RU2802866C2 - Triazolo-pyrimidine compounds and their use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to novel triazolo-pyrimidine compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is selected from amino; ring A is selected from:

Z is selected from halogen, amino, N-(C_1-12alkyl)amino, N,N-(C_1-12alkyl)₂amino, 3-12 membered saturated or unsaturated carbocyclyl, or 3-12 membered saturated or unsaturated a heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S, which may optionally be mono- or independently polysubstituted with R₂; Y represents -WV, where W represents -NH-, C_1-12alkylene, V represents a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl having 1 or 2 heteroatoms, selected from N, O or S, which may optionally be mono- or independently polysubstituted with R₃; each R₁ is independently selected from halogen, cyano, amino, C_1-12alkyl, C_1-12haloalkyl, C_1-12alkoxy, C_1-12haloalkoxy, C_1-12alkyl-OH, N-(C_{1- 12}alkyl)amino, N,N-(C_1-12alkyl)₂amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated heterocyclyl having 1 heteroatom selected from O and S, where the sulfur atom possibly can be oxidized to form S-oxides; each R ₂ is independently selected from halogen, amino, C_1-12alkyl, C_1-12haloalkyl, C_1-12alkoxy, C_1-12haloalkoxy, N-(C_1-12alkyl)amino, N,N-(C_1-12alkyl)₂amino; each R₃ is independently selected from halo, cyano, amino, C_1-12alkyl, C_1-12haloalkyl, C_1-12haloalkoxy, N-(C_1-12alkyl)amino, N,N-(C_1-12alkyl)₂ amino; m is 0, 1, 2, 3, or 4. Also the invention relates to pharmaceutical compositions containing one or more of these compounds as an active ingredient, to the use of these compounds in the treatment of diseases associated with adenosine receptors (AR), such as cancer, such as NSCLC (non-small cell lung cancer), RCC (renal cell carcinoma), prostate cancer and breast cancer, to a method for inhibiting an adenosine receptor, to a combination of one or more of these compounds and an immunotherapeutic or chemotherapeutic agent.

Formula (I)

EFFECT: production of new triazolo-pyrimidine compounds that specifically act on adenosine receptors, in particular A1 and A2, specifically A2a.

34 cl, 4 tbl, 128 ex

Description

FIELD OF THE INVENTION

The present invention relates to new triazolo-pyrimidine compounds that specifically target adenosine receptors (in particular A1 and A2, specifically A2a). The present invention also relates to pharmaceutical compositions containing one or more of these compounds as an active ingredient, and to the use of these compounds in the treatment of diseases associated with adenosine receptors (AR), for example cancer, such as non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), prostate cancer and breast cancer.

BACKGROUND ART

Adenosine is a naturally occurring nucleoside that elicits various physiological responses by interacting with the adenosine receptor family. There are four subtypes of adenosine receptors (A1, A2a, A2b and A3) in humans based on their biochemical and pharmacological properties such as ligand binding characteristics, glycosylation and function.

The inflammatory response helps remove harmful substances from the body, but inflammation is also a nonspecific response that can harm healthy tissue. There is a wide range of pathogenic insults that can initiate the inflammatory response, including infection, allergens, autoimmune stimuli, immune response to transplanted tissue, noxious chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal injury, and tumor growth.

Adenosine receptors have been reported to play a significant role in the downregulation of inflammation in vivo, acting as a physiological "STOP" (termination mechanism) that can limit the immune response and thereby protect normal tissues from excessive immune lysis during the pathogenesis of various diseases. . Adenosine receptors such as A2a, A2b and A3 have been shown to down-regulate the immune response during inflammation and protect tissues from immune lysis. Inhibition of adenosine receptor signaling can be used to enhance and prolong the immune response. Adenosine attenuates prolonged inflammation by acting through the adenosine A2a receptor (Ohta et al., Nature 2001; 414:916-920). The adenosine A2b receptor is involved in the regulation of cell growth (see Adenosine A2b Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153).

Therefore, compounds that target adenosine receptors are needed as pharmacological agents and are of interest as drugs for the treatment of adenosine receptor-associated disease such as cancer (eg, NSCLC (non-small cell lung cancer), RCC (renal cell carcinoma) , prostate or breast cancer), Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV (human immunodeficiency virus), ADA-SCID (severe combined immunodeficiency with adenosine deaminase deficiency), AHF (acute heart failure) and chronic heart failure, chronic obstructive pulmonary disease (COPD), or asthma.

SUMMARY OF THE INVENTION

In one aspect of the present invention there is provided a compound represented by formula (I):

or a pharmaceutically acceptable salt thereof, wherein X, ring Α, Ζ, Y, R ₁ and m are as defined herein.

In one aspect of the present invention there is provided a compound represented by formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein ring A, ring B, ring Q, W, R ₁ , R ₂ , R ₃ , m, n and i are as defined herein.

In one aspect of the present invention there is provided a compound represented by formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein W, R ₁ , R ₂ , R ₃ , n and i are as defined herein.

In another aspect, the present invention also relates to pharmaceutical compositions containing one or more compounds or a pharmaceutically acceptable salt thereof as an active ingredient, and the use of the compound or a pharmaceutically acceptable salt thereof in the treatment of diseases associated with adenosine receptors (AR), for example cancer such as NSCLC, RCC, prostate cancer or breast cancer.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention there is provided a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

X is selected from amino, halogen, hydroxyl, cyano, C _1-12 alkoxyl, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, C _1-12 alkanoylamino,

ring A is a 3- to 12-membered saturated or unsaturated mono- or polycyclic heterocyclyl, and wherein one or more -CH ₂ groups of ring A is optionally substituted with -C(O)- or -S(O) _a- , wherein a=0, 1 or 2,

Ζ is selected from hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, N-(C _1-12 alkyl) amino, N,N-(C _1-12 alkyl) ₂ amino, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl, which may optionally be mono- or independently polysubstituted with R ₂ , and where one or more -CH ₂ - groups in the 3-12 ring system -membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl may optionally be substituted by -C(O)- or -S(O) _a -, where a=0, 1 or 2,

Υ represents -WV, where W represents a bond, O, S, -ΝΗ-, C _1-12 alkylene, C _1-12 alkylene-NH-, V represents C _1-12 alkyl, C _1-12 alkoxyl, C _1-12 alkyl-OH, amino, carbamoyl, urea, carbamate, N-(C _1-12 alkyl) amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl) carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl, which may possibly be mono- or independently is polysubstituted with R ₃ , and wherein one or more -CH ₂ - groups in the ring system of a 3 to 12 membered saturated or unsaturated carbocyclyl or a 3 to 12 membered saturated or unsaturated heterocyclyl may optionally be substituted by -C(O)- or - S(O) _a -, where a=0, 1 or 2,

each R ₁ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl is optional may be mono- or independently polysubstituted with _R4 ,

each R ₂ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl is optional may be mono- or independently polysubstituted with _R5 ,

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl is optional may be mono- or independently polysubstituted with R ₆ ,

wherein each R ₄ , R ₅ or R ₆ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy , C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-( C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino,

m is 0, 1, 2, 3 or 4.

In some embodiments, X is selected from amino, halogen, hydroxyl, cyano, _C1-12 alkoxyl, N-( _C1-12 alkyl)amino, N,N-( _C1-12 alkyl) ₂ amino, or _C1-12 alkanoylamino .

In some embodiments, X is amino.

In some embodiments, Ring A is a 3-12 membered saturated or unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S.

In some embodiments, ring A is a 6- to 10-membered unsaturated mono- or polycyclic heterocyclyl selected from the group consisting of pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, triazinonyl, phenyl-fused ring or pyridinyl-fused ring.

In some embodiments, ring A is a 6-10 membered unsaturated mono- or polycyclic heterocyclyl selected from

In some embodiments, each R ₁ is independently selected from halogen, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, C _1-12 alkyl -OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl or 3-6 membered saturated carbocyclyl or heterocyclyl. In some embodiments, the 3-6 membered saturated carbocyclyl or heterocyclyl is cyclopropyl, cyclobutyl, oxacyclopentanyl, oxetanyl, or 1,1-dioxothietanyl.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, m is 3.

In some embodiments, m is 4.

In some embodiments, Υ is -W-V.

In some embodiments, -W- is C _1-12 alkylene, C _1-12 alkylene-ΝΗ-, or -ΝΗ-. In some embodiments, -W- is C _1-6 alkylene. In some embodiments, -W- is C _1-3 alkylene.

In some embodiments, -W- is methylene or ethylene.

In some embodiments, -W- is methylene.

In some embodiments, V is halogen, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 alkyl-OH, amino, carbamoyl, urea, carbamate, N-(C _1-12 alkyl)amino, N,N -(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, C _1-12 alkanoylamino, which can possibly be mono- or independently polysubstituted with R ₃ .

In some embodiments, V is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl, which may optionally be mono- or independently polysubstituted with R ₃ .

In some embodiments, V is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl selected from:

which may optionally be mono- or independently polysubstituted with R ₃ .

In some embodiments, V is pyrrolidyl, tetrahydrofuryl, thienyl, triazolyl, thiazolyl, phenyl, or pyridinyl, which may optionally be mono- or independently polysubstituted with R ₃ .

In some embodiments, each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, C _1-12 alkanoylamino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, where 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered the saturated or unsaturated heterocyclyl may optionally be mono- or independently polysubstituted with R ₆ .

In some embodiments, -W- is ethylene, V is C _1-12 alkoxy.

In some embodiments, -W- is methylene, V is C _1-12 alkyl, which is further substituted with C _1-12 alkoxy.

In some embodiments, -W- is ethylene, V is methoxyl.

In some embodiments, -W- is methylene, V is pyrrolidyl, tetrahydrofuryl, thienyl, triazolyl, thiazolyl, phenyl, or pyridinyl, which may optionally be mono- or independently polysubstituted with R ₃ , wherein each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, C _1-12 galkanoylamino .

In some embodiments, Z is hydrogen, halogen, cyano, hydroxyl, amino, carbamoyl, urea, carbamate, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, C _{1- 12} alkyl, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl, which may optionally be mono- or independently polysubstituted with R ₂ , wherein each R ₂ is independently selected from halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy.

In some embodiments, Z is halogen, amino, N-(C _1-12 alkyl) amino, or N,N-(C _1-12 alkyl) ₂ amino.

In some embodiments, Z is a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl, which may optionally be mono- or independently polysubstituted with R ₂ .

In some embodiments, Z is a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl selected from:

which may optionally be mono- or independently polysubstituted with R ₂ .

In some embodiments, each R ₂ is independently selected from halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxy, or C _1-12 haloalkoxy.

In another aspect of the present invention there are provided compounds of formula (Ia):

or pharmaceutically acceptable salts thereof, wherein

Ring A is a 6-10 membered unsaturated mono- or polycyclic heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O, or S, wherein one or more -CH ₂ groups of Ring A may optionally be substituted -C(O)- or -S(O) _a -, where a=0, 1 or 2;

ring B is selected from 3 to 12 membered saturated or unsaturated carbocyclyl or 3 to 12 membered saturated or unsaturated heterocyclyl, and wherein one or more -CH ₂ groups of ring B may optionally be substituted by -C(O)- or - S(O) _a -, where a=0, 1 or 2;

ring Q is a 5-6 membered saturated or unsaturated carbocyclyl or 5-6 membered saturated or unsaturated heterocyclyl, wherein one or more -CH ₂ groups of ring Q may optionally be substituted with -C(O)- or -S (O) _a -, where a=0, 1 or 2;

W represents a bond, O, S, imino, C _1-12 alkylene, C _1-12 alkylene-imino;

each R ₁ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, carbamoyl, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, 3- a 10-membered saturated or unsaturated carbocyclyl or a 3-10 membered saturated or unsaturated heterocyclyl, wherein said 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl may optionally be mono- or independently polysubstituted with R ₄ ;

each R ₂ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, carbamoyl, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, carbamoyl, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, carbamoyl, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl ) ₂ carbamoyl, C _1-12 galkanoylamino; And

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

i is 0, 1, 2, 3 or 4.

In some embodiments, ring A is selected from

In some embodiments, ring A is selected from the group consisting of 4-pyridinyl, 4-pyridazinyl, 5-pyridinyl-2-one, imidazo[1,2-a]pyridin-6-yl, [1,2,4]triazolo[ 4,3-a]pyridin-6-yl, 6-benzimidazolyl, 6-benzthiazolyl, quinolin-6-yl or quinoxalin-6-yl.

In some embodiments, each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxyl R ₄ .

In some embodiments, one of R ₁ is selected from cyclopropyl, cyclobutyl, tetrahydrofuryl, oxetanyl, or 1,1-dioxothietanyl, which may optionally be mono- or independently polysubstituted with R ₄ .

In some embodiments, m is 0, 1, or 2.

In some embodiments, m=0, 1 or 2; each R ₁ is independently selected from hydroxyl, fluorine, chlorine, bromine, amino, carbamoyl, urea, carbamate, cyano, methyl, ethyl, n-propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, methoxyl, ethoxyl, difluoromethoxyl, trifluoromethoxyl, trifluoroethoxyl, methylamino, dimethylamino, ethylamino, hydroxymethyl, hydroxyethyl, cyclopropyl, 3-oxacyclopentanyl, 3-oxetanyl or 1,1-dioxothietanyl, which may optionally be further mono- or independently polysubstituted with R ₄ ; and each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl -OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl or C _1-12 alkanoylamino.

In some embodiments, Ring A is 4-pyridinyl, 4-pyridazinyl, 5-pyridinyl-2-one, imidazo[1,2-a]pyridin-6-yl, [1,2,4]triazolo[4,3- a]pyridin-6-yl, 6-benzimidazolyl, 6-benzthiazolyl, quinolin-6-yl or quinoxalin-6-yl; m is 0, 1 or 2; and each R ₁ is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxyl, difluoromethoxyl, methylamino, dimethylamino, hydroxyethyl, cyclopropyl, oxacyclopentanyl, 3-oxetanyl, or 1,1-dioxothietanyl .

In some embodiments, ring Q is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl selected from:

In some embodiments, ring Q is pyrrolidyl, phenyl, or pyridinyl.

In some embodiments, each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 alkoxy, C _1-12 haloalkoxy, N,N-(C _1-12 alkyl)2amino, or C _1-12 alkanoylamino.

In some embodiments, each R ₃ is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, n-propyl, isopropyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, methylamino, dimethylamino, isopropylamino, ethoxy, trifluoroethoxy, or ethylamino.

In some embodiments, each R ₃ is independently selected from amino, cyano, methyl, fluorine, chlorine, difluoromethoxyl, methoxyl, or dimethylamino.

In some embodiments, i is 0.

In some embodiments, i is 1.

In some embodiments, i is 2.

In some embodiments, i is 3.

In some embodiments, i is 4.

In some embodiments, i is 0, 1, or 2.

In some embodiments, i is 0, 1, or 2; each R ₃ is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, n-propyl, isopropyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, methylamino, dimethylamino, isopropylamino, ethoxyl, trifluoroethoxy or ethylamino.

In some embodiments, ring Q is pyrrolidyl, phenyl, or pyridinyl; i=0, 1 or 2; and each R ₃ is independently selected from amino, cyano, methyl, fluorine, chlorine, difluoromethoxyl, methoxyl or dimethylamino.

In some embodiments, ring B is selected from:

In some embodiments, ring B is selected from 1-azetidinyl, 2-oxa-6-aza-spiro[3.4]octan-5-yl, 1-pyrrolidyl, 1-piperazinyl, 2-oxazolyl, 2-thiazolyl, 1-pyrazolyl, 4 -pyrazolyl, 1-[1,2,3]triazolyl, 1-[1,2,5]triazolyl, phenyl, 2-pyridinyl, 3-pyridinyl, 4-morpholinyl or 5-indolyl.

In some embodiments, each R ₂ is independently selected from fluorine, chlorine, cyano, methyl, amino, ethyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, trifluoromethoxyl, ethoxyl, methylamino, dimethylamino, ethylamino, isopropanylamino, hydroxymethyl, or hydroxyethyl.

In some embodiments, each R ₂ is independently selected from cyano, chlorine, fluorine, methyl, methoxyl, difluoromethyl, trifluoromethyl, or dimethylamino.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

In some embodiments, n is 4.

In some embodiments, n is 0, 1, or 2.

In some embodiments, n is 0, 1, or 2; and each R ₂ is independently selected from cyano, chlorine, fluorine, methyl, methoxyl, difluoromethyl, trifluoromethyl or dimethylamino.

In some embodiments, ring B is selected from 1-azetidinyl, 2-oxa-6-aza-spiro[3.4]octan-5-yl, 1-pyrrolidyl, 1-piperazinyl, 2-oxazolyl, 2-thiazolyl, 1-pyrazolyl, 4 -pyrazolyl, 1-[1,2,3]triazolyl, 1-[1,2,5]triazolyl, phenyl, 2-pyridinyl, 3-pyridinyl, 4-morpholinyl or 5-indolyl; n is 0, 1 or 2; and each R ₂ is independently selected from cyano, chlorine, fluorine, methyl, methoxyl, difluoromethyl, trifluoromethyl or dimethylamino.

In yet another aspect of the present invention there are provided compounds of formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein

R ₁ is selected from hydroxyl, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _1-12 alkyl )amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated or unsaturated heterocyclyl, which may optionally be mono- or independently polysubstituted with R ₄ ;

each R ₂ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl)2amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) _2carbamoyl ;

each R ₃ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl) ₂ carbamoyl;

each R ₄ is independently selected from halogen, hydroxyl, cyano, amino, carbamoyl, urea, carbamate, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl- OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, carbamoyl, N-(C _1-12 alkyl)carbamoyl, N,N-(C _1-12 alkyl ) ₂ carbamoyl, C _1-12 alkanoylamino;

W represents a bond, O, S, imino, C _1-12 alkylene, C _1-12 alkylene-imino; And

n is 0, 1, 2, 3 or 4;

i is 0, 1, 2, 3 or 4.

In some embodiments, R ₁ is C _1-12 alkyl.

In some embodiments, R ₁ is methyl.

In some embodiments, R ₁ is isopropyl.

In some embodiments, n=1.

In some embodiments, R ₂ is halogen.

In some embodiments, R ₂ is fluorine.

In some embodiments, R ₂ is halogen and n=1.

In some embodiments, R ₂ is fluorine, and n=1.

In some embodiments, R ₃ is halogen.

In some embodiments, R ₃ is fluorine.

In some embodiments, R ₃ is halogen and i=1.

In some embodiments, R ₃ is fluorine and i=1.

In some embodiments, W is methylene.

In one aspect of the present invention there is provided a compound of formula (I) selected from:

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine,

8-(2-chloropyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine,

2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-8-[2-(trifluoromethyl)pyridin-4-yl]-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine,

2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-8-(2-methoxypyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine ,

2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-8-(pyridazin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine,

2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5- amine,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridine -2(1H)-she,

2-(2,6-difluorobenzyl)-8-(2-(dimethylamino)pyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine,

7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine ,

2-[1-(2,6-difluorophenyl)ethyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine,

2-[(2,6-difluorophenyl)methyl]-8-(2,5-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine,

8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine,

2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine,

2-(2,6-difluorobenzyl)-8-(2,3-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amina,

2-((6-(dimethylamino)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5 -f]pyrimidine-5-amine,

8-(2-chloro-6-methylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine,

6-((5-amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-2-yl)methyl ) picolinonitrile,

5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methyl-1,2-dihydropyridin-2-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( tetrahydrofuran-3-yl)pyridin-2(1H)-one,

5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one,

5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(2H-1,2,3-triazol-2-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(5-methyloxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl) -1-methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-methyloxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl) -1-methylpyridin-2(1H)-one,

5-(5-amino-7-chloro-2-(2,6-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H )-she,

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1,3-dimethylpyridin-2(1H)-one,

6-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-8-yl )-2-methylpyridazin-3(2H)-one,

2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidine-5-amine,

2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine,

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-ethylpyridin-2(1H)-one,

5-(5-amino-2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-cyclopropylpyridin-2(1H)-one,

6-[[5-amino-7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo[1,5-c]pyrimidine -2-yl]methyl]pyridin-2-amine,

8-(2-aminopyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo [1,5-c] pyrimidine-5-amine,

5-[5-amino-7-(3,4-difluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one,

5-(5-amino-7-(3-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-7-(4-(difluoromethyl)phenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one,

5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-(methylamino)pyridin-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidine-5-amine,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(thiazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -methylpyridin-2(1H)-one,

7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo [1,5-c] pyrimidine-5-amine,

7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-M2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2,5 -diamine,

7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine,

2-(2,6-difluorobenzyl)-8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amina,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( oxetan-3-yl)pyridin-2(1H)-one,

8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine,

8-(2-amino-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine,

5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl ]-1-(propan-2-yl)-1,2-dihydropyridin-2-one,

5-(5-amino-7-(4-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

4-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile,

5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( 1,1-dioxidothietane-3-yl)pyridin-2(1H)-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one,

5-[5-amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1H-pyrazol-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-yl]-1-methyl-1,2-dihydropyridin-2-one,

5-(5-amino-7-(2,4-difluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( 2-hydroxyethyl)pyridin-2(1H)-one,

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1,6-dimethylpyridin-2(1H)-one,

5-(5-amino-2-((3,5-difluoropyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one,

7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-1H-benzo[a]imidazol-6-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine,

5-(5-amino-7-(3-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one,

8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine,

8-(1H-benzo[d]imidazol-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine,

5-(5-amino-7-(3,5-difluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-7-(2-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -isopropylpyridin-2(1H)-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-isopropylpyridin-2(1H)-one,

8-(2-amino-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine,

8-(2-chloro-6-methylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidine-5-amine,

4-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-6 -methylpicolinonitrile,

8-(2-cyclopropyl-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine,

2-(2,6-difluorobenzyl)-8-(2-(difluoromethoxy)pyridin-4-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo [1,5-c] pyrimidine-5-amine,

8-(2-(difluoromethoxy)pyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine,

8-(2-(difluoromethoxy)-6-methylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine,

8-(benzo[a]thiazol-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(quinolin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine,

2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(oxazol-2-yl)-[1,2, 4] triazolo[1,5-c]pyrimidin-5-amine,

2-(2,6-difluorobenzyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine,

5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl ]-1-methyl-1,2-dihydropyridin-2-one,

2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(1H-1,2,3-triazol-1-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7-(2H-1,2,3-triazol-2-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-(2-hydroxyethyl)pyridin-2(1H)-one,

7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(quinoxalin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one,

5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-fluoropyridin-2-yl)methyl)-N7,N7-dimethyl-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidine-5,7-diamine,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-1-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine,

(S)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine,

(R)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine,

7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (isomer 1),

7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (isomer 2),

8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1),

8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2),

8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1),

8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2),

2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methyl piperazin-1-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine,

2-(2,6-difluorobenzyl)-7-(3-methoxyazetidin-1-yl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo [1,5-c]pyrimidine--amine,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-oxa-6-azaspiro[3.4]octane- 6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1),

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2),

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1),

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2),

7-(4-fluorophenyl)-2-(2-methoxyethyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine,

7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine,

7-(3-fluoro-1H-pyrazol-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

7-(4-fluoro-1H-pyrazol-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine,

7-(azetidin-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine,

2-(2-(dimethylamino)ethyl)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine,

2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine,

(S)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-1-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidine-5-amine,

7-(azetidin-1-yl)-2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine,

(R)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine,

2-(2-methoxyethyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine, or a pharmaceutically acceptable salt thereof.

Exemplary compounds 1-126 of formula (I) are listed below in Table 1.

It is understood that certain features of the present invention, which for clarity are described in the context of individual embodiments, may also be presented in combination with a single embodiment. Conversely, various features of the present invention, which for brevity are described in the context of a single embodiment, may also be presented separately or in any suitable subcombination.

Linker substituents are described at various places throughout the present specification. In cases where the structure clearly requires a linker group, then it is understood that the Markush variables listed for that group are linker groups; for example, if the structure requires a linker linker group, and the definition of the Markush group for this variable specifies "alkyl", then it is understood that "alkyl" represents an alkylene linker group.

As used herein, the term "substituted" when referring to a chemical group means that the chemical group has one or more hydrogen atoms that have been removed and replaced with substituents. As used herein, the term "substituent" has the usual meaning known in the art and refers to a chemical moiety that is covalently attached to a parent group or, if appropriate, fused to a parent group. As used herein, the term “optionally substituted” or “optionally substituted” means that a chemical group may have no substituents (ie, is unsubstituted) or may have one or more substituents (ie, is substituted). It should be borne in mind that substitution at a given atom is limited by valence.

As used herein, the term "C _ij " indicates a range of numbers of carbon atoms, where i and j are integers, and the range of carbon atoms includes the end points (i.e., i and j) and every integer therebetween, and where j is greater than i. For example, C _1-6 shows a range from one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms and six carbon atoms. In some embodiments, the term "C _1-12 " represents 1 to 12, including 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 carbon atoms.

As used herein, the term "alkyl", either as part of another term or used independently, refers to a saturated or unsaturated hydrocarbon chain, which may be further subdivided into a hydrocarbon chain having at least one double or triple bond (alkenyl or alkynyl) . In some embodiments, alkyl refers to a saturated hydrocarbon chain. The hydrocarbon chain mentioned above may be a straight chain or a branched chain. The term "C _ij alkyl" refers to an alkyl having from i to j carbon atoms. Examples of a saturated alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, higher homologues such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, etc. Examples of unsaturated alkyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, ethynyl, propyn-1-yl, propyn-2-yl, and the like. Examples of "C _1-12 alkyl" are methyl, ethyl, propyl, isopropyl and butyl. Examples of "C _1-3 alkyl" are methyl, ethyl, propyl and isopropyl.

As used herein, the term “alkylene,” whether as part of another term or used independently, refers to divalent alkyl. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 2,2-propylene and the like.

As used herein, the terms "halogen" and "halogen" refer to an atom selected from fluorine, chlorine, bromine or iodine.

As used herein, the term "alkoxy", whether as part of another term or used independently, refers to a group of the formula -O-alkyl. The term "C _ij alkoxy" means that the alkyl group of the alkoxy group has from i to j carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxyl, ethoxyl, propoxyl (eg, n-propoxy and isopropoxy), t-butoxy, and the like. Examples of "C _1-12 alkoxyl" are methoxyl, ethoxyl and propoxyl.

As used herein, the term "C _ij alkyl-OH" refers to a group of the formula "-C _1-12 alkyl-OH", where the alkyl moiety of the group has i to j carbon atoms, and one or more hydroxyl groups may be bonded to any carbon atoms in the alkyl group. In some embodiments, "C _ij alkyl-OH" has one hydroxyl group. Examples of the "C _1-12 alkyl-OH" group are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and 1-hydroxyisopropyl.

As used herein, the term “C _ij haloalkyl” refers to a halogen-substituted (mono- or polysubstituted) C _ij alkyl group. Examples of "C _1-12 haloalkyl" are fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, chloroethyl and bromisopropyl. An example of "difluoroethyl" is 1,1-difluoroethyl. Examples of "trifluoroethyl" are 2,2,2-trifluoroethyl and 1,2,2-trifluoroethyl.

Examples of "C _ij haloalkoxy" are fluoromethoxyl, difluoromethoxyl, or trifluoromethoxyl. Examples of "trifluoroethoxy" are 2,2,2-trifluoroethoxy and 1,2,2-trifluoroethoxy.

Examples of "N-(C _1-12 alkyl)amino" are methylamino and ethylamino.

Examples of "N-(C _1-12 haloalkyl)amino" are fluoromethyl amino, difluoromethyl amino, trifluoromethyl amino, 2-chloroethylamino and 1-bromoisopropylamino.

As used herein, the term “C _ij alkanoyl” refers to C _ij alkylcarbonyl. Examples of "C _1-12 alkanoyl" are propionyl and acetyl.

Examples of "C _1-12 alkanoylamino" are formamido, acetamido and propionylamino.

An example of "C _1-12 alkanoyloxy" is acetoxy.

Examples of "C _1-12 alkoxycarbonyl" are methoxycarbonyl, ethoxycarbonyl, n- and tert-butoxycarbonyl.

As used herein, the term “carbamoyl” refers to an aminocarbonyl group. Examples of "N-(C _1-12 alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N,N-(C _1-12 alkyl) ₂ carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl.

Examples of "N,N-(C _1-12 alkyl) ₂ amino" are di-(N-methyl)amino, di-(N-ethyl)amino and N-ethyl-N-methylamino.

As used herein, the term “carbocyclyl,” either as part of another term or used independently, refers to any ring, including mono- or polycyclic rings (e.g., having 2 or 3 fused, bridged, or spiro rings) in which all ring atoms are carbon atoms , and which contain at least three ring-forming carbon atoms. In some embodiments, the carbocyclyl may contain from 3 to 12 ring-forming carbon atoms (i.e., 3-12 membered carbon atoms), from 3 to 10 ring-forming carbon atoms, from 3 to 9 ring-forming carbon atoms, or from 4 to 8 ring-forming carbon atoms. ring-forming carbon atoms. Carbocyclyl groups may be saturated, partially unsaturated or completely unsaturated. In some embodiments, the carbocyclyl group may be a saturated cyclic alkyl group. In some embodiments, a carbocyclyl group may be an unsaturated cyclic alkyl group that contains at least one double bond in its ring system. In some embodiments, the unsaturated carbocyclyl group may contain one or more aromatic rings. In some embodiments, one or more ring-forming -CH ₂ - groups of a saturated or unsaturated carbocyclyl may be substituted with a -C(O)- group.

In some embodiments, the carbocyclyl group is a monocyclic alkyl group. In some embodiments, the carbocyclyl group is a saturated monocyclic alkyl group. Examples of monocyclic saturated or unsaturated carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, and the like.

As used herein, the term "spiro" ring refers to ring systems having two rings connected through one single common atom; the term "fused" rings refers to ring systems having two rings that share two adjacent atoms; and the term "bridged" rings refers to ring systems with two rings having three or more atoms in common.

A 3-12, 3-10 or 5-6 membered saturated or unsaturated carbocyclyl" is a saturated, partially unsaturated or fully unsaturated mono- or polycyclic ring system having 3 to 12, 3 to 10 or 5 to 6 ring-forming carbon atoms, respectively, wherein one or more than one ring-forming group -CH ₂ - may optionally be replaced by a -C(O)- group.

Examples of "3-12 membered saturated or unsaturated carbocyclyl" are C _3-4 cycloalkyl, cyclohexyl, cyclohexenyl, cyclopentyl, phenyl, naphthyl and bicyclo[1.1.1]pentan-1-yl. Examples of "C _3-4 cycloalkyl" are cyclopropyl and cyclobutyl. Examples of "5-6 membered saturated or unsaturated carbocyclyl" are cyclopentyl and phenyl.

