WO2024188143A1 - Nk-3 receptor antagonist compound, pharmaceutical composition, preparation method therefore and use thereof - Google Patents

Abstract

The present invention relates to an NK-3 receptor antagonist compound or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutical composition comprising same. The compound or the pharmaceutically acceptable salt thereof or the stereoisomer thereof, and the pharmaceutical composition have antagonistic activity against the NK-3 receptor, and can be used as an NK-3 receptor antagonist for preventing or treating diseases related to the activity or expression level of the NK-3 receptor.

Description

NK-3 receptor antagonist compound, pharmaceutical composition, preparation method and application thereof Technical Field

The present invention relates to NK-3 receptor antagonist compounds, including their pharmaceutically acceptable salts and stereoisomers, which are selective antagonists of neurokinin 3 receptor (NK-3) and can be used as therapeutic compounds, especially in the treatment and/or prevention of various CNS diseases or disorders.

Background Art

Tachykinin receptors are targets of a group of structurally related peptides including Substance P (SP), Neurokinin A (NKA), and Neurokinin B (NKB), collectively referred to as "tachykinins". Tachykinins are synthesized in the central nervous system (CNS) and peripheral tissues where they exert a variety of biological activities. Three tachykinin receptors are known, which are named neurokinin-1 (NK-1) receptor, neurokinin-2 (NK-2) receptor, and neurokinin-3 (NK-3) receptor. Tachykinin receptors belong to the rhodopsin-like 7 membrane G-protein-coupled receptors. SP has the highest affinity and is considered to be the endogenous ligand for NK-1, NKA is considered to be the endogenous ligand for the NK-2 receptor, and NKB is considered to be the endogenous ligand for the NK-3 receptor, although some cross-reactivity may exist. NK-1, NK-2, and NK-3 receptors have been identified in different species. NK-1 and NK-2 receptors are expressed in many peripheral tissues, and NK-1 receptors are also expressed in the CNS; whereas NK-3 receptors are primarily expressed in the CNS.

Neurokinin receptors mediate a variety of biological effects of tachykinin stimulation, including transmission of excitatory neuronal signals in the CNS and periphery (e.g., pain), modulation of smooth muscle contractile activity, regulation of immune and inflammatory responses, induction of hypotensive effects by relaxation of peripheral vasculature and stimulation of secretion of endocrine and exocrine glands.

In the CNS, NK-3 receptors are expressed in regions including the medial prefrontal cortex, hippocampus, thalamus and amygdala. In addition, NK-3 receptors are expressed on dopaminergic neurons. The activation of NK-3 receptors has been shown to regulate the release of dopamine, acetylcholine and 5-hydroxytryptamine, suggesting that NK-3 receptor modulators treat a variety of conditions including mental disorders, anxiety disorders, depression, schizophrenia and obesity, pain or inflammation.

Emerging biology has clearly established a role for NK3R/NKB signaling in reproductive neuroendocrinology. NK3R antagonism is a novel non-hormonal approach to treat vasomotor symptoms (VMS) that directly targets the underlying central mechanisms that contribute to the disease. A subpopulation of hypothalamic neurons that co-express the neuropeptides kisspeptin, neurokinin B, and dynorphin (KNDy neurons) project from the arcuate nucleus to the preoptic area of the hypothalamus and play a key role in thermoregulation. These neurons are feedback inhibited by estrogen and stimulated by NK3R activation. As estrogen levels decline during menopause, feedback inhibition of NK3R-mediated signaling is reduced and hypertrophy of KNDy neurons is observed. This altered activity of the neural circuit causes the thermoregulatory center to become hypersensitive to information from peripheral receptors, activating heat dissipation effectors (e.g., sweating, vasodilation), which is the physiological basis for the development of VMS in many menopausal women.

NK3R is a key regulatory component of the hypothalamic-pituitary-gonadal (HPG) axis, where its tonic activation positively regulates the frequency of gonadotropin-releasing hormone (GnRH) pulses. The frequency of GnRH pulses can differentially regulate the levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in the circulating blood. High-frequency pulses stimulate LH release, while low-frequency pulses favor the induction of FSH. Gonadotropins ultimately act on the ovaries and testes to promote gamete production and sex hormone release. Patients with NK3R loss-of-function mutations exhibit a congenital hypogonadotropic hypogonadism phenotype with low plasma LH and a low LH/FSH ratio, which can be restored by exogenous administration of GnRH. NK3R antagonists slow LH pulses and reduce circulating LH levels without affecting FSH. Thus, NK3R antagonists are subtle regulators of gonadotropin secretion, unlike GnRH ligands, which block both LH and FSH, causing plasma estrogens to fall to castrate levels, "NK3R antagonists offer a potentially safer treatment approach due to the reduction, rather than elimination, of GnRH pulse frequency. These findings provide a strong rationale for repositioning NK3R antagonists to address sex hormone disorders such as polycystic ovary syndrome and uterine fibroids."

Astellas' PCT application WO2014/154895 reported the compound Fezolinetant as a NK receptor antagonist. Meanwhile, Chinese patents/patent applications CN102906093B, CN103906750B, CN105229008B, etc. reported a variety of compounds as NK1R/NK2R/NK3R antagonists.

Although a lot of meaningful research has been conducted in this field, there is still a need to continue researching and developing more effective small molecule NK-3 receptor antagonists.

Summary of the invention

The invention provides a NK-3 receptor antagonist with a novel structure, and it is found that the compound with such structure has good NK-3 receptor antagonist activity.

The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof,

in,

(1) X ₁ is independently selected from N, and X ₂ is independently selected from CR ₃ ;

are independently selected from single bonds or double bonds;

When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S;

Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

n is selected from 0, 1, 2, 3;

or (2) X ₁ is independently selected from CR ₃ , and X ₂ is independently selected from N;

are independently selected from double bonds;

When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S;

Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO 2 N(R 3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R 3a , -COOR 3a , -CON(R 3b ) 2 , -N(R 3b ) 2 , -SO ₂ N(R _3b ) 2 , or cyano 10-membered aryl, 5-10-membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

n is selected from 0, 1, 2, 3;

or (3) _X1 is independently selected from N, and _X2 is independently selected from N;

are independently selected from double bonds;

When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S;

Each R ₁ is independently selected from H, halogen, 6-10 membered aryl, or 5-6 membered heteroaryl, wherein the 6-10 membered aryl is optionally substituted with 1, 2, or 3 halogens;

Or two adjacent R ₁ together with the C atom to which they are attached form a 5-6 membered heteroaryl group;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

n is selected from 0, 1, 2, 3.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, _X1 is independently selected from N, _X2 is independently selected from _CR3 , or _X1 is independently selected from _CR3 , _X2 is independently selected from N; _R1 is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, _X1 is independently selected from N, _X2 is independently selected from _CR3 , or _X1 is independently selected from _CR3 , _X2 is independently selected from N; _R1 is selected from H, F, Cl, Br, I, pyrrol-2-yl, pyrrol-3-yl, thiophene-2-yl or thiophene-3-yl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, _X1 is independently selected from N, _X2 is independently selected from N; _R1 is selected from H, F, Cl, Br, I, phenyl, pyrrolyl, or thienyl, and the phenyl is optionally substituted by 1, 2, or 3 F, Cl, Br, I; or two adjacent _R1s together with the C atom to which they are connected form a furan ring, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, when X ₃ is selected from S, X ₄ is selected from CH; when X ₃ is selected from S, X ₄ is selected from N; or when X ₃ is selected from CH, X ₄ is selected from S; other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R ₂ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; the R _3a and R _3b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (＝O); other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, _R4 is selected from H, The invention relates to cyclopropyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or cyclopropyl, and the other variables are as defined herein.

The present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt or a stereoisomer thereof,

in,

are independently selected from single bonds or double bonds;

Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, or C ₁ -C ₃ alkyl;

n is selected from 0, 1, 2, 3.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, pyrrol-2-yl, pyrrol-3-yl, thiophene-2-yl or thiophene-3-yl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R ₂ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, preferably selected from F, Cl, Br, methyl, 1-propynyl, 2-propynyl, pyrrolidinyl, piperazinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -CONH ₂ , -N(CH ₃ ) ₂ ; the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; the R _3a and R _3b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O); other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R ₄ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer,

is selected from single bonds;

Each R ₁ is independently selected from H, F, Cl, Br, I,

_R2 is selected from methyl;

_R3 is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)CH ₃ , -COOH, -COOCH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -SO ₂ NH ₂ , or cyano, preferably selected from F, Cl, Br, methyl, 1-propynyl, 2-propynyl, -CONH ₂ , -N(CH ₃ ) ₂ ;

Each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O);

_R4 is selected from H, or methyl.

In some embodiments of the present invention, the present invention provides a compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof,

in,

are independently selected from single bonds or double bonds;

R _1a is selected from H, halogen, or 5-6 membered heteroaryl;

R _1b is selected from H, or halogen;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, or C ₁ -C ₃ alkyl.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof, R _1a is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof, R _1a is selected from H, F, Cl, Br, I, pyrrol-2-yl, pyrrol-3-yl, thiophene-2-yl or thiophene-3-yl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof, R _1b is selected from H, F, Cl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, preferably selected from F, Cl, Br, methyl, 1-propynyl, 2-propynyl, pyrrolidinyl, piperazinyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -CONH ₂ , -N(CH ₃ ) ₂ ; the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; each of R _3a and R _3b is independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O); other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof, R ₄ is selected from H or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof,

is selected from single bonds;

R _1a is selected from H, F, Cl, Br, I,

R _1b is selected from H, F, or Cl;

_R3 is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)CH ₃ , -COOH, -COOCH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -SO ₂ NH ₂ , or cyano, preferably selected from F, Cl, Br, methyl, 1-propynyl, 2-propynyl, -CONH ₂ , -N(CH ₃ ) ₂ ;

Each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O);

_R4 is selected from H, or methyl.

In some embodiments of the present invention, the present invention provides a compound represented by formula (III), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof,

in,

Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, or C ₁ -C ₃ alkyl;

n is selected from 0, 1, 2, 3.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, pyrrol-2-yl, pyrrol-3-yl, thiophene-2-yl or thiophene-3-yl, and the other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer, R ₂ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer, R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; each of R _3a and R _3b is independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (＝O); other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer, R ₄ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt, or stereoisomer,

_R1 is selected from H, F, Cl, Br, I,

_R2 is selected from methyl;

_R3 is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl Cyclohexyl, -C(O)CH ₃ , -COOH, -COOCH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -SO ₂ NH ₂ , or cyano;

Each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O);

_R4 is selected from H, or methyl.

