Triazolone compounds

Abstract

The present invention discloses triazolone compounds of formula (I) and pharmaceutically acceptable salts thereof. Also described are methods of making and using the compounds of formula (I). The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful as adenosine receptor antagonists, for example, for treating diseases or conditions mediated by adenosine receptors, such as cancer, movement disorders, or attention disorders. #imgabs0#

Description

[0001] Adenosine regulates many physiological functions. Intracellularly, adenosine is involved in energy metabolism, nucleic acid metabolism, and methionine cycling; extracellular adenosine participates in intercellular signaling. For example, extracellular adenosine is a potent immunosuppressant that prevents excessive immune responses during inflammation and infection. Adenosine also acts on other systems, including the cardiovascular system and the central nervous system.

[0002] The effects of adenosine are mediated by a family of G-protein coupled receptors. At least four adenosine receptor subtypes have been identified: A1R, A2aR, A2bR, and A3R. The A1R and A3 subtypes inhibit the activity of the enzyme adenylate cyclase, while the A2a and A2b subtypes stimulate the activity of the same enzyme, thereby regulating the level of cyclic AMP in the cell.

[0003] In the immune system, engagement of the A2a and A2b adenosine receptors is a key regulatory mechanism that protects tissues from excessive immune responses. In tumors, this pathway is hijacked and impedes antitumor immunity, promoting cancer progression. Furthermore, in many cases, the tumor microenvironment contains high levels of extracellular adenosine. Therefore, adenosine receptors, particularly A2aR and A2bR, have been identified as targets for cancer therapy.

[0004] Many adenosine receptor antagonists have been reported. For example, international patent application WO 2006 / 138734 discloses triazolopyrimidine cannabinoid receptor 1 (CB-1) antagonists. WO 2008 / 002596 and WO 2009 / 111449 disclose adenosine A2a receptor antagonists including a triazolone moiety. WO 2012 / 038980 discloses fused tricyclic compounds as adenosine receptor antagonists. WO 2016 / 161282 discloses heterocyclic compounds as LSD1 inhibitors. WO 2018 / 166493 discloses heteroaryl [4,3-c] pyrimidine-5-amine derivatives used as A2a receptor antagonists.

[0005] There remains a need for highly soluble, highly selective and highly potent adenosine receptor antagonists. Summary of the invention

[0006] In one aspect, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] Ring A may be saturated, partially unsaturated or aromatic, and may have the structure:

[0010]

[0011] Y1 It can be N, -CH- or -C=;

[0012] Y 2 Can be O or -CR g =;

[0013] Where R g H, halogen, -R a OR a ;

[0014] R 1 Can be halogen, C 1-3 Alkyl, -OC 1-3 Alkyl, -CO2R a or -NR 7 R 8 ;

[0015] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens;

[0016] or R 1 and R g Together with the atoms to which they are attached, they may form a 5-membered heterocyclic or heteroaryl group having one or two heteroatoms selected from N and O;

[0017] R 2 Can be halogen, C 1-3 Alkyl, -OC 1-3 Alkyl, -CO2R a or -NR 7 R 8 ;

[0018] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens;

[0019] R 3 It can be:

[0020]

[0021] R 4 Can be -(CHR c ) i -(NR a ) j -R 5 ;

[0022] R 5 It can be:

[0023] (1) C 3-8Cycloalkyl, aryl, 3- to 8-membered heterocyclyl, or 3- to 8-membered heteroaryl;

[0024] Wherein the heterocyclic group and the heteroaryl group independently include 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O and S(O) k ;

[0025] Where R 5 One or two ring atoms of are optionally replaced by -C(=O)-;

[0026] (2) a 6- to 11-membered polycyclic cycloalkyl, aryl, heterocyclyl or heteroaryl ring system, wherein each of the heterocyclyl and heteroaryl groups includes 1 to 4 independently selected radicals selected from N, O and S(O) k heteroatoms;

[0027] Where R 5 One or two ring atoms of are optionally replaced by -C(=O)-; or

[0028] (3) C 1-6 Alkyl, -OR a 、-NR a R b , cyano, ‌-OS(O)2-C 1-3 Alkyl, ‌-CO2R a , ‌-C(O)NR a R b , ‌-NR a -C(O)-OR a or ‌-OC(O)-NR a R b ;

[0029] Where R 5 Optionally substituted by one to four groups ‌-XR 6 replace;

[0030] Each X independently can be a bond, -O-, -NR a -、-S(O) k -、-(CH2) m -or-C(O)-;

[0031] Each R 6 independently may be H, halogen, -OR a , C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, heteroaryl, aryl, -CO2R a , ‌-C(O)NR a R b 、-(CH2) n -NR a Rb or cyano;

[0032] wherein each of the heterocyclyl and heteroaryl groups includes 1 to 4 independently selected from N, O and S(O) k heteroatoms;

[0033] Each C 3-8 One or two ring atoms of a cycloalkyl, heterocyclyl, heteroaryl or aryl group are independently optionally replaced by -C(=O)-;

[0034] wherein each of alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl is optionally substituted with one or more substituents independently selected from -R a 、-OR a , ‌-(CH2) n -NR a R b and halogens;

[0035] Each R 7 and each R 8 Independently, it can be R a ;

[0036] or R 7 and R 8 Together with the atoms to which they are attached, they can form a 3- to 8-membered heterocyclic group, which is optionally substituted with one or more substituents independently selected from ‌-OR a and halogens;

[0037] Each R a and each R b can be H, C independently 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 Cycloalkylalkyl;

[0038] Each R a and each R b is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0039] Each R c independently can be H, halogen, C 1-3 Alkyl or -(CH2) n -NR a R b ;

[0040] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens;

[0041] Each Rd independently may be halogen, cyano, -R a OR a ;

[0042] c can be 0, 1, 2, or 3;

[0043] i can be 0, 1, 2, or 3;

[0044] j can be 0 or 1;

[0045] Each k independently can be 0, 1, or 2;

[0046] Each m independently may be 1 or 2; and

[0047] Each n independently can be 0 or 1.

[0048] The compound may be a selective adenosine receptor antagonist relative to CB-1.

[0049] The compound may have a Ki of 100 nM or less for at least one of A2aR and A2bR, and may have a Ki of 10,000 nM or greater for CB-1.

[0050] R 2 It can be -CH3.

[0051] i can be 1, 2, or 3; and each R c It can be H.

[0052] R 5 It may be a 5-membered heterocyclic group or a 5-membered heteroaryl group.

[0053] i can be 1; R c can be H; and R 5 It may be 1,3-oxazolyl which is optionally substituted by one to two -CH3 groups.

[0054] In another aspect, provided is a compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof:

[0055]

[0056] in:

[0057] Y 1 Can be N or CH;

[0058] Y 3 and Y 4 Together they can be -CH=N-, -N=CH-, -CH=CH-, or =CH-O-;

[0059] Each R 1 and each R2 independently may be halogen, C 1-3 Alkyl or -OC 1-3 alkyl;

[0060] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0061] R 4 Can be -CHR c -R 5 ;

[0062] R 5 It can be:

[0063] (1) a 5- or 6-membered heterocyclic group, or a 5- or 6-membered heteroaryl group;

[0064] Wherein the heterocyclic group and the heteroaryl group independently include 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O and S(O) k ;

[0065] Where R 5 One or two ring atoms of are optionally replaced by -C(=O)-;

[0066] wherein heterocyclyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, -R e AND-OR e ;or

[0067] (2) H, halogen or C 1-3 alkyl;

[0068] wherein the alkyl group may be optionally substituted with one or more substituents independently selected from -OH and halogen;

[0069] Each R a and each R b can be H, C independently 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 Cycloalkylalkyl;

[0070] Each R a and each R b is optionally substituted with one or more substituents independently selected from -OH and halogen;

[0071] R c Can be H, halogen, C 1-3 Alkyl or -(CH2) n -NR a R b ;

[0072] wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens;

[0073] R d It can be H or halogen;

[0074] Each R e can independently be H or C 1-6 alkyl;

[0075] wherein alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen; and

[0076] n can be 0 or 1.

[0077] In the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, Y 1 can be N; and R 1 and R 2 may each independently be -CH3.

[0078] In the compound of formula (IIb) or a pharmaceutically acceptable salt thereof, R 2 may be -CH3; and R 5 It may be a 5- or 6-membered heteroaryl group.

[0079] In the compound of formula (IIa) or formula (IIb) or a pharmaceutically acceptable salt thereof, R c can be H; and R 5 It may be C optionally substituted by one to three fluorine 1-3 alkyl.

[0080] In another aspect, provided is a compound selected from the group consisting of:

[0081] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0082] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0083] 5-amino-2-(3,3-difluoropropyl)-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0084] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0085] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0086] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0087] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0088] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0089] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0090] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0091] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0092] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0093] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0094] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0095] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0096] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0097] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0098] 5-amino-8-[(cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0099] 5-amino-8-[(cis)-2,6-dimethyltetrahydropyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0100] 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(4-hydroxy-3,5-dimethyl-phenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0101] 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0102] 5-amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0103] 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyl-2-pyridyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0104] 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(7-methyl-1H-indazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0105] 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(7-methyl-1H-benzoimidazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0106] 5-amino-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0107] 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0108] 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0109] 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0110] 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuterophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0111] 5-amino-8-(7-chloro-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0112] 5-amino-8-(7-methyl-1H-indol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0113] In another aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0114] In another aspect, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating a disease or condition mediated by adenosine receptors.

[0115] The adenosine receptor-mediated disease or condition can be lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, stomach cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors.

[0116] Other features, objects, and advantages will be apparent from the description, and from the claims.

[0117] describe

[0118] The compounds of formula (I), formula (II) and formula (IIb) or pharmaceutically acceptable salts thereof can be used as adenosine receptor antagonists.

[0119] Described herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0120] .

[0121] Ring A is saturated, partially unsaturated or aromatic and has the structure:

[0122] .

[0123] Y 1 It is N, -CH- or -C=.

[0124] Y 2 Is O or -CR g =; where R g H, halogen, -R a OR a .

[0125] R 1 Halogen, C 1-3 Alkyl, -OC 1-3 Alkyl, -CO2R a or -NR 7 R 8 wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens.

[0126] or R 1 and R g Together with the atoms to which they are attached, they form a 5-membered heterocyclic or heteroaryl group having one or two heteroatoms selected from N and O.

[0127] R2 Halogen, C 1-3 Alkyl, -OC 1-3 Alkyl, -CO2R a or -NR 7 R 8 wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens.