As used herein, the term “heterocyclyl” refers to a carbocyclyl group where one or more (e.g., 1, 2, or 3) ring atoms are replaced by heteroatoms, which include, but are not limited to, O, S, N, P, and the like. In some embodiments, the heterocyclyl is a saturated heterocyclyl. In some embodiments, a heterocyclyl is an unsaturated heterocyclyl having one or more double bonds in its ring system. In some embodiments, the heterocyclyl is a partially unsaturated heterocyclyl. In some embodiments, the heterocyclyl is a fully unsaturated heterocyclyl. In some embodiments, an unsaturated heterocyclyl group may contain one or more aromatic rings. In some embodiments, one or more ring-forming -CH ₂ -heterocyclyl groups may optionally be substituted with a -C(O)-, -S-, -S(O)- or -S(O) ₂ - group. In some embodiments, if the heterocyclyl contains sulfur in its ring system, then said ring-forming sulfur atom can optionally be oxidized to form S-oxides. In some embodiments, the heterocyclyl is linked to another portion of the compound through its ring-forming carbon atom. In some embodiments, the heterocyclyl is linked to another portion of the compound through its ring-forming nitrogen atom.

In some embodiments, the 3- to 12-membered saturated or unsaturated mono- or polycyclic heterocyclyl has 1, 2, or 3 heteroatoms selected from N, O, or S.

A 3-12, 3-10, or 5-6-membered saturated or unsaturated heterocyclyl" is a saturated, partially unsaturated, or fully unsaturated mono- or polycyclic ring system (e.g., having 2 or 3 fused, bridged, or spiro rings) having from 3 to 12, 3 to 10 or 5 to 6 ring-forming atoms, respectively, of which at least one ring-forming atom is selected from a nitrogen, sulfur or oxygen atom which, unless specifically stated otherwise, may be bonded to another part compounds via its ring-forming carbon or nitrogen atom, wherein one or more of the ring-forming -CH ₂ - groups of a saturated or unsaturated heterocyclyl may be replaced by a -C(O)-, -S-, -S(O)- or - group S(O) ₂ -, and where, when the heterocyclyl contains a sulfur atom in its ring system, then said ring sulfur atom can possibly be oxidized to form S-oxides.

Exemplary monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1,1-dioxothietanylpyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, piperidyl, piperidyl, piperazinyl, morpholinyl, pyridinyl, pyrazinyl, pyrimidinyl , pyridazinyl, triazinyl, pyridonyl, pyrimidonyl, pyrazinonyl, pyrimidonyl, pyridazonyl, triazinonyl, etc.

Examples of spiroheterocyclyl include, but are not limited to, spiropyranyl, spirooxazinyl, and the like. Examples of fused heterocyclyl include, but are not limited to, a phenyl-fused ring or a pyridinyl-fused ring such as quinolinyl, isoquinolinyl, quinoxalinyl, quinolizinyl, quinazolinyl, azaindolizinyl, pteridinyl, chromium nyl, isochromenyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenazinyl, phenothiazinyl, phenanthridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo [4,3-a]pyridinyl, [1,2,3]triazolo[4,3-a]pyridinyl, etc. Examples of bridged heterocyclyl include, but are not limited to, morphanyl, hexamethylenetetraminyl, 8-aza-bicyclo[3.2.1]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO) and so on.

"Compound" of the present invention includes all stereoisomers, geometric isomers and tautomers of the depicted structures, unless specifically stated otherwise.

The term "stereoisomer" refers to any of the various stereoisomeric configurations (eg, enantiomers, diastereomers and racemates) of asymmetric compounds (eg, those having one or more asymmetrically substituted carbon atoms or "asymmetric centers"). The compounds of the present invention, which contain asymmetric centers, can be isolated in optically active (enantiomers or diastereomers) or optically inactive (racemic) forms. The term "enantiomer" includes pairs of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic mixture". The terms "diastereomers" or "diastereoisomers" cover stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. Some compounds containing one or more asymmetric centers may give rise to enantiomers, diastereomers or other stereoisomeric forms, which can be defined in terms of absolute configuration as (R)- or (S)- for each asymmetric center according to the Cahn-Ingold R-S system -Preloga. Divided connections whose absolute configuration is unknown can be designated by using the term "or" at the asymmetric center. Methods for preparing optically active forms from racemic mixtures are known in the art, such as HPLC resolution or stereoselective synthesis.

The terms "geometric isomers" or "cis and trans isomers" refer to compounds with the same formula, but their functional groups are oriented in different directions in three-dimensional space.

The term "tautomers" includes prototropic tautomers, which are isomeric protonation states of compounds having the same formula and the same net charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imide acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms where the proton can occupy two or more positions in the heterocyclic system, for example, 1H- and 3H- imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomers can be in equilibrium or can be sterically locked into one form by appropriate substitution. Compounds of the present invention identified by name or structure as one particular tautomeric form include other tautomeric forms unless specifically stated otherwise.

"Compound" of the present invention also includes all isotopes of the atoms in the compounds. Isotopes of an atom include atoms that have the same atomic number but different mass numbers. For example, unless specifically stated otherwise, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromide or iodine in a “compound” of the present invention are intended to also include isotopes thereof, such as, without limitation: ¹ Η, ² Н, ³ Н, ¹¹ C, ¹² С, ¹³ С, ¹⁴ С, ¹⁴ N, 15 N, ^{16 О, 17 O} , ¹⁸ O, ³¹ Р, ³² Р, ³² S, ³³ S, ^{34 S} , ³⁶ S, ¹⁷ F, ¹⁹ F, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁷ I and ¹³¹ I. In some embodiments, hydrogen includes protium, deuterium and tritium. In some embodiments, the term "deuterium-substituted" or "deuterium-substituted" is used to replace another hydrogen isoform (eg, protium) in a chemical moiety with deuterium. In some embodiments, carbon includes ¹² C and ¹³ C. In some embodiments, “compound” of the present invention covers only the isotopes of hydrogen in the compound. In some embodiments, a “compound” of the present invention covers only isotopes of atoms found in nature.

It should also be understood that the "compound" of the present invention may exist in solvated forms as well as non-solvated forms, such as, for example, hydrated forms, solid forms, and the present invention covers all such solvated and non-solvated forms.

It should also be understood that the “compound” of the present invention may exist in pharmaceutically acceptable salt forms.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, substances, compositions and/or dosage forms that, within the bounds of sound medical judgment, are suitable for contact with tissues of humans and animals without undue toxicity, irritation, allergic reactions or other problems or complications, and which are commensurate with a reasonable benefit/risk ratio. In some embodiments, compounds, substances, compositions and/or dosage forms that are pharmaceutically acceptable are those approved by a regulatory authority (such as the US Food and Drug Administration, FDA and medicines of China or the European Medicines Agency) or listed in generally accepted pharmacopoeias (such as the US Pharmacopoeia, the Chinese Pharmacopoeia or the European Pharmacopoeia) for use in animals and, more specifically, in humans.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the compounds of the present invention wherein the parent compound is modified by converting an existing acid moiety (e.g., carboxyl, etc.) or a basic moiety (e.g., amine, alkaline, etc.) ) into its salt form. In many cases, the compounds of the present invention are capable of forming acid and/or base addition salts due to the presence of amino and/or carboxyl groups or the like. Pharmaceutically acceptable salts are acid and/or base addition salts that retain the biological effectiveness and properties of the parent compound and that are generally not biologically or otherwise undesirable. Suitable pharmaceutically acceptable salts of the compound of the present invention include, for example, an acid addition salt, which can be obtained from, for example, an inorganic acid (for example, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric acid, etc.) or an organic acid (for example, formic, acetic, propionic, glycolic, oxalic, maleic, malonic, succinic, fumaric, tartaric, trimesic, citric, lactic, phenylacetic, benzoic, mandelic, methanesulfonic, napadisilic, ethanesulfonic, toluenesulfonic, trifluoroacetic, salicylic, sulfosalicylic acid, etc. .). In some embodiments, the pharmaceutically acceptable salt of a compound of the present invention is a salt of formic acid. In some embodiments, the pharmaceutically acceptable salt of a compound of the present invention is a TFA salt.

Suitable pharmaceutically acceptable salts of the compound of the present invention also include, for example, a base addition salt, which can be obtained, for example, from inorganic bases (for example, sodium, potassium, ammonium salts and hydroxide, carbonate, bicarbonate salts of metals from groups I-XII of the Periodic Table tables, such as calcium, magnesium, iron, silver, zinc, copper, etc.) or organic bases (for example, primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc.). Some organic amines include, but are not limited to, isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine. Those skilled in the art will appreciate that addition of acids or bases to form acid/base addition salts other than those presented in the examples may also be possible. Listings of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). In some embodiments, a suitable pharmaceutically acceptable salt of a compound of the present invention is an inorganic base addition salt.

The present invention also covers active intermediates, active metabolites and prodrugs of the compounds of the present invention. As used herein, the term “active intermediate” refers to an intermediate in the synthesis process that exhibits the same or substantially the same biological activity as the final synthesized compound.

As used herein, "active metabolite" refers to the cleaved or end product of a compound of the present invention or a salt or prodrug thereof resulting from metabolism or biotransformation in an animal or human that exhibits the same or substantially the same biological activity as specifically specified connection. Such metabolites may be formed by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic degradation, and the like. the administered compound or a salt or prodrug thereof.

As used herein, “prodrugs” refer to any compounds or conjugates that release the active parent drug when administered to an animal or human subject. Prodrugs can be prepared by modifying functional groups present in compounds such that the modifications are cleaved either by routine manipulation or in vivo from the parent compounds. Prodrugs include compounds wherein a hydroxyl, amino, sulfhydryl or carboxyl group is linked to any group that, when administered to a mammalian subject, is cleaved to form a free hydroxyl, amino, sulfhydryl or carboxyl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of the alcohol and amino functional groups in the compounds of the present invention. The preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

Synthesis method

The synthesis of the compounds provided herein, including their pharmaceutically acceptable salts, is illustrated in the synthesis schemes in the Examples. The compounds provided herein can be prepared using any known organic synthesis methods and can be synthesized according to any of numerous possible synthetic routes, and therefore these schemes are illustrative only and are not intended to limit other possible methods that can be used to prepare connections provided in this document. In addition, the stages in the Diagrams are indicated for better illustration and may be modified as appropriate. The example compound embodiments were synthesized for the purpose of research and potential regulatory submission.

The reactions to prepare the compounds of the present invention can be carried out in suitable solvents, which can be easily selected by one skilled in the art of organic synthesis. Suitable solvents may be solvents that are substantially unreactive with the starting materials (reagents), intermediates or products at the temperatures at which the reactions are carried out, for example at temperatures that may range from the freezing point of the solvent to the boiling point of the solvent. This reaction can be carried out in a single solvent or a mixture of solvents. One skilled in the art can select suitable solvents for a particular reaction step depending on the particular reaction step.

The preparation of the compounds of the present invention may involve protecting and deprotecting various chemical groups. The need for protection and deprotection and the selection of suitable protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein in its entirety via link.

The reactions can be monitored by any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods such as nuclear magnetic resonance spectroscopy (e.g. 1~H or 13C), infrared spectroscopy, spectrophotometry (e.g. UV-vis), mass spectroscopy, or chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS) or thin layer chromatography (TLC). Compounds can be purified by one skilled in the art using a variety of methods, including high performance liquid chromatography (HPLC) (“Preparative LC-MS Purification: Improved Compound Specific Method Optimization” Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi Chem. 2004, 6(6), 874-883, which is incorporated herein by reference in its entirety) and normal phase silica chromatography.

The structures of the compounds in the examples were characterized by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (δ) is given in units of 10 ^-6 (ppm). ¹ H-NMR spectra were recorded in dimethyl sulfoxide-d6 (DMSO- _d6 ), or _CDCl3 , or _CD3OD , or _D2O or acetone- _d6 , or _CD3CN (from Innochem, or Sigma-Aldrich, or Cambridge Isotope Lab., Inc.) on Bruker AVANCE NMR spectrometers (300 MHz or 400 MHz) using ICON-NMR (controlled by TopSpin software) with tetramethylsplane as an internal standard.

MS measurements were carried out on a Shimadzu 2020 mass spectrometer with an electrospray source in the mode of recording positive and negative ions.

High performance liquid chromatography (HPLC) measurements were carried out on Shimadzu LC-20AD systems, or Shimadzu LC-20ADXR systems, or Shimadzu LC-30AD systems using a Shim-pack XR-ODS C18 column (3.0×50 mm, 2.2 µm), or Ascentis Express C18 columns (2.1 × 50 mm, 2.7 µm), or Agilent Poroshell HRN-C18 columns (3.0 × 50 mm, 2.7 µm).

Thin layer chromatography was performed using silica gel plates from Sinopharm Chemical Reagent Beijing Co., Ltd. and Xinnuo Chemical. For thin layer chromatography (TCX) silica gel plates of 175-225 μm were used. To isolate and purify products by TLC, 1.0 mm silica gel plates were used.

The purification chromatography column uses silica gel as the carrier (100-200, 200-300 or 300-400 mesh, produced by Rushanshi Shangbang Xincailiao Co., Ltd. or Rushan Taiyang Desiccant Co., Ltd. etc.), or flash column (20-45 µm C18 reverse phase column manufactured by Agela Technologies) in an Agela Technologies flash system. Column sizes are adjustable according to the number of connections.

Known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from Alfa Aesar, TCI, Sigma-Aldrich, Bepharm, Bide pharmatech, PharmaBlock, Enamine, Innochem and JW&Y PharmLab, etc. .d.

Unless specifically stated otherwise, all reactions were carried out under argon or nitrogen. Under argon or nitrogen atmosphere means that the reaction flask is connected to a cylinder of approximately 1 liter of argon or nitrogen. Hydrogenation is usually carried out under pressure. Unless specifically stated otherwise, the reaction temperature in the examples is ambient temperature, which is 10°C-30°C.

The progress of reactions was monitored by TLC and/or LC-MS. Eluent systems used for the reaction mixtures include the dichloromethane-methanol system and the petroleum ether-ethyl acetate system. Volume ratios of solvents were adjusted according to different polarities of compounds.

The column chromatography elution system used to purify the compounds and the TLC eluent system included a dichloromethane-methanol system and a petroleum ether-ethyl acetate system. Volume ratios of solvents were adjusted according to different polarities of compounds. A small amount of alkaline or acidic agents (0.1%-1%) such as formic acid or acetic acid or TFA or ammonia may be added for adjustment.

The following are abbreviations for the chemicals used in the synthesis of the compounds proposed in this document:

Pharmaceutical composition

The present invention provides pharmaceutical compositions containing at least one compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains more than one compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains one or more compounds of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In general, pharmaceutically acceptable carriers are conventional medical carriers that can be prepared by a method well known in the art. In some embodiments, a compound of the present invention or a pharmaceutically acceptable salt thereof may be admixed with a pharmaceutically acceptable carrier to form a pharmaceutical composition.

The form of the pharmaceutical composition depends on a number of criteria, including, but not limited to, the route of administration, the extent of the disease, or the dose intended to be administered. Pharmaceutical compositions can be prepared for oral, nasal, rectal, subcutaneous, intravenous or intramuscular administration. According to the desired route of administration, pharmaceutical compositions can be prepared in the form of tablets, capsules, pills, powder, granules, sachets, wafers, lozenges, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), spray , ointment, paste, cream, lotion, gel, patch, inhalant or suppository.

In some embodiments, the pharmaceutical compositions contain from about 1 mg to about 1000 mg of a compound of the present invention or a pharmaceutically acceptable salt thereof.

In some embodiments, the pharmaceutical compositions contain one or more compounds of the present invention or a pharmaceutically acceptable salt thereof as a first active ingredient and further contain a second active ingredient. The second active ingredient may be an immunomodulator or antineoplastic agent known in the art, including, but not limited to, a chemotherapeutic agent, an immunotherapeutic agent, cell signal transduction inhibitors, alkylating agents, topoisomerase inhibitors, mitotic inhibitors, antihormonal agents, etc. Examples of such immunomodulators or antineoplastic agents are platinum-based chemotherapeutic agents (eg, cisplatin (DDP), carboplatin (CBP), sulfato-1,2-diaminocyclohexane-platinum (SHP), nedaplatin, oxaliplatin (OXA), laboplatin), docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, CTLA-4 (cytotoxic T-lymphocyte antigen 4) inhibitors, anti-CTLA-4 antibodies, PD-1 (programmed cell death receptor protein 1) inhibitors, PD-L1 (anti-PD ligand) inhibitors -1), anti-PD-1/PD-L1 antibodies, CD39 inhibitors (ectonucleoside triphosphate diphosphohydrolase 1), anti-CD39 antibodies, CD73 inhibitors (ecto-5'-nucleotidase), anti-CD73 antibodies, CCR2 inhibitors (C-C chemokine receptor), anti-CCR2 antibodies, EGFR inhibitors, CDK 4/6 inhibitors, MELK inhibitors, OX40 agonists, antiandrogen inhibitors, IgG4 isotype antibodies, tyrosine kinase inhibitors, DNA methyltransferase inhibitors, Hsp90 inhibitors, FGFR inhibitors, mTOR inhibitors, aromatase inhibitors, VEGF inhibitors, LHRH antagonists, PI3K inhibitors, AKT inhibitors, Aurora kinase inhibitors, MEK inhibitors, HDAC inhibitors, BET inhibitors, PIK3CA inhibitors, proteasome inhibitors, other SERDs, farnesyltransferase inhibitors, anti-VEGF-A antibodies, anti-ErbB3 (Her3) antibodies , proteasome inhibitors, protein kinase Cβ inhibitors, anti-IGF-1R antibodies, anti-HER2 antibodies, SERMs, IGF inhibitors, anti-IgG antibodies, etc. Representative examples of antineoplastic agents for the treatment of cancer or tumors may include, without limitation, cisplatin, carboplatin, SHP, nedaplatin, oxaliplatin, laboplatin, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, vincristine, vinblastine, gemcitabine, cyclophosphamide, chlorambucil, carmustine, methotrexate , fluorouracil, actinomycin, epirubicin, anthracycline, bleomycin, mitomycin-C, irinotecan, topotecan, teniposide interleukin, interferon, tremelimumab, ipilimumab, pembrolizumab, nivolumab, avelumab, durvalumab, atezolizumab, IP H 52, IPH 53, CPI-006, plozalysis umab , MLN1202, cetuximab, lapatinib, erlotinib, gefitinib, neratinib, trastuzumab, ado-trastuzumab emtansine, pertuzumab, MCLA-128, anastrazole, raloxifene, G1T38, tamoxifen, goserelin, enzalutamide, vorinostat, entimostat, sunitinib, pazo panib, bevacizumab, ranibizumab, pegaptanib, cediranib, dasatinib, GDC-0980, gedatolisib, alpelisib, VKM120, copanlisib, AZD8835, GDC-0941, taselisib, temsirolimus, everolimus, sapanisertib, AZD5363, MK2206, panitumumab, pembrolizum b, sorafenib, palbociclib, abemaciclib, ribociclib, crizotinib, dovtinib, ruxolitinib, azacitidine, CC-486, HSP90 ganetespib, Debio 1347, erdafitinib, vitusertib, alisertib, selumetinib, GS-5829, GSK525762, MLN9708, GDC-0810, AFP464, tirifarnib, seri bantumab, bortezomib, enzastraurin, AVE 1642, xentuzumab , dalotuzumab, AMG 479, etc.

Treatment of diseases associated with adenosine receptor, which is defined below, can be used as monotherapy, or it can include, in addition to the compound of the invention, conventional surgery, or radiotherapy, or chemotherapy, or immunotherapy. Such chemotherapy may include one or more of the following chemotherapeutic agents: cisplatin (DDP), carboplatin (CBP), sulfato-1,2-diaminocyclohexaneplatinum (SHP), nedaplatin, oxaliplatin (OXA), laboplatin, docetaxel, paclitaxel, doxorubicin, etoposide or mitoxantrone. Such an immunotherapeutic agent may include one or more of the following antitumor agents: (1) an anti-CTLA-4 antibody; (2) anti-PD-1 antibody; (3) anti-PD-L1 antibody; (4) anti-CD73 antibody; (5) anti-C039 antibody; or (6) anti-CCR2 antibody.

In particular, the anti-CTLA-4 antibody is tremelimumab (which is disclosed in US Pat. No. 6,682,736). In another aspect of the invention, the anti-CTLA-4 antibody is specifically ipilimumab (marketed by Bristol Myers Squib as ^YERVOY® ).

In particular, the anti-PD-L1 antibody is the antibody that is disclosed in US application 20130034559 (Medlmmune). In another aspect of the invention, the anti-PD-L1 antibody is particularly the antibody disclosed in US 2010/0203056 (Genentech/Roche). In another aspect of the invention, in particular, the anti-PD-L1 antibody is the antibody that is disclosed in US 20090055944 (Medarex). In another aspect of the invention, in particular, the anti-PD-L1 antibody is the antibody that is disclosed in US 20130323249 (Sorrento Therapeutics).

Specifically, the anti-PD-1 antibody is MRK-3475 (Merck). In another aspect of the invention, in particular, the anti-PD-1 antibody is nivolumab or an anti-PD-1 antibody, which is disclosed in WO 2006/121168 or US 8,008,449 (Medarex). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody that is disclosed in WO 2009/101611 (CureTech). In another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody that is disclosed in WO2012/145493 (Amplimmune). In another aspect of the invention, in particular, the anti-PD-1 antibody is the antibody that is disclosed in US 7,488,802 (Wyeth/Medlmmune). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody that is disclosed in US 20130280275 (Board of Regents, Univ. of Texas). In another aspect of the invention, in particular, the anti-PD-1 antibody is an antibody that is disclosed in WO 99/42585 (Agonox), WO 95/12673 and WO 95/21915.

Specifically, the anti-CD39 antibody is IPH52 (Innate Pharmaceuticals).

Specifically, the anti-CD73 antibody is CPI-006 (Corvus Pharmaceuticals) or IPH53 (Innate Pharmaceuticals).

Specifically, the anti-CCR2 antibody is plosalizumab (Takeda Pharmaceuticals International Co.) or MLN1202 (Millennium Pharmaceuticals).

According to this aspect of the invention there is provided a combination suitable for use in the treatment of diseases associated with adenosine receptor, in particular cancer, comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and any one or more chemotherapeutic agents listed above, and/or any one or more of the immunotherapies listed in paragraphs (1)-(6) above.

For example, the compounds of the present invention may be presented in combination with an anti-PD1/PD-L1 antibody. In some specific embodiments, the compounds of the present invention may be presented in combination with an anti-PD1/PD-L1 antibody and additionally in combination with an anti-CTLA-4, CD38, CD73 or CCR2 antibody.

According to this aspect of the invention there is provided a combination suitable for use in the treatment of cancer comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, and any one of the immunomodulators or antineoplastic agents listed above.

Thus, in a further aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or chemotherapeutic agent selected from those listed above.

As used herein, when the term “combination” is used, it is understood to refer to simultaneous, separate or sequential administration. In some embodiments, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. If administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention, there is provided a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier, for use in the production of an immunomodulatory agent. or anticancer effect.

According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from those listed above, in association with a pharmaceutically acceptable diluent or carrier, for use in the treatment of NSCLC , RCC, prostate cancer or breast cancer (etc.).

According to a further aspect of the present invention, there is provided a kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with an immunomodulator or antitumor agent selected from those listed above.

According to a further aspect of the present invention, there is provided a kit comprising:

a) a compound of formula (I) or a pharmaceutically acceptable salt thereof in a first unit dosage form;

b) an immunomodulator or antitumor agent selected from those listed above, in a second unit dosage form; And

c) container for said first and second dosage forms.

In addition to their use in therapeutic medicine, the compounds of formula (I) or their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for assessing the activity or expression of adenosine receptors in laboratory animals such as cats , dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In the foregoing, other features of the pharmaceutical compositions, methods, methods, uses and manufacture of medicinal products, alternative and preferred embodiments of the compounds of the present invention described herein are also applicable.

Method of treatment

The present invention provides a method of treating a disease associated with adenosine receptors (including, for example, A1, A2a, and/or A2b, particularly A2a) by administering to a subject a therapeutically effective amount of one or more compounds, a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the present invention.

As used herein, the term "adenosine receptor-associated disease" or "AR-associated disease" refers to a disease whose onset or progression, or both, is associated with genomic changes, expression, overexpression, degradation or activity of AR (adenosine receptor ) (including, for example, A1, A2a, and/or A2b, in particular A2a), depending on the circumstances. Examples include, but are not limited to, inflammatory diseases, cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV, ADA-SCID, acute heart failure (AHF) and chronic heart failure, chronic obstructive pulmonary disease (COPD) , asthma and other diseases. In some embodiments, an AR-associated disease refers to a disease that is treated by inhibiting the effect of the adenosine receptor.

In some embodiments, the AR-associated disease is a cancer, preferably an AR-expressing cancer or an AR-overexpressing cancer. "AR-expressing cancer" is a cancer that involves cancer cells or tumor cells having an AR protein, such as A2a, A1 and/or A2b, present on their cell surface. An “AR-overexpressing cancer” is a cancer that has significantly higher levels of AR protein, such as A2a, A1 and/or A2b, on the cell surface of a cancer or tumor cell compared to non-cancerous tissue cells of the same type. Such overexpression may be caused by gene amplification or increased transcription or translation. Expression or overexpression of the adenosine receptor can be determined by a diagnostic or prognostic assay by assessing elevated levels of AR proteins present on the cell surface (eg, immunohistochemical assay; IH). Alternatively, or additionally, levels of AR-encoding nucleic acid in a cell can be measured, for example by fluorescence in situ hybridization (FISH; see WO 98/45479 published October 1998), Southern blotting or polymerase chain reaction (PCR), such as quantitative real-time PCR (RT-PCR) (Methods 132:73-80 (1990)). In addition to the above assays, various in vivo assays are available to one skilled in the art. For example, cells in a patient's body can be exposed to an antibody, which may be labeled with a detectable label, such as a radioactive isotope, and the binding of the antibody to cells in the patient can be assessed, for example, by an external scan for radioactivity or by analysis of a biopsy taken from a patient previously exposed to the antibody. .

In particular, cancer types include, but are not limited to, lung cancer (eg, non-small cell lung cancer (NSCLC), small cell lung cancer, lung adenocarcinoma, large cell lung cancer, squamous cell lung cancer), renal cell carcinoma (RCC), prostate cancer, breast cancer glands, ovarian cancer, endometrial cancer, cervical cancer, bone cancer, uterine cancer, colon cancer, leukemia, glioblastoma melanoma, chondrosarcoma brain cancer, cholangiocarcinoma, osteosarcoma, lymphoma adenoma, myeloma hepatocellular carcinoma, adrenocortical carcinoma, pancreatic cancer, cancer bladder, liver cancer, stomach cancer, colorectal cancer, esophageal cancer, testicular cancer, skin cancer, kidney cancer, mesothelioma, neuroblastoma, thyroid cancer, head and neck cancer, esophageal cancer, eye cancer, nasopharyngeal or oral cancer. In some embodiments, the cancer is NSCLC, RCC, prostate cancer, or breast cancer. The cancers mentioned here can be at any stage unless specifically stated otherwise. In some embodiments, the cancer is an early stage cancer. In some embodiments, the cancer is a locally advanced cancer. In some embodiments, the cancer is locally advanced and/or metastatic cancer. In some embodiments, the cancer is an invasive cancer. In some embodiments, the cancer is a cancer that is resistant to existing therapeutic agents.

In some embodiments, the compounds or pharmaceutically acceptable salts thereof of the present invention have cancer treatment activity (eg, NSCLC, RCC, prostate cancer, breast cancer). In addition, the compounds of the present invention or pharmaceutically acceptable salts thereof may be useful in the treatment of other diseases associated with adenosine receptors, such as Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV, ADA-SCID, AHF and chronic heart failure, chronic obstructive pulmonary disease (COPD) or asthma.

As used herein, the terms “treating” and “treating” refer to reversing, reducing, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after the development of one or more symptoms. In other embodiments, treatment can be administered in the absence of symptoms. For example, a susceptible individual may be treated prior to the onset of symptoms (eg, in light of symptom history and/or in light of genetic or other susceptibility factors). Treatment can also be carried out after symptoms have disappeared, for example to prevent or delay their recurrence.

The therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof provided herein will depend on various factors known in the art, such as body weight, age, medical history, medications taken, medical condition of the subject, and the possibility of cross-reaction , allergies, sensitivities and adverse side effects, as well as the route of administration and the extent of the disease. One skilled in the art (eg, a physician or veterinarian) may reduce or increase dosages proportionately as circumstances or requirements dictate.

Application of connections

Some embodiments of the present invention provide the use of the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical composition of the present invention in the manufacture of medicaments for the treatment of AR-associated diseases. Exemplary AR-associated diseases include, but are not limited to, cancer (eg, NSCLC, RCC, prostate cancer, or breast cancer) and other diseases.

In such a situation, the present invention also provides a method for screening a patient suitable for treatment with a compound or pharmaceutical composition of the present invention, alone or together with other ingredients (eg, a second active ingredient, eg an antitumor agent). The method includes sequencing tumor samples from patients and detecting AR accumulation or activation.

According to another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a drug.

According to a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for modulating adenosine receptors in a warm-blooded animal such as a human.

The term "modulate", "modulation" or "modulation" as applied to adenosine receptors refers to the action or result of altering the expression, degradation and/or activity of adenosine receptors.

According to a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for the treatment of AR-associated diseases in a warm-blooded animal such as a human.

According to this aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for providing anti-cancer effects in a warm-blooded animal such as a human.

According to a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of NSCLC, RCC, prostate cancer or breast cancer.

According to a further aspect of the present invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament for use in the treatment of breast cancer.

According to a further aspect of the present invention, there is provided a method of modulating adenosine receptors in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

According to a further aspect of the present invention, there is provided a method of treating AR-associated diseases in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

According to a further aspect of the present invention, there is provided a method of providing anticancer effects in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

According to a further aspect of the present invention, there is provided a method of providing anticancer effects in a warm-blooded animal, such as a human, in need of such treatment, comprising (1) determining whether or not the warm-blooded animal has an AR-expressing cancer, and (2) if so, administering to the specified animal, an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above.

According to a further feature of this aspect of the present invention, there is provided a method of treating NSCLC, RCC, prostate cancer or mammary cancer in a warm-blooded animal, such as a human, in need of such treatment, comprising administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof , as defined above.

