# US 11,999,732 B2 · P2X3 receptor antagonists

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- Number: US 11,999,732 B2
- Document ID: US11999732B2
- Status: Granted
- Kind: B2
- Application number: 17/259,511
- Filed: 2019-07-11
- Published: 2021-08-12
- Granted: 2024-06-04
- Earliest claimed: 2018-07-12
- Assignees: Recordati Industria Chimica e Farmaceutica S.p.A.
- Applicants: Recordati Industria Chimica E Farmaceutica SPA
- Inventors: Davide Graziani; Sergio Menegon; Patrizia Angelico; Carlo Riva
- Web page: https://patentgrep.com/patent/US11999732B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- C07D 487/14: Ortho-condensed systems
- C07D 491/22: in which the condensed system contains four or more hetero rings
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to compounds of formula I; and their use as antagonists of P2X3 and P2X2/3 receptor activity, pharmaceutical compositions comprising such compounds, and methods of treatment therewith. Compounds of the invention can be used for the treatment and/or prevention of pain and chronic pain and tolerance to analgesic, respiratory disorders and dysfunctions, and treatment of overactive bladder, bladder pain syndrome, dysuria and in general in genitourinary diseases, cardiovascular disorders and more in general for the potential treatment of visceral organ diseases and disorders characterized by the involvement of P2X3 and P2X2/3 receptors.

## Claims

### Claim 1

A compound according to formula I:
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt or combinations thereof, wherein:
one or two of the A groups comprise nitrogen atoms, and the remaining A groups each comprises carbon atom;
X—Y represents a N—C group;
each R1 independently represents 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-methoxymethylazetidin-1-yl, 3-methoxypyrrolidin-1-yl, 4-acetylpiperazin-1-yl, 4-aminopiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl-carbonyl, 4-methoxypiperidin-1-yl, 4-morpholinyl, dimethylaminopiperidin-1-yl, hydroxymethylpiperidin-1-yl, morpholin-4-ylcarbonyl, tetrahydro-2H-pyran-4-ylamino or tetrahydro-2H-pyran-4-ylaminocarbonyl, (oxetan-3-ylmethyl)amino, 4-(hydroxyacetyl)piperazin-1-yl;
R2 is an optionally substituted, C1-C6 alkyl group, C1-C6 alkoxy group, C4-C14 arylalkyl group, C4-C14 heteroarylalkyl group, C3-C7 cycloalkyl group, a mono-, bi- or tricyclic C6-C14 aryl group or a mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S;
groups R3 and R4 are linked to each other to form a five-membered heterocyclic ring containing 2 or 3 nitrogen atoms or a six-membered heterocyclic ring containing 2 nitrogen atoms, substituted with one or more groups R6;
R5 is O double-bonded directly to the X—Y containing ring;
each R6 independently represents a halogen atom selected from F, Cl, Br or I; or an, optionally substituted, carbonyl, oxo, C1-C6 alkyl, C1-C6 alkoxy or C3-C7 cycloalkyl group, an, optionally substituted, mono-, bi- or tricyclic C6-C14 aryl group or an, optionally substituted, mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S or alternatively, two R6 groups are linked to each other to form a group of the formula -(Zp)- wherein p is an integer of from 3 to 5 and each Z independently represents an oxygen atom or an optionally substituted methylene group, provided that no two adjacent Z moieties represent oxygen atoms; and
n is an integer independently selected from 0 to 3.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein the optional substituents are independently selected from the group consisting of halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, sulphamoyl, C1-C6 alkylsulphamoyl, di(C1-C6)alkylsulphamoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkylcarbonyl(C1-C6)alkyl groups, and from groups of the formulae —NR*R*, —C(═O)—NR*R*, -D, —O-D, —C(═O)-D, —(CH2)q-D, —NR**-D, —C(═O)—NR**-D, —NR**C(═O)-D and —O—C(═O)-D wherein each R* independently represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C1-C6 alkyl group, q is an integer from 1 to 6 and D represents a phenyl group or a C1-C8 heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C1-C6 cycloalkyl group; each group D being further optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C1-C6 alkyl, preferably wherein the optional substituents are selected from the groups consisting of halogen atoms and C1-C6 alkyl groups.

