CN111333587B - Substituted pyrimidine-2, 4 (1H, 3H) -dione derivatives and uses thereof - Google Patents

Abstract

The invention belongs to the technical field of medicaments, and relates to substituted pyrimidine-2, 4 (1H, 3H) -diketone derivatives, application thereof and a pharmaceutical composition containing the compounds, which can be used as gonadotropin releasing hormone receptor antagonists. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the prevention or treatment of sex hormone dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, precocious puberty, and the like.

Description

Substituted pyrimidine-2,4(1H,3H)-dione derivatives and uses thereof

Technical Field

The present invention belongs to the field of pharmaceutical technology, and relates to compounds and pharmaceutical compositions for preventing or treating sex hormone-dependent diseases, and methods and uses thereof. In particular, the present invention discloses substituted pyrimidine-2,4(1H,3H)-dione derivatives that can be used as gonadotropin-releasing hormone receptor antagonists and uses thereof.

Background Art

The secretion of anterior pituitary hormones is feedback controlled by peripheral hormones secreted from the target organs of the corresponding hormones and by secretion-regulatory hormones from the hypothalamus (which is the upper central organ of the anterior pituitary) (hereinafter, in the specification, these hormones are collectively referred to as "hypothalamic hormones"). At present, it has been confirmed that there are nine hormones as hypothalamic hormones, including, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone (GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)). These hypothalamic hormones are believed to express their effects through receptors, and these receptors are believed to exist in the anterior pituitary; and efforts have been made to find receptor-gene expressions specific to these hormones, including in humans. Therefore, antagonists or agonists that specifically and selectively act on these receptors should control the effects of hypothalamic hormones and the secretion of anterior pituitary hormones. Therefore, such antagonists or agonists are expected to prevent or treat anterior pituitary hormone-dependent diseases.

Currently known compounds with GnRH antagonist activity are mostly peptide compounds, for example, GnRH-derived linear peptides (US 5,140,009 and US 5,171,835), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273 (1993)), 5- or 6-position modified decapeptide compounds (WO9846634A1) and 8-position modified decapeptide compounds (EP 0277829B1), etc.

There are many problems to be solved for peptide compounds, which are related to oral absorbability, dosage form, dosage volume, drug stability, sustained action and metabolic stability, etc. Therefore, there is a strong need for oral GnRH antagonists, especially antagonists based on non-peptide compounds, which have excellent therapeutic effects on sex hormone-dependent diseases such as prostate cancer, endometriosis, precocious puberty, etc., and which antagonists not only show transient pituitary-gonadotropin action (acute action) but also have excellent oral absorbability.

Summary of the invention

The following is a summary of some aspects of the present invention, which are not limited thereto. These aspects and other parts are described in more detail below. All references in this specification are incorporated herein by reference in their entirety. When there is a discrepancy between the disclosure of this specification and the referenced documents, the disclosure of this specification shall prevail.

The present invention relates to a class of novel substituted pyrimidine-2,4(1H,3H)-dione derivatives, which have unexpectedly excellent GnRH antagonistic activity and can be used as gonadotropin-releasing hormone receptor antagonists, thereby being used to prevent or treat sex hormone-dependent diseases, including but not limited to prostate cancer, endometriosis, uterine fibroids, precocious puberty, etc.

The compounds of the present invention are stable in nature, have good safety, and have pharmacodynamic and pharmacokinetic advantages, such as a good brain/plasma ratio, good bioavailability or good metabolic stability, and therefore have good prospects for clinical application.

The present invention also provides methods for preparing the compounds and pharmaceutical compositions containing the compounds.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (I),

Wherein, ^R1a , ^R1b , ^R1c , ^R1d , ^R1e , ^R2a , ^R2b , ^R3a , R3b, ^R3c , ^R3d , ^R3e , ^R4 , ^R5a , ^R5b , ^R5c , ^R5d and R have the ^same meanings as described in the present invention.

In some embodiments, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(＝O)NH ₂ , -C(＝O)NHCH ₃ , -C(＝O)N(CH ₃ ) ₂ , -C(＝O)-(C ₁ -C ₆ alkyl), -C(＝O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, or C ₁ -C ₆ alkyl substituted with hydroxy.

In some embodiments, each R ^2a and R ^2b is independently H, D, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, or C ₁ -C ₆ haloalkyl.

In some embodiments, each of R ^3a , R ^3b , R ^3c , R ^3d and R ^3e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₆ alkyl), -C(=O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkoxy, C ₁ -C ₆ alkylthio, C _{1 -C 6 alkylamino, C 1 -C 6 alkyl substituted} with hydroxy, C ₃ -C 6 C ₆ cycloalkyl, heterocyclic group consisting of 3-8 atoms, C _6- C ₁₀ aryl or heteroaryl consisting of 5-10 atoms.

In some embodiments, R ⁴ is H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₆ alkyl), -C(=O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C _{1 -C 6 alkoxy, C 1 -C 6 haloalkoxy} , C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, or C ₁ -C ₆ alkyl substituted with hydroxy.

In some embodiments, each of R ^5a , R ^5b , R ^5c and R ^5d is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₆ alkyl), -C(=O)-(C ₁ -C ₆ alkoxy), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C ₁ -C _{6 alkoxy, C 1 -C 6 haloalkoxy ,} C 1 -C ₆ alkylthio, C ₁ -C ₆ alkylamino, C _{1 -C 6} alkyl substituted with hydroxy, C _{3 -C} 6 ₆ -cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a C _6- C ₁₀ aryl or a heteroaryl consisting of 5-10 atoms.

其中X、y和z具有如本发明所述的含义。In some embodiments, R is -C ₁ -C ₆ alkylene-C(=O)NH ₂ , -C ₁ -C ₆ alkylene-C(=O)NHCH ₃ , -C ₁ -C ₆ alkylene-C(=O)N(CH ₃ ) ₂ , -C ₁ -C ₆ alkylene-C(=O)-(C ₁ -C ₆ alkyl), -C ₁ -C ₆ alkylene-C(=O)-(C ₁ -C ₆ alkoxy), -C ₁ -C ₆ alkylene-S(=O) ₂ NH ₂ , -C ₁ -C ₆ alkylene-S(=O) ₂ NHCH ₃ , -C ₁ -C ₆ alkylene-S(=O) ₂ N(CH ₃ ) ₂ , -C ₁ -C ₆ alkylene-S(=O) _2- (C ₁ -C ₆ alkyl) or

wherein X, y and z have the meanings as defined in the present invention.

In some embodiments, X is -O-, -S-, -C(=O)-, -S(=O) ₂ -, -CH ₂ -, or -NR ⁿ -; wherein R ⁿ has the meaning as described herein.

In some embodiments, ^Rn is H, D, _C1-6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C1 - _C6 haloalkyl, C1- _C6 alkoxy, C1 _- C6 haloalkoxy, _C1 - _C6 alkylthio, C1 _{- C6} alkylamino, _{C1 - C6 alkyl} substituted with hydroxy, _C3-6 cycloalkyl, heterocyclyl consisting of 3-8 atoms, C6-10 aryl, heteroaryl consisting of _5-10 atoms, -C(=O)-( _C1 - _C6 alkyl), -C(=O)-( _C3 - _C6 cycloalkyl), -C(=O)-(heterocyclyl consisting of 3-8 atoms), -S(=O) _2- ( _C1 - _C6 alkyl), -S(=O) _2- ( _C3 - _C6 cycloalkyl), or -S(=O) ₂ -(heterocyclic group consisting of 3 to 8 atoms).

In some embodiments, y is 0, 1, 2, or 3.

In some embodiments, z is 1, 2, or 3.

其中X、y和z具有如本发明所述的含义。In some embodiments, R is -C ₁ -C ₄ alkylene-C(=O)NH ₂ , -C ₁ -C ₄ alkylene-C(=O)NHCH ₃ , -C ₁ -C ₄ alkylene-C(=O)N(CH ₃ ) ₂ , -C ₁ -C ₄ alkylene-C(=O)-(C ₁ -C ₄ alkyl), -C ₁ -C ₄ alkylene-C(=O)-(C ₁ -C ₄ alkoxy), -C ₁ -C ₄ alkylene-S(=O) ₂ NH ₂ , -C ₁ -C ₄ alkylene-S(=O) ₂ NHCH ₃ , -C ₁ -C ₄ alkylene-S(=O) ₂ N(CH ₃ ) ₂ , -C ₁ -C ₄ alkylene-S(=O) ₂ -(C ₁ -C ₄ alkyl) or

wherein X, y and z have the meanings as defined in the present invention.

