34 min, 99.3% (method B). (400 MHz, DMSO) δ: 7.32 (dd, J 4.4, 1.7, 2H), 7.34 – 7.43 (m, 4H), 7.43 – 7.50 (m, 1H), 7.63 (s, 2H), 8.51 (dd, J 4.5, 1.6, 2H). (lxxv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenol (21 mg, 0.078 mmol, 21.81%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenol (91 mg, 0.412 mmol) Mass spectroscopy: m/z 265.1 (M+H) ⁺ (ES ⁺ ); 263.4 (MH)- (ES-), at 2.77 min, 98.4% (method B). (400 MHz, DMSO) δ: 6.69 (d, J 8.7, 2H), 7.12 (d, J 8.6, 2H), 7.26 (s, 2H), 7.31 – 7.44 (m, 5H), 9.59 (s, 1H) . (lxxvi) 6-(2,6-dimethoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (61 mg, 0.196 mmol, 54.8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (109 mg, 0.412 mmol) Mass spectroscopy: m/z 310.2 (M+H) ⁺ (ES ⁺ ); 308.4 (MH)- (ES-), at 4.27 min, 99.6% (method B). (400 MHz, DMSO) δ: 3.79 (s, 6H), 6.29 (s, 2H), 7.35 – 7.49 (m, 5H), 7.58 (s, 2H). (lxxviii) 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (44 mg, 0.154 mmol, 42.8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (96 mg, 0.412 mmol) Mass spectroscopy: m/z 278.2 (M+H) ⁺ (ES ⁺ ); 276.4 (MH)- (ES-), at 3.77 min, 96.8% (method B). (400 MHz, DMSO) δ: 2.33 (s, 6H), 6.97 (s, 2H), 7.35 – 7.43 (m, 4H), 7.43 – 7.50 (m, 1H), 7.58 (s, 2H). (lxxviii) 5-phenyl-6-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-triazine-3-amine (31 mg, 0.098 mmol, 27.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(trifluoromethyl)pyridin-4-ylboronic acid (79 mg, 0.412 mmol) Mass spectroscopy: m/z 318.2 (M+H) ⁺ (ES ⁺ ); 316.4 (MH)- (ES-), at 4.03 min, 100% (method B). (400 MHz, DMSO) δ: 7.37 – 7.45 (m, 4H), 7.46 – 7.53 (m, 1H), 7.63 (dd, J 5.0, 1.2, 1H), 7.75 (s, 1H), 7.77 (s, 2H ), 8.70 (d, J 5.1, 1H). (lxxxix) 6-(2-cyclopropylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (61 mg, 0.206 mmol, 57.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (101 mg, 0.412 mmol) Mass spectroscopy: m/z 290.1 (M+H) ⁺ (ES ⁺ ); 288.4 (MH)- (ES-), at 3.92 min, 97.5% (method B). (400 MHz, DMSO) δ: 0.76 – 0.83 (m, 2H), 0.87 – 0.93 (m, 2H), 1.96 – 2.06 (m, 1H), 6.97 (dd, J 5.1, 1.7, 1H), 7.25 (dd , J 1.6, 0.8, 1H), 7.35–7.44 (m, 4H), 7.44–7.51 (m, 1H), 7.60 (s, 2H), 8.28 (dd, J 5.1, 0.6, 1H). (lxxx) 5-phenyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1,2,4-triazin-3-amine (85 mg, 0.269 mmol, 75%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl- 3,6-dihydro-2H-pyran-4-yl)-1,3,2-dioxaborolane (110 mg, 0.412 mmol) Mass spectroscopy: m/z 311.2 (M+H) ⁺ (ES ⁺ ); 309.4 (MH)- (ES-), at 4.40 min, 98.2% (method B). (400 MHz, DMSO) δ: 1.01 (s, 6H), 1.16 (s, 6H), 2.28 (d, J 1.3, 2H), 5.46 (t, J 1.4, 1H), 7.29 (s, 2H), 7.43 – 7.50 (m, 3H), 7.56 – 7.61 (m, 2H). (lxxxi) 6-(5-chloro-2-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine (10 mg, 0.031 mmol, 8.64%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 5-chloro-2-fluoro-3-methylphenylboronic acid (78 mg, 0.412 mmol) Mass spectroscopy: m/z (Cl) 315.8/317.8 (M+H) ⁺ (ES ⁺ ), at 4.67 min, 97.5% (method B). (400 MHz, DMSO) δ: 2.07 (d, J 1.9, 3H), 7.33–7.47 (m, 6H), 7.50 (dd, J 5.9, 2.8, 1H), 7.60 (s, 2H). (lxxxii) 6-(2,6-dichloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (7 mg, 0.022 mmol, 2.205%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (250 mg, 0.996 mmol) and 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (286 mg, 1.045 mmol) Mass spectroscopy: m/z (2 Cl) 318.0/320.1/322.1 (M+H) ⁺ (ES ⁺ ); 316.3/318.2/320.2 (MH)- (ES-), at 4.34 min, 94.8% (method B). (400 MHz, DMSO) δ: 7.41 – 7.48 (m, 6H), 7.48 – 7.55 (m, 1H), 7.85 (s, 2H). (lxxxiii) 6-(3-bromo-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine (23 mg, 0.055 mmol, 16.47%) 6-iodo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.335 mmol) and 3-bromo-5-(trifluoromethoxy)phenylboronic acid (119 mg, 0.419 mmol) Mass spectroscopy: m/z (Br) 411.8/413.8 (M+H) ⁺ (ES ⁺ ); 410.0/412.0 (MH)- (ES-), at 5.15 min, 98.8% (method B). (400 MHz, DMSO) δ: 7.14 – 7.19 (m, 1H), 7.36 – 7.42 (m, 4H), 7.42 – 7.49 (m, 1H), 7.57 – 7.66 (m, 2H), 7.63 – 7.66 (m, 1H), 7.67–7.70 (m, 1H). (lxxxiv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chloro-6-methoxyphenol (72 mg, 0.215 mmol, 28.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)phenol (248 mg, 0.870 mmol) Mass spectroscopy: m/z (Cl) 329.0/331.1 (M+H) ⁺ (ES ⁺ ); 327.2/329.0 (MH)- (ES-), at 2.61 min, 98.2% (method B). (400 MHz, DMSO) δ: 3.58 (s, 3H), 6.80 (d, J 2.0, 1H), 6.92 (d, J 2.0, 1H), 7.34 – 7.47 (m, 7H), 9.62 (s, 1H) . (lxxxv) 6-(3,5-dichloro-4-ethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (81 mg, 0.214 mmol, 59.8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3,5-dichloro-4-ethoxyphenyl)-4,4,5,5-tetramethyl -1,3,2-dioxaborolane (131 mg, 0.412 mmol) Mass spectroscopy: m/z (2 Cl) 361.8/363.9 (M+H) ⁺ (ES ⁺ ); 360.1/362.1 (MH)- (ES-), at 5.02 min, 95.6% (method B). (400 MHz, DMSO) δ: 1.36 (t, J 7.0, 3H), 4.05 (q, J 7.0, 2H), 7.36 – 7.50 (m, 7H), 7.55 (s, 2H). (lxxxvi) 6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 0.089 mmol, 24.78%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-3-(trifluoromethyl)pyridine-2-amine (119 mg, 0.412 mmol) Mass spectroscopy: m/z 333.7 (M+H) ⁺ (ES ⁺ ); 331.8 (MH)- (ES-), at 3.80 min, 98.4% (method B). (400 MHz, DMSO) δ: 6.66 (s, 2H), 7.32–7.50 (m, 7H), 7.62–7.67 (m, 1H), 8.01–8.09 (m, 1H). (lxxxviii) 4-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (70 mg, 0.219 mmol, 65.5%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (99 mg, 0.385 mmol) Mass spectroscopy: m/z 320.9 (M+H) ⁺ (ES ⁺ ); 319.1 (MH)- (ES-), at 4.37 min, 99.9% (method B). (400 MHz, DMSO) δ: 2.39 (s, 6H), 7.11 – 7.17 (m, 1H), 7.25 (s, 2H), 7.26 – 7.35 (m, 2H), 7.37 – 7.44 (m, 1H), 7.64 (s, 2H). (lxxxviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (54 mg, 0.141 mmol, 42.1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (118 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 369.8/371.9 (M+H) ⁺ (ES ⁺ ); 368.0/370.0 (MH)- (ES-), at 4.99 min, 96.1% (method B). (400 MHz, DMSO) δ: 7.15 – 7.21 (m, 1H), 7.25 – 7.36 (m, 2H), 7.39 – 7.46 (m, 1H), 7.55 – 7.60 (m, 1H), 7.70 (s, 2H) , 7.73–7.77 (m, 1H), 7.84–7.88 (m, 1H). (lxxxix) 6-(2-chloropyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (28 mg, 0.090 mmol, 26.9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (92 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 302.8/304.8 (M+H) ⁺ (ES ⁺ ); 301.0/303.0 (MH)- (ES-), at 3.87 min, 97.1% (method B). (400 MHz, DMSO) δ: 7.16 – 7.23 (m, 1H), 7.27 – 7.38 (m, 3H), 7.41 – 7.48 (m, 1H), 7.49 (dd, J 1.5, 0.7, 1H), 7.80 (s , 2H), 8.35 (dd, J 5.2, 0.7, 1H). (xc) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine (54 mg, 0.171 mmol, 51.1%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2-chloro-6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 316.6/318.6 (M+H) ⁺ (ES ⁺ ); 314.8/316.8 (MH)- (ES-), at 4.05 min, 99.9% (method B). (400 MHz, DMSO) δ: 2.40 (s, 3H), 7.13 – 7.16 (m, 1H), 7.16 – 7.21 (m, 1H), 7.27 – 7.29 (m, 1H), 7.29 – 7.39 (m, 2H) , 7.40–7.48 (m, 1H), 7.78 (s, 2H). (xci) 4-(3-amino-5-(4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (66 mg, 0.206 mmol, 61.7%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (99 mg, 0.385 mmol) Mass spectroscopy: m/z 320.7 (M+H) ⁺ (ES ⁺ ); 318.9 (MH)- (ES-), at 4.40 min, 99.8% (method B). (400 MHz, DMSO) δ: 2.39 (s, 6H), 7.19–7.28 (m, 4H), 7.46 (dd, J 8.8, 5.5, 2H), 7.59 (s, 2H). (xii) 6-(3-chloro-5-propoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine (71 mg, 0.202 mmol, 56.3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3-chloro-5-propoxyphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (106 mg, 0.358 mmol) Mass spectroscopy: m/z (Cl) 341.6/343.6 (M+H) ⁺ (ES ⁺ ); 339.8/341.8 (MH)- (ES-), at 5.14 min, 96.9% (method B). (400 MHz, DMSO) δ: 0.88 (t, J 7.4, 3H), 1.52 – 1.64 (m, 2H), 3.80 (t, J 6.6, 2H), 6.75 – 6.80 (m, 1H), 6.94 – 6.99 ( m, 2H), 7.35–7.47 (m, 5H), 7.50 (s, 2H). (xiii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (65 mg, 0.169 mmol, 50.5%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4, 5,5-tetramethyl-1,3,2-dioxaborolane (118 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 369.4/371.5 (M+H) ⁺ (ES ⁺ ); 367.7/369.7 (MH)- (ES-), at 5.03 min, 95.8% (method B). (400 MHz, DMSO) δ: 7.25 (t, J 8.9, 2H), 7.47 (dd, J 8.8, 5.5, 2H), 7.57 (s, 1H), 7.64 (s, 2H), 7.74 (s, 1H) , 7.84 (s, 1H). (xciv) 6-(2-chloropyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (14 mg, 0.046 mmol, 13.76%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (92 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 302.7/304.7 (M+H) ⁺ (ES ⁺ ); 300.9/302.9 (MH)- (ES-), at 3.90 min, 99.2% (method B). (400 MHz, DMSO) δ: 7.21 – 7.33 (m, 3H), 7.44 – 7.53 (m, 3H), 7.75 (s, 2H), 8.35 (d, J 5.1, 1H). (xv) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (37 mg, 0.117 mmol, 34.9%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2-chloro-6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (98 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 316.7/318.7 (M+H) ⁺ (ES ⁺ ); 314.9/316.9 (MH)- (ES-), at 4.05 min, 99.5% (method B). (400 MHz, DMSO) δ: 2.40 (s, 3H), 7.15 (s, 1H), 7.23 – 7.31 (m, 3H), 7.48 (dd, J 8.9, 5.5, 2H), 7.72 (s, 2H). (xvi) 4-(3-amino-5-(4-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (61 mg, 0.181 mmol, 57.4%) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (81 mg, 0.315 mmol) Mass spectroscopy: m/z (Cl) 336.6/338.6 (M+H) ⁺ (ES ⁺ ); 334.8/336.8 (MH)- (ES-), at 4.67 min, 99.6% (method B). (400 MHz, DMSO) δ: 2.40 (s, 6H), 7.25 (s, 2H), 7.40 – 7.50 (m, 4H), 7.61 (s, 2H). (xviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (62.5 mg, 0.157 mmol, 49.7%) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4, 5,5-tetramethyl-1,3,2-dioxaborolane (111 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 385.3/387.4 (M+H) ⁺ (ES ⁺ ); 383.5/385.5 (MH)- (ES-), at 5.25 min, 96.6% (method B). (400 MHz, DMSO) δ: 7.40 – 7.51 (m, 4H), 7.59 (s, 1H), 7.67 (s, 2H), 7.74 (s, 1H), 7.85 (s, 1H). (xviii) 5-(4-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine (12.7 mg, 0.039 mmol, 12.44%) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (87 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 318.6/320.6 (M+H) ⁺ (ES ⁺ ); 316.8/318.8 (MH)- (ES-), at 4.22 min, 98.2% (method B). (400 MHz, DMSO) δ: 7.27 (dd, J 5.2, 1.5, 1H), 7.41 – 7.54 (m, 5H), 7.77 (s, 2H), 8.35 (dd, J 5.2, 0.6, 1H). (xcix) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (46.1 mg, 0.138 mmol, 43.9%) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-chloro-6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (92 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 332.5/334.6 (M+H) ⁺ (ES ⁺ ); 330.8/332.7 (MH)- (ES-), at 4.37 min, 99.6% (method B). (400 MHz, DMSO) δ: 2.41 (s, 3H), 7.14–7.18 (m, 1H), 7.27–7.31 (m, 1H), 7.42–7.54 (m, 4H), 7.74 (s, 2H). (c) 4-(3-amino-5-(3-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (64.3 mg, 0.190 mmol, 60.3%) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)benzonitrile (81 mg, 0.315 mmol) Mass spectroscopy: m/z (Cl) 336.6/338.6 (M+H) ⁺ (ES ⁺ ); 334.8/336.8 (MH)- (ES-), at 4.59 min, 99.3% (method B). (400 MHz, DMSO) δ: 2.40 (s, 6H), 7.20 (ddd, J 7.8, 1.6, 1.0, 1H), 7.36 (pseudo t, J 7.9, 1H), 7.26 (s, 2H), 7.53 (ddd , J 8.0, 2.2, 1.0, 1H), 7.59 (pseudo t, J 1.7, 1H), 7.64 (s, 2H). (ci) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (67.6 mg, 0.169 mmol, 53.7%) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4, 5,5-tetramethyl-1,3,2-dioxaborolane (111 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 385.3/387.4 (M+H) ⁺ (ES ⁺ ); 383.5/385.6 (MH)- (ES-), at 5.20 min, 96.4% (method B). (400 MHz, DMSO) δ: 7.24 – 7.29 (m, 1H), 7.39 (pseudo td, J 7.8, 0.6, 1H), 7.51 – 7.57 (m, 2H), 7.57 – 7.61 (m, 1H), 7.69 ( s, 2H), 7.75–7.79 (m, 1H), 7.84–7.88 (m, 1H). (cii) 5-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine (32.4 mg, 0.101 mmol, 32.0%) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (87 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 318.6/320.6 (M+H) ⁺ (ES ⁺ ); 316.8/318.8 (MH)- (ES-), at 4.17 min, 99.0% (method B). (400 MHz, DMSO) δ: 7.25 – 7.29 (m, 1H), 7.31 (dd, J 5.2, 1.5, 1H), 7.40 (pseudo t, J 11.9, 1H), 7.49 – 7.53 (m, 1H), 7.54 – 7.61 (m, 2H), 7.80 (s, 2H), 8.36 (dd, J 5.2, 0.6, 1H). (iii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (51.3 mg, 0.154 mmol, 49.0%) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2-chloro-6-methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (92 mg, 0.362 mmol) Mass spectroscopy: m/z (2 Cl) 332.5/334.6 (M+H) ⁺ (ES ⁺ ); 330.8/332.7 (MH)- (ES-), at 4.30 min, 100% (method B). (400 MHz, DMSO) δ: 2.41 (s, 3H), 7.19 – 7.15 (m, 1H), 7.26 (ddd, J 7.8, 1.6, 1.1, 1H), 7.33 – 7.29 (m, 1H), 7.41 (pseudo t, J 7.9, 1H), 7.57 (ddd, J 8.0, 2.2, 1.0, 1H), 7.60 (pseudo t, J 1.7, 1H), 7.78 (s, 2H). (civ) 4-(3-amino-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazin-5-yl)benzonitrile (64.7 mg, 0.171 mmol, 52.5%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (90 mg, 0.326 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane (115 mg, 0.375 mmol) Mass spectroscopy: m/z (Cl) 376.4/378.4 (M+H) ⁺ (ES ⁺ ); 374.6/376.6 (MH)- (ES-), at 4.67 min, 99.4% (method B). (400 MHz, DMSO) δ: 7.54 – 7.58 (m, 1H), 7.57 – 7.62 (m, 2H), 7.65 – 7.81 (m, 3H), 7.83 – 7.87 (m, 1H), 7.87 – 7.93 (m, 2H). (CV) 4-(3-amino-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile (30.5 mg, 0.093 mmol, 28.6%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (90 mg, 0.326 mmol) and 2-chloro-6-methyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (95 mg, 0.375 mmol) Mass spectroscopy: m/z (Cl) 323.6/325.6 (M+H) ⁺ (ES ⁺ ); 321.8/323.8 (MH)- (ES-), at 3.65 min, 98.6% (method B). (400 MHz, DMSO) δ: 2.40 (s, 3H), 7.16 (s, 1H), 7.26 (s, 1H), 7.58 – 7.64 (m, 2H), 7.82 (s, 2H), 7.88 – 7.94 (m , 2H). (ci) 4-(3-amino-5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (57 mg, 52%) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2,6-dimethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (88 mg, 0.341 mmol) Mass spectroscopy: m/z 354, 356(M+H) ⁺ (ES ⁺ ); 352, 354(MH) ^- (ES ^- ), at 4.72 min, 95% (method B). (400 MHz, DMSO) δ: 2.41 (s, 6H), 7.11 – 7.19 (m, 1H), 7.27 (s, 2H), 7.34 – 7.38 (m, 1H), 7.55 – 7.62 (m, 1H), 7.70 (s, 2H). (cvii) 5-(3-chloro-5-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine (18 mg, 16%) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2-chloro-6-methylpyridin-4-ylboronic acid (58.4 mg , 0.341 mmol) Mass spectroscopy: m/z 350, 352 (M+H) ⁺ (ES ⁺ ); 348, 350 (MH) ^- (ES ^- ), at 4.2 min, 95% (method B). (400 MHz, DMSO) δ: 2.42 (s, 3H), 7.19 (s, 1H), 7.20 – 7.26 (m, 1H), 7.30 (s, 1H), 7.38 (s, 1H), 7.58 – 7.66 (m , 1H), 7.84 (s, 2H). (cviii) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (28 mg, 22%) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105 mg, 0.341 mmol) Mass spectroscopy: m/z 403, 405 (M+H) ⁺ (ES ⁺ ); 401, 403 (MH) ^- (ES ^- ), at 5.28 min, 93% (method B). (400 MHz, DMSO) δ: 7.22 (ddd, J 9.3, 2.4, 1.4, 1H), 7.34 – 7.39 (m, 1H), 7.58 – 7.64 (m, 2H), 7.76 (s, 2H), 7.79 (s , 1H), 7.89 (s, 1H). (cix) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (54 mg, 43%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (96 mg, 0.314 mmol) Mass spectroscopy: m/z 387, 389 (M+H) ⁺ (ES ⁺ ); 385, 387 (MH) ^- (ES ^- ), at 5.09 min, 96% (method B). (400 MHz, DMSO) δ: 7.08 – 7.20 (m, 2H), 7.42 (tt, J 9.3, 2.4, 1H), 7.58 (s, 1H), 7.66 – 7.86 (m, 3H), 7.89 (s, 1H ). (cx) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (29 mg, 27%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-chloro-6-methylpyridin-4-ylboronic acid (61.8 mg, 0.361 mmol) Mass spectroscopy: m/z 334, 336 (M+H) ⁺ (ES ⁺ ); 332, 334 (MH) ^- (ES ^- ), at 4.17 min, 98% (method B). (400 MHz, DMSO) δ: 2.42 (s, 3H), 7.11 – 7.18 (m, 2H), 7.17 – 7.20 (m, 1H), 7.25 – 7.31 (m, 1H), 7.44 (tt, J 9.3, 2.4 , 1H), 7.82 (s, 2H). (cxi) 4-(3-amino-5-(3,5-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (48 mg, 45%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (93 mg, 0.361 mmol) Mass spectroscopy: m/z 338 (M+H) ⁺ (ES ⁺ ); 336 (MH) ^- (ES ^- ), at 4.45 min, 100% (method B). (400 MHz, DMSO) δ: 2.41 (s, 6H), 7.05–7.14 (m, 2H), 7.26 (s, 2H), 7.40 (tt, J 9.3, 2.4, 1H), 7.69 (s, 2H). (cxii) 4-(3-amino-5-(3-chloro-4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (35 mg, 33%) 6-bromo-5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2,6-dimethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (88 mg, 0.341 mmol) Mass spectroscopy: m/z 354, 356 (M+H) ⁺ (ES ⁺ ); 352, 354 (MH) ^- (ES ^- ), at 4.67 min, 98% (method B). (400 MHz, DMSO) δ: 2.41 (s, 6H), 7.22 – 7.28 (m, 1H), 7.28 (s, 2H), 7.37 – 7.44 (m, 1H), 7.66 (s, 2H), 7.75 (dd , J 7.2, 2.2, 1H). (iii) 5-(3-chloro-4-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine (40 mg, 38%) 6-bromo-5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2-chloro-6-methylpyridin-4-ylboronic acid (61.8 mg , 0.361 mmol) Mass spectroscopy: m/z 350, 352 (M+H) ⁺ (ES ⁺ ); 348, 350 (MH) ^- (ES ^- ), at 4.39 min, 99% (method B). (400 MHz, DMSO) δ: 2.42 (s, 3H), 7.21 (s, 1H), 7.30 (s, 1H), 7.30 – 7.35 (m, 1H), 7.46 (pseudo t, J 8.9, 1H), 7.66 – 7.91 (m, 3H). (cxiv) 5-(3-chloro-4-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine (9 mg, 9%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-chloropyridin-4-ylboronic acid (61.8 mg, 0.361 mmol) Mass spectroscopy: m/z 336, 338 (M+H) ⁺ (ES ⁺ ); 334, 336 (MH) ^- (ES ^- ), at 4.2 min, 98% (method B). (400 MHz, DMSO) δ: 7.30 (dd, J 5.2, 1.5, 1H), 7.34 (dd, J 8.6, 4.7, 2.2, 1H), 7.42 – 7.51 (m, 1H), 7.53 – 7.57 (m, 1H ), 7.75 (dd, J 7.2, 2.1, 1H), 7.82 (s, 2H), 8.37 (dd, J 5.2, 0.6, 1H). (xv) 5-(3-chloro-4-fluorophenyl)-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazine-3-amine (50 mg, 42%) 6-bromo-5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (91 mg, 0.297 mmol) Mass spectroscopy: m/z 403, 405 (M+H)+ (ES ⁺ ); 401, 403 (MH) ^- (ES ^- ), at 5.22 min, 100% (method B). (400 MHz, DMSO) δ: 7.33 (ddd, J 8.6, 4.7, 2.2, 1H), 7.45 (pseudo t, J 8.9, 1H), 7.61 (s, 1H), 7.63 – 7.76 (m, 3H), 7.78 (s, 1H), 7.88 (s, 1H). (xvi) 4-(3-amino-5-(3,4-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (35 mg, 33%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (93 mg, 0.361 mmol) Mass spectroscopy: m/z 338 (M+H) ⁺ (ES ⁺ ); 336 (MH) ^- (ES ^- ), at 4.49 min, 99% (method B). (400 MHz, DMSO) δ: 2.41 (s, 6H), 7.10 – 7.20 (m, 1H), 7.26 (s, 2H), 7.40 – 7.50 (m, 1H), 7.54 (ddd, J 11.4, 7.8, 2.1 , 1H), 7.65 (s, 2H). (cxviii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (28 mg, 27%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-chloro-6-methylpyridin-4-ylboronic acid (61.8 mg, 0.361 mmol) Mass spectroscopy: m/z 334, 336 (M+H) ⁺ (ES ⁺ ); 332, 334 (MH) ^- (ES ^- ), at 4.15 min, 99% (method B). (400 MHz, DMSO) δ: 2.41 (s, 3H), 7.20 (s, 1H), 7.20 – 7.24 (m, 1H), 7.28 (s, 1H), 7.44 – 7.62 (m, 2H), 7.79 (s , 2H). (cxiii) 6-(2-chloropyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine (10 mg, 10%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-chloropyridin-4-ylboronic acid (56.7 mg, 0.361 mmol) Mass spectroscopy: m/z 320, 322 (M+H) ⁺ (ES ⁺ ); 318, 320 (MH) ^- (ES ^- ), at 4.0 min, 96% (method B). (400 MHz, DMSO) δ: 7.18 – 7.26 (m, 1H), 7.28 (dd, J 5.2, 1.5, 1H), 7.44 – 7.62 (m, 3H), 7.81 (s, 2H), 8.36 (dd, J 5.2, 0.6, 1H). (xix) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (16 mg, 13%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4, 4,5,5-tetramethyl-1,3,2-dioxaborolane (96 mg, 0.314 mmol) Mass spectroscopy: m/z 387, 389 (M+H) ⁺ (ES ⁺ ); 385, 387 (MH) ^- (ES ^- ), at 5.07 min, 95% (method B). (400 MHz, DMSO) δ: 7.17 – 7.26 (m, 1H), 7.43 – 7.57 (m, 2H), 7.59 (s, 1H), 7.71 (s, 2H), 7.76 (s, 1H), 7.87 (s , 1H). (cxx) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (36 mg, 0.087 mmol, 28.7%) 6-bromo-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.305 mmol) and 2-(3-chloro-5-(trifluoromethyl)phenyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 0.351 mmol) Mass spectroscopy: m/z (Cl) 395.3/397.3 (M+H) ⁺ (ES ⁺ ); 393.5/395.5 (MH)- (ES-), at 4.93 min, 95.9% (method B). (400 MHz, DMSO) δ: 3.26 (s, 3H), 4.43 (s, 2H), 7.33 (d, J 8.5, 2H), 7.39 (d, J 8.4, 2H), 7.57 (s, 1H), 7.64 (s, 2H), 7.72 (s, 1H), 7.83 (s, 1H). (xxi) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (23 mg, 0.066 mmol, 21.49%) 6-bromo-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.305 mmol) and 2-chloro-6-methyl-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (89 mg, 0.351 mmol) Mass spectroscopy: m/z (Cl) 342.6/344.5 (M+H) ⁺ (ES ⁺ ); 340.8/342.8 (MH)- (ES-), at 3.93 min, 97.4% (method B). (400 MHz, DMSO) δ: 2.39 (s, 3H), 3.28 (s, 3H), 4.45 (s, 2H), 7.08 – 7.14 (m, 1H), 7.25 – 7.31 (m, 1H), 7.35 (d , J 8.5, 2H), 7.41 (d, J 8.4, 2H), 7.72 (s, 2H). (cxxxii) 6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (23 mg, 0.078 mmol, 23.19%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2,6-dimethylpyridin-4-ylboronic acid (58.1 mg, 0.385 mmol) Mass spectroscopy: m/z 296.8 (M+H) ⁺ (ES ⁺ ); 295.0 (MH)- (ES-), at 3.85 min, 99.6% (method B). (400 MHz, DMSO) δ: 2.40 (s, 6H), 7.10 (s, 2H), 7.20 – 7.31 (m, 2H), 7.40 – 7.53 (m, 2H), 7.68 (s, 2H). (cxxxii) 6-(3-chloro-5-methylphenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (67 mg, 0.212 mmol, 63.3%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 3-chloro-5-methylphenylboronic acid (65.5 mg, 0.385 mmol) Mass spectroscopy: m/z (Cl) 315.6/317.6 (M+H) ⁺ (ES ⁺ ); 313.8/315.8 (MH)- (ES-), at 4.82 min, 99.4% (method B). (400 MHz, DMSO) δ: 2.25 (s, 3H), 7.10–7.17 (m, 2H), 7.19–7.28 (m, 3H), 7.42–7.49 (m, 2H), 7.51 (s, 2H). (cxxxiv) 6-(6-fluoropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (47 mg, 0.173 mmol, 58.