According to a further aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in modulating AR in a warm-blooded animal, such as a human.

According to a further aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of AR-associated diseases in a warm-blooded animal such as a human.

According to this aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in providing anti-cancer effects in a warm-blooded animal, such as a human.

According to an additional feature of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in the treatment of NSCLC, RCC, prostate cancer or breast cancer.

EXAMPLES

The following examples further explain the general methods of the present invention. The compounds of the present invention can be prepared by methods known in the art. The following illustrates detailed methods for preparing the preferred compounds of the present invention. However, they in no way limit the methods for preparing the compounds of the present invention.

Example 1

Preparation of 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1-methylpyridin-2(1H)-one (Compound 1)

SCHEME 1

Step 1. 4-Chloro-6-(4-fluorophenyl)pyrimidin-2-amine

4,6-Dichloropyrimidin-2-amine (30 g, 182.9 mmol, 1 equiv.), (4-fluorophenyl)boronic acid (4-fluorophenyl)boronic acid ( 25.6 g, 182.9 mmol, 1.00 equiv.), K ₂ CO ₃ (50.8 g, 367.7 mmol, 2.0 equiv.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ ( 14.9 g, 18.3 mmol, 0.10 equiv.), 1,4-dioxane (1000 ml), H ₂ O (140 ml). The resulting solution was stirred for 5 hours at 35°C. The solvent was removed and the resulting solution was diluted with 500 ml of water. The resulting solution was extracted with 3×500 ml ethyl acetate and the organic layers were combined. The resulting solution was washed with 2×800 ml sat. NaCl, and the organic layers were combined and dried over anhydrous sodium sulfate. The crude product was recrystallized from a 10:1 DCM:MeOH mixture. This resulted in 30 g (60.86%) of 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine as a brown solid. LC-MS: m/z (ESI (electrospray ionization)), [M+H] ⁺ =224.0. ^1H NMR: (300 MHz, Chloroform-d) δ 7.03 (1H, s), 7.22-7.10 (2H, m), 8.03-7.93 (2H, m).

Step 2: 5-Bromo-4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine Place DMF (1200 ml, 15506.1) in a 2 L round bottom flask, purged with nitrogen and maintained under an inert nitrogen atmosphere mmol, 76.2 equiv.), 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine (45.5 g, 203.5 mmol, 1 equiv.), NBS (43.5 g, 244, 4 mmol, 1.2 equiv.). The resulting solution was stirred for 5 hours at 18°C. The reaction was then quenched by adding 1000 ml of water. The reaction mixture was filtered and the filter cake was combined. This resulted in 31.5 g (46.1%) of 5-bromo-4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine as a gray solid. LC-MS: m/z (PER), M+=304.0. ¹ H NMR: (300 MHz, Methanol-d ₄ ) β7.26-7.11 (2H, hl), 7.69 (2H, ddd).

Step 3. 5-Bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine

EtOH (500 mL, 8606.8 mmol, 82.7 equiv.), 5-bromo-4-chloro-6-(4-fluorophenyl )pyrimidin-2-amine (31.5 g, 104.1 mmol, 1 equiv.), hydrazine hydrate (15.6 ml, 321.0 mmol, 3.1 equiv.). The resulting solution was stirred for 5 hours at 75°C in an oil bath. The solid was collected by filtration. The solid was suspended in MTBE and collected by filtration. This resulted in 28 g (88.40%) of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine as a gray solid. LC-MS: m/z (ESI), M ⁺ =298.0. ¹ H NMR: (400 MHz, Methanol-d ₄ ) δ7.24-7.11 (2H, m), 7.63-7.50 (2H, m).

Step 4. N'-(2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide

Mixture of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (20 g, 67.1 mmol, 1 equiv.), T3R (42.7 g, 134.2 mmol, 2 equiv.) , TEA (20.4 g, 201.3 mmol, 3 equiv.) and 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (20 g, 67.1 mmol, 1 equiv.) in DMF (300 ml) was stirred for 2 hours at room temperature under nitrogen atmosphere. The residue was adjusted to pH 9 with a saturated solution of NaHCO ₃ (aq). The resulting mixture was diluted with water (250 ml). The precipitated solid was collected by filtration and washed with PE to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(3-fluoropyridin-2-yl)acetohydrazide ( 16.3 g, 55.8%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =435.1.

Step 5. 8-Bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(3-fluoropyridin-2-yl)acetohydrazide ( 1.0 g, 2.5 mmol, 1 equiv.) and (E)-(trimethylsilyl M-(trimethylsilyl)ethanimidate) (5.0 ml, 24.6 mmol, 10.0 equiv.) at room temperature, stirred for 2 hours at 120°C, cool to room temperature, add methanol (5.0 ml), concentrate and wash with i-Pr-O-methyl ether/methanol (10/1) to give 8-bromo-7- (4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (850 mg) as off-white solid matter. LC-MS: m/z (ESI), [M+H] ⁺ =417.1.

Stage b. Preparation of 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl1-[1,2,4]-triazolo[1,5-c]pyrimidin-8- yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 1)

8-bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidine was added to a 10 ml sealed tube. -5-amine (120 mg, 0.29 mmol, 1 equiv.), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-2 ,4-dien-1-one (134.7 mg, 0.58 mmol, 2 equiv.), K ₃ PO ₄ (122.1 mg, 0.58 mmol, 2 equiv.) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (23.5 mg, 0.03 mmol, 0.1 equiv.) in 1,4-dioxane (10 ml) and water (1 ml) at 80°C for 2 hours. The target product could be detected by LC-MS. The crude product (80 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 25% B to 34% B in 7 minutes; 254/220 nm; Rt: 6.25 min, giving 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 1) (20 mg, 15.6%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =446. ^1H NMR (400 MHz, Methanol- _d4 ) δ 3.57 (3H, s), 4.50 (2H, d), 6.43 (1H, d), 7.04-7.15 (2H, m), 7.19 (1 Н, dd), 7.42 (1 Н, dt), 7.51-7.61 (2 Н, m), 7.66 (1 Н, ddd), 7.80 (1 Н, d), 8.33 (1 Н, dt).

The compounds listed in the table below were prepared using the methods described in Example 1.

Example 4

Preparation of 2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-8-[2-(trifluoromethyl)-pyridin-4-yl]-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine (Compound 4)

SCHEME 2

Step 1. N'-(2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(2,6-difluorophenyl)acetohydrazide

Mixture of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (2.1 g, 7.04 mmol, 1 equiv.), HATU (5.4 g, 14.1 mmol, 2. 0 equiv.), TEA (2.9 g, 28.18 mmol, 4.0 equiv.) and 2-(2,6-difluorophenyl)acetic acid (1.8 g, 10.6 mmol, 1.5 equiv. .) in DMF (25 ml) was stirred for 3 hours at room temperature under nitrogen atmosphere. The reaction mixture was quenched by adding water (50 ml) at room temperature. The product was collected by filtration and dried in vacuo to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)acetohydrazide (2 g, 62. 8%) as a gray solid. LC-MS: m/z (PER), [M+H] ⁺ =451.9. ^1H NMR: (400 MHz, DMSO-d ₆ ) δ 6.38 (1H, s), 6.93-7.14 (3H, m), 7.20-7.33 (2H, m), 7.33-7.44 (1H, m), 7.48- 7.65 (2H, m), 8.59-8.75 (1H, m), 10.09-10.16 (1H, m).

Step 2. 8-Bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

A mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)acetohydrazide (1.9 g, 4.3 mmol, 1 equiv. ) and (E)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (4.4 g, 21.6 mmol, 5.0 equiv.) in toluene (35 ml) was stirred for 12 hours at 110°C in atmosphere nitrogen. The resulting mixture was concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate/PE (5:1) to give 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (1.3 g, 69.4%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =436.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.55 (1H, s), 7.11 (3H, dt), 7.24-7.36 (2H, m), 7.36-7.47 (1H, m), 7.67-7.77 (2H , m), 8.06 (2Н, s).

Step 3. 2-[(2,6-Difluorophenyl)methyl1-7-(4-fluorophenyl)-8-[2-(trifluoromethyl)pyridin-4-yl]-[1,2.4]triazolo[1,5-c ]pyrimidine-5-amine (Compound 4)

Mixture of 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (100 mg, 0.2 mmol, 1 equiv.) and [2-(trifluoromethyl)pyridin-4-yl]boronic acid (87.9 mg, 0.5 mmol, 2.0 equiv.), and Pd(dppf)Cl ₂ ( 33.7 mg, 0.05 mmol, 0.2 equiv.), and K ₃ PO ₄ (146.7 mg, 0.69 mmol, 3 equiv.) in a mixture of dioxane/H ₂ O (2.4 ml) stirred for 10 hours at 90°C under nitrogen atmosphere. The residue was purified by preparative TLC (PE:EtOAc=2:1 to 1:1), then the crude product (28 mg) was purified by preparative HPLC to give 2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl )-8-[2-(trifluoromethyl)pyridin-4-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 4) (12 mg, 10.20% ) as a white solid. LC-MS: m/z (ESI), [M- ^t Bu+H] ⁺ =501.3. ¹ H NMR (400 MHz, Methanol-d ₆ ) δ 1.30 (s, 1H), 4.32 (s, 2H), 6.96-7.11 (m, 3H), 7.31-7.38 (m, 1H), 7.39-7.45 (m , 2H), 7.59 (d, J=5.0 Hz, 1H), 7.74 (d, J=1.4 Hz, 1H), 8.59 (d, J=5.1 Hz, 1H).

The compounds listed in the table below were prepared using the methods described in Example 4.

Example 7

Preparation of 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine (Compound 7)

SCHEME 3

Step 1. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(G3-thiazol-4-yl)acetohydrazide

In a solution of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (400 mg, 1.3 mmol), 2-(1,3-thiazol-4-yl)acetic acid (384 mg, 2.7 mmol), TEA (543 mg, 5.4 mmol) in DMSO (10 ml) was added HATU (1.27 g, 3.4 mmol). Stirred at 25°C for 4 hours. The resulting mixture was poured into 100 ml of water and filtered. The solid was dried in vacuo to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-4-yl)acetohydrazide (326 mg, 57.4%) as a light brown solid. LC-MS: m/z (PER), [M+H] ⁺ =425.1.

Step 2. 8-Bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine

A mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-4-yl)acetohydrazide (326 mg, 0.8 mmol) and trimethylsilyl-N-(trimethylsilyl)ethanimidate (4 ml) was stirred at 120°C for 16 hours. The resulting solution was quenched with 15 ml of water. Extracted with EtOAc (3x15 ml). The organic layer was dried over Na2S04, filtered and concentrated to dryness. The residual solid was washed with EtOAc/MeOH (5/1, 10 ml) and filtered. The solid was dried in vacuo to give 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c ]pyrimidin-5-amine (164 mg, 52.5%) as a brown solid. LC-MS: m/z (PER), [M+H] ⁺ =405.4. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.40 (s, 2H), 7.33 (dd, 2H), 7.56 (d, 1H), 7.66-7.79 (m, 2H), 8.15 (s, 2H), 9.05 (d, 1H).

Step 3. 7-(4-Fluorophenyl)-8-(2-methylpyridin-4-yl)-2-[(1,3-thiazol-4-yl)methyl1-[1,2,4]triazolo[1, 5-c]pyrimidine-5-amine

Mixture of 8-bromo-7-(4-fluorophenyl)-2-[(pyrazin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (144 mg, 0.4 mmol), (2-methylpyridin-4-yl)boronic acid (11O mg, 0.8 mmol), Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (66 mg, 0.1 mmol) and K ₃ PO ₄ (258 mg, 1.2 mmol) in dioxane (20 ml) and water (5 ml) was stirred at 100°C for 16 hours. Concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1), to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 19×250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 30% B to 55% B in 7 minutes; 220/254 nm; Rt: 6.42 min, giving 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 7) (44.5 mg, 26%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =418.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.38 (s, 3H), 4.37 (s, 2H), 7.01 (dd, 1H), 7.08-7.22 (m, 3H), 7.31-7.42 (m, 2H ), 7.51 (dd, 1H), 8.16 (s, 2H), 8.33 (d, 1H), 9.03 (d, 1H).

Example 8

Preparation of 2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine (Compound 8)

SCHEME 4

Step 1. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(3-chlorophenyl)acetohydrazide

In a solution of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (400 mg, 1.3 mmol), 2-(3-chlorophenyl)acetic acid (458 mg, 2.7 mmol) and TEA (543 mg, 5.4 mmol) in DMSO (10 mL) was added with HATU (1.3 g, 3.4 mmol). The mixture was stirred at 25°C for 4 hours, then poured into 100 ml of water and filtered. The solid was dried in vacuo to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(3-chlorophenyl)acetohydrazide (560 mg, 92%) as sulfur -green solid. LC-MS: m/z (ESI), [M+H] ⁺ =452.1.

Step 2. 8-Bromo-2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

A mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(3-chlorophenyl)-acetohydrazide (663 mg) and trimethylsilyl-N-(trimethylsilyl)ethanimidate (4 ml) was stirred at 120°C for 16 hours. The resulting solution was quenched with 15 ml of water. Extracted with EtOAc (3×15 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residual solid was washed with EtOAc/MeOH (5/1, 12 ml) and filtered. The solid was dried in vacuo to give 8-bromo-2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (305 mg, 48%) as a dark gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =434.1.

Step 3. 2-[(3-Chlorophenyl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine

Mixture of 8-bromo-2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (150 mg, 0. 35 mmol), (2-methylpyridin-4-yl)boronic acid (95 mg, 0.7 mmol), Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (57 mg, 0.1 mmol) and K ₃ PO ₄ (220.8 mg, 1.0 mmol) in dioxane (20 ml) and water (5 ml) was stirred at 100°C for 16 hours. Concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (30:1), to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 40% B to 60% B in 7 minutes; 254/220 nm; Rt: 5.83 min, yielding 2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine (Compound 8) (6.8 mg, 4.4%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =445.2. ^1H NMR (300 MHz, DMSO- _d6 ) δ 2.39 (s, 3H), 4.23 (s, 2H), 7.00 (dd, 1H), 7.08-7.21 (m, 3H), 7.24-7.46 (m, 6H ), 8.16 (s, 2H), 8.33 (d, 1H).

Example 11

Preparation of 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5- amine (Compound 11)

SCHEME 5

Step 1. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(G3-thiazol-2-yl)acetohydrazide

In a solution of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (400 mg, 1.3 mmol), 2-(1,3-thiazol-2-yl)acetic acid (384 mg, 2.7 mmol) and TEA (543 mg, 5.4 mmol) in DMSO (10 ml) was added HATU (1.3 g, 3.4 mmol). Stirred at 25°C for 4 hours. The resulting mixture was poured into 100 ml of water and filtered. The solid was dried in vacuo to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-2-yl)acetohydrazide (336 mg, 59%) as a dark gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =423.4. ^1H NMR (300 MHz, DMSO- _d6 ) δ 4.05 (s, 2H), 6.42 (s, 2H), 7.28 (t, 2H), 7.54-7.70 (m, 3H), 7.75 (d, 1H), 8.75 (s, 1H), 10.22 (s, 1H).

Step 2. 8-Bromo-7-(4-fluorophenyl)-2-[(1.3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

A mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-2-yl)acetohydrazide (336 mg) and trimethylsilyl-N-( trimethylsilyl)ethanimidate (4 ml) was stirred at 120°C for 16 hours. The resulting solution was quenched with 15 ml of water. Extracted with EtOAc (3×15 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The residual solid was washed with EtOAc/MeOH (5/1, 12 ml) and filtered. The solid was dried in vacuo to give 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c ]pyrimidin-5-amine (126 mg, 39%) as a light brown solid. LC-MS: m/z (ESI), [M+H] ⁺ =405.4. ^1H NMR (300 MHz, DMSO) δ 4.65 (s, 2H), 7.26-7.40 (m, 2H), 7.63-7.80 (m, 4H), 8.18 (s, 2H).

Step 3. 7-(4-Fluorophenyl)-8-(2-methylpyridin-4-yl)-2-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine (Compound 11)

Mixture of 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (126 mg, 0.31 mmol), (2-methylpyridin-4-yl)boronic acid (85.2 mg, 0.62 mmol), Pd(dppf)Cl ₂ ⋅CH2Cl ₂ (50.8 mg, 0. 06 mmol) and K ₃ PO ₄ (198.0 mg, 0.93 mmol) in dioxane (20 ml) and water (5 ml) were stirred at 100°C for 16 hours. Concentrated to dryness. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1), to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 35% B in 7 minutes; 254/220 nm; Rt: 5.77 min, giving 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine (Compound 11) (25.7 mg, 15%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =418.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.39 (s, 4H), 4.62 (s, 2H), 6.97-7.05 (m, 1H), 7.09-7.22 (m, 3H), 7.32-7.44 (m , 2H), 7.62-7.78 (m, 2H), 8.22 (s, 2H), 8.33 (dd, 1H).

Example 12

Preparation of 2-[1-(2,6-difluorophenyl)ethyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine (Compound 12)

SCHEME 6

Step 1. 4-Chloro-6-(4-fluorophenyl)-5-iodopyrimidin-2-amine

To a stirred mixture of 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine (2 g, 8.94 mmol, 1 equiv) in AcOH (30 ml) was added NIS (4.0 g, 17.89 mmol , 2 equiv.) in portions at room temperature. The resulting mixture was stirred for 2 days at room temperature. The reaction was monitored by LC-MS. The resulting mixture was diluted with water (100 ml). The precipitated solid was collected by filtration, washed with water (2×50 ml) and dried under vacuum. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (97:3) to give 4-chloro-6-(4-fluorophenyl)-5-iodopyrimidin-2-amine (2 g, 64.0% ) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =350.0. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 7.24-7.36 (m, 4H), 7.51-7.73 (m, 2H).

Step 2. 4-Chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine Into a stirred mixture of 4-chloro-6-(4-fluorophenyl)-5-iodopyrimidin- 2-amine (900 mg, 2.57 mmol, 1 equiv.), (2-methylpyridin-4-yl)boronic acid (705.3 mg, 5.2 mmol, 2.0 equiv.) and Cs ₂ CO ₃ (2516.8 mg, 7.7 mmol, 3 equiv.) in 1,4-dioxane (30 ml) and H ₂ O (5 ml) was added Pd(dppf)Cl ₂ (188.4 mg, 0.26 mmol , 0.1 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 45°C under nitrogen atmosphere overnight. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (97:3) to give 4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2- amine (800 mg, 98.71%) as a brown-yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =315.2.

Step 3. 4-(4-Fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine

Mixture of 4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (460 mg, 1.5 mmol), NH ₂ NH ₂ H ₂ O (219 mg, 4.4 mmol) in EtOH (20 ml) was stirred at 80°C for 3 hours. Concentrated to dryness. The residue was diluted with EtOAc/MeOH (5/1, 12 ml) and filtered. The solid was dried in vacuo to give 4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (420 mg, 92%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =311.2.

Step 4. N-[2-Amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)propanhydrazide

In a solution of 4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (140 mg, 0.45 mmol), 2-(2,6-difluorophenyl)propane acid (168 mg, 0.9 mmol) and TEA (183 mg, 1.8 mmol) in DMSO (6 ml) was added HATU (429 mg, 1.1 mmol). Stir at 25°C for 1 hour. Quenched with water (30 ml) and sat. NaHCO ₃ (30 ml) and filtered. The solid was dried in vacuo to give N-[2-amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)- propanhydrazide (160 mg, 74.12%) as a dark yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =479.3.

Step 5. 2-[1-(2,6-Difluorophenyl)ethyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-G1.2,41 triazolo[1,5-c ]pyrimidine-5-amine (Compound 12)

Mixture of N-[2-amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)propanhydrazide (90 mg, 0. 18 mmol) and trimethylsilyl-N-(trimethylsilyl)ethanimidate (3 ml) were stirred at 120°C for 16 hours. Extinguished with 15 ml of water. Extracted with DCM (3×15 ml). The organic layer was dried over Na2S04, filtered and concentrated to dryness. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 30/1) to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 40% B to 60% B in 7 minutes; 254/220 nm; Rt: 6.27 min, giving 2-[1-(2,6-difluorophenyl)ethyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine (Compound 12) (21.1 mg, 24%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =461.2. ¹ H NMR (300 MHz, DMSO-dδ) δ 1.77 (d, 3H), 2.34 (s, 3H), 4.71 (d, 1H), 6.95-7.20 (m, 6H), 7.35 (ddt, 3H), 8.06 (s, 2H), 8.30 (d, 1H).

Example 13

Preparation of 2-[(2,6-difluorophenyl)methyl]-8-(2,5-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine (Compound 13)

SCHEME 7

Step 1.2.5 - Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Solution/mixture of 4-bromo-2,5-dimethylpyridine (530 mg, 2.8 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1085.1 mg, 4.2 mmol, 1.5 equiv.), AcOK (838.7 mg, 8.5 mmol, 3 equiv.) and Pd(dppf)Cl ₂ (208.4 mg, 0.3 mmol, 0.1 equiv.) in dioxane (10 ml) were stirred for 1 min at 90°C under nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) to obtain 2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine ( 389 mg, 46.9%) as a white semi-solid. LC-MS: m/z (ESI), [M+H] ⁺ =234.3.

Step 2. 2-[(2,6-Difluorophenyl)methyl]-8-(2,5-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine (Compound 13)

In a solution of 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (100 mg , 0.23 mmol, 1 equiv.) and 2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (80.5 mg, 0 .35 mmol, 1.50 equiv.) in dioxane (9 ml) and water (1 ml), K ₃ PO ₄ (146.7 mg, 0.69 mmol, 3 equiv.) and Pd(dppf)Cl ₂ ( 16.9 mg, 0.02 mmol, 0.1 equiv.). After stirring for 2 minutes at 90°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions to give 2-[(2,6-difluorophenyl)methyl]-8-(2,5-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[ 1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 13) (5.8 mg, 5.4%) as a light yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =461.2. ¹ H NMR: (400 MHz, Methanol-d ₄ ) δ 2.1 (s, 3H), 2.7 (s, 3H), 4.3 (s, 2H), 6.9-7.1 (m, 3H), 7.3 (ddd, J= 15.0, 8.4, 6.5 Hz, 1H), 7.4-7.4 (m, 2H), 7.7 (s, 1H), 8.5 (s, 1H).

The compound shown in the table below was prepared using the methods described in Example 13.

Example 15

Preparation of 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine (Compound 15)

SCHEME 8

Step 1. N-[2-Amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(6-chloropyridin-2-yl)acetohydrazide

In a solution of 4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (530 mg, 1.7 mmol), 2-(6-chloropyridin-2-yl )acetic acid (586 mg, 3.4 mmol) and TEA (691 mg, 6.8 mmol) in DMSO (4 ml) was added HATU (1.6 g, 4.3 mmol). The mixture was stirred at 25°C for 2 hours. Extinguished with 100 ml of water. Added 20 ml sat. NaHCO ₃ then filtered. The solid was dried in vacuo to give N-[2-amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(6-chloropyridin-2-yl) )acetohydrazide (600 mg, 75%) as a brown solid. LC-MS: m/z (ESI), [M+H] ⁺ =464.2.

Step 2. 2-[(6-Chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine (Compound 15)

Mixture of N-[2-amino-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-4-yl]-2-(6-chloropyridin-2-yl)acetohydrazide (600 mg, 1.3 mmol) and trimethylsilyl-N-(trimethylsilyl)ethanimidate (4 ml) were stirred at 120°C for 16 hours. The resulting mixture was quenched with 15 ml of water. Extracted with DCM (3×15 ml). The organic layer was separated and dried over Na2S04, filtered and concentrated to dryness. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH=30/1) to give 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4- yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (330 mg) as a light brown solid. 50 mg of this crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 35% B to 40% B in 7 minutes; 254/220 nm; Rt: 6.57 min, giving 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine (Compound 15) (20 mg) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =446.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (s, 3H), 4.35 (s, 2H), 7.00 (dd, 1H), 7.08-7.20 (m, 3H), 7.29-7.43 (m, 4H ), 7.81 (t, 1H), 8.17 (s, 2H), 8.32 (d, 1H).

Example 17

Preparation of 2-((6-(dimethylamino)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1, 5-f]pyrimidine-5-amine (Compound 17)

DIAGRAM 9

Step 1. 2-((6-(Dimethylamino)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,41 triazolo[1 ,5-f]pyrimidine-5-amine (Compound 17)

Into a solution of 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5- c]pyrimidin-5-amine (Comp. 15, 80 mg, 0.18 mmol, 1 equiv.) in DMF (2 ml) was added dimethylamine (1 ml, 2.00 mmol, 11.15 equiv.) in THF ( 1 ml). The final reaction mixture was heated under microwave radiation for 90 min at 190°C. The resulting solution was diluted with 15 ml of EA. The resulting mixture was washed with 3×10 ml of water and 2×10 ml of saturated brine. The organic layer was dried over anhydrous sodium sulfate. The crude product (20 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 19×250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min. This resulted in 10 mg (12.26%) 6-[[5-amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-2-yl]methyl]-N,N-dimethylpyridin-2-amine in the form of a solid. LC-MS: m/z (ESI), [M+H] ⁺ =455.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (3H, s), 2.98 (6H, s), 4.15 (2H, s), 6.45 (2H, d), 7.00 (1H, d), 7.08- 7.22 (3H, m), 7.31-7.46 (3H, m), 8.16 (2H, s), 8.32 (1H, d).

Example 19

Preparation of 6-((5-amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-2-yl) methyl)picolinonitrile (Compound 19)

SCHEME 10

Step 1. 6-((5-Amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-2- yl)methyl)picolinonitrile (Compound 19)

A solution of 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo was placed in an 8 ml vessel [1,5-c]pyrimidin-5-amine (40 mg, 0.09 mmol, 1 equiv.) in THF/H ₂ O (6/2 ml), zinc dicarbonitrile (8.4 mg, 0.07 mmol , 0.80 equiv.), tBuXPhos Pd G3 (14.3 mg, 0.02 mmol, 0.20 equiv.), tBuXphos (18.6 mg, 0.03 mmol, 0.30 equiv.). The resulting solution was stirred for 12 hours at 70°C. The resulting mixture was concentrated under vacuum. The mixture was purified by TLC (DCM:MeOH=20:1) to give a yellow solid (50 mg). The residue was purified by preparative HPLC, column: XBridge Prep OBD C18 19×250 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 40% B to 50% B in 7 minutes; 254, 220 nm; RT: 6.85 min. Fractions containing the product were evaporated to give 6-[[5-amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c ]pyrimidin-2-yl]methyl]pyridin-2-carbonitrile (15 mg, 38.31%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =437.0. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 2.47 (3H, s), 4.48 (2H, s), 6.98-7.06 (2H, m), 7.07-7.11 (1H, m), 7.27-7.32 ( 1H, m), 7.39-7.45 (2H, m), 7.74 (2H, ddd), 7.94 (1H, t), 8.29 (1H, dd).

Example 20

Preparation of 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 20)

SCHEME 11

Step 1: 1,3-Dimethyl 2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate DMSO (20 mL), 3 -(difluoromethoxy)-2-fluoropyridine (1.1 g, 6.7 mmol, 1 equiv.), 1,3-dimethylpropanedioate (1.1 g, 8.1 mmol, 1.2 equiv.), Cs ₂ CO ₃ (6.6 g, 20.2 mmol, 3 equiv.). The resulting solution was stirred for 16 hours at 100°C in an oil bath. The reaction mixture was then quenched by adding 50 ml of water. The resulting solution was extracted with 2×100 ml ethyl acetate and the organic layers were combined. The resulting solution was washed with 3×100 ml brine, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). This gave 1 g (51.7%) 1,3-dimethyl-2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =276.0. ^1H NMR: (400 MHz, DMSO- _d6 ) δ 3.71 (6H, s), 5.21 (1H, s), 7.29 (1H, t), 7.52 (1H, dd), 7.72 (1H, dq), 8.41 (1H, dd).

Step 2. Methyl 2-[3-(difluoromethoxy)pyridin-2-yl] acetate

DMSO (20 mL), 1,3-dimethyl-2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate (950 mg, 3.45 mmol, 1 equiv.), LiCl (365.9 mg, 8.6 mmol, 2.5 equiv.), H ₂ O (62.2 mg, 3.5 mmol, 1 equiv.). The resulting solution was stirred for 5 hours at 120°C in an oil bath. The reaction mixture was then quenched by adding 50 ml of water. The resulting solution was extracted with 3×50 ml ethyl acetate and the organic layers were combined. The resulting solution was washed with 3×50 ml brine, and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was purified on a silica gel column using ethyl acetate/petroleum ether (1:2). This resulted in 480 mg (61.5%) methyl 2-[3-(difluoromethoxy)pyridin-2-yl]acetate as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =218.0. ^1H NMR: (400 MHz, DMSO-d ₆ ) δ 3.63 (3H, s), 3.89 (2H, s), 7.06-7.43 (1H, m), 7.44 (1H, dd), 7.67 (1H, dq) , 8.39 (1H, dd).

Step 3: Sodium 2-[3-(Difluoromethoxy)pyridin-2-yl]acetate EtOH (20 mL), methyl 2-[3 -(difluoromethoxy)pyridin-2-yl]acetate (210 mg, 1.0 mmol, 1 equiv.), NaOH (58.0 mg, 1.5 mmol, 1.5 equiv.). The resulting solution was stirred for 2 hours at 50°C. The mixture solution was filtered, and the filter cake was dried under vacuum. This resulted in 160 mg (72.0%) sodium 2-[3-(difluoromethoxy)pyridin-2-yl]acetate as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =204.0. ¹ H NMR: (400 MHz, D ₂ O) δ 3.67 (2H, s), 6.71 (1H, t), 7.30 (1H, dd), 7.59 (1H, d), 8.21 (1H, dd).

Step 4. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-[3-(difluoromethoxy)pyridin-2-yl]acetohydrazide

DMF (20 mL), EtOAc (20 mL), 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine were placed in a 50 mL round bottom flask, purged with nitrogen and maintained under an inert nitrogen atmosphere. (251.6 mg, 0.8 mmol, 1.0 equiv.), Sodium 2-[3-(difluoromethoxy)pyridin-2-yl] acetate (190 mg, 0.8 mmol, 1 equiv.), TZR ( 537.1 mg, 1.7 mmol, 2 equiv.) and Et ₃ N (170.8 mg, 1.7 mmol, 2 equiv.). The resulting solution was stirred for 16 hours at 15°C. The solvent was removed under vacuum and water (20 ml) was added. The mixture was filtered and the filter cake was combined. This resulted in 186 mg (44.2%) N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-[3-(difluoromethoxy)pyridin-2-yl ]acetohydrazide as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =485.1. ^1H NMR: (400 MHz, DMSO-d ₆ ) δ 3.83 (1H, s), 6.44 (1H, s), 7.22-7.53 (2H, m), 7.51-7.74 (2H, m), 8.41 (1H, d), 8.68 (1H, s), 10.10 (1H, s).