[0128] R 3 yes:

[0129] .

[0130] R 4 Yes-(CHR c ) i -(NR a ) j -R 5 .

[0131] R 5 Yes: (1) C 3-8 Cycloalkyl, aryl, 3- to 8-membered heterocyclyl or 3- to 8-membered heteroaryl; wherein the heterocyclyl and heteroaryl independently include 1 to 4 heteroatoms independently selected from N, O and S(O) k ; where R 5 One or two ring atoms of the cycloalkyl, aryl, heterocyclyl or heteroaryl ring system are optionally replaced by -C(=O)-; (2) a 6- to 11-membered polycyclic cycloalkyl, aryl, heterocyclyl or heteroaryl ring system, wherein each of the heterocyclyl and heteroaryl groups comprises 1 to 4 independently selected radicals selected from N, O and S(O) k heteroatom; where R 5 One or two ring atoms of are optionally replaced by -C(=O)-; or (3) C 1-6 Alkyl, -OR a 、-NR a R b , cyano, ‌-OS(O)2-C 1-3 Alkyl, ‌-CO2R a , ‌-C(O)NR a R b , ‌-NR a -C(O)-OR a or ‌-OC(O)-NR a R b .

[0132] R 5 Optionally 1 to 4 groups ‌-XR 6 replace.

[0133] Each X is independently a bond, -O-, -NRa -、-S(O) k -、-(CH2) m -or -C(O)-.

[0134] Each R 6 are independently H, halogen, -OR a , C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclyl, heteroaryl, aryl, -CO2R a , ‌-C(O)NR a R b 、-(CH2) n -NR a R b or cyano; wherein each of the heterocyclic group and the heteroaryl group includes 1 to 4 independently selected from N, O and S(O) k heteroatom; each C 3-8 One or two ring atoms of a cycloalkyl, heterocyclyl, heteroaryl or aryl group are independently optionally replaced by -C(=O)-; wherein each of the alkyl, cycloalkyl, heterocyclyl, heteroaryl and aryl groups is optionally substituted by one or more substituents independently selected from -R a 、-OR a , ‌-(CH2) n -NR a R b and halogens.

[0135] Each R 7 and each R 8 Independently R a .

[0136] or R 7 and R 8 Together with the atoms to which they are attached, they form a 3- to 8-membered heterocyclyl, which is optionally substituted with one or more substituents independently selected from ‌-OR a and halogens.

[0137] Each R a and each R b Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 Cycloalkylalkyl; wherein each R a and each R b are independently optionally substituted with one or more substituents independently selected from -OH and halogen.

[0138] Each R c are independently H, halogen, C 1-3 Alkyl or -(CH2)n -NR a R b wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens;

[0139] Each R d are independently halogen, cyano, -R a OR a .

[0140] c is 0, 1, 2, or 3.

[0141] i is 0, 1, 2, or 3.

[0142] j is 0 or 1.

[0143] Each k is independently 0, 1 or 2.

[0144] Each m is independently 1 or 2.

[0145] Each n is independently 0 or 1.

[0146] In certain embodiments, R 2 It is -CH3.

[0147] In certain embodiments, i is 1, 2, or 3; and each R c It's H.

[0148] In certain embodiments, R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group.

[0149] In certain embodiments, i is 1; R c is H; and R 5 It is 1,3-oxazolyl optionally substituted by one to two -CH3 groups.

[0150] In certain embodiments, R 5 It is a 6-membered heterocyclic group or a 6-membered heteroaryl group.

[0151] In certain embodiments, Y 1 Yes N; Y 2 It is O; R 1 is -CH3; and R 2 It is CH3.

[0152] In certain embodiments, Y 1 is -CH- or -C=; and Y 2 It's O.

[0153] In certain embodiments, i is 1; R c is H; and R 5It is a 5-membered heterocyclic group or a 5-membered heteroaryl group.

[0154] In certain embodiments, i is 1; R c is H; and R 5 It is a 6-membered heterocyclic group or a 6-membered heteroaryl group.

[0155] In certain embodiments, R 1 and R g Together with the atoms to which they are attached they form a 5-membered heterocyclyl or heteroaryl.

[0156] In certain embodiments, R 1 and R g Together with the atoms to which they are attached, they form a 5-membered heterocyclyl or heteroaryl; and R 2 It is -CH3.

[0157] In certain embodiments, Y 1 Yes N; Y 2 It is O; R 1 is -CH3; R 2 is CH3; and R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group.

[0158] In certain embodiments, Y 1 Yes N; Y 2 It is O; R 1 is -CH3; R 2 is CH3; and R 5 It is a 6-membered heterocyclic group or a 6-membered heteroaryl group.

[0159] In certain embodiments, Y 1 Yes N; Y 2 It is O; R 1 is -CH3; R 2 is CH3; i is 1; R c is H; and R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group.

[0160] In certain embodiments, Y 1 Yes N; Y 2 It is O; R 1 is -CH3; R 2 is CH3; i is 1; R c is H; and R 5 It is a 6-membered heterocyclic group or a 6-membered heteroaryl group.

[0161] Described herein are compounds of formula (IIa) or (IIb) or pharmaceutically acceptable salts thereof:

[0162] .

[0163] Y 1 It is N or CH.

[0164] Y 3 and Y 4 Together they are -CH=N-, -N=CH-, -CH=CH-, or =CH-O-.

[0165] Each R 1 and each R 2 are independently halogen, C 1-3 Alkyl or -OC 1-3 Alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0166] R 4 Yes - CHR c -R 5 .

[0167] R 5 is: (1) a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group; wherein the heterocyclic group and the heteroaryl group independently include 1 to 4 heteroatoms, and the heteroatoms are independently selected from N, O and S(O) k ; where R 5 One or two ring atoms of are optionally replaced by -C(=O)-; wherein heterocyclyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, -R e AND-OR e ; or (2) H, halogen or C 1-3 Alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0168] Each R a and each R b Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-9 Cycloalkylalkyl; wherein each R a and each R b are independently optionally substituted with one or more substituents independently selected from -OH and halogen.

[0169] R c H, halogen, C 1-3 Alkyl or -(CH2) n -NR a R b wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens.

[0170] R d is H or halogen.

[0171] Each R e independently H or C 1-6 Alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halogen.

[0172] n is 0 or 1.

[0173] Compounds of formula (IIa) and formula (IIb) are encompassed by the broader formula (I).

[0174] In certain embodiments of Formula (IIa), Y 1 is N; and R 1 and R 2 Each is independently ‌-CH3.

[0175] In certain embodiments of Formula (IIb), R 2 is -CH3; and R 5 is a 5- or 6-membered heteroaryl group.

[0176] In certain embodiments, R c is H; and R 5 is C optionally substituted by one to three fluorine 1-3 alkyl.

[0177] In certain embodiments, Y 3 and Y 4 Together they are -CH=N-.

[0178] In certain embodiments, Y 3 and Y 4 Together they are -N=CH-.

[0179] In certain embodiments, Y 3 and Y 4 Together they are -CH=CH-.

[0180] In certain embodiments, Y 3 and Y 4 Together they are =CH-O-.

[0181] In certain embodiments of Formula (IIa), R c is H; and R 5 is C optionally substituted by one to three fluorine 1-3 alkyl.

[0182] In certain embodiments of Formula (IIb), R c is H; and R 5 It is 1,3-oxazolyl optionally substituted by one to two -CH3 groups.

[0183] The term "halogen" refers to fluorine, chlorine, bromine and iodine.

[0184] The term "alkyl" refers to a fully saturated straight or branched chain aliphatic group, if specified, having the specified number of carbon atoms (e.g., C 1-10 Alkyl refers to an alkyl group having from one to ten carbons). Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. If no size is specified, "alkyl" refers to a group having from 1 to 10 carbon atoms.

[0185] The term "alkenyl" refers to an unsaturated straight or branched aliphatic group containing at least one carbon-carbon double bond and, if specified, having the specified number of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-butenyl, 3-butenyl, 3-methylbut-1-enyl, 1-pentenyl, and 4-hexenyl. If no size is specified, "alkenyl" refers to a group having 2 to 10 carbon atoms.

[0186] The term "alkynyl" refers to an unsaturated straight or branched aliphatic group containing at least one carbon-carbon triple bond and, if specified, having the specified number of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and but-2-ynyl. If no size is specified, "alkynyl" refers to a group having 2 to 10 carbon atoms.

[0187] Alkenyl and alkynyl groups may contain more than one unsaturated bond, or a mixture of double and triple bonds.

[0188] The term "cycloalkyl" refers to a saturated or unsaturated aliphatic ring containing 3 to 10 carbon ring atoms, one or more of which may be optionally replaced by -C(=O)-. The cycloalkyl group may contain a fused ring and / or a bridged ring, including a fused ring or a bridged ring that is a cycloalkyl. Suitable examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, cyclohexynyl, cycloheptyl, norbornyl, 4-oxocyclohex-1-yl and 3-oxocyclohept-5-ene-1-yl.

[0189] The term "heterocyclyl" refers to a saturated or unsaturated heterocycle containing 3 to 10 ring atoms, wherein 1 to 4 ring atoms are independently N, O or S; and one or more carbon ring atoms may be optionally replaced by -C(=O)-. The ring nitrogen or ring sulfur atoms may be optionally oxidized, including, for example, -N(O)-, -S(O)- or -S(O)2-. The ring nitrogen atoms in the heterocyclyl group may be optionally quaternized, for example, -N +(CH3)2-. The heterocyclyl group may contain fused rings and / or bridged rings, including the case where the fused rings or bridged rings are cycloalkyl or heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

[0190] The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon radical containing 6 to 14 ring atoms. The aryl radical may contain a fused ring, including an aryl ring fused to a cycloalkyl ring, a heterocyclyl ring or an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl and dihydro-1H-indenyl.

[0191] The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic aromatic group containing 6 to 14 ring atoms, wherein 1 to 4 ring atoms are independently N, O or S. The ring nitrogen or ring sulfur atoms independently can be optionally oxidized, including, for example, -N(O)-, -S(O)- or -S(O)2-. The heteroaryl group can contain fused rings and / or bridged rings, including the case where the fused ring or bridged ring is a cycloalkyl, heterocyclyl, aryl or heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, pyridyl, imidazolyl, oxazolyl, thiazolyl, pyrimidinyl, 5,6,7,8-tetrahydroquinolinyl, benzofuranyl, pyrrolopyridinyl, pyrrolopyrimidinyl, triazinyl and tetrazolyl.

