MODIFIER OF A FOUR-MEMBERED RING DERIVATIVE, METHOD OF PREPARATION AND APPLICATION THEREOF

Abstract

A modifier of a four-membered ring derivative, a method of preparation, and its application are provided. In particular, a compound represented by the general formula (IX-A), a method of preparation thereof, a pharmaceutical composition containing the compound, and its use as a G protein-coupled receptor modulator in the treatment or prevention of central nervous system diseases and / or mental illnesses are provided. The definition of each substituent in the general formula (IX-A) is the same as the definition in the specification.

Claims

1. A compound of formula (IX-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from the group consisting of N-containing heterocyclyl from 5 to 6 members, the N-containing heterocyclyl from 5 to 6 members being preferably an oxazolidinonyl; Ra is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, C1-e deuterated alkyl, C1-6 haloalkyl, C1-e alkoxy, C1-e haloalkoxy, C1-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C1-12 aryl, and 5- to 12-membered heteroaryl;Rb is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, wherein the amino, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl 12 members are optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, Ci-6 alkyl, deuterated Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl;Rs is selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-12 aryl, and 5- to 12-membered heteroaryl; preferably, R5 is selected from the group consisting of hydrogen, cyano, halogen, Ci-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C3-6 cycloalkyl, and more preferably is selected from the group consisting of hydrogen and chlorine; or either of the two adjacent R5s is joined to form a 5- to 6-membered heterocycle or a 5- to 6-membered heteroaryl, preferably a 5- to 6-membered heteroaryl containing 1 to 2 N, S or O heteroatoms, and more preferably thienyl; r is 0, 1 or 2; t is 0, 1, 2 or 3, and preferably 2; H , -NHC(O)C2H5, -NHC(O)N(CH3)2, -NHC(O)NHCH3, or when m is 2, then R4 is not -NHC(O)N(CH3)2.; 2. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is further as shown in formula (X) or formula (XA):

3. The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that R4 is selected from the group consisting of a 5- to 6-membered N-containing heterocyclyl, R, '· » Λ' ° A ° >” X '9- V l SR» ' K» , K» and Rn, the 5- to 6-membered N-containing heterocyclyl is preferably an oxazolidinonyl; Ra is selected from the group consisting of hydrogen, cyano, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C3-6 cycloalkyl; preferably, Ra is selected from the group consisting of hydrogen and methyl; Rb is selected from the group consisting of amino, C1-3 alkyl, C1-3 alkoxy.3, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-ium aryl, and 5- to 10-membered heteroaryl, optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C1-3 alkyl, and C1-3 alkoxy; preferably, Rb is selected from the group consisting of amino, methyl, ethyl, methoxy, hydroxyisopropyl, cyclopropyl, azetidinyl, phenyl, pyridyl, furanyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, indolyl, quinolyl, and benzoxazolyl, optionally substituted with one or more substituents selected from the group consisting of fluorine, cyano, hydroxy, methyl, and methoxy; yr is 0, 1, or 2. p / frfrnn / zznz / e / YiAi.

4. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound is further as shown in formula (XI): i ni C1 where: Re is selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; R7 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, Ci-6 alkyl, deuterated Ove alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, Ci-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, 5- to 12-membered heteroaryl, Ree, -C(O)(CH2)n2Ree, -(CH2)n2C(O)NReeRff, -C(O)NReeRff, (CH2)n2C(O)NReeC(O)Rff, -(CH2)n2S(O)m2Ree, -(CH2)n2NReeS(O)m2Rff, -(CH2)n2S(O)m2NReeRff,(CH2)n1 S(O)m2N ReeRff, -(CH2)n2ORee, -C(O)NRee(CH2)n2Rff, -C(O)(CH2)n2ORee, -(CH2)n2SRee, (CH2)n2C(O)ORee, -P(O)ReeRff, -(CH2)n2NReeC(O)Rff and -(CH2)n2NReeS(O)m2Rff, wherein the C1-6 alkyl, deuterated Ci-e alkyl, Ci-e haloalkyl, Ci-e alkoxy, Os haloalkoxy, C2-e alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-i2 aryl and 5- to 12-membered heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, deuterated O.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; preferably, R7 is selected from the group consisting of Ree, -C(O)(CH2)n2Ree, C(O)NReeRff, -C(O)NRff(CH2)n2Ree, -S(O)m2Ree, and “S(O)m2NReeRff,Ree and Rff are each independently selected from the group consisting of hydrogen, amino, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C3-8 cycloalkyl, 3-to-8-membered heterocyclyl, Ce-u aryl, and 5-to-14-membered heteroaryl, wherein the amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkyl, 3-to-8-membered heterocyclyl, Ce-14 aryl, and 5-to-14-membered heteroaryl are optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C1-6 alkyl, C1-6 haloalkyl, and Ci-e alkoxy; Preferably, Ree and Rff are each independently selected from the group consisting of amino, C1-6 alkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 nitrogen atoms, and 5- to 10-membered heteroaryl containing 1 to 2 oxygen, nitrogen, and sulfur atoms.optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C1-6 alkyl and Ci-e alkoxy; and more preferably, Ree and Rff are each independently selected from the group consisting of: (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2C(OH)-, n2 is selected from the group consisting of 0, 1 and 2; m2 is selected from the group consisting of 0, 1 and 2; ym is selected from the group consisting of 0, 1 and 2.

5. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 4, characterized in that Ree and Rttse are each independently selected from the group consisting of hydrogen and the following substituents:

6. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 4, characterized in that, R6 is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-3 alkyl, C1-3 deuterated alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C2-3 alkenyl, and C2-3 alkynyl, and preferably hydrogen; R6 is selected from the group consisting of Ree, -C(O)(CH2)n2Ree, -C(O)NReeRff, C(O)NRff(CH2)n2Ree, “S(O)m2Ree, and “S(O)m2NReeRff; Ree is selected from the group consisting of hydrogen, amino, C1-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C3-8 cycloalkyl, 3-to-8 membered heterocyclyl, C6-14 aryl, and 5-to-14 membered heteroaryl, wherein the amino, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, C3-8 cycloalkyl.8, 3-to-8-membered heterocyclyl, C6-14 aryl, and 5-to-14-membered heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C1-6 alkyl, C1-6 haloalkyl, and Ci-e alkoxy; Preferably, Ree is selected from the group consisting of amino, C1-6 alkyl, C1-6 hydroxyalkyl, C3-6 cycloalkyl, phenyl, naphthyl, biphenyl, 4- to 6-membered heterocyclyl containing 1 to 2 heteroatoms of oxygen, nitrogen, sulfur, and 5- to 10-membered heteroaryl, and more preferably, Ree is selected from the group consisting of: (CH3)2N-, CH3NH-, CH3-, CH3CH2-, CH3CH2NH-, CH3CH2NCH3-, (CH3)2C(OH)-, containing 1 to 2 heteroatoms of oxygen, nitrogen and sulfur, optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, Ci-6 alkyl and Ci-6 alkoxy.6; Rft is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, deuterated Ci-θ alkyl, C1-6 haloalkyl, C1-6 alkoxy, Ci-θ haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, Ce-12 aryl, and 5- to 12-membered heteroaryl; preferably, Rff is selected from the group consisting of hydrogen, cyano, halogen, Ci-3 alkyl, Ci-3 haloalkyl, Ci-3 alkoxy, and C3-e cycloalkyl; and more preferably, Rff is selected from the group consisting of hydrogen and methyl; n2 is selected from the group consisting of O, 1, and 2; and m2 is selected from the group consisting of O, 1, and 2.

7. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 4, characterized in that the compound is further as shown in formula (Xl-A) or formula (Xl-B):

8. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 4 or 7, characterized insofar as it 9. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 4 or 7, characterized in that R is p / frfrnn / zznz / e / YiAi 10. The compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 4, characterized in that the compound is further as shown in formula (XII): wherein: Re is selected from the group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl, wherein the amino, C1-6 alkyl, deuterated C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, haloalkoxy C1-6, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl and 5- to 12-membered heteroaryl, each of the heteroaryl is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, hydroxy, cyano, C1-6 alkyl,C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclyl, C6-12 aryl, and 5- to 12-membered heteroaryl; Preferably, Rs is selected from the group consisting of amino, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, Ce-io aryl, and 5- to 10-membered heteroaryl, wherein the amino, C1-3 alkyl, C1-3 hydroxyalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C6-io aryl, and 5- to 10-membered heteroaryl are optionally further substituted with one or more substituents selected from the group consisting of hydroxy, cyano, C1-3 alkyl, C1-3 alkoxy, and C3-6 cycloalkyl; and more preferably, Rs is further selected from the group consisting of: v is 0 or 1; When v is 0, then R8 is not -C2H5, -N(CH3)2, -NHCH3, -NC2H5CH3, -NHC2H5; when v is 1, then Rs is not phenyl.