Step 5. 8-bromo-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine

Toluene (20 mL, 187.9 mmol, 516.1 equiv.), N-[2-amino-5-bromo- 6-(4-fluorophenyl)pyrimidin-4-yl]-2-[3-(difluoromethoxy)-pyridin-2-yl]acetohydrazide (176 mg, 0.4 mmol, 1 equiv.) and (7)-(trimethylsilyl -N-(trimethylsilyl)ethanimidate) (222.3 mg, 1.1 mmol, 3 equiv.). The resulting solution was stirred for 16 hours at 110°C in an oil bath. The solvent was removed and the residue was purified by recrystallization using DCM:PE (1:1) to give 150 mg (92% purity) 8-bromo-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]- 7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine as a brown solid. LC-MS: m/z (ESI), [M+H] ⁺ =465.0. ^1H NMR: (400 MHz, DMSO- _d6 ) δ 4.42 (1H, s), 6.70 (3H, s), 7.33 (5H,t), 7.73 (2H, d), 8.13 (1H, s), 8.38 (1H, d).

Step 6. 5-(5-Amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c ]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 20)

Dioxane (12 ml), H ₂ O (2 ml), 8-bromo-2-[[3-(difluoromethoxy)pyridine were placed in another 20 ml round flask, which was purged with nitrogen and maintained under an inert atmosphere of nitrogen. -2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (140 mg, 0.3 mmol, 1 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (141.5 mg, 0.60 mmol, 2.00 equiv.), Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (24.6 mg, 0.03 mmol, 0.1 equiv.) and K ₃ PO ₄ (191.6 mg, 0.9 mmol , 3 equiv.). The resulting solution was stirred for 6 hours at 80°C. The resulting solution was extracted with 3×50 ml of dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. The residue was dissolved in 5 ml DCM. The crude product was purified by preparative TLC (DCM:MeOH, 12:1) and preparative HPLC under the following conditions: column: XBridge Prep Phenyl OBD 5 µm, 19 x 250 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 32% B to 45% B in 7 minutes; 254, 220 nm; Rt: 6.93 min. This resulted in 12 mg (7.9%) 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2, 4]triazolo[1,5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 20) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =494.2. ^1H NMR: (400 MHz, MeOD) δ 3.56 (3H, s), 4.50 (2H, s), 6.42 (1H, d), 6.97 (3H, s), 7.09 (2H, m), 7.19 (1H, m), 7.42 (1H, dd), 7.55 (2H, m), 7.70 (1H, m), 7.78 (1H, d), 8.35 (1H, dd).

The compound shown in the table below was prepared using the methods described in Example 20.

Example 21

Preparation of 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one (Compound 21)

SCHEME 12

Step 1. 4.6-Dichloro-5-iodopyrimidin-2-amine

To a stirred mixture of 4,6-dichloropyrimidin-2-amine (40 g, 243.9 mmol) in AcOH (300 ml) was added ICl (79.2 g, 487.8 mmol) in AcOH (100 ml) dropwise at room temperature. temperature in a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with a water/ice mixture at room temperature. The resulting mixture was filtered, the filter cake was washed with ethanol (3×200 ml). The filtrate was concentrated under reduced pressure to give 4,6-dichloro-5-iodopyrimidin-2-amine (50 g, 70.7%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =290.0.

Step 2. 4-Chloro-6-hydrazinyl-5-iodopyrimidin-2-amine

To a stirred mixture of 4,6-dichloro-5-iodopyrimidin-2-amine (10 g, 34.5 mmol) in EtOH (80 ml) was added hydrazine (3.3 mg, 0.1 mmol) dropwise at room temperature in nitrogen atmosphere. The resulting mixture was stirred for 5 hours at 80°C under a nitrogen atmosphere. The mixture was left to cool to room temperature. The precipitated solid was collected by filtration and washed with EtOH (3 x 50 mL) to give 4-chloro-6-hydrazinyl-5-iodopyrimidin-2-amine (8 g, 81.2%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =286.0.

Step 3. N'-(2-Amino-6-chloro-5-iodopyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)-acetohydrazide

Into a stirred mixture of 4-chloro-6-hydrazinyl-5-iodopyrimidin-2-amine (10 g, 35 mmol) and 2-(3-fluoropyridin-2-yl)acetic acid (6.5 g, 42 mmol) in DMF (100 ml) DIEA (13.6 g, 105.1 mmol) and HATU (20 g, 52.6 mmol) were added in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction mixture was quenched by adding water (500 ml) at room temperature. The precipitated solid was collected by filtration and washed with MeOH (50 ml) and EtOAc (3 x 50 ml) to give N-(2-amino-6-chloro-5-iodopyrimidin-4-yl)-2-(3-fluoropyridine -2-yl)acetohydrazide (7 g, 47.3%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =423.1.

Step 4. 7-Chloro-2-((3-fluoropyridin-2-yl)methyl)-8-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

To a stirred mixture of N-(2-amino-6-chloro-5-iodopyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide (10 g, 0.02 mol) in (7)-( trimethylsilyl-N-(trimethylsilyl)ethanimidate) (40 ml) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The mixture was left to cool to room temperature. The reaction mixture was quenched with a water/ice mixture at room temperature. The precipitated solid was collected by filtration and washed with ethanol (2 x 20 ml) and EA (3 x 50 ml) to give 7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-iodo-[ 1,2,4]triazolo[1,5-c]pyrimidin-5-amine (6 g, 62.7%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =405.0.

Step 5. 5-(5-Amino-7-chloro-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c1pyrimidin-8-yl)-1 -methylpyridin-2(1H)-one

To a stirred mixture of 7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (1 g, 2.5 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (871.6 mg , 3.7 mmol) in 1,4-dioxaene (10 ml) and H ₂ O (2 ml), K ₃ PO ₄ (1.6 g, 7.4 mmol) and Pd(amphos)Cl ₂ (350 mg) were added , 0.5 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl/MeOH 10:1) to give 5-[5-amino-7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo [1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (500 mg, 52.4%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =386.2.

Step 6. 5-[5-Amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 21)

To a stirred solution of 1,3-oxazole (200 mg, 2.9 mmol, 4.0 eq.) in THF (3.0 mL) was added n-butyllithium (1.3 mL, 3.2 mmol, 4.4 eq. .) dropwise at -78°C under nitrogen, stirred for 30 min, add ZnCh (l M in THF, 5.8 ml, 5.8 mmol, 8.0 eq.) dropwise at -78°C , stirred for 1 hour at -30°C, warmed to room temperature, added 5-[5-amino-7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4 ]triazolo[1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (100 mg, 0.73 mmol, 1 eq.) and Pd(PPd ₃ ) ₄ ( 60 mg, 1.4 mmol, 0.2 eq.), degassed under nitrogen, heated for 15 hours at 80°C. The mixture was left to cool to room temperature. The residue was purified by preparative TLC (DCM/MeOH=30/1) and washed with ethanol to give 5-[5-amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1,3-oxazol-2 -yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 21) (30 mg, 27, 7%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =419.2. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 3.41 (s, 3H), 4.43 (s, 2H), 6.36 (d, J=9.6 Hz, 1H) 7.29-7.26 (m, 1H), 7.42-7.34 (m, 2H), 7.75-7.70 (m, 2H), 8.20-8.16(brs, 2H), 8.21 (s, 1H), 8.33 (d, J=4.8 Hz, 1H).

Example 22

Preparation of 5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)- 1-methylpyridin-2(1H)-one (Compound 22)

DIAGRAM 13

Step 1. 5-Bromo-4.6-dichloropyrimidine-2-amine

To a stirred mixture of 4,6-dichloropyrimidin-2-amine (2.46 g, 1 equiv.) and NaOAc (6.15 g) in AcOH (150 ml), Br ₂ (3.24 g) was added dropwise at room temperature in a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LC-MS. The resulting mixture was concentrated under reduced pressure. The crude product was precipitated by adding water (300 ml) and stirred for 1 hour. The precipitated solid was collected by filtration and washed with MTBE (2×50 ml). The resulting solid was dried under vacuum to give 5-bromo-4,6-dichloropyrimidin-2-amine (3.4 g, 93.32%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =242.0. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 7.69 (s, 2H).

Step 2. 5-Bromo-4-chloro-6-hydrazinylpyrimidin-2-amine

A mixture of 5-bromo-4,6-dichloropyrimidin-2-amine (1.9 g, 7.82 mmol, 1 equiv.), NH ₂ NH ₂ ⋅H ₂ O (1.2 g, 23.97 mmol, 3 .06 equiv.) in EtOH (30 ml) was stirred at 80°C for 2 hours. Concentrated to dryness. The residue was diluted with MTBE (50 ml) and filtered. The solid was dried in vacuo to give 5-bromo-4-chloro-6-hydrazinylpyrimidin-2-amine (1.9 g, 93.71%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =238.1.

Step 3. N'-(2-Amino-5-bromo-6-chloropyrimidin-4-yl)-2-(2.6-difluorophenyl)-acetohydrazide

In a mixture of 5-bromo-4-chloro-6-hydrazinylpyrimidin-2-amine (1.9 g, 8.0 mmol, 1 equiv.), 2-(2,6-difluorophenyl)acetic acid (2.7 g, 15.9 mmol, 2 equiv.), TEA (3.2 g, 31.9 mmol, 4 equiv.) in DMSO (10 ml) was added HATU (6.1 g, 15.9 mmol, 2 equiv.). Stirred at 25°C for 2 hours. Pour into 150 ml of water. 50 ml of sat. was added to the mixture. NaHCO ₃ and filtered. The solid was dried in vacuo to give H-(2-amino-5-bromo-6-chloropyrimidin-4-yl)-2-(2,6-difluorophenyl)-acetohydrazide (1.6 g, 51.2%) in as a light brown solid. LC-MS: m/z (ESI), [M+H] ⁺ =392.0

Step 4. 8-Bromo-7-chloro-2-(2,6-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

A mixture of N-(2-amino-5-bromo-6-chloropyrimidin-4-yl)-2-(2,6-difluorophenyl)-acetohydrazide (0.6 g, 1.5 mmol, 1 equiv.) and (E )-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (10 ml) was stirred at 120°C for 4 hours. The mixture was cooled to room temperature and poured into water, then filtered. The solid was dried in vacuo to give 8-bromo-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (450 mg, 78.6%) as a brown solid. LC-MS: m/z (ESI), [M+H] ⁺ =374.0

Step 5. 5-(5-Amino-7-chloro-2-(2,6-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin- 2(1H)-on

In a stirred solution of 8-bromo-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (5.0 g, 13.35 mmol, 1 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one ( 7845.3 mg, 33.37 mmol, 2.50 equiv.) in a mixture of dioxane/H ₂ O=10:1 (50.0 ml) was added K ₃ PO ₄ (639.3 mg, 26.70 mmol, 2 .0 equiv.) and PdAMPHOS (7561.4 mg, 10.68 mmol, 0.8 equiv.) in portions at 90°C under nitrogen atmosphere. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /EtOAc (3:1) to give 5-[5-amino-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1. 2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (1.5 g, 27.9%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =403.2

Step 6. 5-(5-Amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one (Compound 22)

To a stirred solution of 1,3-oxazole (100 mg, 1.5 mmol) in THF (2.0 ml) n-butyllithium (0.7 ml, 1.6 mmol) was added dropwise at -78°C under N ₂ . After stirring for 30 minutes, ZnCl ₂ (1Mb THF, 2.9 ml, 2.9 mmol) was added dropwise at -78°C. The mixture was stirred for 1 hour at -30°C. Then 5-[7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-a]pyridin-8-yl]-1- was added to it. methyl-1,2-dihydropyridin-2-one (100 mg, 0.25 mmol) and Pd(PPd ₃ ) ₄ (57.4 mg, 0.05 mmol). The mixture was stirred for 15 hours at 80°C under N ₂ atmosphere. The mixture was left to cool to room temperature and purified by preparative TLC (DCM/MeOH=30/1). The crude material was washed with ethanol and dried to give 5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c] pyrimidin-8-yl)-1-methylpyridin-2(1H)-one (Compound 22) (20 mg, 18.5%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =436.2. ¹ H NMR (400 MHz, DMSO, d ₆ ) δ 3.41 (s, 3H), 4.25 (s, 2H), 6.36 (d, J=9.2 Hz, 1H), 7.15-7-08 (m, 2H ), 7.29-7.26(m, 1H), 7.44-7.34 (m, 2H), 7.53 (d, J=2.4 Hz, 1H), 8.15-8.05 (brs, 2H), 8.20 (s, 1H).

The compounds listed in the table below were prepared using the methods described in Example 22.

Example 23

Preparation of 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1- (tetrahydrofuran-3-yl)pyridin-2(1H)-one (Compound 23)

SCHEME 14

Step 1. 5-Bromo-1-(oxolan-3-yl)-G2-dihydropyridin-2-one

K ₂ CO ₃ (4.8 g, 34.5 mmol, 3 equiv.), 3-bromoxolane (5.2 g, 34.5 mmol, 3.00 equiv.) and 5- bromo-1,2-dihydropyridin-2-one (2 g, 11.5 mmol, 1 equiv.) in DMF (3 ml) at 80°C for 6 hours. The target product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give 5-bromo-1-(oxolan-3-yl)-1,2-dihydropyridin-2-one (600 mg, 22.1 %) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =244.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 1.24 (1H, s), 1.99 (1H, m), 2.42 (1H, dtd), 3.84-3.66 (2H, m), 3.88 (1H, dd), 4.06 (1H, td), 5.31 (1H, ddt), 6.39 (1H, d), 7.53 (1H, dd), 7.70 (1H, d).

Step 2. 1-(Oxolan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one

5-bromo-1-(oxolan-3-yl)-1,2-dihydropyridin-2-one (600 mg, 2.5 mmol, 1 equiv.), 4,4,5, was added to a 30 ml sealed tube. 5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (936.3 mg, 3.7 mmol, 1, 50 equiv.), AcOK (482.5 mg, 4.92 mmol, 2 equiv.) and Pd(dppf)Cl ₂ ⋅CH ₂ Cl ₂ (200.7 mg, 0.3 mmol, 0.1 equiv.) in dioxane (2 ml) at 90°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 1-(oxolan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-dihydropyridin-2-one (500 mg, 69.9%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =292.2.

Step 3. 5-(5-Amino-2-(2.6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1- (tetrahydrofuran-3-yl)pyridin-2(1H)-one (Compound 23)

8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5 was added to a 10 ml sealed tube -amine (100 mg, 0.2 mmol, 1 equiv.), 1-(oxolan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1,2-dihydropyridin-2-one (134.1 mg, 0.5 mmol, 2.0 equiv.), K ₃ PO ₄ (122.2 mg, 0.6 mmol, 2.5 equiv.) and Pd(dppf)Cl ₂ Ch ₂ Cl ₂ (18.8 mg, 0.023 mmol, 0.1 equiv.) in dioxane (7 ml) and water (0.7 ml) at 80°C for 2 hours. The target product could be detected by LC-MS. The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19×150 mm; mobile phase A: water (10 mmol/l nh ₄ hco ₃ +0.1% nh ₃ h ₂ o), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 39% B to 39% B in 8 minutes; 254/220 nm; Rt: 7.7 min to give 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-yl)-1-(tetrahydrofuran-3-yl)pyridin-2(1H)-one (Compound 23) (30 mg, 25.0%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =519.3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.54-1.55 (1 H, m), 2.33 (1 H, dq), 3.53-3.59 (3 H, m), 3.74 (1 H, dd), 4.24 (2 Н, s), 5.35 (1 Н, td), 6.30 (1 Н, d), 7.07-7.18 (3 Н, m), 7.18-7.26 (2 Н, m), 7.34-7.45 (1 Н, m), 7.42-7.51 (3 N, m), 8.00 (2 N, s).

Example 24

Preparation of 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 24)

SCHEME 15

Step 1. 5-[5-Amino-2-[(2,6-difluorophenyl)methyl]-7-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-c] pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one

Mixture of 5-[5-amino-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-methyl -1,2-dihydropyridin-2-one (80 mg, 0.20 mmol, 1 equiv.), K ₃ PO ₄ (126.5 mg, 0.6 mmol, 3 equiv.), Pd(dppf)Cl ₂ (29.1 mg, 0.04 mmol, 0.2 equiv.) and 2-methyl-5-(3,3,4,4-tetramethylboran-1-yl)pyridine (64.1 mg, 0.3 mmol , 1.5 equiv.) in dioxane (1 ml) and water (1 ml) was stirred for 2 hours at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 19 × 250 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 45% B in 8 minutes; 254/220 nm; Rt: 7.5 min to give 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(6-methylpyridin-3-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 24) (37.7 mg, 41.3%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =460.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (s, 3H), 3.3 (d, J=15.8 Hz, 3H), 6.3 (d, J=9.4 Hz, 1H), 7.0- 7.2 (m, 3H), 7.2 (d, J=8.1 Hz, 1H), 7.3-7.5 (m, 1H), 7.6-7.7 (m, 2H), 7.9 (s, 1H), 8.5 (dd, J=2.3, 0.8 Hz, 1H).

Example 25

Preparation of 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(2H-1,2,3-triazol-2-yl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 25)

SCHEME 16

Step 1. 5-[5-Amino-2-[(2,6-difluorophenyl)methyl]-7-(2H-[2,3-triazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 25)

Into a stirred mixture of 5-[5-amino-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl]-1 -methyl-1,2-dihydropyridin-2-one (step 5, Comp. 22, 80 mg, 0.20 mmol, 1 equiv.) and 2H-1,2,3-triazole (20.6 mg, 0. 30 mmol, 1.5 equiv.) in DMSO (5 ml) was added K ₃ PO ₄ (126.5 mg, 0.60 mmol, 3 equiv.) at room temperature in an air atmosphere. The resulting mixture was stirred for 12 hours at 100°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 × 150 mm 5 μm; mobile phase A: water (0.05%NH ₃ -H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 23% B to 30% B in 7 minutes; 254/220 nm; Rt: 6.28 min, giving 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(2H-1,2,3-triazol-2-yl)-[1, 2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 25) (10 mg) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =436.2. ^1H NMR: (400 MHz, DMSO) δ 3.35 (s, 3H), 4.28 (s, 2H), 6.25 (d, 1H), 6.84 (dd, 1H), 7.13 (t, 2H), 7.41 (t, 1H), 7.63 (d, 1H), 8.03 (s, 2H).

Example 28

Preparation of 5-(5-amino-7-chloro-2-(2,6-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2( 1H)-she (Conn. 28)

DIAGRAM 17

Step 1. 5-(5-Amino-7-chloro-2-(2,6-difluorobenzyl)-[1,2.4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2( 1H)-on (Conn. 28)

The crude product (step 5, Comp. 22, 40 mg) was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 19 × 250 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 50% B in 8 minutes; 254/220 nm; Rt: 7.48 min, yielding 5-[5-amino-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 28) (25.8 mg, 64.5%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =403.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.20 (2H, s), 6.45 (1H, d), 7.11 (2H, t), 7.39 (1H, tt), 7.50 (1H, dd), 7.87 ( 1H, d), 8.28 (2H, s).

Example 30

Preparation of 6-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-8- yl)-2-methylpyridazin-3(2H)-one (Compound 30)

DIAGRAM 18

Step 1. 1-Methyl-6-oxo-1,6-dihydropyridazin-3-ylboronic acid

6-bromo-2-methyl-2,3-dihydropyridazin-3-one (100 mg, 0.53 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (161 mg, 0.63 mmol, 1.20 equiv.), Pd(dppp) Cl ₂ (31 mg, 0.1 mmol, 0.10 equiv.) in dioxane (10 ml) and KOAc (156 mg, 1.6 mmol, 3.00 equiv.). The resulting mixture was stirred for 3 hours at 80°C under a nitrogen atmosphere in an oil bath. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was applied to a silica gel column and eluted with dichloromethane/methanol (10:6). The collected fractions were combined and concentrated in vacuo to give (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (174 mg) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =155.0. ¹ H-NMR (300 MHz, MeOD-d ₄ ) δ 3.82 (3H, s), 6.81 (1H, d), 7.53 (1H, d).

Step 2. 6-(5-Amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin- 8-yl)-2-methylpyridazin-3(2H-one (Compound 30)

(1-Methyl-6-oxo-1,6-dihydropyridazin-3-yl)boronic acid (132.8 mg, 0.86 mmol, 3.00 equiv.), 8-bromo-7, was placed in a 40 mL vessel. -(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (120 mg, 0.29 mmol , 1 equiv.) in dioxane (10 ml), Pd(dppf)Cl ₂ (63.1 mg, 0.09 mmol, 0.30 equiv.) and K ₃ PO ₄ solution (183.2 mg, 0.86 mmol, 3.00 equiv.) in water (2.5 ml). The resulting mixture was stirred for 15 hours at 80°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: column, XBridge RP, 30 x 150 mm, 5 µm; mobile phase A: water (0.1% NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 16% B to 45% B in 8 minutes; 254/220 nm; Rt: 6.12 min. The resulting product was concentrated in vacuo to give 6-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5- c]pyrimidin-8-yl]-2-methyl-2,3-dihydropyridazin-3-one (Compound 30) (5 mg, 3.89%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =447.2. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 3.70 (3H, s), 4.51 (2H, d), 6.88 (1H, d), 7.06-7.15 (2H, m), 7.34 (1H, d) , 7.41 (1H, dt), 7.46-7.56 (2H, m), 7.65 (1H, ddd), 8.32 (1H, dt).

Example 31

Preparation of 2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine (Compound 31)

DIAGRAM 19

Step 1. 4-Methoxy-6-(1,3-oxazol-2-yl)pyrimidin-2-amine

To a stirred solution of 1,3-oxazole (17 g, 248 mmol, 2 equiv.) in THF (150 ml) was added n-butyllithium (2.5 M in hexane) (110 ml, 272.8 mmol, 2.2 equiv. .) dropwise at -78°C under nitrogen, stirred for 30 min, add ZnCl ₂ (1M in THF, 496 ml, 496 mmol, 4.0 equiv.) dropwise at -78°C, stir for 1 hour at -30°C, warmed to room temperature, added 4-chloro-6-methoxy-1,6-dihydropyrimidin-2-amine (20 g, 124 mmol, 1 equiv.) and Pd(PPh ₃ ) ₄ ( 7.2 g, 6.2 mmol, 0.05 equiv.), degassed under nitrogen, heated overnight at 80°C. The mixture was left to cool to room temperature. The reaction mixture was quenched with a water/ice mixture at room temperature. The mixture/residue was basified to pH=11 with NH ₃ ⋅H ₂ O. The aqueous layer was extracted with EtOAc (3 x 500 ml) and dried. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (0-1/20), to give 4-methoxy-6-(1,3-oxazol-2-yl)pyrimidin-2-amine (21 g ) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.87 (s, 3H), 6.59 (s, 1H), 6.93 (s, 2H), 7.44 (d, J=0.7 Hz, 1H), 8.27 ( d, J=0.8 Hz, 1H).

Step 2. 5-Bromo-4-methoxy-6-(oxazol-2-yl)pyrimidin-2-amine

To a stirred mixture of 6-methoxy-4-(1,3-oxazol-2-yl)-1,6-dihydropyrimidin-2-amine (5.6 g, 28.84 mmol, 1 equiv.) in DCM (200 ml ) NBS (7.7 g, 43.26 mmol, 1.5 equiv.) was added in portions at room temperature, stirred for 5 hours. The reaction mixture was quenched by adding aq. Na ₂ SO ₃ (sat.) at room temperature. The aqueous layer was extracted with CH ₂ Cl ₂ (3 x 50 ml), dried and concentrated under reduced pressure. The residue was washed with EA/MTBE to give 5-bromo-6-methoxy-4-(1,3-oxazol-2-yl)-1,6-dihydropyrimidin-2-amine (5.6 g, 71.11%) in as a light yellow solid. ¹ H NMR: 400 MHz, DMSO-d ₆ ) δ 3.94 (s, 3H), 7.08 (s, 2H), 7.49 (d, J=0.7 Hz, 1H), 8.31 (d, J=0.7 Hz, 1H).

Step 3. 5-Bromo-4-hydrazinyl-6-(oxazol-2-yl)pyrimidin-2-amine

To a stirred mixture of 5-bromo-4-methoxy-6-(oxazol-2-yl)pyrimidin-2-amine (7 g, 26 mmol, 1 equiv.) in n-BuOH (70 ml) was added NH ₂ NH ₂ H ₂ O (32 ml, 648 mmol, 25 equiv.) at room temperature, then the mixture was stirred at reflux for 10 minutes. The mixture was immediately filtered. The aqueous layer was concentrated under reduced pressure. The residue was washed with DCM/MeOH/MTBE to obtain (8 g) as a light yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =271.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.47 (s, 3H), 6.58 (s, 3H), 7.44 (d, J=0.8 Hz, 1H), 8.26 (d, J=0.8 Hz, 2H).

Step 4. N'-(2-Amino-5-bromo-6-(oxazol-2-yl)pyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide

Into a stirred solution of 5-bromo-6-hydrazinyl-4-(1,3-oxazol-2-yl)-1,6-dihydropyrimidin-2-amine (2.5 g, 9.2 mmol, 1 equiv.) and 2-(3-fluoropyridin-2-yl)acetic acid (2840.2 mg, 18.3 mmol, 2.0 equiv.) in DMSO (50 ml) was added HATU (6961.5 mg, 18.3 mmol, 2 .0 equiv.) and DIEA (3549.4 mg, 27.5 mmol, 3.0 equiv.) in portions at room temperature, stirred for 1 hour. The residue was purified by reverse phase flash chromatography under the following conditions: C18 silica gel column; mobile phase CH ₃ CN in water; gradient from 0% to 25% in 90 minutes; UV detector 220 nm/254 nm, and concentrated to give N'-(2-amino-5-bromo-6-(oxazol-2-yl)pyrimidin-4-yl)-2-(3-fluoropyridin-2-yl) )acetohydrazide (2.5 g, 66.6%) as a white solid. ¹ H NMR: (300 MHz, DMSO-d ₆ ) δ 3.81 (s, 1H), 6.63 (s, 2H), 7.38 (dt, J=8.6, 4.5 Hz, 1H), 7.45 (d, J= 5.4 Hz, 1H), 7.68 (t, J=9.1 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H), 8.35 (d, J=4.7 Hz, 1H), 8.91 (s, 1H), 10.13 (s, 1H).

Step 5. 8-Bromo-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine

N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(3-fluoropyridin-2-yl)acetohydrazide ( 2.5 g, 6.1 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (10 ml) at room temperature, heated for 1 hour at 120°C, slowly poured into methanol (35 ml), filtered and dried to give 8-bromo-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine (1.7 g, 71.1%) as an off-white solid. ^1H NMR: (300 MHz, DMSO-d ₆ ) δ 4.44 (d, J=2.1 Hz, 2H), 7.41 (dt, J=8.6, 4.4 Hz, 1H), 7.51 (d, J= 0.8 Hz, 1H), 7.73 (ddd, J=9.9, 8.3, 1.4 Hz, 1H), 8.27 (s, 2H), 8.30-8.38 (m, 2H).

Step 6. 2-((3-Fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 31)

Into a stirred solution of 8-bromo-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine (50.0 mg, 0.4 mmol, 2.0 equiv.) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2 -a]pyridine (62.7 mg, 0.4 mmol, 2.0 equiv.) in a mixture of dioxane/H ₂ O (5.5 ml) was added Pd(dppf)Cl ₂ (28.1 mg, 0.038 mmol, 0.2 equiv.) and K ₃ PO ₄ (122.1 mg, 0.6 mmol, 3.0 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1, 2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-ethyl-1,2-dihydropyridin-2-one (50.0 mg, 22.7%) as a dark brown solid . The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 25% B to 40% B in 7 minutes; 254, 220 nm; Rt: 6.35 min to give 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7-(1,3-oxazole -2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 31) (8.9 mg) as a white solid. LC-MS: m/z (PER), [M+H] ⁺ =428.2. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 4.42 (2H, d), 7.05 (1H, dd), 7.26 (1H, d), 7.38 (1H, dt), 7.52-7.77 (3H, m), 7.95 (1H, s), 8.11-8.41 (4H, m), 8.54-8.64 (1H, m).

The compounds listed in the table below were prepared using the methods described in Example 31.

Example 33

Preparation of 2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine (Compound 33)

SCHEME 20

Step 1. Preparation of N'-(2-amino-5-bromo-6-(oxazol-2-yl)pyrimidin-4-yl)-2-(3-fluoropyridin-2-yl)acetohydrazide

In a solution of 5-bromo-4-hydrazinyl-6-(1,3-oxazol-2-yl)pyrimidin-2-amine (4 g, 14.756 mmol, 1 equiv.), 2-(2,6-difluorophenyl)acetic acid acid (3.81 g, 22.134 mmol, 1.5 equiv.), DIE A (4.77 g, 36.890 mmol, 2.5 equiv.) in DMF (50 ml) was added HATU (8.42 g, 22.134 mmol , 1.5 equiv.). Stir at 25°C for 1 hour. Extinguished with water (250 ml). The precipitated solid was collected by filtration and washed with water (2 x 100 ml) and MTBU:MeOH=5:1 (100 ml). The resulting solid was dried under vacuum. We obtained N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)acetohydrazide (4.8 g, 76. 50%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =425.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.63 (s, 2H), 6.60 (s, 2H), 7.09 (d, J=7.6 Hz, 2H), 7.27-7.39 (m, 1H), 7.45 (d, J=6.0 Hz, 1H), 8.27 (s, 1H), 8.90-8.96 (m, 1H), 10.11-10.20 (m, 1H).

Step 2. 8-Bromo-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1.2,4]triazolo[1,5-c]pyrimidin-5-amine

N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(2,6-difluorophenyl)acetohydrazide (2 .5 g, 5.880 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (10 ml) at room temperature, then heated for 1 hour at 120°C. The mixture was left to cool to room temperature. The mixture was slowly poured into methanol (50 ml). The resulting mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration and washed with MeOH:MTBU=1:1 (20 ml) and dried to give 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(1,3-oxazole -2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (1.3 g, 54.30%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =407.0. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.26 (s, 2H), 7.12 (t, J=7.8 Hz, 2H), 7.32-7.53 (m, 2H), 8.21 (s, 2H), 8.33 (d, J=0.8 Hz, 1H).

