Fusion tricyclic compounds as PDE3 / PDE4 biinhibitors

Abstract

To provide compounds that have both PDE3 / PDE4 inhibitory activity.SOLUTION: There is provided a fused tri-cyclic compound as PDE3 / PDE4 dual inhibitor, and a use thereof in the preparation of therapeutic drugs for PDE3 / PDE4 associated diseases, particularly a use thereof in treating chronic obstructive pulmonary disease (COPD) or the like. Specifically there are provided compound of formula (I) and a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Claims

1. A compound of formula (I), its stereoisomer or tautomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (In the formula, ring Cy is selected from a 5-membered heterocyclyl group containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and nitrogen, or a 5-membered heteroaryl group containing at least 1 ring atom selected from N, O, and S. Here, the 5-membered heterocyclyl group or 5-membered heteroaryl group is optionally substituted by one or more groups selected from an amino group, a hydroxy group, ═O, a halogen, a cyano group, C １－１２ alkyl group, -C(O)NH ２ , -C(O)NH(C １－６ alkyl), -C(O)N(C １－６ alkyl) ２ , -COOH, -C(O)O(C １－６ alkyl) or C １－１２ alkoxy group, and here, the C １－１２ alkyl group or C １－１２ alkoxy group is optionally substituted by one or more groups selected from a halogen, an amino group, or a hydroxy group, The ring atoms of the aforementioned ring Cy contain at least one nitrogen atom, L is -N(R ６ )-,-N(R ６ )C(O)-, -C(O)N(R ６ )-, -O-, -S-, -OC(O)-, -C(O)O-, -CH ２ N(R) ６ )C(O)-,-CH ２ C(O)N(R) ６ )-,-S(O) ２ NH-, -NHS(O) ２ -, or selected from single bonds 、 n is 1, 2, 3, or 4. E １ ha- (CH ２ ) ｍ - is selected from, where m is 1, 2 or 3, E ２ is selected from -O-, -NH-, -S-, or single bonds, R ３ , R ４ , R ５ Each is independently hydrogen, halogen, or C １－６ Selected from alkyl groups, where the C １－６ The alkyl group may optionally be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups. Each R ６ Each of these independently consists of hydrogen, a hydroxyl group, or C １－３ Selected from alkyl groups, where the C １－３ The alkyl group may be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups, as desired.

