Triazolone compound

Abstract

Described herein are triazalone compounds of formula (I): JPEG2023519363000059.jpg3243 and pharmaceutically acceptable salts thereof. Methods for preparing and using the compounds of formula (I) are also described. The compounds of formula (I) and their pharmaceutically acceptable salts may be useful as adenosine receptor antagonists in the treatment of diseases or conditions mediated by adenosine receptors, such as cancer, movement disorders, or attention disorders.

Description

Background Art

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

[0002] The actions of adenosine are mediated by a family of G protein-coupled receptors. At least four subtypes of adenosine receptors, A1R, A2aR, A2bR, and A3R, have been identified. 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 intracellular cyclic AMP levels.

[0003] In the immune system, the involvement of A2a and A2b adenosine receptors is an important regulatory mechanism that protects tissues against excessive immune responses. In tumors, this pathway is hijacked to interfere with anti-tumor immunity and promote cancer progression. Furthermore, in many cases, the tumor microenvironment contains high levels of extracellular adenosine. Therefore, adenosine receptors, especially A2aR and A2bR, have been identified as targets for cancer therapy.

[0004] Numerous adenosine receptor antagonists have been reported. For example, international application WO2006 / 138734 discloses triazolopyrimidine cannabinoid receptor 1 (CB-1) antagonists. WO2008 / 002596 and WO2009 / 111449 disclose adenosine A2a receptor antagonists containing a triazolone moiety. WO2012 / 038980 discloses condensed tricyclic compounds as adenosine receptor antagonists. WO2016 / 161282 discloses heterocyclic compounds as LSD1 inhibitors. WO2018 / 166493 discloses heteroaryl[4,3-c]pyrimidin-5-amine derivatives for use as A2a receptor antagonists. Summary of the Invention Problems to be Solved by the Invention

[0005] There remains a need for highly soluble, highly selective, and extremely potent adenosine receptor antagonists. Means for Solving the Problems

[0006] Summary In one aspect, a compound of formula (I): [Chemical formula] is provided, or a pharmaceutically acceptable salt thereof, wherein: Ring A can be saturated, partially unsaturated or aromatic and has the structure: [Chemical formula] and can have; Y 1 can be N, -CH- or -C=; Y 2 can be O or -CR g =; wherein R g is H, halo, -R a or -OR a ; R 1is Halo, C 1-3 alkyl, -O-C 1-3 alkyl, -CO2R a or -NR 7 R 8 and may be; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo; or R 1 and R g together with the atom to which they are attached can form a 5-membered heterocyclyl or heteroaryl having 1 to 2 heteroatoms selected from N and O; R 2 is Halo, C 1-3 alkyl, -O-C 1-3 alkyl, -CO2R a or -NR 7 R 8 and may be; wherein alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo; R 3 is:

Chemical formula

[0007] The compound can be a selective adenosine receptor antagonist for CB-1.

[0008] The compound can have a K of 100 nM or less for at least one of A2aR and A2bR i and a K of 10,000 nM or more for CB-1 i and can have.

[0009] R 2 can be -CH3.

[0010] i can be 1, 2 or 3; and each R c can be H.

[0011] R 5 can be a 5-membered heterocyclyl or 5-membered heteroaryl.

[0012] i can be 1; R c can be H; and R 5 can be 1,3-oxazolyl optionally substituted with 1 to 2 -CH3.

[0013] In another aspect, a compound of formula (IIa) or (IIb):

Chemical formula

[0014] In the compound of formula (IIa) or a pharmaceutically acceptable salt thereof, Y 1 may be N; and R 1 and R 2 may each independently be -CH3.

[0015] In the compound of formula (IIb) or a pharmaceutically acceptable salt thereof, R 2 may be -CH3; and R 5 may be a 5- or 6-membered heteroaryl.

[0016] In the compound of formula (IIa) or formula (IIb) or a pharmaceutically acceptable salt thereof, R c may be H; and R 5 may be C 1-3 alkyl optionally substituted with 1 to 3 fluoros.

[0017] In another aspect, there is provided a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 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-piperidyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-benzimidazol-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-pentadeuteriophenyl)-[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.

[0018] In other aspects, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or additive.

[0019] In other aspects, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition mediated by an adenosine receptor.

[0020] Diseases or conditions mediated by an adenosine receptor 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.

[0021] Other features, objects and advantages will be apparent from the specification and drawings and claims.

Mode for Carrying Out the Invention

[0022] Description The compounds of formula (I), formula (II) and formula (IIb) or their pharmaceutically acceptable salts are useful as adenosine receptor antagonists.

[0023] Formula (I):

Chem.

[0024] Ring A is saturated, partially unsaturated or aromatic and has the structure:

Chem.

[0025] Y 1 is N, -CH- or -C=.

[0026] Y 2 is O or -CR g =; where R g is H, halo, -R a or -OR a is.

[0027] R 1 is halo, C 1-3 alkyl, -O-C 1-3 alkyl, -CO2R a or -NR 7 R 8 is; where the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo.

[0028] or R 1 and R g together with the atom to which they are attached form a 5-membered heterocyclyl or heteroaryl having 1 to 2 heteroatoms selected from N and O.

[0029] R 2 is halo, C 1-3Alkyl, -O-C 1-3 Alkyl, -CO2R a Or -NR 7 R 8 wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo.

[0030] R 3 is:

Chemical formula

[0031] R 4 is -(CHR c ) i -(NR a ) j -R 5 as follows.

[0032] R 5 is (1) C 3-8 cycloalkyl, aryl, 3- to 8-membered heterocyclyl or 3- to 8-membered heteroaryl; wherein the heterocyclyl and heteroaryl each independently contain 1 to 4 heteroatoms selected from N, O and S(O) k ; wherein one or two ring atoms of R 5 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 contains 1 to 4 heteroatoms selected from N, O and S(O) k ; wherein one or two ring atoms of R 5 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 -O-C(O)-NR a R b is.

[0033] R 5 is optionally substituted with 1 to 4 groups -X-R 6 .

[0034] Each X is independently a bond, -O-, -NR a -, -S(O) k -, -(CH2) m - or -C(O)-.

[0035] Each R 6 is independently H, halo, -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 heterocyclyl and heteroaryl contains 1 to 4 heteroatoms independently selected from N, O and S(O) k ; wherein one or two ring atoms of each C 3-8 cycloalkyl, heterocyclyl, heteroaryl or aryl are independently optionally substituted with -C(=O)-; 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 halo.