In some embodiments, X is -O-, -S-, or ^-NRn- ; wherein Rn has the meaning as described herein.

In some embodiments, ^Rn is H, D, _C1-4 alkyl, _C2 - _C4 alkenyl, _C2 - _C4 alkynyl, _C1 - _C4 haloalkyl, -C(＝O)-( _C1 - _C4 alkyl), -C(＝O)-( _C3 - _C6 cycloalkyl), -C(＝O)-(heterocyclyl consisting of 3-6 atoms), -S(＝O) _2- ( _C1 - _C4 alkyl), -S(＝O) _2- ( _C3 - _C6 cycloalkyl), or -S(＝O) _2- (heterocyclyl consisting of 3-6 atoms).

In other embodiments, R is

In some embodiments, each R ^2a and R ^2b is independently H, D, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, or C ₁ -C ₄ haloalkyl.

In other embodiments, each ^R2a and ^R2b is independently H, D, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl _, propynyl _, -CHF2, _{-CF3 , -CHFCH2F} , _{-CF2CHF2 , -CH2CF3 ,} or _-CH2CF2CHF2 .

In some embodiments, each of R ^3a , R ^3b , R ^3c , R ^3d and R ^3e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₁ -C ₄ alkoxy), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₆ alkylamino, C ₁ -C 4 alkyl substituted with hydroxy, C ₃ -C ₄ alkoxy, _C6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, C6 _{- C10} aryl or heteroaryl consisting of 5-10 atoms.

In other embodiments, each of R ^3a , R ^3b , R ^3c , R ^3d and R ^3e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-OCH ₃ , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ , -OCF 2 ₃ , _-OCHFCH2F , -OCF2CHF2 _{, -OCH2CF3} , -OCH2CF2CHF2, methylthio _, ethylthio _, methylamino, dimethylamino, ethylamino, hydroxymethyl, _{2 -} hydroxyethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, _piperidinyl , piperazinyl, morpholinyl, phenyl, _indenyl , naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In some embodiments, ^R4 is H, D, F, Cl, Br, I, -CN, _-NO2 , _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-( _C1 - _C4 alkyl), -C(=O)-( _C1 - _{C4 alkoxy), C1 - C4} alkyl, C2 _{- C4} alkenyl, _C2 - _C4 alkynyl, C1- _{C4 haloalkyl, C1-C4 alkoxy ,} C1 _{- C4} haloalkoxy, C1 _{- C4} alkylthio, _C1 - _C4 alkylamino, or _C1 - _C4 alkyl substituted with hydroxy.

In other embodiments, ^R4 is H, D, F, Cl, Br, I, _-CN , -NO2, _-NH2 , -OH, -SH, -COOH, -C(=O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , _-C (=O) _-CH3 , -C(=O _{) -OCH3} , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl _, -CHF2, -CF3 _{, -CHFCH2F} , -CF2CHF2, -CH2CF3, _-CH2CF2CHF2 , methoxy, _ethoxy , _n - _{propyloxy , isopropyloxy} , _-OCHF2 , _-OCF3 , -OCHFCH2F, _-OCF2CHF2 , _{-OCH 2} CF ₃ , -OCH ₂ CF ₂ CHF ₂ , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl.

In some embodiments, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(＝O)NH ₂ , -C(＝O)NHCH ₃ , -C(＝O)N(CH ₃ ) ₂ , -C(＝O)-(C _{1 -C} alkyl), -C(＝O)-(C _{1 -C} alkoxy), C ₁ -C alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylamino, or C _{1 -C 4 alkyl} substituted with hydroxy.

In other embodiments, each of R ^1a , R ^1b , R ^1c , R ^1d and R ^1e is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-CH ₃ , -C(=O)-OCH ₃ , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF ₂ , -CF ₃ , -CHFCH ₂ F, -CF ₂ CHF ₂ , -CH ₂ CF ₃ , -CH ₂ CF ₂ CHF ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, -OCHF ₂ , -OCF 2 _3. -OCHFCH ₂ F, -OCF ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CF ₂ CHF ₂ , methylthio, ethylthio, methylamino, dimethylamino, ethylamino, hydroxymethyl or 2-hydroxyethyl.

In some embodiments, each of R ^5a , R ^5b , R ^5c and R ^5d is independently H, D, F, Cl, Br, I, -CN, -NO ₂ , -NH ₂ , -OH, -SH, -COOH, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -C(=O)N(CH ₃ ) ₂ , -C(=O)-(C ₁ -C ₄ alkyl), -C(=O)-(C ₁ -C ₄ alkoxy), C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C 1 -C ₄ alkylthio, C ₁ -C ₄ alkylamino, C _{1 -C 4} alkyl substituted with hydroxy, C _{3 -C} 4 ₆ -cycloalkyl, a heterocyclic group consisting of 3-6 atoms, a C _6- C ₁₀ aryl or a heteroaryl consisting of 5-10 atoms.

In other embodiments, each of R ^5a , R ^5b , R ^5c and R ^5d is independently H, D, F, Cl, Br, I, —CN, —NO ₂ , —NH ₂ , —OH, —SH, —COOH, —C(═O)NH ₂ , —C(═O)NHCH ₃ , —C(═O)N(CH _{3 ) 2 ,} —C(═O)—CH 3 , —C(═O)—OCH ₃ , methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, —CHF ₂ , —CF ₃ , —CHFCH ₂ F, —CF ₂ CHF ₂ , —CH ₂ CF ₃ , —CH ₂ CF ₂ CHF ₂ , methoxy, ethoxy, n-propyloxy, isopropyloxy, —OCHF ₂ , —OCF ₃ , _-OCHFCH2F , -OCF2CHF2 _{, -OCH2CF3} , -OCH2CF2CHF2 _, methylthio _, ethylthio _, methylamino, dimethylamino, ethylamino, hydroxymethyl, _{2 -} hydroxyethyl _, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, phenyl, indenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, indolyl or quinolinyl.

In some embodiments, the compound of the present invention is a compound represented by formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the compound represented by formula (II).

Wherein, R ^2a , R ^2b , R ⁴ , R ^5d and R have the meanings as defined in the present invention.

In some embodiments, the compound of the present invention is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound having one of the following structures:

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound disclosed in the present invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant or any combination thereof.

In another aspect, the present invention relates to use of the compound or pharmaceutical composition disclosed in the present invention in preparing a medicament for preventing or treating sex hormone-dependent diseases.

In some embodiments, the sex hormone-dependent disease of the present invention is sex hormone-dependent cancer, bone metastasis of sex hormone-dependent cancer, prostate hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease, infertility, irritable bowel syndrome, benign or malignant tumors that are independent of hormones and sensitive to LH-RH (luteinizing hormone releasing hormone), or hot flashes.

On the one hand, the present invention relates to the use of the compound or pharmaceutical composition disclosed in the present invention in the preparation of a drug, which can be used as a reproduction regulator, a contraceptive, an ovulation inducer, or the drug is used to prevent postoperative recurrence of sex hormone-dependent cancer.

In another aspect, the present invention relates to use of the compound or pharmaceutical composition disclosed in the present invention in preparing a medicament for antagonizing gonadotropin-releasing hormone (GnRH).

In another aspect, the present invention relates to methods for preparing, separating and purifying the compounds represented by formula (I) or formula (II).

The biological test results show that the compounds of the present invention have strong antagonistic activity against gonadotropin-releasing hormone (GnRH), so the compounds provided by the present invention can be used as good GnRH receptor antagonists.

Any embodiment of any aspect of the present invention can be combined with other embodiments, as long as they do not conflict. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical features in other embodiments, as long as they do not conflict.