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (75 mg, 0.299 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (77 mg, 0.344 mmol) Mass spectroscopy: m/z 268.2 (M+H) ⁺ (ES ⁺ ); 266.3 (MH)- (ES-), at 3.54 min, 98.5% (method B). (400 MHz, DMSO) δ: 7.17 (ddd, J 8.5, 2.8, 0.5, 1H), 7.53 (s, 2H), 7.35 – 7.48 (m, 5H), 7.86 – 7.94 (m, 1H), 8.13 – 8.19 (m, 1H). (cxxv) 6-(3,5-dimethylisoxazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine (8 mg, 0.030 mmol, 10.02%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (75 mg, 0.299 mmol) and 5-dimethylisoxazol-4-ylboronic acid (42.1 mg, 0.299 mmol) Mass spectroscopy: m/z 268.2 (M+H) ⁺ (ES ⁺ ); 266.4 (MH)- (ES-), at 3.48 min, 96.2% (method B). (400 MHz, DMSO) δ: 1.85 (s, 3H), 2.02 (s, 3H), 7.38 – 7.55 (m, 7H). (cxxvi) 6-(3,5-diisopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine (84.5 mg, 0.254 mmol, 70.9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-(3,5-diisopropylphenyl)-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (119 mg, 0.412 mmol) Mass spectroscopy: m/z 333.3 (M+H) ⁺ (ES ⁺ ); 331.5 (MH)- (ES-), at 5.24 min, 100% (254 nm). (400 MHz, DMSO) δ: 1.06 (d, J 6.9, 12H), 2.78 (hept, J 6.8, 2H), 6.96–7.06 (m, 3H), 7.31–7.45 (m, 7H). (cxxviii) 6-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine (80 mg, 0.214 mmol, 59.7%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-fluoro-5-(2,2,2-trifluoroethoxy)phenylboronic acid (98 mg, 0.412 mmol ) Mass spectroscopy: m/z 365.2 (M+H) ⁺ (ES ⁺ ); 363.4 (MH)- (ES-), at 4.43 min, 97.4% (method B). (400 MHz, DMSO) δ: 4.73 (q, J 8.8, 2H), 6.76 (ddd, J 9.5, 2.3, 1.4, 1H), 6.89 – 6.94 (m, 1H), 6.99 (dt, J 10.7, 2.3, 1H), 7.52 (s, 2H), 7.34–7.48 (m, 5H). (cxxiii) N-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(trifluoromethyl)phenyl)acetamide (99 mg, 0.255 mmol, 71.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-2-(trifluoromethyl)phenyl)acetamide (136 mg, 0.412 mmol) Mass spectroscopy: m/z 374.1 (M+H) ⁺ (ES ⁺ ); 372.3 (MH)- (ES-), at 3.52 min, 98.9% (method B). (400 MHz, DMSO) δ: 2.04 (s, 3H), 7.34–7.48 (m, 5H), 7.49–7.68 (m, 5H), 9.55 (s, 1H). (cxxxix) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-fluorobenzonitrile (43 mg, 0.147 mmol, 40.9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-cyano-4-fluorophenylboronic acid (68.0 mg, 0.412 mmol) Mass spectroscopy: m/z 292.1 (M+H) ⁺ (ES ⁺ ); 290.3 (MH)- (ES-), at 3.79 min, 99.3% (method B). (400 MHz, DMSO) δ: 7.34 – 7.42 (m, 4H), 7.42 – 7.47 (m, 1H), 7.50 (t, J 9.2, 1H), 7.57 (s, 2H), 7.67 (ddd, J 8.8, 5.3, 2.3, 1H), 7.89 (dd, J 6.2, 2.3, 1H). (cxxx) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-N,N-dimethylbenzamide (80 mg, 0.251 mmol, 69.9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(dimethylcarbamoyl)phenylboronic acid (80 mg, 0.412 mmol) Mass spectroscopy: m/z 320.2 (M+H) ⁺ (ES ⁺ ); 318.4 (MH)- (ES-), at 3.30 min, 100% (method B). (400 MHz, DMSO) δ: 2.60 (s, 3H), 2.89 (s, 3H), 7.19 – 7.24 (m, 1H), 7.31 – 7.38 (m, 3H), 7.38 – 7.47 (m, 6H), 7.48 – 7.52 (m, 1H). (cxxxi) 6-(1-methyl-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine (43 mg, 0.168 mmol, 47.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (86 mg, 0.412 mmol) Mass spectroscopy: m/z 253.2 (M+H) ⁺ (ES ⁺ ); 251.4 (MH)- (ES-), at 3.15 min, 98.8% (method B). (400 MHz, DMSO) δ: 3.77 (s, 3H), 7.04 (d, J 0.7, 1H), 7.24 (s, 2H), 7.43 – 7.56 (m, 5H), 7.64 (s, 1H). (cxxxii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one (33 mg, 0.115 mmol, 32.1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridin-2(1H)-one (97 mg, 0.412 mmol) Mass spectroscopy: m/z 280.1 (M+H) ⁺ (ES ⁺ ); 278.4 (MH)- (ES-), at 2.92 min, 97.4% (method B). (400 MHz, DMSO) δ: 3.39 (s, 3H), 6.14 (dd, J 7.0, 2.0, 1H), 6.32 (d, J 1.7, 1H), 7.38 – 7.54 (m, 5H), 7.56 – 7.70 ( m, 3H). (cxxxiii) 6-(3-morpholinophenyl)-5-phenyl-1,2,4-triazine-3-amine (65 mg, 0.192 mmol, 53.6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)phenyl)morpholine (119 mg, 0.412 mmol) Mass spectroscopy: m/z 334.3 (M+H) ⁺ (ES ⁺ ); 332.4 (MH)- (ES-), at 4.07 min, 98.6% (method B). (400 MHz, DMSO) δ: 2.87 – 3.02 (m, 4H), 3.58 – 3.72 (m, 4H), 6.74 (d, J 7.7, 1H), 6.86 – 6.94 (m, 2H), 7.16 (t, J 7.6, 1H), 7.28–7.45 (m, 7H). (cxxxiv) 6-(1-benzyl-1H-pyrazol-4-yl)-5-phenyl-1,2,4-triazin-3-amine (78 mg, 0.237 mmol, 66.1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (117 mg, 0.412 mmol) Mass spectroscopy: m/z 329.3 (M+H) ⁺ (ES ⁺ ); 327.5 (MH)- (ES-), at 4.07 min, 99.8% (method B). (400 MHz, DMSO) δ: 5.26 (s, 2H), 7.12 – 7.18 (m, 2H), 7.20 (d, J 0.7, 1H), 7.26 (s, 2H), 7.27 – 7.37 (m, 3H), 7.40–7.53 (m, 5H), 7.67 (d, J 0.7, 1H). (cxxxv) 6-(2-methoxypyrimidin-5-yl)-5-phenyl-1,2,4-triazin-3-amine (34 mg, 0.119 mmol, 33.2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-methoxypyrimidin-5-ylboronic acid (63.5 mg, 0.412 mmol) Mass spectroscopy: m/z 281.2 (M+H) ⁺ (ES ⁺ ); 279.4 (MH)- (ES-), at 3.42 min, 98.2% (method B). (400 MHz, DMSO) δ: 3.91 (s, 3H), 7.38 – 7.49 (m, 5H), 7.55 (s, 2H), 8.50 (s, 2H). (cxxxvi) 6-(6-methoxypyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine (50 mg, 0.176 mmol, 49.1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 6-methoxypyridin-3-ylboronic acid (63.0 mg, 0.412 mmol) Mass spectroscopy: m/z 280.1 (M+H) ⁺ (ES ⁺ ); 278.4 (MH)- (ES-), at 3.88 min, 98.3% (method B). (400 MHz, DMSO) δ: 3.84 (s, 3H), 6.78 (dd, J 8.6, 0.7, 1H), 7.34 – 7.48 (m, 7H), 7.60 (dd, J 8.6, 2.5, 1H), 8.10 ( dd, J 2.5, 0.7, 1H). (cxxxviii) 6-(3-(methylsulfinyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine (70 mg, 0.217 mmol, 60.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 3-(methylsulfinyl)phenylboronic acid (76 mg, 0.412 mmol) Mass spectroscopy: m/z 311.1 (M+H) ⁺ (ES ⁺ ); 309.3 (MH)- (ES-), at 3.29 min, 96.0% (method B). (400 MHz, DMSO) δ: 2.58 (s, 3H), 7.32 – 7.47 (m, 5H), 7.47 – 7.57 (m, 4H), 7.58 – 7.60 (m, J 1.3, 1H), 7.63 (dt, J 7.3, 1.7, 1H). (cxxxviii) 4-(3-amino-6-(2-chloropyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile (11.3 mg, 0.036 mmol, 10.93%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (90 mg, 0.326 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (90 mg, 0.375 mmol) Mass spectroscopy: m/z (Cl) 309.6/311.7 (M+H) ⁺ (ES ⁺ ); 307.9/309.9 (MH)- (ES-), at 3.50 min, 97.3% (method B). (400 MHz, DMSO) δ: 7.25 (dd, J 5.2, 1.5, 1H), 7.51 (dd, J 1.5, 0.7, 1H), 7.58 – 7.65 (m, 2H), 7.85 (s, 2H), 7.89 – 7.94 (m, 2H), 8.34 (dd, J 5.2, 0.6, 1H). (cxxxix) 4-(3-amino-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (47 mg, 0.132 mmol, 43.2%) 6-bromo-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.305 mmol) and 2,6-dimethyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (78 mg, 0.305 mmol) Mass spectroscopy: m/z 346.6 (M+H) ⁺ (ES ⁺ ); 344.8 (MH)- (ES-), at 4.25 min, 96.7% (method B). (400 MHz, DMSO) δ: 2.38 (s, 6H), 4.43 (s, 2H), 7.23 (s, 2H), 7.32 (d, J 8.5, 2H), 7.39 (d, J 8.4, 2H), 7.67 (s, 2H). (cxl) 6-(2-chloropyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (26 mg, 0.077 mmol, 25.3%) 6-bromo-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.305 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.351 mmol) Mass spectroscopy: m/z (Cl) 328.6/330.5 (M+H) ⁺ (ES ⁺ ); 326.8/328.8 (MH)- (ES-), at 3.79 min, 97.4% (method B). (400 MHz, DMSO) δ: 3.29 (s, 3H), 4.45 (s, 2H), 7.28 (dd, J 5.2, 1.5, 1H), 7.35 (d, J 8.5, 2H), 7.42 (d, J 8.4 , 2H), 7.48 (dd, J 1.5, 0.7, 1H), 7.74 (s, 2H), 8.33 (dd, J 5.2, 0.7, 1H). (cxli) 6(E)-5-phenyl-6-styryl-1,2,4-triazine-3-amine (27 mg, 0.098 mmol, 27.5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and (E)-styrylboronic acid (61.0 mg, 0.412 mmol) Mass spectroscopy: m/zz 275.1 (M+H) ⁺ (ES ⁺ ), at 4.78 min, 93.2% (method B). (400 MHz, DMSO) δ: 7.09 (d, J 16.0, 1H), 7.28 (t, J 7.3, 1H), 7.36 (t, J 7.5, 2H), 7.44 (s, 2H), 7.49 (d, J 7.3, 2H), 7.55–7.62 (m, 4H), 7.64–7.70 (m, 2H). (cxlii) 6-(3-amino-5-phenyl-1,2,4-triazin-6-yl)indolin-2-one (34 mg, 0.111 mmol, 31.0%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol) and 2-oxoindoline-6-ylboronic acid (72.9 mg, 0.412 mmol) Mass spectroscopy: m/z 304.7 (M+H) ⁺ (ES ⁺ ); 302.9 (MH)- (ES-), at 3.47 min, 99.1% (method B). (400 MHz, DMSO) δ: 3.48 (s, 2H), 6.80 (dd, J 7.6, 1.6, 1H), 6.86 – 6.90 (m, 1H), 7.11 (d, J 7.7, 1H), 7.31 – 7.47 ( m, 7H), 10.38 (s, 1H). (cxiii) tert-butyl 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate (120 mg, 0.308 mmol, 42.9%) 6-bromo-5-phenyl-1,2,4-triazin-3-amine (90 mg, 0.358 mmol) and 6-(tert-butoxycarbonyl(methyl)amino)pyridin-3-ylboronic acid (181 mg, 0.717 mmol ) Mass spectroscopy: m/z 379.5 (M+H) ⁺ (ES ⁺ ); 377.8 (MH)- (ES-), at 4.53 min, 97.1% (method B). (400 MHz, DMSO) δ: 1.45 (s, 9H), 3.28 (s, 3H), 7.35 – 7.48 (m, 5H), 7.49 (s, 2H), 7.60 (dd, J 8.7, 0.8, 1H), 7.66 (dd, J 8.7, 2.4, 1H), 8.30 (dd, J 2.4, 0.8, 1H). (cxliv) 5-(3-chloro-5-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine (22 mg, 22%) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol), 2-chloropyridin-4-ylboronic acid (53.7 mg, 0.341 mmol) Mass spectroscopy: m/z 336, 338 (M+H)+ (ES ⁺ ); 334, 336 (MH) ^- (ES ^- ), at 4.27 min, 100% pure (method B). (400 MHz, DMSO) δ: 7.24 (dd, J 9.2, 2.4, 1.4 Hz, 1H), 7.30 (dd, J 5.2, 1.4 Hz, 1H), 7.39 (t, J 1.4 Hz, 1H), 7.53 (dd , J 1.4, 0.6 Hz, 1H), 7.59–7.65 (m, 1H), 7.85 (s, 2H), 8.38 (dd, J 5.2, 0.6 Hz, 1H). (cxlv) 6-(2-chloropyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine (22 mg, 22%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol), 2-chloropyridin-4-ylboronic acid (56.7 mg, 0.361 mmol) Mass spectroscopy: m/z 320, 322 (M+H)+ (ES ⁺ ); 318, 320 (MH) ^- (ES ^- ), at 3.98 min, 98% pure (method B) (400 MHz, DMSO) δ: 7.11 – 7.24 (m, 2H), 7.30 (dd, J 5.1, 1.4 Hz, 1H), 7.43 (tt, J 9.3, 2.4 Hz, 1H), 7.53 (dd, J 1.4, 0.6 Hz, 1H), 7.84 (s, 2H), 8.38 (dd, J 5.1, 0.6 Hz, (cxlvi) 4-(3-amino-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile (32 mg, 30%) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.284 mmol), 2,6-dimethyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (84 mg, 0.326 mmol) Mass spectroscopy: m/z 368 (M+H) ⁺ (ES ⁺ ); 366 (MH) ^- (ES ^- ), at 4.42 min, 99% pure (method B). (400 MHz, DMSO) δ: 2.39 (s, 6H), 7.15 – 7.21 (m, 2H), 7.24 ( ^s , 2H), 7.31 (t, 2J _HF 72 Hz, 1H), 7.43 – 7.48 (m, 2H), 7.57 (s, 2H). (cxlvii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine (15 mg, 14%) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.284 mmol), 2-chloro-6-methylpyridin-4-ylboronic acid (55.9 mg, 0.326 mmol) Mass spectroscopy: m/z 364, 366 (M+H) ⁺ (ES ⁺ ); 362, 364 (MH) ^- (ES ^- ), at 4.14 min, 98% pure (method B). (400 MHz, DMSO) δ: 2.40 (s, 3H), 7.17 (s, 1H), 7.22 (d, J 8.7 Hz, 2H), 7.27 (d, J 0.7 Hz, 1H), 7.33 (t, ² J _HF 72 Hz, 1H), 7.46–7.51 (m, 2H), 7.71 (s, 2H). (cxlviii) 6-(2-chloropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine (17 mg, 17%) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.284 mmol), 2-chloropyridin-4-ylboronic acid (51.4 mg, 0.326 mmol) Mass spectroscopy: m/z 350, 352 (M+H) ⁺ (ES ⁺ ); 348, 350 (MH) ^- (ES ^- ), at 4.0 min, 98% pure (method B) (400 MHz, DMSO) δ: 7.21 (d, J 8.7 Hz, 2H), 7.29 (dd, J 5.2, 1.5 Hz, 1H), 7.34 (t, ² J _HF 72 Hz, 1H), 7.46 – 7.55 (m , 3H), 7.73 (s, 2H), 8.35 (dd, J 5.2, 0.6 Hz, 1H). (cxlix) 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (67 mg, 54%) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.284 mmol), 2-(3-chloro-5-(trifluoromethyl)phenyl)-4 ,4,5,5-tetramethyl-1,3,2-dioxaborolane (87 mg, 0.284 mmol) Mass spectroscopy: m/z 417, 419 (M+H) ⁺ (ES ⁺ ); 415, 417 (MH) ^- (ES ^- ), at 5.02 min, 95% pure (method B). (400 MHz, DMSO) δ: 7.17 – 7.23 (m, 2H), 7.31 (t, 2J ^HF ₇₂ Hz, 1H), 7.44 – 7.50 (m, 2H), 7.56 – 7.59 (m, 1H), 7.63 ( s, 2H), 7.74–7.75 (m, 1H), 7.84–7.85 (m, 1H). (cl) 5-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2-chlorophenol (16 mg, 15%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol), 4-chloro-3-hydroxyphenylboronic acid (57.7 mg, 0.334 mmol) Mass spectroscopy: m/z 317, 319 (M+H) ⁺ (ES ⁺ ); 315, 317 (MH) ^- (ES ^- ), at 2.68 min, 97% pure (method B). (400 MHz, DMSO) δ: 6.64 (dd, J 8.2, 2.0 Hz, 1H), 7.07 (d, J 2.0 Hz, 1H), 7.23 (d, J 8.2 Hz, 1H), 7.34 – 7.48 (m, 7H ), 10.26 (s, 1H). (cli) 4-(3-amino-6-(3-chloro-4-hydroxyphenyl)-1,2,4-triazin-5-yl)benzonitrile (21 mg, 23%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (75 mg, 0.272 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (76 mg, 0.299 mmol) Mass spectroscopy: m/z (Cl) 324.2/326.3 (M+H)+ (ES+); 322.1/324.2 (MH)- (ES-), at 2.48 min, 95.4% pure (method B). (400 MHz, DMSO) δ: 6.80 – 6.93 (m, 1H), 6.99 (dd, J 8.4, 2.2 Hz, 1H), 7.36 (d, J 2.2 Hz, 1H), 7.53 – 7.64 (m, 2H), 7.48 (s, 2H), 7.84–7.93 (m, 2H), 10.44 (s, 1H). (clii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol (180mg, 65%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (200 mg, 0.797 mmol), 3-hydroxy-5-(trifluoromethoxy)phenylboronic acid (265 mg, 1.195 mmol) Mass spectroscopy: m/z 349 (M+H) ⁺ (ES ⁺ ); 347 (MH) ^- (ES ^- ), at 3.22 min, 100% pure (method B). (400 MHz, DMSO) δ: 6.55 – 6.56 (m, 1H), 6.64 – 6.65 (m, 1H), 6.87 – 6.91 (m, 1H), 7.31 – 7.53 (m, 7H), 10.15 (s, 1H) . (cliii) 5-(3-chloro-5-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (40 mg, 40%) 6-bromo-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol), 2,6-dimethyl-4-(4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (79 mg, 0.341 mmol) Mass spectroscopy: m/z 330(M+H) ⁺ (ES ⁺ ); 328 (MH) ^- (ES ^- ), at 4.27 min, 98% pure (method B). (400 MHz, DMSO) δ: 2.37 (s, 6H), 7.02 (s, 2H), 7.18 (ddd, J = 9.3, 2.4, 1.4 Hz, 1H), 7.36 (t, J 1.4 Hz, 1H), 7.56 – 7.61 (m, 1H), 7.70 (s, 2H). (cliv) 5-(3,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (50 mg, 49%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol), 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.361 mmol) Mass spectroscopy: m/z 314 (M+H) ⁺ (ES ⁺ ); 312 (MH) ^- (ES ^- ), at 3.95 min, 97% pure (method B) (400 MHz, DMSO) δ: 2.37 (s, 6H), 7.01 (s, 2H), 7.04 – 7.16 (m, 2H), 7.38 – 7.44 (m, 1H), 7.70 (s, 2H). (clv) 5-(3,4-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.314 mmol), 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.361 mmol) Mass spectroscopy: m/z 314(M+H) ⁺ (ES ⁺ ); 313 (MH) ^- (ES ^- ), at 3.97 min, 99% pure (method B). (400 MHz, DMSO) δ: 2.37 (s, 6H), 7.01 (s, 2H), 7.15 – 7.23 (m, 1H), 7.42 – 7.56 (m, 2H), 7.65 (s, 2H). (clvi) 5-(3-chloro-4-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (38 mg, 38%) 6-bromo-5-(3-chloro-4-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.297 mmol), 2,6-dimethyl-4-(4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (79 mg, 0.341 mmol) Mass spectroscopy: m/z 330(M+H) ⁺ (ES ⁺ ); 328 (MH) ^- (ES ^- ), at 4.2 min, 97% pure (method B). (400 MHz, DMSO) δ: 2.37 (s, 6H), 7.02 (s, 2H), 7.29 (ddd, J 8.6, 4.7, 2.2 Hz, 1H), 7.40 – 7.45 (m, 1H), 7.65 (s, 2H), 7.73 (dd, J 7.2, 2.2 Hz, 1H). (clvii) 5-(4-(difluoromethoxy)phenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (36 mg, 37%) 6-bromo-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.284 mmol), 2,6-dimethyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (76 mg, 0.326 mmol) Mass spectroscopy: m/z 344(M+H) ⁺ (ES ⁺ ); 342 (MH) ^- (ES ^- ), at 3.93 min, 99% pure (method B). (400 MHz, DMSO) δ: 2.35 (s, 6H), 6.99 (s, 2H), 7.15 – 7.23 (m, 2H), 7.32 (t, 2J ^HF ₇₂ Hz, 1H), 7.43 – 7.49 (m, 2H), 7.58 (s, 2H). (clviii) 6-(2,6-dimethylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine (42 mg, 41%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.334 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (78 mg, 0.334 mmol) Mass spectroscopy: m/z 295.0 (MH)- (ES-), at 3.82 min, 98.1% purity (method B). (400 MHz, DMSO) δ: 2.36 (s, 6H), 7.02 (s, 2H), 7.17 (d, J 7.7 Hz, 1H), 7.25 – 7.36 (m, 2H), 7.38 – 7.45 (m, 1H) , 7.66 (s, 2H). (clix) 5-(4-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (33 mg, 34%) 6-bromo-5-(4-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (73.5 mg, 0.315 mmol) Mass spectroscopy: m/z 312.7/314.7 (M+H) ⁺ (ES ⁺ ); 310.9/312.9 (MH)-(ES-), at 4.17 min, 100% pure (method B). (400 MHz, DMSO) δ: 2.39 (s, 6H), 7.07 (s, 2H), 7.41 – 7.51 (m, 4H), 7.67 (s, 2H). (clx) 4-(3-amino-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile (27 mg, 27%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (90 mg, 0.326 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyridine (76 mg, 0.326 mmol) Mass spectroscopy: m/z 303.8 (M+H) ⁺ (ES ⁺ ); 302.0 (MH)-(ES-), at 3.47 min, 98.5% pure (method B). (400 MHz, DMSO) δ: 2.36 (s, 6H), 7.01 (s, 2H), 7.55 – 7.64 (m, 2H), 7.73 (s, 2H), 7.85 – 7.95 (m, 2H). (clxi) 5-(3-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (31 mg, 32%) 6-bromo-5-(3-chlorophenyl)-1,2,4-triazine-3-amine (90 mg, 0.315 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (73.5 mg, 0.315 mmol) Mass spectroscopy: m/z 312.7/314.7 (M+H) ⁺ (ES ⁺ ); 310.9/312.9 (MH)- (ES-), at 4.10 min, 100% pure (method B). (400 MHz, DMSO) δ: 2.35 (s, 6H), 7.00 (s, 2H), 7.22 – 7.25 (m, 1H), 7.37 (dd, J 11.9, 4.2 Hz, 1H), 7.51 – 7.60 (m, 2H), 7.65 (s, 2H). (clxi) 6-(2,6-dimethylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine (32 mg, 32%) 6-bromo-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine (90 mg, 0.305 mmol) and 2,6-dimethyl-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (71.1 mg, 0.305 mmol) Mass spectroscopy: m/z 322.7 (M+H) ⁺ (ES ⁺ ); 320.9 (MH)- (ES-), at 3.72 min, 98.5% pure (method B). (400 MHz, DMSO) δ: 2.36 (s, 6H), 3.28 (s, 3H), 4.44 (s, 2H), 7.03 (s, 2H), 7.31 – 7.34 (m, 2H), 7.37 – 7.43 (m , 2H), 7.62 (s, 2H). (clxiii) 4-(3-amino-6-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,2,4-triazin-5-yl)benzonitrile (10mg, 10%) 4-(3-amino-6-bromo-1,2,4-triazin-5-yl)benzonitrile (75 mg, 0.272 mmol) and 2-chloro-6-methoxy-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (85 mg, 0.299 mmol) Mass spectroscopy: m/z (Cl) 354.2/356.0 (M+H) ⁺ (ES ⁺ ); 352.1/354.0 (MH)- (ES-), at 2.56 min, 94.6% pure (method B). (400 MHz, DMSO) δ: 3.60 (s, 3H), 6.81 (d, J 2.0 Hz, 1H), 6.92 (d, J 2.0 Hz, 1H), 7.45 (s, 2H), 7.56 – 7.64 (m, 2H), 7.84–7.93 (m, 2H), 9.67 (s, 1H). (clxiv) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol (43 mg, 40%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 4-chloro-3-hydroxyphenylboronic acid (61.8 mg, 0.358 mmol) Mass spectroscopy: m/z 299, 301 (M+H) ⁺ (ES ⁺ ); 297, 299 (MH) ^- (ES ^- ), at 2.55 min, 99% pure (method B). (400 MHz, DMSO) δ: 6.64 (dd, J = 8.2, 2.0 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.34 – 7.47 ( m, 7H), 10.26 (s, 1H). (clxv) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine
(20 mg, 13%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.421 mmol) Mass spectroscopy: m/z 387.84/389.77 [M+H] ⁺ (ES) ⁺
99.70% at 4.60 min (method B). (400 MHz DMSO) δ: 7.25-7.32 (m, 1H), 7.48-7.57 (q, 1H), 7.58-7.66 (m, 1H), 7.78(s, 1H), 7.82 (s, 1H), 7.93- 7.99 (broad C, 2H) (clxvi) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine
(26 mg, 17%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.421 mmol) Mass spectroscopy: m/z 387.87/389.78
[M+H]+ (ES) ⁺
99.17% at 4.59 min (Method B). (400 MHz DMSO) δ: 7.20-7.25 (m, 2H), 7.46-7.51 (m, 1H), 7.77 (s, 1H), 7.81 (s, 1H), 8.00 (broad s, 2H) (clxvii) 6-[2-(ethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (6 mg, 0.2%) 6-bromo-5-phenyl-1,2,4-triazin-3-amine and 2-ethylamino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 6-methylpyridine (crude product from borylation step) Mass Spectroscopy: m/z 307.1
[M+H]+ (ES) ⁺
93.7% at 1.024 min (Method B). (400 MHz DMSO) δ: 1.03 (t, 3H), 2.18 (s, 3H), 3.94 (s, 2H), 6.28 (s, 1H), 6.34 (s, 1H) 7.37-7.50 (m, 5H). (clxviii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine
(16 mg, 11%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.42 mmol) Mass spectroscopy: m/z 370/372 (M+H) ⁺ (ES ⁺ ); 368/370 (MH)- (ES-), at 3.83 min, 100% (method C). (400 MHz, DMSO) δ: 7.24 (d, J 7.5 Hz, 1 H), 7.33 - 7.43 (m, 2 H), 7.43 - 7.53 (m, 1 H), 7.76 (s, 1 H), 7.79 ( s, 1 H), 7.96 (broad C, 2 H). (clixix) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (13 mg, 9%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.42 mmol) Mass spectroscopy: m/z 370/372 (M+H) ⁺ (ES ⁺ ); 368/370 (MH)-(ES-), at 3.84 min, 100% (method C). (400 MHz, DMSO) δ: 7.23 - 7.41 (m, 2 H), 7.46 - 7.65 (m, 2 H), 7.76 (s, 1 H), 7.79 (1 H, s), 7.90 (broad C, 2H). (clxx) 6-{2-[ethyl(methyl)amino]-6-methylpyridin-4-yl}-5-phenyl-1,2,4-triazin-3-amine (16 mg, 10%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (126 mg, 0.5 mmol) and 2-ethyl(methyl)amino-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-methylpyridine (276 mg, crude) Mass spectroscopy: m/z 321 (M+H) ⁺ (ES ⁺ ), at 3.88 min, 100% (method C). (400 MHz, DMSO) δ: 0.86 (t, J 8 Hz, 3H) 2.25 (s, 3 H) 2.81 (s, 3 H) 4.11 (kv, J 8 Hz, 2 H) 6.17 (s, 1 H) 6.49 (s, 1 H) 7.32 - 7.47 (m, 5 H) 7.50 (broad s, 2 H). (clxxi) 6-[2-(dimethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (13mg, 8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (126 mg, 0.5 mmol) and crude 2-dimethylamino-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-6-methylpyridine (234 mg, crude) Mass spectroscopy: m/z 307 (M+H) ⁺ (ES ⁺ ) at 3.43 min, >99% (method C). (400 MHz, DMSO) δ: 2.24 (s, 3 H) 2.86 (s, 6 H) 6.25 (s, 1 H) 6.46 (s, 1 H) 7.34 - 7.47 (m, 5 H) 7.47 - 7.57 (m , 2H). (clxxxii) 1-[6-(2,6-d ₆ -dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine
(13.3 mg, 4%) 6-bromo-5-phenyl-1,2,4-triazin-3-amine (310 mg, 1.24 mmol) and 1-[6-(2,6-d ₆ -dimethylpyridin-4-yl)-5-phenyl -1,2,4-triazine-3-amine (crude, 1.17 g) Mass spectroscopy:m/z 284.1 (M+H)⁺ (ES⁺) at 2.48 min, 100% (method C). (400 MHz, CDCl ₃ ) δ: 5.49 (s, 2H), 7.02 (s, 2H), 7.33-7.39 (m, 2H), 7.43-7.49 (m, 3H). (clxxxiii) 6-[2-d ₃ -methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (28.5 mg, 12%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (178 mg, 0.71 mmol) and 2-(d ₃ )methyl-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (226 mg, 0.78 mmol) Mass spectroscopy: m/z 335.1 (M+H) ⁺ (ES ⁺ ); 333.1 (MH) ^- (ES ^- ) at 3.56 min, 100% (method C). (400 MHz, CDCl ₃ ) δ: 5.57 (s, 2H), 7.37-7.52 (m, 7H). (clxxxiv) 5-(4-fluorophenyl)-6-[2-d ₃ -methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (93.3 mg, 38%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (189 mg, 0.70 mmol) and 2-(d ₃ )methyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (225 mg, 0.78 mmol) Mass spectroscopy: m/z 353.1 (M+H) ⁺ (ES ⁺ ); 351.1 (MH) ^- (ES ^- ) at 3.68 min, 100% (method C). (400 MHz, CDCl ₃ ) δ: 5.57 (s, 2H), 7.06-7.12 (m, 2H), 7.45-7.50 (m, 3H), 7.51-7.53 (m, 1H). (clxxxv) 6-(2,6-dimethylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine (32 mg, 57%) 6-bromo-5-(2-fluorophenyl)-1,2,4-triazine-3-amine (50 mg, 0.19 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-pyridine (68 mg, 0.29 mmol) Mass spectroscopy: m/z 296.0 (M+H) ⁺ (ES ⁺ ), at 2.20 min, 100% (method C). (400 MHz, DMSO)
δ: 2.31 (s, 6H), 6.93 (s, 2H), 7.18 (t, J 7.8, 1H), 7.37 (t, J 6.5, 1H), 7.54-7.66 (m, 6H) (clxxxvi) 6-(2-chloro-6-methylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine (21 mg, 35%) 6-bromo-5-(2-fluorophenyl)-1,2,4-triazine-3-amine (50 mg, 0.19 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-methylpyridine (74 mg, 0.29 mmol) Mass spectroscopy: m/z 315.9 (M+H) ⁺ (ES ⁺ ), at 2.66 min, 100% (method C). (400 MHz, DMSO)
δ: 2.31(s, 3H), 7.06(s, 1H). 7.21 (t, J 7.8, 1H), 7.27 (s, 1H), 7.40 (t, J 6.5, 1H), 7.56-7.63 (m, 1H), 7.64-7.69 (m, 1H), 7.80-7.90 (br .C, 2H) (clxxvii) 6-(2,6-dimethylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine (20 mg, 36%) 6-bromo-5-(4-methoxyphenyl)-1,2,4-triazine-3-amine (50 mg, 0.18 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-pyridine (63 mg, 0.27 mmol) Mass spectroscopy: m/z 308.0 (M+H) ⁺ (ES ⁺ ), at 2.31 min, 100% (method C). (400 MHz, DMSO)
δ: 2.37 (s, 6H), 3.78 (s, 3H), 6.95 (d, J 9.0, 2H), 7.02 (s, 2H), 7.39 (d, J 9.0, 2H), 7.45-7.55 (broad s , 2H) (clxxviii) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine (10 mg, 17%) 6-bromo-5-(4-methoxyphenyl)-1,2,4-triazine-3-amine (50 mg, 0.18 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-methylpyridine (68 mg, 0.27 mmol) Mass spectroscopy: m/z 328.0 (M+H) ⁺ (ES ⁺ ), at 2.72 min, 100% (method C). (400 MHz, DMSO)
δ: 2.42 (s, 3H), 3.80 (s, 3H) 6.98 (d, J 8.8, 2H), 7.18 (s, 1H), 7.31 (s, 1H), 7.41 (d, J 8.8, 2H), 7.37 -7.43 (s, 2H) (clxxxix) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (42 mg, 32%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.40 mmol) and (2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-6-methylpyridine (108 mg, 0.40 mmol) Mass spectroscopy: m/z 314.1 (M+H) ⁺ (ES ⁺ ), at 1.38 min, 100% (method A). (400 MHz, DMSO)
δ: 2.46 (s, 3H), 6.83 (t, J 55.0, 1H), 7.33 (s, 1H), 7.38-7.45 (m, 5H), 7.47-7.52 (m, 1H), 7.62-7.75 (br. C, 2H) (clxxx) 6-[2-chloro-6-(difluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (27 mg, 20%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(difluoromethyl)-pyridine (151 mg, 0.52 mmol) Mass spectroscopy: m/z 333.9 (M+H) ⁺ (ES ⁺ ), at 1.56 min, 100% (method C). (400 MHz, DMSO)
δ: 6.94 (t, J 54.5, 1H), 7.41-7.48(m, 4H), 7.50-7.56 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H) (clxxxi) 6-[2-chloro-6-(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine (13 mg, 10%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(fluoromethyl)-pyridine (141 mg, 0.52 mmol) Mass spectroscopy: m/z 316.0 (M+H) ⁺ (ES ⁺ ), at 3.12 min, 100% (method C). (400 MHz, DMSO)
δ: 5.43 (d, J 46.4, 2H), 7.33 (s, 1H), 7.41-7.46 (m, 5H), 7.47-7.53 (m, 3H) (clxxxii) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (32 mg, 26%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (100 mg, 0.37 mmol) and (2-(difluoromethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (110 mg, 0.41 mmol) Mass spectroscopy: m/z 332.0 (M+H) ⁺ (ES ⁺ ), at 1.42 min, 100% (method A). (400 MHz, DMSO)
δ: 2.49(s, 3H), 6.82(t, J 55.0 Hz, 1H), 7.19-7.31(m, 1H), 7.36(s, 1H), 7.44(s, 1H), 7.46-7.52(m, 2H ), 7.54-7.58 (, 2H) (clxxxiii) 6-[2,6-bis(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine (10 mg, 8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.40 mmol) and 2,6-bis-(fluoromethyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-6-methylpyridine (140 mg, 0.52 mmol) Mass spectroscopy: m/z 314.0 (M+H) ⁺ (ES ⁺ ), at 1.33 min, 95% (method A). (400 MHz, DMSO) δ: 5.43(d, J 46.9Hz, 4H), 7.38-7.45(m, 6H), 7.47-7.51(m, 1H), 7.65-7.75(broad s, 2H). (clxxxiv) 6-[2-(fluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine (10 mg, 8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.40 mmol) and (2-(fluoromethyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-6-methylpyridine (151 mg, 0.60 mmol) Mass spectroscopy: m/z 296.0 (M+H) ⁺ (ES ⁺ ), at 2.58 min, 100% (method C). (400 MHz, DMSO)
δ: 2.40(s, 3H), 5.37 (d, J 46.9 Hz, 2H), 7.20 (s, 2H), 7.38-7.45 (m, 4H), 7.46-7.51 (m, 1H), 7.60-7.72 (br .s, 2H) (clxxxv) 6-(2-chloro-6-methylpyridin-4-yl)-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine
(24 mg, 18%) 6-bromo-5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (129 mg, 0.42 mmol) Mass spectroscopy: m/z 334.0 (M+H) ⁺ (ES+); at 2.87 min, 95% (method C). (400 MHz, DMSO) δ: 2.40 (s, 3H), 7.12 (s, 1H), 7.25 – 7.32 (m, 2H), 7.42 – 7.49 (m, 1H), 7.51 – 7.56 (m, 1H), 7.89 (broad s, 2H). (clxxxvi) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine
(18 mg, 12%) 6-bromo-5-(2-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.42 mmol) Mass spectroscopy: m/z 368.1(M+H) ⁺ (ES+), 370 (MH) ^- (ES-) ; at 3.85 min, 95% (method C). (400 MHz, DMSO) δ: 7.20 – 7.26 (m, 1H), 7.38 – 7.45 (m, 1H), 7.56 – 7.74 (m, 3H), 7.78 (s, 1H). (clxxxvii) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine
(17 mg, 11%) 6-bromo-5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (129 mg, 0.42 mmol) Mass spectroscopy: m/z 386.1(MH) ^- (ES-); at 3.93 min, 95% (method C). (400 MHz, DMSO) δ: 7.27 – 7.35 (m, 1H), 7.45 – 7.52 (m, 1H), 7.52 – 7.58 (m, 1H), 7.79 (s, 1H), 7.82 (s, 1H), 8.08 (broad C, 2H). (clxxxviii) 6-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine
(20 mg, 26%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (50 mg, 0.20 mmol) and 2-cyclopropyl -4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (66 mg, 0.21 mmol) Mass spectroscopy: m/z 358 (M+H) ⁺ (ES+); at 4.43 min, 100% (method C). (400 MHz, DMSO) δ: 0.79 – 0.84 (m, 2H), 0.97 – 1.03 (m, 2H), 2.10 – 2.17 (m, 1H), 7.39 – 7.46 (m, 6H), 7.47 – 7.53 (m, 1H), 7.61 (broad s, 2H). (clxxxix) 6-[2-ethyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine
(37 mg, 55%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (50 mg, 0.20 mmol) and 2-ethyl -4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (63 mg, 0.21 mmol) Mass spectroscopy: m/z 346.0 (M+H) ⁺ (ES+), 344.2 (MH) ^- (ES-) ; at 4.08 min, 100% (method C). (400 MHz, DMSO) δ: 1.10 (t, 3H, J 8.0 Hz), 2.75 (q, 2H, J 8.0), 7.40 – 7.44 (m, 4H), 7.47 – 7.53 (m, 2H). 7.57 (s, H), 7.76 (broad C, 2H). (cxc) 6-(2-cyclopropyl-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine
(32 mg, 46%) 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (70 mg, 0.23 mmol) and potassium cyclopropyl trifluoroborate salt (340 mg, 2.30 mmol) Mass spectroscopy: m/z 304.1 (M+H) ⁺ (ES+); at 3.22 min, 100% (method C). (400 MHz, DMSO) δ: 0.70 – 0.76 (m, 2H), 0.82 – 0.89 (m, 2H), 1.88 – 1.97 (m, 1H), 2.32 (s, 3H), 6.88 (s, 1H), 6.97 (s, 1H), 7.38–7.43 (m, 4H), 7.45–7.52 (m, 1H), 7.54–7.62 (broad C, 2H). (cxci) 5-(2-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (65.3 mg, 47%) 6-bromo-5-(2-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy:m/z 350.0 (M+H)⁺ (ES+) at 3.30 min, ~98% (method C). (400 MHz, DMSO) δ: 2.51 (s, 3H), 7.17 – 7.22 (m, 1H), 7.38 – 7.42 (m, 2H), 7.56 – 7.63 (m, 2H), 7.67 – 7.71 (m, 1H) , 7.88 (broad C, 2H). (cxcii) 5-(3-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (72.8 mg, 52%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy: m/z 350.0 (M+H) ⁺ (ES ⁺ ) at 3.24 min, ~98% (method C). (400 MHz, CDCl ₃ )
δ: 2.61 (s, 3H), 5.62 (broad s, 2H), 7.10–7.20 (m, 1H), 7.18–7.23 (m, 1H), 7.28–7.35 (m, 2H), 7.48–7.50 (m , 2H). (cxiii) 5-(4-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (78.9 mg, 56%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (108 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy: m/z 350.0 (M+H) ⁺ (ES ⁺ ) at 3.26 min, 98% (method C). (400 MHz, CDCl ₃ )
δ: 2.61 (s, 3H), 5.58 (broad s, 2H), 7.07–7.11 (m, 2H), 7.46–7.52 (m, 4H). (cxciv) 5-(2,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (61.7 mg, 42%) 6-bromo-5-(2,5-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy: m/z 368.0 (M+H) ⁺ (ES ⁺ ) at 3.38 min, 98% (method C). (400 MHz, DMSO) δ: 2.53 (s, 3H), 7.25 – 7.30 (m, 1H), 7.44 – 7.50 (m, 2H), 7.55 – 7.59 (m, 1H), 7.65 (s, 1H), 7.95 (broad s, 2H). (cxv) 5-(3,4-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (40.0 mg, 27%) 6-bromo-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy: m/z 368.0 (M+H) ⁺ (ES ⁺ ) at 4.34 min, 100% (method B). (400 MHz, DMSO) δ: 2.54 (s, 3H), 7.22–7.24 (m, 1H), 7.46–7.57 (m, 3H), 7.62 (s, 1H), 7.81 (broad s, 2H). (cxvi) 5-(3,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine (73.3 mg, 49%) 6-bromo-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine (115 mg, 0.40 mmol) and 2-methyl-6-trifluoromethyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (121 mg, 0.42 mmol) Mass spectroscopy: m/z 368.0 (M+H) ⁺ (ES ⁺ ) at 3.53 min, ~98% (254 nm). (400 MHz, DMSO) δ: 2.54 (s, 3H), 7.16–7.19 (m, 2H), 7.42–7.49 (m, 2H), 7.64 (s, 1H), 7.81 (broad s, 2H). (cxcvii) 6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine
(40.2 mg, 18%) 6-bromo-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (150 mg, 0.56 mmol) and 2-(azetide-1-yl)-6-trifluoromethyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (192 mg, 0.59 mmol) Mass spectroscopy: m/z 391.0 (M+H) ⁺ (ES ⁺ ) at 3.89 min, ~98% (method C). (400 MHz, CDCl ₃ )
δ: 2.27 – 2.35 (quint, J 7.4, 2H), 3.89 (t, J 7.4, 4H), 5.52 (broad s, 2H), 6.54 (s, 1H), 6.83 (s, 1H), 7.06 – 7.10 (m, 2H), 7.49–7.53 (m, 2H). (cxcviii) 6-[2-methyl-6-(morpholin-4-yl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (43.0 mg, 12%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (251 mg, 1.0 mmol) and 2-methyl-6-(morpholin-4-yl)-4-(4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (320 mg, 1.05 mmol) Mass spectroscopy: m/z 349.1 (M+H) ⁺ (ES ⁺ ) at 1.16 min, ~95% (method B). (400 MHz, CDCl ₃ )
δ: 2.33 (s, 3H), 3.39 – 3.42 (m, 2H), 3.76 – 3.78 (m, 2H), 5.49 (broad s, 2H), 6.52 (s, 1H), 6.55 (s, 1H), 7.34–7.38 (m, 2H), 7.43–7.45 (m, 1H), 7.50–7.52 (m, 2H). (cxcix) 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-ethylphenyl)-1,2,4-triazin-3-amine (6 mg, 6%) 6-bromo-5-(4-methylphenyl)-1,2,4-triazine-3-amine (94 mg, crude, taken as 0.17 mmol) and 2-chloro-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-6-methylpyridine (128 mg, 0.506 mmol) Mass spectroscopy: m/z 324.2 (MH) ^- (ES-) at 2.16 min, 97% (method B) (400 MHz, DMSO) δ: 1.18 (t, 3H), 2.40 (s, 3H), 2.64 (q, 2H), 7.22 (s, 1H), 7.55 (m, 3H), 7.38 (m, 2H) ( NH ₂ not visible) (cc) 5-(2,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine (12 mg, 12%) 6-bromo-5-(2,5-difluorophenyl)- 1,2,4-triazine-3-amine (90 mg, 0.314 mmol) and 2,6-dimethyl-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (110 mg, 0.47 mmol) Mass spectroscopy: m/z 314.3 (M+H) ⁺ (ES+) at 0.97 min, 100% (method B) (400 MHz, DMSO) δ: 2.34 (s, 6H), 6.98 (s, 2H), 7.26 (m, 1H), 7.44 (m, 1H), 7.54 (m, 1H), 1.78 (broad s, 2H ) (cci) 6-(2,6-dimethylpyridin-4-yl)-5-(4-methylphenyl)-1,2,4-triazin-3-amine (16 mg, 17%) 6-bromo-5-(4-methylphenyl)-1,2,4-triazine-3-amine (85 mg, 0.32 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (112 mg, 0.48 mmol) Mass spectroscopy: m/z 293.3 (M+H) ⁺ (ES+) at 1.06 min, 99% (method B) (400 MHz, DMSO) δ: 2.31 (s, 3H), 2.36 (s, 6H), 6.99 (s, 2H), 7.20 (m, 2H), 7.33 (m, 2H), 7.53 (broad s, 2H ). (ccii) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine (17 mg, 20%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (70 mg, 0.26 mmol) and (2-(difluoromethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (70 mg, 0.26 mmol) Mass spectroscopy: m/z 332.3, M ⁺ (ESI+) at 1.84 min, 96% (method B). (400 MHz, CDCl ₃ )
δ: 2.51 (s, 3H), 5.51 (broad s, 2H), 6.55 (t, 1H), 7.13 (m, 1H), 7.29 (m, 1H), 7.32 (m, 1H), 7.40 (s, 1H), 7.44 (s, 1H) (cciii) 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine (20 mg, 23%) 6-bromo-5-(3-fluorophenyl)-1,2,4-triazine-3-amine (70 mg, 0.26 mmol) and (2-(difluoromethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-6-methylpyridine (70 mg, 0.26 mmol) Mass spectroscopy: m/z 332.3, M ⁺ (ESI+) at 1.80 min, 96% (method B). (400 MHz, CDCl ₃ )
δ: 2.55 (s, 3H), 5.54 (broad s, 2H), 6.51 (t, 1H), 7.00 (m, 1H), 7.30 (s, 1H) 7.32 (m, 1H), 7.43 (s, 1H ), 7.50 (m, 1H), 7.58 (m, 1H). (cciv) 6-(3,5-dichlorophenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine (23 mg, 7%) 6-bromo-5-(pyridin-2-yl)-1,2,4-triazine-3-amine (0.25 g, 0.99 mmol) and 3,5-dichlorophenylboronic acid (0.20 g, 1.09 mmol) HPLC purity: 98.56%; (268 nm).
Mass spectroscopy: (ESI +ve) 318.0 [M+H] ⁺ _, 316.1 [M+H] ^- . (400 MHz, DMSO) δ: 7.26 (m, 2H), 7.49 (m, 1H), 7.54 (m, 1H), 7.68 (broad s, 2H), 7.91 (m, 1H), 8.00 (t, 1H ), 8.43 (d, 1H). (ccv) 6-(3-chloro-5-methylphenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine (12 mg, 5%) 6-bromo-5-(pyridin-2-yl)-1,2,4-triazin-3-amine (0.20 g, 0.79 mmol) and 3-chloro-5-methylphenylboronic acid (0.175 g, 1.03 mmol) HPLC purity: 99.60%; (266 nm).
Mass spectroscopy: (ESI +ve) 298.2 [M+H] ⁺ _. (400 MHz, DMSO) δ: 2.22 (s, 3H), 6.99 (s, 1H), 7.07 (s, 1H), 7.18 (s, 1H), 7.45-7.48 (m, 1H), 7.56 (broad s , 2H), 7.79 (d, 1H), 7.94–7.98 (m, 1H), 8.44 (d, 1H). (ccvi) 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (50 mg, 5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.70 g, 2.8 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1.02 g, 3.34 mmol) HPLC purity: 96.75% (272 nm)
Mass spectroscopy: (ESI +ve) 352.1 [M+H] ⁺ _. ^one H NMR:(400 MHz, DMSO) δ: 7.44 (m, 5H), 7.69 (s, 1H), 7.88 (s, 1H), 7.84 (broad s, 2H). (ccvii) 6-[2,6-bis(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine (0.10 g, 13%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.52 g, 2.07 mmol) and 2,6-bis(trifluoromethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (1.0 g, 3.1 mmol) HPLC purity:98.90% (232 nm)
Mass spectroscopy:(ESI+ve) 386.1[M+H]⁺, (ESI -ve) 384.2 [M-H]^- _. ^one H NMR:(400 MHz, DMSO) δ: 7.48 (m, 5H), 7.93 (broad s, 2H), 8.03 (s, 2H). (cviii) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-2-yl)-1,2,4-triazin-3-amine (30 mg, 10%) 6-bromo-5-(pyridin-2-yl)-1,2,4-triazin-3-amine (0.225 g, 0.89 mmol) and 3-chloro-5-(trifluoromethyl)-phenylboronic acid (0.260 g, 1.16 mmol) HPLC purity: 99.87%; (268 nm).
Mass spectroscopy: (ESI +ve) 352.1 [M+H] ⁺ _. ( 400 MHz, DMSO) δ: 7.45-7.48 (m, 2H), 7.65 (s, 1H), 7.70 (broad s, 2H), 7.77 (s, 1H), 7.91 (m, 1H), 8.0 (m , 1H), 8.36 (d, 1H). (ccix) 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine (0.32 g, 35%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.70 g, 2.78 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-trifluoromethyl-pyridine (1.2 g, 4.1 mmol) HPLC purity:98.81% (269 nm)
Mass spectroscopy:(ESI +ve) 332.0 [M+H]⁺, (ESI -ve) 330.2 [M-H]^- _. (400 MHz, DMSO) δ: 2.48 (s, 3H), 7.38 (m, 5H), 7.47 (s, 1H), 7.58 (s, 1H), 7.73 (broad s, 2H). (ccx) 6-(3,5-dimethylphenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine (16 mg, 7%) 6-bromo-5-(pyridin-2-yl)-1,2,4-triazin-3-amine (0.20 g, 0.79 mmol) and 3,5-dimethylphenylboronic acid (0.15 g, 1.02 mmol) HPLC purity: 98.96%; (268 nm).
Mass spectroscopy: (ESI +ve) 277.9 [M+H] ⁺ _. (400 MHz, DMSO) δ: 2.12 (s, 6H), 6.81 (s, 2H), 6.88 (s, 1H), 7.40-7.43 (m, 3H), 7.64-7.66 (m, 1H), 7.89 (m , 1H), 8.43 (m, 1H). (ccxi) 6-[2-(dimethylamino)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (83 mg, 33%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.5 g, 1.99 mmol) and 2-dimethylamino-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (0.98 g, 3.9 mmol) HPLC purity: 99.18% (272 nm)
Mass spectroscopy: (ESI +ve) 292.8 [M+H] ⁺ _. (400 MHz, DMSO) δ: 2.97 (s, 6H), 6.46 (m, 1H), 6.56 (m, 1H), 7.37-7.47 (m, 5H), 7.54 (broad s, 2H), 7.99 (m , 1H). (ccii) 6-(2-bromo-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (76 mg, 22%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.25 g, 0.90 mmol) and 2-bromo-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-methylpyridine (0.44 g, 1.4 mmol) HPLC purity: 98.71% (272 nm)
Mass spectroscopy: (ESI +ve) 341.9 [M] ⁺ , 343.9 [M] ⁺ _. (400 MHz, DMSO) δ: 2.38 (s, 3H), 7.25 (s, 1H), 7.30 (s, 1H), 7.47 (m, 5H), 7.72 (broad C, 2H). (cciii) 6-(2,6-dimethyl-1-oxypyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine (87 mg, 15%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.50 g, 1.99 mmol) and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine- N -oxide (0.74 g, 2.98 mmol) HPLC purity: 98.85% (294 nm)
Mass spectroscopy: (ESI +ve) 293.7 [M+H] ⁺ , (ESI –ve) 292.0 [MH] ^- _. (400 MHz, CDCl ₃ ) δ: 2.48 (s, 6H), 5.66 (broad s, 2H), 7.24 (s, 1H), 7.28 (s, 1H), 7.49 (m, 2H), 7.52 (m, 3H). (ccxiv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-6-methylpyridine-2-carbonitrile (140 mg, 49%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.25 g, 0.99 mmol) and 2-cyano-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-methylpyridine (0.36 g, 1.4 mmol) HPLC purity: 99.18% (272 nm)
Mass spectroscopy: (ESI +ve) 288.9 [M+H] ⁺ _. (400 MHz, DMSO) δ: 2.48 (s, 3H), 7.45-7.52 (m, 5H), 7.61 (s, 1H), 7.63 (s, 1H), 7.79 (broad s, 2H). (ccxv) 6-(3,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazine-3-amine (3 mg, 1%) 6-bromo-5-(pyridin-3-yl)-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 3,5-dichlorophenylboronic acid (0.22 g, 1.19 mmol) HPLC purity: 98.66% (266 nm)
Mass spectroscopy: (ESI +ve) 317.9 [M+H] ⁺ _, 315.9 [M+H] ^- (400 MHz, DMSO) δ: 7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.62 (m, 1H), 7.69 (bd s, 2H), 7.82 (m, 1H), 8.59 (m , 1H), 8.63 (m, 1H). (ccxvi) 6-(3-chloro-5-methylphenyl)-5-(pyridin-3-yl)-1,2,4-triazine-3-amine (11 mg, 5%) 6-bromo-5-(pyridin-3-yl)-1,2,4-triazin-3-amine (0.19 g, 0.75 mmol) and 3-chloro-5-methylphenylboronic acid (0.166 g, 0.98 mmol) HPLC purity: 92.24% (218 nm)
Mass spectroscopy: (ESI +ve) 297.9.0 [M+H] ⁺ _, 295.9 [M+H] ^- (400 MHz, DMSO) δ: 2.25 (s, 3H), 6.82 (s, 1H), 7.15-7.17 (m, 1H), 7.27 (s, 1H), 7.40 (m, 1H), 7.59 (broad s , 2H), 7.77 (m, 1H), 8.56 (m, 1H), 8.61 (m, 1H). (ccxviii) 6-(3,5-dichlorophenyl)-5-(pyrimidin-2-yl)-1,2,4-triazine-3-amine (40 mg, 6%) 6-bromo-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.5 g, 1.98 mmol) and 3,5-dichlorophenylboronic acid (0.414 g, 2.18 mmol) HPLC purity: 97.14% (210 nm)
Mass spectroscopy: (ESI +ve) 318.9 [M+H] ⁺ _, 316.9 [M+H] ^- . (400 MHz, DMSO) δ: 7.21 (s, 2H), 7.58 (s, 1H), 7.65 (t, 1H), 7.84 (broad s, 2H), 8.93 (d, 2H). (ccxiii) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.130 g, 19%) 6-bromo-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.50 g, 1.98 mmol) and 3-chloro-5-(trifluoromethyl) phenylboronic acid (0.488 g, 2.18 mmol ) HPLC purity: 93.30% (202 nm)
Mass spectroscopy: (ESI +ve) 353.0 [M+H] ⁺ ,351.0 [M+H] ^- . _. (400 MHz, DMSO) δ: 7.38 (s, 1H), 7.64 (m, 2H), 7.86 (m, 3H), 8.91 (d, 2H). (ccxix) 6-[2-bromo-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (30 mg, 8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.25 g, 0.9 mmol) and 2-bromo-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (0.52 g, 1.48 mmol) HPLC purity: 94.90% (272 nm)
Mass spectroscopy: (ESI +ve) 396.1 [M+H] ⁺ , 397.9 [M+H] ⁺ _. (400 MHz, DMSO) δ: 7.47 (m, 5H), 7.74 (s, 1H), 7.84 (s, 1H), 7.88 (broad s, 2H). (ccxxx) 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1,2,4-triazin-3-amine (8 mg, 3%) 6-bromo-5-(pyridin-3-yl)-1,2,4-triazin-3-amine (0.20 g, 0.79 mmol) and 3-chloro-5-(trifluoromethyl)phenylboronic acid (0.21 g, 0.95 mmol ) HPLC purity: 91.22% (266 nm)
Mass spectroscopy: (ESI +ve) 351.8 [M+H] ⁺ _, 349.9 [M+H] ^- (400 MHz, DMSO) δ: 7.41 (m, 1H), 7.62 (s, 1H), 7.72 (broad s, 2H), 7.76-7.80 (m, 2H), 7.87 (s, 1H), 8.58 (m , 1H), 8.62-8.64 (m, 1H). (ccxxi) 6-(3-chloro-5-methylphenyl)-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (130 mg, 22%) 6-bromo-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine (0.5 g, 1.98 mmol) and 3-chloro-5-methylphenylboronic acid (0.650 g, 2.18 mmol) HPLC purity: 95.27% (266 nm)
Mass spectroscopy: (ESI +ve) 299.0 [M+H] ⁺ _, (400 MHz, DMSO) δ: 2.21 (3H, s), 6.98 (m, 2H), 7.21 (s, 1H), 7.62 (t, 1H), 7.74 (s, 2H), 8.90 (d, 2H)