In some embodiments of the present invention, the present invention provides a compound represented by formula (IIIA), or a pharmaceutically acceptable salt or stereoisomer thereof,

in,

R _1a is selected from H, halogen, or 5-6 membered heteroaryl;

R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ;

Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl;

Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O);

R ₄ is selected from H, or C ₁ -C ₃ alkyl.

In some embodiments of the present invention, in the compound represented by formula (IIIA), or a pharmaceutically acceptable salt thereof, R _1a is selected from H, F, Cl, Br, I, Other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (IIIA), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; each of R _3a and R _3b is independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (═O); other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (IIIA), or a pharmaceutically acceptable salt thereof, R ₄ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IIIA), its pharmaceutically acceptable salt or stereoisomer,

R _1a is selected from H, F, Cl, Br, I,

_R3 is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C(O)CH ₃ , -COOH, -COOCH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -SO ₂ NH ₂ , or cyano;

Each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (=O);

_R4 is selected from H, or methyl.

In some embodiments of the present invention, the present invention provides a compound represented by formula (IV), a pharmaceutically acceptable salt or stereoisomer thereof,

in,

When X ₃ is selected from S, X ₄ is selected from CH or N; or when X ₃ is selected from CH, X ₄ is selected from S;

Each R ₁ is independently selected from H, halogen, 6-10 membered aryl, or 5-6 membered heteroaryl, wherein the 6-10 membered aryl is optionally substituted with 1, 2, or 3 halogens;

Or two adjacent R ₁ together with the C atom to which they are attached form a 5-6 membered heteroaryl group;

R ₂ is selected from H, or C ₁ -C ₃ alkyl;

R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl;

n is selected from 0, 1, 2, 3.

In some embodiments of the present invention, in the compound represented by formula (IV), its pharmaceutically acceptable salt or stereoisomer, when X ₃ is selected from S, X ₄ is selected from CH; when X ₃ is selected from S, X ₄ is selected from N; or when X ₃ is selected from CH, X ₄ is selected from S; other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IV), its pharmaceutically acceptable salt or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, phenyl, pyrrolyl, or thienyl, and the phenyl is optionally substituted by 1, 2, or 3 F, Cl, Br, I; Or two adjacent R ₁ together with the C atom to which they are attached form a furan ring, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IV), its pharmaceutically acceptable salt or stereoisomer, R ₁ is selected from H, F, Cl, Br, I, phenyl, 4-fluorophenyl, pyrrol-2-yl, pyrrol-3-yl, thiophen-2-yl or thiophen-3-yl; or two adjacent R ₁ together with the C atom to which they are connected form (The C atom marked with * is the C atom to which R ₁ is attached), and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IV), its pharmaceutically acceptable salt or stereoisomer, R ₂ is selected from H, or methyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IV), its pharmaceutically acceptable salt or stereoisomer, R ₄ is selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or cyclopropyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, the present invention provides a compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof,

in,

When X ₃ is selected from S, X ₄ is selected from CH or N; or when X ₃ is selected from CH, X ₄ is selected from S;

R _1a is selected from H, halogen, 6-10 membered aryl, or 5-6 membered heteroaryl, wherein the 6-10 membered aryl is optionally substituted with 1, 2, or 3 halogens;

R _1b is selected from H, or halogen;

R _1c is selected from H, or halogen;

R _1d is selected from H, or halogen;

R _1e is selected from H, or halogen;

Alternatively, R _1b and R _1c or R _1d and R _1e together with the C atom to which they are attached form a 5-6 membered heteroaryl group;

R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl.

In some embodiments of the present invention, in the compound represented by formula (IVA), its pharmaceutically acceptable salt or stereoisomer, when X ₃ is selected from S, X ₄ is selected from CH; when X ₃ is selected from S, X ₄ is selected from N; or when X ₃ is selected from CH, X ₄ is selected from S; other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1a is selected from H, F, Cl, Br, I, Other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1b is selected from H, F, or Cl; and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1c is selected from H, F, or Cl; and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1d is selected from H, F, or Cl; and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1e is selected from H, F, or Cl; Other variables are as defined herein.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R _1b and R _1c or R _1d and R _1e together with the C atom to which they are attached form (The C atom marked with * is the C atom to which R ₁ is attached), and other variables are as defined in the present invention.

In some embodiments of the present invention, in the compound represented by formula (IVA), or a pharmaceutically acceptable salt thereof, R ₄ is selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or cyclopropyl, and other variables are as defined in the present invention.

In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

The present invention also provides a pharmaceutical composition, comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections or various sustained-release preparations, etc. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously or topically). The dosage can be appropriately adjusted according to the patient's age, gender and disease type, and the general daily dose is about 1-200 mg.

The present invention also provides the use of the above compounds or their pharmaceutically acceptable salts and stereoisomers as modulators of NK-3 (neurokinin-3) receptors, preferably as antagonists of NK-3 receptors. At the same time, the present invention also provides the use of the above compounds or their pharmaceutically acceptable salts and stereoisomers for treating and/or preventing diseases related to the activity or expression of NK-3 (neurokinin-3) receptors.

The present invention provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts and stereoisomers for treating and/or preventing patient diseases, and the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs. The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs, and the drugs are used to prevent or treat diseases related to the activity or expression of NK-3 (neurokinin-3) receptors. The diseases associated with the activity or expression of NK-3 (neurokinin-3) receptors include: depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorder, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, including irritable bowel syndrome (IBS) and inflammatory bowel disease, vomiting, preeclampsia, airway-related diseases, including chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough, urinary incontinence, reproductive disorders, contraception and sex hormone-dependent diseases, including but not limited to benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male-type Alopecia, endometriosis, puberty abnormalities, uterine fibrosis, uterine fibroids, uterine leiomyoma, hormone-dependent cancers, hyperandrogenism, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans), ovarian theca cell hyperplasia (HAIR-AN with luteinizing theca cell hyperplasia in the ovarian stroma), other manifestations of high intraovarian androgen concentrations (such as follicular maturation arrest, atresia, anovulation, dysmenorrhea, dysfunctional uterine bleeding, infertility), androgen-producing tumors (masculinizing ovarian tumors or adrenal tumors), menorrhagia and adenomyosis, vasomotor symptoms (VMS), Including menopausal hot flashes, hot flashes and night sweats.

Definition and Description

Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and/or dosage forms that are, within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit/risk ratio.

The "pharmaceutically acceptable salts" mentioned in the present invention refer to salts of the compounds of the present invention, which are prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids and bases. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; they also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic functional groups and can be converted into any acid addition salt.

Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention. Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomers are recovered. In addition, the separation of enantiomers and diastereomers is usually achieved by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (such as the formation of carbamates from amines).

The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of the salt is: in water or an organic solvent or a mixture of the two, through the reaction of these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid to prepare.

The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein, using an appropriate isotopically labeled reagent in place of an otherwise non-labeled reagent.

Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group, which may be monosubstituted (eg, _-CH2F ) or polysubstituted. (such as -CF ₃ ), which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). For example, C ₁ -C ₆ represents 1 to 6 carbons, and C _1-10 is selected from C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ ; examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, s-butyl, t-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (such as n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), etc.

Unless otherwise specified, the term "alkenyl" is used to refer to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one carbon-carbon double bond. The alkenyl group may contain 2-10 carbon atoms (i.e., C _2-10 alkenyl), and more preferably contains 2-6 carbon atoms (i.e., C _2-6 alkenyl). For example, "C _2-6 alkenyl" means that the group is an alkenyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically 2, 3, 4, 5 or 6). Examples of alkenyl groups include, but are not limited to, vinyl (i.e., -CH=CH ₂ ), 1-propenyl (i.e., -CH=CHCH ₃ ), 2-propenyl (i.e., allyl, -CH ₂ CH=CH ₂ ), and the like.

Unless otherwise specified, the term "alkynyl" is used to refer to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl group may contain 2-10 carbon atoms (i.e., C _2-10 alkynyl), and further preferably contains 2-6 carbon atoms (i.e., C _2-6 alkynyl). For example, "C _2-6 alkynyl" means that the group is an alkynyl group, and the number of carbon atoms on the carbon chain is between 2-6 (specifically, 2, 3, 4, 5 or 6). Examples of alkynyl groups include, but are not limited to, ethynyl (i.e., -C≡CH), 1-propynyl (i.e., -C≡CCH ₃ ), 2-propynyl (i.e., propargyl, -CH ₂ C≡CH), and the like.

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

Unless otherwise specified, "haloalkyl" is used to indicate that an alkyl group is substituted with one or more halogen atoms, wherein the alkyl group has the meaning as described herein. For example, the term "C ₁ -C ₆ haloalkyl" is intended to include C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ alkyl groups substituted with one or more halogen atoms. Unless otherwise specified, examples of C ₁ -C ₆ haloalkyl groups include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2-difluoroethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl, and pentachloroethyl.

Unless otherwise specified, the term "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom is saturated, can be monosubstituted or polysubstituted, can be monovalent, divalent or polyvalent. Examples of these cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heterocyclic group preferably contains 3-14 ring atoms, and further preferably contains 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, etc.

Unless otherwise specified, "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated π electron system, such as phenyl and naphthyl, with phenyl being preferred.

Unless otherwise specified, "heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more carbocyclic or heterocyclic groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. The 5-membered heteroaryl of heteroatoms includes, but is not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms includes, but is not limited to, triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms includes, but is not limited to, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom includes, but is not limited to, pyridyl. Exemplary 6-membered heteroaryl containing two heteroatoms includes, but is not limited to, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms includes, but is not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom includes, but is not limited to, azacycloheptatrienyl, oxacycloheptatrienyl and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indolinyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

DETAILED DESCRIPTION

The present invention is further described below in conjunction with specific embodiments and test examples, but the scope of the present invention is not limited in any form.