Detailed description of the present invention

Definitions and general terms

Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. It should be appreciated by those skilled in the art that many methods and materials similar or equivalent to those described herein can be used to practice the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless otherwise indicated, the following definitions used in the present invention shall apply. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that refer to one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

"Pharmaceutically acceptable" refers to compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

The term "optionally substituted with" can be used interchangeably with the term "unsubstituted or substituted with", i.e., the structure is unsubstituted or substituted with one or more substituents described herein, including, but not limited to, D, F, Cl, Br, I, _N3 , -CN, _-NO2 , -NH2, -OH, -SH, -COOH, -C ₍ =O) _NH2 , -C(=O) _NHCH3 , -C(=O)N( _CH3 ) ₂ , -C(=O)-(alkyl), -C(=O)-(alkoxy), alkyl, alkoxy, alkylthio, alkylamino, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -alkylene-C(=O) _NH2 , -alkylene-C(=O) _NHCH3 , -alkylene-C(=O)N( _CH3 ) ₂ , -alkylene-C(═O)-(alkyl), -alkylene-C(═O)-(alkoxy), -alkylene-S(═O)2NH2, -alkylene-S( _{═O )2NHCH3} , -alkylene-S(═O) _2N ( _CH3 ) ₂ , _-alkylene -S(═O) _{2- (} alkyl), -C(═O)-(cycloalkyl), -C(═O)-(heterocyclyl), -S(═O) _2- (alkyl), -S(═O) _2- (cycloalkyl), -S(═O) _2- (heterocyclyl) and the like.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl.

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is connected.

The terms "halogen" and "halo" are used interchangeably herein to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1 to 6 carbon atoms; in other embodiments, the alkyl group contains 1 to 4 carbon atoms; and in still other embodiments, the alkyl group contains 1 to 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu, -C(CH ₃ ) ₃ ), and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms. Unless otherwise specified, an alkylene group contains 1-10 carbon atoms. In some embodiments, an alkylene group contains 1-6 carbon atoms; in other embodiments, an alkylene group contains 1-4 carbon atoms; in yet other embodiments, an alkylene group contains 1-2 carbon atoms. Such examples include, but are not limited to, methylene ( _-CH2- ), ethylene ( _{-CH2CH2- )} , isopropylene (-CH( _CH3 ) _CH2- ), and the like. The alkylene group is optionally substituted with one or more substituents described herein.

The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 ^double bond, wherein the alkenyl group may be optionally substituted with one or more substituents as described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH= _CH2 ), allyl ( _-CH2CH = _CH2 ), 1-propenyl (i.e., propenyl, -CH=CH- _CH3 ), and the like.

The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH ₂ C≡CH), 1-propynyl (i.e., propynyl, -C≡C-CH ₃ ), and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms; in other embodiments, the alkoxy group contains 1-4 carbon atoms; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, _-OCH3 ), ethoxy (EtO, _-OCH2CH3 ), 1-propoxy (n-propyloxy, n-PrO, n-propoxy, _-OCH2CH2CH3 ), ₂ -propoxy (isopropyloxy _, i-PrO, i-propoxy, -OCH(CH3 _{) 2} ), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), _{2 -} methyl-1-propoxy ( _i - _BuO , i-butoxy, _-OCH2CH ( _CH3 ) ₂ ) _, 2-butoxy (s-BuO, s-butoxy, -OCH( _CH3 ) _CH2CH3 ), 2-methyl-2-propoxy (t- _BuO , t-butoxy, -OC( _CH3 ) ₃ ),etc.

The term "alkylthio" means an alkyl group attached to the rest of the molecule via a sulfur atom, wherein the alkyl group has a meaning as described herein. Unless otherwise specified, the alkylthio group contains 1-12 carbon atoms. In some embodiments, the alkylthio group contains 1-6 carbon atoms; in other embodiments, the alkylthio group contains 1-4 carbon atoms; in yet other embodiments, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, and the like.

The term "alkylamino" or "alkylamino" means that the amino group is independently substituted by one or two alkyl groups, including "N-alkylamino" and "N,N-dialkylamino", wherein the alkyl group has the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N-dimethylamino (dimethylamino), N,N-diethylamino (diethylamino) and the like. The alkylamino group is optionally substituted by one or more substituents described herein.

The term "hydroxy-substituted alkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; such examples include, but are not limited to, hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl, and the like.

The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted by one or more halogen atoms, wherein the alkyl and alkoxy groups have the meanings as described herein, and such examples include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoromethoxy, etc. In some embodiments, C ₁ -C ₆ haloalkyl includes fluorine-substituted C ₁ -C ₆ alkyl; in other embodiments, C ₁ -C ₄ haloalkyl includes fluorine-substituted C ₁ -C ₄ alkyl; in yet other embodiments, C ₁ -C ₂ haloalkyl includes fluorine-substituted C ₁ -C ₂ alkyl.

The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms. In some embodiments, the cycloalkyl contains 3-10 ring carbon atoms, such as C _3- C ₁₀ cycloalkyl; in other embodiments, the cycloalkyl contains 3-8 ring carbon atoms, such as C _3- C ₈ cycloalkyl; in yet other embodiments, the cycloalkyl contains 3-6 ring carbon atoms, such as C _3- C ₆ cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Among them, as described in the present invention, C _3- C ₈ cycloalkyl includes C _3- C ₆ cycloalkyl; the C _3- C ₆ cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be optionally substituted with one or more substituents described in the present invention.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocyclyl is non-aromatic and does not contain any aromatic ring. Unless otherwise specified, the heterocyclyl may be a carbon group or a nitrogen group, and the -CH ₂ - group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to S-oxide. The nitrogen atom of the ring may be optionally oxidized to N-oxide. The term "heterocyclyl" may be used interchangeably with the term "heterocycle". As described in the present invention, the heterocyclyl may be composed of 3-8 atoms or 3-6 atoms, wherein the atoms are optionally selected from C, N, O or S and at least one atom is N, O or S; wherein the heterocyclyl composed of 3-8 atoms includes heterocyclyl composed of 3-6 atoms; the heterocyclyl composed of 3-6 atoms includes heterocyclyl composed of 3-5 atoms. Specifically, the heterocyclic group consisting of 3 to 6 atoms includes, but is not limited to, oxirane, aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl, etc. The heterocyclic group may be optionally substituted with one or more substituents described herein.

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, 2,3-dihydro-1H-indenyl, naphthyl and anthracenyl. The aryl group can be optionally substituted with one or more substituents described herein. Unless otherwise specified, the group "C _6- C ₁₀ aryl" refers to an aryl group containing 6-10 ring carbon atoms.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen and sulfur, and the heteroaryl has one or more points of attachment to the rest of the molecule. When a -CH ₂ - group is present in the heteroaryl group, the -CH ₂ - group may be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) at any reasonable position (which may be C or N). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms, which means that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; in other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms, which means that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl and the like.

The term "j-k atoms" means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j; "j-k" includes j, k and any natural number between the two. For example, "3-8 atoms", "3-6 atoms", "5-10 atoms" or "5-6 atoms" means that the cyclic group is composed of 3-8, 3-6, 5-10 or 5-6 ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.

The term "prodrug" used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (II) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1- C ₂₄ ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.

"Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describepharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts. The present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _C1 - _C8 sulfonates and aromatic sulfonates.

The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof. The term "hydrate" refers to an association formed when the solvent molecule is water.

When the solvent is water, the term "hydrate" may be used. In one embodiment, one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.

As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

The terms "prevent" or "prevention" refer to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease."Therapeutically effective amount" may vary with the compound, the disease and its severity, as well as the condition, age, weight, sex, etc. of the subject to be treated.

Unless otherwise stated, all suitable isotopic variations, stereoisomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts and prodrugs thereof of the compounds of the present invention are encompassed within the scope of the present invention.

In structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.

Nitrogen oxides of the compounds of the invention are also included within the scope of the invention. Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.

The compound shown in formula (I) or formula (II) may exist in the form of a salt. In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal treated therewith. In other embodiments, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying the compound shown in formula (I) or formula (II) and/or for separating the enantiomer of the compound shown in formula (I) or formula (II).