The following compounds were prepared according to a modified version of the general procedure described for Example 1. In these cases, the reactions were carried out using palladium acetate (1.5 mol.%), dppf (3.0 mol.%), copper bromide (1.5 eq.), cesium carbonate ( 2.0 equiv.) and DMF (0.8 ml).

No. Product (output) Derived from LCMS NMR (cxxxii) 6-(6-chloropyridin-2-yl)-5-phenyl-1,2,4-triazine-3-amine (7 mg, 6%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.398 mmol), 6-chloropyridin-2-ylboronic acid (141 mg, 0.896 mmol) Mass spectroscopy: m/z 284.7 (M+H) ⁺ (ES ⁺ ), at 3.75 min, 99.2% purity (method B). (400 MHz, DMSO) δ: 7.31 – 7.39 (m, 4H), 7.39 – 7.46 (m, 1H), 7.47 (dd, J = 8.0, 0.8 Hz, 1H), 7.66 (s, 2H), 7.77 (dd , J = 7.6, 0.8 Hz, 1H), 7.95 (t, J = 7.8 Hz, 1H). (cxxxii) 6-(4-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine (3 mg, 5% 6-bromo-5-phenyl-1,2,4-triazine-3-amine (50 mg, 0.199 mmol), and 4-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)pyridine (110 mg, 0.448 mmol) Mass spectroscopy: m/z 290.6 (M+H) ⁺ (ES ⁺ ); 288.9 (MH)- (ES-), at 3.93 min, 99.4% pure (method B). (400 MHz, _CDCl3 ) δ: 0.89 – 1.01 (m, 4H), 1.97 – 2.06 (m, 1H), 5.50 (s, 2H), 6.98 (dd, J = 5.2, 1.7 Hz, 1H), 7.26 – 7.29 (m, 1H), 7.33–7.41 (m, 2H), 7.43–7.50 (m, 3H), 8.35 (d, J = 4.8 Hz, 1H). (cxxxiv) 5-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine (27 mg, 29%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.398 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-6-(trifluoromethyl)pyridine (245 mg, 0.896 mmol) Mass spectroscopy: m/z 318.6 (M+H) ⁺ (ES ⁺ ); 316.9 (MH)- (ES-), at 4.09 min, 98.9% pure (method B). (400 MHz, DMSO) δ: 7.27 – 7.35 (m, 4H), 7.36 – 7.44 (m, 1H), 7.69 (s, 2H), 7.84 (dd, J 7.4, 1.3 Hz, 1H), 8.11 – 8.23 ( m, 2H). (ccxxxv) 5-phenyl-6-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazin-3-amine (10 mg, 8%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (100 mg, 0.398 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-4-(trifluoromethyl)pyridine (245 mg, 0.896 mmol) Mass spectroscopy: m/z 318.7 (M+H) ⁺ (ES ⁺ ); 316.9 (MH)- (ES-), at 4.12 min, 98.5% pure (method B). (400 MHz, DMSO) δ: 7.26 – 7.38 (m, 4H), 7.38 – 7.45 (m, 1H), 7.69 (s, 2H), 7.74 (dd, J 5.1, 1.1 Hz, 1H), 8.18 (s, 1H), 8.63 (d, J 5.1 Hz, 1H). (cxxxvi) 6-(6-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine (2 mg, 3%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (50 mg, 0.199 mmol), 2-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (110 mg, 0.448 mmol) Mass spectroscopy: m/z 290.3 (M+H) ⁺ (ES ⁺ ), at 1.85 min, 98.4% purity (method B). (400 MHz, _CDCl3 ) δ: 0.21 – 0.32 (m, 2H), 0.55 – 0.64 (m, 2H), 1.77 (tt, J 8.1, 4.7 Hz, 1H), 5.41 (s, 2H), 7.11 (dd , J 7.7, 1.0 Hz, 1H), 7.28–7.42 (m, 5H), 7.61–7.68 (m, 1H), 7.75 (dd, J 7.7, 1.0 Hz, 1H). (cxxxviii) 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyrazin-2-ol (2 mg, 2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (80 mg, 0.319 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) pyrazin-2-ol (159 mg, 0.717 mmol) Mass spectroscopy: m/z 267.2 (M+H) ⁺ (ES ⁺ ), at 1.52 min, 96.4% purity (method B). (400 MHz, CDCl3) δ: 5.34 (s, 2H), 7.42–7.52 (m, _3H ), 8.03–8.09 (m, 3H), 8.31 (d, J 2.6 Hz, 1H), 8.57 (d, J 7.5 Hz, 1H).