[0036] Each R 7 and each R 8 are independently R a .

[0037] or R 7 and R 8 together with the atom to which they are attached, optionally form a 3- to 8-membered heterocyclyl substituted with one or more substituents independently selected from -OR a and halo.

[0038] Each R a and each R b is independently H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl; wherein each R a and each R b is independently optionally substituted with one or more substituents independently selected from -OH and halo.

[0039] Each R c is independently H, halo, C 1-3 alkyl or -(CH2) n -NR a R b ; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo; Each R d is independently halo, cyano, -R a or -OR a .

[0040] c is 0, 1, 2 or 3.

[0041] i is 0, 1, 2 or 3.

[0042] j is 0 or 1.

[0043] Each k is independently 0, 1 or 2.

[0044] Each m is independently 1 or 2.

[0045] Each n is independently 0 or 1.

[0046] In certain embodiments, R 2 is -CH3.

[0047] In certain embodiments, i is 1, 2, or 3; and each R c is H.

[0048] In certain embodiments, R 5 is a 5 - membered heterocyclyl or 5 - membered heteroaryl.

[0049] In certain embodiments, i is 1; R c is H; and R 5 is 1,3 - oxazolyl optionally substituted with 1 - 2 -CH3 groups.

[0050] In certain embodiments, R 5 is a 6 - membered heterocyclyl or 6 - membered heteroaryl.

[0051] In certain embodiments, Y 1 is N; Y 2 is O; R 1 is -CH3; and R 2 is CH3.

[0052] In certain embodiments, Y 1 is -CH- or -C=; and Y 2 is O.

[0053] In certain embodiments, i is 1; R c is H; and R 5 is a 5 - membered heterocyclyl or 5 - membered heteroaryl.

[0054] In certain embodiments, i is 1; R c is H; and R 5 is a 6 - membered heterocyclyl or 6 - membered heteroaryl.

[0055] In certain embodiments, R 1 and Rg They combine with the atoms to which they are attached to form a 5-membered heterocyclyl or heteroaryl.

[0056] In certain embodiments, R 1 and R g combine with the atoms to which they are attached to form a 5-membered heterocyclyl or heteroaryl; and R 2 is -CH3.

[0057] In certain embodiments, Y 1 is N; Y 2 is O; R 1 is -CH3; R 2 is CH3; and R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl.

[0058] In certain embodiments, Y 1 is N; Y 2 is O; R 1 is -CH3; R 2 is CH3; and R 5 is a 6-membered heterocyclyl or 6-membered heteroaryl.

[0059] In certain embodiments, Y 1 is N; Y 2 is O; R 1 is -CH3; R 2 is CH3; i is 1; R c is H; and R 5 is a 5-membered heterocyclyl or 5-membered heteroaryl.

[0060] In certain embodiments, Y 1 is N; Y 2 is O; R 1 is -CH3; R 2 is CH3; i is 1; R c is H; and R 5 is a 6-membered heterocyclyl or 6-membered heteroaryl.

[0061] Formula (IIa) or (IIb):

Chemical formula

[0062] Y 1 is N or CH.

[0063] Y 3 and Y 4 together are -CH=N-, -N=CH-, -CH=CH- or =CH-O-.

[0064] Each R 1 and each R 2 is independently halo, C 1-3 alkyl or -O-C 1-3 alkyl; where the alkyl is optionally substituted with one or more substituents independently selected from -OH and halo.

[0065] R 4 is -CHR c -R 5 is.

[0066] R 5 is (1) a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; where the heterocyclyl and heteroaryl independently contain 1 to 4 heteroatoms selected from N, O and S(O) k ; where one or two ring atoms of R 5 are optionally replaced by -C(=O)-; where the heterocyclyl and heteroaryl are optionally independently substituted with one or more substituents selected from halo, -R e and -OR e ; or (2) H, halo or C 1-3 alkyl; where the alkyl is optionally substituted with one or more substituents independently selected from -OH and halo.

[0067] Each R a and each R b is, independently, H, C 1-6 alkyl, C 3-8 cycloalkyl or C 4-9 cycloalkylalkyl; wherein each R a and each R b is, independently, optionally substituted with one or more substituents independently selected from -OH and halo.

[0068] R c is H, halo, C 1-3 alkyl or -(CH2) n -NR a R b ; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OR a and halo.

[0069] R d is H or halo.

[0070] Each R e is, independently, H or C 1-6 alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from -OH and halo.

[0071] n is 0 or 1.

[0072] The compounds of formula (IIa) and formula (IIb) are included in the broad formula (I).

[0073] In certain embodiments of formula (IIa), Y 1 is N; and R 1 and R 2 are each independently -CH3.

[0074] In certain embodiments of formula (IIb), R 2 is -CH3; and R 5 is a 5- or 6-membered heteroaryl.

[0075] In one embodiment, R c is H; and R 5 is C 1-3 alkyl optionally substituted with 1 to 3 fluoro.

[0076] In one embodiment, Y 3 and Y 4 together are -CH=N-.

[0077] In one embodiment, Y 3 and Y 4 together are -N=CH-.

[0078] In one embodiment, Y 3 and Y 4 together are -CH=CH-.

[0079] In one embodiment, Y 3 and Y 4 together are =CH-O-.

[0080] In one embodiment of formula (IIa), R c is H; and R 5 is C 1-3 alkyl optionally substituted with 1 to 3 fluoro.

[0081] In one embodiment of formula (IIb), R c is H; and R 5 is 1,3-oxazolyl optionally substituted with 1 to 2 -CH3.

[0082] The term "halo" refers to fluoro, chloro, bromo and iodo.

[0083] The term "alkyl", if specified, refers to a fully saturated straight-chain or branched aliphatic group having a specified number of carbon atoms (e.g., C 1-10"Alkyl" refers to an alkyl group having 1 to 10 carbons. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. If no size is specified, "alkyl" refers to a group having 1 to 10 carbon atoms.

[0084] The term "alkenyl" refers to an unsaturated straight-chain or branched aliphatic group containing at least one carbon-carbon double bond and having a specific number of carbon atoms if specified. 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.