Any structural formula provided by the present invention is also intended to represent the isotopically unenriched form and isotopically enriched form of these compounds. Isotopically enriched compounds have the structure described by the general formula provided by the present invention, except that one or more atoms are replaced by atoms with selected atomic weight or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the present invention relates to an intermediate for preparing a compound represented by formula (I) or formula (II).

Pharmaceutical compositions, preparations and administration of the compounds of the present invention

The present invention provides a pharmaceutical composition, comprising a compound represented by formula (I) or formula (II) or a single stereoisomer thereof, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. In some embodiments of the present invention, the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, adjuvant or excipient, and optionally, other therapeutic and/or preventive ingredients.

Suitable carriers, adjuvants and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel H.C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (2004) Lippincott, Williams & Wilkins, Philadelphia; Gennaro A.R. et al., Remington: The Science and Practice of Pharmacy (2000) Lippincott, Williams & Wilkins, Philadelphia; and Rowe R.C., Handbook of Pharmaceutical Excipients (2005) Pharmaceutical Press, Chicago.

It should also be recognized that, when used in therapy, certain compounds of the present invention may exist in free form or, if appropriate, in the form of pharmaceutically acceptable derivatives thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of these esters, or any other adducts or derivatives that, when administered to a patient in need thereof, can directly or indirectly provide the compounds of the present invention or their metabolites or residues.

Suitable pharmaceutically acceptable excipients can be different according to selected concrete dosage form. In addition, pharmaceutically acceptable excipients can be selected according to their specific functions in the composition. Suitable pharmaceutically acceptable excipients include excipients of the following types: diluents, fillers, adhesives, disintegrating agents, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers. The technician can recognize that some pharmaceutically acceptable excipients can provide more than one function, and provide optional functions, depending on how many of these excipients there are in the preparation and which other excipients there are in the preparation.

The pharmaceutical compositions disclosed in the present invention are prepared using techniques and methods known to those skilled in the art. Some common methods described in the art can be found in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Therefore, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof, the process comprising mixing the various ingredients. The pharmaceutical composition comprising a compound disclosed herein can be prepared by mixing at, for example, ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated into dosage forms suitable for administration to a patient via a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, such as suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

In some embodiments, the compounds disclosed in the present invention can be formulated into oral dosage forms. In other embodiments, the compounds disclosed in the present invention can be formulated into inhalation dosage forms. In other embodiments, the compounds disclosed in the present invention can be formulated into nasal dosage forms. In yet other embodiments, the compounds disclosed in the present invention can be formulated into transdermal dosage forms. In still other embodiments, the compounds disclosed in the present invention can be formulated into topical dosage forms.

The pharmaceutical composition provided by the present invention can be provided in the form of compressed tablets, triturated tablets, chewable lozenges, fast-dissolving tablets, multiple compressed tablets, enteric-coated tablets, sugar-coated tablets or film-coated tablets.

The pharmaceutical composition provided by the present invention can be provided in the form of soft capsules or hard capsules, which can be prepared from gelatin, methylcellulose, starch or calcium alginate.

Pharmaceutical composition provided by the invention can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration as used in the present invention includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

Pharmaceutical composition provided by the invention can be formulated into any dosage form suitable for parenteral administration, including solution, suspension, emulsion, micelle, liposome, microsphere, nano system and the solid form suitable for making solution or suspension in liquid before injection. Such dosage form can be prepared according to conventional methods known to the technicians in pharmaceutical science field (referring to Remington:The Science and Practice of Pharmacy, the same).

On the other hand, the pharmaceutical composition disclosed in the present invention can be formulated into any dosage form suitable for inhalation administration to a patient, such as a dry powder, an aerosol, a suspension or a solution composition.

Pharmaceutical compositions suitable for transdermal administration can be prepared as discontinuous patches, intended to remain in close contact with the patient's epidermis for an extended period of time. For example, active ingredients can be delivered from the patch by ion permeation, as generally described in Pharmaceutical Research, 3(6), 318(1986).

Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Uses of the compounds and pharmaceutical compositions of the present invention

The compounds and pharmaceutical compositions provided by the present invention have excellent GnRH antagonistic activity and low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproduction toxicity, cardiotoxins, drug interactions and carcinogenicity). Moreover, the compounds or pharmaceutical compositions are excellent in oral absorbability, sustainability of action, stability and pharmacokinetics. In addition, the compounds or pharmaceutical compositions are rarely affected by plasma components. Therefore, the compounds or pharmaceutical compositions of the present invention can be safely used in mammals (e.g., humans, monkeys, cattle, horses, dogs, cats, rabbits, rats and mice, etc.), and plasma sex hormone concentrations are controlled by utilizing GnRH receptor antagonism to inhibit gonadotropin secretion, thereby preventing and/or treating diseases that depend on male or female hormones and diseases caused by excessive amounts of these hormones, etc.

Specifically, the compound or pharmaceutical composition of the present invention is suitable for preventing and/or treating sex hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer, pituitary tumors, etc.), bone metastasis of sex hormone-dependent cancers, prostate hypertrophy, uterine fibroids, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multilocular ovary syndrome, polycystic ovary syndrome, acne, alopecia, Alzheimer's disease (Alzheimer's disease, Alzheimer's type and mixed type of senile dementia), etc. The compound of the present invention is also suitable for regulating male and female reproduction (e.g., pregnancy regulators and menstrual cycle regulators, etc.). The compound or pharmaceutical composition of the present invention can also be used as a male or female contraceptive or as a female ovulation inducer. Based on the rebound effect after drug withdrawal, the compound or pharmaceutical composition of the present invention can be used to treat infertility. In addition, the compound or pharmaceutical composition of the present invention can be used as a medicament for preventing and/or treating benign or malignant tumors that are independent of hormones and sensitive to LH-RH. In addition, the compounds or pharmaceutical compositions of the present invention can be used as agents for preventing and/or treating irritable bowel syndrome and preventing postoperative recurrence of sex hormone-dependent cancers (agents for preventing postoperative recurrence of prostate cancer; agents for preventing postoperative recurrence of breast cancer or ovarian cancer before or after menopause; in particular, agents for preventing postoperative recurrence of breast cancer or ovarian cancer before menopause).

In addition, the compounds or pharmaceutical compositions of the present invention are suitable for regulating animal estrus, improving meat quality and promoting animal growth in animal husbandry. The compounds of the present invention are also suitable for fish spawning promoters.

The compounds or pharmaceutical compositions of the present invention may also be used to inhibit the transient increase in plasma testosterone concentration (flare phenomenon), which is observed upon administration of a GnRH superagonist such as leuprorelin acetate. The compounds of the present invention may be used in combination with superagonists such as leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and lecirelin. Leuprorelin acetate is particularly preferred.

It is also particularly advantageous to use the compound or pharmaceutical composition of the present invention in combination with at least one selected from the following substances, the substances being steroidal or non-steroidal antiandrogens or antiestrogens, chemotherapeutic agents, GnRH antagonistic peptides, α-reductase inhibitors, α-receptor inhibitors, aromatase inhibitors, 17β-hydroxysteroid dehydrogenase inhibitors, adrenal androgen production inhibitors, kinase inhibitors, hormone therapy drugs, and drugs that inhibit cell growth factors or their receptors.

The above-mentioned “chemotherapeutic agents” include ifosfamide, adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, etc. The above-mentioned “GnRH antagonist peptides” include non-oral GnRH antagonist peptides, such as cetrorelix, ganirelix, and abarelix, etc.

The compounds and pharmaceutical compositions of the present invention are useful for human treatment and can also be used in veterinary treatment of pets, introduced species of animals and mammals in farm animals. Other examples of animals include horses, dogs and cats. Here, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

In some embodiments, the compounds disclosed herein or pharmaceutical compositions comprising the compounds disclosed herein can be administered once, or several times at different time intervals within a specified time period according to a dosing regimen. The compounds disclosed herein can be administered simultaneously with one or more other therapeutic agents, or before or after them. The compounds of the present invention can be administered separately with other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical composition.