Example 1 Synthesis of Compound (±) 1

1. Dissolve chloroacetaldehyde (13.5 g, 11.1 mL, 1.50 eq) and compound 1-1 (5.00 g, 1.00 eq) in 50 mL of acetonitrile, add NaHCO ₃ (7.70 g, 3.57 mL, 2.00 eq), and stir at 80° C. for 12 hours. After the reaction is completed, concentrate the reaction solution to obtain a crude product. The crude product was purified by column chromatography to give compound 1-2 (brown solid, 5.00 g, yield: 82.0%), MS (ESI) m/z: [M+H] ⁺ = 134.1, ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 7.96 (d, J = 4.5 Hz, 1H), 7.85-7.79 (m, 1H), 7.74-7.72 (m, 1H), 7.65 (s, 1H), 2.92-2.86 (m, 3H).

2. Add DMF (40 mL), compound 1-2 (4.00 g, 1.00 eq), and NIS (8.11 g, 1.20 eq) to a 100 mL three-necked flask and stir at 40 °C for 2 hours. After the reaction is complete, add water and extract with ethyl acetate. Combine the organic phases, dry, and concentrate to obtain a crude product. The crude product is purified by column chromatography to obtain compound 1-3 (black solid, 5.50 g, yield: 70.7%). MS (ESI) m/z: [M+H] ⁺ = 259.9, ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.21 (d, J = 4.6 Hz, 1H), 7.90-7.80 (m, 2H), 2.74 (s, 3H).

3. Add compound 1-3 (5.50 g, 1.00 eq) to 45 mL of tetrahydrofuran, cool the reaction solution to -78 °C and add i-PrMgCl.LiCl (1.30 M, 32.7 mL, 2.00 eq). After stirring at -78 °C for 1 hour, add Sn(Bu) ₃ Cl (13.8 g, 11.4 mL, 2.00 eq). After the reaction is completed, add saturated aqueous ammonium chloride solution to quench, extract with dichloromethane, combine the organic phases, dry, and concentrate to obtain a crude product. The crude product is purified by column chromatography to obtain compound 1-4 (light yellow oil, 5.49 g, yield: 61.3%) MS (ESI) m/z: [M+H] ⁺ = 424.2, ¹ H NMR (400MHz, CHLOROFORM–d)δ＝7.86(d,J＝4.6Hz,1H),7.71(d,J＝4.6Hz,1H),7.68(s,1H),2.90(s,3H),1.66-1.48(m,6H),1.40-1.32(m,6H),1.28-1.13(m,6H), 0.89(t,J＝7.3Hz,9H).

4. Compound 1-4 (2.50 g, 1.00 eq), 5-bromo-3-methyl-1,2,4-thiadiazole (2.12 g, 2.00 eq) and Pd(PPh ₃ ) ₄ (342 mg, 0.05 eq) were added to 50 mL of dioxane and stirred at 100° C. for 4 hours. After the reaction was complete, the reaction solution was directly concentrated and dried to obtain a crude product, which was purified by column chromatography to obtain compound 1-5 (white solid, 1.21 g, yield: 88.4%). MS (ESI) m/z: [M+H] ⁺ = 232.1, ¹ H NMR (400 MHz, CHLOROFORM–d) δ = 9.36 (d, J = 4.5 Hz, 1H), 8.31 (s, 1H), 8.07 (d, J = 4.6 Hz, 1H), 2.98 (s, 3H), 2.79 (s, 3H).

5. Add compound 1-5 (1.21 g, 1.00 eq), acetic acid (31.4 mg, 29.9 μL, 0.10 eq), Pt/C (2.00 g, 5% purity, 0.09 eq) to 20 mL of anhydrous ethanol in an argon environment. Replace the argon with hydrogen, and react at 100°C and 3 MPa for 30 hours. After the reaction, filter the reaction solution and spin dry to obtain a crude product. The crude product was separated and purified by preparative separation to obtain compound 1-6 (white solid, 170 mg, yield: 13.8%). MS (ESI) m/z: [M+H] ⁺ = 236.0, δ = 7.64 (s, 1H), 4.59-4.50 (m, 1H), 4.28-4.17 (m, 2H), 3.52-3.44 (m, 1H), 3.29-3.19 (m, 1H), 2.67 (s, 3H), 1.61 (d, J = 6.6 Hz, 3H)

6. Add compound 1-6 (145 mg, 1.00 eq) and DIEA (159 mg, 215 μL, 2.00 eq) to 1.5 mL of dichloromethane. Then dissolve p-fluorobenzoyl chloride in 0.5 mL of dichloromethane, add to the reaction solution, and stir at 20°C for 2 hours. After the reaction is completed, add water, extract with dichloromethane, dry, filter, concentrate and spin dry to obtain a crude product. The crude product was separated and purified by preparative plate to obtain compound (±) 1 (white solid, 118 mg, yield: 53.3%). MS (ESI) m/z: [M+H] ⁺ = 358.1, ¹ H NMR (400 MHz, CHLOROFORM–d) δ = 7.67 (s, 1H), 7.51-7.46 (m, 2H), 7.16 (t, J = 8.6 Hz, 2H), 5.84-5.43 (m, 1H), 4.84-4.78 (m, 1H), 4.30-4.17 (m, 1H), 3.56 (br t, J = 10.4 Hz, 1H), 2.67 (s, 3H), 1.69 (d, J = 6.9 Hz, 3H).

Example 2 Synthesis of Compound (±) 2

1. At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.02g, 10.51mmol), 1-hydroxybenzotriazole (1.42g, 10.51mmol), N,N-diisopropylethylamine (2.83g, 21.90mmol, 3.81mL) and 4-chloro-3-fluorobenzoic acid (1.53g, 8.76mmol) were added to a solution of 3-methyl-2-oxo-piperazine (1g, 8.76mmol) in dichloromethane (10mL) in sequence, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, water (15mL) was added to quench the reaction, and then extracted with dichloromethane (15mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 18/82-17/83) to give compound 2-1 (1.6 g, 5.91 mmol, yield 67.47%, purity 100%). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.05-8.04 (m, 1H), 7.69 (t, J = 8.0 Hz 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.86-4.38 (m, 1H), 4.37-3.87 (m, 1H), 3.86-3.49 (m, 1H), 3.37 (s, 1H), 3.08 (s, 1H), 1.37 (d, J = 6.4 Hz, 3H).

2. Under nitrogen protection, add a solution of tin tetrachloride (769.9 mg, 2.96 mmol) in xylene (3 mL) to a solution of compound 2-1 and 2,2-dimethoxyethylamine (2.33 g, 22.17 mmol, 2.41 mL) in xylene (27 mL) at room temperature. Then heat to 140 °C and stir for 12 hours. After the reaction is completed, cool to room temperature, add the reaction solution to 30 mL of saturated sodium bicarbonate aqueous solution to quench, and then extract with dichloromethane (100 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC to obtain compound 2-2 (635 mg, 2.10 mmol, yield 28.38%, purity 99%). MS (ESI) m/z: 294.0 [M+H] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.71 (t, J = 8.0 Hz, 1H), 7.62-7.59 (m, 1H), 7.35 (d, J = 8.0 Hz,), 7.10 (s, 1H), 6.89 (s, 1H), 5.53-5.51 (m, 1H), 4.02-3.57 (m, 4H), 1.49 (d, J = 6.8 Hz, 3H).

3. At 0°C, N-iodosuccinimide (627.3 mg, 2.79 mmol) was added to a solution of compound 2-2 in N,N-dimethylformamide (1.5 mL) in batches. Then the mixture was warmed to room temperature and stirred for 2 hours. After the reaction was completed, ethyl acetate (10 mL) was added for dilution, and then the mixture was washed with saturated aqueous sodium sulfite solution (10 mL*3), saturated sodium bicarbonate (10 mL*3) and brine (10 mL*3) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/80-19/81) to obtain compound 2-3 (550 mg, 1.30 mmol, yield 60.68%, purity 75.68%). MS(ESI)m/z:420.0[M+H] ⁺ ; ¹ H NMR(DMSO-d ₆ ,400MHz)δ7.72-7.68(m,1H),7.63-7.58(m,1H),7.37-7.35(m,1H),7.06(s,1H),5.56-5.51(m,1H),4.01-3 .61(m,4H),1.47(d,J＝6.4Hz,3H).

4. Dissolve compound 2-3 (550 mg, 1.31 mmol) in tetrahydrofuran (5 mL), add dropwise to isopropylmagnesium chloride and lithium chloride (1.3 M tetrahydrofuran solution, 4.03 mL) at 0°C under nitrogen protection, and then stir at 0°C for 0.5 hours. Add tributyltin chloride (1.56 g, 4.79 mmol, 1.29 mL) at 0°C. Then warm to 25°C and stir for 1 hour. Add saturated ammonium chloride (15 mL) to the reaction mixture at 25°C for quenching, and then extract with ethyl acetate (15 mL*3). Wash the separated organic phase with 90 mL of brine, dry with anhydrous Na ₂ SO ₄ , and filter and concentrate under reduced pressure to obtain the crude product compound 2-4 (360 mg, crude). The crude product is used directly in the next step without purification. MS (ESI) m/z: 584.2 [M+H] ⁺ .

5. Under nitrogen protection, tetrakis(triphenylphosphine)palladium (71.38mg, 61.77μmol), cuprous iodide (117.65mg, 617.74μmol) and 5-bromo-3-methyl-1,2,4-thiadiazole (110.60mg, 617.74μmol) were added to a solution of compound 2-4 (360mg, 617.74μmol) in dioxane (4mL). The reaction solution was replaced with nitrogen and heated to 90°C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, quenched with water (15mL), and then extracted with ethyl acetate (15mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC to obtain compound (±) 2 (63.58mg, 161.44μmol, yield 26.13%, purity 99.5%). MS (ESI) m/z: 392.1[M+H] ⁺ ; HPLC: Rt=1.790min, purity 99.5%; ¹ H NMR (DMSO-d _6, 400MHz) δ7.87 (s, 1H), 7.75-7.70 (m, 1H), 7.65-7.62 (m, 1H), 7.39 (d, J= 7.6Hz, 1H) ,5.63-5.60(m,1H),4.57-4.54(m,1H),4.36-4.17(m,1H),3.94-3.85(m,1H),3.69-3.64(m,1H),3.06(s,3H),1.56(d,J＝6.8Hz,3H).