[0192] The term "polycyclic ring system" refers to a cycloalkyl, heterocyclyl, aryl or heteroaryl group comprising two or more fused and / or bridged rings.

[0193] Some of the compounds described herein may exist in more than one stereoisomeric form. Unless otherwise indicated, the description of such compounds is intended to include all geometric and optical isomers, including racemates.

[0194] Some compounds described herein may exhibit tautomerism. The structural formulas herein generally represent only one of the possible tautomeric forms of such compounds. It should be understood that the structural formulas are intended to include all tautomeric forms of such compounds.

[0195] The term "pharmaceutically acceptable salt" refers to those salts of compounds of formula (I) that retain the biological activity of the free compound and that can be administered to humans and / or animals as a drug. The desired salt of the basic functional group of the compound can be prepared by treating the compound with an acid. Some examples of suitable inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Some examples of suitable organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. The desired salt of the acidic functional group of the compound can be prepared by treating the compound with a base. Some examples of suitable inorganic salts of acidic compounds include, but are not limited to, alkali metal and alkaline earth metal salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts. Some examples of suitable organic salts of acidic compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, N,N'-dibenzylethylenediamine, and triethylamine salts.

[0196] The compounds of formula (I) may contain the atoms in any isotopic form thereof. In this regard, embodiments of the invention that may be mentioned include those in which: (a) the compounds of formula (I) are not isotopically enriched or labeled with respect to any atom of the compound; and (b) the compounds of formula (I) are isotopically enriched or labeled with respect to one or more atoms of the compound.

[0197] The use of in the formulae herein refers to the points of attachment between the various groups.

[0198] Exemplary compounds of formula (I) or pharmaceutically acceptable salts thereof include:

[0199] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0200] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0201] 5-amino-2-(3,3-difluoropropyl)-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0202] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0203] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0204] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0205] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0206] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0207] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0208] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0209] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0210] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0211] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0212] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0213] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0214] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0215] 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0216] 5-amino-8-[(cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0217] 5-amino-8-[(cis)-2,6-dimethyltetrahydropyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0218] 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(4-hydroxy-3,5-dimethyl-phenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0219] 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0220] 5-amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0221] 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyl-2-pyridyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0222] 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(7-methyl-1H-indazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0223] 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(7-methyl-1H-benzoimidazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0224] 5-amino-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0225] 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0226] 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0227] 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0228] 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuterophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one;

[0229] 5-amino-8-(7-chloro-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and

[0230] 5-amino-8-(7-methyl-1H-indol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

[0231] The compound of formula (I) may be an adenosine receptor antagonist, ie, an antagonist of one or more of A1R, A2aR, A2bR and A3R. The term "adenosine receptor antagonist" refers to a compound that binds to an adenosine receptor and antagonizes its activity, for example, a compound of formula (I).

[0232] In some cases, the compound of formula (I) is a selective adenosine receptor antagonist. The term "selective" refers to the property of the compound of formula (I), which is an adenosine receptor antagonist but is substantially inactive against other biological targets. The term "substantially inactive" as used herein describes a compound that (i) has a significantly weaker affinity for a given receptor than its affinity for adenosine receptors; (ii) does not show substantial agonist or antagonist activity against a given receptor; or both (i) and (ii).

[0233] The term "selective adenosine receptor antagonist" refers to a compound that exhibits a binding affinity for one or more adenosine receptor subtypes that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold greater than its affinity for a given receptor. In other words, the ratio of binding Ki values ​​(given receptor: adenosine receptor) can be at least 100, at least 1,000, or at least 10,000.

[0234] In particular, selective adenosine receptor antagonists may be substantially inactive at other G-protein coupled receptors, such as the cannabinoid receptors, known as CB-1 and CB-2.

[0235] The compound of formula (I) may have a binding affinity Ki for A2aR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less.

[0236] The compound of formula (I) may have a binding affinity Ki for A2bR of, for example, 100 nM or less, 10 nM or less, or 1 nM or less.

[0237] The compound of formula (I) may have a binding affinity Ki for CB-1 of, for example, 1,000 nM or greater, 10,000 nM or greater, 13,000 nM or greater.

[0238] The compounds of formula (I) may be selective adenosine receptor antagonists relative to CB-1.

[0239] The compounds of formula (I) may be active as adenosine receptor antagonists but are substantially inactive towards CB-1.

[0240] The compounds of formula (I) may also be selective between different subtypes of adenosine receptors. In certain embodiments, the compounds of formula (I) are A2aR-selective; A2bR-selective; or dual A2aR / A2bR-selective.

[0241] A2aR-selective compounds exhibit binding affinity for A2aR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than their binding affinity for each of A1R, A2bR, and A3R.

[0242] A2bR-selective compounds exhibit binding affinity for A2bR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than their binding affinity for each of A1R, A2aR, and A3R.

[0243] Dual A2aR / A2bR-selective compounds exhibit a binding affinity for A2aR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than their binding affinity for each of A1R and A3R. Dual A2aR / A2bR-selective compounds also exhibit a binding affinity for A2bR that is at least 100-fold, at least 1,000-fold, or at least 10,000-fold stronger than their binding affinity for each of A1R and A3R. Additionally, for dual A2aR / A2bR-selective compounds, the ratio of the binding affinity for A2aR to the binding affinity for A2bR is less than 100.

[0244] In one embodiment, a pharmaceutical composition is provided, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

[0245] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as finely divided powders or liquid aerosols), administration by insufflation (e.g., as finely divided powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular metered administration, or as suppositories for rectal metered administration).

[0246] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethylparaben or propylparaben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to alter their disintegration and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, in either case, using conventional coating agents and procedures well known in the art.

[0247] Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or oil (such as peanut oil, liquid paraffin or olive oil).

[0248] The compounds of formula (I) can be used to treat diseases or conditions mediated by adenosine receptors. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by adenosine receptors is provided. In certain embodiments, the disease or condition is mediated by A2aR; in other embodiments, by A2bR; in still other embodiments, by both A2aR and A2bR.

[0249] Some examples of diseases or conditions mediated by adenosine receptors include cancer, including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, stomach cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glial cancer, melanoma or other solid tumors; movement disorders, including Parkinson's disease and Huntington's disease; and attention disorders, including attention deficit disorder and attention deficit-hyperactivity disorder. Other diseases and conditions mediated by adenosine receptors are known.

[0250] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by an adenosine receptor.

[0251] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors).

[0252] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition mediated by an adenosine receptor, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0253] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors), wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0254] In one embodiment, a method of treating a disease or condition mediated by adenosine receptors is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0255] In one embodiment, a method for treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors) is provided, which comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.

[0256] In one embodiment, a method of treating a disease or condition mediated by adenosine receptors is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0257] In one embodiment, a method for treating cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors) is provided, which comprises administering to a subject in need of such treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0258] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a disease or condition mediated by adenosine receptors.

[0259] In one embodiment, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors).

[0260] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament for treating a disease or condition mediated by an adenosine receptor, wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0261] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided for use in the preparation of a medicament for the treatment of cancer (including lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors), wherein the compound is a selective adenosine receptor antagonist relative to CB-1.

[0262] Compounds of formula (I) can be prepared according to the following general schemes.

[0263] Schemes 1a and 1b illustrate the preparation of intermediate 6-substituted-4-hydrazino-2-aminopyrimidine compounds of formula (IV).

[0264] Option 1a

[0265]

[0266] Option 1b

[0267]

[0268] Scheme 2 illustrates the conversion of compounds of formula (IV) to intermediate 7-substituted-5-amino-8-bromo-[1,2,4]triazolo[4,3-c]pyrimidin-3-one compounds of formula (V). Briefly, compounds of formula (IV) are treated with triphosgene to achieve closure of the triazolone ring, followed by (CH3)3PhN + Br3 - Bromination.

[0269] Solution 2

[0270]

[0271] Scheme 3a illustrates the conversion of compounds of formula (V) to compounds of formula (I). 4Alkylation of the compound of formula (V) can be achieved using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by alkylation; alcohol tosylation followed by alkylation; or alcohol chlorination followed by alkylation.

[0272] Option 3a

[0273]

[0274] Alternatively, compounds such as R 4 -Br can be used for direct alkylation of compounds of formula (V).

[0275] Optionally, after alkylation of the compound of formula (V) R can be further modified 4 .

[0276] Scheme 3b illustrates an alternative route for the conversion of compounds of formula (V) to compounds of formula (I). In Scheme 3b, [Pg] represents a reagent suitable for installing the protecting group represented by Pg. 4 Alkylation of the compound of formula (Va) can be achieved using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by alkylation; alcohol tosylation followed by alkylation; alcohol chlorination followed by alkylation.

[0277] Option 3b

[0278]

[0279] Alternatively, compounds such as R 4 -Br can be used for direct alkylation of compounds of formula (Va).

[0280] Optionally, after alkylation of the compound of formula (V) R can be further modified 4 .

[0281] Scheme 3c illustrates an alternative route for the conversion of compounds of formula (V) to compounds of formula (I). Step 1 of Scheme 3c is the same as in Scheme 3a, i.e., using R 4 Alkylation of the compound of formula (V) can be achieved using a variety of methods, for example, Mitsonobu reaction; alcohol mesylation followed by alkylation; alcohol tosylation followed by alkylation; or alcohol chlorination followed by alkylation. 4 -Br can be used for direct alkylation of compounds of formula (V).

[0282] Step 2 of Scheme 3c illustrates the case where Ring A includes an aliphatic amine as the point of attachment. In this case, the product of Step 1 can be reacted directly with a Ring A precursor compound, as shown in Scheme 3c.

[0283] Solution 3c

[0284]

[0285] Optionally, the compound of formula (I) may be further modified, for example, to form a different compound of formula (I).

[0286] Example

[0287] General techniques

[0288] LCMS Method A

[0289] Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, Column: WatersXBridge C8 3.5µ, 4.6 x 50 mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 5, 8.0 / 100, 8.1 / 100, 8.5 / 5, 10.0 / 5. (Solvent A = 1 mL of TFA in 1000 mL of Milli-Q water; Solvent B = 1 mL of TFA in 1000 mL of MeCN); Injection volume 1µL (variable); UV detection 220 to 400 nm; Column temperature 25°C; 2.0 mL / min.

[0290] Note: For UV-inactive compounds, an ELSD detector (Polymer Laboratories PL-ELS 2100ICE) was connected to the above instrument.