General synthetic steps

To describe the present invention, the following examples are listed. However, it should be understood that the present invention is not limited to these examples, which are only provided to provide methods for practicing the present invention.

Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I) or formula (II). The following reaction schemes and examples are provided to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of the non-exemplified compounds of the invention can be successfully accomplished by one skilled in the art by modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

In the examples described below, all temperatures are set forth in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

The chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.

¹ H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz NMR spectrometer. ¹ H NMR spectra were recorded using CDCl ₃ , DMSO-d ₆ , CD ₃ OD or acetone-d ₆ as solvents (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broadened), brs (broadened singlet), dd (doublet of doublets), ddd (doublet ofdoublet of doublets), ddt (doublet of doublet of triplets), dt (doublet of triplets), dq (doublet of quartets), td (triplet of doublets), tt (triplet of triplets), qd (quartet ofdoublets). The coupling constant, J, is expressed in Hertz (Hz).

The determination conditions of low-resolution mass spectrometry (MS) data were: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1×30 mm, 3.5 microns, 6 min, flow rate of 0.6 mL/min. Mobile phase: 5%-95% (CH ₃ CN containing 0.1% formic acid) in (H ₂ O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.

The pure compounds were analyzed using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column model: NOVASEP 50/80 mm DAC) with UV detection at 210 nm/254 nm.

The following abbreviations are used throughout this invention:

The following synthetic schemes describe procedures for preparing compounds disclosed herein, wherein R has the definition set forth herein unless otherwise stated.

Intermediate Synthesis Scheme 1

The intermediate compound represented by formula ( 11 ) can be prepared by the following process: the compound represented by formula ( 1 ) reacts with urea to obtain the compound represented by formula ( 2 ); then the compound represented by formula ( 2 ) reacts with the compound represented by formula ( 3 ) to obtain the compound represented by formula ( 4 ). The compound represented by formula ( 4 ) is brominated to obtain the compound represented by formula ( 5 ). The compound represented by formula ( 5 ) reacts with the compound represented by formula ( 6 ) to obtain the compound represented by formula ( 7 ); the compound represented by formula ( 7 ) reacts with the compound represented by formula ( 8 ) to obtain the compound represented by formula ( 9 ). The compound represented by formula ( 9 ) reacts with boron tribromide to obtain the compound represented by formula ( 10 ). The amino group of the compound represented by formula ( 10 ) is protected to obtain the intermediate compound represented by formula ( 11 ).

Synthesis Scheme 1

The compound represented by formula ( 14 ) can be prepared by the following process: the compound represented by formula ( 11 ) reacts with the compound represented by formula ( 12 ) to obtain the compound represented by formula ( 13 ); the compound represented by formula ( 13 ) removes the protecting group to obtain the target product represented by formula ( 14 ).

合成方案2Wherein, L is a leaving group, such as: F, Cl, Br, I,

Synthesis Scheme 2

The compound represented by formula ( 15 ) can be prepared by the following process: aminoalkylation of the compound represented by formula ( 14 ) to obtain the target product represented by formula ( 15 ).

The compounds, pharmaceutical compositions and applications of the present invention are further described below in conjunction with the examples.

Example

Example 1 Synthesis of (R)-4-(3-(3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyramide

Step 1) Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)urea

Add (2-fluoro-6-(trifluoromethyl)phenyl)methanamine (1.5 g, 25.89 mmol) and urea (6.22 g, 104.00 mmol) to a 100 mL single-necked round-bottom flask, add concentrated hydrochloric acid (12 M, 3 mL) and water (11 mL), and react at 100 ° C for 12 hours; stop the reaction, cool to room temperature, add ice water (20 mL), and filter to obtain a white solid; add the obtained white solid to ethyl acetate (40 mL), stir for 10 minutes and then filter, and dry the filter cake at 50 ° C for 16 hours to obtain the title compound as a white solid (4.6 g, 75%).

MS(ESI,pos.ion)m/z:237.2[M+H] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm) 7.63–7.57 (m, 3H), 6.17 (t, J = 4.5 Hz, 1H), 5.49 (s, 2H), 4.37 (d, J = 4.7 Hz,2H).

Step 2) Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

1-(2-Fluoro-6-(trifluoromethyl)benzyl)urea (4.0 g, 17.0 mmol) and sodium iodide (3.82 g, 25.5 mmol) were added to a 100 mL single-necked round-bottom flask, and acetonitrile (35 mL) was added; under nitrogen protection, after cooling in a low-temperature bath at 0°C, diketene (2 mL) was added dropwise, and then trimethylsilyl chloride (3.3 mL) was added, and the temperature was slowly raised to 25°C and the reaction was continued for 16 hours; water (30 mL) was added and the reaction was continued for 5 hours; the reaction was stopped, filtered, and the filter cake was dried at 50°C overnight to obtain the title compound as a white solid (4.5 g, 88%).

MS(ESI,pos.ion)m/z:303.1[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.96 (s, 1H), 7.54 (d, J = 7.8Hz, 1H), 7.41 (dd, J = 13.2, 7.9Hz, 1H), 7.28–7.22 ( m,1H),5.35(s,2H),2.15(s,3H).

Step 3) Synthesis of 5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

1-(2-Fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (4.5 g, 15.0 mmol) and acetic acid (23 mL) were added to a 100 mL single-necked round-bottom flask at 25°C, and then liquid bromine (1.5 mL) was added dropwise, and the reaction was continued for 14 hours; the reaction was stopped, water (30 mL) was added, and the mixture was filtered after stirring for 10 minutes. The filter cake was dried at 50°C overnight to obtain the title compound as a white solid (5.44 g, 96%).

MS(ESI,pos.ion)m/z:381.0[M+H] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.75 (s, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.47 (dd, J = 13.2, 7.9Hz, 1H), 7.32 (s, 1H),5.50(s,2H),2.44(s,3H).

Step 4) (R)-tert-butyl (2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo- Synthesis of 2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate

5-Bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (2.2 g, 5.8 mmol) and tetrahydrofuran (35 mL) were added to a 100 mL single-necked round-bottom flask at 25°C, (R)-tert-butyl(2-hydroxy-1-phenylethyl)carbamate (1.7 g, 7.2 mmol) and triphenylphosphine (2.3 g, 8.7 mmol) were added, and then diethyl azodicarboxylate (2.0 g, 8.5 mmol) was added, and the reaction was continued to stir for 14 hours; the reaction was stopped, the mixture was dried under reduced pressure, and the title compound was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to obtain the title compound as a white solid (3.42 g, 99%).

MS(ESI,pos.ion)m/z:500.2[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.59 (s, 3H), 8.15 (s, 1H), 7.59 (dd, J = 13.2, 7.8Hz, 1H), 7.54–7.47 (m, 1H ),7.26(s,3H),5.35(d,J＝4.9Hz,2H),4.92(dd,J＝14.9,8.6Hz,1H),4.09(dd,J＝19.4,10.4Hz,1H),4.01 (dd,J＝6.4,2.8Hz,1H),2.54(s,3H),1.32(s,9H).

Step 5) (R)-tert-butyl(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)- Synthesis of 4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate

(R)-tert-butyl (2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (5.1 g, 16.7 mmol), (2-fluoro-3-methoxy-phenyl)boronic acid (4.25 g, 25.0 mmol), potassium carbonate (6.98 g, 50.0 mmol), 2-dicyclohexylphosphine-2',4' , 6'-triisopropylbiphenyl (810 mg, 1.67 mmol), palladium acetate (190 mg, 0.83 mmol) and toluene (160 mL) were added to a 250 mL single-mouth round-bottom flask and reacted at 110 ° C for 16 hours under nitrogen protection; the reaction was stopped, cooled to room temperature, filtered, the filtrate was decompressed and dried, and column chromatography was separated and purified (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (7.25 g, 67%). MS (ESI, pos.ion) m/z: 546.2 [M + H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.67 (d, J = 7.7 Hz, 1H), 7.57 (dt, J = 19.7, 8.2 Hz, 2H), 7.30–7.21 (m, 6H), 7.17(t,J＝6.0Hz,2H),5.33(s,2H),4.94(d,J＝7.0Hz,1H),4.04(dd,J＝13.7,7.5Hz,2H),3.86(s,3H ),2.10(s,3H),1.34(s,9H).