Example 3 Synthesis of Compound (±) 5

N-bromosuccinimide (2.99 g, 16.79 mmol) was added to a solution of compound (±) 1 (4 g, 11.19 mmol) in N, N-dimethylformamide (40 mL) in batches. Then, it was heated to 70°C and stirred for 12 hours. After the reaction was completed, water (20 mL) was added at room temperature to quench, and then extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with sodium carbonate (60 mL*3), sodium sulfite (60 mL*3) and saturated sodium chloride (60 mL*3), dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain 3.5 g of crude product. 100 mg of the crude product was purified by slurrying with acetonitrile (10 mL) at 25°C to obtain compound (±) 5 (93.57 mg, 204.49 μmol, purity 95.35%). MS (ESI) m/z: 438.0 [M+H] ⁺ ; HPLC: Rt=1.962min, purity: 95.35%; ¹ H NMR (CDCl _3, 400MHz) δ7.52-7.40 (m, 2H), 7.17 (t, J=7.6Hz, 2H), 5.86-5.27 (m, 1H), 5.11-4.89 (m,1H),4.69-4.24(m,2H),3.63-3.38(m,1H),2.68(s,3H),1.69(d,J＝6.8Hz,3H).

Example 4 Synthesis of Compound (±) 6

At room temperature, N-chlorosuccinimide (112.09 mg, 839.38 μmol) was added to a solution of compound (±) 1 (200 mg, 559.59 μmol) in N,N-dimethylformamide (3 mL). The mixture was then heated to 60°C for 12 hours. After the reaction, the reaction mixture was diluted with 30 mL of ethyl acetate, washed with 60 mL of saturated sodium bicarbonate solution and brine (20 mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product. At room temperature, the compound (±) 6 (62.91 mg, 153.53 μmol, yield 27.44%, purity 95.63%) was obtained by slurrying with acetonitrile. MS (ESI) m/z: 392.1[M+H] ⁺ , HPLC: Rt=1.932min, purity 95.63%; ¹ H NMR (CDCl ₃ , 400MHz) δ7.50-7.46 (m, 2H), 7.19-7.15 (m, 2H), 5.88-5.25 (m, 1H), 5.03-4.98 (m, 1H),4.76-4.13(m,2H),3.59-3.53(m,1H),2.68(s,3H),1.69(d,J＝6.8Hz,3H).

Example 5 Synthesis of Compound (±) 8

1. Add cuprous cyanide (41.06 mg, 458.40 μmol, 100.14 μL) to a solution of compound (±) 5 (50 mg, 114.60 μmol) in dimethyl sulfoxide (2 mL), and place the reaction solution in a microwave tube and heat at 150 ° C for 2 hours. After the reaction is completed, add water (5 mL) at room temperature for quenching, and then extract with ethyl acetate (5 mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product is purified by HPLC column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 23%-53% B/min to obtain compound (±) 13.

2. At 0°C, potassium carbonate (18.07 mg, 130.75 μmol) and hydrogen peroxide (210 mg, 1.85 mmol, 177.97 μL) were added to a mixed solution of compound (±) 13 (100 mg, 261.50 μmol) in tetrahydrofuran (8 mL) and pure water (2 mL), and then the temperature was raised to room temperature for reaction for 1 hour. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (20 mL), sodium sulfite solution (20 mL) and pure water (20 mL), extracted with ethyl acetate (3*15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with acetonitrile (5 mL) at room temperature to obtain compound (±) 8 (71.52 mg, 178.61 μmol, yield 68.30%, purity 98.60%). MS (ESI) m/z: 401.1 [M+H] ⁺ ; HPLC: RT=1.537min, purity: 98.60%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ7.84-7.78 (m, 1H), 7.68-7.65 (m, 1H), 7.57-7.52 (m, 2H), 7.37-7.32 (m ,2H),5.82-5.52(m,1H),4.95-4.92(m,1H),4.37-4.30(m,1H),4.18-3.99(m,1H),3.71-3.63(m,1H),2.60(s,3H),1.62(d,J＝6.4Hz,3H).

Example 6 Synthesis of Compound (±) 9

To a solution of compound (±) 5 (200 mg, 458.40 μmol) in dioxane (5 mL) were added tert-butyl carbamate (120.82 mg, 1.03 mmol), tris(dibenzylideneacetone)dipalladium (20.99 mg, 22.92 μmol), cesium carbonate (448.07 mg, 1.38 mmol) and 4,5-dihydropyridine at room temperature. Phenylphosphine-9,9-dimethylxanthene (26.52 mg, 45.84 μmol). After the reaction solution was replaced with nitrogen, the temperature was raised to 100°C and the reaction was carried out for 12 hours. After the reaction was completed, water (15 mL) was added at room temperature to quench the reaction, and then extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with 90 mL of brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1-0/1), and then purified by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia hydroxide v/v)-acetonitrile]; gradient: 28%-58% B/min) to obtain compound (±) 9 (51.08 mg, 134.40 μmol, yield 31.28%, purity 97.99%). MS (ESI) m/z: 373.1 [M+H] ⁺ ; HPLC: Rt=1.490min, purity: 97.99%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ7.60-7.57 (m, 2H), 7.34-7.30 (m, 2H), 6.11 (s, 2H), 5.60-5.12 (m, 1H) ,4.34-4.20(m,1H),4.17-3.79(m,2H),3.74-3.54(m,1H),2.53-2.51(m,3H),1.52(d,J＝6.8Hz,3H).

Example 7 Synthesis of Compound (±) 10

Compound (±) 5 (200 mg, 458.40 μmol) was dissolved in a mixed solvent of dioxane (2 mL) and water (0.4 mL), and then 2,4,6-trimethyl-1,3,5,2,4,6-trioxytriborane (172.63 mg, 687.60 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (33.54 mg, 45.84 μmol) and potassium carbonate (190.06 mg, 1.38 mmol) were added. The reaction liquid was replaced with nitrogen and heated to 90 °C and stirred for 12 hours. After the reaction was completed, water (5 mL) was added at room temperature for quenching, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by HPLC (column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 23%-53% B/min) to give compound (±)10 (16.55 mg, yield 16.52%, purity 99.86%). MS (ESI) m/z: 372.0 [M+H] ⁺ ; HPLC: Rt=1.712min, purity 99.84%; ¹ H NMR (CDCl ₃ , 400MHz) δ7.55-7.38 (m, 2H), 7.17-7.03 (m, 2H), 5.68-5.52 (m, 1H), 4.90-4.87 (m, 2 H),4.26-4.20(m,1H),3.55-3.48(m,1H),2.67-2.63(m,3H),1.68(d,J＝6.8Hz,3H).

Example 8 Synthesis of Compound (±) 12

Tetrakis(triphenylphosphine)palladium (79.46 mg, 68.76 μmol) was added to a tetrahydrofuran (3 mL) solution of compound (±) 5 (300 mg, 687.60 μmol) and tributyl(prop-1-ynyl)stannane (1.13 g, 3.44 mmol), and the reaction solution was replaced with nitrogen and heated to 60°C and stirred for 12 hours. After the reaction was completed, water (5 mL) was added to the reaction mixture at room temperature, and then extracted with ethyl acetate (10 mL*3). The separated organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography (column: Waters Xbridge 150*25 mm*5 μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 28%-58% B/min) to obtain compound (±) 12 (20.66 mg, yield 20.60%, purity 99.72%). MS (ESI) m/z: 396.1[M+H] ⁺ ; HPLC: Rt=1.927min, purity 99.72%; ¹ H NMR (CDCl ₃ , 400MHz) δ7.53-7.46 (m, 2H), 7.22-7.11 (m, 2H), 5.60-5.49 (m, 1H), 5.01-4.97 (m, 1 H),4.28-4.23(m,2H),3.80-3.36(m,1H),2.67(s,3H),2.25(s,3H),1.68(d,J＝6.8Hz,3H).

Example 9 Synthesis of Compound (±) 13

Cuprous cyanide (41.06 mg, 458.40 μmol, 100.14 μL) was added to a solution of compound (±) 5 (50 mg, 114.60 μmol) in dimethyl sulfoxide (2 mL), and the reaction solution was placed in a microwave tube and heated at 150 ° C for 2 hours. After the reaction was completed, water (5 mL) was added at room temperature for quenching, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 23%-53% B/min to obtain compound (±) 13 (21.41 mg, 53.39μmol, yield 13.61%, purity 95.36%). MS (ESI) m/z: 383.1 [M+H] ⁺ ; HPLC: Rt=1.811min, purity 99.37%; ¹ H NMR (CDCl ₃ ,400MHz)δ7.50-7.48(m,2H),7.18(t,J＝8.4Hz,2H),5.63-5.60(m,1H),5.17-4.81(m,1H),4.39-4.21(m,1H),3.60-3.53(m,1H),2.73-2.67(m,1H), 2.74(s,3H),1.71(d,J＝6.8Hz,3H).

Example 10 Synthesis of Compound (±) 20

At room temperature, bis[(tetrabutylammonium iodide)copper(I) iodide](69.38mg, 82.51μmol), dimethylglycine(17.02mg, 165.02μmol), imidazole(33.70mg, 495.07μmol, 1.2eq) and potassium carbonate(114.04mg, 825.12μmol) were added to a solution of compound (±)5(180mg, 412.56μmol) in dimethyl sulfoxide(5mL). The reaction solution was replaced with nitrogen, added to a sealed tube and reacted at 100°C for 12 hours. After the reaction was completed, the reaction mixture was quenched with water(20mL), the aqueous phase was separated and extracted with ethyl acetate(3*15mL), and the combined organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by alkaline integration to give compound (±) 20 (53 mg, 123.77 μmol, yield 15.00%, purity 98.89%). MS (ESI) m/z: 424.1 [M+H] ⁺ ; HPLC: RT=1.552min, purity 98.89%; ¹ H NMR (CDCl ₃ , 400MHz) δ7.72 (s, 1H), 7.53 (dd, J ₁ = 5.2Hz, J ₂ = 8.4Hz, 2H), 7.33 (s, 1H), 7.20 (t, J＝ 8.8Hz,2H),7.13(s,1H),5.83-5.46(m,1H),4.97-4.92(m,1H),4.76-4.51(m,1H),4.39-4.30(m,1H),3.76-3.59(m,1H),2.68(s,3H),1.75(d,J＝6.8Hz ,3H).