2. E ２ The group is selected from -O-, -S-, or a single bond, and the ring Cy is selected from a 5-membered heterocyclyl group containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and nitrogen, or a 5-membered heteroaryl group containing at least one ring atom selected from N, O, and S, where the 5-membered heterocyclyl group or 5-membered heteroaryl group may optionally be an amino group, a hydroxyl group, =O, a halogen, a cyano group, or C １－６ Alkyl alkyl group, -C(O)NH ２ , -C(O)NH(C １－３ Alkyl), -C(O)N(C １－３ Alkyl) ２ , -COOH, -C(O)O(C １－３ Alkyl), C １－６ C substituted with an alkoxy group or one or more halogens １－６ Substituted with one or more groups selected from alkyl groups, Upon request, E ２ The ring is selected from -O-, -S-, or a single bond, and the ring Cy is selected from a 5-membered heterocyclyl group containing 1 to 3 heteroatoms independently selected from sulfur, oxygen, and nitrogen, or a 5-membered heteroaryl group containing at least one ring atom selected from N, O, and S, where the 5-membered heteroaryl group can optionally be an amino group, a hydroxyl group, a halogen, a cyano group, or C １－６ Alkyl alkyl group, -C(O)NH ２ , -C(O)NH(C １－３ Alkyl), -C(O)N(C １－３ Alkyl) ２ , -COOH, -C(O)O(C １－３ Alkyl), C １－６ C substituted with an alkoxy group or one or more halogens １－６ It is substituted with one or more groups selected from alkyl groups, where the five-membered heterocyclyl group is optionally substituted with one or more =O groups. Upon request, E ２ The bond is selected from -O-, -S-, or a single bond, and the ring Cy is an oxazolidine-2-one group, an imidazolyl group, a pyrazollyl group, an oxazollyl group, a triazollyl group, or an oxy A group selected from sadiazolyl, tetrazolyl, thiadiazolyl, or isoxazolyl, where the imidazolyl, pyrazolyl, oxazolyl, triazolyl, oxadiazolyl, tetrazolyl, thiadiazolyl, or isoxazolyl group may optionally be an amino group, hydroxyl group, halogen, cyano group, or C １－６ alkyl group, C １－６ C substituted with an alkoxy group or one or more halogens １－６ Substituted with one or more groups selected from alkyl groups, Upon request, E ２ The first member is selected from -O-, -S-, or a single bond, and the ring Cy is selected from a five-membered heteroaryl group containing at least one ring atom selected from N, O, and S, where the five-membered heteroaryl group can optionally be an amino group, a hydroxyl group, a fluorine group, a chlorine group, a bromine group, an iodine group, a cyano group, or a C group. １－３ Alkyl alkyl group, -C(O)NH ２ , -C(O)O(C １－３ Alkyl), C １－３ C substituted with an alkoxy group or one or more halogens １－３ Substituted with one or more groups selected from alkyl groups, Upon request, E ２ The bond is selected from -O-, -S-, or a single bond, and the ring Cy is selected from an imidazolyl group, a pyrazolyl group, a triazolyl group, or a tetrazolyl group, where the imidazolyl group, pyrazolyl group, triazolyl group, or tetrazolyl group can optionally be an amino group, a hydroxyl group, a fluorine group, a chlorine group, a bromine group, an iodine group, a cyano group, or a C group. １－３ alkyl group, C １－３ C substituted with an alkoxy group or one or more halogens １－３ Substituted with one or more groups selected from alkyl groups, Upon request, E ２ The bond is selected from -O-, -S-, or a single bond, and the ring Cy is N, O, S or Selected from a five-membered heteroaryl group containing at least one ring atom, the five-membered heteroaryl group can optionally be an amino group, a hydroxyl group, a fluorine group, a chlorine group, a cyano group, a methyl group, or -C(O)NH ２ , -C(O)OCH ３ Substituted with one or more groups selected from methoxy groups or trifluoromethyl groups, Upon request, E ２ The compound of formula (I) according to claim 1, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein is selected from -O-, -S-, or a single bond, the ring Cy is selected from a triazolyl group, and the triazolyl group is optionally substituted with one or more groups selected from a hydroxyl group or a methyl group.