[0085] The term "alkynyl" refers to an unsaturated straight-chain or branched aliphatic group containing at least one carbon-carbon triple bond and having a specific number of carbon atoms if specified. 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.

[0086] Alkenyl groups and alkynyl groups may contain more than one unsaturated bond or a mixture of double and triple bonds.

[0087] The term "cycloalkyl" refers to a saturated or unsaturated aliphatic ring containing 3 to 10 carbon ring atoms, where one or more of the carbon ring atoms may optionally be replaced by -C(=O)-. Cycloalkyl groups may include fused or bridged rings where the fused and / or bridged rings are 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-en-1-yl.

[0088] The term "heterocyclyl" refers to a saturated or unsaturated heterocyclic ring containing 3 to 10 ring atoms, where 1 to 4 ring atoms are independently N, O, or S, and one or more carbocyclic atoms may optionally be replaced by -C(=O)-. Ring nitrogen or ring sulfur atoms may optionally be oxidized, for example, to include -N(O)-, -S(O)-, or -S(O)2-. The ring nitrogen atom of a heterocyclyl group may optionally be quaternized, for example, -N + (CH3)2-. The heterocyclyl group may include fused or bridged rings where the cycloalkyl or heterocyclyl group is a fused and / or bridged ring. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, dihydropyranyl, dihydropyridinyl, tetrahydropyranyl, octahydroquinolinyl, octahydroindolizinyl, and decahydroquinolinyl.

[0089] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group containing 6 to 14 ring atoms. Aryl may include fused rings, including cycloalkyl, heterocyclyl, or aryl rings fused to an aryl ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, and dihydro-1H-indenyl.

[0090] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic aromatic group containing 6 to 14 ring atoms, with 1 to 4 ring atoms independently being N, O, or S. Ring nitrogen or ring sulfur atoms may optionally be oxidized, for example, including -N(O)-, -S(O)-, or -S(O)2-. The heteroaryl group may include fused and / or bridged rings where the fused 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.

[0091] The term "polycyclic ring system" refers to a cycloalkyl, heterocyclyl, aryl, or heteroaryl group containing two or more fused and / or bridged rings.

[0092] Some of the compounds described herein may exist in more than one stereoisomeric form. The description of such compounds is intended to include all geometric and optical isomers, including racemates, unless otherwise specified.

[0093] Some of the compounds described herein may exhibit tautomerism. The structural descriptions herein typically represent only one of the possible tautomeric forms of such compounds. It should be understood that the structural descriptions are intended to include all tautomeric forms of such compounds.

[0094] The term "pharmaceutically acceptable salt" refers to salts of the compounds of formula (I) that retain the biological activity of the free compound and can be administered to humans and / or animals as a medicine. The desired salts of the basic functional groups 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 salts of the acidic functional groups of the compound can be prepared by treating the compound with a base. Some examples of suitable inorganic salts of acid compounds include alkali metal and alkaline earth salts such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts, but are not limited thereto. Some examples of suitable organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, Ν,Ν'-dibenzylethylenediamine, and triethylamine salts.

[0095] The compounds of formula (I) may contain the designated atoms in any of their isotopic forms. In this regard, embodiments of the invention that may be specifically noted include: (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.

[0096] Wherein in the formula here

Chemical formula

[0097] Exemplary compounds of formula (I) or pharmaceutically acceptable salts thereof include the following. 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-piperidyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-benzimidazol-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-pentadeuteriophenyl)-[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.

[0098] The compound of formula (I) can be an adenosine receptor antagonist, i.e., an antagonist of one or more of A1R, A2aR, A2bR, and A3R. The term "adenosine receptor antagonist" refers to a compound, e.g., a compound of formula (I) that binds to an adenosine receptor and antagonizes its activity.

[0099] In some cases, the compound of formula (I) is a selective adenosine receptor antagonist. The term "selective" refers to the property of a compound of formula (I) that is an adenosine receptor antagonist but is substantially inactive against other biological targets. The term "substantially inactive" as used herein refers to a compound that (i) has a significantly lower affinity for a certain receptor compared to its affinity for an adenosine receptor; (ii) does not exhibit substantial agonist or antagonist activity against a certain receptor; or both (i) and (ii).

[0100] 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 greater, at least 1,000-fold greater, or at least 10,000-fold greater than its affinity for a certain receptor. In other words, the binding K i value ratio (certain receptor: adenosine receptor) can be at least 100, at least 1,000, or at least 10,000.

[0101] In particular, the selective adenosine receptor antagonist can be substantially inactive against other G protein-coupled receptors such as the cannabinoid receptors designated as CB-1 and CB-2.

[0102] The compound of formula (I) can have a binding affinity K i for A2aR, for example, of 100 nM or less, 10 nM or less, or 1 nM or less.

[0103] The compound of formula (I) can have a binding affinity K i for A2bR, for example, of 100 nM or less, 10 nM or less, or 1 nM or less.

[0104] The compound of formula (I) can have a binding affinity K i for CB-1, for example, of 1,000 nM or more, 10,000 nM or more, 13,000 nM or more.

[0105] The compound of formula (I) can be a selective adenosine receptor antagonist for CB-1.

[0106] The compound of formula (I) can be active as an adenosine receptor antagonist but substantially inactive against CB-1.

[0107] The compound of formula (I) can also be selective among various adenosine receptor subtypes. In certain embodiments, the compound of formula (I) is A2aR-selective; A2bR-selective; or dual A2aR / A2bR-selective.

[0108] An A2aR-selective compound exhibits a binding affinity for A2aR that is at least 100-fold stronger, at least 1,000-fold stronger or at least 10,000-fold stronger than its binding affinity for each of A1R, A2bR and A3R.

[0109] An A2bR-selective compound is at least 100-fold stronger, at least 1,000-fold stronger or at least 10,000-fold stronger than its binding affinity for each of A1R, A2aR and A3R.

[0110] A dual A2aR / A2bR-selective compound exhibits a binding affinity for A2aR that is at least 100-fold stronger, at least 1,000-fold stronger or at least 10,000-fold stronger than its binding affinity for each of A1R and A3R. The dual A2aR / A2bR-selective also exhibits a binding affinity for A2bR that is at least 100-fold stronger, at least 1,000-fold stronger or at least 10,000-fold stronger than its binding affinity for each of A1R and A3R. Further, for a dual A2aR / A2bR-selective compound, the ratio of the binding affinity of A2aR to the binding affinity of A2bR is less than 100.