Alternative procedure for the preparation of 5,6-biaryl-3-amino-1,2,4-triazines

The Suzuki reaction to form 5,6-biaryl-3-amino-1,2,4-triazines can alternatively be carried out with palladium-containing catalysts such as dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) or dichloro[1,1'-bis(di-tert-butylphosphino)]ferrocene palladium(II). Residual palladium can then be removed from the triazine solution by treatment with a suitable scavenger such as mercaptopropyl-functionalized silica gel (Quadrasil-MP; available from Johnson Matthey) or 2,4,6-trimercaptotriazine grafted onto macroporous polystyrene (MP-TMT; available from Biotage) .

A typical alternative procedure to the standard procedure for Example 1(xcv):

6-Bromo-5-(4-fluorophenyl)-1,2,4-triazine-3-amine (1 mol. equiv.), 2-chloro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-6-methylpyridine (1 mol. equiv.) and K ₂ CO ₃ (1.5 mol. equiv.) were suspended in a mixture of 1,4-dioxane and water (2:1; 10 ml solvent per gram of bromtriazine). The resulting mixture was degassed, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol.%) was added, and boiled until complete disappearance of bromtriazine according to LCMS data. The cooled reaction mixture was then diluted with water, extracted with dichloromethane and passed through a phase separator. The organic phase was evaporated under reduced pressure and purified by gradient flash chromatography using a mixture of ethyl acetate and hexanes as eluent to give 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2 ,4-triazine-3-amine (61%).

A typical alternative procedure to the standard procedure for Example 1(ccix):

6-Bromo-5-phenyl-1,2,4-triazine-3-amine (1 mol. equiv.), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-6-(trifluoromethyl)pyridine (1 mol. equiv.) and K ₂ CO ₃ (1.5 mol. equiv.) were suspended in a mixture of 1,4-dioxane and water (2:1; 10 ml of solvent per gram of bromtriazine). The resulting mixture was degassed, dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphino]palladium(II) (2 mol.%) was added, and boiled until complete disappearance of bromtriazine according to LCMS data. The cooled reaction mixture was then diluted with water, extracted with dichloromethane and passed through a phase separator. The organic phase was evaporated under reduced pressure and purified by gradient flash chromatography using a mixture of ethyl acetate and hexanes as eluent to give 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2, 4-triazine-3-amine (90%).

General procedure for removing palladium impurities from 5,6-biaryl-3-amino-1,2,4-triazines

Quadrasil-MP (42 mg) or MP-TMT (35 mg) was added to a solution of 5,6-biaryl-3-amino-1,2,4-triazine derivative (100 mg) in DCM (1.5 ml). The resulting mixture was heated to 50 ^° C. for 24 hours and then filtered. Then the filtrate was evaporated under reduced pressure and, if necessary, the procedure was repeated.

Quadrasil-MP is available from Johnson Matthey, MP-TMT is available from Biotage.

Example 2

General procedure for the preparation of 5-aryl-3,6-diamino-1,2,4-triazines

Intermediate D, 6-halo-5-aryl-1,2,4-triazine-3-amine derivative (0.80 mmol) was dissolved in dioxane or N-methyl-2-pyrrolidone (5 ml) and amine (1.60 mmol) was added and aqueous solution of K ₂ CO ₃ (0.22 g, 1.60 mmol in 0.5 ml of water). The mixture was heated in a microwave oven for two hours at 140°C with monitoring by TLC (hexane/ethyl acetate, 1:1). At the end of the reaction, the mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, dried over Na ₂ SO ₄ and evaporated in vacuo. Crude product B was purified by gradient flash chromatography or preparative HPLC.

(i) 5-phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine

5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazine-3-amine (18 mg, 18%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.21 g, 0.80 mmol) and piperidine (0.14 g, 1.60 mmol) according to the general procedure described in Example 2.

HPLC purity: 96.95% (264 nm)

Mass spectroscopy: (ESI +ve) 256.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 1.56-1.62 (m, 6H), 3.03 (m, 4H), 4.89 (s, 2H), 7.44-7.55 (m, 3H), 8.12 (m, 2H ).

(ii) 6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Morpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (50 mg, 20%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.21 g, 0.80 mmol) and morpholine (0.126 g, 1.44 mmol) according to the general procedure described in Example 2.

HPLC purity: 94.87% (265 nm)

Mass spectroscopy: (ESI +ve) 257.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 2.88 (t, 4H), 3.59 (t, 4H), 6.75 (s, 2H), 7.54 (m, 3H), 8.06 (m, 2H).

(iii) 6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (30 mg, 14%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.21 g, 0.80 mmol) and 3-methylpiperidine (0.21 g, 1.92 mmol) according to the general procedure described in Example 2.

HPLC purity: 98.87% (215 nm)

Mass spectroscopy: (ESI +ve) 270.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 0.75 (d, 3H), 0.97 (m, 1H), 1.45 (m, 2H), 1.65 (m, 2H), 2.20 (m, 2H), 3.14 ( m, 2H), 6.65 (s, 2H), 7.49 (m, 3H), 8.04 (m, 2H).

(iv) 6-(2,6-dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazine-3-amine

6-(2,6-dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was obtained from 6-bromo-5-phenyl-1,2, 4-triazine-3-amine (0.30 g, 1.19 mmol) and 2,6-dimethylmorpholine (0.27 g, 2.39 mmol) according to the general procedure described in Example 2.

HPLC purity: 90% (271 nm)

Mass spectroscopy: (ESI +ve) 286.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 1.10 (s, 6H), 2.52 (t, 2H), 3.23 (d, 2H), 3.71 (m, 2H), 5.06 (broad, 2H), 8.07 ( m, 3H), 8.07 (d, 2H).

(v) 6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(4,4-Difluoropiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (39 mg, 14%) was obtained from 6-chloro-5-phenyl-1,2, 4-triazine-3-amine (0.20 g, 0.96 mmol), K ₂ CO ₃ (0.23 g, 1.67 mmol) and 4,4-difluoropiperidine hydrochloride (0.22 g, 1.45 mmol) according to the general procedure described in Example 2.

HPLC purity: 98.48% (262 nm)

Mass spectroscopy: (ESI +ve) 292.0 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 1.97 (m, 4H), 3.04 (m, 4H), 6.76 (s, 2H), 7.51 (m, 3H), 8.06 (m, 2H).

(vi) 6-(3,3-dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazine-3-amine

6-(3,3-dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (54 mg, 10%) was obtained from 6-bromo-5-phenyl-1,2, 4-triazine-3-amine (0.50 g, 1.99 mmol) and 3,3-dimethylpiperidine (0.27 g, 2.39 mmol) according to the general procedure described in Example 2.

HPLC purity: 88% (274 nm)

Mass spectroscopy: (ESI +ve) 284.1 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 0.89 (s, 6H), 1.24 (m, 2H), 1.40 (m, 2H), 2.65 (m, 2H), 2.70 (m, 2H), 6.67 (s , 2H), 7.49 (m, 3H), 7.94 (m, 2H).

(vii) 5-phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine

5-phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (50 mg, 8%) was obtained from 6-bromo-5-phenyl-1,2 ,4-triazine-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethyl)piperidine (0.40 g, 2.58 mmol) according to the general procedure described in Example 2.

HPLC purity: 97.6% (263 nm)

Mass spectroscopy: (ESI +ve) 324.1 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 1.35 (m, 1H), 1.48 (m, 1H), 1.57 (m, 1H), 1.90 (m, 1H), 2.48 (m, 2H), 2.73 (m , 1H), 3.05 (m, 1H), 3.50 (m, 1H), 6.74 (s, 2H), 7.50 (s, 3H), 8.02 (m, 2H).

(viii) 6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(Octahydroquinolin-1(2H)-yl)-5-phenyl-1,2,4-triazine-3-amine (39 mg, 7%) was obtained from 6-bromo-5-phenyl-1,2,4 -triazine-3-amine (1.00 g, 3.96 mmol) and decahydroquinoline (0.60 g, 4.36 mmol) according to the general procedure described in Example 2.

HPLC purity: 98.75% (282 nm)

Mass spectroscopy: (ESI +ve) 310.1 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 0.83 (m, 1H), 1.41 (m, 6H), 1.54 (m, 6H), 2.62 (m, 1H), 2.80 (m, 2H), 6.93 (broad s, 2H), 7.47 (m, 3H), 8.15 (m, 2H).

(ix) 6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (33 mg, 4%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.70 g, 2.78 mmol), K ₂ CO ₃ (0.80 g, 5.85 mmol) and 3-methoxypiperidine hydrochloride (0.52 g, 3.34 mmol) according to the general procedure described in Example 2.

HPLC purity: 99.32% (266 nm)

Mass spectroscopy: (ESI +ve) 286.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 1.36 (m, 1H), 1.45 (m, 1H), 1.59 (m, 1H), 1.84 (m, 1H), 2.48 (m, 1H), 2.60 (m , 1H), 3.03 (m, 4H), 3.25 (m, 2H), 7.57 (m, 3H), 7.26 (broad s, 2H), 7.99 (m, 2H).

(x) 6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine

6-(3-Ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (10 mg, 2%) was obtained from 6-bromo-5-phenyl-1,2,4- triazine-3-amine (0.60 g, 2.40 mmol) and 3-ethynylpiperidine hydrochloride (0.42 g, 2.87 mmol) according to the general procedure described in Example 2.

HPLC purity: 95.99% (266 nm)

Mass spectroscopy: (ESI +ve) 280.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 1.08-1.80 (m, 5H), 2.64 (m, 2H), 2.86 (m, 2H), 3.23 (t, 1H), 6.7 (broad s, 2H) , 7.48 (m, 3H), 8.06 (d, 2H).

(xi) 6-(2,6-dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-(2,6-Dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (110 mg, 20%) was obtained from 6-bromo-5-(4 -fluorophenyl)-1,2,4-triazine-3-amine (0.50 g, 1.87 mmol) and 2,6-dimethylmorpholine (1.06 g, 9.36 mmol) according to the general procedure described in Example 2.

HPLC purity: 93.61% (264 nm)

Mass spectroscopy: (ESI +ve) 304 [M+H]+

¹ H NMR: (400 MHz, DMSO) δ: 1.12 (d, 6H), 2.54 (m, 2H), 3.19 (d, 2H), 3.30 (m, 2H), 5.13 (broad s, 2H), 7.16 (m, 2H), 8.16 (m, 2H).

The compounds listed below were prepared by reacting the indicated starting compounds with potassium carbonate (83 mg, 0.60 mmol) in 1,4-dioxane (0.8 ml) and water (0.2 ml) at 140°C for 18 h, unless a shorter reaction time was indicated :

No. Product (output) Derived from LCMS NMR (xi) 6-(2-ethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine (60 mg, 35%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 2-ethylmorpholine (344 mg, 2.99 mmol) Mass spectroscopy: m/z 286 (M+H) ⁺ (ES ⁺ ), at 4.03 min, 100% (method B). (400 MHz, DMSO) δ: 0.73 (t, J 7.5, 3H), 1.22 – 1.44 (m, 2H), 2.38 – 2.47 (m, 1H), 2.65 – 2.77 (m, 1H), 3.02 (d, J 12.2, 1H), 3.12 (d, J 12.2, 1H), 3.33 (s, 1H), 3.48 – 3.58 (m, 1H), 3.77 (d, J 11.1, 1H), 6.74 (s, 2H), 7.48 – 7.57 (m, 3H), 8.01–8.08 (m, 2H). (xiii) 5-phenyl-6-(6-oxa-9-azaspiro[4.5]decan-9-yl)-1,2,4-triazin-3-amine (48 mg, 25%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 6-oxa-9-azaspiro[4.5]decane hydrochloride (425 mg, 2.390 mmol) Mass spectroscopy: m/z 312 (M+H) ⁺ (ES ⁺ ), at 4.24 min, 97% purity (method B). (400 MHz, DMSO) δ: 1.27 – 1.44 (m, 2H), 1.47 – 1.76 (m, 6H), 2.71 – 2.81 (m, 2H), 2.84 (s, 2H), 3.47 – 3.63 (m, 2H) , 6.77 (s, 2H), 7.48–7.57 (m, 3H), 7.94–8.01 (m, 2H). (xiv) 6-(2,2-diethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine (47 mg, 25%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 2,2-diethylmorpholine (428 mg, 2.99 mmol) Mass spectroscopy: m/z 314 (M+H) ⁺ (ES ⁺ ), at 4.64 min, 100% (method B). (400 MHz, DMSO) δ: 0.67 (t, J 7.5, 6H), 1.33 (d.sq., J 14.8, 7.5, 2H), 1.65 (d.s.q., J 14.9, 7.5, 2H), 2.71 – 2.82 ( m, 4H), 3.47–3.58 (m, 2H), 6.78 (s, 2H), 7.45–7.57 (m, 3H), 7.85–7.95 (m, 2H). (xv) 6-(2,2-dimethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine (41 mg, 24%); received in 6 hours 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 2,2-dimethylmorpholine (344 mg, 2.99 mmol) Mass spectroscopy: m/z 286 (M+H) ⁺ (ES+), at 4.03 min, 98% (method B). (400 MHz, DMSO) δ: 1.14 (s, 6H), 2.69 – 2.77 (m, 2H), 2.79 (s, 2H), 3.49 – 3.62 (m, 2H), 6.77 (s, 2H), 7.48 – 7.56 (m, 3H), 7.92–8.00 (m, 2H). (xvi) (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-methylpiperidin-3-yl)methanol (35 mg, 19%); received in 6 hours 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), (3-methylpiperidin-3-yl)methanol (386 mg, 2.99 mmol) Mass spectroscopy: m/z 300 (M+H) ⁺ (ES ⁺ ), at 4.10 min, 99% (method B). (400 MHz, DMSO) δ: 0.88 (s, 3H), 1.10 – 1.20 (m, 1H), 1.31 – 1.45 (m, 3H), 2.54 – 2.63 (m, 1H), 2.63 – 2.72 (m, 1H) , 2.75 – 2.93 (m, 2H), 3.23 (d, J 5.6, 2H), 4.51 (t, J 5.5, 1H), 6.68 (s, 2H), 7.47 – 7.55 (m, 3H), 7.92 – 8.00 ( m, 2H). (xviii) 6-(3-(methoxymethyl)piperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine (75 mg, 42%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), cis-3-(methoxymethyl)piperidine (386 mg, 2.99 mmol) Mass spectroscopy: m/z 300 (M+H) ⁺ (ES ⁺ ), at 4.4 min, 100% (method B). (400 MHz, DMSO) δ: 0.95 – 1.12 (m, 1H), 1.37 – 1.60 (m, 2H), 1.61 – 1.73 (m, 1H), 1.80 – 1.94 (m, 1H), 2.37 – 2.47 (m, 1H), 2.50–2.58 (m, 1H), 3.03–3.21 (m, 6H), 3.28–3.34 (m, 1H), 6.68 (s, 2H), 7.47–7.56 (m, 3H), 7.99–8.09 ( m, 2H). (xiii) 1-(1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanol (80mg, 43%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol) and 1-(piperidin-3-yl)ethanol (77 mg, 0.597 mmol) Mass spectroscopy: m/zm/z 300 (M+H) ⁺ (ES ⁺ ), at 3.98 min, 96% (method B). (400 MHz, DMSO) δ: 0.91 – 1.03 (m, 1H), 1.22 – 1.32 (m, 2H), 1.38 – 1.59 (m, 2H), 1.59 – 1.69 (m, 1H), 1.69 – 1.80 (m, 1H), 2.28 – 2.38 (m, 1H), 2.47 – 2.56 (m, 1H), 3.07 – 3.16 (m, 1H), 3.18 – 3.30 (m, 3H), 4.25 – 4.38 (m, 1H), 6.68 ( s, 2H), 7.46–7.57 (m, 3H), 7.99–8.09 (m, 2H). (xix) (1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)methanol (18mg, 10%) piperidin-3-ylmethanol (344 mg, 2.99 mmol), 6-bromo-5-phenyl-1,2,4-triazin-3-amine (150 mg, 0.597 mmol) Mass spectroscopy:m/z 286 (M+H)⁺ (ES⁺), at 3.78 min, 94% (method B). (400 MHz, DMSO) δ: 0.94 – 1.08 (m, 1H), 1.34 – 1.57 (m, 2H), 1.61 – 1.74 (m, 2H), 2.38 – 2.61 (m, 2H), 3.04 (s, 1H) , 3.13 – 3.46 (m, 3H), 4.44 (t, J = 5.3 Hz, 1H), 6.67 (s, 2H), 7.45 – 7.57 (m, 3H), 7.98 – 8.11 (m, 2H). (xx) 1-(1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanone (13mg, 7%) 1-(piperidin-3-yl)ethanone (380 mg, 2.99 mmol), 6-bromo-5-phenyl-1,2,4-triazin-3-amine (150 mg, 0.597 mmol) Mass spectroscopy: m/z 298 (M+H) ⁺ (ES ⁺ ); at 3.92 min, 95.06% (method B). (400 MHz, DMSO) δ: 1.30 – 1.51 (m, 2H), 1.52 – 1.63 (m, 1H), 1.85 – 1.96 (m, 1H), 2.01 (s, 3H), 2.62 – 2.71 (m, 1H) , 2.71–2.83 (m, 1H), 2.95–3.12 (m, 1H), 3.31–3.46 (m, 2H), 6.72 (s, 2H), 7.46–7.56 (m, 3H), 7.97–8.08 (m, 3H). (xxi) 6-(Octahydroisoquinolin-2( 1H )-yl)-5-phenyl-1,2,4-triazine-3-amine (54.2 mg, 2.1%); received in 8 hours 6-bromo-5-phenyl-1,2,4-triazine-3-amine (2.00 g, 7.96 mmol) and perhydroisoquinoline (2.21 g, 15.9 mmol) HPLC purity: 97.40% (277 nm); mass spectroscopy: (ESI +ve) m/z 310.1 [M+H] ⁺ (400 MHz, DMSO) δ: 0.85 (m, 3H), 1.14 (m, 4H), 1.36 (m, 2H), 1.54 (m, 3H), 2.26 (m, 1H), 2.51 (m, 1H), 3.10 (m, 2H), 6.61 (broad s, 2H), 7.48 (m, 3H), 8.04 (dd, 2H). (xxi) N ⁶ -(4-methyl-1,3-thiazol-2-yl)-5-phenyl-1,2,4-triazine-3,6-diamine (10 mg, 1%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (1.00 g, 3.98 mmol) and 2-amino-4-methylthiazole (1.36 g, 11.95 mmol) HPLC purity: 99.03% (298 nm); mass spectroscopy: (ESI +ve) m/z 284.9 [M+H] ⁺ (400 MHz, DMSO) δ: 2.10 (s, 3H), 6.18 (s, 1H), 6.53 (broad s, 2H), 7.48 (m, 3H), 8.15 (m, 2H), 11.61 (broad, 1H ). (xiii) 5-phenyl-6-[4-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine (20 mg, 2%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (1.0 g, 3.9 mmol) and 4-trifluoromethyl piperidine hydrochloride (0.9 g, 4.8 mmol) HPLC purity: 99.9% (218 nm); mass spectroscopy: (ESI +ve) m/z 323.9 [M] ⁺ (400 MHz, DMSO) δ: 1.46 (m, 2H), 1.75 (m, 2H), 2.34 (m, 1H) 2.66 (m, 2H), 3.23 (m, 2H), 6.72 (s, 2H), 7.51 (m, 3H), 8.02 (m, 2H). (xxiv) 5-phenyl-6-(3-phenylpiperidin-1-yl)-1,2,4-triazin-3-amine (62 mg, 31%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 3-phenylpiperidine (482 mg, 2.99 mmol) Mass spectroscopy: m/z 332 (M+H) ⁺ (ES ⁺ ), at 4.92 min, 100% (method B). (400 MHz, DMSO) δ: 1.51 – 1.77 (m, 3H), 1.83 – 1.92 (m, 1H), 2.58 – 2.72 (m, 2H), 2.74 – 2.84 (m, 1H), 3.24 (d, J 11.7 , 1H) 3.34 (d, J 11.7, 1H), 6.67 (s, 2H), 7.04–7.12 (m, 2H), 7.13–7.20 (m, 1H), 7.20–7.28 (m, 2H), 7.52–7.58 (m, 3H), 8.03–8.13 (m, 2H). (xxv) (4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)methanol (40mg, 23%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), morpholin-2-ylmethanol (350 mg, 2.99 mmol) Mass spectroscopy: m/z 288 (M+H) ⁺ (ES ⁺ ), at 2.95 min, 100% (method B). (400 MHz, DMSO) δ: 2.51 – 2.58 (m, 1H), 2.63 – 2.74 (m, 1H), 2.91 – 3.02 (m, 1H), 3.33 (s, 3H), 3.47 – 3.58 (m, 2H) , 3.70–3.79 (m, 1H), 4.67 (t, J 5.8, 1H), 6.76 (s, 2H), 7.47–7.56 (m, 3H), 8.03–8.11 (m, 2H). (xxiv) 5-phenyl-6-(3-(propoxymethyl)pyrrolidin-1-yl)-1,2,4-triazine-3-amine (39 mg, 20%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 3-(propoxymethyl)pyrrolidine (428 mg, 2.99 mmol) Mass spectroscopy: m/z 314 (M+H) ⁺ (ES ⁺ ), at 4.64 min, 95% (method B). (400 MHz, DMSO) δ: 0.80 (t, J 7.4, 3H), 1.37 – 1.58 (m, 3H), 1.81 – 1.94 (m, 1H), 2.29 – 2.40 (m, 2H), 2.85 (dd, J 10.3, 6.4, 1H), 3.00–3.13 (m, 3H), 3.18–3.30 (m, 3H), 6.38 (s, 2H), 7.45–7.53 (m, 3H), 7.69–7.79 (m, 2H). (xxiv) 2-(1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)propan-2-ol (56mg, 31%) 6-bromo-5-phenyl-1,2,4-triazin-3-amine (150 mg, 0.597 mmol), 2-(piperidin-3-yl) propan-2-ol (257 mg, 1.792 mmol) Mass spectroscopy: m/z 314 (M+H) ⁺ (ES ⁺ ), 4.22 min, 100% (method B). (400 MHz, DMSO) δ: 0.86 (s, 6H), 1.00 – 1.13 (m, 1H), 1.38 – 1.52 (m, 2H), 1.58 – 1.69 (m, 1H), 1.78 – 1.88 (m, 1H) , 2.30 (pseudo t, J 11.6, 1H), 2.42–2.50 (m, 1H), 3.20–3.28 (m, 1H), 3.31–3.38 (m, 1H), 4.07 (s, 1H), 6.65 (s, 2H), 7.45–7.56 (m, 3H), 7.97–8.09 (m, 2H). (xxiii) 6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-5-phenyl-1,2,4-triazin-3-amine (16 mg, 9%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), octahydropyrrolo[1,2-a]pyrazine (377 mg, 2.99 mmol) Mass spectroscopy: m/z 297 (M+H) ⁺ (ES ⁺ ), at 4.17 min, 100% (method B). (400 MHz, DMSO) δ: 1.21 – 1.35 (m, 2H), 1.55 – 1.73 (m, 2H), 1.96 – 2.20 (m, 3H), 2.69 – 2.81 (m, 1H), 2.81 – 3.03 (m, 2H), 3.06–3.19 (m, 1H), 3.29–3.36 (m, 2H), 6.71 (s, 2H), 7.46–7.56 (m, 3H), 8.00–8.09 (m, 2H). (xxxix) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-ethylpiperidin-3-ol (42 mg, 23%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 3-ethylpiperidin-3-ol (386 mg, 2.99 mmol) Mass spectroscopy: m/z 300 (M+H) ⁺ (ES ⁺ ), at 4.14 min, 97% (method B). (400 MHz, DMSO) δ: 0.79 (t, J 7.4, 3H), 1.23 (s, 1H), 1.32 – 1.52 (m, 4H), 1.54 – 1.68 (m, 1H), 2.59 – 2.69 (m, 1H ), 2.69–2.80 (m, 1H), 2.86–2.98 (m, 2H), 4.21 (s, 1H), 6.73 (s, 2H), 7.46–7.55 (m, 3H), 8.01–8.10 (m, 2H ). (xxx) 2-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)ethanol (42 mg, 22%); received in 3 hours 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 2-(morpholin-2-yl)ethanol (392 mg, 2.99 mmol) Mass spectroscopy: m/z 302 (M+H) ⁺ (ES ⁺ ), at 3.22 min, 96% (method B). (400 MHz, DMSO) δ: 1.34 – 1.61 (m, 2H), 2.48 – 2.58 (m, 1H), 2.62 – 2.74 (m, 1H), 2.91 – 3.02 (m, 1H), 3.09 – 3.20 (m, 1H), 3.27 – 3.42 (m, 2H), 3.46 – 3.56 (m, 1H), 3.56 – 3.67 (m, 1H), 3.68 – 3.78 (m, 1H), 4.39 (t, J 5.1, 1H), 6.74 (s, 2H), 7.47–7.58 (m, 3H), 7.99–8.12 (m, 2H).