11. The compound, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 10, characterized in that the compound of formula (XII) is further as shown in formula (XII-A) or formula (XII-B): A . A f N j ' Cl AX -γ- Cl O fl o ......-Jj α Rs., ·,X .. '-—J i? . . Y · '' H (XΠ A) H (XII B) O 12. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, characterized in that, R4 is; or 1 II Rb is selected from the group consisting of C3-6 cycloalkyl and 5- to 10-membered heteroaryl containing 1 to 2 atoms of nitrogen, oxygen, sulfur, optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, amino, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; Rs is selected from the group consisting of hydrogen, halogen, and C1.3 alkyl; t is 1, 2, or 3; when r is 0 and Rb is 0, 'O 'Λ”' / then Rb is substituted by at least one substituent; íj [II / i—I when r is 0 and Rb is 0 ' then Rb is substituted by at least one substituent.

13. The compound, its stereoisomer, or its pharmaceutically acceptable salt according to claim 12, characterized in that Rb is selected from the group consisting of C3.6 cycloalkyl, nitrogen- or oxygen-containing 5- to 6-membered heteroaryl, and nitrogen-containing 9- to 10-membered condensed heteroaryl, optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy; and preferably, Rb is selected from the group consisting of cyclopropyl, pyridyl, furanyl, thiazolyl, oxazolyl, isoxazolyl, and quinolyl, optionally further substituted with one or more substituents selected from the group consisting of halogen, C1-3 and C1-3 alkyl, and C1-3 haloalkyl.

14. The compound, its stereoisomer or its pharmaceutically acceptable salt according to any of claims 1 to 13, characterized in that the specific structure of the compound is as follows: p / frfrnn / zznz / e / γΐΛΐ p / frfrnn / zznz / e / YiAi 15. A method for preparing the compound of formula (XII), the stereoisomer thereof, or its pharmaceutically acceptable salt according to claim 10, characterized in that it comprises the following step of reacting a compound of formula (XII-1) with an acyl chloride or a carboxylic acid of formula (XII-2) to obtain the compound of formula (XII), its stereoisomer, or its pharmaceutically acceptable salt.

16. A compound of pharmaceutically acceptable formula thereof, (XII-1), a stereoisomer thereof or a ci salt (Mil) 17. A method for preparing the compound of formula (XII-1), the stereoisomer thereof, or its pharmaceutically acceptable salt according to claim 16, characterized in that it comprises the following step of deprotecting a compound of formula (XII-3) to obtain the compound of formula (XII-1), its stereoisomer, or its pharmaceutically acceptable salt; wherein: Pgi is an amino protecting group, selected from the group consisting of allyloxycarbonyl, trifluoroacetyl, 2,4-dimethoxybenzyl, nitrobenzenesulfonyl, trityl, fluorenemethoxycarbonyl, p-toluenesulfonyl, formate, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, and p-methoxyphenyl, and preferably tert-butoxycarbonyl; Optionally, react a compound of formula (XII-4) with a compound of formula (XII-5) to obtain the compound of formula (XII-3), its stereoisomer, or its pharmaceutically acceptable salt;Pg2 is a hydroxy protecting group, selected from the group consisting of methyl, tere-butyl, triphenyl, methylthiomethyl ether, 2-methoxyethoxymethyl ether, methoxymethyl ether, p-methoxybenzyl ether, pivaloyl, benzyl ether group, methoxymethyl, trimethylsilyl, tetrahydrofuranyl, tere, -butyldisylyl, acetyl, benzoyl and p-toluenesulfonyl, and preferably p-toluenesulfonyl.

18. A pharmaceutical composition comprising a therapeutically effective dose of the compound, its stereoisomer or its pharmaceutically acceptable salt according to any of claims 1 to 14, and one or more pharmaceutically acceptable vehicles, diluents or excipients.

19. The pharmaceutical composition according to claim 18, wherein the therapeutically effective dose is from 0.1 to 500 mg, preferably from 0.1 to 100 mg, more preferably from 0.1 to 50 mg, more preferably from 0.1 to 20 mg, more preferably from 0.5 to 10 mg, and most preferably from 0.5 to 5 mg.

20. Use of the compound, its stereoisomer or its pharmaceutically acceptable salt according to any of claims 1 to 14, or the pharmaceutical composition according to claim 18 in the preparation of a G protein-coupled receptor modulating drug, particularly a dopamine D3 receptor modulating drug and a 5-HT2A receptor modulating drug.

21. Use of the compound, its stereoisomer, or its pharmaceutically acceptable salt according to any of claims 1 to 14, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for treating or preventing a disease of the central nervous system and / or a psychiatric disease or disorder, wherein the disease of the nervous system and / or the psychiatric disease is preferably selected from the group consisting of schizophrenia, sleep disorder, mood disorder, schizophrenia spectrum disorder, spastic disorder, memory disorder and / or cognitive disorder, movement disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, depression, autism, senile dementia, Alzheimer's disease, seizures, neuralgia, detoxification,Symptomatic major depressive disorder and mania.