[0111] In certain embodiments, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or additive thereof.

[0112] 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 fine powders or liquid aerosols), administration by insufflation (e.g., as fine powders) or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular dosing or as suppositories for rectal dosing).

[0113] Pharmaceutically acceptable additives suitable for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may or may not be coated, and may be coated to modify the active ingredient upon disintegration in the gastrointestinal tract or to improve stability and / or appearance, in which case conventional coating agents and methods known in the art are used.

[0114] 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 such as calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0115] The compounds of formula (I) are useful for the treatment of diseases or conditions mediated by adenosine receptors. In certain embodiments, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by an adenosine receptor. In certain embodiments, the disease or condition is A2aR; in other embodiments, A2bR; and in still other embodiments, mediated by both A2aR and A2bR.

[0116] Some examples of diseases or conditions mediated by adenosine receptors include cancers such as 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; 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.

[0117] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0118] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of 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, glioma, melanoma or other solid tumors).

[0119] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition mediated by an adenosine receptor, wherein the compound is a selective adenosine receptor antagonist for CB-1.

[0120] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of 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, glioma, melanoma or other solid tumors), wherein the compound is a selective adenosine receptor antagonist for CB-1.

[0121] In one embodiment, there is provided a method for treating a disease or condition mediated by an adenosine receptor, the method comprising administering to a subject in need of such treatment an effective amount of a disease or condition mediated by an adenosine receptor.

[0122] In one embodiment, there is provided a method for treating 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, glioma, melanoma or other solid tumors) 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.

[0123] In one embodiment, there is provided a method for treating a disease or condition mediated by an adenosine receptor 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 for CB-1.

[0124] In one embodiment, there is provided a method for treating 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, glioma, melanoma or other solid tumors) 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 for CB-1.

[0125] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by an adenosine receptor.

[0126] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of 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, glioma, melanoma or other solid tumors).

[0127] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for use in the treatment of a disease or condition mediated by an adenosine receptor, wherein the compound is a CB-1 selective adenosine receptor antagonist.

[0128] In one embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament 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 CB-1 selective adenosine receptor antagonist.

[0129] The compound of formula (I) can be prepared according to the following general scheme.

[0130] Schemes 1a and 1b describe the preparation of the intermediate 6-substituted-4-hydrazino-2-aminopyrimidine compound of formula (IV).

Chemical formula

Chemical formula

[0131] Scheme 2 describes the conversion of the compound of formula (IV) to the intermediate 7-substituted-5-amino-8-bromo-[1,2,4]triazolo[4,3-c]pyrimidin-3-one compound of formula (V). Briefly, the compound of formula (IV) is treated with triphosgene to close the triazolone ring, followed by bromination with (CH3)3PhN + Br3 - and bromination.

Chemical formula

[0132] Scheme 3a describes the conversion of a compound of formula (V) to a compound of formula (I). R 4 The alkylation of the compound of formula (V) using R can be carried out using a variety of methods, for example, Mitsunobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.

Chemical formula

[0133] Alternatively, the compound of formula (V) can be directly alkylated using a compound such as R 4 -Br.

[0134] Optionally, R 4 can be further modified after the alkylation of the compound of formula (V).

[0135] Scheme 3b describes an alternative route for the conversion of a compound of formula (V) to a compound of formula (I). In Scheme 3b, [Pg] represents a reagent suitable for introducing a protecting group shown as Pg. R 4 The alkylation of the compound of formula (Va) using R can be carried out using a variety of methods, for example, Mitsunobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction.

Chemical formula

[0136] Alternatively, the compound of formula (Va) can be directly alkylated using a compound such as R 4 -Br.

[0137] Optionally, R 4 can be further modified after the alkylation of the compound of formula (V).

[0138] Scheme 3c describes an alternative route for the conversion of a compound of formula (V) to a compound of formula (I). Step 1 of Scheme 3c is the same as that of Scheme 3a, i.e., R 4 The alkylation of the compound of formula (V) using R 4 can be carried out using a variety of methods, such as Mitsunobu reaction; alcohol mesylation followed by an alkylation reaction; alcohol tosylation followed by an alkylation reaction; or alcohol chlorination followed by an alkylation reaction. Alternatively, the compound of formula (V) can be directly alkylated using a compound such as R

[0139] Step 2 of Scheme 3c illustrates the case where ring A contains an aliphatic amine as the point of attachment. In this case, the product of step 1 can be reacted directly with the ring A precursor compound as shown in Scheme 3c.

Chemical formula

[0140] Optionally, the compound of formula (I) can be further modified to form, for example, a different compound of formula (I).

Examples

[0141] General techniques LCMS method A Equipment: Agilent Technologies 1200 Series, Agilent LC / MSD SL, column: Waters XBridge C8 3.5 μ, 4.6×50 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 1 μL (may vary); UV detection 220 - 400 nm; column temperature 25 °C; 2.0 mL / min. Note: For UV-inactive compounds, connect an ELSD detector (Polymer Laboratories PL-ELS 2100 ICE) to the above equipment.

[0142] LCMS Method B Equipment: Agilent Technologies 1200 Series, Agilent LC / MSD SL, Column: Atlantis dC18 5μ, 4.6×50mm. 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 TFA in 1000 mL of Milli-Q water; Solvent B = 1 mL of TFA in 1000 mL of MeCN); Injection volume 1 μL (variable); UV detection 210 - 400 nm; Column temperature 25 °C; 1.5 mL / min.

[0143] LCMS Method C Equipment: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5μ, 4.6×50mm. 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 1 μL (variable); UV detection 210 - 400 nm; Column temperature 25 °C; 1.5 mL / min.

[0144] LCMS Method D Equipment: Agilent Technologies 1200 Series, Agilent 6130 Quadrupole LC / MS, Column: Zorbax C18 5μ, 4.6×50mm. Gradient [time (min) / Solvent B (%)]: 0.0 / 10, 4.0 / 95, 5.0 / 95, 5.5 / 10, 7.0 / 10. (Solvent A = 1000 mL of Milli-Q aqueous solution of 770.08 mg of ammonium acetate; Solvent B = MeCN); Injection volume 1 μL (variable); UV detection 210 - 400 nm; Column temperature 25 °C; 1.2 mL / min.