Step 3. 2-[(2,6-Difluorophenyl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(1,3-oxazol-2-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine

Into a solution of 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine (50 mg, 0.1 mmol, 1 equiv.) and (2,6-dimethylpyridin-4-yl)boronic acid (27.8 mg, 0.2 mmol, 1.5 equiv.) in dioxane ( 3 ml) and H ₂ O (0.3 ml), K ₃ PO ₄ (78.2 mg, 0.4 mmol, 3 equiv.) and Pd(dppf)Cl ₂ (18.0 mg, 0.02 mmol) were added , 0.2 equiv.). After stirring for 2 hours at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (15:1). The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 40% B in 7 minutes; 254, 220 nm; Rt: 5.9 min, giving 2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(1,3-oxazol-2-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 33) (8.6 mg, 16.2%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =434.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 2.4 (s, 6H), 4.2 (s, 2H), 6.9 (s, 2H), 7.1 (t, J=7.8 Hz, 2H), 7.3 ( d, J=0.8 Hz, 1H), 7.3-7.4 (m, 1H), 8.1 (d, J=0.8 Hz, 1H), 8.2 (s, 1H).

The compounds listed in the table below were prepared using the methods described in Example 33.

Example 34

Preparation of 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1-ethylpyridin-2(1H)-one (Compound 34)

SCHEME 21

Stage 1. 5-Bromo-1-ethylpyridin-2(1H)-one

A mixture of 5-bromo-1,2,5,6-tetrahydropyridin-2-one (3.0 g, 17.0 mmol, 1.0 equiv.) and Cs ₂ CO ₃ (16.7 g, 51.3 mmol , 3.0 equiv.) in DMF was stirred for 5 min at room temperature under nitrogen atmosphere. To the above mixture, iodoethane (8.0 g, 51.3 mmol, 3.0 equiv.) was added dropwise over 5 min at room temperature. The resulting mixture was further stirred for 40 minutes at room temperature. The residue was purified by preparative TLC (PE/EtOAc 5:1) to give 5-bromo-1-ethyl-1,2,5,6-tetrahydropyridin-2-one (1.4 g, 41.7%) as light yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =202.1.

Step 2. 1-Ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

Into a stirred solution of 5-bromo-1-ethyl-1,2-dihydropyridin-2-one (500.0 mg, 2.5 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1256.8 mg, 4.9 mmol, 2.0 equiv.) in dioxane (20 ml) Pd(dppf)Cl ₂ (362.1 mg, 0.5 mmol, 0.2 equiv.) and KOAc (728.6 mg, 7.4 mmol, 3.0 equiv.) were added in portions at room temperature in nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine- 2-one (460.0 mg, 74.6%) as a yellow-green solid. LC-MS: m/z (ESI), [M+H] ⁺ =250.3.

Stage_3._5-(5-Amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-ethylpyridin-2(1H)-one (Compound 34)

Into a stirred solution of 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (95.5 mg, 0. 4 mmol, 2.0 equiv.) and 8-bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5- c]pyrimidin-5-amine (80.0 mg, 0.2 mmol, 1 equiv.) in a mixture of 1,4-dioxane/H ₂ O (5.5 ml) was added Pd(dppf)Cl ₂ (28.1 mg, 0.038 mmol, 0.2 equiv.) and K ₃ PO ₄ (122.1 mg, 0.6 mmol, 3.0 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 80°C under a nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1, 2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-ethyl-1,2-dihydropyridin-2-one (50.0 mg, 22.7%) as a dark brown solid . The crude product (20 mg) was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ ⋅H ₂ O), yielding 5-[5-amino-7-(4-fluorophenyl)-2-[(3- fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-ethyl-1,2-dihydropyridin-2-one (Compound 34) ( 2.0 mg) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =460.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.00 (3H,t), 3.76 (2H,q), 4.42 (2H,d), 6.31 (1H,d), 7.14-7.27 (3H,m), 7.43 (4H, ddd), 7.72 (1H, t), 7.99 (2H, s), 8.34 (1H, d).

Example 35

Preparation of 5-(5-amino-2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1-methylpyridin-2(1H)-one (Compound 35)

SCHEME 22

Step 1. 2-(6-Aminopyridin-2-yl)acetic acid

To a stirred solution of ethyl 2-(6-aminopyridin-2-yl)acetate (1 g, 5.55 mmol, 1 equiv.) in EtOH (20 ml) was added NaOH (0.3 g, 8.32 mmol, 1 .5 equiv.) in portions at room temperature. The resulting mixture was stirred for 3 hours at 50°C under a nitrogen atmosphere. The precipitated solid was collected by filtration to give sodium 2-(6-aminopyridin-2-yl)acetate (0.8 g, 82.79%) as a white solid. ^1H NMR (deuterium oxide, 400 MHz) δ 3.48 (2H, s), 6.54 (1H, d), 6.65 (1H, d), 7.49 (1H, t).

Step 2. N'-(2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(6-aminopyridin-2-yl)acetohydrazide

A mixture of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (0.8 g, 2.68 mmol, 1 equiv.), T3R (1.3 g, 4.0 mmol, 1. 5 equiv.), TEA (0.8 g, 8.0 mmol, 3 equiv.) and sodium 2-(6-aminopyridin-2-yl) acetate (0.5 g, 2.7 mmol, 1 equiv.) in DMF (15 ml) was stirred for 2 hours at room temperature under nitrogen atmosphere. The product was precipitated by adding water. The resulting solid was dried under vacuum to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(6-aminopyridin-2-yl)acetohydrazide (0.31 g , 26.7%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =432.0.

Step 3. 2-((6-aminopyridin-2-yl)methyl)-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

A mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(6-aminopyridin-2-yl)acetohydrazide (310 mg, 0.7 mmol, 1 equiv. ) and (E)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (729.5 mg, 3.6 mmol, 5 equiv.) in toluene (15 ml) were stirred for 12 hours at 110°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was recrystallized from MeOH/MTBE (1/1, 12 ml) to give 6-[[5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-2-yl]methyl]pyridin-2-amine (150 mg, 50.5%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =416.2.

Step 4. 5-(5-Amino-2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one

A mixture of 6-[[5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]methyl]pyridin-2-amine ( 140 mg, 0.3 mmol, 1 equiv.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (27.6 mg, 0.03 mmol, 0.1 equiv.), K ₃ PO ₄ (215.2 mg , 1.01 mmol, 3 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (158.9 mg, 0.7 mmol, 2 equiv.) in 1,4-dioxane (6 ml) and water (1 ml) was stirred for 15 hours at 50°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) to obtain the crude product (80 mg), which was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 x 150 mm, 5 μm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 15% B to 35% B in 7 minutes; 254, 220 nm; Rt: 6.35 min, giving 5-[5-amino-2-[(6-aminopyridin-2-yl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 35) (50 mg, 33.2%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =443.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 4.08 (2H, s), 5.84 (2H, s), 6.28 (2H, t), 6.40 (1H, d), 7.13 (1H, dd), 7.20 ( 2H, t), 7.28 (1H, t), 7.44-7.53 (2H, m), 7.67 (1H, d), 8.00 (2H, s).

Example 36

Preparation of 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1-cyclopropylpyridin-2(1H)-one (Compound 36)

SCHEME 23

Step 1. 5-Bromo-1-cyclopropyl-1,2-dihydropyridin-2-one

Mixture of 5-bromo-1,2-dihydropyridin-2-one (2 g, 11.49 mmol, 1 equiv.) and cyclopropylboronic acid (2.0 g, 23.3 mmol, 2.0 equiv.), Cu(AcO) ₂ (2.1 g, 0.01 mmol, 1 equiv.), Na ₂ CO ₃ (2.4 g, 22.6 mmol, 2 equiv.), 4,4-di-tert-butyl-2,2 -dipyridyl (3.1 g, 0.01 mmol, 1 equiv.) in CH ₂ ClCH ₂ Cl (50 ml). The resulting mixture was stirred for 12 hours at 70°C under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (20:1) to give 5-bromo-1-cyclopropyl-1,2-dihydropyridin-2-one (600.0 mg, 24.4% ) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =214.0. ^1H NMR (400 MHz, DMSO-d ₆ ) δ (300 MHz, CDCl ₃ ) δ 0.86 (2H, tdd), 1.13 (2H, m), 3.31 (1H, tt), 6.48 (1H, m), 7.34 (2H, m).

Step 2. 1-Cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one

5-bromo-1-cyclopropyl-1,2-dihydropyridin-2-one (200 mg, 0.9 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (355.89 mg, 1.4 mmol, 1.5 equiv.), AcOK (183.4 mg, 1.9 mmol, 2 equiv.) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (76.3 mg, 0.1 mmol, 0.1 equiv.) in dioxane (10 ml) at 90°C for 2 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridinium- 2-one (100 mg, 41.0%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =262.3.

Step 3. 5-[5-Amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-cyclopropyl-1,2-dihydropyridin-2-one (Compound 36)

8-bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidine was added to a 20 ml sealed tube. -5-amine (100 mg, 0.24 mmol, 1 equiv.), 1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1, 2-dihydropyridin-2-one (125.2 mg, 0.48 mmol, 2.0 equiv.), K ₃ PO ₄ (101.8 mg, 0.48 mmol, 2 equiv.) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (19.6 mg, 0.024 mmol, 0.1 equiv.) in dioxane (5 ml) and water (0.5 ml) at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 12:1) to give 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1, 2,4]triazolo[1,5-c]pyrimidin-8-yl]-1-cyclopropyl-1,2-dihydropyridin-2-one (Compound 36) (5 mg, 4.42%) as a white solid substances. LC-MS: m/z (ESI), [M+H] ⁺ =472.2. ^1H NMR:(400 MHz, DMSO- _d6 ) δ 1.24-0.83 (m, 4H), 1.48 (s, 2H), 3.07 (s, 1H), 3.51 (1H, s), 4.22 (1H, s) , 4.39 (8H, dd), 5.00 (2H, d), 5.73 (2H, ddt), 6.35 (2H, d), 7.23 (1H, s), 7.32-7.13 (6H, m), 7.41 (8H, ddd ), 7.72 (2H, t), 8.01 (4H, s), 8.34 (2H, d).

Example 37

Preparation of 2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine (Compound 37)

SCHEME 24

Step 1. 6-[[5-Amino-7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-[1,2.4]triazolo[1,5-c] pyrimidin-2-yl]methyl]pyridin-2-amine

Into a solution of 6-[[5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]methyl]pyridin-2-amine (100 mg, 0.24 mmol, 1 equiv.) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (88 .4 mg, 0.4 mmol, 1.5 equiv.) in dioxane (10 ml) and H ₂ O (1 ml), K ₃ PO ₄ (153.7 mg, 0.7 mmol, 3 equiv.) was added and Pd(dppf)Cl ₂ (35.3 mg, 0.05 mmol, 0.2 equiv.). After stirring for 2 hours at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC/silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (15:1). The crude product (100 mg) was further purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 25% B to 35% B in 7 minutes; 254/220 nm; Rt: 6.1 min, giving 2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(imidazo[1,2-a]pyridin-6-yl)- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 37) (58.1 mg, 53.1%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =452.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.3 (s, 2H), 6.6 (d, J=6.9 Hz, 2H), 7.1-7.2 (m, 2H), 7.3 (d, J=9 ,4 Hz, 1H), 7.4-7.5 (m, 2H), 7.6 (t, J=7.8 Hz, 1H), 7.7 (d, J=9.4 Hz, 1H), 7.9 (s, 1H) , 8.2 (d, J=1.7 Hz, 2H), 8.8 (s, 1H).

Example 39

Preparation of 5-[5-amino-7-(3,4-difluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (25 mg, 27.89%) (Compound 39)

SCHEME 25

Step 1. 5-[5-Amino-7-(3,4-difluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2.4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 39)

5-[5-amino-7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 was added to a 10 ml vessel -yl]-1-methyl-1,2-dihydropyridin-2-one (90 mg, 0.233 mmol, 1 equiv.) and (3,4-difluorophenyl)boronic acid (73.68 mg, 0.467 mmol, 2 equiv. ), Pd(dppf)Cl ₂ (31.6 mg, 0.04 mmol, 0.2 equiv.), K ₃ PO ₄ (148.56 mg, 0.700 mmol, 3 equiv.), dioxane (1 ml) and H ₂ O (0.2 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (3 x 10 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ +0.l% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 22% B to 32% B in 7 minutes; 254/220 nm; Rt: 6.55 min to give 5-[5-amino-7-(3,4-difluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[ 1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 39) (25 mg, 23.1%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =464.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.41 (s, 2H), 6.29 (d, J=8.9 Hz, 1H), 7.18 (d, J=26.0 Hz, 2H), 7.43 ( d, J=24.3 Hz, 3H), 7.68 (d, J=13.2 Hz, 2H), 8.02 (s, 2H), 8.32 (s, 1H).

The compounds listed in the table below were prepared using the methods described in Example 39.

Example 42

Preparation of 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 42)

SCHEME 26

Step 1. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-2-yl)acetohydrazide

Into a stirred mixture of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 mg, 0.7 mmol, 1 equiv.) and 2-(1,3-thiazol-2-yl)acetic acid acid (115.3 mg, 0.8 mmol, 1.2 equiv.) in DMF (2 ml) was added HATU (382.6 mg, 1.01 mmol, 1.5 equiv.) and DIEA (260.1 mg, 2 .0 mmol, 3 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water (20 ml) at room temperature. The precipitated solid was collected by filtration and washed with water (3 x 20 ml) to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3- thiazol-2-yl)acetohydrazide (170 mg, 59.9%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =423.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.05 (s, 2H), 6.44 (s, 2H), 7.28 (t, J=8.9 Hz, 2H), 7.55-7.63 (m, 2H), 7.66 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.3 Hz, 1H), 8.76 (s, 1H), 10.22 (s, 1H).

Step 2. 8-Bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2.4]triazolo[1,5-c]pyrimidin-5-amine

To a stirred mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(1,3-thiazol-2-yl)acetohydrazide (150 mg, 0.35 mmol , 1 equiv.) in toluene (4 mL), (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (216.3 mg, 1.1 mmol, 3 equiv.) was added in portions at room temperature under nitrogen. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine (100 mg, 69.63%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =405.1. ¹ H NMR (400 MHz, Methanol) δ 4.71 (s, 2H), 7.17-7.25 (m, 2H), 7.57 (d, J=3.4 Hz, 1H), 7.75 (d, J=3.4 Hz , 1H), 7.78-7.84 (m, 2H).

Step 3. 5-[5-Amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl1-[1,2,4]triazolo[1,5-c]pyrimidine -8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 42)

Into a stirred mixture of 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine (100 mg, 0.25 mmol, 1 equiv.) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- dihydropyridin-2-one (116.0 mg, 0.49 mmol, 2 equiv.) in 1,4-dioxane (3 ml) and H ₂ O (0.6 ml) was added K ₃ PO ₄ (156.9 mg , 0.74 mmol, 3 equiv.) and Pd(dppf)Cl ₂ (36.1 mg, 0.05 mmol, 0.2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified using an XBridge Shield RP18 OBD column, 5 µm, 19 x 150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 35% B in 8 minutes; 254/220 nm; Rt: 6.45 min to give 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[ 1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 42) (35 mg, 32.72%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =434.2. ^1H NMR (400 MHz, Methanol) δ 3.57 (s, 3H), 4.68 (s, 2H), 6.44 (d, J=9.3 Hz, 1H), 7.06-7.14 (m, 2H), 7.22 (dd , J=9.3, 2.5 Hz, 1H), 7.57 (td, J=5.8, 2.5 Hz, 3H), 7.74 (d, J=3.4 Hz, 1H), 7.81 (d, J=2 ,4 Hz, 1H).

Example 43

Preparation of 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-(methylamino)pyridin-4-yl)-[1,2,4]triazolo[1, 5-c]pyrimidine-5-amine (Compound 43)

DIAGRAM 27

Stage 1. (2-(Methylamino)pyridin-4-yl)boronic acid

Pd(dppf)Cl ₂ (391.2 mg, 0.5 mmol, 0.2 equiv.), K ₃ PO ₄ (1134.9 mg, 5.3 mmol, 2 equiv.), 4-bromo-N- methylpyridin-2-amine (500 mg, 2.7 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolane-2- yl)-1,3,2-dioxaborolane (821.7 mg, 3.2 mmol, 1.2 equiv.) was dissolved in 10 ml of dioxane. The mixture was stirred at 90°C for 2 hours. LC-MS indicated that the reaction was complete. The crude product was purified on a silica gel column eluting with MeOH-DCM (1:10) and the product was further purified by preparative HPLC to give the product as a light yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =153.2.

Step 2. 7-(4-Fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-(methylamino)-pyridin-4-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine (Compound 43)

(2-(Methylamino)pyridin-4-yl)boronic acid (100 mg, 0.66 mmol, 1 equiv.), 8-bromo-7-(4-fluorophenyl)-2-((3-methylpyridin-2- yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (271.9 mg, 0.66 mmol, 1 equiv.), Pd(dppf)Cl ₂ (96, 3 mg, 0.13 mmol, 0.2 equiv.), K ₃ PO ₄ (419.1 mg, 1.97 mmol, 3 equiv.) was dissolved in 5 ml of a mixture of dioxane/H ₂ O (5:1). The mixture was stirred at 80°C for 3 hours. LC-MS indicated that the reaction was complete. The crude product was purified on a silica gel column eluting with MeOH-DCM (1:10) and the product was further purified by preparative HPLC to give 26.6 mg of product (Compound 43) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =445.2. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 2.81 (s, 3H), 4.47 (d, J=2.1 Hz, 2H), 6.41 (dd, J=5.7, 1.6 Hz, 1H), 6.61 (s, 1H), 7.03 (t, J=8.8 Hz, 2H), 7.33-7.54 (m, 3H), 7.56-7.69 (m, 1H), 7.74-7.82 (m, 1H), 8.26- 8.37 (m, 2H).

Example 45

Preparation of 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine (Compound 45)

SCHEME 28

Step 1. Preparation of 4-(benzylthio)-2,6-dichloropyrimidine

To a stirred solution of 2,4,6-trichloropyrimidine (6.5 g, 35.73 mmol) in dioxane (10 ml) was added phenylmethanethiol (4.43 g, 35.73 mmol) and K ₂ CO ₃ (4.93 g , 35.73 mmol) at 0°C. The mixture was then stirred at room temperature for 16 hours. The mixture was then concentrated and the residue was poured into water and then extracted with ethyl acetate (2 x 25 ml). The organic solution was then concentrated to give crude 4-(benzylthio)-2,6-dichloropyrimidine (9.6 g, yield: 99.5%) as a yellow solid, which could be used in the next step without further purification. LC-MS m/z (ESI), [M+H] ⁺ =271.2.

Step 2. Preparation of 4-(benzylthio)-2-chloro-6-(4-fluorophenyl)pyrimidine

In a mixture of 4-(benzylthio)-2,6-dichloropyrimidine (9.6 g, 35.6 mmol), 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.98 g, 35.56 mmol) in dioxane (100 ml) and water (10 ml) was added Na ₂ CO ₃ (9.96 g, 71.12 mmol) and Pd(dppf)Cl ₂ (2.6 g, 3.56 mmol). The mixture was then stirred at 80°C for 4 hours under N ₂ atmosphere. The mixture was concentrated, and water (25 ml) and ethyl acetate (100 ml) were added to the residue. The organic solution was then concentrated to give the crude product, which was further purified using a flash column (0-5% ethyl acetate in petroleum ether) to give 4-(benzylthio)-2-chloro-6-(4-fluorophenyl)pyrimidine (11, 6 g, 98%) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =331.2.

Step 3. Preparation of 4-(benzylthio)-N-(tert-butyl)-6-(4-fluorophenyl)-pyrimidin-2-amine

A solution of 4-(benzylthio)-2-chloro-6-(4-fluorophenyl)pyrimidine (11.6 g, 35.15 mmol) in 2-methylpropan-2-amine (20.55 g, 281.8 mmol) was stirred at 110 °C for 40 hours. The mixture was then concentrated and the residue was further purified using a flash column (330 g) (0-5% ethyl acetate in petroleum ether) to give the title product, 4-(benzylthio)-N-(tert-butyl)-6-(4 -fluorophenyl)pyrimidin-2-amine (12 g, yield: 93.0%) as a yellowish oil. LC-MS: m/z (ESI), [M+H] ⁺ =368.6.

Step 4. Preparation of 4-(benzylthio)-5-bromo-N-(tert-butyl)-6-(4-fluorophenyl)-pyrimidin-2-amine

NBS (5, 3 g, 29.96 mmol). The mixture was then stirred at room temperature for 1 hour. The mixture was concentrated and the residue was purified using a flash column (0-5% ethyl acetate in petroleum ether) to give the desired 4-(benzylthio)-5-bromo-N-(tert-butyl)-6-(4-fluorophenyl)pyrimidine -2-amine (5.50 g, yield: 41%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =446.2.

Step 5. Preparation of 4-(benzylthio)-N-(tert-butyl)-6-(4-fluorophenyl)-5-(2-methyl pyridin-4-yl)pyrimidin-2-amine

In a mixture of 4-(benzylthio)-5-bromo-N-(tert-butyl)-6-(4-fluorophenyl)pyrimidin-2-amine (3.7 g, 8.31 mmol) and (2-methylpyridin-4 -yl)boronic acid (1.71 g, 12.47 mmol) in dioxane (50 ml) and water (50 ml) was added Na ₂ CO ₃ (2.28 g, 16.63 mmol) and Pd(PPh ₃ ) ₄ (0.96 g, 0.83 mmol). The mixture was then stirred at 80°C for 8 hours under N ₂ atmosphere. The mixture was concentrated, and water (25 ml) and ethyl acetate (100 ml) were added to the residue. The organic phase was then concentrated to give the crude product, which was further purified using a flash column (0-5% ethyl acetate in petroleum ether) to give 4-(benzylthio)-N-(tert-butyl)-6-(4-fluorophenyl) -5-(2-methylpyridin-4-yl)pyrimidin-2-amine (2.2 g, yield: 58%) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =459.4.

Step 6. Preparation of N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine

In a solution of 4-(benzylthio)-N-(tert-butyl)-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (1.7 g, 3.71 mmol ) 1 drop of acetic acid and 1 drop of water were added to 20 ml of acetonitrile. The solution was then cooled to 0°C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.45 g, 7.42 mmol) was added. The mixture was stirred for 3 hours at this temperature. The solution was diluted with 40 ml of Na ₂ SO ₃ solution in water and then extracted with DCM (20 ml x 2). The organic layer was collected and concentrated. The crude material was purified using a column (0-5% EA in PE) to obtain the target N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidine -2-amine (1.0 g, 73% yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =371.2.

Step 7. Preparation of N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine

A solution of N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (0.9 g, 2.34 mmol) in dioxane (3 ml) was added hydrazine (1.17 g, 23.4 mmol). The mixture was then stirred at 100°C for 16 hours. 20 ml of sat. was added to the solution. brine and the resulting solid was collected, washed with 15 ml of 20% ethyl acetate in petroleum ether, then dried to give the title N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridinium- 4-yl)-pyrimidin-2-amine (0.79 g, 88% yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =367.4.

Step 8. Preparation of 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1, 5-c]pyrimidine-5-amine (Compound 45)

A mixture of N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (0.020 g, 0.05 mmol), 2-( 6-methylpyridin-2-yl)acetic acid (0.019 g, 0.12 mmol) in POCl ₃ (0.5 ml) was stirred in a sealed tube at 140°C for 4 hours. The mixture was concentrated and 2 ml of TFA was added to the residue. The resulting mixture was stirred in a sealed tube at 100°C for 2 hours. The mixture was concentrated and purified by C18 flash chromatography, eluting with a gradient of 5% to 60% acetonitrile in water (0.05% ammonia). The pure fractions were evaporated to dryness to give 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (Compound 45) (5 mg, 21.8% yield). LC-MS: m/z (ESI), [M+H] ⁺ =426.4. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.37 (s, 3H) 2.41 (s, 3H) 4.29 (s, 2H) 7.00 (d, J=5.39 Hz, 1H) 7.07-7.18 (m, 5H) 7.35 (t, J=6.64 Hz, 2H) 7.60 ( t, J=7.57 Hz, 1H) 8.15 (br s, 2H) 8.31 (d, J=5.04 Hz, 1H).

Example 46

Preparation of 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-N ² -(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2 ,5-diamine (Compound 46)

DIAGRAM 29

Step 1. Preparation of N5-(tert-butyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2 ,5-diamine

A solution of N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2-methylpyridin-4-yl)pyrimidin-2-amine (0.2 g, 0.55 mmol) in dichloromethane (1.5 ml) was added cyanobromide (0.06 g, 0.6 mmol) at 0°C. The mixture was then stirred at this temperature for 1 hour. The mixture was concentrated, and 0.2 ml of DIEA and 5 ml of ethyl acetate were added to the residue. The solid was then collected and dried to give N5-(tert-butyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-2,5-diamine (0.15 g, 70.2%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =392.4.

Step 2. Preparation of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carbonitrile

Into the mixture N5-(tert-butyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2,5 -diamine (0.050 g, 0.13 mmol), 2-bromopyridine (0.041 g, 0.26 mmol) in 5 ml of dioxane was added Pd(OAc) ₂ (0.058 g, 0.026 mmol), 1,1'-bis(di -tert-butylphosphino)ferrocene (0.014 g, 0.026 mmol) and tBuONa (0.036 g, 0.38 mmol). The mixture was then stirred at 80°C for 8 hours under N ₂ atmosphere. The mixture was then concentrated and the residue was poured into water (20 ml) and then extracted with ethyl acetate (3 x 20 ml). The organic solution was then concentrated and the residue was purified by flash chromatography on silica, eluting with a gradient of 10% to 50% ethyl acetate in petroleum ether. The pure fractions were evaporated to dryness to give 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carbonitrile (0.04 g, 68% yield) as yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =459.4.

Step 3. Preparation of 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-N ² -(pyridin-2-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-2,5-diamine (Compound 46)

A solution of 3-amino-6-(2,6-dimethylpyridin-4-yl)-5-(4-fluorophenyl)pyrazine-2-carbonitrile (60 mg, 0.188 mmol) in TFA (2 ml) was stirred at 90°C in for 1 hour in a microwave reactor. The solution was then concentrated and the crude material was washed with 30 ml of methanol to obtain the target 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-N ² -(pyridin-2-yl)-[1,2, 4]triazolo[1,5-c]pyrimidine-2,5-diamine (Comp. 46) (0.023 g, 32.9% yield) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =413.5 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.37-2.43 (m, 3H) 6.88-7.06 (m, 2H) 7.14 (br s, 2H) 7.22-7.28 (m, 1H) 7.35-7.45 (m, 2H) 7.68-7.82 (m, 1H) 7.89-8.15 (m, 2H) 8.18-8.28 (m, 1H) 8.30-8.43 (m, 2H) 10.11-10.22 (m, 1H).

Example 47

Preparation of 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine (Compound 47)

SCHEME 30

Step 1. Preparation of 4-(benzylthio)-N-(tert-butyl)-5-(2,6-dimethylpyridin-4-yl)-6-(4-fluorophenyl)pyrimidin-2-amine

To a mixture of 4-(benzylthio)-5-bromo-N-(tert-butyl)-6-(4-fluorophenyl)pyrimidin-2-amine (3.2 g, 7.19 mmol) and (2,6-dimethylpyridine -4-yl)boronic acid (1.63 g, 10.79 mmol) in dioxane (50 ml) and water (50 ml) was added Na ₂ CO ₃ (1.52 g, 14.38 mmol) and Pd(PPh ₃ ) ₄ (0.83 g, 0.72 mmol). The mixture was then stirred at 80°C for 8 hours under N ₂ atmosphere. The mixture was concentrated, and water (25 ml) and ethyl acetate (100 ml) were added to the residue. The organic solution was then concentrated to give the crude product, which was further purified using a flash column (0-5% ethyl acetate in petroleum ether) to give 4-(benzylthio)-N-(tert-butyl)-5-(2,6- dimethylpyridin-4-yl)-6-(4-fluorophenyl)pyrimidin-2-amine (2.4 g, yield: 71%) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =474.4.

Step 2. Preparation of N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-amine

In a solution of 4-(benzylthio)-N-(tert-butyl)-6-(4-fluorophenyl)-5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-amine (1.35 g, 2. 86 mmol) 1 drop of AcOH and 1 drop of water were added to 20 ml of acetonitrile. The solution was then cooled to 0°C and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.23 g, 6.29 mmol) was added. The mixture was stirred for 3 hours at this temperature. The solution was then poured into 40 ml of Na ₂ SO ₃ solution in water and then extracted with DCM (2 x 20 ml). The organic layer was collected and concentrated. The crude material was purified using a column (0-5% EA in PE) to obtain the target N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2,6-dimethylpyridin-4-yl )pyrimidin-2-amine (0.90 g, 82% yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =385.2.

Step 3. Preparation of N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-amine

In a solution of N-(tert-butyl)-4-chloro-6-(4-fluorophenyl)-5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-amine (0.9 g, 2.34 mmol ) in dioxane (3 ml) was added hydrazine (1.17 g, 23.4 mmol). The mixture was then stirred at 100°C for 16 hours. 20 ml of sat. was added to the solution. brine and the resulting solid was collected, washed with 15 ml of 20% ethyl acetate in petroleum ether, then dried to give the title N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2,6- dimethylpyridin-4-yl)pyrimidin-2-amine (0.8 g, 88%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =381.3.

Step 4. Preparation of 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (Compound 47)

A mixture of N-(tert-butyl)-4-(4-fluorophenyl)-6-hydrazinyl-5-(2,6-dimethylpyridin-4-yl)pyrimidin-2-amine (0.060 g, 0.16 mmol) and 2 -(6-methylpyridin-2-yl)acetic acid (0.054 g, 0.36 mmol) in POCl ₃ (1 ml) was stirred in a sealed tube at 140°C for 2 hours. The mixture was concentrated, and 2 ml of TFA was added to the residue. The resulting mixture was stirred in a sealed tube at 100°C for 2 hours. The mixture was concentrated and the residue was purified by C18 flash chromatography, eluting with a gradient of 5% to 60% acetonitrile in water (0.05% ammonia). The pure fractions were evaporated to dryness to give 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (Compound 47) (0.02 g, 37.1% yield). LC-MS: m/z (ESI), [M+H] ⁺ =440.5. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 2.31 (s, 6H) 2.39-2.45 (m, 3H) 4.29 (s, 2H) 6.89 (s, 2H) 7.04-7.19 (m, 4H) 7.35 (t, J=6.48 Hz, 2H) 7.59 (t, J =7.72 Hz, 1H) 8.13 (br s, 2H).