Step 6) (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-hydroxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)- Synthesis of 6-methylpyrimidine-2,4(1H,3H)-dione

(R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (7.25 g, 11.2 mmol) and dichloromethane (60 mL) were added to a 250 mL single-necked round-bottom flask. After cooling at -78°C for half an hour under nitrogen protection, boron tribromide (23 mL) was added dropwise, and the reaction was continued with stirring for 3 hours; then the temperature was transferred to 25°C for 12 hours, the reaction was stopped, water (30 mL) was added, and the aqueous phase was extracted with dichloromethane (40 mL) after separation. The organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain the title compound as a white solid (5.82 g, 98%).

MS(ESI,pos.ion)m/z:532.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 9.93 (s, 1H), 7.94 (s, 2H), 7.66 (d, J = 6.3Hz, 1H), 7.62–7.52 (m, 2H), 7.35(d,J＝8.1Hz,5H),7.05–6.93(m,2H),6.63–6.41(m,1H),5.33(s,2H),4.47(t,J＝6.8Hz,1H),4.31 –4.11(m,2H),2.13(s,3H).

Step 7) (R)-tert-butyl(2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4- Synthesis of methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate

At 25°C, (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-hydroxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (1.68 g, 3.16 mmol) and dichloromethane (18 mL) were added to a 100 mL single-necked round-bottom flask, and then triethylamine (0.67 mL, 4.8 mmol) and di-tert-butyl dicarbonate (697 mg, 3.16 mmol) were added, and the reaction was continued to stir for 5 hours; the reaction was stopped, the mixture was dried under reduced pressure, and the title compound was separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 4/1) to obtain the title compound as a white solid (1.21 g, 60%).

MS(ESI,pos.ion)m/z:532.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 9.86 (s, 1H), 7.65 (d, J = 7.5Hz, 1H), 7.55 (dt, J = 19.8, 8.1Hz, 2H), 7.25– 7.20(m,6H),7.03–6.92(m,2H),5.31(s,2H),4.93(d,J＝6.9Hz,1H),4.02(dd,J＝14.1,7.0Hz,2H),2.09 (s,3H),1.33(s,9H).

Step 8) (R)-methyl 4-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)- Synthesis of (( ...

(R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.5 g, 0.79 mmol) and N,N-dimethylformamide (8.0 mL) were added to a 100 mL single-necked round-bottom flask, potassium carbonate (221 mg, 1.58 mmol) and methyl 4-bromobutyrate (286 mg, 1.58 mmol) were added, and the mixture was reacted at 70°C for 12 hours; the reaction was stopped, and water (50 mL) was added after cooling to room temperature, and then ethyl acetate was added for extraction (50 mL×2), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a viscous liquid (456 mg, 79%).

MS(ESI,pos.ion)m/z:632.7[M+H-100] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.57 (d, J = 7.8Hz, 1H), 7.40 (d, J = 9.7Hz, 3H), 7.34 (t, J = 7.5Hz, 2H), 7.27 (d,J＝9.6Hz,2H),7.12(t,J＝8.0Hz,1H),6.99(t,J＝7.9Hz,1H),6.84(t,J＝6.7Hz,1H),4.46–4.31 (m,1H),4.16–4.08(m,4H),3.70(s,3H),2.57(t,J＝7.2Hz,2H),2.16(dd,J＝6.6,5.0Hz,2H),2.10( s,3H),1.41(s,9H).

Step 9) (R)-4-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl) Synthesis of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyric acid

At 25°C, (R)-methyl 4-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyrate (456 mg, 0.62 mmol) and methanol (10 mL) were added to a 100 mL single-necked round-bottom flask, lithium hydroxide (45 mg, 1.84 mmol, dissolved in 2 mL of water) was added, and the reaction was continued to stir for 14 hours; the reaction was stopped, citric acid was added to adjust the pH to 5, water (50 mL) was added, and then ethyl acetate was added for extraction (40 mL×2), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (dichloromethane/methanol (v/v)=10/1) to obtain the title compound as a white solid (433 mg, 97%).

MS(ESI,pos.ion)m/z:618.6[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.62–7.50 (m, 3H), 7.28–7.19 (m, 5H), 7.15 (t, J ＝6.8Hz,2H),5.32(s,2H),4.97–4.88(m,1H),4.08(t,J＝6.3Hz,2H),4.02(d,J＝7.8Hz,2H),2.41(t ,J＝7.3Hz,2H),2.10(s,3H),2.00–1.95(m,2H),1.33(s,9H).

Step 10) (R)-4-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoro Synthesis of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyramide

(R)-4-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butanoic acid (258 mg, 0.36 mmol), ammonium chloride (48 mg, 0.89 mmol), HATU (150 mg, 0.39 mmol) and N,N- Dimethylformamide (4 mL) was added to a 100 mL single-necked round-bottom flask, and then diisopropylethylamine (139 mg, 1.08 mmol) was added, and the reaction was continued with stirring for 12 hours; the reaction was stopped, water (30 mL) was added, and then dichloromethane was extracted (50 mL × 2), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 1/2) to obtain the title compound as a white solid (231 mg, 89.5%).

MS(ESI,pos.ion)m/z:617.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.6 Hz, 1H), 7.60–7.49 (m, 2H), 7.33 (s, 2H), 7.26–7.22 (m, 6H) ),7.14(t,J＝7.1Hz,2H),6.77(s,1H),5.32(s,2H),4.99–4.88(m,1H),4.08–3.99(m,4H),2.25(t, J＝7.3Hz,2H),2.10(s,3H),1.98–1.92(m,2H),1.33(s,9H).

Step 11) (R)-4-(3-(3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl Synthesis of (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyramide

At 25°C, (R)-4-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyramide (256 mg, 0.36 mmol) and dichloromethane (10 mL) were added to a 100 mL single-necked round-bottom flask, and then methanesulfonic acid (0.105 g, 1.07 mmol) was added, and the reaction was continued to stir for 5 hours. The reaction was stopped, saturated sodium bicarbonate solution (30 mL) was added, and then extracted with dichloromethane (30 mL×3), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (dichloromethane/methanol (v/v)＝20/1) to obtain the title compound as a white solid (189 mg, 85.1%).

MS(ESI,pos.ion)m/z:617.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.65 (d, J = 6.8 Hz, 1H), 7.60–7.52 (m, 2H), 7.34 (s, 1H), 7.26 (t, J = 4.9 Hz,4H),7.20–7.08(m,3H),6.78(s,1H),6.76–6.59(m,1H),5.34(s,2H),4.16–4.10(m,1H),4.05(t, J＝6.3Hz,2H),3.98–3.85(m,2H),2.25(t,J＝7.4Hz,2H),2.09(s,3H),1.99–1.92(m,2H).

Example 2 Synthesis of (R)-2-(3-(3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetamide

Step 1) (R)-methyl 2-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)- Synthesis of (( ...

The title compound of this step was prepared by referring to the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.5 g, 0.79 mmol), methyl 2-bromoacetate (242 mg, 1.58 mmol) and potassium carbonate (221 mg, 1.58 mmol) in N,N-dimethylformamide (6 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a colorless viscous substance (542 mg, 97%).

MS(ESI,pos.ion)m/z:604.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.67 (d, J = 7.7Hz, 1H), 7.62–7.51 (m, 2H), 7.28–7.20 (m, 6H), 7.17–7.08 (m ,2H),5.33(s,2H),4.96–4.84(m,3H),4.10–3.98(m,2H),3.72(s,3H),2.11(s,3H),1.34(s,9H).

Step 2) (R)-2-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl) Synthesis of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetic acid

The title compound of this step was prepared by referring to the method described in Step 9 of Example 1, i.e., (R)-methyl 2-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetate (0.542 g, 0.77 mmol) and lithium hydroxide (57 mg, 2.28 mmol) in methanol (5 mL). The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (410 mg, 77%).