Example 11 Synthesis of Compound (±) 22

1. Under nitrogen protection, add a tetrahydrofuran (10 mL) solution of compound 22-1 to isopropylmagnesium chloride-lithium chloride (1.3M tetrahydrofuran solution, 7.05 mL) at 0°C, stir at this temperature for 30 min, and then add tributyltin chloride (3.19 g, 9.80 mmol, 2.64 mL). Then warm to room temperature and stir for 2 hours. After the reaction is completed, add saturated ammonium chloride (60 mL) to the reaction solution at room temperature to quench, and then extract with ethyl acetate (20 mL*3). The organic phases are combined, washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 22-2 (1.33 g, crude product).

2. At room temperature, compound 22-2 (650 mg, 1.08 mmol), tetrakis(triphenylphosphine)palladium (52.21 mg, 45.18 μmol) and CuI (8.60 mg, 45.18 μmol) were added to a solution of compound (±) 5 (197.13 mg, 451.81 μmol) in dioxane (1 mL). The reaction liquid was replaced with nitrogen and heated to 100°C for 12 hours under stirring. After the reaction was completed, water (10 mL) was added to quench the reaction, and then extracted with ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 21/79-20/80) to obtain compound 22-3 (104 mg, 153.07 μmol, yield 33.88%, purity 85.98%). MS (ESI) m/z: 666.2 [M+H] ⁺ .

3. Add 4.0M hydrochloric acid/dioxane (2.5 mL) to a solution of compound 22-3 in dioxane (2.5 mL), and stir at room temperature for 2 hours. After the reaction is completed, add saturated sodium bicarbonate (10 mL) to the reaction mixture to quench, and then extract with ethyl acetate (10 mL*3). The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by HPLC (column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonium bicarbonate)-acetonitrile], gradient: 22%-52% B, 9min) to give compound (±) 22 (31.49mg, 73.91μmol, yield 37.85%, purity 99.39%). MS (ESI) m/z: 424.0 [M+H] ⁺ ; HPLC: Rt=1.480min, purity 99.39%; ¹ H NMR (DMSO-d ₆ ,400MHz)δ12.64-12.33(m,1H),7.90(s,1H),7.62-7.54(m,3H),7.33(t,J＝8.8Hz,2H),5.63-5.50(m,1H),4.85-4.82(m,1H),4.34-4.27(m,1H),3.99 -3.63(m,2H),2.56(s,3H),1.60(d,J=6.8Hz,3H).

Example 12 Synthesis of Compound (±) 27

Compound (±) 5 (200 mg, 458.40 μmol) was dissolved in a mixed solution of dioxane (2 mL) and water (0.4 mL), and 6-fluoropyridine-3-boric acid (172.63 mg, 687.60 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (33.54 mg, 45.84 μmol) and potassium carbonate (190.06 mg, 1.38 mmol) were added. After nitrogen replacement of the reaction liquid, the temperature was raised to 90 ° C and stirred for 12 hours. After the reaction was completed, water (5 mL) was added at room temperature for quenching, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by HPLC (column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 23%-53% B/min) to give compound (±) 27 (27.71 mg, yield 27.45%, purity 99.06%). MS (ESI) m/z: 453.0 [M+H] ⁺ ; HPLC: Rt=1.832min, purity: 99.06%; ¹ H NMR (CDCl ₃ , 400MHz) δ 8.41-8.39 (m, 1H), 8.07-7.85 (m, 1H), 7.54-7.47 (m, 2H), 7.19-7.15 (m, 2H),7.05-7.02(m,1H),5.70-5.58(m,1H),4.91-4.83(m,1H),4.31-4.25(m,2H),3.62-3.61(m,1H),2.67(s,3H),1.87(d,J＝6.8Hz,3H).

Example 13 Synthesis of Compound (±) 32

At room temperature, Pd ₂ (dba) ₃ (20.99 mg, 22.92 μmol), cesium carbonate (448.07 mg, 1.38 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.52 mg, 45.84 μmol) were added to a solution of compound (±) 5 (200 mg, 458.40 μmol) and 1-methylpiperazine (68.87 mg, 687.60 μmol, 76.27 μL) in dioxane (5 mL). After the reaction solution was replaced with nitrogen, the temperature was raised to 100°C and the reaction was carried out for 12 hours. After the reaction was completed, water (10 mL) was added at room temperature to quench the reaction mixture, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with 60 mL of brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1-0/1) and then by high performance liquid chromatography (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia hydroxide v/v)-acetonitrile]; gradient The compound (±) 32 (50.33 mg, 110.21 μmol, yield 50.20%, purity 99.75%) was obtained by purification; MS (ESI) m/z: 456.2 [M+H] ⁺ ; HPLC: Rt = 1.756 min, purity: 99.75%; ¹ H NMR (CDCl ₃ ,400MHz)δ7.49-7.45(m,2H),7.15(t,J=8.8Hz,2H),6.09-5.16(m,1H),5.10-4.39(m,2H),4.30-4.13(m,1H),3.69-3.42(m,1H),3.22-2.99(m,4H),2 .84-2.57(m,7H),2.40(s,3H),1.66(d,J＝6.8Hz,3H).

Example 14 Synthesis of Compound (±) 35

Potassium carbonate (85.53 mg, 618.84 μmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (15.09 mg, 20.63 μmol) were added to a mixed solution of compound (±) 5 (90 mg, 206.28 μmol) and (2,5-difluoro-4-pyridyl)boric acid (49.17 mg, 309.42 μmol) in dioxane (2 mL) and water (0.4 mL) at room temperature. The mixture was then replaced with nitrogen and heated to 100 °C and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, water (10 mL) was added to quench the reaction, and then extracted with ethyl acetate (15 mL*3). The organic phases were combined, washed with 100 mL of brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate=1:1) and then by HPLC column (Waters Xbridge 150*25mm*5μm; mobile phase: [water (ammonia hydroxide v/v)-gradient: 35%-65% B/min) to obtain compound (±) 35 (38.65 mg, 82.15μmol, yield 39.83%, purity 100%). MS (ESI) m/z: 471.1 [M+H] ⁺ ; HPLC: Rt=1.891min, purity: 100%; ¹ H NMR (DMSO-d ₆ , 400MHz) δ8.34 (s, 1H), 7.63-7.60 (m, 2H), 7.51-7.42 (m, 1H), 7.33 (t, J = 8.8Hz, 2H) ,5.96-5.23(m,1H),4.50-4.47(m,1H),4.36-4.24(m,1H),4.17-3.62(m,2H),2.61(s,3H),1.63(d,J＝7.2Hz,3H).

Example 15 Synthesis of Compound (±)40

To a mixed solution of compound (±) 1 (500 mg, 1.40 mmol) in acetonitrile (10 mL) and dichloroethane (5 mL) was added 1-chloromethyl-4-fluoro-1,4-deoxybicyclo[2.2.2]octane di(tetrafluoroborate) (1.98 g, 5.60 mmol). The mixture was stirred at 25°C for 1 hour. After the reaction was completed, water (5 mL) was added at room temperature for quenching, and then extracted with ethyl acetate (5 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by HPLC column: Waters Xbridge 150*25mm*5μm, mobile phase: [water (ammonia hydroxide v/v)-acetonitrile], gradient: 30%-60% B, 10 min to obtain compound (±) 40 (26.67 mg, 71.05μmol, yield 26.67%, purity 96.32%). MS (ESI) m/z: 376.0 [M+H] ⁺ ; HPLC: Rt=1.877 min, purity 96.32%; ¹ H NMR (DMSO-d ₆ ,400MHz)δ7.61-7.57(m,2H),7.34-7.30(m,2H),5.47-5.39(m,1H),4.65-4.62(m,1H),4.30-4.24(m,2H),3.70-3.68(m,1H),2.66-2.57(m,3H),1.5 4(d,J＝6.8Hz,3H).

Example 16 Synthesis of Compound (±)42

1. Add diisopropylethylamine (13.84g, 107.06mmol), O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (20.35g, 53.53mmol) and methyl 2-aminopropionate (4.98g, 35.69mmol) to a dimethylformamide solution (50mL) of 4-fluorobenzoic acid (5g, 35.69mmol). The reaction solution was stirred at 25°C for 2 hours. Quenched with water (50mL), and then extracted with ethyl acetate (50mL*3). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica chromatography (petroleum ether/ethyl acetate = 7/1 to 3/1) to obtain compound 42-1 (7g, 31.08mmol, yield 87.10%). ¹ H NMR (CDCl ₃ ,400MHz) δ7.88-7.77(m,2H),7.17-7.05(m,2H),6.73(br s,1H),4.83–4.75(m,1H),3.79(d,J=2.0Hz,3H),1.59-1.46(m,3H).MS(ESI)m/z:2 26.1[M+H] ⁺ .

2. Add water (3 mL) and lithium hydroxide monohydrate (2.79 g, 66.60 mmol) to a solution of 42-1 (5 g, 22.20 mmol) in methanol (20 mL), and stir the reaction solution at 25°C for 1 hour. Adjust the reaction solution to pH = 5 with dilute hydrochloric acid (1 M) and extract with ethyl acetate (30 mL*3). Wash the organic phase with brine (30 mL*3), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 42-2 (3.5 g, 16.57 mmol, yield 74.65%). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.86-7.81 (m, 2H), 7.18-7.10 (m, 2H), 4.85–4.76 (m, 1H), 1.59 (d, J = 7.2 Hz, 3H). MS (ESI) m/z: 212.0 [M+H] ⁺ .

3. Add diisopropylethylamine (3.67 g, 28.41 mmol), O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (5.40 g, 14.21 mmol) and 2,2-dimethoxyethylamine (0.996 g, 9.47 mmol) to a solution of 42-2 (2 g, 9.47 mmol) in dimethylformamide (20 mL), and stir the mixture at 25 ° C for 1 hour. Add water (20 mL) to the mixture to quench it and extract it with ethyl acetate (20 mL*3). The organic phase was washed with brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (petroleum ether/ethyl acetate = 10/1 to 2/1) to obtain 42-3 (2 g, 6.70 mmol, yield 70.80%). ¹ H NMR (CDCl ₃ ,400MHz) δ7.85-7.79(m,2H),7.17-7.06(m,2H),6.80(brs,1H),6.17(br s,1H),4.65(t,J＝7.2Hz,1H),4.40(t,J＝5.2Hz,1H),3.50(t,J＝5.2 Hz,2H),3.40(s,6H),1.49(d,J＝6.8Hz,3H).MS(ESI)m/z:321.2[M+H] ⁺ .