[0145] Preparative HPLC Method A Equipment: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 0.1% TFA in H2O, B - MeOH, Column: YMC Actus Triart C18 (30mm×250mm) 5μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0146] Preparative HPLC Method B Equipment: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 0.1% HCOOH in H2O, B - MeCN, Column: YMC Actus Triart C8 (20mm×250mm) 5μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 20 / 95, 23 / 95, 24 / 10, 26 / 10.

[0147] Preparative HPLC Method C Equipment: Agilent Technologies 1260 Infinity II Series LC. Solvent: A - 10mM NH4HCO3 aqueous solution, B - MeOH or MeCN, Column: XBridge C8 (19mm×150mm), 5μm or YMC Actus Triart C18 (30mm×250mm) 5μm. Gradient [time (min) / solvent B (%)]: 0.0 / 10, 15 / 95, 18 / 95, 19 / 10, 21 / 10.

[0148] Synthetic route of the intermediate Synthetic Route 1 Intermediate 1, 5 - Amino - 8 - bromo - 7 - phenyl - [1,2,4]triazolo[4,3 - c]pyrimidin - 3(2H) - one

Chemical Structure

[0149] Procedure 2; To a stirred suspension of 4-chloro-6-phenylpyrimidin-2-amine (350 g, 1.70 mol) in EtOH (4.0 L) was added hydrazine hydrate (255 g, 5.1 mol), and the mixture was heated at 90 °C for 15 h. The reaction was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (1 L) and 10% sodium bicarbonate solution (1 L). The resulting solid was collected by filtration through a Buchner funnel, washed with diethyl ether (200 mL) and dried under reduced pressure to give 4-hydrazinyl-6-phenylpyrimidin-2-amine (250 g, 73%) as an off-white solid. LCMS (Method C): m / z 202 (M+H) + (ES +), 0.69 minutes, UV activity 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)

[0150] Step 3; To a solution of 3,4-hydrazinyl-6-phenylpyrimidin-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 minutes. The reaction was carefully quenched with ice-cold H2O (10 L) with vigorous stirring. After the foaming ceased, the reaction mixture was concentrated under reduced pressure. The resulting solid was collected by filtration on a Buchner funnel, washed with H2O (1 L), and dried under reduced pressure to give 5-amino-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (200 g, 70%) as a yellow solid. LCMS (Method C): m / z 228 (M+H) + (ES + ), 1.64 minutes, UV activity 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)

[0151] 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 a N2 atmosphere, CaCO3 (88 g, 0.88 mol) was added, followed by (CH3)3PhN + Br3 -(331 g, 0.88 mol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a Buchner funnel, washed with small portions of MeOH / DCM (1:1), and dried under reduced pressure to afford Intermediate 1, 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (160 g, 59%) as an off-white solid. The data for the title compound are given in Table 2.

[0152] Synthetic Route 2 Intermediate 3, 5-amino-8-bromo-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

Chemical Structure

[0153] Synthetic Route 3 Intermediate 4,5-Amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one

Chem.

[0154] Step 2; Pd(PPh3)4 (107 g, 0.093 mol) was added at room temperature to a suspension of degassed 4-chloro-6-hydrazinylpyrimidin-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), and the resulting reaction mixture was heated at 110 °C for 15 h. The reaction mixture was concentrated under reduced pressure to remove 1,4-dioxane. The obtained residue was vigorously stirred with H2O (4 L) to obtain a solid, which was filtered through a Buchner funnel and washed with MeOH (1 L). The solid was dried under reduced pressure to obtain 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 49%) as a green solid. LCMS (Method C): m / z 220 (M+H) + (ES + ), 0.76 min, UV active 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)

[0155] Step 3; A solution of 4-(4-fluorophenyl)-6-hydrazinylpyrimidin-2-amine (200 g, 0.91 mol) in dry THF (3.0 L) was cooled to -30 °C under N2, and triphosgene (538 g, 1.82 mol) was added portionwise. The mixture was stirred at the same temperature for 1 h. The reaction was carefully quenched with ice-cold H2O (10 L) with vigorous stirring. After the foaming ceased, the reaction mixture was concentrated under reduced pressure. The resulting solid was collected by filtration on a Buchner funnel, washed with H2O (1 L), and dried under reduced pressure to give 5-amino-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (150 g, 67%) as a yellow solid. LCMS (Method C): m / z 246 (M+H) + (ES + ), 1.77 min, UV active 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)

[0156] Step 4; This reaction was carried out in 2 × 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) under a N2 atmosphere, CaCO3 (66 g, 0.66 mol) was added, followed by (CH3)3PhN + Br3 -(250 g, 0.66 mol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through a Buchner funnel, washed with small portions of MeOH / DCM (1:1), and dried under reduced pressure to obtain Intermediate 26, 5-amino-8-bromo-7-(4-fluorophenyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (120 g, 60%) as an off-brown solid. The data for the title compound are in Table 2.

[0157] Synthetic Route 4 Intermediate 15, 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoxazole

Chemical formula

[0158] Step 2; A suspension of 2-amino-5-bromo-3-methylphenol (900 mg, 4.45 mmol) and triethoxymethane (10 mL) was heated at 100 °C for 1 h. The reaction mixture was partitioned 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 mesh (230 - 400) and eluting with a gradient of 5 - 10% EtOAc in petroleum ether to afford 6-bromo-4-methylbenzo[d]oxazole (400 mg, 43%) as a brown solid. LCMS (Method C): m / z 212 (M+H) + (ES + ), 2.30 min, UV active 1 1H 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)

[0159] Step 3; A solution of 6-bromo-4-methylbenzo[d]oxazole (200 mg, 0.94 mmol), bis(pinacolato)diboron (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 at 100 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford 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.

[0160] Synthetic Route 5 Intermediate 18, 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole

Chemical Structure

[0161] Step 2; 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) were added KOAc (516 mg, 5.27 mmol), Pin2B2 (664 mg, 2.60 mmol) and Pd(PPh3)4 (196 mg, 0.17 mmol), and the resulting reaction mixture was heated at 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 give a crude product (600 mg) which was used in the next step without purification.

[0162] Synthetic Route 6 Intermediate 27, 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

Chem.

[0163] Synthetic route of the example compound Synthetic Route a:S N Typical production method of alkylated triazolopyrimidinone via Ar substitution 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

Chem.