[0291] LCMS method B

[0292] Instrument: Agilent Technologies 1200 Series, Agilent LC / MSD SL, Column: AtlantisdC185µ, 4.6x50mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 2.5 / 95, 4.5 / 95, 4.6 / 10, 6.0 / 10. (Solvent A = 1 mL of TFA in 1000 mL of Milli-Q water; Solvent B = 1 mL of TFA in 1000 mL of MeCN); Injection volume 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.5 mL / min.

[0293] LCMS Method C

[0294] Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5µ, 4.6 x 50mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 2.5 / 95, 4.5 / 95, 4.6 / 10, 6.0 / 10. (Solvent A = 1 mL of formic acid in 1000 mL of Milli-Q water; Solvent B = MeCN); Injection volume 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.5 mL / min.

[0295] LCMS Method D

[0296] Instrument: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5µ, 4.6 x 50mm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 10, 7.0 / 10. (Solvent A = 770.08 mg ammonium acetate in 1000 mL Milli-Q water; Solvent B = MeCN); Injection volume 1µL (variable); UV detection 210 to 400 nm; Column temperature 25°C; 1.2 mL / min.

[0297] Preparative HPLC (prep-HPLC) Method A

[0298] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A- 0.1% TFA in H2O, B- MeOH, Column: YMC Actus Triart C18 (30 mm x 250 mm) 5µm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0299] Preparative HPLC Method B

[0300] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A- 0.1% HCOOH in H2O, B- MeCN, Column: YMC Actus Triart C8 (20 mm x 250 mm) 5µm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0301] Preparative HPLC Method C

[0302] Instrument: Agilent Technologies 1260 Infinity II Series LC. Solvent: A- 10 mM NH4HCO3 in H2O, B- MeOH or MeCN, Column: Xbridge C8 (19 mm X 150mm), 5µm or YMC ActusTriart C18 (30 mm x 250 mm) 5µm. Gradient [Time (min) / Solvent B (%)]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0303] 5. Synthesis of intermediates

[0304] Synthesis route 1

[0305] Intermediate 1, 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0306]

[0307] Step 1; The reaction was carried out as 2 x 250 g batches. To a degassed suspension of phenylboronic acid (250 g, 2.05 mol), 4,6-dichloro-2-aminopyrimidine (672 g, 4.10 mol) and K2CO3 (848 g, 6.15 mol) in CH3CN (15 L) and H2O (2 L) was added Pd(PPh3)4 (118 g, 0.10 mol) at room temperature and the resulting reaction mixture was heated to 90 °C for 6 h. The reaction mixture was concentrated under reduced pressure. The resulting residue was vigorously stirred with H2O (4 L) and DCM (10 L), and the undissolved solids were filtered off through a Buchner funnel and rinsed with DCM (3 L). The filtrate was placed in a separatory funnel, the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography using 230-400 silica mesh and eluting with 0-15% EtOAc in petroleum ether to afford 4-chloro-6-phenylpyrimidin-2-amine (350 g, 41%) as an off-white solid.

[0308] LCMS (Method A): m / z 206 (M+H) + (ES + ), at 2.53 min, UV-active.

[0309] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.05 - 8.03 (m, 2H), 7.52 - 7.47 (m,3H), 7.21 (s, 1H). No exchangeable -NH2 protons were observed.

[0310] Step 2: To a stirred suspension of 4-chloro-6-phenylpyrimidine-2-amine (350 g, 1.70 mol) in EtOH (4.0 L), hydrazine hydrate (255 g, 5.1 mol) was added, and the mixture was heated to 90 °C for 15 h. The reactants were concentrated under reduced pressure. The resulting residue was triturated with ether (1 L) and 10% sodium bicarbonate solution (1 L). The resulting solid was collected by filtration through a Buchner funnel, rinsed with ether (200 mL) and dried under vacuum to provide 4-hydrazine-6-phenylpyrimidine-2-amine (250 g, 73%) as an off-white solid.

[0311] LCMS (Method C): m / z 202 (M+H) + (ES + ), at 0.69 min, UV-active.

[0312] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.94 - 7.91 (m, 2H), 7.84 (s, 1H), 7.48- 7.42 (m, 3H), 6.47 (s, 1H), 6.00 (s, 2H), 4.25 (s, 2H).

[0313] Step 3: To a solution of 4-hydrazino-6-phenylpyrimidine-2-amine (250 g, 1.24 mol) in dry THF (3.0 L) cooled to -30°C under N2, triphosgene (735 g, 2.48 mol) was added portionwise, and the mixture was stirred at the same temperature for 45 min. The reactants were carefully quenched into ice-cold H2O (10 L) under vigorous stirring. After effervescence ceased, the reaction mass was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with H2O (1 L) and dried under vacuum to provide 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-one (200 g, 70%) as a yellow solid.

[0314] LCMS (Method C): m / z 228 (M+H) + (ES + ), at 1.64 min, UV-active.

[0315] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 12.46 (s, 1H), 8.05 - 7.98 (m, 3H), 7.65 (s, 1H), 7.50 - 7.44 (m, 3H), 6.93 (s, 1H).

[0316] Step 4: To a suspension of 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 0.88 mol) in DCM / MeOH 1:1 (2 L) under N2 atmosphere, CaCO3 (88 g, 0.88 mol) was added, followed by (CH3)3PhN + Br3 -(331 g, 0.88 mol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with a small portion of MeOH / DCM (1:1), and dried under vacuum to provide the intermediate 1,5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (160 g, 59%) as a light brown solid. The data for the title compound are shown in Table 2.

[0317] Synthetic route 2

[0318] Intermediate 3, 5-amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0319]

[0320] To a solution of 3,3,3-trifluoropropane-1-ol (400 mg, 3.6 mmol) in DCM (10 mL) was added TEA (1.3 mL, 9.6 mmol) at 0°C, followed by dropwise addition of methanesulfonyl chloride (0.4 mL, 4.8 mmol). The resulting reaction mixture was stirred for 1 h. The reactants were partitioned between DCM (20 mL) and brine solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 3,3,3-trifluoropropyl methanesulfonate. The intermediate was added to a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1 g, 3.2 mmol) and K2CO3 (1.3 g, 9.6 mmol) in MeCN (20 mL), and the reaction mixture was stirred at 80°C for 15 h. The reaction mixture was dissolved in EtOAc (50 mL) and H o (50 mL). The organic layer was separated, dried over anhydrous Na sO and concentrated under reduced pressure. The crude product was ground with MeOH (5 mL), filtered through a Buchner funnel, and dried under vacuum to provide 5-amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-3 (2H)-one (700 mg, 53%) as an off-white solid. The data for the title compound are shown in Table 2.

[0321] 7. Synthetic route 3

[0322] Intermediate 4, 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

[0323]

[0324] Step 1; To a stirred suspension of 4,6-dichloropyrimidine-2-amine (400 g, 2.43 mol) in EtOH (5 L) was added hydrazine hydrate (365 g, 7.31 mol) and the mixture was heated to 90 °C for 15 h. The reaction mass was concentrated under reduced pressure. The obtained residue was triturated with ether (1 L) and 10% sodium bicarbonate solution (1 L). The obtained solid was collected by filtration through a Buchner funnel, rinsed with ether (200 mL) and dried under vacuum to provide 4-chloro-6-hydrazinopyrimidine-2-amine (300 g, 77%) as an off-white solid.

[0325] LCMS (Method C): m / z 160 (M+H) + (ES + ), at 0.37 min, UV-active.

[0326] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.10 (s, 1H), 6.36 (s, 2H), 5.97 (s, 1H), 4.26 (s, 2H).

[0327] Step 2: Pd(PPh3)4(107 g, 0.093 mol) was added to a degassed suspension of 4-chloro-6-hydrazinopyrimidine-2-amine (300 g, 1.87 mol), 4-fluorophenylboronic acid (313 g, 2.24 mol) and K2CO3(774 g, 5.61 mol) in 1,4-dioxane (6 L) and H2O (1 L) at room temperature, and the resulting reaction mixture was heated to 110°C for 15 h. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The resulting residue was vigorously stirred with H2O (4 L) to obtain a solid, which was filtered through a Buchner funnel and rinsed with MeOH (1 L). The solid was dried under vacuum to provide 4-(4-fluorophenyl)-6-hydrazinopyrimidine-2-amine (200 g, 49%) as a green solid.

[0328] LCMS (Method C): m / z 220 (M+H) + (ES + ), at 0.76 min, UV-active.

[0329] 1 H NMR: (400 MHz, DMSO- d6) δ: 8.00 - 7.96 (m, 2H), 7.854 (s,1H), 7.29 - 7.24 (m, 2H), 6.45 (s, 1H), 6.01 (s, 2H), 4.24 (s, 2H).

[0330] Step 3: Triphosgene (538 g, 1.82 mol) was added portionwise to a solution of 4-(4-fluorophenyl)-6-hydrazinopyrimidin-2-amine (200 g, 0.91 mol) in dry THF (3.0 L) cooled to -30°C under N2, and the mixture was stirred at the same temperature for 1 h. The reactants were carefully quenched into ice-cold H2O (10 L) under vigorous stirring. After effervescence ceased, the reaction mass was concentrated under reduced pressure. The resulting solid was collected by filtration through a Buchner funnel, rinsed with H2O (1 L) and dried under vacuum to provide 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 67%) as a yellow solid.

[0331] LCMS (Method C): m / z 246 (M+H) + (ES + ), at 1.77 min, UV-active.

[0332] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 12.43 (s, 1H), 8.19 - 8.01 (m, 2H), 7.95 - 7.52 (m, 2H), 7.50 - 7.27 (m, 2H), 6.92 (s, 1H).

[0333] Step 4: This reaction was carried out in 2 x 75 g batches. To a suspension of 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 0.66 mol) in DCM / MeOH 1:1 (2 L) was added CaCO3 (66 g, 0.66 mol) under N2 atmosphere followed by (CH3)3PhN + Br3 -(250 g, 0.66 mol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was filtered through a Buchner funnel, rinsed with a small portion of MeOH / DCM (1:1), and dried under vacuum to provide intermediate 26, 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (120 g, 60%) as a light brown solid. The data for the title compound are shown in Table 2.

[0334] 8. Synthetic route 4

[0335] Intermediate 15, 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

[0336]

[0337] Step 1: To a stirred solution of 2-amino-3-methylphenol (5 g, 40.65 mmol) in MeCN (100 mL) was added NBS (8.6 g, 48.78 mmol) at 0°C, and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H2O (50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using a silica gel mesh (230-400) and eluted with a gradient of 5-10% EtOAc in petroleum ether to provide 2-amino-5-bromo-3-methylphenol (1 g, 13%) as a brown solid.