3. The cyclic Cy is a structural unit. 【Chemistry 2】 Selected from, During the ceremony, 【Transformation 3】 represents a single bond or a double bond, T １ , T ２ , T ３ , and T ４ These are independently C=O and C(R) １ ), C (R １ ) ２ , O, N(R ２ ), selected from N or S, Each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－１２ alkyl group, or C １－１２ Selected from alkoxy groups, where the C １－１２ Alkyl alkyl group or C １－１２ The alkoxy group may be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups, as desired. Each R ２ Each of these independently consists of hydrogen, a hydroxyl group, or C １－３ Selected from alkyl groups, where the C １－３ The alkyl group may optionally be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups. Desirably, T １ is selected from C(R １ ), C(R １ ), or N, and T ２ , T ２ , and T ３ are each independently selected from C(R ４ ), C(R １ ), O, N(R １ ), N, or S,​​​​ Desirably, T １ is selected from C(R １ ), or N, and T ２ , T ３ , and T ４ are each independently selected from C(R １ ), O, N(R ２ ), N, or S, Structural units, upon request 【Chemistry 4】 So, T １ is C(R １ ) or selected from N, T ２ , T ３ , and T ４ Each is independent C(R １ ), N (R ２ ), or selected from N, Structural units, upon request 【Transformation 5】 So, T １ is C(R １ ) ２ Selected from, T ２ , T ３ , and T ４ These are independently C=O and C(R) １ ) ２ , or selected from O, Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－６ alkyl group, or C １－６ Selected from alkoxy groups, where the C １－６ Alkyl alkyl group or C １－６ The alkoxy group may be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups, as desired. Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－６ alkyl group, or C １－３ Selected from alkoxy groups, where the C １－６ Alkyl alkyl group or C １－３ The alkoxy group may be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups, as desired. Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－６ alkyl group, or C １－３ Selected from alkoxy groups, where the C １－６ The alkyl group may optionally be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups. Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－３ alkyl group, or C １－３ Selected from alkoxy groups, where the C １－３ Alkyl alkyl group or C １－３ The alkoxy group may be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups, as desired. Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－３ alkyl group, or C １－３ Selected from alkoxy groups, where the C １－３ The alkyl group may optionally be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups. Upon request, each R １ Each of these is independently hydrogen, amino group, hydroxyl group, halogen, cyano group, and C １－３ alkyl group, or C １－３ Selected from alkoxy groups, where the C １－３ The alkyl group may optionally be substituted with one, two, or three halogens, amino groups, or hydroxyl groups. Upon request, each R １ Each of these is independently selected from hydrogen, amino group, hydroxyl group, fluorine, chlorine, cyano group, methyl group, methoxy group, or trifluoromethyl group. Upon request, each R １ Each of these independently consists of hydrogen, an amino group, a hydroxyl group, or C １－６ Selected from alkyl groups, where the C １－６ The alkyl group may optionally be substituted with one or more groups selected from halogens, amino groups, or hydroxyl groups. Upon request, each R １ Each of these is independently a hydrogen atom, a hydroxyl group, or C １－３ Selected from alkyl groups, Upon request, each R １ Each is independently selected from hydrogen, a hydroxyl group, or a methyl group. Upon request, each R ２ Each of these independently consists of hydrogen, a hydroxyl group, or C １－３ Selected from alkyl groups, where the C １－３ The alkyl group may optionally be substituted with one or more halogens, amino groups, or hydroxyl groups. Upon request, each R ２ Each of these independently consists of hydrogen, a hydroxyl group, or C １－３ Selected from alkyl groups, where the C １－３ The alkyl group may optionally be substituted with one, two, or three halogens, amino groups, or hydroxyl groups. Upon request, each R ２ Each is independently selected from hydrogen, a hydroxyl group, or a methyl group. Upon request, each R ２ Each of the following compounds of formula (I) according to claim 1, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein each is independently selected from a hydrogen or a methyl group.

4. L is -N(R ６ )-,-N(R ６ )C(O)-, -C(O)N(R ６ )-, -O-, -S-, -OC(O)-, -C(O)O-, -CH ２ N(R) ６ )C(O)-,-CH ２ C(O)N(R) ６ )-,-S(O) ２ NH-, or -NHS(O) ２ - Selected from, Structural unit 【Transformation 6】 Selected from, Structural units, upon request 【Transformation 7】 Selected from, Structural units, upon request 【Transformation 8】 Selected from, Structural units, upon request 【Chemistry 9】 Selected from, Structural units, upon request 【Chemistry 10】 A compound of formula (I) according to claim 3, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

5. Lは-N(R ６ )-、-N(R ６ )C(O)-、-C(O)N(R ６ )-、-H ２ N (R ６ )C(O)-,-CH ２ C(O)N(R) ６ )-,-S(O) ２ NH-, -NHS(O) ２ - or selected from single bonds, Upon request, L is -N(R ６ )-,-N(R ６ )C(O)-, -C(O)N(R ６ ) -, -CH ２ N(R) ６ )C(O)-,-S(O) ２ Selected from NH- or single bond, Upon request, L is -N(R ６ )-,-N(R ６ )C(O)-, -C(O)N(R ６ ) -, or -S(O) ２ Selected from NH- Upon request, L is -N(R ６ )-,-N(R ６ )C(O)-, or -C(O)N(R ６ ) - Selected from, Upon request, L can be -NH-, -NHC(O)-, -C(O)NH- or -C(O)N(OH)-, -S(O) ２ Selected from NH- or single bond, A compound of formula (I) according to any one of claims 1 to 3, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is optionally selected from -NH-, -NHC(O)-, -C(O)NH-, or -C(O)N(OH)-.

6. n is selected from 1, 2, or 3. If desired, n is selected from 1 or 2. A compound of formula (I) according to any one of claims 1 to 4, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein n is optionally selected to be 2.