The compounds listed in the table below were prepared using the methods described in Example 47.

Example 50

Preparation of 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1- (oxetan-3-yl)pyridin-2(1H)-one (Compound 50)

SCHEME 31

Step 1. Preparation of 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine

To a mixture of 4,6-dichloropyrimidin-2-amine (10 g, 61 mmol), (4-fluorophenyl)boronic acid (8.8 g, 63 mmol), Pd ₂ (dba) ₃ (50 mg, 0.055 mmol) in water (15 ml). The resulting mixture was heated at 70°C for 30 minutes under N ₂ atmosphere. The mixture was then diluted with water (300 ml) and filtered. The solid was washed with water (100 ml) then dried to give the crude product (14 g, 102% yield) as a yellow solid, which was used in the next step without further purification. LC-MS: m/z (ESI), [M+H] ⁺ =224.3.

Step 2. Preparation of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine

To a mixture of 4-chloro-6-(4-fluorophenyl)pyrimidin-2-amine (600 mg, 2.7 mmol) in 1-butanol (4 ml) was added hydrazine hydrate (2 ml). The resulting mixture was heated at 100°C for 30 minutes. The mixture was then filtered. The solid was washed with 1-butanol (5 ml) and dried to give 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (550 mg, 93% yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =220.3.

Step 3. Preparation of N'-(2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(2,6-difluorophenyl)acetohydrazide

A mixture of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (550 mg, 2.5 mmol) and 2-(2,6-difluorophenyl)acetic acid (450 mg, 2.6 mmol) in DMF ( 6 ml) HATU (1.1 g, 2.9 mmol) and DIEA (500 mg, 3.9 mmol) were added at 20°C. The resulting mixture was stirred at 20°C for 10 minutes. The mixture was purified using C18-40 g (MeCN/water=5%-70%) to give N'-(2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(2,6- difluorophenyl)acetohydrazide (720 mg, 77% yield) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =374.3.

Step 4. Preparation of 2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

Mixture of N'-(2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)-2-(2,6-difluorophenyl)-acetohydrazide (700 mg, 1.9 mmol) in POCl ₃ (10 ml) heated at 140°C for 45 min in a microwave reactor. The mixture was then concentrated. The residue was purified using C18-40 g (MeCN/water=5%-80%) to give 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (360 mg, 54% yield) as a white solid substances. LC-MS: m/z (ESI), [M+H] ⁺ =356.3.

Step 5. Preparation of 8-bromo-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

To a mixture of 2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (300 mg, 0.84 mmol) in DMF (10 ml) was added with NBS (200 mg, 1.1 mmol). The resulting mixture was stirred at 20°C for 30 minutes. The mixture was then diluted with water and filtered. The solid was purified using C18-40 g (MeCN/water=5%-90%) to give 8-bromo-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine (320 mg, 87% yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =434.1, 436.1.

Step 6. Preparation of 5-(5-amino-2-(2.6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -(oxetan-3-yl)pyridin-2(1H)-one (Compound 50)

To a mixture of 8-bromo-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (30 mg, 0.069 mmol ), 1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (25 mg, 0.090 mmol), Pd ₂ (dba) ₃ (5 mg, 0.0055 mmol), tricyclohexylphosphine (3 mg, 0.011 mmol) and K ₃ PO ₄ (30 mg, 0.014 mmol) in dioxane (3 ml) added water (1 ml ). The resulting mixture was hermetically sealed and heated at 120°C for 15 minutes in a microwave reactor. The mixture was filtered and the filtrate was purified using C18-40 g (MeCN/water=5%-80%) to give 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)- [1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-(oxetan-3-yl)pyridin-2(1H)-one (Compound 50) (13 mg, 37% -y yield) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =505.3. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 4.56 (t, J=6.94 Hz, 2H) 4.72 (s, 2H) 4.91-4.95 (m, 2H) 5.59 (quin, J=7.01 Hz, 1H) 6.42 (d, J=9.46 Hz, 1H) 6.99 (br t, J=8.04 Hz, 2H) 7.11-7.19 (m, 2H) 7.31-7.37 (m, 1H) 7.52 (dd, J=9.46, 2.21 Hz, 1H) 7.57 (br dd, J=8.51, 5.36 Hz, 2H) 7.72-7.78 (m, 1H).

The compound shown in the table below was prepared using the methods described in Example 50.

Example 55

Preparation of 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1-isopropylpyridin-2(1H)-one (Compound 55)

SCHEME 32

Step 1. 5-Bromo-1-isopropylpyridin-2(TH)-one

5-bromo-1,2-dihydropyridin-2-one (1 g, 5.74 mmol, 1 equiv.), 2-iodopropane (1.95 g, 11.48 mmol, 2.0 equiv.), was added to a 40 ml sealed tube. 00 equiv.) and K ₂ CO ₃ (2.38 g, 17.22 mmol, 3.00 equiv.) in 1,4-dioxane (25 ml) at 80°C for 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give 5-bromo-1-(propan-2-yl)-1,2-dihydropyridin-2-one (1 g, 80.53 %) as a white solid.

Step 2. 1-Isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2(1H)-one

Add 5-bromo-1-(propan-2-yl)-1,2-dihydropyridin-2-one (1 g, 4.63 mmol, 1 equiv.) to a 50 mL 3-neck round bottom flask, 4.4 ,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.76 g, 6.94 mmol , 1.50 equiv.), AcOK (0.91 g, 9.26 mmol, 2 equiv.) and Pd(dppf)Cl ₂ CH ₂ Cl ₂ (0.38 g, 0.463 mmol, 0.1 equiv.) in 1,4-dioxane (10 ml) at 85°C for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (5:1), to give 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1,2-dihydropyridin-2-one (0.9 g, 73.90%) as a white solid.

Step 3. 5-(5-Amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-isopropylpyridin-2(1H)-one (Compound 55)

8-bromo-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidine was added to a 100 ml round bottom flask. -5-amine (500 mg, 1.19 mmol, 1 equiv.), 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1,2-dihydropyridin-2-one (630 mg, 2.395 mmol, 2.00 equiv.), Pd(DtBPF)Cl ₂ (775 mg, 0.119 mmol, 0.10 equiv.) and K ₃ PO ₄ (762.5 mg, 3.59 mmol, 3.00 equiv.) in 1,4-dioxane (12.5 ml) and water (2 ml) at 90°C for 6 hours under nitrogen. The target product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (20:1), to obtain 450 mg of crude product. It was dissolved in DCM/EtOH (1/1, 10 ml), then DCM was removed under reduced pressure, the precipitated solid was collected by filtration and washed with EtOH (2 x 5 ml) to give 5-(5-amino-7- (4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-isopropylpyridin-2(1H )-she (Compound 55) (350 mg, 61%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =474.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 0.9 (d, J=6.8 Hz, 6H), 4.4 (d, J=2.1 Hz, 2H), 4.9 (p, J=6.8 Hz, 1H), 6.3 (d, J=9.3 Hz, 1H), 7.1-7.2 (m, 2H), 7.3 (dd, J=9.3, 2.5 Hz, 1H), 7.3-7.5 (m, 4H), 7.71 (ddd, J=9.8, 8.3, 1.3 Hz, 1H), 7.97 (s, 2H), 8.3 (dt, J=4.7, 1.6 Hz, 1H).

Example 58

Preparation of 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 58)

SCHEME 33

Step 1. Preparation of N-[2-amino-5-bromo-6-(4-fluorophenyl)-3,4-dihydropyrimidin-4-yl]-2-(1,3-thiazol-4-yl)acetohydrazide

5-Bromo-4-(4-fluorophenyl)-6-hydrazinyl-1,6-dihydropyrimidin-2-amine (314.48 mg, 1.048 mmol, 1.50 equiv.) and 2-( 1,3-thiazol-4-yl)acetic acid (100 mg, 0.699 mmol, 1 equiv.), HATU (398.40 mg, 1.048 mmol, 1.50 equiv.), DIEA (361.12 mg, 2.794 mmol , 4 equiv.) and DMF (10 ml) at room temperature. The mixture was then stirred at 25°C for 3 hours. The product was precipitated by adding water. The precipitated solid was collected by filtration and washed with MeOH (10 mL x 3) to give N-[2-amino-5-bromo-6-(4-fluorophenyl)-3,4-dihydropyrimidin-4-yl]-2- (1,3-thiazol-4-yl)acetohydrazide (140 mg, 47.13%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =425.1.

Step 2. Preparation of 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl1-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amine

N-[2-amino-5-bromo-6-(4-fluorophenyl)-3,4-dihydropyrimidin-4-yl]-2-(1,3-thiazol-4-yl)acetohydrazide was added to a 40 ml vessel (110 mg, 0.259 mmol, 1 equiv.), (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (157.85 mg, 0.776 mmol, 3.00 equiv.) and toluene (5 ml) at room temperature . The mixture was then stirred at 105°C for 15 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 12:1) to give 8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine (50 mg, 47.7%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =407.1.

Step 3. Preparation of 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl1-[1,24]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 58)

8-bromo-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c] was added to a 10 ml vessel. pyrimidin-5-amine (40 mg, 0.10 mmol, 1 equiv.), (1-methyl-6-oxo-1,6-dihydropyridin-3-yl)boronic acid (22.6 mg, 0.15 mmol , 1.5 equiv.), Pd(dppf)Cl ₂ (14.4 mg, 0.02 mmol, 0.2 equiv.), K ₃ PO ₄ (41.9 mg, 0.20 mmol, 2 equiv. ), dioxane (1 ml) and H ₂ O (0.2 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (10 ml x 3) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue/crude product was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeOH in water, gradient from 10% to 50% in 10 min; detector: UV 254 nm, yielding 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1 ,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 58) (10 mg, 23.37%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =434.2, ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 3.56 (s, 3H), 4.46 (d, J=1, 0 Hz, 2H), 6.43 (d, J=9.3 Hz, 1H), 7.02-7.14 (m, 2H), 7.19 (dd, J=9.3, 2.5 Hz, 1H), 7.46-7.61 (m , 3H), 7.79 (d, J=2.5 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H).

Example 60

Preparation of 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1- (1,1-dioxidothietane-3-yl)pyridin-2(1H)-one (Compound 60)

SCHEME 34

Step 1. 1-(1,1-Dioxidothietan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

To a stirred mixture of 3-(5-bromo-2-oxo-1,2-dihydropyridin-1-yl)-1-lambda6-thietane-1,1-dione (800 mg, 2.876 mmol, 1 equiv.) and 4,4, 5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (876.54 mg, 3.452 mmol, 1. 2 equiv.) in dioxane (20 ml) was added Pd(dppf)Cl ₂ (234.90 mg, 0.288 mmol, 0.1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under a nitrogen atmosphere. The residue was purified by preparative TLC (PE/EtOAc=12:1) to give 3-[2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1, 2-dihydropyridin-1-yl]-1lambdab-thietane-1,1-dione (380 mg, 40.62%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =326.2.

Step 2. 5-(5-Amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)- 1-(1,1-dioxidothietan-3-yl)pyridin-2(1H)-one (Compound 60)

Into a stirred solution of 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (80 mg, 0.18 mmol, 1 equiv.) and 3-[2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine -1-yl]-1lambda6-thietane-1,1-dione (119.8 mg, 0.37 mmol, 2 equiv.) in dioxane (6 ml) and H ₂ O (1 ml) was added Pd(dppf)Cl ₂ (15.0 mg, 0.02 mmol, 0.1 equiv.) and K ₃ PO ₄ (117.3 mg, 0.55 mmol, 3 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 80°C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (5 x 20 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 30 x 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 31% B to 46% B in 7 minutes; 254/220 nm; t _R =6.80 min, yielding 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c] pyrimidin-8-yl)-1-(1,1-dioxidothietan-3-yl)pyridin-2(1H)-one (Compound 60) (18 mg, 17.68%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =553.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ: 3.72 (s, 1H), 4.23 (s, 4H), 4.67 (s, 2H), 5.52 (s, 1H), 6.31 (d, J=9, 5 Hz, 1H), 7.14 (dt, J=26.8, 8.7 Hz, 4H), 7.44 (d, J=38.9 Hz, 3H), 7.94 (d, J=41.8 Hz, 3H).

Example 63

Preparation of 5-[5-amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1H-pyrazol-1-yl)-[1,2,4]triazolo[1,5-c] pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 63)

SCHEME 35

Step 1. 5-[5-Amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1H-pyrazol-1-yl)-[1,2,4]triazolo[1,5- c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 63)

Into a stirred mixture of 5-[5-amino-7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl] -1-methyl-1,2-dihydropyridin-2-one (100 mg, 0.3 mmol) and 1H-pyrazole (35.3 mg, 0.5 mmol) in DMF (2 ml) was added K ₃ PO ₄ ( 165.1 mg, 0.8 mmol) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 days at 100°C in a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by preparative HPLC under the following conditions: column: Atlantis Prep T3 OBD, 19 x 250 mm, 10 µm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 16% B to 16% B in 10 minutes; 254/220 nm; Rt: 8.22 min to give 5-[5-amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1H-pyrazol-1-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 63) (15 mg, 13.8%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =418.2. ¹ NMR (300 MHz, Methanol-d ₄ ) δ: 3.57 (s, 3H), 4.44-4.53 (m, 1H), 6.40-6.50 (m, 2H), 7.12 (dd, J=9.3, 2.5 Hz , 1H), 7.43 (dt, J=8.7, 4.5 Hz, 1H), 7.60 (d, J=1.2 Hz, 1H), 7.68 (t, J=9.0 Hz, 1H), 7.77 ( d, J=2.4 Hz, 1H), 8.22 (d, J=2.6 Hz, 1H), 8.33 (d, J=4.8 Hz, 1H).

Example 65

Preparation of 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1- (2-hydroxyethyl)pyridin-2(1H)-one (Compound 65)

SCHEME 36

Stage 1. 1-(2-Hydroxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

4,4,5,5-Tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane) (4.37 g, 17.2 mmol, 1.50 equiv.), 5-bromo-1-(2-hydroxyethyl)-1,2-dihydropyridin-2-one) (2.5 g, 11.465 mmol, 1 equiv.), KOAc ( 2.25 g, 22.9 mmol, 2 equiv.) and Pd(dppf)Ch (1.68 g, 2.3 mmol, 0.2 equiv.) were dissolved in 30 ml of 1,4-dioxane/H ₂ mixture O(10:1). The mixture was stirred at 90°C for 3 hours. LC-MS indicated that the reaction was complete. The crude product was purified by a silica gel column eluting with MeOH-DCM (1:10) and the product was further purified by TLC to give 1-(2-hydroxyethyl)-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (600.0 mg, 19.74%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =266.3.

Step 2. 5-(5-Amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)- 1-(2-hydroxyethyl)pyridin-2(1H)-one (Compound 65)

1-(2-Hydroxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (150 mg, 0.57 mmol, 1 equiv.), 8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine-5 -amine (245.7 mg, 0.57 mmol, 1.00 equiv.), Pd(dppf)Cl ₂ (82.8 mg, 0.11 mmol, 0.2 equiv.) and K ₃ PO ₄ (240 .2 mg, 1.13 mmol, 2.00 equiv.) was dissolved in 4 ml of a mixture of dioxane/H ₂ O (5:1). The mixture was stirred at 90°C for 2 hours. LC-MS indicated that the reaction was complete. The crude product was purified on a silica gel column, eluting with DCM:CH ₃ OH (10:1), and the product was further purified by preparative HPLC to give 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4- fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-(2-hydroxyethyl)pyridin-2(1H)-one (Compound 65) (16.5 mg , 5.92%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =493.3. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 3.78 (t, J=5.3 Hz, 2H), 4.06 (t, J=5.3 Hz, 2H), 4.29 (s, 2H), 6.45 (d, J=9.3 Hz, 1H), 6.94-7.07 (m, 4H), 7.08 (d, J=8.8 Hz, 1H), 7.25 (dd, J=9.3, 2.5 Hz, 1H ), 7.26-7.40 (m, 1H), 7.54 (dd, J=8.8, 5.4 Hz, 2H), 7.68 (d, J=2.4 Hz, 1H).

Example 66

Preparation of 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl)-1,6-dimethylpyridin-2(1H)-one (Compound 66)

SCHEME 37

Stage!. 5-Bromo-1,6-dimethylpyridin-2(1H)-one

5-Bromo-6-methyl-1,2-dihydropyridin-2-one (5 g, 26.592 mmol, 1 equiv.), iodomethane (7.55 g, 53.185 mmol, 2.00 equiv.), K ₂ CO ₃ (7.35 g, 53.185 mmol, 2.00 equiv.) in 10 mL DMF at room temperature. The mixture was stirred at 80°C for 2 hours. LC-MS indicated that the reaction was complete. The crude product was purified on a silica gel column eluting with PE:EA=10:1 to give 5-bromo-1,6-dimethyl-1,2-dihydropyridin-2-one (2.3 g, 42.81%) in as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =202.2.

Step 2. 1,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one

5-Bromo-1,6-dimethyl-1,2-dihydropyridin-2-one (1.5 g, 7.42 mmol, 1 equiv.), 4,4,5,5-tetramethyl-2-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.26 g, 8.91 mmol, 1 equiv.), Pd(dppf)Cl ₂ (1.09 g, 1.49 mmol, 0.2 equiv.), K ₃ PO ₄ (3.15 g, 14.85 mmol, 2 equiv.) in 10 ml DMF at room temperature. The mixture was stirred at 80°C for 2 hours. LC-MS indicated that the reaction was complete. The crude product was purified on a silica gel column, eluting with PE:EA=1:1 to give 1,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin-2-one (800 mg, 43.15%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =493.3.

Step 3. 5-(5-Amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1,6-dimethylpyridin-2(1H)-one (Compound 66)

1,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (203.0 mg, 0.81 mmol, 1.7 equiv.), 8-bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c ]pyrimidin-5-amine (200 mg, 0.48 mmol, 1 equiv.), Pd(AMPHOS) ₂ Cl ₂ (67.9 mg, 0.10 mmol, 0.20 equiv.), K ₃ PO ₄ ( 203.5 mg, 0.96 mmol, 2 equiv.) was dissolved in 6 ml of a mixture of dioxane/H ₂ O (5:1). The mixture was stirred at 90°C for 1 hour. LC-MS indicated that the reaction was complete. The crude product was purified using a silica gel column, eluting with DCM:CH ₃ OH (10:1), and the product was further purified by preparative HPLC to give the product, 5-[5-amino-7-(4-fluorophenyl)-2-[( 3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl]-1,6-dimethyl-1,2-dihydropyridin-2-one (Compound 66) (35.1 mg, 15.94%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =460.3. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.15 (s, 3H), 3.57 (s, 3H), 4.46 (d, J=2.1 Hz, 2H), 6.38 (d, J=9, 3 Hz, 1H), 6.99-7.11 (m, 2H), 7.16 (d, J=9.3 Hz, 1H), 7.39 (dt, J=8.6, 4.4 Hz, 1H), 7.44-7.55 (m , 2H), 7.63 (ddd, J=9.7, 8.4, 1.4 Hz, 1H), 8.30 (dt, J=4.8, 1.4 Hz, 1H).

Example 67

Preparation of 5-(5-amino-2-((3,5-difluoropyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one (Compound 67)

SCHEME 38

Step 1. 1,3-Dimethyl 2-(3,5-difluoropyridin-2-yl)propanedioate Mixture of 2,3,5-trifluoropyridine (5.0 g, 37.6 mmol, 1.0 equiv.), 1,3- dimethyl propanedioate (7.4 g, 56.0 mmol, 1.5 equiv.) and Cs ₂ CO ₃ (24.5 g, 75.2 mmol, 2.0 equiv.) in DMSO (100.0 ml) stirred for 10 hours at 100°C under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (4 x 50 ml). The combined organic layers were washed with H2O (3 x 50 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (20:1) to give 1,3-dimethyl-2-(3,5-difluoropyridin-2-yl)propanedioate (8.1 g, 79.13% ) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =246.2.

Step 2. Methyl 2-(3,5-difluoropyridin-2-yl) acetate

A mixture of 1,3-dimethyl 2-(3,5-difluoropyridin-2-yl)propanedioate (8.1 g, 33.0 mmol, 1 equiv.) and LiCl (2.8 g, 66.1 mmol, 2. 0 equiv.) in DMSO (100.0 ml) and H ₂ O (10.0 ml) was stirred for 10 hours at 110°C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 100 ml). The combined organic layers were washed with H ₂ O (4 x 10 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (9:1) to give methyl 2-(3,5-difluoropyridin-2-yl)acetate (3.3 g, 48.04%) as light - yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =188.2.

Step 3. 2-(3,5-Difluoropyridin-2-yl)acetic acid

A mixture of methyl 2-(3,5-difluoropyridin-2-yl)acetate (3.3 g, 17.6 mmol, 1.0 equiv.) and LiOH (0.4 g, 16.7 mmol, 1.0 equiv.) in MeOH (30 ml) and H ₂ O (3.0 ml) was stirred for 6 hours at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give the crude product, which was washed with MeCN (10 x 7 ml) then dried to give 2-(3,5-difluoropyridin-2-yl)acetic acid (3.0 g, 93.4% ) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =174.2.

Step 4. N-[2-Amino-6-(4-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-4-yl]-2-(3 ,5-difluoropyridin-2-yl)acetohydrazide

A mixture of 5-[2-amino-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one (60 mg, 0.2 mmol, 1 equiv. ), 2-(3,5-difluoropyridin-2-yl)acetic acid (63.7 mg, 0.4 mmol, 2.0 equiv.), T3P (117.0 mg, 0.4 mmol, 2.0 equiv.) and DIEA (71.3 mg, 0.6 mmol, 3.0 equiv.) in DMSO (5.0 ml) were stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was extracted with CH ₂ Cl ₂ (5 x 20 ml). The combined organic layers were washed with H ₂ O (3×5 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give N-[2-amino-6-(4-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydropyridine-3 -yl)pyrimidin-4-yl]-2-(3,5-difluoropyridin-2-yl)acetohydrazide (80 mg, 89.5%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =482.3.

Step 5. 5-[5-Amino-2-[(3,5-difluoropyridin-2-yl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c] pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 67)

A mixture of N-[2-amino-6-(4-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-4-yl]-2-(3.5 -difluoropyridin-2-yl)acetohydrazide (70.0 mg, 0.2 mmol, 1.0 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (89.0 mg, 0.4 mmol , 3.0 equiv.) was stirred for 2 hours at 120°C under a nitrogen atmosphere. The resulting mixture was added to MeOH (20 ml) and filtered. The filter cake was washed with MeOH (5 × 10 ml). The crude product was purified by preparative HPLC to give 5-[5-amino-2-[(3,5-difluoropyridin-2-yl)methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 67) (18 mg, 26.5%) as a white solid. LC-MS: m/z (ESI), [M-tert-Bu+H] ⁺ =464.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.28 (s, 1H), 6.30 (d, J=9.3 Hz, 1H), 7.11 (dd, J=9.3, 2.6 Hz, 1H), 7.16-7.27 (m, 1H), 7.41-7.52 (m, 1H), 7.70 (d, J=2.6 Hz, 1H), 8.00 (td, J=7.9, 3.1 Hz, 2H), 8.18 ( dd, J=3.0, 1.9 Hz, 1H).

Example 68

Preparation of 7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 68)

SCHEME 39

Step 1. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl1-2-(2-methyl-1,3-thiazol-4-yl)acetohydrazide

Into a stirred mixture of 5-bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 mg, 0.7 mmol) and 2-(2-methyl-1,3-thiazol-4-yl)acetic acid acid (126.5 mg, 0.8 mmol) in DMF (5 ml) added HATU (382.6 mg, 1.0 mmol, 1.5 equiv.) and DIEA (260.1 mg, 2.0 mmol) portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with water (3 x 20 ml) to give H-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(2-methyl- 1,3-thiazol-4-yl)acetohydrazide (130 mg, 44.3%) as a gray solid. LC-MS: m/z (ESI), [M+H] ⁺ =437.0.

Step 2. 1-[5-Amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]-2-(2-methyl -1,3-thiazol-4-yl)ethan-1-one

To a stirred mixture of N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-(2-methyl-1,3-thiazol-4-yl)acetohydrazide (130 mg, 0.3 mmol) and (E)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (151.2 mg, 0.7 mmol) in toluene (3 ml). The resulting mixture was stirred for 3 hours at room temperature under a nitrogen atmosphere. The reaction mixture was quenched with water at room temperature. The precipitated solid was collected by filtration and washed with water (3 x 20 ml) to give 1-[5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5- c]pyrimidin-2-yl]-2-(2-methyl-1,3-thiazol-4-yl)ethan-1-one (100 mg, 75.2%) as a light yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ =418.0.

Step 3. 7-(4-Fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-2-[(2-methyl-1,3-thiazol-4-yl)methyl]- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 68)

Into a stirred mixture of 8-bromo-7-(4-fluorophenyl)-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c ]pyrimidin-5-amine (80 mg, 0.2 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (93.2 mg, 0.4 mmol) in 1,4-dioxane (3 ml) and H ₂ O (0.6 ml) was added K ₃ PO ₄ (127.2 mg, 0.6 mmol) and Pd( dppf)Cl ₂ (27.9 mg, 0.04 mmol, 0.2 equiv.) in portions at room temperature under nitrogen. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified using an XBridge Shield RP18 OBD column, 5 μm, 19 × 150 mm; mobile phase A: water (10 mmol/l NH ₄ HCO ₃ ), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 25% B to 35% B in 8 minutes; 254/220 nm; Rt: 6.45 min to give 7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-2-[(2-methyl-1,3-thiazol-4 -yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 68) (5 mg, 5.7%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ =457.2. ¹ H NMR (300 MHz, Methanol-d ₄ ) δ: 2.66 (s, 3H), 4.34 (s, 2H), 7.04 (t, J=8.7 Hz, 2H), 7.21 (s, 1H), 7.52 (dd, J=8.7, 5.4 Hz, 2H), 7.63 (d, J=9.7 Hz, 1H), 7.78 (d, J=9.3 Hz, 1H), 8.05 (d, J=2 ,1 Hz, 1H), 8.20 (s, 1H), 8.96 (s, 1H).

Example 71

Preparation of 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 71)

SCHEME 40

Step 1. 1,3-Dimethyl 2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate Mixture of 3-(difluoromethoxy)-2-fluoropyridine (20 g, 122.6 mmol, 1 equiv.) and 1,3-dimethyl -propanedioate (24.3 g, 183.9 mmol, 1.5 equiv.) and Cs ₂ CO ₃ (79.9 g, 245.3 mmol, 2.0 equiv.) in DMSO (200.0 ml) were stirred for 10 hours at 100°C in a nitrogen atmosphere. The reaction mixture was quenched with H ₂ O (300.0 ml) at room temperature. The resulting mixture was extracted with EA (3 x 200 ml). The combined organic layers were washed with H ₂ O (2 x 200 ml), dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE: EtOAc=9:1), to give 1,3-dimethyl 2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate (27.3 g, 72.8 %) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =276.2.

Step 2. Methyl 2-[3-(difluoromethoxy)pyridin-2-yl]acetate

A mixture of 1,3-dimethyl-2-[3-(difluoromethoxy)pyridin-2-yl]propanedioate (27.3 g, 99.2 mmol, 1 equiv.) and LiCl (8.4 g, 198.1 mmol, 2.0 equiv.) in DMSO (250.0 ml) and H ₂ O (25 ml) was stirred for 10 hours at 110°C under nitrogen atmosphere. The reaction mixture was quenched with H ₂ O (300.0 ml) at room temperature. The resulting mixture was extracted with EA (3 x 250 ml). The combined organic layers were washed with H ₂ O (2 x 250 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc=20:1) to give methyl 2-(3-(difluoromethoxy)pyridin-2-yl)acetate (14.5 g, 67.4%) in in the form of yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ =218.2.

Step 3. Sodium 2-[3-(Difluoromethoxy)pyridin-2-yl]acetate

A mixture of methyl 2-[3-(difluoromethoxy)pyridin-2-yl]acetate (5.0 g, 23.0 mmol, 1 equiv.) and LiOH (0.6 g, 25.1 mmol, 1.1 equiv. .) in MeOH (50.0 ml) and H ₂ O (5.0 ml) was stirred for 6 hours at room temperature under nitrogen atmosphere. The mixture was acidified to pH=5 aq. HCl (1.1 eq). The resulting mixture was concentrated under vacuum. The residue was redissolved in CH ₃ CN (100.0 ml). After filtration, the filtrate was concentrated under reduced pressure to obtain 2-[3-(difluoromethoxy)-pyridin-2-yl]acetic acid (3.0 g, 59.0%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =204.2.

Step 4. 2-[2-[2-Amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]hydrazin-1-yl]-1-[3-(difluoromethoxy )pyridin-2-yl]ethan-1-one

Mixture of 2-[3-(difluoromethoxy)pyridin-2-yl]acetic acid (899.3 mg, 4.4 mmol, 2.0 equiv.) and HATU (1683.2 mg, 4.4 mmol, 2.0 equiv.) equiv.) in DMSO (20.0 ml) was stirred for 10 min, then 5-bromo-4-hydrazinyl-6-(1,3-oxazol-2-yl)pyrimidin-2-amine (600 mg, 2 .2 mmol, 1.0 equiv.) and DIEA (858.2 mg, 6.6 mmol, 3.0 equiv.) and stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was added to H ₂ O (50 ml) and filtered, the filter cake was washed with H ₂ O (2 × 10 ml). This resulted in 2-[2-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]hydrazin-1-yl]-1-[3-( difluoromethoxy)pyridin-2-yl]ethan-1-one (740.0 mg, 67.4%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ =458.1.

Step 5. 8-Bromo-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1, 5-c]pyrimidine-5-amine

Mixture of 2-[2-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]hydrazin-1-yl]-1-[3-(difluoromethoxy)pyridine -2-yl]ethan-1-one (700 mg, 1.53 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (939.6 mg, 4.62 mmol, 3 .01 equivalent)

stirred for 1 hour at 120°C under nitrogen atmosphere. The resulting mixture was added to MeOH (20 ml) and filtered, the filter cake was washed with MeOH (5×10 ml). This led to the preparation of 8-bromo-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine (370.0 mg, 53.9%) as a white solid. LC-MS: m/z (PER), [M+H] ⁺ = 440.1.