[0338] LCMS (Method C): m / z 202 (M+H) + (ES + ), at 1.54 min, UV-active.

[0339] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 6.62 (s, 2H), 4.38 (s, 2H), 2.03 (s,3H). No exchangeable -OH protons were observed.

[0340] Step 2: A suspension of 2-amino-5-bromo-3-methylphenol (900 mg, 4.45 mmol) and triethoxymethane (10 mL) was heated to 100 °C for 1 h. The reaction mixture was distributed between EtOAc (50 mL) and H2O (30 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica gel sieve (230-400) and eluted with a gradient of 5-10% EtOAc in petroleum ether to provide 6-bromo-4-methylbenzo [d] oxazole (400 mg, 43%) as a brown solid.

[0341] LCMS (Method C): m / z 212 (M+H) + (ES + ), at 2.30 min, UV-active.

[0342] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.74 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.46-7.45 (m, 1H), 2.54 (s, 3H).

[0343] Step 3: A stirred solution of 6-bromo-4-methylbenzo[d]oxazole (200 mg, 0.94 mmol), bisvaleryldiboron (262 mg, 1.03 mmol) and KOAc (276 mg, 2.82 mmol) in 1,4-dioxane (25 mL) was degassed with N2 gas for 5 min, then PdCl2(dppf).DCM (76 mg, 0.094 mmol) was added, and the resulting reaction mixture was heated to 100°C for 2 h. The reaction mixture was concentrated under reduced pressure to provide crude 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (250 mg), which was used in the next step without purification.

[0344] Synthetic route 5

[0345] Intermediate 18, 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

[0346]

[0347] Step 1: NaH (60% dispersion in mineral oil) (113 mg, 4.73mmol) and SEM-Cl (0.59 mg, 3.55 mmol) were added to a solution of 5-bromo-7-methyl-1H-indazole (500 mg, 2.36 mmol) in THF (15 mL) at 0 ° C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was distributed between EtOAc (10 mL) and H2O (10mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by Biotage-Isolera using 10 g silica snaps and eluted with a gradient of 0-100% EtOAc in petroleum ether to provide 5-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (700 mg, 70%) as a brown colloid.

[0348] LCMS (Method C): m / z 341 (M+H) + (ES + ), at 3.14 min, UV-active.

[0349] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.08 (s, 1H), 7.86 (s, 1H), 7.37 (s,1H), 5.81 (s, 2H), 3.47 (t, J = 8.4 Hz, 2H), 2.71 (s, 3H), 0.85 (t, J = 8.4Hz, 2H), 0.77 (s, 9H).

[0350] Step 2; KOAc (516 mg, 5.27 mmol), Pin2B2 (664 mg, 2.60 mmol) and Pd(PPh3)4 (196 mg, 0.17 mmol) were added to a solution of 5-bromo-7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (600 mg, 1.75 mmol) in 1,4-dioxane (20 mL), and the resulting reaction mixture was heated to 100 ° C for 16 h. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (30 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide a crude product (600 mg), which was used in the next step without purification.

[0351] 10. Synthetic route 6

[0352] Intermediate 27, 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

[0353]

[0354] To a solution of 5-bromo-7-methyl-1H-indole (600 mg, 2.85 mmol) in 1,4-dioxane (15 mL) was added KOAc (839 mg, 8.86 mmol), Pin2B2 (1.1 g, 4.28 mmol) and Pd(dppf).DCM (239 g, 0.28 mmol). The resulting reaction mixture was heated to 90 °C for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (30 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide crude 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (600 mg), which was used in the next step without purification.

[0355] Synthetic route of the examples

[0356] Synthesis route a: via S N Typical procedure for the preparation of alkylated triazolopyrimidinones by Ar displacement

[0357] Example 1-1, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0358]

[0359] 5-Amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.49 mmol) and cis- -The mixture of 2,6-dimethylmorpholine (2 mL) was heated in a preheated 120 ° C oil bath in a sealed vial for 15 h. The reactant was cooled and distributed between EtOAc (10 mL) and H2O (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC method (method-A). The fraction was concentrated under reduced pressure, and the obtained residue was distributed between 10% MeOH (10 mL) and 10% NaHCO3 solution (10 mL) in DCM. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 5-amino-8-[(cis)-2,6-dimethylmorpholine-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-3-one (22 mg, 10%) as a white solid. The data for the title compound are shown in Table 3.

[0360] Synthetic route b

[0361] Example 1-2, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0362]

[0363] Step 1: To a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.98 mmol), 3-fluoropropane-1-ol (92 mg, 1.18 mmol) and triphenylphosphine (385 mg, 1.47 mmol) in THF (10 mL) was added di-tert-butyl azodicarboxylate (332 mg, 1.47 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 60 min. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by Biotage-Isolera using a 25 g silica snap and eluted with a gradient of 0-100% EtOAc in petroleum ether to provide 5-amino-8-bromo-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (160 mg, 44%) as an off-white solid.

[0364] LCMS (Method B): m / z 366 (M+H) + (ES + ), at 2.55 min, UV-active.

[0365] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.63 - 7.45 (m, 5H), 4.65 - 4.43 (m,2H), 3.94 (t, J = 6.8 Hz, 2H), 2.13 - 2.06 (m, 2H). No exchangeable -NH2 protons were observed.

[0366] Step 2: Prepared in a similar manner to route a to provide 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (18 mg, 13%) as a white solid. The data for the title compound are shown in Table 3.

[0367] Synthetic route c

[0368] Example 1-3, 5-amino-2-(3,3-difluoropropyl)-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0369]

[0370] Step 1: To a suspension of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2 g, 6.55 mmol) and K2CO3 (2.7 g, 19.65 mmol) in MeCN (40 mL) was added 3-bromo-1,1-dimethoxypropane (1.4 g, 7.86 mmol) at room temperature, and the reaction was stirred at 80°C for 5 h. The mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was triturated with diethyl ether (10 mL), decanted and dried under vacuum to afford 5-amino-8-bromo-2-(3,3-dimethoxypropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.2 g, 45%) as an off-white solid.

[0371] LCMS (Method B): m / z 408 (M+H) + (ES + ), at 2.68 min, UV-active.

[0372] 1H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.61 (m, 2H), 7.48 - 7.43 (m,3H), 4.47 (t, J = 5.6 Hz, 1H), 3.85 (t, J = 7.2 Hz, 2H), 3.26 (s, 6H), 1.99 -1.94 (m, 2H). No exchangeable -NH2 protons were observed.

[0373] Step 2: To a solution of 5-amino-8-bromo-2-(3,3-dimethoxypropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.2 g, 2.94 mmol) in 1,4-dioxane (10 mL) was added 2N HCl (30 mL) at room temperature and the reaction was stirred for 2 h. The reaction was concentrated under reduced pressure and the residue was partitioned between EtOAc (30 mL) and saturated NaHCO3 solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanal as a brown gum (assumed quantitative), which was used in the next step without further purification.

[0374] LCMS (Method B): m / z 362 (M+H) + (ES + ), at 2.32 min, UV-active.

[0375] Step 3: To a solution of 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanal (0.6 g, 1.65 mmol) in DCM (15 mL) was added DAST (0.58 g, 3.63 mmol) at -78°C. The reaction was stirred at room temperature for 15 h, then carefully quenched by dropwise addition of saturated sodium bicarbonate solution (40 mL) and extracted with DCM (2 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 25 g silica snap and eluted with a gradient of 0-40% EtOAc in hexanes to afford 5-amino-8-bromo-2-(3,3-difluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.2 g, 31%) as an off-white solid.

[0376] LCMS (Method B): m / z 384 (M+H) + (ES + ), at 2.80 min, UV-active.

[0377] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.63 - 7.61 (m, 2H), 7.48 - 7.45 (m,3H), 6.35 - 6.05 (m, 1H), 3.99 (t, J = 6.8 Hz, 2H), 2.39 - 2.22 (m, 2H). No exchangeable -NH2 protons were observed.

[0378] Step 4: Prepared in a similar manner to route a to provide 5-amino-2-(3,3-difluoropropyl)-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (11 mg, 11%) as a yellow solid. The data for the title compound are shown in Table 3.

[0379] Synthesis route d: Alkylation reaction followed by S N Typical procedure for the preparation of alkylated triazolopyrimidinones by Ar displacement

[0380] Example 1-4, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0381]

[0382] Step 1: To a stirred solution of 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.6 mmol) and 1-bromopropane (95 mg, 0.78 mmol) in MeCN (5 mL) and DMSO (5 mL) was added K2CO3 (123 mg, 1.9 mmol). The reaction mixture was heated to 75°C in a sealed tube for 12 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), and the organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 10 g silica snap and eluted with a gradient of 0-100% EtOAc in petroleum ether to afford 5-amino-8-bromo-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (125 mg, 54%) as a white solid.

[0383] LCMS (Method B): m / z 348 (M+H) + (ES + ), at 2.83 min, UV-active.

[0384] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.62 - 7.60 (m, 2H), 7.47 - 7.43 (m,3H), 3.78 (t, J = 6.8 Hz, 2H), 1.77 - 1.71 (m, 2H), 0.90 (t, J = 7.2 Hz, 3H). No exchangeable -NH2 protons were observed.

[0385] Step 2: Prepared in a similar manner to route a to provide 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (29 mg, 22%) as a white solid. The data for the title compound are shown in Table 3.

[0386] Synthesis route e: via alcohol mesylation and displacement reaction, followed by S N Ar substitution for alkylated triazolopyrimidone Typical procedures

[0387] Example 1-7, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0388]

[0389] Step 1: at 0℃ to ( STo a solution of )-(1-methylpyrrolidin-2-yl)methanol (123 mg, 1.07 mmol) and TEA (300 mg, 1.17 mmol) in DCM (10 mL) was added methanesulfonyl chloride (134 mg, 1.17 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (20 mL) and H2O (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the mesylated intermediate. The intermediate was taken up in MeCN (10 mL) and 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.98 mmol) and K2CO3 (405 mg, 2.94 mmol) were added. The resulting reaction mixture was heated to 70 °C in a sealed tube for 6 h. The reaction mixture was distributed between EtOAc (20 mL) and H o (20 mL). The organic layer was separated, dried over anhydrous Na sO and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 25 g silica gel snaps, and eluted with the gradient of 0-100% EtOAc in petroleum ether to provide ( S )-5-amino-8-bromo-2-((1-methylpyrrolidin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one.