[0164] Synthetic Route b 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 [Chemical formula] Step 1; 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-fluoropropan-1-ol (92 mg, 1.18 mmol) and triphenylphosphine (385 mg, 1.47 mmol) in THF (10 mL) was added with di-tert-butyl azodicarboxylate (332 mg, 1.47 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 60 minutes. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by Biotage-Isolera using 25 g silica snap, eluting with a petroleum ether solution with a gradient of 0 - 100% EtOAc to obtain 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. LCMS (Method B): m / z 366 (M+H) + (ES + ), 2.55 min, UV active 1 1H 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). Exchangeable -NH2 protons were not observed

[0165] Step 2; Prepared by a method according to Route a to obtain 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 of the title compound are in Table 3.

[0166] Synthetic Route c Examples 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 [Chemistry] To a suspension of Project 1; 5-amino-8-bromo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2g, 6.55 mmol) and K2CO3 (2.7g, 19.65 mmol) in MeCN (40 mL) at room temperature was added 3-bromo-1,1-dimethoxypropane (1.4g, 7.86 mmol), and the reaction mixture 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 reduced pressure to give 5-amino-8-bromo-2-(3,3-dimethoxypropyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (1.2g, 45%) as an off-white solid. LCMS (Method B): m / z 408 (M+H) + (ES + ), 2.68 min, UV active 1 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). Exchangeable -NH2 protons were not observed

[0167] In a solution of 2-(3,3-dimethoxypropyl)-5-amino-8-bromo-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) at room temperature, 2N HCl (30 mL) was added, and the reaction mixture was stirred for 2 hours. The reaction mixture 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 give 3-(5-amino-8-bromo-3-oxo-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-2(3H)-yl)propanal (assumed to be quantitative) as a brown gum, which was used in the next step without further purification. LCMS (Method B): m / z 362 (M+H) + (ES + ), 2.32 min, UV active

[0168] In 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) at -78 °C, DAST (0.58 g, 3.63 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, then saturated sodium bicarbonate solution (40 mL) was carefully added dropwise to quench the reaction, and the mixture was extracted with DCM (2 × 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 25 g silica snap and eluting with a hexane solution with a gradient of 0 - 40% EtOAc to give 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. LCMS (Method B): m / z 384 (M+H) + (ES + ), 2.80 min, UV active 11H 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). Exchangeable -NH2 protons were not observed

[0169] Step 4; Prepared by a method according to Route a to give 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 of the title compound are in Table 3

[0170] Synthetic Route d: Alkylation reaction, followed by S N Typical production method of alkylated triazolopyrimidinone via Ar substitution Examples 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

Chemical Structure

[0171] Step 2; Prepared in a manner according to Route a to obtain 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 of the title compound is in Table 3

[0172] Synthetic Route e: Alcohol mesylation and substitution reaction, followed by S N Typical production method of alkylated triazolopyrimidinone via Ar substitution Examples 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

Chemical Structure

[0173] Process 2; Prepared by a method according to Route a to give 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. Data for the title compound are in Table 3.

[0174] Synthetic Route f Examples 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

Chemical Structure

[0175] Step 2; Prepared in a manner according to Route a to give 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 (35 mg, 16%) as a yellow solid. The data of the title compound are in Table 3

[0176] Synthetic Route g: Alcohol mesylation and substitution reaction, followed by S N Typical production method of alkylated triazolopyrimidinone via Ar substitution and benzyl deprotection Examples 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 [Chemical formula] Step 1; Conducted using Intermediate 9 in a manner according to Route e, Step 1 to give (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%) as a pale yellow solid LCMS (Method A): m / z 495 (M + H) + (ES + ), 3.55 minutes, UV active 11H 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). Exchangeable -NH2 protons were not observed

[0177] Step 2; A mixture of (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-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 mixture was partitioned 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 snap, eluting with a hexane solution with a gradient of 0 - 40% EtOAc to give 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, 88%) as a yellow gum LCMS (Method A): m / z 530 (M+H) + (ES + ), 3.32 min, UV active

[0178] 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 for 15 h under a H2 atmosphere (balloon pressure). The reaction mixture was filtered through celite and washed 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 partitioned 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 give 5-amino-8-(cis-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%). Data for the title compound are given in Table 3.

[0179] Synthetic Route h Examples 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 [Chemical formula] A solution of 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 (50 mg, 0.11 mmol) and 33% aqueous HCHO (0.012 mL, 0.13 mmol) in MeCN (2 mL) was added with sodium triacetoxyborohydride (35 mg, 0.17 mmol) at room temperature and stirred for 10 minutes. The reaction mixture was partitioned between EtOAc (10 mL) and aqueous salt 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 partitioned between EtOAc (2 mL) and saturated NaHCO3 solution (2 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give 5-amino-8-(cis-2,6-dimethylmorpholino)-2-(((S)-4-methylmorpholin-3-yl)methyl)-7-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (13 mg, 25%) as a yellow solid. The data of the title compound are in Table 3.

[0180] Route i 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 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 [Chemical Structure] 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 several minutes, then Pd(PPh3)4 (42 mg, 0.04 mmol) was added. The vessel was sealed and heated at 100 °C for 15 h. The reaction mixture was partitioned between H2O (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The crude product was purified by preparative HPLC (Method-A) to give 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 (120 mg, 74%) as an off-white solid. Data for the title compound are in Table 3.

[0181] 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 vessel was heated at 60 °C for 15 h under an H2 pressure of 5 kg / cm 2 2. The mixture was cooled and concentrated. The crude product was purified by preparative HPLC (Method-A) to give 5-amino-8-((cis)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-7-phenyl-2-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (8.5 mg, 8%) as an off-white solid. Data for the title compound are in Table 3.

[0182] Route j 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

Chemical Structure

[0183] 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) were 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 reaction was heated in a sealed tube at 120 °C for 4 h. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (15 mL), the organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by elution with a hexane gradient of 0 - 100% EtOAc using a 25 g silica snap on Biotage-Isolera to give 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. LCMS (Method A): m / z 471 (M+H) + (ES + ), 2.66 min, UV active 1 1H 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)

[0184] To a mixture of 3;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 at 60 °C for 16 h. The reaction mixture was quenched by addition of 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 partitioned between sodium bicarbonate (10 mL) and EtOAc (10 mL). The organic layer was separated, dried over Na2SO4 and concentrated to dryness to afford 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. Data for the title compound are in Table 3.