7. R ３ , R ４ , and R ５ Each is independently halogen or C １－３ Selected from alkyl groups, where the C １－３ The alkyl group may optionally be substituted with one, two, or three halogens, amino groups, or hydroxyl groups. Upon request, R ３ , R ４ , and R ５ Each of these is independently selected from a halogen or a methyl group, where the methyl group is optionally substituted with one, two or three halogens, amino groups or hydroxyl groups. Upon request, R ３ , R ４ , and R ５ A compound of formula (I) according to any one of claims 1 to 4, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently a methyl group.

8. Each R ６ Each of these is independently selected from hydrogen, a hydroxyl group, or a methyl group, where the methyl group is optionally substituted with one, two, or three halogens, amino groups, or hydroxyl groups. Upon request, each R ６ Each is independently selected from hydrogen, a hydroxyl group, or a methyl group. Upon request, each R ６ Each of the following compounds of formula (I) according to any one of claims 1 to 4, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein each is independently selected from hydrogen or a hydroxyl group.

9. E １ ha- (CH ２ ) ２ - or - (CH ２ ) ３ A compound of formula (I) according to any one of claims 1 to 4, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from among the above.

10. E ２ The compound of formula (I) according to any one of claims 1 to 4, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein -O- or a chemical bond is selected.

11. Selected from the compounds of formula (II-2), 【Chemistry 11】 In the formula, R ６ It is hydrogen, E １ ha- (CH ２ ) ２ - and E ２ It is a single bond, Structural unit 【Chemistry 12】 teeth 【Chemistry 13】 And, R １ and R ２ A compound of formula (I) according to claim 1, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, to which the definition of claim 3 applies.

12. The aforementioned 【Chemistry 14】 teeth, 【Chemistry 15】 A compound according to claim 11, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, further comprising a pharmaceutically acceptable excipient, carrier, or diluent.

14. The use of a compound according to any one of claims 1 to 12, a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13 in the manufacture of a therapeutic agent for PDE3 and / or PDE4-related disorders, wherein the PDE3 and / or PDE4-related disorder is optionally selected from chronic obstructive pulmonary disease or asthma, and optionally the treatment of the PDE3 and / or PDE4-related disorder is optionally selected from anti-inflammatory and / or bronchodilation effects.

15. A drug for the treatment of mammalian PDE3 and / or PDE4-related disorders, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12, a stereoisomer or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 13, wherein the PDE3 and / or PDE4-related disorder is optionally selected from chronic obstructive pulmonary disease or asthma, and optionally the treatment of the mammalian PDE3 and / or PDE4-related disorder is optionally selected from anti-inflammatory and / or bronchodilation effects.

16. A pharmaceutical composition comprising the following compounds, their stereoisomers or tautomers, or pharmaceutically acceptable salts thereof, further comprising pharmaceutically acceptable excipients, carriers, or diluents, wherein the route of administration is inhalation. 【Chemistry 16】

17. A drug for the treatment of mammalian PDE3 and / or PDE4-related disorders, administered by inhalation, comprising a therapeutically effective amount of the following compound, its stereoisomer or tautomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 16, wherein the PDE3 and / or PDE4-related disorder is optionally selected from chronic obstructive pulmonary disease or asthma, and optionally the treatment of the mammalian PDE3 and / or PDE4-related disorder is optionally selected from anti-inflammatory and / or bronchodilatory effects. 【Chemistry 17】

18. The use of the following compounds, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in claim 16, in the manufacture of a drug for the treatment of PDE3 and / or PDE4-related disorders administered by inhalation, wherein the PDE3 and / or PDE4-related disorder is optionally selected from chronic obstructive pulmonary disease or asthma, and optionally the treatment of the PDE3 and / or PDE4-related disorder is optionally selected from anti-inflammatory and / or bronchodilatory effects. [Chemistry 18]

19. Method 1: 【Chemistry 19】 Method 2: 【Chemistry 20】 Method 3: 【Chemistry 21】 or Method 4: 【Chemistry 22】 Selected from, In the formula, the ring Cy, L, n, E １ , E ２ , R ３ , R ４ , R ５ or R ６ A method for producing a compound of formula (I), wherein the definition described in claim 1 is applied as the definition of [the compound].

20. The use of the following compounds in the production of a compound of formula (I) described in Claim 1, a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemistry 23】 In the formula, n, E １ , E ２ , R ３ , R ４ , or use as defined in claim 1.

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