[0390] LCMS (Method B): m / z 403 (M+H) + (ES + ), at 1.94 min, UV-active.

[0391] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.16 (s, 2H), 7.64 - 7.61 (m, 2H), 7.46 - 7.44 (m, 3H), 3.93 - 3.88 (m, 1H), 3.76 - 3.69 (m, 1H), 2.98 - 2.94(m, 1H), 2.27 (s, 3H), 2.20 - 2.19 (m, 1H), 2.13 - 2.03 (m, 1H), 1.87 - 1.85 (m, 2H), 1.74 - 1.67 (m, 2H).

[0392] Step 2: Prepared in a similar manner to route a to provide 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (40 mg, 18%) as an off-white solid. The data for the title compound are shown in Table 3.

[0393] Synthetic route f

[0394] Example 1-8, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0395]

[0396] Step 1: To a solution of DMAP (19.9 mg, 0.16 mmol), TEA (247.5 mg, 2.45 mmol) and tosyl chloride (342.0 mg, 1.79 mmol) in DCM (20 mL) was added ( R )-(tetrahydrofuran-2-yl)methanol (199.9 mg, 1.96 mmol), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was partitioned between DCM (20 mL) and H2O (20 mL). The organic layer was separated and concentrated under reduced pressure to give the tosylated intermediate. The tosylated intermediate was placed in DMSO (30 mL) and 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (500 mg, 1.63 mmol) and K2CO3 (676 mg, 4.09 mmol) were added and then heated to 80°C for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL). The organic layer was separated and concentrated under reduced pressure to provide ( R )-5-amino-8-bromo-7-phenyl-2-((tetrahydrofuran-2-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (400 mg, 62%). The crude product was used in the next step without further purification.

[0397] LCMS (Method A): m / z 390 (M+H) + (ES + ), at 2.38 min, UV-active.

[0398] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.80 - 7.77 (m, 1H), 7.64 - 7.60 (m,2H), 7.50 - 7.44 (m, 2H), 4.23 - 4.02 (m, 1H), 4.00 - 3.96 (m, 2H), 3.86 -3.79 (m, 2H), 3.74 -3.66 (m, 2H), 1.99 - 1.91 (m, 2H). No exchangeable -NH2 protons were observed.

[0399] Step 2: Prepared in a similar manner to route a to provide 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[[(2 R The data for the title compound are shown in Table 3.

[0400] Synthetic route g: via alcohol mesylation and displacement reaction, followed by S N Ar displacement and benzyl deprotection to prepare alkylated Typical Procedure for Triazolopyrimidone

[0401] Example 1-10, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0402]

[0403] Step 1; proceeding in a similar manner to route e, step 1 using intermediate 9, to provide ( S )-5-amino-2-((4-benzylmorpholin-3-yl)methyl)-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.4 g, 55%).

[0404] LCMS (Method A): m / z 495 (M+H) + (ES + ), at 3.55 min, UV-active.

[0405] 1 H NMR: (400 MHz, DMSO- d6) δ: 7.64 - 7.60 (m, 2H), 7.49 - 7.44 (m,3H), 7.35 - 7.23 (m, 5H), 4.09 - 4.02 (m, 3H), 3.75 - 3.71 (m, 2H), 3.59 -3.45 (m, 4H), 2.75 -2.68 (m, 1H), 2.25 - 2.22 (m, 1H). No exchangeable -NH2 protons were observed.

[0406] Step 2: (S)-5-amino-2-((4-benzylmorpholin-3-yl)methyl)-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (400 mg, 0.8 mmol) and cis- - The mixture of 2,6-dimethylmorpholine (2 mL) was placed in a sealed vial and heated at 120 ° C for 15 h in a preheated oil bath. The reaction mass was distributed between EtOAc (30 mL) and H2O (30 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 25 g silica snaps and eluted with a gradient of 0-40% EtOAc in hexane to provide 5-amino-2-(((S)-4-benzylmorpholine-3-yl)methyl)-8-((cis)-2,6-dimethylmorpholine)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-one (380 mg, 88%) as a yellow colloid.

[0407] LCMS (Method A): m / z 530 (M+H) + (ES + ), at 3.32 min, UV-active.

[0408] Step 3; To a mixture of 5-amino-2-(((S)-4-benzylmorpholin-3-yl)methyl)-8-((cis)-2,6-dimethylmorpholino)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (380 mg, 0.7 mmol) in MeOH (20 mL) was added Pd(OH)2(50 mg), and the reaction mixture was stirred under H2 atmosphere (balloon pressure) for 15 h. The reaction mixture was filtered through celite and rinsed with MeOH (20 mL). The filtrate was concentrated under reduced pressure and purified by preparative HPLC (Method A). The fractions were concentrated under reduced pressure and the resulting residue was distributed between EtOAc (15 mL) and saturated NaHCO3 solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 5-amino-8-(cis)-2,6-dimethylmorpholino)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one. - 2,6-dimethylmorpholino)-2-(((S)-morpholin-3-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (65 mg, 22%). The data for the title compound are shown in Table 3.

[0409] Synthetic pathway

[0410] Example 1-12, 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0411]

[0412] To 5-amino-8-[(cis)-2,6-dimethylmorpholine-4-yl]-2-[[(3S)-morpholine-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidine-3-one (50 mg, 0.11mmol) and 33% HCHO aqueous solution (0.012 ml, 0.13 mmol) in MeCN (2 mL) was added sodium triacetoxyborohydride (35 mg, 0.17 mmol) and stirred for 10 min at room temperature. The reaction mixture was distributed between EtOAc (10 mL) and saline solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative HPLC (method-C). The collected fractions were concentrated under reduced pressure, and the resulting residue was distributed between EtOAc (2 mL) and saturated NaHCO3 solution (2 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide 5-amino-8-(cis-- 2,6-dimethylmorpholino)-2-((( S The data for the title compound are shown in Table 3.

[0413] Pathway i

[0414] Example 2-1, 5-amino-8-[(cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0415] Example 2-2, 5-amino-8-[(cis)-2,6-dimethyltetrahydropyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0416]

[0417] Step 1: A mixture of 5-amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 mg, 0.37 mmol), 2-((cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97 mg, 0.41 mmol) and K2CO3 (153 mg, 1.11 mmol) in 1,4-dioxane (10 mL) and H2O (5 mL) was degassed for a few minutes, and then Pd(PPh3)4 (42 mg, 0.04 mmol) was added. The vessel was sealed and heated to 100°C for 15 h. The reaction mixture was dissolved in 4% paraformaldehyde (2% ethyl acetate) and 4% paraformaldehyde (2% ethyl acetate).The reaction mixture was distributed between H o (20 mL) and EtOAc (20 mL).The organic layer was separated, through anhydrous Na sO dried and concentrated.The crude product was purified by preparative HPLC (method-A) to provide 5-amino-8-((cis)-2,6-dimethyl-3,6-dihydro-2H-pyrans-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidine-3 (2H)-one (120 mg, 74%) as off-white solid.The data presentations of title compound are in Table 3.

[0418] Step 2: A solution of 5-amino-8-((cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (0.1 g, 0.23 mmol) in MeOH (10 mL) was degassed with nitrogen for several minutes, 10% Pd / C (20 mg) was added, and the container was heated at 5 kg / cm 2 The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.The mixture was stirred for 2 hours at room temperature for 3 hours.

[0419] Pathway

[0420] Example 3-1, 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(4-hydroxy-3,5-dimethyl-phenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0421]

[0422] Step 1; proceeded in a similar manner to route e, step 1 using intermediates 1 and 11 in THF to provide 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 44%) as a yellow solid.

[0423] 1 H NMR: (400 MHz, DMSO- d6 ) δ : 8.56 (s, 1H), 7.80 (m, 1H), 7.75 (d, J= 7.6 Hz, 2H), 7.63 - 7.61 (m, 4H), 5.17 (s, 2H). No exchangeable - NH2 protons were observed.

[0424] Step 2: To a solution of 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (300 mg, 0.7 mmol) in 1,4-dioxane (20 mL) and H2O (5 mL) was added K2CO3 (299 mg, 2.17 mmol), (4-methoxy-3,5-dimethylphenyl)boronic acid (156 mg, 0.86 mmol) and Pd(PPh3)4 (83 mg, 0.07 mmol). The reactants were heated to 120°C in a sealed tube for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (15 mL), and the organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 25 g silica snap and eluted with a gradient of 0-100% EtOAc in hexanes to afford 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(4-methoxy-3,5-dimethylphenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (230 mg, 34%) as an off-white solid.

[0425] LCMS (Method A): m / z 471 (M+H) + (ES + ), at 2.66 min, UV-active.

[0426] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.56 (s, 1H), 7.75 (d, J = 7.6 Hz,2H), 7.42 - 7.61 (m, 5H), 7.56 (s, 2H), 6.80 - 6.77 (m, 2H), 5.12 (s, 2H), 3.60 (s, 3H), 1.98 (d, J = 2.0 Hz, 6H).

[0427] Step 3: To a mixture of 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(4-methoxy-3,5-dimethylphenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 0.42 mmol) in MeCN (15 mL) was added TMSI (2 mL) at room temperature, and the reaction mixture was heated to 60 ° C for 16 h. The reaction mixture was quenched by adding sodium carbonate solution (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The crude compound was purified by preparative HPLC (method A). The collected fractions were concentrated, and the resulting residue was distributed between sodium bicarbonate (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to dryness to provide 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(4-hydroxy-3,5-dimethyl-phenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (50 mg, 26%) as a yellow solid. The data for the title compound are shown in Table 3.

[0428] Pathway k

[0429] Example 4-1, 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0430]

[0431] Step 1: To a stirred solution of 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (5 g, 15.4 mmol) in DCM (250 mL) was added TEA (4.6 g, 46.20 mmol) and SEM-Cl (2.3 g, 13.8 mmol) at 0°C, and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with H2O (50 mL) and extracted with DCM (2 x 100 mL). The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica gel mesh (230-400) and eluted with 5-10% EtOAc in petroleum ether to afford 5-amino-8-bromo-7-(4-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (4.0 g, 57%) as an off-white solid.

[0432] LCMS (Method C): m / z 454 (M+H) + (ES + ), at 1.90 min, UV-active.

[0433] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.71-7.67 (m, 2H), 7.31 - 7.28 (m,2H), 5.18 (s, 2H), 3.65-3.60 (m, 2H), 1.17 (s, 2H), 0.02 (s, 9H). No exchangeable -NH2 protons were observed.