[0185] Route k 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 [Chemical formula] In Project 1; to a 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), TEA (4.6 g, 46.20 mmol) and SEM-Cl (2.3 g, 13.8 mmol) were added 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 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography using silica mesh (230 - 400) and eluting with a petroleum ether solution of 5 - 10% EtOAc to give 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. LCMS (Method C): m / z 454 (M+H) + (ES + ), 1.90 min, UV active 1 1H 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). Exchangeable -NH2 protons were not observed

[0186] Project 2; 5-Amino-8-bromo-7-(4-fluorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (4g, 8.8mmol), 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (4g crude, 10.5mmol) and a solution of K2CO3 (3.64g, 26.4mmol) in 1,4-dioxane (100mL) and H2O (10mL) were degassed with N2 for 5 minutes. Pd(PPh3)4 (1g, 0.88mmol) was added and the resulting reaction mixture was heated at 120 °C for 5 hours. The reaction was partitioned between EtOAc (100 × 2mL) and H2O (100mL). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by Biotage-Isolera using 50g silica snap and eluting with a petroleum ether solution of 30 - 40% EtOAc to give 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 (1.5g, 34%) as a yellow solid. LCMS (Method C): m / z 507 (M+H) + (ES + ), 2.48 min, UV active 1 1H 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). Exchangeable -NH2 proton was not observed

[0187] A solution of 3;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 minutes. The reaction mixture was concentrated under reduced pressure. The crude product was dissolved in MeOH (10 mL), DIPEA (1.7 mL, 14.7 mmol) was added dropwise at 0 °C, and the resulting reaction mixture was heated at 70 °C for 3 hours. The precipitate was filtered off and dried to give 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. Data for the title compound are in Table 2.

[0188] Procedure 4; To a solution of 3,3,3-trifluoropropan-1-ol (220 mg, 1.92 mmol) and TEA (0.5 mg, 5.78 mmol) in DCM (10 mL) at 0 °C was added methanesulfonyl chloride (0.1 mg, 2.31 mmol) dropwise, and the resulting reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between DCM (50 mL) and H2O (50 mL), the organic layer was separated and concentrated under reduced pressure to obtain the mesylation intermediate. The mesylation intermediate was dissolved 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), K2CO3 (660 mg, 4.78 mmol) was added, and the reaction mixture was heated at 50 °C for 16 hours. 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, 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 give 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. Data for the title compound are in Table 3.

[0189] Route l: Alcohol mesylation and substitution reaction, followed by typical production method of triazolopyrimidinone via Suzuki coupling reaction 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

Chemical Structure

[0190] Procedure 2; Prepared by a method according to Step 2 of Route k and purified by preparative HPLC (Method A) to obtain 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 of the title compound are in Table 3.

[0191] Route m: Alcohol mesylation and substitution reaction, followed by typical production method of alkylated triazolopyrimidinone via Suzuki coupling and deprotection 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 [Chemical Structure] Step 1; According to the method similar to Step 1 of Route e, using Intermediates 1 and 11, 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%) was obtained as an off-white solid. LCMS (Method B): m / z 415 (M+H) + (ES + ), 2.64 min, UV active 1 1H 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). Exchangeable -NH2 proton was not observed

[0192] In a mixture of 2;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), Pd(PPh3)4 (28 mg, 0.02 mmol) and K2CO3 (727 mg, 5.27 mmol) were added, and the resulting reaction mixture was heated at 120 °C for 5 hours. The reaction was partitioned between EtOAc (15 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 Biotage-Isolera using a 25 g silica snap, eluting with a gradient of petroleum ether solution of 0 - 100% EtOAc to give 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, 25%) as a yellow solid. LCMS (Method C): m / z 597 (M+H) + (ES + ), 1.77 min, UV active

[0193] For Process 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 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in MeOH (10 mL), DIPEA (3.5 ml, 20.52 mmol) was added, and then the mixture was heated at 70 °C for 3 hours. The obtained solid was collected by filtration through a Buchner funnel, washed with H2O (10 mL), and dried. The crude product was purified by preparative HPLC (Method-A). The collected fractions were concentrated, the obtained 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, concentrated, and 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 (30 mg, 15%) was obtained as a yellow solid. The data of the title compound are shown in Table 3.

[0194] Route n: Alcohol tosylation and substitution reaction, followed by typical production method of alkylated triazolopyrimidinone via Suzuki coupling Examples 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 [Chemical formula] For Process 1; Prepared according to Process 1 of Route f, using Intermediates 1 and 22, purified by eluting with a petroleum ether gradient of (0-100%) EtOAc using silica (230-400) mesh on Biotage Isolera to obtain 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. LCMS (Method C): m / z 401 (M+H) + (ES + ), 1.93 min, UV active 1 1H NMR: (400 MHz, DMSO-d6) δ: 7.82 (s, 1H), 7.37 - 7.30 (m, 5H), 4.89 (s, 2H), 2.39 (s, 3H). Exchangeable -NH2 proton was not observed

[0195] Step 2; Route m, Prepared in a manner analogous to Step 2 to give 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. Data for the title compound are in Table 3

[0196] Route o Examples 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

Chemical Structure

[0197] Route p: Alcohol tosylation and substitution reaction, followed by typical production method of alkylated amine analog via Suzuki coupling and deprotection Examples 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

Chemical Structure

[0198] Step 2; Route m, prepared by a method analogous to Step 2, 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, 35%) was obtained as a yellow solid. LCMS (Method C): m / z 601 (M+H) + (ES + ), 2.86 min, UV active

[0199] 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 minutes. The reaction mixture was concentrated under reduced pressure. The crude material was dissolved in methanolic ammonia (4M solution) at 0 °C and heated at 70 °C for 3 hours. The resulting precipitate was filtered and dried. The crude product was purified by preparative HPLC (Method-A). The collected fractions were concentrated, 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, concentrated, and 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%) was obtained as an off-white solid. The data of the title compound are shown in Table 3.