Step 6. 5-(5-Amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 71)

A mixture of 8-bromo-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1,5- c]pyrimidin-5-amine (150.0 mg, 0.3 mmol, 1.0 equiv.), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1,2-dihydropyridin-2-one (160.9 mg, 0.7 mmol, 2.0 equiv.), Pd(dppf)Cl ₂ (50.1 mg, 0.1 mmol, 0 .2 equiv.) and K ₃ PO ₄ (218.0 mg, 1.0 mmol, 3.0 equiv.) in a mixture of dioxane/H ₂ O (10/1, 0.8 ml) was stirred for 10 hours at 90°C in a nitrogen atmosphere. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1). The crude product was washed with EtOH (3×8 ml). This resulted in 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one (Compound 71) (80.0 mg, 49.1%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 467.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.43 (s, 3H), 4.41 (s, 2H), 6.28-6.56 (m, 1H), 7.21-7.29 (m, 1H), 7.34 (s, 1H ), 7.36-7.48 (m, 1H), 7.67 (d, J=8.2 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 8.15 (s, 1H), 8.21 (s, 1H), 8.36 (dd, J=4.7, 1.4 Hz, 1H).

The compound shown in the table below was prepared using the methods described in Example 71.

Example 72

Preparation of 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[ 1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 72)

SCHEME 41

Step 1. Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridine

6-bromo-[1,2,4]triazolo[4,3-a]pyridine (500 mg, 2.525 mmol, 1 equiv), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (705.31 mg, 2.777 mmol, 1.1 equiv.), AcOK (495 .61 mg, 5.050 mmol, 2 equiv.), Pd(dppf)Cl ₂ (184.75 mg, 0.252 mmol, 0.1 equiv.) and dioxane (3 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4] triazolo[4,3-a]pyridine (350 mg, 56.56%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 164.

Step 2. Preparation of 7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-8-[[1,2,4]triazolo[4,3-a]pyridin-6-yl ]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 72)

[[1,2,4]triazolo[4,3-a]pyridin-6-yl]boronic acid (249.95 mg, 1.534 mmol, 8 equiv.), 8-bromo-7- (4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (80 mg, 0.192 mmol, 1 equiv .), K ₃ PO ₄ (81.40 mg, 0.383 mmol, 2 equiv.), Pd(dppf)Cl ₂ (28.06 mg, 0.038 mmol, 0.2 equiv.), dioxane (2 ml) and H ₂ O (0.4 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH = 10:1) to obtain the crude product. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Shield RP18 OBD, 5 µm, 19×150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 ml/min; gradient: from 20% B to 40% B in 7 minutes; 254/220 nm; Rt: 6.67 min, yielding 7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-8-[[1,2,4]triazolo[4,3-a] pyridin-6-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 72) (20 mg, 22.90%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 456.3. ^1H NMR (300 MHz, DMSO-d ₆ ) δ 4.40 (d, J=2.1 Hz, 2H), 7.00-7.20 (m, 3H), 7.37 (dt, J=8.5, 4.4 Hz, 1H ), 7.42-7.51 (m, 2H), 7.62-7.74 (m, 2H), 8.12 (s, 2H), 8.30 (dt, J=4.7, 1.6 Hz, 1H), 8.57 (t, J=1 .4 Hz, 1H), 9.28 (s, 1H).

Example 83

Preparation of 4-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)- 6-methylpicolinonitrile (Compound 83)

SCHEME 42

Step 1. 6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-carbonitrile

AcOK (996.2 mg, 10.2 mmol, 2 equiv.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (414.5 mg, 0.51 mmol, 0.1 equiv.) were added to a 40 ml sealed tube. ), 4-bromo-6-methylpyridin-2-carbonitrile (1 g, 5.1 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.9 g, 7.6 mmol, 1.5 equiv.) in dioxane (20 ml) at 90°C for 2 hours. The target product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeOH in water, gradient from 10% to 20% in 10 min; detector: UV 254 nm, yielding 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-carbonitrile (700 mg, 56.5% ) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 163.3.

Step 2 4-[5-Amino-2-[(2,6-difluorophenyl)methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1,5-c ]pyrimidin-8-yl]-6-methylpyridin-2-carbonitrile (Compound 83)

8-bromo-2-[(2,6-difluorophenyl)methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1,5] was added to a 10 ml sealed tube -c]pyrimidin-5-amine (100 mg, 0.25 mmol, 1 equiv.), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridine-2-carbonitrile (120.0 mg, 0.5 mmol, 2 equiv.), K ₃ PO ₄ (105 mg, 0.5 mmol, 2 equiv.) and Pd(dppr)Cl ₂ CH ₂ Cl ₂ (20 mg, 0.025 mmol, 0.1 equiv.) in dioxane (10 ml) and water (1 ml) at 80°C for 2 hours. The target product could be detected by LC-MS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc 1:1) to give 4-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(1,3-oxazol-2-yl)-[1 ,2,4]triazolo[1,5-c]pyrimidin-8-yl]-6-methylpyridin-2-carbonitrile (Compound 83) (50 mg, 45.8%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 445.2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 2.53 (3H, s), 4.25 (2H, s), 7.12 (2H, t), 7.31 (1H, s), 7.33-7.48 (1H , m), 7.58 (1 Н, d), 7.80 (1 Н, d), 8.22 (1 Н, s), 8.37 (2 Н, s).

Example 89

Preparation of 7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-8-(quinolin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine (Compound 89)

SCHEME 43

Step 1. Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

6-Bromoquinoline (300 mg, 1.442 mmol, 1 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (369.82 mg, 1.456 mmol, 1.01 equiv.), AcOK (283.02 mg, 2.884 mmol, 2.00 equiv.), Pd(dppf )Cl ₂ (211.01 mg, 0.288 mmol, 0.20 equiv.) and dioxane (10 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH = 20:1) to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (150 mg, 40, 78%) as an off-white solid. LC-MS: m/z (PER), [M+H] ⁺ = 257.3.

Step 2. Preparation of 7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-8-(quinolin-6-yl)-[1,2,4]triazolo[1,5- c]pyrimidin-5-amine (Compound 89)

6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (97.8 mg, 0.38 mmol, 2 equiv.) and 8- bromo-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (80 mg, 0 .19 mmol, 1 equiv.), K ₃ PO ₄ (81.4 mg, 0.38 mmol, 2 equiv.), Pd(dppf)Cl ₂ (28.1 mg, 0.04 mmol, 0.2 equiv. .), dioxane (2 ml) and H ₂ O (0.4 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (10 ml x 3) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30 × 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 30% B to 45% B in 7 minutes; 254/220 nm; Rt: 7.02 min to give 7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-8-(quinolin-6-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine (Compound 89) (30 mg, 33.61%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 466.2. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.39 (d, J=2.0 Hz, 2H), 7.04 (t, J=8.9 Hz, 2H), 7.36 (dd, J=8.7, 5 ,4 Hz, 3H), 7.44-7.56 (m, 2H), 7.67 (dd, J=9.9, 8.3 Hz, 1H), 7.83-7.92 (m, 2H), 8.02 (s, 2H), 8.22 ( d, J=8.3 Hz, 1H), 8.29 (dd, J=4.8, 1.8 Hz, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H).

Example 92

Preparation of 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8- yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 92)

SCHEME 44

Step 1. 4-Methoxy-6-(pyridin-2-yl)pyrimidin-2-amine

To 1,4-dioxane (25.00 ml) was added 4-chloro-6-methoxypyrimidin-2-amine (500 mg, 3.133 mmol, 1 equiv.), 2-(tributylstannyl)pyridine (1730.36 mg, 4.700 mmol , 1.5 equiv.), Pd(PPh ₃ ) ₄ (362.09 mg, 0.313 mmol, 0.1 equiv.) and KF (364.08 mg, 6.267 mmol, 2 equiv.) at room temperature. The resulting mixture was stirred for 3 hours at 120°C under a nitrogen atmosphere. The reaction mixture was quenched by adding aq. KF (50 ml) at room temperature. The resulting mixture was stirred for 5 hours at room temperature under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×35 ml). The combined organic layers were washed with water (3×30 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (4:1-2:1) to give 4-methoxy-6-(pyridin-2-yl)pyrimidin-2-amine (500 mg, 78.91% ) as an off-white solid. LC-MS: m/z (PER), [M+H] ⁺ = 203.2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.88 (s, 3H), 6.74 (s, 2H), 6.91 (s, 1H), 7.50 (ddd, J=7.6, 4.7, 1.2 Hz, 1H ), 7.95 (td, J=7.7, 1.8 Hz, 1H), 8.26 (dt, J=7.8, 1.1 Hz, 1H), 8.68 (ddd, J=4.8, 1.9, 0.9 Hz, W ).

Step 2. 5-Bromo-4-methoxy-6-(pyridin-2-yl)pyrimidin-2-amine

To a stirred solution of 4-methoxy-6-(pyridin-2-yl)pyrimidin-2-amine (500 mg, 2.473 mmol, 1 equiv.) in DCM (20 mL) was added NBS (660.12 mg, 3.709 mmol, 1 equiv. .5 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 hours. The reaction was monitored by LC-MS. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with CH ₂ Cl ₂ (2×50 ml). The combined organic layers were washed with water (2×50 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure to obtain 5-bromo-4-methoxy-6-(pyridin-2-yl)pyrimidin-2-amine (550 mg, 79.13%) as a light yellow solid. LC-MS: m/z (PER), [M+H] ⁺ = 281.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 3.94 (s, 3H), 6.95 (s, 2H), 7.46 (ddd, J=7.6, 4.9, 1.2 Hz, 1H), 7.54-7.61 (m , 1H), 7.91 (td, J=7.7, 1.8 Hz, 1H), 8.62-8.68 (m, 1H).

Step 3. 5-[2-Amino-4-methoxy-6-(pyridin-2-yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one

In a solution of 5-bromo-4-methoxy-6-(pyridin-2-yl)pyrimidin-2-amine (450 mg, 1.601 mmol, 1 equiv.) and 1-methyl-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-2-one (564.5 mg, 2.4 mmol, 1.5 equiv.) in dioxane (20 ml) and H ₂ O (2 ml) added K ₃ PO ₄ (1019.4 mg, 4.8 mmol, 3 equiv.) and Pd(dppf)Cl ₂ (234.3 mg, 0.30 mmol, 0.2 equiv.) . After stirring for 2 hours at 80°C under nitrogen, the residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH (12/1)) to obtain 5-[2-amino-4-methoxy-6-(pyridine-2- yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one (230 mg, 33.7%) as a dark yellow solid. LC-MS: m/z (PER), [M+H] ⁺ = 310.2.

Step 4. 5-[2-Amino-4-hydrazinyl-6-(pyridin-2-yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one

Into a stirred solution/mixture of 5-[2-amino-4-methoxy-6-(pyridin-2-yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one (100 mg, 0 .3 mmol, 1 equiv.) in n-BuOH (3 ml) and NH ₂ NH ₂ ⋅H ₂ O (1 ml) at 110°C in a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 6 ml MTBE to obtain 5-[2-amino-4-hydrazinyl-6-(pyridin-2-yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one (80 mg, 80.0%) as a dark yellow solid. LC-MS: m/z (PER), [M+H] ⁺ = 310.2.

Step 5. N-[2-Amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(pyridin-2-yl)pyrimidin-4-yl]-2- (2,6-difluorophenyl)acetohydrazide

Into a stirred solution of 5-[2-amino-4-hydrazinyl-6-(pyridin-2-yl)pyrimidin-5-yl]-1-methyl-1,2-dihydropyridin-2-one (90 mg, 0.3 mmol, 1 equiv.) and 2-(2,6-difluorophenyl)acetic acid (75.1 mg, 0.4 mmol, 1.5 equiv.) in DMF (3 ml) was added HATU (221.25 mg, 0 .6 mmol, 2 equiv.) and DIEA (112.8 mg, 0.9 mmol, 3 equiv.) at 0°C in a nitrogen atmosphere. The mixture was stirred at 0°C-10°C for 30 minutes. The resulting mixture was washed with 10 ml MeOH to give N-[2-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(pyridin-2-yl)pyrimidin-4- yl]-2-(2,6-difluorophenyl)acetohydrazide (50 mg, 37.1%) as a dark yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 464.2.

Step 6. 5-[5-Amino-2-[(2,6-difluorophenyl)methyl]-7-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 92)

Into a stirred solution/mixture of N-[2-amino-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(pyridin-2-yl)pyrimidin-4-yl]- 2-(2,6-difluorophenyl)acetohydrazide (40 mg, 0.09 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (351.2 mg, 1.7 mmol, 20 .00 equiv.) in toluene (3 ml) at 100°C in a nitrogen atmosphere. The crude product (30 mg) was purified by preparative HPLC to give 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(pyridin-2-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one (Compound 92) (3 mg, 7.8%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 446.2. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 3.6 (s, 3H), 4.3 (s, 2H), 6.4 (d, J=9.2 Hz, 1H), 6.9-7.1 (m, 2H), 7.2 (dd, J=9.3, 2.6 Hz, 1H), 7.3-7.4 (t, 1H), 7.4-7.5 (t, 1H), 7.7-7.8 (t, 2H), 7.9 (td, J=7.8 , 1.8 Hz, 1H), 8.5 (dd, J=3.9, 2.5 Hz, 1H).

Example 93/94

Preparation of 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7-(1H-1,2,3-triazol-1-yl) )-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 93) and 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1, 2-a]pyridin-6-yl]-7-(2H-1,2,3-triazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine ( Connection 94)

SCHEME 45

Step 1. 2-[(3-Fluoropyridin-2-yl)methyl1-8-[imidazo[1,2-a1pyridin-6-yl]-7-(1H-1,2,3-triazol-1-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine

7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-[1,2,4] was added to a 10 ml vessel. triazolo[1,5-c]pyrimidin-5-amine (130 mg, 0.329 mmol, 1 equiv.), 2H-1,2,3-triazole (45.48 mg, 0.659 mmol, 2 equiv.), K ₃ PO ₄ (244.63 mg, 1.152 mmol, 3.5 equiv.) and NMP (5 ml) at room temperature. The mixture was then stirred at 100°C under nitrogen atmosphere for 3 hours. The resulting mixture was extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine (3 x 10 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep C18 OBD, 5 µm, 19 x 150 mm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 14% B to 32% B in 7 minutes; 254/220 nm; Rt: 4.67 min, yielding 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7-(1H-1,2 ,3-triazol-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine; trifluoroacetic acid (Comp. 93) (7 mg, 3.93%) as a white solid, LC-MS: m/z (ESI), [M+H] ⁺ = 427.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.43 (d, J=2.1 Hz, 2H), 7.38 (dt, J=8.6, 4.4 Hz, 1H), 7.55 (dd, J=9.4 , 1.6 Hz, 1H), 7.70 (ddd, J=9.9, 8.3, 1.4 Hz, 1H), 7.82-7.95 (m, 2H), 8.19 (d, J=2.1 Hz, 1H), 8.31 (dt, J=4.7, 1.6 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.67 (s, 2H) , 8.95 (t, J=1.3 Hz, 1H): and 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7 -(2H-1,2,3-triazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 94) (8 mg, 5.33% ) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 427.1. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.43 (d, J=2.1 Hz, 2H), 7.38 (dt, J=8.6, 4.4 Hz, 1H), 7.55 (dd, J=9.4 , 1.6 Hz, 1H), 7.70 (ddd, J=9.9, 8.3, 1.4 Hz, 1H), 7.82-7.95 (m, 2H), 8.19 (d, J=2.1 Hz, 1H), 8.31 (dt, J=4.7, 1.6 Hz, 1H), 8.41 (A, J=2.1 Hz, 1H), 8.48 (d, J=1.2 Hz, 1H), 8.67 (s, 2H) , 8.95 (t, J=1.3 Hz, 1H).

Example 100

Preparation of 2-[(3-fluoropyridin-2-yl)methyl]-N7,N7-dimethyl-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo [1,5-c]pyrimidine-5,7-diamine (Compound 100)

SCHEME 46

Step 1. 7-Chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine

To a stirred mixture of 7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-iodo-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (3 g, 7.415 mmol, 1 equiv.), K ₃ PO ₄ (6.30 g, 29.661 mmol, 4 equiv.) and [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (2.61 g , 14.831 mmol, 2 equiv.) in dioxane (20 ml) and H ₂ O (2 ml) was added Pd(dppf)Cl ₂ (813.86 mg, 1.112 mmol, 0.15 equiv.) in portions at room temperature in the atmosphere nitrogen. The mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with water (50 ml). The resulting mixture was filtered and the filter cake was washed with water (3×20 ml). The filtrate was concentrated under reduced pressure. The resulting mixture was washed with CH ₂ Cl ₂ (50 ml), the resulting mixture was filtered, and the filter cake was washed with CH ₂ Cl ₂ (3×20 ml). The filtrate was concentrated under reduced pressure to give 7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine (2 g, 65.9%) as a brown solid. LC-MS: m/z (PER), [M+H] ⁺ = 409.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.40 (3H, d), 4.35 (2H, d), 7.25 (1H, dd), 7.31-7.44 (2H, m), 7.58 (1H, dd) , 7.67 (1H, ddd), 8.21-8.65 (4H, t).

Step 2. 2-[(3-Fluoropyridin-2-yl)methyl]-N7,N7-dimethyl-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2,4 ]triazolo[1,5-c]pyrimidine-5,7-diamine (Compound 100)

Into a stirred mixture of 7-chloro-2-[(3-fluoropyridin-2-yl)methyl]-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine (100 mg, 0.245 mmol, 1 equiv.) and K ₂ CO ₃ (135.22 mg, 0.978 mmol, 4 equiv.) in NMP (1 ml) dimethylamine solution was added (165.42 mg, 3.669 mmol, 15 equiv.) in THF dropwise at room temperature under nitrogen atmosphere. The mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was filtered. The crude product was purified by preparative HPLC under the following conditions: column: X Bridge Prep OBD C18 30 × 150 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 24% B to 34% B in 7 minutes; 254; 220 nm; Rt: 6.48 min, giving 2-[(3-fluoropyridin-2-yl)methyl]-N7,N7-dimethyl-8-[3-methylimidazo[1,2-a]pyridin-6-yl]- [1,2,4]triazolo[1,5-c]pyrimidine-5,7-diamine(Comp. 100) (29 mg, 28.4%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 418.2. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (3H, d), 2.79 (6H, s), 4.23 (2H, d), 7.25 (1H, dd), 7.30-7.39 (2H, m) , 7.49 (1H, dd), 7.54-7.72 (3H, m), 8.28 (2H, ddd).

The compounds listed in the table below were prepared using the methods described in Example 100.

Example 103

Preparation of (S)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 103)

SCHEME 47

Step 1. 4-(4-Fluorophenyl)-6-methoxy-5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrimidin-2-amine

In a solution of 5-bromo-4-(4-fluorophenyl)-6-methoxypyrimidin-2-amine (1000 mg, 3.354 mmol, 1 equiv.) and 1-methyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole (1298.81 mg, 5.032 mmol, 1.5 equiv.) in dioxane (30 ml) and H ₂ O (6 ml) were added K ₃ PO ₄ (1424.06 mg, 6.709 mmol, 2 equiv.) and Pd(dppf)Cl ₂ (490.88 mg, 0.671 mmol, 0.2 equiv.). After stirring for 2 hours at 100°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1), to give 4-(4-fluorophenyl)-6-methoxy-5-(1-methyl-1H-1,3-benzodiazol- 6-yl)pyrimidin-2-amine (847 mg, 72.2%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 350.3.

Step 2. 4-(4-Fluorophenyl)-6-hydrazinyl-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine

4-(4-fluorophenyl)-6-methoxy-5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrimidin-2-amine (450 mg, 1.288 mmol, 1 equiv.) was added to the vessel. , hydrazine (5 ml) and dioxane (5 ml) at room temperature. The resulting mixture was stirred for 3 hours at 100°C in an air atmosphere. The product was precipitated by adding water. The resulting mixture was filtered and the filter cake was washed with methyl tert-butyl ether (3×30 ml). The filtrate was concentrated under reduced pressure. The resulting solid was dried under vacuum to give 4-(4-fluorophenyl)-6-hydrazinyl-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (375 mg, 83. 3%) as an off-white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 350.3.

Step 3. (S)-2-(1-Methylpyrrolidin-2-yl)acetic acid hydrochloride

In a solution of (S)-2-(pyrrolidin-2-yl)acetic acid hydrochloride (500 mg, 3.019 mmol, 1 equiv.) and formaldehyde (1.5 ml, 0.050 mmol, 0.02 equiv.) in MeOH (10 mL, 0.312 mmol, 0.10 equiv.) was added 10% Pd/C (150 mg) under nitrogen in a round bottom flask. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen atmosphere using a hydrogen cylinder, filtered through a celite filter and concentrated under reduced pressure to give (S)-2-(1-methylpyrrolidin-2-yl)acetic acid hydrochloride (446 mg , 82.2%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 144.3.

Step 4. (S)-N'-(2-Amino-6-(4-fluorophenyl)-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-4-yl)-2 -(1-methylpyrrolidin-2-yl)acetohydrazide

4-(4-fluorophenyl)-6-hydrazinyl-5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrimidin-2-amine (150 mg, 0.429 mmol, 1 equiv.) was added to the vessel. , 2-[(2S)-1-methylpyrrolidin-2-yl]acetic acid (153.69 mg, 1.073 mmol, 2.50 equiv.), HATU (195.90 mg, 0.515 mmol, 1.20 equiv.) , DIPEA (166.47 mg, 1.288 mmol, 3.00 equiv.) and DMF (5 ml) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 12:1) to give (S)-N'-(2-amino-6-(4-fluorophenyl)-5-(1-methyl-1H-benzo[d] imidazol-6-yl)pyrimidin-4-yl)-2-(1-methylpyrrolidin-2-yl)acetohydrazide (120 mg, 58.9%) as a brown solid. LC-MS: m/z (ESI), [M+H] ⁺ = 475.2.

Step 5. (S)-7-(4-Fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 103)

N-[2-amino-6-(4-fluorophenyl)-5-(1-methyl-1H-1,3-benzodiazol-6-yl)pyrimidin-4-yl]-2-[(2S) was added to the vessel. -1-methylpyrrolidin-2-yl]acetohydrazide (120 mg, 0.253 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (3 ml) at room temperature. The resulting mixture was stirred for 2 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 19 × 250 mm, 5 µm; mobile phase A: water (0.05% NH ₃ H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 29% B to 39% B in 8 minutes; 254/220 nm; t _R : 6.45 min, yielding (S)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin- 2-yl)methyl)-[1,2,4]triazolo-[1,5-c]pyrimidin-5-amine (Compound 103) (8 mg, 6.9%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 457.2. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.61 (3H, d), 1.74-1.91 (1H, m), 2.11 (1H, q), 2.26 (3H, s), 2.57-2.70 (2H, m), 2.93 (1H, t), 3.12 (1H, dd), 3.74 (3H, s), 6.96-7.13 (3H, m), 7.36 (2H, dd), 7.48-7.59 (2H, m), 7.95 (2H, s), 8.19 (1H, s).

Example 104

Preparation of (R)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 104)

SCHEME 48

Step 1. Methyl 2-[(2R)-1-methylpyrrolidin-2-yl]acetate hydrochloride

In a solution of methyl 2-[(2R)-pyrrolidin-2-yl]acetate hydrochloride (20 mg, 0.111 mmol, 1 equiv.) and formaldehyde (10.03 mg, 0.334 mmol, 3 equiv., 37%) in MeOH (1 mL) Pd/C (20 mg, 0.188 mmol, 1.69 equiv.) was added under nitrogen in a round bottom flask. The mixture was hydrogenated at room temperature for 2 hours under a hydrogen atmosphere using a hydrogen cylinder, filtered through a celite filter and concentrated under reduced pressure to give methyl 2-[(2R)-1-methylpyrrolidin-2-yl]acetate hydrochloride (14 mg, 64.9%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 158.3.

Step 2. 2-[(2R)-1-Methylpyrrolidin-2-yl1acetic acid

Methyl 2-[(2R)-1-methylpyrrolidin-2-yl]acetate (21 mg, 0.134 mmol, 1 equiv.), NaOH (6.41 mg, 0.160 mmol, 1.20 equiv.), and MeOH (2 ml) at room temperature. The resulting mixture was stirred for 3 hours at 70°C under a nitrogen atmosphere. The mixture was neutralized to pH 7 with acetic acid. The resulting mixture was concentrated under vacuum. The residue was dissolved in acetic acid (5 ml). The resulting mixture was concentrated in vacuo to give 2-[(2R)-1-methylpyrrolidin-2-yl]acetic acid (12 mg, 62.7%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 142.3.

Step 3. N-[2-Amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-[(2R)-1-methyl-pyrrolidin-2-yl]acetohydrazide

5-Bromo-4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 mg, 0.671 mmol, 1 equiv.), 2-[(2R)-1-methylpyrrolidin-2-yl]acetic acid was added to the vessel. acid (288.18 mg, 2.013 mmol, 3.00 equiv.), HATU (306.10 mg, 0.805 mmol, 1.20 equiv.), DIPEA (173.41 mg, 1.342 mmol, 2.00 equiv.) and DMF (7 ml) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 10:1) to give N-[2-amino-5-bromo-6-(4-fluorophenyl)pyrimidin-4-yl]-2-[(2R)-1 -methylpyrrolidin-2-yl]acetohydrazide (130 mg, 45.7%) as a light brown solid. LC-MS: m/z (ESI), [M+H] ⁺ = 423.2

Step 4. 8-Bromo-7-(4-fluorophenyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-[1,2,4]-triazolo[1,5-c] pyrimidine-5-amine

(Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (288.36 mg, 1.417 mmol, 3 equiv.), toluene (5 mL), and N-[2-amino-5-bromo -6-(4-fluorophenyl)pyrimidin-4-yl]-2-[(2R)-1-methylpyrrolidin-2-yl]acetohydrazide (200 mg, 0.472 mmol, 1 equiv.) at room temperature. The resulting mixture was stirred for 3 hours at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 12:1) to give 8-bromo-7-(4-fluorophenyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine (140 mg, 73.1%) as a light brown solid. LC-MS: m/z (ESI), [M+H] ⁺ = 407.2

Step 5. (R)-7-(4-Fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)- [1,2,4]triazolo[1,5-c]pyrimidin-5-amine (Compound 104)

In a solution of 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole (248.40 mg, 0.962 mmol, 3. 00 equiv.) and 8-bromo-7-(4-fluorophenyl)-2-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-[1,2,4]triazolo[1,5-c ]pyrimidin-5-amine (130 mg, 0.321 mmol, 1 equiv.) in dioxane (3 ml, 0.034 mmol, 0.11 equiv.) and H ₂ O (0.5 ml, 0.028 mmol, 0.09 equiv. ) K ₃ PO ₄ (204.27 mg, 0.962 mmol, 3.00 equiv.) and Pd(dppf)Cl ₂ (46.94 mg, 0.064 mmol, 0.20 equiv.) were added. After stirring for 2 hours at 100°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 19 × 250 mm, 5 µm; mobile phase A: water (0.05% NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 20 ml/min; gradient: from 28% B to 39% B in 8 minutes; 254:220 nm; t _R : 6.75 min, yielding (R)-7-(4-fluorophenyl)-8-(3-methyl-3H-benzo[d]imidazol-5-yl)-2-((1-methylpyrrolidin- 2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine (Compound 104) (5 mg, 3.4%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 457.4. ¹ H-NMR (400 MHz, Methanol-d ₄ ) δ 1.68-1.86 (3H, m), 1.96-2.05 (1H, m), 2.34 (1H, q), 2.43 (3H, s), 2.75-2.89 ( 2H, m), 3.08-3.19 (1H, m), 3.22-3.29 (1H, m), 3.88 (3H, s), 6.94 (2H, t), 7.11 (1H, dd), 7.40-7.47 (2H, m), 7.59 (1H, d), 7.62 (1H, d), 8.17 (1H, s).

Example 106-1/106-2

Preparation of 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4 ]triazolo[1,5-f]pyrimidin-5-amine (Ex. 106-1) and 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl )-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine (Exp. 106-2)

SCHEME 49

Step 1. N'-(2-Amino-5-bromo-6-(oxazol-2-yl)pyrimidin-4-yl)-2-(tetrahydrofuran-2-yl)acetohydrazide

Into a stirred solution of 5-bromo-4-hydrazinyl-6-(1,3-oxazol-2-yl)pyrimidin-2-amine (600 mg, 2.213 mmol, 1 equiv.) and 2-(oxolan-2-yl) acetic acid (288.06 mg, 2.213 mmol, 1.00 equiv.) in DMF was added DIEA (858.19 mg, 6.640 mmol, 3.00 equiv.) and T ₃ P (1408.51 mg, 4.427 mmol, 2 .00 equiv.) drop by drop at 0°C in an air atmosphere. The resulting mixture was stirred at room temperature for 4 hours. The resulting mixture was concentrated under vacuum. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2- (oxolan-2-yl)acetohydrazide (500 mg, 58.95%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 385.0. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.54-1.65 (1H, m), 1.85 (2H, hept), 2.00 (1H, dq), 2.30 (1H, dd), 2.46 (1H, t) , 3.59 (1H, p), 3.76 (1H, q), 4.13 (1H, h), 6.32-6.72 (1H, m), 7.46 (1H, s), 8.28 (1H, s), 9.39 (1H, d ).

Step 2. 8-Bromo-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine

N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(oxolan-2-yl)acetohydrazide (500 mg) was added to a 40 ml vessel , 1.305 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (20 ml) at room temperature. The resulting mixture was stirred for 12 hours at 120°C in an air atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to give 8-bromo-7-(1,3-oxazol-2-yl)-2-[(oxolan-2-yl)methyl]-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine (340 mg, 71.35%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 365.0. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.66 (1H, ddt), 1.78-1.96 (2H, m), 1.97-2.13 (1H, m), 2.90-3.11 (2H, m), 3.62 ( 1H, td), 3.78 (1H, td), 4.32 (1H, p), 7.52 (1H, s), 8.25 (2H, s), 8.35 (1H, s).

Step 3. 8-(3-Methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2 ,4]triazolo[1,5-f]pyrimidine-5-amine

8-bromo-7-(1,3-oxazol-2-yl)-2-[(oxolan-2-yl)methyl]-[1,2,4]triazolo[1,5-] was added to a 40 ml vessel. c]pyrimidin-5-amine (246 mg, 0.674 mmol, 1 equiv.), [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (296.36 mg, 1.684 mmol, 2.50 equiv.), Pd(dppf)Cl ₂ (98.58 mg, 0.135 mmol, 0.2 equiv.) and K ₃ PO ₄ (428.96 mg, 2.021 mmol, 3.0 equiv.) in dioxane (20 ml )/water (3 ml) at room temperature. The resulting mixture was stirred for 15 hours at 100°C under a nitrogen atmosphere and then concentrated in vacuo. The residue was purified by preparative TLC (CH ₂ Cl ₂ /MeOH 20:1) to obtain 8-[3-methylimidazo[1,2-a]pyridin-6-yl]-7-(1,3-oxazol-2-yl) -2-[(oxolan-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (100 mg, 35.65%) as a yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 417.3. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.63 (1H, dq), 1.82 (2H, tq), 2.00 (1H, dq), 2.39 (3H, s), 2.97 (2H, qd), 3.58 (1H, q), 3.75 (1H, q), 4.25 (1H, p), 7.10 (1H, dd), 7.26 (1H, s), 7.40 (1H, d), 7.48-7.57 (1H, m), 8.16 (1H, s), 8.17-8.41 (3H, t).