### Claim 3

A compound according to formula I:
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt or combinations thereof, wherein:
one or two of the A groups comprise nitrogen atoms, and the remaining A groups each comprises carbon atom;
X—Y represents a N—C group;
each R1 independently represents H, morpholinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, or derivative thereof,
R2 is an optionally substituted, C1-C6 alkyl group, C1-C6 alkoxy group, C4-C14 arylalkyl group, C4-C14 heteroarylalkyl group, C3-C7 cycloalkyl group, a mono-, bi- or tricyclic C6-C14 aryl group or a mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S;
groups R3 and R4 are linked to each other to form a five-membered heterocyclic ring containing 2 or 3 nitrogen atoms or six-membered heterocyclic ring containing 2 b nitrogen atoms, substituted with one or more groups R6;
R5 is O double-bonded directly to the X—Y containing ring;
each R6 independently represents a halogen atom selected from F, Cl, Br or I; or an, optionally substituted, carbonyl, oxo, C1-C6 alkyl, C1-C6 alkoxy or C3-C7 cycloalkyl group, an, optionally substituted, mono-, bi- or tricyclic C6-C14 aryl group or an, optionally substituted, mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S or alternatively, two R6 groups are linked to each other to form a group of the formula -(Zp)- wherein p is an integer of from 3 to 5 and each Z independently represents an oxygen atom or an optionally substituted methylene group, provided that no two adjacent Z moieties represent oxygen atoms; and
n is an integer independently selected from 0 to 3.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein R2 is an optionally substituted benzyl group or derivative thereof.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein R2 is selected from the group comprising 3,5-dimethoxybenzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl or 4-chloro-2,6-difluorobenzyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R6 is selected from the group comprising phenyl, (1-phenyl)ethyl, 1-ethyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yloxy)methyl, (tetrahydro-2H-pyran-4-yl)ethyl, 3,5-dimethyl-1,2oxazol-4-yl, 2-hydroxypyridin-3-yl, 2-methylpyridin-3-yl, morpholin-4-yl-carbonyl, pyridin-3-yl-methyl, oxo, methyl, ethyl, iso-propyl, tertiary-butyl, methylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, (propan-2-yloxy)methyl, tertiary-butoxymethyl, prop-1-en-2-yl, propan-2-yl-acetamide, cyclopropyl, cyclobutyl, cyclohexyl, or 1-methylcyclopropyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein -(Zp)- represents a group selected from —O—(CH2)2—O—, —O—(CH2)3—O—, —O—(CH2)2—, —O—(CH2)3—, —CH2—O—CH2—, and —(CH2)2—O—(CH2)2.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 9 (depends on 8)

A method for the treatment of chronic pain and cancer pain, overactive bladder, irritable bowel syndrome (IBS) and Burning Mouth Syndrome (BMS) relating to migraines and itches comprising administering to a subject in need of treatment an effective amount of a pharmaceutical composition according to claim 8.