MS(ESI,pos.ion)m/z:590.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.67 (d, J = 7.6Hz, 1H), 7.62–7.51 (m, 2H), 7.25–7.22 (m, 6H), 7.16–7.05 (m ,2H),5.33(s,2H),4.93(dd,J＝11.0,3.3Hz,1H),4.79(s,2H),4.09–3.98(m,2H),2.11(s,3H),1.34( s,9H).

Step 3) (R)-4-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoro)- Synthesis of (methyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetamide

The title compound of this step was prepared by the method described in Step 10 of Example 1, i.e., (R)-2-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetic acid (0.41 g, 0.59 mmol), ammonium chloride (79 mg, 1.48 mmol), HATU (251 mg, 0.65 mmol) and diisopropylethylamine (0.3 mL, 2.0 mmol) in N,N-dimethylformamide (6 mL). The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 100/1) to give the title compound as a white solid (328 mg, 80.8%).

MS(ESI,pos.ion)m/z:589.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.67 (d, J = 7.6Hz, 1H), 7.62–7.47 (m, 3H), 7.31–7.21 (m, 5H), 7.17–7.11 (m ,1H),7.07(t,J＝7.6Hz,1H),5.33(s,2H),5.00–4.89(m,1H),4.55(s,2H),4.12–3.96(m,2H),2.11( s,3H),1.34(s,9H).

Step 4) (R)-2-(3-(3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl Synthesis of (2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetamide

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-2-(3-(3-(2-((tert-butyloxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)acetamide (0.328 g, 0.48 mmol) and methanesulfonic acid (0.14 g, 1.43 mmol) in dichloromethane (6 mL). The crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (233 mg, 82.6%).

MS(ESI,pos.ion)m/z:589.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 6.7Hz, 1H), 7.59–7.53 (m, 2H), 7.49 (s, 1H), 7.43 (s, 1H), 7.30–7.23(m,4H),7.22–7.16(m,1H),7.13(t,J＝7.8Hz,1H),7.07(t,J＝8.0Hz,1H),6.82–6.63(m,1H) ,5.36(s,2H),4.55(s,2H),4.14(dd,J＝12.7,6.3Hz,1H),4.01–3.85(m,2H),2.11(s,3H).

Example 3 Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-(oxetan-3-yloxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) (R)-tert-butyl (2-(5-(2-fluoro-3-(oxetan-3-yloxy)phenyl)-3-(2-fluoro-6-(trifluoro)phenyl)- methyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate become

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.45 g, 0.71 mmol), oxetan-3-yl 4-methylbenzenesulfonate (243 mg, 1.06 mmol) and cesium carbonate (232 mg, 0.71 mmol) in N,N-dimethylformamide (8 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to give the title compound as a white solid (349 mg, 71%).

MS(ESI,pos.ion)m/z:588.0[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.62–7.51 (m, 2H), 7.29–7.18 (m, 6H), 7.12 (dd, J ＝15.2,7.5Hz,1H),6.84(t,J＝8.0Hz,1H),5.38–5.29(m,3H),4.95(dd,J＝12.8,6.3Hz,3H),4.64–4.56(m, 2H),4.09–3.96(m,2H),2.11(s,3H),1.34(s,9H).

Step 2) (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-(oxetan-3-yloxy)phenyl)-1- Synthesis of (2-Fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl(2-(5-(2-fluoro-3-(oxetan-3-yloxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.33 g, 0.48 mmol) and phosphoric acid (1.5 mL) in dichloromethane (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (148 mg, 52%).

MS(ESI,pos.ion)m/z:588.0[M+H] ⁺ ;

¹ H NMR (600MHz, DMSO-d ₆ ) δ (ppm) 7.65 (dd, J＝7.0, 2.8Hz, 1H), 7.59–7.53 (m, 2H), 7.29–7.22 (m, 6H), 7.20–7.17 (m,1H),7.15–7.11(m,1H),5.35(s,2H),5.18–5.10(m,1H),4.58–4.53(m,1H),4.13(dd,J＝14.5,7.7Hz ,1H),3.99–3.82(m,5H),2.10(s,3H).

Example 4 Synthesis of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) tert-butyl((R)-2-(5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6- (Trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamic acid Synthesis of esters

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.5 g, 0.79 mmol), ((3S)-tetrahydrofuran-3-yl)4-methylbenzenesulfonate (287 mg, 1.18 mmol) and cesium carbonate (258 mg, 0.79 mmol) in N,N-dimethylformamide (6 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (495 mg, 89%).

MS(ESI,pos.ion)m/z:602.2[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.6 Hz, 1H), 7.60–7.49 (m, 2H), 7.28–7.20 (m, 6H), 7.15 (t, J ＝5.4Hz,2H),5.32(s,2H),5.08(s,1H),4.97–4.87(m,1H),4.10–3.98(m,2H),3.97–3.80(m,4H),3.80– 3.74(m,1H),2.24(dd,J＝13.8,6.0Hz,1H),2.10(s,3H),2.04–1.96(m,1H),1.33(s,9H).

Step 2) 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)benzene Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., tert-butyl ((R)-2-(5-(2-fluoro-3-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.45 g, 0.64 mmol) and methanesulfonic acid (189 mg, 1.93 mmol) in dichloromethane (8 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (384 mg, 99%).

MS(ESI,pos.ion)m/z:602.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.65 (d, J = 6.7 Hz, 1H), 7.61–7.52 (m, 2H), 7.29–7.23 (m, 4H), 7.19 (dd, J ＝7.8,3.8Hz,1H),7.14(t,J＝5.3Hz,2H),6.79–6.61(m,1H),5.35(s,2H),5.08(s,1H),4.16–4.10(m, 1H),3.95–3.82(m,5H),3.77(td,J＝8.1,5.0Hz,1H),2.29–2.19(m,1H),2.09(s,3H),2.04–1.97(m,1H) .

Example 5 Synthesis of 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) tert-butyl((R)-2-(5-(2-fluoro-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6- (Trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamic acid Synthesis of esters

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.5 g, 0.79 mmol), ((3R)-tetrahydrofuran-3-yl)4-methylbenzenesulfonate (287 mg, 1.18 mmol) and cesium carbonate (258 mg, 0.79 mmol) in N,N-dimethylformamide (6 mL). The crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (484 mg, 87%).

MS(ESI,pos.ion)m/z:602.2[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.62–7.50 (m, 2H), 7.28–7.20 (m, 6H), 7.15 (t, J ＝5.9Hz,2H),5.33(s,2H),5.09(t,J＝4.8Hz,1H),4.99–4.89(m,1H),4.11–3.73(m,7H),2.30–2.20(m, 1H),2.11(s,3H),2.06–1.98(m,1H),1.34(s,9H).

Step 2) 3-((R)-2-amino-2-phenylethyl)-5-(2-fluoro-3-(((S)-tetrahydrofuran-3-yl)oxy)benzene Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., tert-butyl ((R)-2-(5-(2-fluoro-3-(((S)-tetrahydrofuran-3-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.47 g, 0.67 mmol) and methanesulfonic acid (197 mg, 2.01 mmol) in dichloromethane (8 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (371 mg, 92%).

MS(ESI,pos.ion)m/z:602.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.65 (d, J = 6.8 Hz, 1H), 7.60–7.52 (m, 2H), 7.29–7.23 (m, 4H), 7.21–7.17 (m ,1H),7.17–7.10(m,2H),6.80–6.61(m,1H),5.35(s,2H),5.08(t,J＝4.7Hz,1H),4.16–4.09(m,1H), 3.96–3.81(m,5H),3.81–3.74(m,1H),2.30–2.19(m,1H),2.10(s,3H),2.05–1.98(m,1H).

Example 6 Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) (R)-tert-butyl(2-(5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-3-(2-fluoro-6- (Trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamic acid Synthesis of esters

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.5 g, 0.79 mmol), tetrahydropyran-4-yl 4-methylbenzenesulfonate (304 mg, 1.18 mmol) and cesium carbonate (258 mg, 0.79 mmol) in N,N-dimethylformamide (8 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (466 mg, 82%).