4. Dissolve 42-3 (2 g, 6.70 mmol, 1 eq) in a hydrochloric acid/dioxane (1 M, 20 mL) solution and stir at 25°C for 6 hours. Concentrate the reaction solution under reduced pressure to obtain a crude product. The crude product was purified by silica chromatography (petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain compound 42-4 (0.3 g, 1.24 mmol, yield 20%, purity 97%). ¹ H NMR (CDCl ₃ , 400 MHz) δ7.61 (s, 2H), 7.16-7.09 (m, 2H), 5.93 (s, 1H), 5.70 (s, 1H), 5.19 (d, J = 3.6 Hz, 1H), 1.43 (d, J = 6.8 Hz, 3H). MS (ESI) m/z: 235.0 [M+H] ⁺ .

5. Add 42-4 (20 mg, 85.39 μmol, 1 eq) and 3-methyl-1,2,4-thiadiazole-5-carbohydrazide (13.51 mg, 85.39 μmol, 1 eq) to phosphorus oxychloride (654.6 mg, 4.27 mmol) and stir at 80°C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain compound (±) 42. MS(ESI)m/z:357.0[M+H] ⁺ . ¹ H NMR (CDCl ₃ ,400MHz) δ7.66-7.60(m,2H),7.57(d,J＝6.0Hz,1H),7.18(t,J＝8.4Hz,2H),6.69-6.41(m,1H),6.25(d,J＝6.4Hz,1 H),2.77(s,3H),1.59(d,J＝6.8Hz,3H).

Example 17 Synthesis of Compound (±)94

1. To a solution of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (compound (±) 5, 250 mg, 573 μmol) in dioxane (15 mL) were added cesium carbonate (560.08 mg, 1.72 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33.15 mg, 57.3 μmol), tris(dibenzylideneacetone)dipalladium (52.47 mg, 57.3 μmol) and methylamine hydrochloride (58.03 mg, 859.5 μmol) at room temperature. The reaction solution was replaced with nitrogen, added to a sealed tube and reacted at 100°C for 12 hours. After the reaction was completed, the reaction mixture was quenched with water (20 mL), the aqueous phase was separated and extracted with ethyl acetate (3*15 mL), the combined organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain compound (±) 39 (76.5 mg, 197.96 μmol, 34.55% yield, 95.36% purity). MS (ESI) m/z: 387.3[M+H]+; HPLC: Rt=1.364min, purity: 95.36%; ¹ H NMR (400MHz, CHLOROF ORM-d) δ7.51-7.44 (m, 2H), 7.15 (t, J=8.4Hz, 2H), 6.37 (d, J=4.4Hz, 1H), 5.67-4 .35(m,2H),4.25-4.08(m,2H),3.65-3.47(m,1H),3.11(d,J＝5.2Hz,3H),2.61(s,3H),1.67(d,J＝7.2Hz,3H).

2. At room temperature, acetic acid (310.79 mg, 5.18 mmol, 296.27 μL) and formaldehyde aqueous solution (839.98 mg, 10.35 mmol, 770.62 μL, 37% purity) were added to a solution of compound (±) 39 (400 mg, 993.67 μmol) in dichloromethane (10 mL) . After the reaction solution was stirred at room temperature for 3 hours, sodium acetate borohydride (2.19 g, 10.35 mmol, 10 eq) was added to the reaction solution. The reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, the reaction mixture was quenched with water (30 mL), the aqueous phase was separated and extracted with ethyl acetate (3*15 mL), and the organic matter was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified to obtain compound (±) 94 (61 mg, 151.25 μmol, 14.61% yield, 99.3% purity). MS (ESI) m/z: 401.1[M+H]+; HPLC: Rt＝1.322min, purity: 99.3%; 1H NMR (400MHz, CHLOROFORM-d) δ7.49-7.44(m,2H),7.14(t,J＝8.4Hz,2H),6.03-5.12(m,1H),4.94(dd,J＝ 13.6,3.2Hz,1H),4.89-4.27(m,1H),4.26-4.09(m,1H),3.55(s,1H),2.76(s,6H),2.62(s,3H),1.66(d,J＝6.8Hz,3H).

Example 18 Synthesis of Compound (±) 95

1. Pd-PEPPSI-IHEPTCl (334.44 mg, 343.80 μmol, 0.05 eq) and cesium carbonate (8.4 g, 25.78 mmol, 3.75 eq) were added to a solution of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (compound (±) 5, 3 g, 6.88 mmol, 1 eq) and pyrrolidine (1.47 g, 20.63 mmol, 1.72 mL, 3 eq) in dioxane (40 mL). Then, the mixture was heated to 105°C under nitrogen protection and stirred for 5 hours. After the reaction was completed, the reaction solution was poured into 300 mL of water and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to dryness under reduced pressure. The crude product was purified by column chromatography to obtain a light yellow solid (±) 95 (1.9 g, 4.45 mmol). MS (ESI) m/z: 427.2 [M+H] ⁺ .

2. Compound (±) 95 (2.4 g, 5.42 mmol, 1 eq) was separated and purified by SFC (column model: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: A phase carbon dioxide-B phase isopropanol (0.1% ammonia water)-gradient: 25% B). The fraction was dried by spin drying to obtain two products. Peak 1 was dissolved in methanol (20 mL) and 4M hydrochloric acid dioxane solution (20 mL), and then dried by spin drying and freeze drying to obtain white solid 95A (804 mg, 1.89 mmol, 27.42% yield, 98.58% purity). MS (ESI) m/z: 427.2 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d4) δ7.71-7.54(m,2H),7.27(t,J＝8.7Hz,2H),6.10-5.54(m,1H),4.68(br dd,J＝3.1,13.3Hz,1H),4.39-4.01(m,2H),3.81(br s,1H) ,3.47-3.32(m,4H),2.66(s,3H),2.15-2.00(m,4H),1.76(d,J=6.9Hz,3H). RT=1.603min, ee%=98.7%. Peak 2 was dissolved in methanol (20 mL) and 4M hydrochloric acid dioxane solution (20 mL), spin-dried and lyophilized to obtain white solid 95B (829 mg, 1.94 mmol, 28.27% yield, 98.13% purity). MS (ESI) m/z: 427.2 [M+H] ⁺ . ¹ H NMR (400MHz, METHANOL-d ₄ ) δ7.71-7.54(m,2H),7.27(t,J＝8.7Hz,2H),6.10-5.54(m,1H),4.68(br dd,J＝3.1,13.3Hz,1H),4.39-4.01(m,2H),3.81(br s,1H ),3.47-3.32(m,4H),2.66(s,3H),2.15-2.00(m,4H),1.76(d,J＝6.9Hz,3H). RT=1.821min, ee%=97%.

Example 19 Synthesis of Compound (±)96

1. To a solution of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (1.5 g, 3.44 mmol) in dioxane (15 mL) was added (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium (334.44 mg, 343.80 μmol), 3,3-difluoropyrrolidine hydrochloride (740.35 mg, 5.16 mmol) and cesium carbonate (3.36 g, 10.31 mmol) at 25°C. The system was heated to an external temperature of 106°C and stirred for 12 hours under nitrogen protection. After the reaction was completed, the reaction mixture was cooled to 25°C and quenched with water (5 mL), then diluted with ethyl acetate (5 mL), extracted with ethyl acetate (5 mL×3), the combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was slurried with acetonitrile (10 mL) for 3 min and filtered to collect the filter cake to obtain a yellow solid (±) 96 (1.38 g, 2.74 mmol, yield 79.66%, purity 99.02%)]. MS (ESI) m/z: 463.1 [M+H] ⁺ .

2. Compound (±) 96 (2.01 g, 4.34 mmol) was subjected to chiral separation (column: (S, S) whelk-01 (250 mm*30 mm, 10 um), mobile phase: [A phase carbon dioxide-B phase isopropanol (0.1% ammonia water), B%: 52%, isobaric elution mode) to obtain two chiral single products. Peak 1 (600 mg) was dissolved in methanol (1 mL) and dioxane hydrochloride (2 M, 5 mL), and the solvent was removed by vortexing, and distilled water (50 mL) was added and freeze-dried to obtain yellow solid 96A (555.64 mg, 1.10 mmol, 83.15% yield, 98.97% purity). MS (ESI) m/z: 463.2 [M+H] ⁺ . ¹ H NMR (400MHz,CDCl ₃ )δ7.50-7.47(m,2H),7.18-7.14(m,2H),5.72-4.45(m,3H),4.40-4.16(m,1H),3.73-3.40(m,5H),2.81-2.55(m,3H),2.55-2.44(m,2H),1.80-1.72(m,3H).RT＝2.137min,ee％＝99.68%.Peak 2 (762.96mg) was dissolved in methanol (1mL) and dioxane hydrochloride (2M,5mL), the solvent was removed by vortexing, distilled water (50mL) was added and freeze-dried to give yellow solid 96B (762.96mg, 1.52mmol, 81.92%, purity 99.15%). MS(ESI)m/z:463.2[M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.49(s,2H),7.16(t,J=7.6Hz,2H),5.65(br s,1H),4.90-4.87(m,1H),4.58(s,1H),4.26(s,1H),3.70-3.56(m,5H),2.66(s,3H),2.55-2.48(m,2H ),1.79(s,3H). RT=2.363min,ee%=97.92%.

Example 20 Synthesis of Compound (±) 97

1. At room temperature, cesium carbonate (448.07 mg, 1.38 mmol, 3 eq.) and Pd-PEPPSI-IHEPTCl (38.51 mg, 45.84 μmol, 0.1 eq.) were added to a solution of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (compound (±) 5, 200 mg, 458.40 μmol, 1 eq.) and (3S,4S)-3,4-difluoropyrrolidine hydrochloride (197.43 mg, 1.38 mmol, 3 eq.) in dioxane (4 mL). The reaction solution was purged with nitrogen three times and then heated to 100°C for 12 hours. After the reaction, the mixture was cooled to room temperature, filtered under reduced pressure, extracted and concentrated, and purified by reverse phase chromatography (column model: Phenomenex luna C18 (150*25mm, 10um); mobile phase: [water(HCl)-ACN]; gradient: 33%-63% B over 10min) to obtain a light yellow solid (±) 97 (98 mg, 195.62 μmol, 36.19% yield, 99.598% purity). MS (ESI) m/z: 463.2 [M+H] ⁺ .