[0434] Step 2: A solution of 5-amino-8-bromo-7-(4-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (4 g, 8.8 mmol), 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (4 g crude, 10.5 mmol) and K2CO3 (3.64 g, 26.4 mmol) in 1,4-dioxane (100 mL) and H2O (10 mL) was degassed with N2 for 5 min. Pd(PPh3)4 (1 g, 0.88 mmol) was added and the resulting reaction mixture was heated to 120°C for 5 h. Reaction mass is in EtOAc (100x2 mL) and H o (100 mL) between distribution.Organic layer is separated, through anhydrous Na sO dry and under reduced pressure concentrate.Crude product is purified by Biotage-Isolera using 50 g silica gel snaps (silica snap), eluted with 30-40% EtOAc in petroleum ether, to provide 5-amino-7-(4-fluorophenyl)-8-(4-methylbenzo [d] oxazole-6-yl)-2-((2-(trimethylsilyl) ethoxy) methyl)-[1,2,4] triazol [4,3-c] pyrimidine-3 (2H)-one (1.5 g, 34%) as yellow solid.

[0435] LCMS (Method C): m / z 507 (M+H) + (ES + ), at 2.48 min, UV-active.

[0436] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.75 (s, 1H), 7.59 - 7.56 (m, 3H),7.08 - 7.04 (m, 3H), 5.06 (s, 2H), 3.62 - 3.58 (m, 2H), 2.42 (s, 3H), 0.88 -0.85 (m, 2H), 0.01 (s,9H). No exchangeable -NH2 protons were observed.

[0437] Step 3: A solution of 5-amino-7-(4-fluorophenyl)-8-(4-methylbenzo[d]oxazol-6-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2.5 g, 4.9 mmol) in TFA (10 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The crude product was taken in MeOH (10 mL) and DIPEA (1.7 mL, 14.7 mmol) was added dropwise at 0°C, and the resulting reaction mixture was heated to 70°C for 3 h. The precipitate was filtered and dried to provide 5-amino-7-(4-fluorophenyl)-8-(4-methylbenzo[d]oxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1 g, 56%) as a yellow solid. The data for the title compound are shown in Table 2.

[0438] Step 4: Methanesulfonyl chloride (0.1 mg, 2.31 mmol) was added dropwise to a solution of 3,3,3-trifluoropropane-1-ol (220 mg, 1.92 mmol) and TEA (0.5 mg, 5.78 mmol) in DCM (10 mL) at 0°C, and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (50 mL) and H2O (50 mL), and the organic layer was separated and concentrated under reduced pressure to obtain the mesylated intermediate. The mesylated intermediate was placed in DMSO (20 mL), 5-amino-7-(4-fluorophenyl)-8-(4-methylbenzo[d]oxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (600 mg, 1.59 mmol) and K2CO3 (660 mg, 4.78 mmol) were added, and the reaction mixture was heated to 50 °C for 16 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), the organic layer was separated and concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A), the collected fractions were concentrated and the residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (130 mg, 17%) as a yellow solid. The data for the title compound are shown in Table 3.

[0439] Route 1: Typical preparation of triazolopyrimidone via alcohol mesylation and displacement reaction followed by Suzuki coupling reaction program

[0440] Example 4-2, 5-amino-2-[(5-chloro-2-pyridyl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0441]

[0442] Step 1; To a stirred solution of (5-chloropyridin-2-yl)methanol (797 mg, 5.5 mmol) and TEA (1.4 mL, 13.8 mmol) in DCM (20 mL) at 0°C was added methanesulfonyl chloride (620 mg, 5.5 mmol) dropwise and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (2 x 20 mL) and H2O (20 mL), the combined organics were separated and concentrated under reduced pressure to give the mesylated intermediate. The mesylated intermediate was taken up in DMSO (20 mL) and 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.5 g, 4.6 mmol), K2CO3 (1.90 g, 13.8 mmol) were added and the resulting reaction mixture was heated to 60°C for 2 h. The reaction mixture is in EtOAc (2 x 20mL) and H o (30x3 mL) between distribution, the organic matter of merging is separated and concentrated under reduced pressure. The crude product is purified by preparative HPLC (method A), the fraction collected is concentrated and residue is diluted with EtOAc (10 mL), washed with 10% sodium bicarbonate solution (10mL). The organic layer is separated, through anhydrous Na sO dry and concentrated to provide 5-amino-8-bromo-2-((5-chloropyridin-2-yl) methyl)-7-(4-fluorophenyl)-[1,2,4] triazol [4,3-c] pyrimidine-3 (2H)-one (1.5 g, 68%) as light brown solid.

[0443] LCMS (Method C): m / z 449 (M+H) + (ES + ), at 2.45 min, UV-active.

[0444] Step 2: Prepared in a similar manner to route k, step-2, and purified by preparative HPLC (method A) to provide 5-amino-2-[(5-chloro-2-pyridyl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (150 mg, 12%) as a yellow solid. The data for the title compound are shown in Table 3.

[0445] twenty four. Route m: Preparation of alkylated tris by mesylation of alcohol and displacement reaction, followed by Suzuki coupling and deprotection Typical procedures for oxazolopyrimidone

[0446] Example 4-4, 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(7-methyl-1H-indazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0447]

[0448] Step 1; proceeded in a similar manner to route e step 1 using intermediates 1 and 11 to provide 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (170 mg, 41%) as an off-white solid.

[0449] LCMS (Method B): m / z 415 (M+H) + (ES + ), at 2.64 min, UV-active.

[0450] 1 H NMR: (400 MHz, DMSO- d6 ) δ : 8.56 (s, 1H), 7.80 (m, 1H), 7.75 (d, J= 7.6 Hz, 2H), 7.63 - 7.61 (m, 4H), 5.17 (s, 2H). No exchangeable - NH2 protons were observed.

[0451] Step 2: To a mixture of 5-amino-8-bromo-2-((5-fluoropyridin-2-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (726 mg, 1.7 mmol) and 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (600 mg, 1.75 mmol) in 1,4-dioxane (20 mL) and H2O (0.4 mL) were added Pd(PPh3)4 (28 mg, 0.02 mmol) and K2CO3 (727 mg, 5.27 mmol), and the resulting reaction mixture was heated to 120°C for 5 h. Reactant is in EtOAc (15 mL) and H o (10 mL) between distribution.Organic layer is separated, through anhydrous Na sO dry and under reduced pressure concentrate.Crude product is purified by Biotage-Isolera using 25 g silica gel snaps (silica snap), and by the gradient elution of the EtOAc in petroleum ether of desired compound 0-100%, to provide 5-amino-2-((5-fluoropyridine-2-yl) methyl)-8-(7-methyl isophthalic acid-((2-(trimethylsilyl) ethoxy) methyl)-1H-indazole-5-yl)-7-phenyl-[1,2,4] triazol [4,3-c] pyrimidine-3 (2H)-one (250 mg, 25%) as yellow solid.

[0452] LCMS (Method C): m / z 597 (M+H) + (ES + ), at 1.77 min, UV-active.

[0453] Step 3: A suspension of 5-amino-2-((5-fluoropyridin-2-yl)methyl)-8-(7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (250 mg, 0.42 mmol) in TFA (5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum. The resulting residue was placed in MeOH (10 mL) and DIPEA (3.5 ml, 20.52 mmol) was added and then heated to 70 ° C for 3 h. The resulting solid was collected by filtration through a Buchner funnel, rinsed with H2O (10 mL) and dried. The crude product was purified by preparative HPLC (method-A). The collected fractions were concentrated, and the resulting residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(7-methyl-1H-indazole-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (30 mg, 15%) as a yellow solid. The data for the title compound are shown in Table 3.

[0454] Route n: Preparation of alkylated triazolopyrimidone via tosylation of alcohol and displacement reaction followed by Suzuki coupling Typical procedures

[0455] Example 4-6, 5-amino-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0456]

[0457] Step 1; prepared in a similar manner to route f, step 1 using intermediates 1 and 22 and purified by Biotage Isolera using silica gel (230-400) mesh eluting with a gradient of EtOAc in petroleum ether (0-100%) to afford 5-amino-8-bromo-2-((5-methyloxazol-4-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (70 mg, 41%) as a yellow solid.

[0458] LCMS (Method C): m / z 401 (M+H) + (ES + ), at 1.93 min, UV-active.

[0459] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 7.82 (s, 1H), 7.37-7.30 (m, 5H), 4.89 (s, 2H), 2.39 (s, 3H). No exchangeable -NH2 protons were observed.

[0460] Step 2: Prepared in a similar manner to route m step 2 to provide 5-amino-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one (90 mg, 41%) as an off-white solid. The data for the title compound are shown in Table 3.

[0461] Pathway

[0462] Example 4-7, 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0463]

[0464] To a solution of tosyl chloride (376 mg, 1.98 mmol), DMAP (16 mg, mmol) in DCM (25 mL) was added TEA (0.4 mL, 3.96 mmol) and (2,5-dimethyloxazol-4-yl)methanol (202 mg, 1.59 mmol) at 0°C and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (2 x 20 mL) and H2O (10 mL). The organic layer was separated and concentrated to provide a tosylated intermediate. The tosylated intermediate was placed in DMSO (15 mL) containing 5-amino-7-(4-fluorophenyl)-8-(4-methylbenzo[d]oxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (500 mg, 1.32 mmol) and KCO (546 mg, 3.9 mmol), and the resulting reaction mixture was heated to 80 °C for 3 h. The reaction mixture was distributed between EtOAc (100 mL) and H0 (50 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by preparative HPLC (method A), the collected fractions were concentrated under reduced pressure, and the residue was diluted with EtOAc (30 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide 5-amino-2-((2,5-dimethyloxazol-4-yl)methyl)-7-(4-fluorophenyl)-8-(4-methylbenzo[d]oxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (125 mg, 19%) as an off-white solid. The data for the title compound are shown in Table 3.

[0465] Route p: Preparation of alkylated amines via tosylation of alcohols and displacement reactions followed by Suzuki coupling and deprotection Typical procedures for similar objects

[0466] Example 4-8, 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one

[0467]

[0468] Step 1: To a solution of tosyl chloride (380 mg, 2.002 mmol), TEA (0.7 mL, 4.620 mmol) and DMAP (18 mg, 0.154 mmol) in DCM (10 mL) at 0°C, (5-methyloxazol-4-yl)methanol (209 mg, 1.8 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between DCM (20 mL) and H2O (20 mL). The organic layer was separated and concentrated under reduced pressure to provide a tosylated intermediate. The tosylated intermediate was taken up in DMSO (20 mL) and 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (500 mg, 1.5 mmol) and K2CO3 (620 mg, 4.620 mmol) were added, and the resulting reaction mixture was heated to 80°C for 2 h. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL). The organic layer was separated and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using a 25 g silica snap and eluted with a gradient of 0-100% EtOAc in petroleum ether to afford 5-amino-8-bromo-7-(4-fluorophenyl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 mg, 31%) as an off-white solid.