Step 4. 8-(3-Methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2 ,4]triazolo[1,5-f]pyrimidin-5-amine (Ex. 106-1) and 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2 -yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine (Ex. 106-2)

The crude product (60 mg) was purified by preparative chiral HPLC under the following conditions: column: Lux 5 μm Cellulose-4, 2.12 × 25 cm, 5 μm; mobile phase A: hexane (8 mmol/l NH ₃ ⋅MeOH)-HPLC, mobile phase B: MeOH: EtOH = 1:1-HPLC; flow rate: 20 ml/min; gradient: from 50 V to 50 V in 21 minutes; 254/220 nm; RT1: 13.027; RT2: 17.308, giving 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[ 1,2,4]triazolo[1,5-f]pyrimidin-5-amine (Exp. 106-1) (25 mg, 31.25%) and 8-(3-methylimidazo[1,2-a]pyridine -6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine ( Ex. 106-2) (25 mg, 31.25%) as a white solid. (Exp. 106-1) LC-MS: m/z (ESI), [M+H] ⁺ = 417.1. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 1.74 (1H, ddt), 1.96 (2H, dddd), 2.08-2.20 (1H, m), 2.51 (3H, d), 2.99-3.17 (2H, m), 3.83 (2H, dtd), 4.38-4.49 (1H, m), 7.17 (1H, dd), 7.28 (1H, d), 7.41 (1H, d), 7.55 (1H, dd), 7.90 (1H , d), 8.37 (1H, t); (Exp. 106-2) LC-MS: m/z (ESI), [M+H] ⁺ = 417.2. ¹ H-NMR (400 MHz, MeOD-d ₄ ) δ 1.68-2.17 (4H, m), 2.51 (3H, d), 2.99-3.18 (2H, m), 3.68-3.81 (1H, m), 3.91 ( 1H, q), 4.43 (1H, p), 7.18 (1H, dd), 7.28 (1H, d), 7.41 (1H, d), 7.55 (1H, dd), 7.90 (1H, d), 8.36 (1H , t).

Example 107-1/107-2

Preparation of 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4 ]triazolo[1,5-f]pyrimidin-5-amine (Compound 107-1) and 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl )-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[1,5-1]pyrimidin-5-amine (Compound 107-2)

SCHEME 50

Step 1. N-[2-Amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(oxolan-3-yl)acetohydrazide

To a 100 mL 3-neck round bottom flask, add 5-bromo-4-hydrazinyl-6-(1,3-oxazol-2-yl)pyrimidin-2-amine (400 mg, 1.476 mmol, 1 equiv.) and DMF at room temperature. To the above mixture, T ₃ P (1878.02 mg, 5.902 mmol, 4 equiv.) and DIEA (953.55 mg, 7.378 mmol, 5 equiv.) were added dropwise over 1 min at 0°C. To the above mixture, 2-(oxolan-3-yl)acetic acid (193 mg, 1.483 mmol, 1.01 equiv.) was added dropwise over 5 min at 0°C. The resulting mixture was stirred for another 1 hour at -3°C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 1 × 12 ml PE. The precipitated solid was collected by filtration and washed with EtOAc (1×4 ml). This resulted in N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(oxolan-3-yl)acetohydrazide (1000 mg, 159 .16%, crude) as a yellow oil. LC-MS: m/z (ESI), [M+H] ⁺ = 385.0.

Step 2. 8-Bromo-7-(1,3-oxazol-2-yl)-2-[(oxolan-3-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine

N-[2-amino-5-bromo-6-(1,3-oxazol-2-yl)pyrimidin-4-yl]-2-(oxolan-3-yl)acetohydrazide (2 g, 5.219 mmol, 1 equiv.) and (Z)-(trimethylsilyl-N-(trimethylsilyl)ethanimidate) (8 ml) at room temperature. The resulting mixture was stirred for 2 hours at 120°C in an air atmosphere. The mixture was left to cool to 35°C. The resulting mixture was diluted with MeOH (10 ml). The resulting mixture was filtered. This resulted in 8-bromo-7-(1,3-oxazol-2-yl)-2-[(oxolan-3-yl)methyl]-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine (600 mg, 30.82%) as a dark yellow solid. LC-MS: m/z (ESI), [M+H] ⁺ = 365.1 ^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.55-1.77 (2H, m), 2.00-2.09 (1H, m ), 2.62-2.77 (1H, m), 2.90 (2H, d), 3.41-3.46 (1H, m), 3.58-3.71 (1H, m), 3.71-3.88 (2H, m), 7.51 (1H, d ), 8.20 (2H, s), 8.34 (1H, d).

Step 3. 8-(3-Methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetoahydrofuran-3-yl)methyl)-[1,2 ,4]triazolo[1,5-f]pyrimidin-5-amine (Compound 107-1) and 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2 -yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine (Compound 107-2)

Into a stirred mixture of 8-bromo-7-(1,3-oxazol-2-yl)-2-[(oxolan-3-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine (400 mg, 1.095 mmol, 1 equiv.) and [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (385.51 mg, 2.191 mmol, 2.00 equiv.) in solvents (dioxane: H ₂ O = 10:1), Pd(dppf)Cl ₂ (160.29 mg, 0.219 mmol, 0.2 equiv.) and K ₃ PO ₄ (813.75 mg, 3.834 mmol, 3 .50 equiv.) in portions at room temperature in an air atmosphere. The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The aqueous layer was extracted with EtOAc (3×20 ml). The residue was purified by reverse phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: ACN in water, gradient: 50% to 100% in 20 min; detector: UV 254 nm. The crude product was purified by preparative chiral HPLC under the following conditions: column: CHIRALPAK IG, i.d. (inner diameter) 2.0 cm, length 25 cm (5 µm); mobile phase A: hexane: DCM = 3:1 (10 mM NH ₃ -MEON)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 ml/min; gradient: from 50 V to 50 V in 36 min; 220/254 nm; RT1: 16.167; RT2: 23.294, yielding 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[ 1,2,4]triazolo[1,5-f]pyrimidin-5-amine (50 mg, 49.70%) as a gray solid and 8-(3-methylimidazo[1,2-a]pyridine-6 -yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-5-amine (50 mg , 49.70%) as a gray solid. (Exp. 107-1) LC-MS: m/z (ESI), [M+H] ⁺ = 417.1 ¹ H-NMR (300 MHz, Methanol-d ₄ ) δ 1.67-1.84 (1H, m) , 2.06-2.23 (1H, m), 2.52 (3H, d), 2.80-2.85 (1H, m), 2.94-3.03 (2H, m), 3.56-3.59 (1H, m), 3.77-3.82 (1H, m), 3.85-4.00 (2H, m), 7.16-7.20 (1H, m), 7.28 (1H, d), 7.42 (1H, d), 7.54-7.57 (1H, m), 7.91 (1H, d) , 8.36 (1H, d); (Exp. 107-2) LC-MS: m/z (ESI), [M+H] ⁺ = 417.2 ¹ H-NMR (300 MHz, Methanol-d ₄ ) δ 1.75-1.79 (1H, m) , 2.06-2.23 (1H, m), 2.51 (3H, d), 2.80-2.84 (1H, m), 2.98 (2H, d), 3.56-3.61 (1H, m), 3.77-3.80 (1H, m) , 3.88-3.94 (2H, m), 7.16-7.20 (1H, m), 7.28 (1H, d), 7.42 (1H, d), 7.54-7.57 (1H, m), 7.91 (1H, d), 8.35 -8.37 (1H, t).

The compounds listed in the table below were prepared using the methods described in Examples 106-1/106-2 and 107-1/107-2.

Example 121

Preparation of 2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine (Compound 121)

SCHEME 51

Step 1. 7-Chloro-2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine

To a stirred mixture of 8-bromo-7-chloro-2-[(2,6-difluorophenyl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (100 mg, 0.267 mmol , 1 equiv.) and [3-methylimidazo[1,2-a]pyridin-6-yl]boronic acid (93.96 mg, 0.534 mmol, 2.00 equiv.) in dioxane (5 ml) was added PdAMPHOS (18 .90 mg, 0.027 mmol, 0.1 equiv.), water (1 ml) and K ₃ PO ₄ (170.01 mg, 0.801 mmol, 3 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred further overnight at 70°C. The mixture was left to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (5 ml) and dried under vacuum to give 7-chloro-2-[(2,6-difluorophenyl)methyl]-8-[3-methylimidazo[1,2-a]pyridinium- 6-yl]-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (60 mg, 52.78%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 426.2.

Step 2. 2-(2,6-Difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1,5- c]pyrimidin-5-amine (Compound 121)

Into a stirred mixture of 7-chloro-2-[(2,6-difluorophenyl)methyl]-8-[3-methylimidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine (100 mg, 0.235 mmol, 1 equiv.) and morpholine (41 mg, 0.470 mmol, 2 equiv.) in NMP (5 ml) was added K ₂ CO ₃ (64.91 mg , 0.470 mmol, 2 equiv.) in portions at room temperature in an air atmosphere. The resulting mixture was further stirred overnight at 100°C. The mixture was left to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH (3×20 ml). The filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 30×150 mm, 5 µm; mobile phase A: water (0.05%NH ₃ ⋅H ₂ O), mobile phase B: ACN; flow rate: 60 ml/min; gradient: from 33% B to 44% B in 7 minutes; 254; 220 nm; Rt: 6.45 min to give 2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (10.6 mg, 10.01%) as a white solid. LC-MS: m/z (ESI), [M+H] ⁺ = 477.4. ^1H NMR (300 MHz, DMSO- _d6 ) δ 2.3 (3H, d), 3.1 (4H,d), 3.5 (4H,d), 4.1 (2H, s), 7.0 (2H, t), 7.3 ( 2H, d), 7.5 (2H, d), 7.7(2H, s), 8.4 (1H, s).

The compounds listed in the table below were prepared using the methods described in Example 121.

Example 127: Binding Affinities for Different Adenosine Receptors

The binding affinity and specificity of the compounds for different human adenosine receptor subtypes (hA1, hA2A, hA2B and hA3) were characterized using cell membrane chromatography binding assays.

Compounds at different concentrations were incubated with hA1 membrane (from PerkinElmer) and [ ³ H]-8-cyclopentyl-1,3-dipropylxanthine (DPCPX) for 50 min at 25°C, meanwhile 100 μl of 0.5% solution PEI was added to the UNFILTER-96 GF/B filter plate for 60 min at 4°C, then the UNIFILTER-96 GF/B filter plate was washed twice with 50 ml of wash buffer, the membrane mixture was transferred to the UNIFILTER-96 GF/B filter plate, and the filter plate was washed 4 times and then incubated at 55°C for 10 minutes. Finally, 40 μl of ULTIMA GOLD was added to each well and the CPM (counts per minute) was read using TopCount.

Compounds at different concentrations were incubated with hA2a membrane (from PerkinElmer) and [ ³ H]-CGS21680 for 90 min at 25°C, while 100 μl of 0.5% PEI solution was added to the UNFILTER-96 GF/B filter plate for 60 min at 4°C, then the UNIFILTER-96 GF/B filter plate was washed twice with 50 ml of washing buffer, the membrane mixture was transferred to the UNIFILTER-96 GF/B filter plate, and the filter plate was washed 4 times, and then incubated at 55 °C for 10 min. Finally, 40 µl of ULTIMA GOLD was added to each well and the CPM was read using TopCount.

Compounds at various concentrations were incubated with hA2b membrane (from PerkinElmer) and [ ³ H]-DPCPX for 60 min at 27°C, and binding reactions were stopped by rapid filtration through UNIFILTER-96 GF/C plates coated with 0.5% BSA , using a cell harvester. The filter plates were then washed three times with ice-cold wash buffer and dried at 37°C for 120 min. Finally, 50 μL of scintillation cocktail was added to each well and the CPM was read using TopCount.

Compounds at various concentrations were incubated with hA3 membrane (from PerkinElmer) and [ ¹²⁵ I]-AB-MECA for 60 min at 27°C, and binding reactions were stopped by rapid filtration through UNIFILTER-96 GF/C plates coated with 0.5 % BSA (bovine serum albumin), using a cell harvester. The filter plates were then washed three times with ice-cold wash buffer and dried at 37°C for 120 min. Finally, 50 μL of scintillation cocktail was added to each well and the CPM was read using TopCount.

The binding affinities and specificities of exemplary compounds for human A1, A2a, A2b and A3 receptors are shown in Table 3 below. Blank cells in the tables below indicate that there is no data.

Example 128: FLIPR™ and cAMP Inhibition Assay

hADORA1/CHO cells (hA1 expressing) (Genscript) were seeded at 1 x 10 ⁴ cells per well in 384-well polystyrene plates one day before the start of the experiment. On the day of the experiment, the supernatant was removed and replaced with 40 μl of dye (FLIPR calcium 5 assay kit) per well and the plates were incubated for 60 minutes at 37°C plus 5% CO ₂ . Test compounds were then added at different concentrations for inhibition assays using FLIPR™ (Fluorescence Imaging Plate Reader). After incubation for 400 seconds with compound, 10 μM adenosine was added to the wells and the signal was captured by FLIPR.

hA2a/CHO, hA2b/CHO and mA2a/CHO(Genscript) were seeded at 5×10 ³ cells per well in 384-well polystyrene plates on the day of the experiment. The compounds were preincubated with cells for 30 min at 37°C, 5% CO ₂ . Then 10 µM adenosine was added to the wells and incubated for 30 min at 37°C, 5% CO ₂ . Detection reagent (CISBIO) was added and the plates were incubated for 60 min at room temperature. The signal was captured via Envision.

FLIPR™ and cAMP (cyclic adenosine monophosphate) inhibition activity of exemplary compounds in cell lines overexpressing different adenosine receptors is presented in Table 4 below.

Claims (201)

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, where X is selected from amino, ring A selected from: Z is selected from halogen, amino, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, 3-12 membered saturated or unsaturated carbocyclyl or 3-12 membered saturated or unsaturated heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S, which may optionally be mono- or independently polysubstituted with R ₂ , Y is -WV, where W is -NH-, C _1-12 alkylene, V is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl having 1 or 2 heteroatoms selected from N, O or S, which may optionally be mono- or independently polysubstituted with R ₃ , each R ₁ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _{1- 12} alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated heterocyclyl having 1 heteroatom selected from O and S, where the sulfur atom can possibly be oxidized to form S-oxides, each R ₂ is independently selected from halogen, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-( C _1-12 alkyl) ₂ amino, each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl)2 _a mino, m is 0, 1, 2, 3 or 4. 2. A compound according to claim 1, where W represents C _1-6 alkylene, possibly C _1-3 alkylene. 3. The connection according to claim 1, where V is selected from: 4. The compound of claim 1, wherein each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkoxy, or N,N-(C _1-12 alkyl) ₂ amino. 5. A compound according to claim 1, wherein each R ₁ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 halkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl -OH, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino or 3-6 membered saturated carbocyclyl or heterocyclyl and optionally 3-6 membered saturated carbocyclyl or heterocyclyl is cyclopropyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl. 6. A compound according to claim 1, where Z represents a halogen, a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S, which may optionally be mono- or independently polysubstituted with R ₂ . 7. A compound according to claim 6, wherein the 3-12 membered saturated or unsaturated carbocyclyl or the 3-12 membered saturated or unsaturated heterocyclyl is selected from: 8. The compound of claim 1, wherein each R ₃ is independently selected from halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, or C _1-12 haloalkoxy. 9. The compound according to claim 1, where W represents methylene. 10. Compound of formula (Ia) or a pharmaceutically acceptable salt thereof, where ring A is selected from: ring B is selected from a 3-12 membered saturated or unsaturated carbocyclyl or a 3-12 membered saturated or unsaturated heterocyclyl having 1, 2 or 3 heteroatoms selected from N, O or S; ring Q is a 5-6 membered saturated or unsaturated carbocyclyl or a 5-6 membered saturated or unsaturated heterocyclyl having 1 or 2 heteroatoms selected from N, O or S; W represents imino, C _1-12 alkylene, each R ₁ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _{1- 12} alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated heterocyclyl having 1 heteroatom selected from O and S, where the sulfur atom can possibly be oxidized to form S-oxides, each R ₂ is independently selected from halogen, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-( C _1-12 alkyl) ₂ amino, each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino; And m is equal to 0, 1, 2, 3 or 4, n is 0, 1, 2, 3 or 4, i is 0, 1, 2, 3 or 4. 11. The connection according to claim 10, where ring B is selected from: 12. The connection according to claim 10, where the ring Q is selected from: 13. The compound according to claim 10, where each R ₁ is independently selected from fluorine, chlorine, cyano, amino, methyl, ethyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, methylamino, trifluoromethoxy, dimethylamino, isopropanylamino, ethoxyl, trifluoroethoxy, ethylamino , cyclopropyl, hydroxyethyl, oxacyclopentanyl, oxetanyl or 1,1-dioxothietanyl. 14. The compound according to claim 10, where each R ₂ is independently selected from fluorine, chlorine, methyl, amino, ethyl, methoxyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, ethoxyl, methylamino, dimethylamino, ethylamino, isopropanylamino. 15. The compound according to claim 10, where each R ₃ is independently selected from fluorine, chlorine, cyano, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxyl, methylamino, dimethylamino, isopropylamino, trifluoroethoxy, ethylamino. 16. A compound according to claim 10, wherein ring A is pyridonyl, ring B is phenyl, ring Q is pyridinyl. 17. The compound according to claim 10, where W represents methylene. 18. Compound of formula (Ib) Formula (Ib) or a pharmaceutically acceptable salt thereof, where R ₁ is selected from cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, C _1-12 alkyl-OH, N-(C _1-12 alkyl) amino, N,N-(C _1-12 alkyl) ₂ amino, 3-10 membered saturated or unsaturated carbocyclyl or 3-10 membered saturated heterocyclyl having 1 heteroatom selected from O and S, where a sulfur atom may optionally be oxidized to form S-oxides; each R ₂ is independently selected from halogen, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 alkoxyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-( C _1-12 alkyl) ₂ amino; each R ₃ is independently selected from halogen, cyano, amino, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 haloalkoxy, N-(C _1-12 alkyl)amino, N,N-(C _1-12 alkyl) ₂ amino; W represents imino, C _1-12 alkylene; And n is 0, 1, 2, 3 or 4; i is 0, 1, 2, 3 or 4. 19. The compound according to claim 18, where R ₁ represents C _1-12 alkyl. 20. The compound according to claim 18, where R ₂ is halogen, n = 1. 21. The compound according to claim 18, where R ₃ is halogen, i = 1. 22. The compound according to claim 18, where W represents methylene. 23. A compound selected from the group consisting of: 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 8-(2-chloropyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 2-[(2,6-difluorophenyl)methyl]-7-(4-fluorophenyl)-8-[2-(trifluoromethyl)pyridin-4-yl]-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine, 2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-8-(2-methoxypyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine , 2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-8-(pyridazin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine, 2-[(3-chlorophenyl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5- amine, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridine -2(1H)-she, 2-(2,6-difluorobenzyl)-8-(2-(dimethylamino)pyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine, 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-2-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine , 2-[1-(2,6-difluorophenyl)ethyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo [1,5-c] pyrimidine-5-amine, 2-[(2,6-difluorophenyl)methyl]-8-(2,5-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine, 2-[(6-chloropyridin-2-yl)methyl]-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 2-(2,6-difluorobenzyl)-8-(2,3-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amina, 2-((6-(dimethylamino)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5 -f]pyrimidine-5-amine, 8-(2-chloro-6-methylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine, 6-((5-amino-7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-f]pyrimidin-2-yl)methyl ) picolinonitrile, 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methyl-1,2-dihydropyridin-2-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( tetrahydrofuran-3-yl)pyridin-2(1H)-one, 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one, 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(2H-1,2,3-triazol-2-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl]-1-methyl-1,2-dihydropyridin-2-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(5-methyloxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl) -1-methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-methyloxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl) -1-methylpyridin-2(1H)-one, 5-(5-amino-7-chloro-2-(2,6-difluorobenzyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-methylpyridin-2(1H )-she, 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1,3-dimethylpyridin-2(1H)-one, 6-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-f]pyrimidin-8-yl )-2-methylpyridazin-3(2H)-one, 2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine, 2-[(2,6-difluorophenyl)methyl]-8-(2,6-dimethylpyridin-4-yl)-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine, 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-ethylpyridin-2(1H)-one, 5-(5-amino-2-((6-aminopyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-cyclopropylpyridin-2(1H)-one, 6-[[5-amino-7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-[1,2,4]triazolo[1,5-c]pyrimidine -2-yl]methyl]pyridin-2-amine, 8-(2-aminopyridin-4-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 5-[5-amino-7-(3,4-difluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one, 5-(5-amino-7-(3-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-7-(4-(difluoromethyl)phenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one, 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(2-(methylamino)pyridin-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-5-amine, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(thiazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -methylpyridin-2(1H)-one, 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2-methylpyridin-4-yl)-[1,2,4]triazolo[1,5-c] pyrimidine-5-amine, 7-(4-fluorophenyl)-8-(2-methylpyridin-4-yl)-N2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2,5 -diamine, 7-(4-fluorophenyl)-2-((6-methylpyridin-2-yl)methyl)-8-(2,6-dimethylpyridin-4-yl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine, 2-(2,6-difluorobenzyl)-8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-5 -amina, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( oxetan-3-yl)pyridin-2(1H)-one, 8-(2,6-dimethylpyridin-4-yl)-7-(4-fluorophenyl)-2-((3-methoxypyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine, 8-(2-amino-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine, 5-[5-amino-7-(4-fluorophenyl)-2-[(3-fluoropyridin-2-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl ]-1-(propan-2-yl)-1,2-dihydropyridin-2-one, 5-(5-amino-7-(4-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 4-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-7-yl)benzonitrile, 5-[5-amino-7-(4-fluorophenyl)-2-[(1,3-thiazol-4-yl)methyl]-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl]-1-methyl-1,2-dihydropyridin-2-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( 1,1-dioxidothietane-3-yl)pyridin-2(1H)-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(4-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(4-(trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-c]pyrimidin- 8-yl)-1-methylpyridin-2(1H)-one, 5-[5-amino-2-[(3-fluoropyridin-2-yl)methyl]-7-(1H-pyrazol-1-yl)-[1,2,4]triazolo[1,5-c]pyrimidine -8-yl]-1-methyl-1,2-dihydropyridin-2-one, 5-(5-amino-7-(2,4-difluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1-( 2-hydroxyethyl)pyridin-2(1H)-one, 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1,6-dimethylpyridin-2(1H)-one, 5-(5-amino-2-((3,5-difluoropyridin-2-yl)methyl)-7-(4-fluorophenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one, 7-(4-fluorophenyl)-8-[imidazo[1,2-a]pyridin-6-yl]-2-[(2-methyl-1,3-thiazol-4-yl)methyl]-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine, 5-(5-amino-7-(3-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-2-[[3-(difluoromethoxy)pyridin-2-yl]methyl]-7-(1,3-oxazol-2-yl)-[1,2,4]triazolo[1, 5-c]pyrimidin-8-yl)-1-methyl-1,2-dihydropyridin-2-one, 8-([1,2,4]triazolo[4,3-a]pyridin-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1 ,2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-7-(4-fluorophenyl)-8-(imidazo[1,2-a]pyridin-6-yl)-[1,2,4 ]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-(difluoromethoxy)pyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2 ,4]triazolo[1,5-c]pyrimidin-5-amine, 8-(1H-benzo[d]imidazol-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine, 5-(5-amino-7-(3,5-difluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-methylpyridin-2(1H)-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(3-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-7-(2-chlorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 5-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl)-1 -isopropylpyridin-2(1H)-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8 -yl)-1-isopropylpyridin-2(1H)-one, 8-(2-amino-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine, 8-(2-chloro-6-methylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine, 4-(5-amino-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl) -6 -methylpicolinonitrile, 8-(2-cyclopropyl-6-methylpyridin-4-yl)-2-(2,6-difluorobenzyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine, 2-(2,6-difluorobenzyl)-8-(2-(difluoromethoxy)pyridin-4-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo [1,5-c] pyrimidine-5-amine, 8-(2-(difluoromethoxy)pyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine, 8-(2-(difluoromethoxy)-6-methylpyridin-4-yl)-2-((3-fluoropyridin-2-yl)methyl)-7-(oxazol-2-yl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine, 8-(benzo[d]thiazol-6-yl)-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5- c]pyrimidine-5-amine, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(quinolin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine, 2-((3-fluoropyridin-2-yl)methyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(oxazol-2-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine, 2-(2,6-difluorobenzyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine, 5-[5-amino-2-[(2,6-difluorophenyl)methyl]-7-(pyridin-2-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl ]-1-methyl-1,2-dihydropyridin-2-one, 2-((3-fluoropyridin-2-yl)methyl)-8-(imidazo[1,2-a]pyridin-6-yl)-7-(1H-1,2,3-triazol-1-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-[(3-fluoropyridin-2-yl)methyl]-8-[imidazo[1,2-a]pyridin-6-yl]-7-(2H-1,2,3-triazol-2-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 5-(5-amino-7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-(2-hydroxyethyl)pyridin-2(1H)-one, 7-(4-fluorophenyl)-2-((3-fluoropyridin-2-yl)methyl)-8-(quinoxalin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin- 5-amine, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(1-methyl-1H-indol-5-yl)-[1,2,4]triazolo[1,5 -c]pyrimidin-8-yl)-1-methylpyridin-2(1H)-one, 5-(5-amino-2-((3-fluoropyridin-2-yl)methyl)-7-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-c]pyrimidin-8-yl )-1-methylpyridin-2(1H)-one, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-fluoropyridin-2-yl)methyl)-N7,N7-dimethyl-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[ 1,5-c]pyrimidine-5,7-diamine, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-1-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1, 5-c]pyrimidin-5-amine, (S)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine, (R)-7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine, 7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (isomer 1), 7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4]triazolo[ 1,5-c]pyrimidin-5-amine (isomer 2), 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1), 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2), 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1), 8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-2-((tetrahydrofuran-3-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2), 2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(4-methylpiperazin-1-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine, 2-(2,6-difluorobenzyl)-7-(3-methoxyazetidin-1-yl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo [1,5-c]pyrimidin-5-amine, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-oxa-6-azaspiro[3.4]octane- 6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1), 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2), 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 1), 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(3-methylmorpholino)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine (isomer 2), 7-(4-fluorophenyl)-2-(2-methoxyethyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1,5-c ]pyrimidine-5-amine, 7-(4-fluorophenyl)-8-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1,2,4] triazolo[1,5-c]pyrimidin-5-amine, 7-(3-fluoro-1H-pyrazol-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 7-(4-fluoro-1H-pyrazol-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl) -[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-5-amine, 7-(azetidin-1-yl)-2-((3-fluoropyridin-2-yl)methyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2, 4]triazolo[1,5-c]pyrimidin-5-amine, 2-(2-(dimethylamino)ethyl)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo[1, 5-c]pyrimidine-5-amine, 2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-morpholino-[1,2,4]triazolo[1,5-c]pyrimidine -5-amine, (S)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(pyrrolidin-1-yl)-[1,2,4]triazolo[1 ,5-c]pyrimidin-5-amine, 7-(azetidin-1-yl)-2-(2,6-difluorobenzyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-[1,2,4]triazolo [1 ,5-c]pyrimidin-5-amine, (R)-7-(4-fluorophenyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-2-((1-methylpyrrolidin-2-yl)methyl)-[1, 2,4]triazolo[1,5-c]pyrimidin-5-amine, 2-(2-methoxyethyl)-8-(3-methylimidazo[1,2-a]pyridin-6-yl)-7-(oxazol-2-yl)-[1,2,4]triazolo [1,5 -c]pyrimidin-5-amine, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition having the activity of adenosine receptor inhibitors, which contains one or more compounds according to any one of paragraphs. 1-23 and a pharmaceutically acceptable carrier. 25. The use of one or more compounds according to any one of paragraphs. 1-23 in the manufacture of a medicament for the treatment of a disease associated with an adenosine receptor. 26. Use according to claim 25, wherein the adenosine receptor associated disease is cancer, Parkinson's disease, epilepsy, cerebral ischemia and stroke, depression, cognitive impairment, HIV (human immunodeficiency virus), severe combined immunodeficiency with adenosine deaminase deficiency (ADA) -SCID), acute heart failure and chronic heart failure, chronic obstructive pulmonary disease (COPD) or asthma. 27. Use according to claim 26, wherein the cancer is NSCLC (non-small cell lung cancer), RCC (renal cell carcinoma), prostate cancer or breast cancer. 28. Use according to claim 25, where the drug is used in combination with radiotherapy, chemotherapy or immunotherapy. 29. A method of inhibiting an adenosine receptor, comprising administering to a subject an effective amount of one or more compounds according to any one of claims. 1-23 or the pharmaceutical composition according to claim 24. 30. The method of claim 29, further comprising administering to the subject one or more immunotherapeutic agents or chemotherapeutic agents. 31. The method of claim 29, further comprising administering radiotherapy to the subject. 32. The combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-23 and an immunotherapeutic agent or a chemotherapeutic agent, wherein the combination has adenosine receptor inhibitory activity. 33. The combination according to claim 32, where the specified immunotherapeutic agent is selected from the group consisting of anti-PD-1/PD-L1 antibodies (antibody to programmed cell death receptor protein 1/its ligand PD-L1), anti-CTLA- 4 antibodies (anti-cytostatic T-lymphocyte antigen-4), anti-CD73 antibodies (anti-ecto-5'-nucleotidase), anti-CD39 antibodies (anti-ectonucleoside triphosphate diphosphohydrolase 1), anti-CCR2 antibodies (anti-C-C chemokine receptor 2) and any combination thereof. 34. The combination of claim 32, wherein said chemotherapeutic agent is selected from the group consisting of platinum-based chemotherapeutic agents (cisplatin, oxaliplation, docetaxel, paclitaxel, doxorubicin, etoposide, mitoxantrone, and any combination thereof).