Example 3

General procedure for the preparation of 3-amino-5-aryl-6-aryloxy-1,2,4-triazines

To a solution of intermediate D, 6-halo-5-aryl-1,2,4-triazine-3-amine, (1.99 mmol) in DMSO (5 ml), a phenolic derivative (7.90 mmol), NaOH (0.31 g, 7.9 mmol) and cesium carbonate (0.64 g, 1.99 mmol). The resulting mixture was stirred at 90°C overnight with monitoring by TLC (hexane/ethyl acetate, 7:3). At the end of the reaction, the mixture was diluted with water (15 ml) and extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were dried over sodium sulfate and evaporated in vacuo. Crude product C was purified by gradient flash chromatography using a mixture of ethyl acetate and hexane (eg 15%) as eluent or by preparative HPLC.

(i) 6-Phenoxy-5-phenyl-1,2,4-triazine-3-amine

6-Phenoxy-5-phenyl-1,2,4-triazine-3-amine (78 mg, 14%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.5 g , 1.99 mmol) and phenol (0.74 g, 7.90 mmol) according to the general procedure described in Example 3.

HPLC purity: 99.67% (210 nm)

Mass spectroscopy: (ESI +ve) 265.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 7.08 (s, 2H), 7.13 (m, 3H), 7.36 (m, 2H), 7.52 (m, 3H), 8.07 (m, 2H).

(ii) 6-(3-aminophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazine-3-amine (25 mg, 8%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.30 g, 1.19 mmol) and 3-aminophenol (0.19 g, 1.78 mmol) according to the general procedure described in Example 3.

HPLC purity: 89.7% (238 nm)

Mass spectroscopy: (ESI +ve) 338.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 5.19 (s, 2H), 6.15 (m, 2H), 6.27 (m, 1H), 6.93 (m, 1H), 7.10 (s, 2H), 7.48-7.56 (m, 3H), 8.04 (d, 2H).

(iii) 6-(3-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (78 mg, 23%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.30 g, 1.19 mmol) and 3-fluorophenol (0.27 g, 2.39 mmol) according to the general procedure described in Example 3.

HPLC purity: 99.67% (244 nm)

Mass spectroscopy: (ESI +ve) 283.1 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.29 (s, 2H), 6.87-6.95 (m, 3H), 7.33 (m, 1H), 7.48-7.58 (m, 3H), 8.23 (m, 2H ).

(iv) 5-phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazine-3-amine

5-Phenyl-6-[2-(propan-2-yl)phenoxy]-1,2,4-triazin-3-amine (20 mg, 7%) was obtained from 6-bromo-5-phenyl-1,2 ,4-triazine-3-amine (0.40 g, 1.59 mmol) and 2-isopropylphenol (0.43 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 96.5% (245 nm)

Mass spectroscopy: (ESI +ve) 307.1 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 1.25 (d, 6H), 3.16 (m, 1H), 5.19 (s, 2H), 7.00 (m, 1H), 7.20 (m, 2H), 7.36 ( m, 1H), 7.38-7.59 (m, 3H), 8.31 (m, 2H).

(v) 5-phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazine-3-amine

5-Phenyl-6-[3-(trifluoromethyl)phenoxy]-1,2,4-triazine-3-amine (21 mg, 4%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine -3-amine (0.40 g, 1.59 mmol) and 3-(trifluoromethyl)phenol (0.52 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 88.72% (245 nm)

Mass spectroscopy: (ESI +ve) 332.9 [M+H] ⁺

¹ H NMR: (400 MHz, d ₆ -DMSO) δ: 7.10 (s, 2H), 7.49-7.63 (m, 5H), 7.61-7.63 (m, 2H), 8.07-8.09 (d, 2H).

(vi) 6-(4-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(4-Fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (35 mg, 8%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.40 g, 1.59 mmol) and 4-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 96.39% (244 nm)

Mass spectroscopy: (ESI +ve) 283.1 [M+H] ⁺

¹ H NMR: (400 MHz, d ₆ -DMSO) δ: 7.03 (s, 2H), 7.20-7.22 (m, 4H), 7.50-7.56 (m, 3H), 8.08 (dd, 2H).

(vii) 6-(2-fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(2-Fluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (44 mg, 10%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.40 g, 1.59 mmol) and 2-fluorophenol (0.36 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 90.06% (244 nm)

Mass spectroscopy: (ESI +ve) 283.1 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 7.04 (s, 2H), 7.25 (m, 2H), 7.37 (m, 2H), 7.53-8.11 (m, 3H), 8.12 (m, 2H).

(viii) 6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(4-Methoxyphenoxy)-5-phenyl-1,2,4-triazine-3-amine (45 mg, 13%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.30 g, 1.19 mmol) and 4-methoxyphenol (0.30 g, 2.39 mmol) according to the general procedure described in Example 3.

HPLC purity: 92.08% (218 nm)

Mass spectroscopy: (ESI +ve) 295.1 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 3.81 (s, 3H), 5.29 (s, 2H), 6.92 (d, 2H), 7.08 (d, 2H), 7.50-7.59 (m, 3H), 8.29 (m, 2H).

(ix) 6-[4-fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazine-3-amine

6-[4-Fluoro-3-(trifluoromethyl)phenoxy]-5-phenyl-1,2,4-triazine-3-amine (198 mg, 36%) was obtained from 6-bromo-5-phenyl-1,2 ,4-triazine-3-amine (0.40 g, 1.59 mmol) and 4-fluoro-3-(trifluoromethyl)phenol (0.57 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 95% (235 nm)

Mass Spectroscopy: (ESI +ve) 350.9 [M+H] ⁺ , (ESI -ve) 349.1[MH] ^- .

¹ H NMR: (400 MHz, DMSO) δ: 7.05 (s, 2H), 7.50-7.62 (m, 5H), 7.75 (m, 1H), 8.10 (m, 2H).

(x) 5-phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazine-3-amine

5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazine-3-amine (22 mg, 3%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine -3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenol (0.42 g, 2.39 mmol) according to the general procedure described in Example 3.

HPLC purity: 95.6% (235 nm)

Mass spectroscopy: (ESI +ve) 348.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.17 (s, 2H), 7.08 (m, 3H), 7.39 (t, 1H) 7.54 (m, 3H), 8.21 (d, 2H).

(xi) 6-(3-chlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (147 mg, 31%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine-3- amine (0.40 g, 1.58 mmol), 3-chlorophenol (0.40 g, 3.16 mmol) and K ₂ CO ₃ (432 mg, 3.15 mmol) according to the general procedure described in Example 3.

HPLC purity: 98% (245 nm)

Mass spectroscopy: (ESI +ve) 298.9 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 7.12 (s, 2H), 7.14 (m, 1H), 7.21 (m, 1H), 7.35 (m, 1H), 7.40 (m, 1H), 7.55 (m , 3H), 8.06 (m, 2H).

(xii) 6-(3,5-dichlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Dichlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (89 mg, 17%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.40 g, 1.59 mmol) and 3,5-dichlorophenol (0.52 g, 3.18 mmol) according to the general procedure described in Example 3.

HPLC purity: 99.03% (246 nm)

Mass spectroscopy: (ESI +ve) 332.9 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 7.15 (s, 2H), 7.40 (m, 3H), 7.54 (m, 3H), 8.02 (d, 2H).

(xiii) 6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine

6-(3,5-Difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (101 mg, 17%) was obtained from 6-bromo-5-phenyl-1,2,4-triazine- 3-amine (0.50 g, 1.99 mmol) and 3,5-difluorophenol (0.31 g, 3.98 mmol) according to the general procedure described in Example 3.

HPLC purity: 90.33% (244 nm)

Mass spectroscopy: (ESI +ve) 300.9 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl ₃ ) δ: 5.46 (broad s, 2H), 6.65 (m, 1H), 6.71 (m, 2H), 7.50 (m, 2H), 7.58 (m, 1H), 8.12 (m, 2H).

The compounds listed below were prepared by reacting the indicated starting compounds according to the general procedure described in Example 3.

No. Product (output) Derived from LCMS NMR (xiv) 6-(3,5-dimethylphenoxy)-5-phenyl-1,2,4-triazine-3-amine (26 mg, 5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.40 g, 1.59 mmol) and 3,5-(dimethyl)phenol (0.39 g, 2.07 mmol) HPLC purity: 96.6% (246 nm); mass spectroscopy: (ESI +ve) m/z 293.0 [M+H] ⁺ (400 MHz, DMSO) δ: 2.22 (s, 6H), 6.71 (s, 2H), 6.76 (s, 1H) 7.06 (s, 2H), 7.52 (m, 3H), 8.05 (d, 2H). (xv) 6-(3-chloro-5-methoxyphenoxy)-5-phenyl-1,2,4-triazine-3-amine (120 mg, 23%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.40 g, 1.59 mmol) and 3-chloro-5-methoxyphenol (0.50 g, 31.8 mmol) HPLC purity: 98% (245 nm); mass spectroscopy: (ESI +ve) m/z 328.9 [M+H] ⁺ (400 MHz, DMSO) δ: 3.74 (s, 3H), 6.75 (m, 1H), 6.82 (m, 1H), 6.85 (m, 1H), 7.12 (s, 2H), 7.53 (m, 3H), 8.03 (m, 2H).

The compounds listed below were prepared by heating a mixture of the phenolic derivative and the bromotriazine derivative (indicated) with DBU (270 µl, 1.792 mmol) at 110 ^° C. overnight:

No. Product (output) Derived from LCMS NMR (xvi) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridin-4(1H)-one (29 mg, 0.109 mmol, 27.5%) 6-chloro-5-phenyl-1,2,4-triazine-3-amine (0.082 g, 0.398 mmol), DBU (0.298 µl, 1.990 mmol) and pyridin-4-ol (189 mg, 1.990 mmol) Mass spectroscopy: m/z 266.2 (M+H) ⁺ (ES ⁺ ); 264.4 (MH)-(ES-), at 2.45 min, 100% (method B). (400 MHz, DMSO) δ: 6.08–6.16 (m, 2H), 7.42–7.55 (m, 5H), 7.68–7.77 (m, 4H). (xviii) 6-(4-methylphenoxy)-5-phenyl-1,2,4-triazine-3-amine (51 mg, 51%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), p-cresol (194 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 279.82 (M+H) ⁺ (ES ⁺ ), at 4.75 min, 99% (method B). (400 MHz, DMSO) δ: 2.28 (s, 3H), 7.00–7.04 (m, 2H), 7.05 (s, 2H), 7.12–7.22 (m, 2H), 7.49–7.60 (m, 3H), 8.04 – 8.13 (m, 2H). (xiii) 6-(4-chlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (38 mg, 35%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 4-chlorophenol (230 mg, 1.792 mmol), and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 299.6 (M+H) ⁺ (ES ⁺ ), at 4.77 min, 99% (method B). (400 MHz, DMSO) δ: 7.12 (s, 2H), 7.18 – 7.25 (m, 2H), 7.40 – 7.46 (m, 2H), 7.49 – 7.60 (m, 3H), 8.03 – 8.11 (m, 2H) . (xix) 6-(3,4-difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 3,4-difluorophenol (233 mg, 1.792 mmol), and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 301.64 (M+H) ⁺ (ES ⁺ ); 299.94 (MH) ^- (ES ^- ), at 4.59 min, 97% (method B). (400 MHz, DMSO) δ: 7.03 – 7.11 (m, 1H), 7.11 (s, 2H), 7.41 – 7.51 (m, 3H), 7.51 – 7.61 (m, 3H), 8.03 – 8.11 (m, 2H) . (xx) 6-[(6-methoxypyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 6-methoxypyridin-3-ol (224 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 296.0 (M+H) ⁺ (ES ⁺ ); 4.59 min, 95% (method B). (400 MHz, DMSO) δ: 3.85 (s, 3H), 6.88 (dd, J 8.9, 0.5, 1H), 7.00 (s, 2H), 7.52 – 7.63 (m, 3H), 7.68 (dd, J 8.9, 3.0, 1H), 8.11 (dd, J 2.9, 0.5, 1H), 8.12–8.16 (m, 2H). (xxi) 6-[(2-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 2-methylpyridin-3-ol (196 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 280.73 (M+H) ⁺ (ES ⁺ ); 278.94 (MH) ^- (ES ^- ), at 3.90 min, 99% (method B). (400 MHz, DMSO) δ: 2.38 (s, 3H), 7.05 (s, 2H), 7.28 (ddd, J 8.2, 4.7, 0.5, 1H), 7.52 – 7.63 (m, 4H), 8.11 – 8.18 (m , 2H), 8.31 (dd, J 4.7, 1.4, 1H). (xxi) 6-[(6-chloropyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 6-chloropyridin-3-ol (232 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 300.70 (M+H) ⁺ (ES ⁺ ), at 3.90 min, 97% (method B). (400 MHz, DMSO) δ: 7.14 (s, 2H), 7.51 – 7.63 (m, 4H), 7.83 (dd, J 8.7, 3.0, 1H), 8.06 – 8.13 (m, 2H), 8.42 (dd, J 3.0, 0.5, 1H). (xiii) 4-[(3-amino-5-phenyl-1,2,4-triazin-6-yl)oxy]benzonitrile 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 4-hydroxybenzonitrile (213 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 290.72 (M+H) ⁺ (ES ⁺ ); 288.96 (MH) ^- (ES ^- ), at 4.09 min, 99% (method B). (400 MHz, DMSO) δ: 7.28 (s, 2H), 7.34 – 7.39 (m, 2H), 7.48 – 7.59 (m, 3H), 7.82 – 7.90 (m, 2H), 8.00 – 8.05 (m, 2H) . (xxiv) 6-{[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol (298 mg, 1.792 mmol ) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 337.60 (M+H) ⁺ (ES ⁺ ); 335.81 (MH) ^- (ES ^- ), at 4.35 min, 97% (method B). (400 MHz, DMSO) δ: 3.79 (s, 3H), 6.58 (s, 1H), 7.27 (s, 2H), 7.52 – 7.66 (m, 3H), 8.04 – 8.12 (m, 2H). (xxv) 6-[(1-methyl-1H-benzimidazol-5-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 1-methyl-1H-benzo[d]imidazol-5-ol (266 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 319.69 (M+H) ⁺ (ES ⁺ ), at 4.05 min, 99% (method B). (400 MHz, DMSO) δ: 3.85 (s, 3H), 7.01 (s, 2H), 7.14 (dd, J 8.7, 2.2, 1H), 7.42 (d, J 2.1, 1H), 7.51 – 7.63 (m, 4H), 8.12–8.19 (m, 2H), 8.26 (s, 1H). (xxiv) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)pyridazin-4(1H)-one 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), pyridazin-4-ol (172 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 267.80 ⁺ (ES ⁺ ); 266.01 (MH) ^- (ES ^- ), at 2.80 min, 96% (method B). (400 MHz, DMSO) δ: 6.54 (dd, J 8.0, 3.1, 1H), 7.41 – 7.56 (m, 5H), 7.74 (dd, J 3.1, 0.6, 1H), 7.90 (s, 2H), 8.60 ( dd, J 8.0, 0.6, 1H). (xxiv) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dichloropyridin-4(1H)-one (10 mg, 5%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (150 mg, 0.597 mmol), 3,5-dichloropyridin-4-ol (490 mg, 2.99 mmol) Mass spectroscopy: m/z 334.55 (M+H) ⁺ (ES ⁺ ), at 3.05 min, 96% (method B). (400 MHz, DMSO) δ: 7.44 – 7.60 (m, 5H), 7.94 (s, 2H), 8.42 (s, 2H). (xxiii) 6-(2,4-dichlorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (16 mg, 13%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 2,4-dichlorophenol (292 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 333.5 (M+H)+ (ES+), at 5.03 min, 98% purity (method B). (400 MHz, DMSO) δ: 7.10 (s, 2H), 7.42 – 7.51 (m, 2H), 7.54 – 7.64 (m, 3H), 7.80 (d, J 2.4, 1H), 8.11 – 8.18 (m, 2H ). (xxxix) 6-(2,4-difluorophenoxy)-5-phenyl-1,2,4-triazine-3-amine (12 mg, 11%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 2,4-difluorophenol (233 mg, 1.792 mmol) and DBU (270 µl, 1.792 mmol) Mass spectroscopy: m/z 301.67 (M+H) ⁺ (ES ⁺ ), 99% (method B). (400 MHz, DMSO) δ: 7.06 (s, 2H), 7.12–7.21 (m, 1H), 7.44–7.65 (m, 5H), 8.09–8.18 (m, 2H). (xxx) 5-phenyl-6-(pyridin-3-yloxy)-1,2,4-triazine-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), pyridin-3-ol (170 mg, 1.792 mmol) Mass spectroscopy: m/z 266.76 (M+H) ⁺ (ES ⁺ ); 264.96 (MH) ^- (ES ^- ), at 3.70 min, 99% (method B). (400 MHz, DMSO) δ: 7.11 (s, 2H), 7.45 (ddd, J 8.4, 4.7, 0.6, 1H), 7.50 – 7.63 (m, 3H), 7.69 (ddd, J 8.4, 2.8, 1.4, 1H ), 8.05–8.15 (m, 2H), 8.41 (dd, J 4.7, 1.3, 1H), 8.53 (d, J 2.5, 1H). (xxxi) 6-[(4-methylpyridin-3-yl)oxy]-5-phenyl-1,2,4-triazin-3-amine 6-bromo-5-phenyl-1,2,4-triazine-3-amine (90 mg, 0.358 mmol), 4-methylpyridin-3-ol (196 mg, 1.792 mmol) Mass spectroscopy: m/z 280.79 (M+H) ⁺ (ES ⁺ ), at 3.97 min, 99% (method B). (400 MHz, DMSO) δ: 2.19 (s, 3H), 7.02 (s, 2H), 7.39 (d, J 4.9, 1H), 7.54 – 7.64 (m, 3H), 8.13 – 8.21 (m, 2H), 8.32 (d, J 4.8, 1H), 8.39 (s, 1H). (xxxii) 5-phenyl-6-(p-tolylthio)-1,2,4-triazine-3-amine (407 mg, 1.383 mmol, 69.4%) 6-bromo-5-phenyl-1,2,4-triazine-3-amine (0.50 g, 1.991 mmol) and 4-methylbenzenethiol (1.24 g, 9.96 mmol) Mass spectroscopy: m/z 295.2 (M+H) ⁺ (ES ⁺ ), at 4.77 min, 100% (method B). (400 MHz, DMSO) δ: 2.26 (s, 3H), 7.09–7.15 (m, 4H), 7.44 (s, 2H), 7.46–7.55 (m, 3H), 7.67–7.72 (m, 2H).

Example 4

Preparation of (i) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol; and (ii) 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate

Step 1: 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol (890 mg, 85%) was obtained by demethylation of 6-(3-chloro-5-methoxyphenyl)-5- phenyl-1,2,4-triazine-3-amine (1.2 g, 3.84 mmol; see above) with BBr ₃ (5 ml) at -70°C for 2 h and then another 16 h at room temperature. The resulting mixture was poured into water (25 ml) and extracted with dichloromethane (3 x 30 ml). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting crude product was purified by gradient flash chromatography using 30% ethyl acetate in hexane as eluent to give the title compound.

HPLC purity: 96.94% (262 nm)

Mass spectroscopy: (ESI +ve) 298.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 6.68 (m, 1H), 6.75 (m, 2H), 7.35-7.45 (m, 7H), 9.98 (s, 1H).

Step 2: 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (2.5 g, 90%) was obtained from 3-(3-amino-5-phenyl-1, 2,4-triazin-6-yl)-5-chlorophenol (1.5 g, 5.03 mmol). This alcohol was dissolved in DCM (15 ml), cooled to 0°C and triethylamine (0.66 g) was added for 10 minutes. Trifluoromethanesulfonyl chloride was then added at 0 ^° C., the mixture was warmed to room temperature and kept at this temperature for 1.5 h. The mixture was then poured into water (25 ml) and extracted with dichloromethane (3 x 30 ml); the combined organic extracts were dried over Na ₂ SO ₄ and evaporated in vacuo. The crude product was used in the next step without purification.

Mass spectroscopy: (ESI +ve) 431.0 [M+H] ⁺ , (ESI -ve) 429.0 [MH] ⁺ .

General procedure for Pd-catalyzed cross-coupling of 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate

3-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.65 g, 1.51 mmol) was dissolved in DMF (10 ml), and LiCl was successively added to the resulting solution (0.21 g) and a suitable coupling partner (1.81 mmol) in the form of an organotin compound or boronic acid. The resulting mixture was stirred at room temperature for 5-10 minutes, then tetrakis(triphenylphosphine)palladium(0) (0.087 g, 0.075 mmol) was added and boiled (90 ^o C) for 4-5 hours. The reaction mixture was then poured into water (25 ml) and extracted with an organic solvent such as DCM or ethyl acetate (3 x 30 ml). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated in vacuo and the isolated target substance was purified by gradient flash chromatography using ethyl acetate/hexane as eluent.