2. Compound (±)97 (98 mg) was separated and purified by SFC (column model: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [CO ₂ -MeOH]; gradient: 48% MeOH) to obtain compound 97A (peak 1) (16 mg, 31.07 μmol, light yellow solid) MS (ESI) m/z: 463.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ,400MHz) δ7.65-7.58(m,2H),7.37-7.26(m,2H),5.49(d,J＝9.2Hz,1H),5.41-5.32(m,1H),5.30-4.68(m,1H),4.63(d,J＝12.4Hz,1H), 4.29-4.15(m,1H),4.13-3.91(m,1H),3.90-3.72(m,2H),3.72-3.56(m,1H),3.36(d,J＝12.4Hz,1H),3.28(br s,1H),2.56(s,3H),1.55(d,J＝6.8Hz,3H) . 1.305 min, de% = 100.00%. Compound 97B (peak 2) (42 mg, 84.18 μmol, light yellow solid). MS (ESI) m/z: 463.2 [M+H] ⁺ . ¹ H NMR (DMSO-d ₆ ,400MHz) δ7.60-7.57(m,2H),7.34-7.29(m,2H),5.51-5.49(m,1H),5.41-5.32(m,1H),5.30-4.68(m,1H),4.63(d,J＝12.4Hz,1H),4. 29-4.15(m,1H),4.13-3.91(m,1H),3.90-3.72(m,3H),3.36-3.28(m,2H),2.56(s,3H),1.55(d,J＝6.8Hz,3H). 1.519min,de%=100.00%.

Example 21 Synthesis of Compound (±)98

1. At room temperature, add Pd-PEPPSI-IHEPTCl (577.68 mg, 687.6 μmol) and cesium carbonate (6.72 g, 20.63 mmol) to a dioxane solution (50 mL) of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (compound (±) 5, 3 g, 6.88 mmol) and (S)-3-methylpyrrolidine hydrochloride (2.17 g, 13.75 mmol). After the reaction solution was replaced with nitrogen, the temperature was raised to 100°C and the reaction was carried out for 12 hours. After the reaction was completed, the reaction solution was cooled to room temperature and diluted with 100 mL of water and extracted with 50 mL of ethyl acetate. The combined organic phase was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1-1/1) to obtain compound (±) 98 (2 g, 4.51 mmol, yield 66%, purity 99%). MS (ESI) m/z: 441.1 [M+H] ⁺ .

2. A total of 2 g of compound (±) 98 was subjected to SFC separation and purification (column model: Daicel chiralcel OX; mobile phase: A phase carbon dioxide-B phase methanol (0.1% ammonia water); gradient: 35% B). Peak 1 obtained by separation and concentration under reduced pressure was dissolved in 30 ml of acetonitrile, 80 ml of 0.1% hydrochloric acid aqueous solution was added, and the acetonitrile was removed by concentrated under reduced pressure and the remaining aqueous phase was lyophilized to obtain 98A (peak 1) (956.9 mg, 2.0 mmol). MS (ESI) m/z: 441.1 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.61-7.57(m,2H),7.35-7.29(m,2H),5.51(br s,1H),4.62(d,J＝12.4Hz,1H),4.23-4.17(m,2H),3.67-3.64(m,1H),3.32-3.1 5(m,3H)2.87(t,J=8.4Hz,1H),2.56(s,3H),2.37-2.30(m,1H),2.17-2.07(m,1H),1.60-1.45(m,4H),1.08(d,J=6.8Hz,3H). RT=0.938min, ee%=100%. Peak 2 obtained by separation and concentration under reduced pressure was dissolved in 30 ml of acetonitrile, 80 ml of 0.1% hydrochloric acid aqueous solution was added, the acetonitrile was removed by concentration under reduced pressure, and the remaining aqueous phase was lyophilized to obtain 98B (peak 2) (913.3 mg, 1.9 mmol). MS (ESI) m/z: 441.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.61-7.56(m,2H),7.36-7.29(m,2H),5.51(br s,1H),4.62(d,J=12.4Hz,1H),4.24-4.12(m,1H),3.91(s,1H),3.66(s,1H),3. 32-3.20(m,3H),2.82-2.78(m,1H),2.54(s,3H),2.38-2.28(m,1H),2.14-2.02(m,1H),1.59-1.46(m,4H),1.08(d,J＝6.8Hz,3H).RT＝1.409min,ee%＝99.0 96%.

Example 22 Synthesis of Compound (±) 99

1. At room temperature, Pd-PEPPSI-IHEPTCl (673.96 mg, 802.20 μmol) and cesium carbonate (7.84 g, 24.07 mmol) were added to a dioxane solution (80 mL) of (2-bromo-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (compound (±) 5, 3.5 g, 8.02 mmol) and (R)-3-methylpyrrolidine hydrochloride (1.95 g, 16.04 mmol). The reaction solution was replaced with nitrogen and heated to 100°C for 12 hours. After the reaction, the reaction solution was diluted with 100 ml of water, extracted three times with 50 ml of ethyl acetate, and the combined organic phase was washed with 100 ml of saturated brine, dried over anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain a crude product. The crude product was purified by column chromatography (SiO2, petroleum ether/ethyl acetate = 10/1-1/1) to obtain compound (±) 99 (2.5 g, 5.66 mmol, yield 70%, purity 99%). MS (ESI) m/z: 441.2 [M+H] ⁺ .

2. Compound (±) 99 (2.5 g) was subjected to SFC separation and purification (column model: Daicel chiral pka AD; mobile phase: A phase carbon dioxide-B Phase ethanol (0.1% ammonia water); gradient: 20% B). Peak 1 obtained by separation and concentration under reduced pressure was dissolved in 30 ml of acetonitrile, 80 ml of 0.1% hydrochloric acid aqueous solution was added, and the acetonitrile was removed by concentration under reduced pressure and the remaining aqueous phase was lyophilized to obtain 99A (980.7 mg, 2.04 mmol). MS (ESI) m/z: 441.2 [M+H] ⁺ . ^1. 33-3.20(m,3H),2.82-2.78(m,1H),2.54(s,3H),2.38-2.29(m _, 1H),2.13-2.05(m,1H),1.60-1.45(m,4H),1.07(d,J＝6.8Hz,3H). RT=1.424min,ee%=100%. Peak 2 was separated and concentrated under reduced pressure and dissolved in 30 ml of acetonitrile, 80 ml of 0.1% hydrochloric acid solution was added, the acetonitrile was removed and concentrated under reduced pressure, and the remaining aqueous phase was lyophilized to obtain 99B (986 mg, 2.04 mmol). MS (ESI) m/z: 441.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.61-7.56(m,2H),7.36-7.29(m,2H),5.51(br s,1H),4.62(d,J＝12.4Hz,1H),4.19-4.17(m,1H),3.98-3.83(m,2H),3.32-3.2 0(m,3H),2.87(t,J＝8.0Hz,1H),2.54(s,3H),2.38-2.28(m,1H),2.14-2.02(m,1H),1.59-1.46(m,4H),1.08(d,J＝6.8Hz,3H). RT=1.649min,ee%=98.382%.

Example 23 Synthesis of Compound (±) 100

Cesium carbonate (2.06 g, 6.32 mmol, 3 eq), 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine hydrochloride (447.84 mg, 2.31 mmol, 1.1 eq, HCl) and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ether; 3-chloropyridine; dichloropalladium (205.12 mg, 210.88 μmol, 0.1 eq) were added to a dioxane solution (20 mL) of compound (±) 5 (920 mg, 2.11 mmol, 1 eq) at 25°C. The mixture was stirred at 115°C for 12 hours. The reaction mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was diluted with water (50 mL) and extracted with dichloromethane (60 mL×2). The organic phase was concentrated under reduced pressure to obtain a crude product. The yellow solid (±)100 (0.1 g, 203.14 μmol, yield 9.63%, purity 96.6%) was obtained by HPLC purification. MS (ESI) m/z: 476.3 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl3) δ8.50 (d, J = 4.8Hz, 1H), 7.66–7.58 (m, 1H), 7.52-7.47 (m, 2H), 7.25-7.22 (m, 1H), 7.19–7.13 (m, 2H), 5.63–5.43 (m, 1H), 4.91–4. 56(m,5H),4.28–3.96(m,2H),3.64–3.49(m,1H),2.66(s,3H),1.68(d,J＝6.8Hz,3H).

2. Perform chiral separation on compound (±)100 (column model: (s,s) 1 (250mm*30mm, 10um); mobile phase: CO ₂ -ACN/i-PrOH (0.1% NH ₃ H ₂ O); gradient: 50%-50% B over 3.6min) after separation, the solvent was spin-dried and diluted with 0.1% hydrochloric acid aqueous solution: acetonitrile (1:1.5). Finally, compound 100A (R)-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)(4-fluorophenyl)methanone (0.956 g, 1.87 mmol, yield 33.38%, purity 100%, HCl) was obtained by freeze drying. MS(ESI)m/z:476.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (d, J = 4.8 Hz, 1H), 7.82 (br d, J = 7.6 Hz, 1H), 7.65-7.56 (m, 2H), 7.38-7.28 (m, 3H), 5.83-5.24 (m, 1H), 4.78-4.51 (m, 5H), 4.32-4.13(m,1H),4.06-3.78(m,1H),3.52-3.18(m,1H),2.59(s,3H),1.57(d,J＝6.4Hz,3H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-110.61. RT=1.788 min, ee%=92.324%. Compound 100B (S)-(2-(5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone (0.874 g, 1.66 mmol, yield 29.75%, purity 97.47%, HCl). MS (ESI) m/z: 476.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.51 (br d, J = 4.4Hz, 1H), 7.87 (d, J = 7.6Hz, 1H), 7.68-7.53 (m, 2H), 7.44-7.26 (m, 3H), 5.87-5.05 (m, ^1H ), 4.80-4.55 (m, 5H ₎ " %.