### Claim 10

A compound according to formula I:
or an enantiomer, diastereomer, N-oxide, or a pharmaceutically acceptable salt or combinations thereof, wherein:
one or two of the A groups comprise nitrogen atoms, and the remaining A groups each comprise a carbon atom;
X—Y represents a N—C group;
each R1 is selected from the group comprising 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-methoxymethylazetidin-1-yl, 3-methoxypyrrolidin-1-yl, 4-acetylpiperazin-1-yl, 4-aminopiperidin-1-yl, 4-hydroxypiperidin-1-yl, 4-hydroxypiperidin-1-yl-carbonyl, 4-methoxypiperidin-1-yl, 4-morpholinyl, dimethylaminopiperidin-1-yl, hydroxymethylpiperidin-1-yl, morpholin-4-ylcarbonyl, tetrahydro-2H-pyran-4-ylamino or tetrahydro-2H-pyran-4-ylaminocarbonyl;
R2 is an optionally substituted, C1-C6 alkyl group, C1-C6 alkoxy group, C4-C14 arylalkyl group, C4-C14 heteroarylalkyl group, C3-C7 cycloalkyl group, a mono-, bi- or tricyclic C6-C14 aryl group or a mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S;
groups R3 and R4 are linked to each other to form a five- or six-membered b heterocyclic ring containing from 2 to 3 nitrogen heteroatoms, substituted with one or more groups R6;
R5 is O double-bonded directly to the X—Y containing ring;
each R6 independently represents a halogen atom selected from F, Cl, Br or I; or an, optionally substituted, carbonyl, oxo, C1-C6 alkyl, C1-C6 alkoxy or C3-C7 cycloalkyl group, an, optionally substituted, mono-, bi- or tricyclic C6-C14 aryl group or an, optionally substituted, mono-, bi- or tricyclic C1-C13 heterocyclic group containing from 1 to 5 heteroatoms selected from N, O or S or alternatively, two R6 groups are linked to each other to form a group of the formula -(Zp)- wherein p is an integer of from 3 to 5 and each Z independently represents an oxygen atom or an optionally substituted methylene group, provided that no two adjacent Z moieties represent oxygen atoms; and
n is an integer independently selected from 0 to 3.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein the optional substituents are independently selected from the group consisting of halogen atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxy, mercapto, nitro, cyano, oxo, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, C1-C6 alkylthio, C1-C6 alkylsulphonyl, C1-C6 alkylcarbonyl, sulphamoyl, C1-C6 alkylsulphamoyl, di(C1-C6)alkylsulphamoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkylcarbonyl(C1-C6)alkyl groups, and from groups of the formulae —NR*R*, —C(═O)—NR*R*, -D, —O-D, —C(═O)-D, —(CH2)q-D, —NR**-D, —C(═O)—NR**-D, —NR**C(═O)-D and —O—C(═O)-D wherein each R* independently represents a hydrogen atom or a C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylcarbonyl, phenyl or benzyl group, R** represents a hydrogen atom or a C1-C6 alkyl group, q is an integer from 1 to 6 and D represents a phenyl group or a C1-C8 heterocyclic group containing from 1 to 3 heteroatoms selected from N, O and S; a C1-C6 cycloalkyl group; each group D being further optionally substituted with from 1 to 3 groups independently selected from halo, hydroxy, cyano, nitro and C1-C6 alkyl, preferably wherein the optional substituents are selected from the groups consisting of halogen atoms and C1-C6 alkyl groups.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein R2 is an optionally substituted benzyl group or derivative thereof.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein R2 is selected from the group comprising 3,5-dimethoxybenzyl, 4-methoxybenzyl, 4-methylbenzyl, 4-chlorobenzyl or 4-chloro-2,6-difluorobenzyl.

### Claim 14 (depends on 10)

The compound according to claim 10, wherein R6 is selected from the group comprising phenyl, (1-phenyl)ethyl, 1-ethyl-1H-pyrazol-3-yl, 1-ethyl-1H-pyrazol-5-yl, (tetrahydro-2H-pyran-4-yl)methyl, (tetrahydro-2H-pyran-4-yloxy)methyl, (tetrahydro-2H-pyran-4-yl)ethyl, 3,5-dimethyl-1,2oxazol-4-yl, 2-hydroxypyridin-3-yl, 2-methylpyridin-3-yl, morpholin-4-yl-carbonyl, pyridin-3-yl-methyl, oxo, methyl, ethyl, iso-propyl, tertiary-butyl, methylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 2,2,2-trifluoroethyl, methoxymethyl, methoxyethyl, (propan-2-yloxy)methyl, tertiary-butoxymethyl, prop-1-en-2-yl, propan-2-yl-acetamide, cyclopropyl, cyclobutyl, cyclohexyl, or 1-methylcyclopropyl.

### Claim 15 (depends on 10)

The compound according to claim 10, wherein -(Zp)-represents a group selected from —O—(CH2)2—O—, —O—(CH2)3—O—, —O—(CH2)2—, —O—(CH2)3—, —CH2—O—CH2—, and —(CH2)2—O—(CH2)2.