(i) 6-(3-chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazine-3-amine (54 mg, 11%) was obtained from 3-(3-amino-5-phenyl-1,2 ,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.65 g, 1.51 mmol) and tri-n-butyl(vinyl)tin (0.57 g, 1.81 mmol) according to the general procedure described for Example 4.

HPLC purity: 98.35% (248 nm)

Mass spectroscopy: (ESI +ve) 309.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 5.27 (d, 1H), 5.72 (d, 1H), 6.62 (dd, 1H), 7.23 (m, 1H), 7.44 (m, 6H), 7.51 (m , 1H), 7.57 (broad s, 2H).

(ii) 6-(3-chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine (20 mg, 7%) was obtained from 3-(3-amino-5-phenyl-1,2 ,4-triazin-6-yl)-5-chlorophenyl trifluoromethanesulfonate (0.40 g, 0.93 mmol) and tri-n-butyl(cyclopropyl)tin (0.37 g, 1.11 mmol) according to the general procedure described for Example 4.

HPLC purity: 95.98% (227 nm)

Mass spectroscopy: (ESI +ve) 322.9 [M+H] ⁺ .

¹ H NMR: (400 MHz, CDCl3) δ: 0.47 (m, 2H), 0.87 (m, 2H), 1.36 (m, 1H), 5.58 (broad s, 2H), 6.84 (s, 1H), 7.06 (s, 1H), 7.26 (s, 1H), 7.37 (m, 2H), 7.45 (m, 3H).

Example 5: other synthetic methods

(i) 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine

Stage 1: Selenium dioxide (30.0 g, 270 mmol) was dissolved in dioxane (450 ml) and heated to 50 ^o C. 3,5-dichloroacetophenone (30.0 g, 158 mmol) was added at this temperature, and the resulting mixture was boiled for 4 hours. At the end of the reaction, the mixture was filtered through celite and evaporated in vacuo. (3,5-Dichlorophenyl)(oxo)acetic acid was isolated and purified by column chromatography using ethyl acetate/hexane (28 g, 80%) as eluent.

Mass spectroscopy: (ESI –ve) 217 [MH] ^-

Step 2: (3,5-dichlorophenyl)(oxo)acetic acid (28.0 g, 129.0 mmol) was dissolved in ethanol (280 ml) and a catalytic amount of sulfuric acid and methyl hydrazinecarbimidothioate (20.5 g, 193.5 mmol) were added successively. The resulting mixture was stirred for 1 hour at 78°C. At the end of the reaction (TLC) the mixture was evaporated in vacuo, poured into water (150 ml) and extracted with dichloromethane (3 x 250 ml). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated in vacuo and purified by gradient flash chromatography to give 6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (19 d, 46%).

Mass spectroscopy: (ESI +ve) 287.9 [M-H]⁺, (ESI -ve) 286.0 [M-H]⁺

¹ H NMR: (400 MHz, DMSO) δ: 2.49 (s, 3H), 7.73 (m, 1H), 8.05 (d, 2H), 14.32 (s, 1H).

Stage 3: 6-(3,5-dichlorophenyl)-3-(methylthio)-1,2,4-triazin-5-ol (2.0 g, 6.96 mmol) was dissolved in 1,4-dioxane (20 ml) and cooled to 15 ^° C. TEA (1.76 g, 17.4 mmol) was added dropwise to the solution, and methanesulfonyl chloride (1.99 g, 17.42 mmol) was added after 5 minutes. After stirring at room temperature for 3 hours, LCMS showed the presence of 6-(3,5-dichlorophenyl)-3-(methylsulfanyl)-1,2,4-triazin-5-yl methanesulfonate, and the crude mixture was directly used in the next stages.

Mass spectroscopy: (ESI +ve) 366.9 [MH] ⁺

Step 4: K ₂ CO ₃ ( 1.0 g, 7.2 mmol) and 3-methylpiperidine (1.68 g, 16.9 mmol) and the resulting mixture was stirred at room temperature overnight. At the end of the reaction (TLC, ethyl acetate/hexane, 1:1), the reaction mixture was poured into water (25 ml) and extracted with dichloromethane or ethyl acetate (3 x 25 ml). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated in vacuo and purified by flash chromatography using 15% ethyl acetate in hexane as eluent to give 6-(3,5-dichlorophenyl)-5-(3-methylpiperidine-1- yl)-3-(methylsulfanyl)-1,2,4-triazine (0.8 g, 40%).

Mass spectroscopy: (ESI +ve) 369.0 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 0.67 (m, 3H), 1.07 (m, 2H), 1.35 (m, 1H), 1.53 (m, 2H), 1.67 (m, 1H), 2.45 (s , 3H), 2.74 (m, 1H), 3.64 (m, 1H), 3.76 (s, 1H), 7.60 (d, 2H), 7.64 (m, 1H).

Stage 5: m-CPBA (0.654 g, 3.78 mmol) was added to a solution of 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfanyl)-1,2,4- triazine (0.4 g, 1.08 mmol) in DCM (5 ml) at -15°C, and the resulting mixture was stirred at the same temperature until the reaction was complete according to TLC (8 h). The reaction mixture was quenched by adding saturated aqueous NaHCO ₃ (15 ml) and was extracted with ethyl acetate (3 x 15 ml). The combined organic extracts were dried over Na ₂ SO ₄ and evaporated under reduced pressure to give crude 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl)-1,2,4 -triazine (1.0 g, 91%), which was used without further purification.

Step 6: 6-(3,5-Dichlorophenyl)-5-(3-methylpiperidin-1-yl)-3-(methylsulfonyl)-1,2,4-triazine (0.25 g, 0.625 mmol) was dissolved in THF (5 ml), and anhydrous gaseous NH ₃ was passed through the resulting solution for 1 hour. At the end of the reaction (TLC), the reaction mixture was poured into water (15 ml) and extracted with dichloromethane or ethyl acetate (3 x 15 ml). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated in vacuo, was added 1N. HCl solution for 10 minutes and extracted with ethyl acetate. The separated aqueous layer was neutralized by adding K ₂ CO ₃ and was extracted with ethyl acetate (3 x 150 ml); the organic phases were dried over Na ₂ SO ₄ and purified by gradient flash chromatography to give 6-(3,5-dichlorophenyl)-5-(3-methylpiperidin-1-yl)-1,2,4-triazin-3-amine ( 0.01 g, 1%).

HPLC purity: 88.07% (218 nm)

Mass spectroscopy: (ESI +ve) 338.9 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 0.90 (m, 1H), 1.16 (m, 2H), 1.42 (m, 2H), 1.58 (s, 1H), 1.72 (m, 1H), 2.52 (m , 3H), 2.61 (m, 1H), 2.79 (m, 1H), 7.64 (s, 2H), 7.76 (s, 1H), 7.64 (broad s, 2H).

(ii) 6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazine-3-amine

6-(6-(Methylamino)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine (49.5 mg, 0.177 mmol, 71.4%) was obtained from 5-(3-amino-5 -phenyl-1,2,4-triazin-6-yl)pyridin-2-yl(methyl)carbamate (see above), by removing the BOC-protecting group with trifluoroacetic acid (0.4 ml) in dichloromethane (1.6 ml) for 1 hours at room temperature.

HPLC purity: 99.7% (254 nm) at 3.45 min.

Mass spectroscopy: (ESI +ve) 279.8 [M+H] ⁺

¹ H NMR: (400 MHz, DMSO) δ: 2.74 (d, J 4.8, 3H), 6.36 (dd, J 8.7, 0.7, 1H), 6.62 – 6.75 (m, 1H), 7.27 (s, 2H), 7.30 (dd, J 8.7, 2.4, 1H), 7.36–7.47 (m, 5H), 7.90 (dd, J 2.4, 0.6, 1H).

(iii) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol

4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (see above; 140 mg, 0.530 mmol) was reacted with AcOH (2 ml) and 1-iodopyrrolidine-2 ,5-dione (119 mg, 0.530 mmol). The reaction mixture was stirred at room temperature for 1 hour, then evaporated in vacuo and purified by column chromatography (88 mg, 64%).

HPLC purity: 99% (254 nm) at 3.1 min.

Mass spectroscopy: (ESI +ve) 517 [M+H] ⁺ ; (ESI -ve) 515 [MH] ^-

¹ H NMR: (400 MHz, DMSO) δ: 7.35 – 7.50 (m, 7H), 7.64 (s, 2H), 9.69 (s, 1H).

(iv) 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol

4-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-phenol (see above; 140 mg, 0.530 mmol) was reacted with AcOH (2 ml) and 1-iodopyrrolidine-2 ,5-dione (119 mg, 0.530 mmol). The reaction mixture was stirred at room temperature for 1 hour, then evaporated in vacuo and purified by column chromatography (35 mg, 32%).

HPLC purity: 99% (254 nm) at 2.7 min.

Mass spectroscopy: (ESI +ve) 391 [M+H] ⁺ ; (ESI -ve) 389 [MH] ^-

¹ H NMR: (400 MHz, DMSO) δ: 6.77 (d, J 8.4 Hz, 1H), 7.06 (dd, J 8.4, 2.2 Hz, 1H), 7.28 – 7.47 (m, 7H), 7.68 (d, J 2.2 Hz, 1H), 10.51 (s, 1H).

(v) 6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine

6-(3-Methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine was obtained from 3-(3-amino-5-phenyl-1,2,4-triazine -6-yl)-5-(trifluoromethoxy)phenol (100 mg, 0.287 mmol). The indicated phenol was dissolved in THF (2 ml) and iodomethane (17.87 µl, 0.287 mmol) was added at 0°C. After ~15 minutes, the mixture was allowed to slowly warm to room temperature. The solvent was removed in vacuo; water (2 ml) and DCM (2 ml) were added and the layers were separated using a phase separation cartridge. The organic layer was evaporated to dryness in vacuo and purified by column chromatography (33 mg, 32%).

HPLC purity: 100% (254 nm) at 4.82 min.

Mass spectroscopy: (ESI +ve) 363 [M+H] ⁺ ; (ESI -ve) 361 [MH] ^-

¹ H NMR: (400 MHz, DMSO) δ: 3.71 (s, 3H), 6.75 – 6.76 (m, 1H), 6.89 – 6.90 (m, 1H), 7.00 – 7.01 (m, 1H), 7.32 – 7.48 ( m, 5H), 7.53 (s, 2H).

(vi) N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide

Stage 1: Obtaining N-(5-bromo-2-hydroxyphenyl)acetamide

2-Amino-4-bromophenol (1 g, 5.32 mmol) was dissolved in DCM (10 ml) and cooled to 10 ^o C. Then triethylamine (0.65 g, 6.38 mmol) was added dropwise and stirred for another 5 minutes before adding acetyl chloride (0.54 d, 6.91 mmol). The complete reaction was monitored by TLC (hexane/ethyl acetate, 7:3), then the reaction was quenched with saturated sodium bicarbonate solution (30 ml). The aqueous layer was extracted with ethyl acetate (3 x 30 ml) and the combined organic phases were dried over Na ₂ SO ₄ and evaporated in vacuo. The crude residue (0.57 g, 47%) was used in the next step without further purification.

TLC R _f : 0.6 (hexane/ethyl acetate, 7:3).

Mass spectroscopy: (ESI +ve) 230.9 [M+H] ⁺ , (ESI -ve) 229.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 2.07 (s, 3H), 6.78 (d, 1H), 7.04 (d, 1H), 8.04 (d, 1H), 9.26 (s, 1H), 10.15 (s , 1H).

Step 2: Preparation of N-(5-bromo-2-methoxyphenyl)acetamide

N-(5-Bromo-2-hydroxyphenyl)acetamide (0.56 g, 2.43 mmol) was dissolved in anhydrous DMF (7.0 ml) and K ₂ CO ₃ (0.85 g, 6.09 mmol) was added. The resulting mixture was heated to 70 ^° C. for 30 minutes, after which methyl iodide (0.69 g, 4.87 mmol) was added. After stirring for another 16 hours at 60 ^° C., the reaction was quenched with water (25 ml) and the aqueous layer was extracted with ethyl acetate (3 x 30 ml). The combined aqueous layers were dried over Na ₂ SO ₄ and evaporated in vacuo. The resulting residue (0.54 g, 92%) was used in the next step without further purification.

Mass spectroscopy: (ESI +ve) 244.9 [M+H] ⁺ .

TLC R _f : 0.8 (hexane/ethyl acetate, 7:3).

Step 3: Preparation of N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide

N-(5-Bromo-2-methoxyphenyl)acetamide (0.52 g, 2.13 mmol) was dissolved in DME (10 mL) and palladium(II) dibenzylideneacetone (65 mg, 0.11 mmol), triphenylphosphine (40 mg, 0.15 mmol), bis(pinacolato)diborone (0.65 g, 2.56 mmol) and potassium acetate (0.63 g, 6.4 mmol). The resulting mixture was heated to 150 ^° C. overnight then quenched with water (30 ml). The aqueous layer was extracted with ethyl acetate (3 x 30 ml), the combined organic phases were dried over Na ₂ SO ₄ and evaporated in vacuum. The crude residue (1.08 g, 91%) was used in the next step without further purification.

Mass spectroscopy: (ESI +ve) 292.1 [M+H] ⁺ .

TLC R _f : 0.5 (hexane/ethyl acetate, 7:3).

Step 4: Preparation of N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide

N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.170 g, 25%) was obtained from 6-bromo-5-phenyl-1 ,2,4-triazine-3-amine (0.5 g, 1.99 mmol) and N-[2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl]acetamide according to the general procedure described in Example 1.

HPLC purity: 97.62% (283 nm).

Mass spectroscopy: (ESI +ve) 336.1 [M+H] ⁺ .

NMR: (400 MHz, DMSO) δ: 2.04 (s, 3H), 3.79 (s, 3H), 6.82 (d, 1H), 6.90 (d, 1H), 7.33 (m, 4H), 7.39 (m, 3H ), 8.13 (s, 1H), 9.13 (s, 1H).

(vii) N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide

N-[5-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide was obtained by O-demethylation of N-[5-(3-amino-5-phenyl- 1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.05 g, 0.15 mmol; see above). The methyl ether was dissolved in DCM (5 ml), cooled to -78 ^° C. and boron tribromide (5.25 mmol, 1.32 g) was added. The resulting mixture was gradually heated to room temperature and at this temperature for another 16 hours. The reaction mixture was poured into water (15 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic extracts were dried over Na ₂ SO ₄ , evaporated in vacuo and purified by gradient flash chromatography using 30% ethyl acetate in hexane as eluent to give the title compound (0.30 g, 85%).

HPLC purity: 96.15% (219 nm).

Mass spectroscopy: (ESI +ve) 322.0 [M+H] ⁺ .

¹ H NMR: (400 MHz, DMSO) δ: 2.05 (s, 3H), 6.71 (m, 2H), 7.43 (m, 5H), 8.00 (m, 1H), 8.49 (broad s, 2H), 9.26 (s, 1H), 10.26 (broad s, 1H).

(viii) 6-(2-Methyl-6-d ₃ -methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

Stage 1: Obtaining 2,4,6-tri(d ₃ -methyl)cyclotriboroxane-pyridine complex

A solution of trimethylborate (10.0 ml) in THF (100 ml) was cooled under N ₂ to -78°C, and a solution of methyl-d ₃ -magnesium iodide (50.0 ml, 1M solution in diethyl ether, 50.0 mmol) was added dropwise over 1 hour. After stirring at -78ºC for another 1.5 hours, 1M aqueous HCl solution (25 ml) was added dropwise over about 5 minutes and the mixture was allowed to warm to room temperature. Saturated sodium chloride solution (20 ml) was added, the mixture was filtered through a thin layer of celite, washing the celite layer with diethyl ether (50 ml). The phases were separated and the aqueous phase was extracted with diethyl ether (3 x 50 ml). The combined organic phases were washed with water (50 ml) and saturated sodium chloride solution (50 ml), then evaporated in vacuo to a volume of about 25 ml. Pyridine (10 ml) was added and the resulting light yellow solution was stirred at room temperature for 19.5 h, then evaporated in vacuo to give the title compound (1.39 g, crude) as a light yellow semi-solid, which was used further without purification.

LCMS: m/z 214.1 [M+H] ⁺ (ESI +ve), 0.3 min (method A).

Stage 2: Synthesis of 6-(2-methyl-6-d ₃ -methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine

A mixture of 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (70.4 mg, 0.236 mmol), crude 2,4,6-tri(d ₃ ) methylcyclotriboroxane-pyridine complex (504 mg, approximately 2.36 mmol), 1M aqueous solution of sodium carbonate (0.59 ml, 0.59 mmol) and tetrakis(triphenylphosphine)palladium(0) (27.2 mg, 0.024 mmol) in 1,4-dioxane ( 3 ml) and water (2 ml) in a sealed ampoule were heated in a microwave reactor at 150ºC for 20 minutes. After evaporation in vacuo, DCM (10 ml) and water (10 ml) were added and the phases were separated. The aqueous phase was extracted with dichloromethane (2 x 5 ml) and the combined organic phases were evaporated in vacuo. Purification by gradient flash chromatography (SiO ₂ , 5-40% Solvent A in B. Solvent A: CH ₂ Cl ₂ , Solvent B: 7 N NH ₃ in MeOH/MeOH/CH ₂ Cl ₂ 5:5:90) gave the title compound as a yellow solid (30.5 mg, 46%).

LCMS m/z 281.1 (M+H) ⁺ (ES ⁺ ) at 2.26 min, 100% (method C).

NMR (400 MHz, CDCl ₃ ) δ: 2.47 (s, 3H), 5.44 (s, 2H), 7.02 (s, 2H), 7.33-7.39 (m, 2H), 7.43-7.49 (m, 3H).

(ix) 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one

Step 1: Preparation of 1-(3,5-dimethylpyridin-4-yl)-3,5-dimethylpyridinium chloride

3,5-Lutidine (1.0 g, 9.3 mmol) was added to SOCl ₂ (2.0 ml, 27.9 mmol) at -10°C. The resulting mixture was heated to 120°C and stirred for another 2-3 hours. The complete course of the reaction was monitored by TLC (ethyl acetate/hexane, 1:1), then the mixture was precipitated with ethyl acetate. The target product was separated by filtration and used in the next step without further purification (1.79 g, 90%).

Mass: (ESI +ve) 214.1 [M+H] ⁺

TLC R _f : 0.05 (methanol/chloroform, 3:7).

Stage 2: Obtaining 3,5-dimethylpyridin-4-ol

1-(3,5-Dimethylpyridin-4-yl)-3,5-dimethylpyridinium chloride (1.0 g, 4.7 mmol) and anhydrous H ₃ PO ₃ (0.97 g, 11.7 mmol) were heated without solvent to 150-160°C in sealed ampoule for 8 hours with monitoring by TLC (methanol/chloroform 5:5). At the end of the reaction, the mixture was diluted with ethanol and acetone (1:1, 50 ml), filtered and evaporated in vacuo. The product was purified on Dowex 50 resin.

Mass: (ESI +ve) 124.0 [M+H] ⁺

TLC R _f : 0.38 (methanol/chloroform, 2:8).

Step 3: Preparation of 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one

1-(3-Amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one (40 mg, 5%) was obtained from 6-bromo-5 -phenyl-1,2,4-triazine-3-amine (0.70 g, 2.7 mmol), 3,5-dimethylpyridin-4-ol (0.45 g, 3.7 mmol) and K ₂ CO ₃ (0.93 g, 6.7 mmol) according to the general procedure described in Example 3.

HPLC purity: 92.33% (286 nm).

Mass spectroscopy: (ESI +ve) 294.1 [M+H] ⁺

¹ H NMR: (400 MHz, CDCl3) δ: 1.77 (s, 6H), 7.44 (m, 5H), 7.66 (s, 2H), 7.74 (broad s, 2H).

(x) 6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine was obtained from 5-phenyl-6-(2-chloro- 6-methyl-pyridin-4-yl)-1,2,4-triazine-3-amine (100 mg, 0.34 mmol) and azetidine (96 mg, 0.11 ml, 1.69 mmol) according to the general procedure from Synthesis 4a.

LCMS: (ES ⁺ ) 319.1 (M+H) ⁺ at 4.02 min, 99% (method C).

¹ H NMR: (400 MHz, DMSO) δ: 2.22 (s, 3H), 2.22–2.28 (m, 2H), 3.76 (t, J 7.3, 4H), 5.99 (s, 1H), 6.47 (s, 1H ), 7.39–7.50 (m, 5H), 7.52 (broad s, 2H).

(xi) 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine

6-[2-(Azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine (6.0 mg, 4%) was obtained from 5-(4-fluorophenyl)-6-(2-chloro-6-methyl-pyridin-4-yl)-1,2,4-triazin-3-amine (150 mg, 0.48 mmol) and azetidine (136 mg, 0.16 ml, 2.38 mmol) according to the general procedure from Synthesis 4a.

LCMS: (ES ⁺ ) 337.1 (M+H) ⁺ at 4.18 min, 97% (method C).

¹ H NMR: (400 MHz, DMSO) δ: 2.23 (s, 3H), 2.24 – 2.30 (m, 2H), 3.79 (t, J 7.6, 4H), 6.52 (s, 1H), 6.86 (s, 1H ), 7.24–7.29 (m, 2H), 7.48–7.50 (m, 2H), 7.55 (broad s, 2H).

(xii) 6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine

6-[2-(Azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine (20.0 mg, 19%) was obtained from 5 -phenyl-6-(2-chloro-6-trifluoromethyl-pyridin-4-yl)-1,2,4-triazine-3-amine (100 mg, 0.28 mmol) and azetidine according to the general procedure from Synthesis 4a.

LCMS: (ES ⁺ ) 373.0 (M+H) ⁺ at 4.52 min, 99% (method C).

¹ H NMR: (400 MHz, DMSO) δ: 2.27 – 2.35 (m, 2H), 3.89 (t, J 7.5, 4H), 6.03 (s, 1H), 6.46 (s, 1H), 7.41 – 7.53 (m , 5H), 7.69 (broad s, 2H).

Example 6

The compounds of Examples 1-5 were found to be active in the biological tests described above. The biological activity determined in Test A includes IC ₅₀ and pKi values for the human A _2a and A ₁ receptors, and the compounds of Examples 1-5 were found to have pKi values greater than 5 (or 6) for at least one of these receptors (for example, as shown for some of the compounds in the table below).