[0200]

Table 1-1

Table 1-2

[0201]

Table 2-1

Table 2-2

[0202]

Table 3-1

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

[0203] Example 5: Adenosine Receptor Binding Assay The inhibition binding assay was performed using 0.2 μg of membrane prepared from HEK293 cells infected with BacMam human adenosine A 2A receptor or 1.4 μg of membrane prepared from HEK293 cells infected with BacMam human adenosine A1 receptor. The membrane was incubated with various concentrations of the compound and 1 nM 3 [H]ZM241385 (HEK293-hA 2A ) or3 In the presence of H]DPCPX(CHO-hA1), at 25 °C for 1 hour, in 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). The assay was then stopped by rapid filtration through a GF / B grade Unifilter using a TomTec cell harvester, followed by washing 5×0.5 ml with ddH2O. Nonspecific binding was defined in the presence of 1 μM CGS15943 (HEK293-hA 2A ) or 1 μM DPCPX (CHO-hA1). The bound radioactivity was determined by liquid scintillation counting, and the inhibition curves were analyzed using a four-parameter logistic equation. IC 50 value to chi Using the Cheng-Prusoff equation, the KD value derived from the saturation binding assay was used to convert to the K i value. The results are summarized in Table 4.

[0204]

Table 4

[0205] Example 6: CB-1 Receptor Binding and Antagonism Receptor binding : The affinity of a compound for the agonist site of the human CB-1 cannabinoid receptor in transfected CHO cells was determined by a radioligand binding assay: Cell membrane homogenates (20 μg protein) were incubated in a buffer containing 50 mM Tris-HCl (pH 7.4), 5 mM MgCl2, 2.5 mM EDTA and 0.3% BSA for 120 minutes at 37 °C in the absence or presence of the test compound and 0.5 nM 3 H]CP 55940. Nonspecific binding was determined in the presence of 10 μM WIN 55212-2. After incubation, the samples were rapidly filtered under reduced pressure through a glass fiber filter (GF / B, Packard) pre-impregnated with 0.3% PEI, and washed 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 filter was dried and then the radioactivity was counted using a scintillation counter (Topcount, Packard) with a scintillation cocktail (Microscint 0, Packard). The standard reference compound is CP 55940, which was tested at several concentrations in each experiment to obtain a competition curve for calculating IC 50 50.

[0206] Receptor antagonism : Determined by measuring the effect on agonist-induced cAMP modulation using the HTRF detection method, the evaluation of the antagonist activity of the compound on the human CB1 receptor expressed in transfected CHO cells. The cells were suspended in HBSS buffer (Invitrogen) supplemented with 20 mM HEPES (pH 7.4) and then dispensed into microplates at a density of 5.10 3 cells / well and pre-incubated for 5 minutes at room temperature in the presence of any of the following: HBSS (stimulated control), 3 μM or various concentrations (IC 50 determined) of the reference antagonist AM 281 (basal control) or the test compound. Thereafter, the reference agonist CP 55940 and the adenylyl cyclase activator NKH 477 were added at final concentrations of 3 nM and 3 μM, respectively. For basal control measurements, CP 55940 was removed from the wells containing 3 μM AM 281. After incubation at 37 °C for 20 minutes, the cells were lysed and a fluorescent acceptor (D2-labeled cAMP) and a fluorescent donor (anti-cAMP antibody labeled with europium cryptate) were added. After 60 minutes at room temperature, the fluorescence transfer was measured using a microplate reader (Rubystar, BMG) at λ ex= 337 nm and λ em Measure at 620 and 665 nm. Determine the cAMP concentration by dividing the signal measurement value at 665 nm by the measurement value at 620 nm (ratio). Express the results as percent inhibition of the control response to 3 nM CP 55940. The standard reference antagonist is AM 281, which is tested at several concentrations in each experiment to create a concentration-response curve for calculating the IC 50 value. In Table 5, the blank for K i indicates that the observed binding was too weak for measurement of the K i value.

[0207]

Table 5

[0208] Other embodiments are within the scope of the following claims. Furthermore, the present invention encompasses the following aspects. 1. A compound of formula (I):

Chemical formula

Chemical formula

Chem.

Chem.

Claims

1. A compound of formula (IIa) or (IIb): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein: Y １ is N or CH; Y ３ and Y ４ are integrated and are -CH=N-, -N=CH-, -CH=CH- or =CH-O-; Each R １ and each R ２ is independently halo, C １－３ alkyl or -O-C １－３ alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from —OH and halo; R ４ is - CHR ｃ -R ５ and; R ５ is: (1) a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl; Here, the heterocyclyl and heteroaryl each independently contain 1 to 4 heteroatoms selected independently from N, O, and S(O) ｋ and; Here, one or two ring atoms of R ５ are optionally substituted by -C(=O)-; Here, the heterocyclyl and heteroaryl are optionally and independently substituted with one or more substituents selected from halo, -R ｅ and -OR ｅ ; or (2) H, halo or C １－３ alkyl is; wherein the alkyl is optionally substituted with one or more substituents independently selected from —OH and halo; Each R ａ and each R ｂ is independently H, C １－６ alkyl, C ３－８ cycloalkyl or C ４－９ cycloalkylalkyl; Here, each R ａ and each R ｂ is independently substituted with one or more substituents independently selected, in some cases, from -OH and halo; R ｃ is H, halo, C １－３ alkyl or -(CH ２ ) ｎ -NR ａ R ｂ and; Here, the alkyl is optionally substituted with one or more substituents independently selected from -OR ａ and halo; R ｄ is H or halo; Each R ｅ is independently H or C １－６ alkyl; wherein the alkyl is optionally substituted with one or more substituents independently selected from —OH and halo; k is 0, 1 or 2; and n is 0 or 1, a compound or a pharmaceutically acceptable salt thereof.

2. Y １ is N; and R １ and R ２ each independently represents -CH ３ is A compound of formula (IIa) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ２ is -CH ３ and; and R ５ The compound of formula (IIb) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is a 5- or 6-membered heteroaryl.

4. R ｃ is H; and R ５ is C optionally substituted with 1 to 3 fluoro １－３ alkyl A compound of formula (IIa) or formula (IIb) according to claim 1 or a pharmaceutically acceptable salt thereof.

5. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of: 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-piperidyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-pyridyl)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-benzimidazol-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-pentadeuteriophenyl)-[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.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or additive.

7. An agent for treating a disease or condition mediated by an adenosine receptor, comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

8. The agent for treatment according to claim 7, wherein the disease or condition mediated by an adenosine receptor 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.

Images