[0469] LCMS (Method C): m / z 419 (M+H) + (ES + ), at 1.97 min, UV-active.

[0470] 1 H NMR: (400 MHz, DMSO- d6 ) δ: 8.19 (s, 1H), 7.69-7.66 (m, 2H), 7.32-7.27 (m, 2H), 4.91 (s, 2H), 2.00 (s, 3H). No exchangeable -NH2 protons were observed.

[0471] Step 2; prepared in a similar manner to route m, step 2 to provide 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one as a yellow solid (250 mg, 35%).

[0472] LCMS (Method C): m / z 601 (M+H) + (ES + ), at 2.86 min, UV-active.

[0473] Step 3; A suspension of 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-5-yl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (250 mg, 0.42 mmol) in TFA (1.5 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The crude material was placed in a methanolic ammonia solution (4 M solution) at 0°C and heated to 70°C for 3 h. The resulting precipitate was filtered and dried. The crude product was purified by preparative HPLC (Method-A). The collected fractions were concentrated and the residue was diluted with EtOAc (10 mL) and washed with 10% sodium bicarbonate solution (10 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to provide 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-((5-methyloxazol-4-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (57 mg, 30%) as an off-white solid. The data for the title compound are shown in Table 3.

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485] Example 5: Adenosine receptor binding assay

[0486] Use human adenosine A from BacMam 2A Inhibition binding assays were performed using 0.2 μg of membranes prepared from HEK293 cells infected with the BacMam human adenosine A1 receptor or 1.4 μg of membranes prepared from HEK293 cells infected with the BacMam human adenosine A1 receptor. The membranes were incubated at 25°C in the presence of various concentrations of the test compounds and 1 nM [ 3 H]ZM241385(HEK293-hA 2A )or[ 3 H]DPCPX(CHO-hA1) in the presence of 50 mM Tris-HCl (HEK293-hA 2A ; pH 7.4) or 50 mM Tris-HCl, 100 mM NaCl, 10 mM MgCl2 (CHO-hA1; pH 7.4) for 1 h. The assay was then terminated by rapid filtration onto GF / B grade Unifilter plates using a TomTec cell harvester followed by 5 x 0.5 ml washes with ddH2O. 2A Nonspecific binding was defined in the presence of 1 μM DPCPX (CHO-hA1) or 1 μM DPCPX (CHO-hA1). Bound radioactivity was determined by liquid scintillation counting, and inhibition curves were analyzed using a four-parameter logistic equation. Using KD values ​​derived from saturation binding studies, IC 50 The values ​​were converted to Ki values. The results are summarized in Table 4.

[0487]

[0488] Example 6: CB-1 Receptor Binding and Antagonism

[0489] Receptor binding: Evaluation of the affinity of compounds for the agonist site of the human CB-1 cannabinoid receptor in transfected CHO cells determined in a radioligand binding assay: Cell membrane homogenates (20 µg of protein) were incubated with 0.5 nM [ 3 H]CP 55940 were incubated at 37°C for 120 min. Nonspecific binding was determined in the presence of 10 µM WIN 55212-2.

[0490] After incubation, the samples were quickly filtered under vacuum through a glass fiber filter (GF / B, Packard) pre-soaked with 0.3% PEI and rinsed several times with ice-cold buffer containing 50 mM Tris-HCl (pH 7.4) and 0.5% BSA using a 96-sample cell harvester (Unifilter, Packard). The filters were dried and radioactivity was counted in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard).

[0491] The standard reference compound was CP 55940, which was tested at various concentrations in each experiment to generate a competition curve from which its IC 50 .

[0492] Receptor antagonism : Evaluation of compounds for antagonist activity towards human CB1 receptor expressed in transfected CHO cells as determined by measuring their effects on agonist-induced cAMP modulation using the HTRF assay.

[0493] The cells were suspended in HBSS buffer (Invitrogen) supplemented with 20 mM HEPES (pH 7.4) and then incubated at 5.10 3 Cells were plated at a density of 10 cells / well in a microtiter plate and pre-incubated for 5 min at room temperature in the presence of either: HBSS (stimulated control), 5-mercaptoethanol at 3 µM (basal control), or various concentrations (IC 50 The reference antagonist AM281, or the test compound, was determined.

[0494] Thereafter, the reference agonist CP 55940 and the adenylate cyclase activator NKH 477 were added at final concentrations of 3 nM and 3 µM, respectively.

[0495] For basal control measurements, CP 55940 was omitted from wells containing 3 µM AM 281.

[0496] After incubation at 37°C for 20 min, cells were lysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescence donor (anti-cAMP antibody labeled with europium cryptate) were added.

[0497] After 60 min at room temperature, the samples were analyzed using a microplate reader (Rubystar, BMG) at λ ex = 337 nm and λ em = 620 and 665 nm. The cAMP concentration was determined by dividing the signal measured at 665 nm by the signal measured at 620 nm (ratio).

[0498] Results are expressed as percent inhibition of the control response to 3 nM CP 55940.

[0499] The standard reference antagonist was AM 281, which was tested at various concentrations in each experiment to generate a concentration-response curve from which its IC 50 value.

[0500] In Table 5, K i A blank entry indicates that the observed binding was too weak to measure K i value.

[0501]

[0502] Other implementations are within the scope of the following claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: Ring A is saturated, partially unsaturated or aromatic and has the structure: Y 1 is N, -CH- or -C=; Y 2 Is O or -CR g =; Where R g H, halogen, -R a OR a ; R 1 Halogen, C 1-3 Alkyl or -OC 1-3 alkyl; wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens; or R 1 and R g Together with the atoms to which they are attached, they form a 5-membered heterocyclyl or heteroaryl group having one to two heteroatoms selected from N and O; R 2 Is halogen or C 1-3 alkyl; wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OR a and halogens; R 3 yes: R 4 Yes-(CHR c ) i -(NR a ) j -R 5 ; R 5 yes: (1) aryl, 3- to 8-membered heterocyclic group or 3- to 8-membered heteroaryl group; wherein aryl is a monocyclic, bicyclic or tricyclic aromatic hydrocarbon group containing 6 to 14 ring atoms; and wherein the heterocyclyl and heteroaryl groups independently include 1 to 4 heteroatoms independently selected from N and O; or (2) C 1-6 Alkyl, -OR a , cyano, -CO2R a or -NR a -C(O)-OR a ; Where R 5 Optionally, one to four groups -XR 6 replace; Each X is independently a bond, -O-, -NR a -or-C(O)-; Each R 6 are independently H, halogen, -OR a 、-CO2R a or cyano; Each R a Independently H, C 1-6 Alkyl or C 3-8 Cycloalkyl; Each R a is optionally substituted with one or more substituents independently selected from -OH and halogen; Each R c It is H; Each R d are independently halogen, cyano, -R a OR a ; c is 0, 1, 2, or 3; i is 1, 2, or 3; and j is 0 or 1.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 2 It is -CH3.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: R 5 It is a 5-membered heterocyclic group or a 5-membered heteroaryl group.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: i is 1; and R 5 It is 1,3-oxazolyl optionally substituted by one to two -CH3 groups.

5. A compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof: in: Y 1 is N; Y 3 and Y 4 together are -CH=N-, -N=CH-, -CH=CH-, or =CH-O-; R 1 and R 2 It is CH3; R 4 Yes - CHR c -R 5 ; R 5 yes: (1) a 5- or 6-membered heterocyclic group or a 5- or 6-membered heteroaryl group; wherein the heterocyclyl and heteroaryl groups independently include 1 to 4 heteroatoms independently selected from N and O; wherein heterocyclyl and heteroaryl are optionally substituted by one or more substituents independently selected from halogen, -R e AND-OR e ;or (2) H, halogen or C 1-3 alkyl; wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OH and halogen; R c is H or halogen; R d is H or a halogen; and Each R e independently H or C 1-6 alkyl; Wherein the alkyl group is optionally substituted with one or more substituents independently selected from -OH and halogen.

6. The compound of formula (IIb) according to claim 5, wherein: R 5 is a 5- or 6-membered heteroaryl group.

7. The compound of formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof according to claim 5, wherein: R 5 is C optionally substituted by one to three fluorine 1-3 alkyl.

8. A compound selected from the following or a pharmaceutically acceptable salt thereof: 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-(3-fluoropropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-(3,3-difluoropropyl)-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-(4-fluorophenyl)-2-propyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(2S)-1-methylpyrrolidin-2-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[[(2R)-tetrahydrofuran-2-yl]methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-[2-(1-piperidinyl)ethyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-morpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3S)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[[(3R)-4-methylmorpholin-3-yl]methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(5-fluoro-2-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-2-[(2-methoxy-3-pyridinyl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(pyridazin-3-ylmethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethylmorpholin-4-yl]-7-phenyl-2-(2-phenylethyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-[(cis)-2,6-dimethyltetrahydropyran-4-yl]-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(4-hydroxy-3,5-dimethyl-phenyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(5-chloro-2-pyridinyl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyl-2-pyridyl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(5-fluoro-2-pyridinyl)methyl]-8-(7-methyl-1H-indazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(5-fluoro-2-pyridyl)methyl]-8-(7-methyl-1H-benzoimidazol-5-yl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(4-methyl-1,3-benzoxazol-6-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-2-[(2,5-dimethyloxazol-4-yl)methyl]-7-(4-fluorophenyl)-8-(4-methyl-1,3-benzoxazol-6-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-7-(4-fluorophenyl)-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(7-methyl-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-(2,3,4,5,6-pentadeuterophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; 5-amino-8-(7-chloro-1H-indazol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one; and 5-amino-8-(7-methyl-1H-indol-5-yl)-2-[(5-methyloxazol-4-yl)methyl]-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3-one.

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient.

10. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease or condition mediated by adenosine receptors.

11. The use of claim 10, wherein the disease or condition mediated by adenosine receptors is lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, brain cancer, gastric cancer, liver cancer, kidney cancer, endometrial cancer, thyroid cancer, bladder cancer, glioma, melanoma or other solid tumors.

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