Experimental Example 1. In vitro antagonistic activity screening - in vitro affinity and antagonistic activity testing of NK3 receptor

1. NK3 receptor affinity test

48 μL of reaction buffer (50 mM Tris, 10 mM magnesium chloride, 0.1% bovine serum albumin) and 2 μL of diluted positive control compound Fezolinetant (MCE) or test compound (0.5 nM-1000 nM, 10 final concentrations of 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51 nM) were added to each well of a 96-deep-well plate, and the mixture was shaken at 600 rpm/min for 5 min. 100 μL of a mixture of a membrane target system (neurokinin NK3 (human) membrane prepared in CHO-K1 cells, Perkin Elmer) and reaction buffer was added to each well, and the mixture was shaken at 600 rpm/min for 5 min. Add 50 μL of isotope [ ³ H]-SB-222200 (ART) with a final concentration of 0.8 μM/mL to each well, centrifuge at low speed for 5 seconds, shake at 600 rpm/min for 5 minutes, and incubate at 27°C for 2 hours. Add 150 μL of 0.5% bovine serum albumin to each well of UNIFILTER-96GF/C plate (PerkinElmer) for pre-incubation and incubate at 4°C for 1 hour. Wash the pre-incubated UNIFILTER-96GF/C plate twice with a cell harvester. Transfer the reaction system in the deep-well plate to the UNIFILTER-96GF/C plate with a cell harvester, and then wash the UNIFILTER-96GF/C plate 4 times with washing solution. Place the washed UNIFILTER-96GF/C plate in a 55°C oven and dry for 10 minutes. 40 μL of Lutima Gold (Perkin Elmer, Cat. No. 77-16061) was added to each well of the UNIFILTER-96 GF/C plate, and the reading was performed using a Microbeta2 instrument (Perkin Elmer). The inhibition rate was calculated, and the data were processed using XLfit 5.3.1.3 software, and the IC ₅₀ value of the compound was obtained using a nonlinear fitting formula. The experimental results are shown in Table 1, and the affinity IC ₅₀ value of the compound of the present invention for the NK3 receptor is less than 500 nM.

Inhibition rate % = (negative control average - CPM) / (negative control average - positive control average) * 100

2. Effects on intracellular calcium flux in cells stably expressing hNK3 receptor

Flp In-293-NK3Stable Pool cell line (Pharmaron) was cultured in complete medium (DMEM, High Glucose + 10% FBS + 2mM GlutaMAX + 1×PS + 200μg/ml Hygromycin B) to 70% to 90% confluence. The cells were digested and resuspended in cell seeding medium (DMEM, High Glucose + 10% FBS + 2mM GlutaMAX), and 12,000 cells/well/25μL were inoculated into 384-well cell culture plates and cultured at 37°C, 5% CO ₂ for 22h. Freeze-thaw 20× FLIPR Calcium 6 Kit Component A to room temperature and dilute it to 2× working concentration with assay buffer (1×HBSS + 20mM HEPES). The cell culture plate was equilibrated at room temperature for 10 min, the culture medium was removed, 20 μL of experimental buffer and 20 μL of 2×Component A were added, and the mixture was centrifuged at 200 g for 3-5 s at room temperature and then allowed to stand at 37°C for 2 h. The positive control compound Fezolinetant (MCE) and the working solution of the compound to be tested (6×) were prepared. Neurokinin B TFA was diluted to 3.75 nM (6×) with the experimental buffer, and 50 μL was transferred to a 384-well plate (Corning, 3657). The cell culture plate was removed and allowed to stand at room temperature for 10 min, and 10 μL of the 6× compound working solution (10 final concentrations were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52, 0.51 nM) was added to the corresponding experimental wells of the 384-well cell culture plate and incubated at room temperature for 30 min. 10 μL of diluted Neurokinin B TFA was added to the corresponding experimental wells using FLIPR Tetra (Molecular Devices) to read the calcium signal. Data was collected once every 1 second. Under the irradiation of 470-495 nm excitation light, the corresponding fluorescence emission signal was captured at 515-575 nm. The total acquisition time was 3 minutes, and the output result was the maximum signal value. The IC ₅₀ of the compound was calculated using the GraphPad nonlinear fitting formula: Y=Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope)), X: log value of compound concentration, Y: agonist rate % or inhibitory rate %. The experimental results are shown in Table 1. The IC ₅₀ value of the antagonist activity of the compound of the present invention on NK3 receptor is less than 1000 nM.

Table 1 Affinity and antagonistic activity of the compounds of the present invention to hNK3 receptor

Experimental Example 2 Study on tissue distribution in rats

Rats: SD rats, male, weighing about 220 g.

Instruments: water purifier, Millipore; electronic balance, Mettler Toledo; high-speed desktop centrifuge, Thermo; water bath constant temperature oscillator, Shanghai Yiheng Technology Co., Ltd.; vortex oscillator, Thermo; LC-MS/MS, AB SCIEX.

method:

Tissue distribution test: Fezolinetant and test compound administration groups, 9 SD rats were randomly divided into 3 groups, 3 rats in each group, and fasted for 12 hours before administration. 5 mg/kg dose was administered by gavage, and 3 rats were taken at 0.5h, 2h, and 8h after administration. After cardiac perfusion with chloral hydrate anesthesia, plasma and whole brain tissue were collected. After pretreatment, plasma and tissue samples were used for LC-MS/MS to determine the concentration of compounds in each tissue sample. The test results are shown in Table 2.

Table 2 Tissue distribution of SD rats after intragastric administration

Conclusion: Compared with Fezolinetant, the drug concentration of the compound of the present invention in the target organ brain is higher than that of Fezolinetant, and it has better brain penetration ability.

Claims (12)

The compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,
in: (1) X ₁ is independently selected from N, and X ₂ is independently selected from CR ₃ ; are independently selected from single bonds or double bonds; When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S; Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl; R ₂ is selected from H, or C ₁ -C ₃ alkyl; R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl; Each R _3c is selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O); R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl; n is selected from 0, 1, 2, 3; or (2) X ₁ is independently selected from CR ₃ , and X ₂ is independently selected from N; are independently selected from double bonds; When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S; Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl; R ₂ is selected from H, or C ₁ -C ₃ alkyl; R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl; Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O); R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl; n is selected from 0, 1, 2, 3; or (3) _X1 is independently selected from N, and _X2 is independently selected from N; are independently selected from double bonds; When X ₃ is selected from S, X ₄ is selected from CH or N, or when X ₃ is selected from CH, X ₄ is selected from S; Each R ₁ is independently selected from H, halogen, 6-10 membered aryl, or 5-6 membered heteroaryl, wherein the 6-10 membered aryl is optionally substituted with 1, 2, or 3 halogens; Or two adjacent R ₁ together with the C atom to which they are attached form a 5-6 membered heteroaryl group; R ₂ is selected from H, or C ₁ -C ₃ alkyl; R ₄ is selected from H, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl or C ₃ -C ₆ cycloalkyl; n is selected from 0, 1, 2, 3. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, wherein the structural formula of the compound is as shown in formula (II),
in, are independently selected from single bonds or double bonds; Each R ₁ is independently selected from H, halogen, or 5-6 membered heteroaryl; R ₂ is selected from H, or C ₁ -C ₃ alkyl; R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; Each R _3a and R _3b is independently selected from H, or C ₁ -C ₃ alkyl; Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O); R ₄ is selected from H, or C ₁ -C ₃ alkyl; n is selected from 0, 1, 2, 3. The compound according to claim 2, its pharmaceutically acceptable salt or stereoisomer, wherein the structural formula of the compound is as shown in Formula (IIA),
in, are independently selected from a single bond or a double bond; R _1a is selected from H, halogen, or 5-6 membered heteroaryl; R _1b is selected from H, or halogen; R ₃ is selected from H, halogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, wherein the 5-6 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl is optionally substituted by 1, 2, 3/4, or 5 R _3c ; R _3a and R _3b are each independently selected from H, or C ₁ -C ₃ alkyl; Each R _3c is independently selected from H, halogen, C ₁ -C ₃ alkyl, OH, or oxo (═O); R ₄ is selected from H, or C ₁ -C ₃ alkyl. The compound according to claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, wherein the _R2 is selected from H or methyl. The compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 4, wherein the R ₁ is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl; the R _1a is selected from H, F, Cl, Br, I, pyrrolyl, or thienyl; and the R _1b is selected from H, F, or Cl. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R ₃ is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, 1-propynyl, 2-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridinyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl, -C(O)R _3a , -COOR _3a , -CON(R _3b ) ₂ , -N(R _3b ) ₂ , -SO ₂ N(R _3b ) ₂ , or cyano, the pyrrolidinyl, piperazinyl, morpholinyl, phenyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, thiazolyl, pyridyl, isoindolyl, 6,7-dihydro-5H-pyrrolo[3,4-b]pyridinyl is optionally substituted by 1, 2, 3, 4, or 5 R _3c ; the R _3a and R _3b are each independently selected from H, methyl, ethyl, n-propyl, or isopropyl; each R _3c is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, OH, or oxo (＝O). The compound, pharmaceutically acceptable salt or stereoisomer thereof according to any one of claims 1 to 6, wherein R ₄ is selected from H, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, or cyclopropyl. The following compounds, pharmaceutically acceptable salts or stereoisomers thereof, are selected from:


A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 8, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 9 in the preparation of a drug for preventing or treating a disease related to the activity or expression of NK-3 receptor. According to the use of claim 10, the diseases related to the activity or expression of NK-3 receptors include: depression, anxiety, psychosis, schizophrenia, psychotic disorders, bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), pain, convulsions, obesity, inflammatory diseases, vomiting, preeclampsia, airway-related diseases, urinary incontinence, reproductive disorders, contraception and sex hormone-dependent diseases, vasomotor symptoms. According to the use according to claim 11, the inflammatory diseases include irritable bowel syndrome (IBS) and inflammatory bowel disease; the airway-related diseases include chronic obstructive pulmonary disease, asthma, airway hyperresponsiveness, bronchoconstriction and cough; the contraceptive and sex hormone-dependent diseases include benign prostatic hyperplasia (BPH), prostatic hyperplasia, metastatic prostate cancer, testicular cancer, breast cancer, ovarian cancer, androgen-dependent acne, male pattern baldness, endometriosis, puberty abnormalities, uterine fibrosis, uterine fibroids, uterine leiomyoma, hormone-dependent cancer, hyperandrogenemia, hirsutism, virilization, polycystic ovary syndrome (PCOS), premenstrual dysphoric disorder (PMDD), HAIR-AN syndrome, ovarian theca cell hyperplasia (HAIR-AN with luteinized theca cell hyperplasia in ovarian stroma), other manifestations of high ovarian androgen concentrations, androgen-producing tumors, menorrhagia and adenomyosis; the vasomotor symptoms include menopausal hot flashes, hot flashes and night sweats.