Example pKiA2a pKi A1 1(vi) 7.29 7.25 1(ix) 7.70 7.81 1(xiii) 8.40 7.36 1(xv) 7.11 8.45 1(xviii) 6.75 6.91 1(xxiv) 6.97 8.03 1(xxx) 6.30 Not def. 1(xxxv) 7.19 8.20 1(xli) 8.68 7.83 1(xlii) 8.86 9.84 1(xliii) 7.74 8.54 1(li) 8.66 6.87 1(lvi) 8.22 7.33 1(lxxii) 6.99 8.52 1(lxxvii) 8.11 7.29 1(lxxxx) 7.45 9.35 1(lxxx) 6.61 6.01 1(xc) 8.07 7.26 1(xv) 7.86 6.67 1(cxxxiv) 5.62 7.62 1(cxlvi) 6.31 7.40 1(cliv) 7.56 6.77 1(clviii) 7.98 6.96 1(clix) 7.81 7.07 1(clxix) 8.40 6.99 1(clxxiv) 8.07 6.89 1(clxxvi) 8.03 6.93 1(clxxxx) 8.62 7.52 1(clxxx) 8.90 7.76 1(clxxxi) 8.71 7.17 1(cxci) 8.26 7.36 1(cxiii) 8.34 6.93 1(cciv) 7.21 5.97 1(ccix) 8.59 7.60 1(ccxi) 7.71 8.74 1(ccii) 8.66 7.68 1(ccxiii) 7.51 7.12 1(ccxviii) 6.58 5.25 2(iii) 7.31 5.37 2(iv) 7.79 <5 2(vi) 7.39 <5 2(xxii) 5.07 6.71 2(xxv) 5.53 7.49 3(i) 7.17 <5 3(v) 5.96 ND 3(xvi) 7.41 7.15 3(xxi) 6.22 8.07 3(xxiv) 7.39 8.46 3(xxxii) 5.82 7.00 4(ii) 7.89 7.43 5(vii) 6.73 8.69 5(viii) 7.91 7.26 5(ix) 7.77 7.62 5(x) 8.52 8.05 5(xi) 7.76 6.90

Example 7

The compounds of Example 1 (vi) and Example 1 (xliii) (dosage 2-10 mg/kg or 0.3-3 mg/kg, po, respectively; time to test 120 min) were found to reverse cataleptic behavior in rats that prior to this, haloperidol was administered in a dose dependent manner, ED ₅₀ values were 9.8 and 0.27 mg/kg (po), respectively; used the procedure described above for Test B. Similarly, it was found that the compounds of Examples 1 (xiii), 1 (li), 1 (lvi), 1 (lxxvii), 1 (xc), 1 (xcv), 1 ( cliv), 1 (clviii), 1 (clix), 1 (ccix), 1 (cxci), 1 (cxciii), 1 (clxix), 1 (clxxix), 1 (clxxxiv), 1 (ccxii), and 5 ( x), reversed cataleptic behavior in rats previously treated with haloperidol in a statistically significant manner at a dosage of 1 mg/kg (po) (time to test 120 minutes, according to the procedure of test B.

Abbreviations

m-CPBA = m-chloroperoxybenzoic acid

bmim = 1-butyl-3-methylimidazolium

DXM = dichloromethane

DME = dimethoxyethane

DMF dimethylformamide

DMSO = dimethyl sulfoxide

ESI = electrospray ionization

EtOAc = ethyl acetate

FT = Fourier transform

HPLC = high performance liquid chromatography

IR = infrared

LC = liquid chromatography

MS = mass spectrometry

NMP = N-methyl-pyrrolidinone

NMR = nuclear magnetic resonance

rt = room temperature

THF = tetrahydrofuran

TLC = thin layer chromatography

The prefixes n-, sec-, i-, t- and tert- have their usual meanings: normal, secondary, iso- and tertiary.

Claims (402)

1. Use of a compound in the manufacture of a medicament for the treatment of cancer mediated by A1 receptor and/or A2a receptor activity, wherein the compound is a compound of formula A1

where A is Cy ^AA or Het ^AA ; Cy ^AA is a 6-membered aromatic, carbocyclic system wherein the Cy ^AA group has at position 3, relative to the point of attachment to the triazine ring, an R ^4a substituent and optionally has one or more additional R ^4a substituents; Het ^AA is a 6-membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated, and which contains one or two heteroatoms selected from O and N, wherein the Het ^AA group is in position 3, relative to the point of attachment to the triazine ring, R ^4b substituent and optionally has one or more additional R ^4b substituents; B is Cy ^BB or Het ^BB ; Cy ^BB is phenyl optionally having one or more R ^4c substituents; Het ^BB is a 6-membered aromatic heterocyclic group which contains one or two N atoms; R ^4a - R ^4c are, in each case independently, (a) a halogen atom, (b) CN (c) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, where C _1-6 alkyl optionally has one or more substituents selected from halogen atoms and OR ^5a , (d) Cy ³ , (e) Het ^a , (f) OR ⁸ , (g) S(O) _r R ^9a , (h) S(O) ₂ N(R ^9b )(R ^9c ), (i) N(R ^9d )S(O) ₂ R ^9e , (k) B ⁷ -C(G ¹ )-B ⁸ -R ^9h , (l)=O, (m)=S, G ¹ is, in each case independently, O; R ⁸ is, in each case independently, H, C _1-6 alkyl, where C _1-6 alkyl optionally has one or more substituents selected from halogen atoms; Cy ³ is, at each occurrence independently, a 3-6 membered aromatic or fully saturated carbocycle; Het ^a is, in each occurrence independently, a 4-6 membered heterocyclic ring which is fully saturated and which contains one or two heteroatoms selected from O and N; B ⁷ - B ⁸ represent, independently in each case, a single bond or N(RN3); R ^N3 is H, C _1-6 alkyl; R ^5a , R ^9a , R ^9d , R ^9e , R ^9f , R ^9g and R ^9h are, independently in each case, (a) H (b) C _1-6 alkyl; r is, in each case independently, 0, 1 or 2; or a pharmaceutically acceptable salt thereof, provided that the connection is not: (a) 5-(2-chlorophenyl)-6-(3,4-dimethoxyphenyl)-[1,2,4]triazin-3-ylamine or (b) 5-(2-chlorophenyl)-6-(3,4,5-trimethoxyphenyl)-[1,2,4]triazin-3-ylamine. 2. Use according to claim 1, wherein A is Cy ^AA' , Het ^AA' , Het ^AA'' or Het ^AA''' and Cy ^AA' is a 6-membered aromatic, carbocyclic system where the Cy ^AA' group has at position 3, relative to the point of attachment to the triazine ring, the substituent R ^4a and has at position 4, relative to the point of attachment to the triazine ring, the substituent OR ⁸ , and optionally has one or more additional substituents R ^4a ; Het ^AA' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, and which contains one or two heteroatoms selected from O and N, wherein the Het ^AA' group has in position 3, relative to the point of attachment to the triazine ring, substituent R ^4b , and has in position 4, relative to the point of attachment to the triazine ring, substituent OR ⁸ , and optionally has one or more additional substituents R ^4b ; Het ^AA'' is a 6-membered heterocyclic group, which may be aromatic, fully saturated or partially unsaturated, this group contains in position 4, relative to the point of attachment to the triazine ring, N-atom, and optionally has an additional heteroatom, selected from O and N, wherein said Het ^AA'' group has at position 3, relative to the point of attachment to the triazine ring, an R ^4b substituent, and optionally has one or more additional R ^4b substituents; and Het ^AA''' is a 6-membered heterocyclic group which may be aromatic, fully saturated or partially unsaturated, and which contains one or two heteroatoms selected from O and N, said group Het ^AA''' having at position 3, relative to the point of attachment to the triazine ring, substituent R ^4b , and has in position 4, relative to the point of attachment to the triazine ring, a substituent in the form of an oxo group (=O), and optionally has one or more additional substituents R ^4b . 3. Application according to claim 1 or 2, in which: when A is Cy ^AA or Cy ^AA' , the 6-membered carbocycle additionally has at position 5, relative to the point of attachment to the triazine ring, a R ^4a substituent; or when A is Het ^AA or Het ^AA' , Het ^AA'' or Het ^AA''' , the 6-membered heterocyclic ring additionally has an R ^4b substituent at position 5, relative to the point of attachment to the triazine ring. 4. Application according to any one of paragraphs. 1-3, in which: (1) R ^4a and R ^4b are, in each case independently, halogen atom, CN, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl (wherein C _1-6 alkyl optionally has one or more substituents selected from a halogen atom and OR ^5a ), Cy ³ , Het ^a , ^OR8 , S(O) _r R ^9a , B ⁷ -C (G ¹ ) -B ⁸ -R ^9h , =O, (2) R ^4c and R ^4b are, in each case independently, halogen atom, CN, C _1-3 alkyl (which may optionally have one or more substituents selected from a halogen atom and OR ^5a ), ^OR8 or B ⁷ -C(G ¹ ) -B ⁸ -R ^9h ; and/or (3) G ¹ is, in each case independently, O. 5. Application according to any one of paragraphs. 1-4, in which: (1) R ⁸ is, in each case independently, h, C _1-6 alkyl, where C _1-6 alkyl optionally has one or more substituents selected from halogen atoms; or (5) R ^5a , R ^9a , R ^9d , R ^9e , R ^9f , R ^9g and R ^9h are, independently in each case, H or C _1-6 alkyl. 6. Use according to claim 5, in which: (1) R ⁸ is, in each case independently, h, C _1-6 alkyl which optionally has one or more substituents selected from halogen atoms; (2) B ⁷ - B ⁸ independently represent a single bond or N(R ^N3 ); (4) R ^N3 is H or C _1-3 alkyl. 7. Application according to any one of paragraphs. 1-6 where A is a 6-membered Cy ^AA or Het ^AA group which is: has no substituents in the ortho positions; has a substituent at one or both meta positions; and, if necessary, has a substituent in the para position, where the substituents correspond to the data in paragraphs. 1-5 definitions for Cy ^AA or Het ^AA groups. 8. Application according to any one of paragraphs. 1-7, where the compound of formula A1 is represented by a compound of formula Ixd, Iyd or Izd,

respectively, where: rr1 is 0 or 1; rr2 and rr3 are independently 0 or 1; ss and tt are, independently in each case, 0 or 1, provided that ss and tt cannot both be 0; R ^4a' has the same meanings as R ^4a ; R ^4b' has the same meanings as R ^4b ; L ¹ and L ² are both single bonds; and B, R ^4a and R ^4b correspond to the definitions given in any of paragraphs. 1-6. 9. Application according to any one of paragraphs. 1-8, in which R ^4a and R ^4b are, in each case independently, cyclopropyl, iodine, bromine, chlorine, fluorine, ethyl, methyl, d ₃ -methyl, iso-propyl, -C≡CH, CF ₃ , CHF ₂ , CH ₂ F , CH ₂ CF ₃ , CF ₂ CF ₃ , CN, =O, OH, OCH(CH ₃ ) ₂ , OCH ₃ , OCH ₂ CH ₃ , S(O) ₂ CH ₃ , S(O)CH ₃ , SCH ₃ , azetidine, morpholine or dioxolane. 10. Application according to any one of paragraphs. 1-9, where the compound of formula A1 is selected from the list, which includes: 6-(3-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(5-chloro-2-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-methylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazine-3-amine; 5-phenyl-6-(3,4,5-trifluorophenyl)-1,2,4-triazine-3-amine; 6-(2,6-dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-chlorophenyl)-5-(3-methoxyphenyl)-1,2,4-triazine-3-amine; 5-phenyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazine-3-amine; 6-(3,5-difluorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-[3-fluoro-5-(trifluoromethyl)phenyl]-5-phenyl-1,2,4-triazine-3-amine; 6-(3,5-dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(5-chloropyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-chloro-4-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-fluoro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3,3-dimethylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-bromophenyl)-5-phenyl-1,2,4-triazine-3-amine; 5-phenyl-6-[3-(trifluoromethyl)piperidin-1-yl]-1,2,4-triazin-3-amine; 6-(3,4-dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-fluorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)benzonitrile; 6-(3,5-dimethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3,5-dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3,4-dimethylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-[3-(dimethylamino)phenyl]-5-phenyl-1,2,4-triazine-3-amine; N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]acetamide; N-[3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl]methanesulfonamide; 6-(3-trifluoromethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 5-phenyl-6-[3-(propan-2-yl)phenyl]-1,2,4-triazine-3-amine; 6-(3,5-dichlorophenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 6-(3,5-bis(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenol; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylphenol; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol; 6-(2-chloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-(methylsulfonyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3,5-dichloro-4-methoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(4-methoxy-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chloro-5-(dimethylamino)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethyl)benzonitrile; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chloro-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-(methylthio)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-methoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-ethoxy-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-t-butyl-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorobenzonitrile; 6-(3-ethylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-methoxy-6-(trifluoromethyl)pyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-methyl-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazin-3-amine; 5-phenyl-6-(3-(2,2,2-trifluoroethoxy)phenyl)-1,2,4-triazine-3-amine; 6-(3-(methoxymethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one; 6-(3-methyl-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-methoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 1-(3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)phenyl)ethanone; 6-(4-fluoro-3-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(4-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-bromo-5-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 5-phenyl-6-m-tolyl-1,2,4-triazine-3-amine; 6-(2,6-dimethoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-phenyl-6-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-triazine-3-amine; 6-(2-cyclopropylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-phenyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1,2,4-triazin-3-amine; 6-(5-chloro-2-fluoro-3-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2,6-dichloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-bromo-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chloro-6-methoxyphenol; 6-(3,5-dichloro-4-ethoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-5-phenyl-1,2,4-triazin-3-amine; 4-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-5-(4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(3-chloro-5-propoxyphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 6-(2-chloropyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-5-(4-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-chlorophenyl)-1,2,4-triazine-3-amine; 5-(4-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-chlorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-5-(3-chlorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chlorophenyl)-1,2,4-triazine-3-amine; 5-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-chlorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazin-5-yl)benzonitrile; 4-(3-amino-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile; 4-(3-amino-5-(3-chloro-5-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 5-(3-chloro-5-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chloro-5-fluorophenyl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-5-(3,5-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 4-(3-amino-5-(3-chloro-4-fluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 5-(3-chloro-4-fluorophenyl)-6-(2-chloro-6-methylpyridin-4-yl)-1,2,4-triazin-3-amine; 5-(3-chloro-4-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine; 5-(3-chloro-4-fluorophenyl)-6-(3-chloro-5-(trifluoromethyl)phenyl)-1,2,4-triazine-3-amine; 4-(3-amino-5-(3,4-difluorophenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(2-chloro-6-methylpyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine; 6-(2-chloropyridin-4-yl)-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,4-difluorophenyl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-methylphenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 6-(3,5-diisopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-fluoro-5-(2,2,2-trifluoroethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine; N-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(trifluoromethyl)phenyl)acetamide; 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-fluorobenzonitrile; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-N,N-dimethylbenzamide; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-1-methylpyridin-2(1H)-one; 6-(3-(morpholin-4-yl)phenyl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-(methylsulfinyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 4-(3-amino-6-(2-chloropyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile; 4-(3-amino-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(2-chloropyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine; 6-(3-methoxypiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-ethynylpiperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(2,6-dimethylmorpholin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-(2-ethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine; 6-(2,2-diethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine; 6-(2,2-dimethylmorpholino)-5-phenyl-1,2,4-triazine-3-amine; (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-methylpiperidin-3-yl)methanol; 6-(3-(methoxymethyl)piperidin-1-yl)-5-phenyl-1,2,4-triazin-3-amine; 1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanol; (1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)methanol; 1-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)ethanone; 5-phenyl-6-(3-phenylpiperidin-1-yl)-1,2,4-triazin-3-amine; (4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)methanol; 2-(1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)piperidin-3-yl)propan-2-ol; 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3-ethylpiperidin-3-ol; 2-(4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)morpholin-2-yl)ethanol; 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dichloropyridin-4(1H)-one; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-chlorophenol; 6-(3-chloro-5-ethenylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3-chloro-5-cyclopropylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 5-(3-chloro-5-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2-chloropyridin-4-yl)-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine; 4-(3-amino-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-6-yl)-2,6-dimethylbenzonitrile; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine; 6-(2-chloropyridin-4-yl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-(difluoromethoxy)phenyl)-1,2,4-triazine-3-amine; 5-(3-amino-5-(3-fluorophenyl)-1,2,4-triazin-6-yl)-2-chlorophenol; 4-[3-amino-6-(3-chloro-4-hydroxyphenyl)-1,2,4-triazin-5-yl]benzonitrile; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol; 5-(3-chloro-5-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 5-(3,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 5-(3,4-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 5-(3-chloro-4-fluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 5-(4-(difluoromethoxy)phenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 5-(4-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 4-(3-amino-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-5-yl)benzonitrile; 5-(3-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(4-(methoxymethyl)phenyl)-1,2,4-triazin-3-amine; 4-(3-amino-6-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,2,4-triazin-5-yl)benzonitrile; 5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol; 6-(6-chloropyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(4-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-phenyl-6-(6-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazine-3-amine; 5-phenyl-6-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-triazine-3-amine; 6-(6-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-diiodophenol; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol; 6-(3-methoxy-5-(trifluoromethoxy)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol; 5-(3-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,4-difluorophenyl)-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3,5-difluorophenyl)-1,2,4-triazin-3-amine; 6-[2-(ethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-{2-[ethyl(methyl)amino]-6-methylpyridin-4-yl}-5-phenyl-1,2,4-triazin-3-amine; 6-[2-(dimethylamino)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 1-[6-(2,6-d6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 5-(4-fluorophenyl)-6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-methoxyphenyl)-1,2,4-triazin-3-amine; 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-chloro-6-(difluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-chloro-6-(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine; 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2,6-bis(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine; 6-[2-(fluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazine-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine; 6-[2-cyclopropyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-ethyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-cyclopropyl-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-(2-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(3-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(4-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(2,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(3,4-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(3,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2-methyl-6-(morpholin-4-yl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-ethylphenyl)-1,2,4-triazin-3-amine; 5-(2,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(4-methylphenyl)-1,2,4-triazin-3-amine; 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazin-3-amine; 6-(3,5-dichlorophenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-methylphenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2,6-bis(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-2-yl)-1,2,4-triazin-3-amine; 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(3,5-dimethylphenyl)-5-(pyridin-2-yl)-1,2,4-triazine-3-amine; 6-[2-(dimethylamino)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-bromo-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(2,6-dimethyl-1-oxypyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-6-methylpyridine-2-carbonitrile; 6-(3,5-dichlorophenyl)-5-(pyridin-3-yl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-methylphenyl)-5-(pyridin-3-yl)-1,2,4-triazine-3-amine; 6-(3,5-dichlorophenyl)-5-(pyrimidin-2-yl)-1,2,4-triazine-3-amine; 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyrimidin-2-yl)-1,2,4-triazin-3-amine; 6-[2-bromo-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[3-chloro-5-(trifluoromethyl)phenyl]-5-(pyridin-3-yl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-methylphenyl)-5-(pyrimidin-2-yl)-1,2,4-triazine-3-amine; N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide; N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide; 6-(2-methyl-6-d3-methylpyridin-4-yl)-5-phenyl-1,2,4-triazine-3-amine; 1-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-3,5-dimethylpyridin-4(1H)-one; 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; and 6-[2-(azetidin-1-yl)-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine. 11. Application according to any one of paragraphs. 1-10, where the compound of formula A1 is selected from the following: 6-(3,5-dichlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(3,5-bis(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-chloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-chloro-5-methylphenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-methyl-5-(trifluoromethyl)phenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2-methoxypyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-bromo-5-chlorophenyl)-5-phenyl-1,2,4-triazine-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-phenyl-6-(2-(trifluoromethyl)pyridin-4-yl)-1,2,4-triazine-3-amine; 6-(2-cyclopropylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(2,6-dichloropyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-fluorophenyl)-1,2,4-triazine-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(4-chlorophenyl)-1,2,4-triazine-3-amine; 5-(4-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3-chlorophenyl)-1,2,4-triazine-3-amine; 5-(3-chlorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-(3-chloro-5-(trifluoromethyl)phenyl)-5-(3,5-difluorophenyl)-1,2,4-triazine-3-amine; 5-(3-chloro-4-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-(3-chloro-5-methylphenyl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine; 3-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-5-(trifluoromethoxy)phenol; 5-(3,5-difluorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 6-(2,6-dimethylpyridin-4-yl)-5-(3-fluorophenyl)-1,2,4-triazin-3-amine; 5-(4-chlorophenyl)-6-(2,6-dimethylpyridin-4-yl)-1,2,4-triazin-3-amine; 4-(3-amino-6-(3-chloro-4-hydroxy-5-methoxyphenyl)-1,2,4-triazin-5-yl)benzonitrile; 6-(4-cyclopropylpyridin-2-yl)-5-phenyl-1,2,4-triazin-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-iodophenol; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-(propan-2-yloxy)phenol; 5-(3-fluorophenyl)-6-(2-chloropyridin-4-yl)-1,2,4-triazine-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(2-fluorophenyl)-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2-fluorophenyl)-1,2,4-triazine-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-(2,5-difluorophenyl)-1,2,4-triazin-3-amine; 6-(2-cyclopropyl-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; 5-(2-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(3-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(4-fluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 5-(3,5-difluorophenyl)-6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 6-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-bromo-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-(azetidin-1-yl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2,6-dimethylphenol; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 5-(4-fluorophenyl)-6-[2-d3-methyl-6-(trifluoromethyl)pyridin-4-yl]-1,2,4-triazin-3-amine; 6-[2-(difluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-chloro-6-(difluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-[2-chloro-6-(fluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine; 6-[2-(fluoromethyl)-6-methylpyridin-4-yl]-5-phenyl-1,2,4-triazine-3-amine; 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine; 6-(2-bromo-6-methylpyridin-4-yl)-5-phenyl-1,2,4-triazin-3-amine; and N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide. 12. Use according to claim 1, wherein the compound of formula A1 is selected from the group consisting of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine and 6-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-5-phenyl-1,2,4-triazin-3-amine, or a pharmaceutically acceptable salt thereof. 13. Application according to any one of paragraphs. 1-12, in which: B is a Cy ^BB or Het ^BB group which is either unsubstituted or has one or more substituents selected from fluorine, CN, OR ⁸ or C _1-6 alkyl optionally having one or more substituents selected from halogen atoms and OR ^5a where R ^5a and R ⁸ correspond to the definitions given in any of paragraphs. 1-9. 14. Use according to claim 13, in which B is a Cy ^BB or Het ^BB group which either has no substituents or is substituted by a fluorine atom in position 4, relative to the point of attachment to the triazine ring. 15. The use of claim 1 wherein the cancer is selected from the group consisting of prostate cancer, rectal cancer, kidney cancer, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, breast cancer, bowel cancer, bladder cancer , brain cancer, nervous tissue cancer, melanoma, pineal cancer and lung cancer. 16. Use according to claim 15 wherein the cancer is selected from the group consisting of rectal cancer, pancreatic cancer, colon cancer, brain cancer, nervous tissue cancer and lung cancer. 17. Use of 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazine-3-amine or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer mediated by the activity of the A1 receptor and/or the A2a receptor. 18. Use according to claim 17 wherein the cancer is selected from the group consisting of rectal cancer, pancreatic cancer, colon cancer, brain cancer, nervous tissue cancer and lung cancer.