### Claim 16 (depends on 1)

The compound according to claim 1, the compound being selected from the group consisting of:
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-3-methyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2-methyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2-ethyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-3-ethyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2,3-dimethyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-cyclopropyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-(methoxymethyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-cyclopropyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-(methoxymethyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(4-methoxypiperidin-1-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-[3-(methoxymethyl)azetidin-1-yl]-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
8-[4-(hydroxymethyl)piperidin-1-yl]-6-(4-methoxybenzyl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
8-[4-(dimethylamino)piperidin-1-yl]-6-(4-methoxybenzyl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-cyclohexyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
3-cyclohexyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-cyclohexyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-cyclohexyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-ethyl-6-(4-methoxybenzyl)-8-[(3r)-3-methoxypyrrolidin-1-yl]-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-3-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-cyclobutyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-(2,2-dimethylpropyl)-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-2-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-ethyl-6-(4-methoxybenzyl)-8-[3-(methoxymethyl)azetidin-1-yl]-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-2′,3′,5′,6′-tetrahydrospiro[imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,4′-pyran]-5(6H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-2,2′,3′,5′,6,6′-hexahydro-5h-spiro[imidazo[1,2-c]pyrido[2,3-e]pyrimidine-3,4′-pyran]-5-one;
8-(4-aminopiperidin-1-yl)-6-(3,5-dimethoxybenzyl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-cyclohexyl-6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
3-cyclohexyl-6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-2-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-yl)-3-phenyl-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2-(propan-2-yl)-8-(tetrahydro-2H-pyran-4-ylamino)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-ethyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(4-hydroxypiperidin-1-yl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-ethyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
3-ethyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-2-(morpholin-4-ylcarbonyl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(morpholin-4-ylcarbonyl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2-(2,2,2-trifluoroethyl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
2-(tert-butoxymethyl)-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-5-oxo-2-(propan-2-yl)-n-(tetrahydro-2H-pyran-4-yl)-2,3,5,6-tetrahydroimidazo[1,2-c]pyrido[2,3-e]pyrimidine-8-carboxamide;
6-(3,5-dimethoxybenzyl)-5-oxo-2-(propan-2-yl)-2,3,5,6-tetrahydroimidazo[1,2-c]pyrido[2,3-e]pyrimidine-8-carboxylic acid;
6-(3,5-dimethoxybenzyl)-8-(morpholin-4-ylcarbonyl)-2-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-(cyclohexylmethyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-2-(3-methylbutyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-(3-methylbutyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,5(3H,6H)-dione;
6-(4-methoxybenzyl)-2-(2-methoxyethyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-methoxybenzyl)-3-(2-methoxyethyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
3-(tert-butoxymethyl)-6-(4-methoxybenzyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
3-tert-butyl-6-(4-chlorobenzyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,5(3H,6H)-dione;
3-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,5(3H,6H)-dione;
6-(3,5-dimethoxybenzyl)-2,3-dimethyl-8-{[(oxetan-3-yl)methyl]amino}imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
2-(2-methylpropyl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-methylbenzyl)-2-(2-methylpropyl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-2-(2-methylpropyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-chloro-2,6-difluorobenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-2-ethyl-3-methyl-8-{[(oxetan-3-yl)methyl]amino}imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-3-ethyl-2-methyl-8-{[(oxetan-3-yl)methyl]amino}imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-3-methyl-8-(morpholin-4-yl)-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-8-[4-(hydroxyacetyl)piperazin-1-yl]-2-(2-methylpropyl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-2,3-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-2,3-dimethyl-8-(morpholin-4-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-3-methyl-8-[(oxetan-3-ylmethyl)amino]-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
8-(4-acetylpiperazin-1-yl)-6-(3,5-dimethoxybenzyl)-3-methyl-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-8-(4-methoxypiperidin-1-yl)-2,3-dimethylimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
5-(3,5-dimethoxybenzyl)-8,9-dimethyl-3-(morpholin-4-yl)imidazo[1,2-c]pteridin-6(5h)-one;
6-(3,5-dimethoxybenzyl)-8-(4-methoxypiperidin-1-yl)-3-methyl-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-8-[3-(methoxymethyl)azetidin-1-yl]-3-methyl-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-3-methyl-8-(morpholin-4-yl)-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-methyl-8-(morpholin-4-yl)-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-methyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-8-[3-(methoxymethyl)azetidin-1-yl]-3-methyl-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-3-methyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-[(4-hydroxypiperidin-1-yl)carbonyl]-3-methyl-2-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(6H)-one;
3-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-3-[(tetrahydro-2H-pyran-4-yloxy)methyl]pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(pyridin-3-ylmethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-3-methyl-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-(1-methylcyclopropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
2-[6-(4-chlorobenzyl)-8-(morpholin-4-yl)-5-oxo-5,6-dihydropyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-3-yl]-n-(propan-2-yl)acetamide;
6-(4-methoxybenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-[(2-hydroxypyridin-3-yl)methyl]-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-[(2-methylpyridin-3-yl)methyl]-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-(1-ethyl-1h-pyrazol-5-yl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-(2-methylpropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-(1-ethyl-1h-pyrazol-3-yl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-3-(3,5-dimethyl-1,2-oxazol-4-yl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
9,9-dimethyl-5-(4-methylbenzyl)-3-{[(oxetan-3-yl)methyl]amino}-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(3,5-dimethoxybenzyl)-9-methyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(3,5-dimethoxybenzyl)-9,9-dimethyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(4-chlorobenzyl)-3-[3-(methoxymethyl)azetidin-1-yl]-9,9-dimethyl-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(3,5-dimethoxybenzyl)-10-ethyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(3,5-dimethoxybenzyl)-8-ethyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
10-ethyl-5-(4-methoxybenzyl)-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
8-ethyl-5-(4-methoxybenzyl)-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(4-chlorobenzyl)-10-ethyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
5-(4-chlorobenzyl)-8-ethyl-3-(morpholin-4-yl)-5,8,9,10-tetrahydro-6H-pyrido[2,3-e]pyrimido[1,2-c]pyrimidin-6-one;
6-(4-methoxybenzyl)-2-(2-methylpropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;
2-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-morpholino-2-(2,2,2-trifluoroethyl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-morpholino-3-(2,2,2-trifluoroethyl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(3,5-dimethoxybenzyl)-2,2-dimethyl-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,5(3H,6H)-dione;
6-(4-methoxybenzyl)-8-(morpholin-4-yl)-3-(propan-2-yl)imidazo[1,2-c]pyrido[2,3-e]pyrimidine-2,5(3H,6H)-dione;
6-(4-chlorobenzyl)-8-(4-hydroxypiperidin-1-yl)-3-(propan-2-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-2-(1-methylcyclopropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;
3-tert-butyl-6-[(5-chloropyridin-2-yl)methyl]-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-3-(1-methylcyclopropyl)-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
2-tert-butyl-8-(4-hydroxypiperidin-1-yl)-6-(4-methoxybenzyl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;
3-tert-butyl-8-(4-hydroxypiperidin-1-yl)-6-(4-methoxybenzyl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
9-tert-butyl-5-(4-chlorobenzyl)-3-(morpholin-4-yl)[1,2,4]triazolo[1′,5′:1,6]pyrimido[5,4-c]pyridazin-6(5h)-one;
8-(4-aminopiperidin-1-yl)-3-tert-butyl-6-(4-chlorobenzyl)[1,2,4]triazolo[4′,3′:1,6]pyrimido[5,4-c]pyridazin-5(6H)-one;
3-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)[1,2,4]triazolo[4′,3′:1,6]pyrimido[5,4-c]pyridazin-5(6H)-one;
3-tert-butyl-6-(4-chlorobenzyl)-8-(piperazin-1-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
2-tert-butyl-6-(4-chlorobenzyl)-8-(piperazin-1-yl)pyrido[2,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one;
3-(tert-butyl)-6-(4-chlorobenzyl)-8-(3-methoxypyrrolidin-1-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
3-tert-butyl-6-(4-chlorobenzyl)-8-(tetrahydro-2H-pyran-4-ylamino)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
3-tert-butyl-6-[(5-methylthiophen-2-yl)methyl]-8-(morpholin-4-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-(tetrahydro-2H-pyran-4-ylmethyl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
8-(4-acetylpiperazin-1-yl)-6-(4-chlorobenzyl)-3-(propan-2-yl)pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-chlorobenzyl)-8-(morpholin-4-yl)-3-[(tetrahydro-2H-pyran-4-yloxy)methyl]pyrido[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
3-tert-butyl-6-(4-methoxybenzyl)-8-(morpholin-4-yl)pyrido[3,4-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(4-methoxybenzyl)-3-(1-methylcyclopropyl)-8-(morpholin-4-yl)pyrido[3,4-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
3-tert-butyl-6-(4-chlorobenzyl)-8-(morpholin-4-yl)[1,2,4]triazolo[4′,3′:1,6]pyrimido[5,4-c]pyridazin-5(6H)-one;
3-tert-butyl-6-(4-chlorobenzyl)-8-(morpholin-4-yl)pyrido[3,4-e][1,2,4]triazolo[4,3-c]pyrimidin-5(6H)-one;
6-(3,5-dimethoxybenzyl)-2-(2,2-dimethylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one; and
6-(3,5-dimethoxybenzyl)-3-(2,2-dimethylpropyl)-8-(morpholin-4-yl)-2,6-dihydroimidazo[1,2-c]pyrido[2,3-e]pyrimidin-5(3H)-one.