MS(ESI,pos.ion)m/z:616.2[M+H-100] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm)7.66(d,J＝7.7Hz,1H),7.61–7.50(m,2H),7.25–7.20(m,7H),7.13(dd,J＝15.3,7.6Hz,1H),5.32(s,2H),4.99–4.88(m,1H),4.59(s,1H),4.02 (d,J＝8.1Hz,1H),3.86(d,J＝11.5Hz,2H),3.49(t,J＝10.1Hz,2H),3.43–3.38(m,2H),2.10(s,3H),1.99(dd,J＝8.9,3.9Hz,2H),1.67–1.57(m,2H),1.34( s,9H).

Step 2) (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)benzene Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl(2-(5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (406 mg, 0.57 mmol) and methanesulfonic acid (167 mg, 1.7 mmol) in dichloromethane (6 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (310 mg, 89%).

MS(ESI,pos.ion)m/z:616.2[M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm)7.66(s,1H),7.61–7.51(m,2H),7.30–7.21(m,5H),7.19(d,J＝4.5Hz,1H),7.12(dd,J＝15.8,8.0Hz,1H),6.71–6.69(m,1H),5.34(s,2H),4.58( d,J＝1.1Hz,1H),4.12(t,J＝6.1Hz,1H),3.96–3.93(m,2H),3.88–3.83(m,2H),3.48(t,J＝9.9Hz,2H),2.09(s,3H),2.02–1.95(m,2H),1.62(d,J＝8.9Hz, 2H).

Example 7 Synthesis of (R)-3-(2-(dimethylamino)-2-phenylethyl)-5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

(R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (67 mg, 0.11 mmol) and formaldehyde aqueous solution (0.09 mL, 1.0 mmol, 37%) were added to a 100 mL single-necked round-bottom flask at 25°C, and then acetic acid ( 0.012mL, 0.21mmol) was stirred for 2 hours, sodium cyanoborohydride (35mg, 0.53mmol) was added, and the stirring reaction was continued for 12 hours; the reaction was stopped, saturated sodium bicarbonate solution (20mL) was added, and then extracted with dichloromethane (30mL×2), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (dichloromethane/methanol (v/v)＝20/1) to obtain the title compound as a white solid (41mg, 59%).

MS(ESI,pos.ion)m/z:644.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.64 (d, J = 7.5Hz, 1H), 7.60–7.50 (m, 2H), 7.27–7.20 (m, 4H), 7.15–7.07 (m ,3H),6.66(m,1H),5.32(s,2H),4.58(td,J＝8.3,4.3Hz,1H),4.51–4.35(m,1H),3.97( ddd,J＝19.1,12.9,6.7Hz,1H),3.86(dd,J＝9.6,5.6Hz,2H),3.79(t,J＝7.6Hz,1H),3.52–3.44(m,2H),2.07 (d,J＝6.9Hz,2H),2.01(s,3H),1.98(s,3H),1.68–1.56(m,2H).

Example 8 Synthesis of (R)-5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) (R)-tert-butyl (2-(5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6- (Trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamic acid Synthesis of esters

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.43 g, 0.68 mmol), (1-acetyl-4-piperidinyl) 4-methylbenzenesulfonate (303 mg, 1.02 mmol) and cesium carbonate (221 mg, 0.68 mmol) in N,N-dimethylformamide (8 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (435 mg, 84%).

MS(ESI,pos.ion)m/z:657.2[M+H-100] ⁺ ;

¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.58 (d, J = 7.8Hz, 1H), 7.49–7.30 (m, 7H), 7.13 (t, J = 7.9Hz, 1H), 7.04 (t, J＝7.8Hz,1H),6.90(dd,J＝9.9,5.5Hz,1H),5.55(s,2H),4.45–4.30(m,1H),4.15–4.08(m,1H),3.81–3.60 (m,4H),3.52–3.32(m,2H),2.13(s,3H),2.10(s,3H),1.97–1.86(m,4H),1.41(s,9H).

Step 2) (R)-5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenylethyl Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl(2-(5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.35 g, 0.46 mmol) and methanesulfonic acid (196 mg, 2.0 mmol) in dichloromethane (6 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (281 mg, 93%).

MS(ESI,pos.ion)m/z:657.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 6.9 Hz, 1H), 7.59–7.48 (m, 2H), 7.30–7.23 (m, 5H), 7.19 (dd, J ＝10.3,5.1Hz,1H),7.15–7.09(m,1H),6.71(dt,J＝12.8,6.7Hz,1H),5.35(s,2H),4.74–4. 59(m,1H),4.16–4.08(m,1H),4.00–3.81(m,3H),3.72–3.62(m,1H),3.29–3.20(m,2H),2.10(s,3H), 2.02(s,3H),1.94–1.85(m,2H),1.69–1.63(m,1H),1.58–1.51(m,1H).

Example 9 Synthesis of (R)-5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-(dimethylamino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

(R)-5-(3-((1-acetylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (204 mg, 0.31 mmol) and formaldehyde aqueous solution (0.19 mL, 2.6 mmol, 37%) were added to a 100 mL single-necked round-bottom flask at 25°C, and then acetic acid ( 0.038mL, 0.63mmol) was stirred for 1 hour, sodium cyanoborohydride (82mg, 1.25mmol) was added, and the stirring reaction was continued for 12 hours; the reaction was stopped, saturated sodium bicarbonate solution (20mL) was added, and then extracted with dichloromethane (30mL×2), the organic phases were combined, dried under reduced pressure, and separated and purified by column chromatography (dichloromethane/methanol (v/v)＝20/1) to obtain the title compound as a white solid (189mg, 88%).

MS(ESI,pos.ion)m/z:685.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.65 (d, J = 7.5Hz, 1H), 7.60–7.50 (m, 2H), 7.26 (brs, 5H), 7.16–7.10 (m, 3H) ),5.32(s,2H),4.62(d,J＝3.3Hz,1H),4.49–4.35(m,1H),4.06–3.81(m,3H),3.72–3.64(m,1H),3.31– 3.18(m,2H),2.09–2.00(m,12H),1.96–1.87(m,2H),1.69–1.62(m,1H),1.57–1.50(m,1H).

Example 10 Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-((1-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) (R)-tert-butyl(2-(5-(2-fluoro-3-((1-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)-3-(2- (6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)amino Synthesis of formate esters

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.3 g, 0.47 mmol), (1-methylsulfonyl-4-piperidinyl) 4-methylbenzenesulfonate (237 mg, 0.71 mmol) and cesium carbonate (154 mg, 0.47 mmol) in N,N-dimethylformamide (6 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (308 mg, 81.8%).

MS(ESI,pos.ion)m/z:693.2[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.67 (s, 1H), 7.62–7.51 (m, 2H), 7.28–7.20 (m, 7H), 7.18–7.12 (m, 1H), 5.33 (s,2H),4.97–4.89(m,1H),4.60–4.54(m,1H),4.11–3.96(m,2H),3.36(dd,J＝6.7,4.5Hz,2H),3.18–3.12 (m,2H),2.90(s,3H),2.11(s,3H),2.06–2.00(m,2H),1.79(ddd,J＝9.1,7.9,4.0Hz,2H),1.33(s,9H ).

Step 2) (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-((1-(methylsulfonyl)piperidin-4-yl)oxy) Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl(2-(5-(2-fluoro-3-((1-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.308 g, 0.39 mmol) and methanesulfonic acid (114 mg, 1.16 mmol) in dichloromethane (6 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (242 mg, 89.9%).

MS(ESI,pos.ion)m/z:693.2[M+H] ⁺ ;

¹ H NMR (400 MHz, DMSO-d ₆ )δ(ppm)7.66(d,J＝7.0Hz,1H),7.61–7.53(m,2H),7.30–7.22(m,6H),7.21–7.17(m,1H),7.16–7.11(m,1H),5.35(s,2H),4.57(s,1H),4.13(dd,J＝7.5 ,4.7Hz,1H),3.91(ddd,J＝16.0,14.1,7.7Hz,2H),3.36(s,2H),3.14(t,J＝8.2Hz,2H),2.90(s,3H),2.10(s,3H),2.02(d,J＝4.1Hz,2H),1.78(d,J＝8.2Hz ,2H).

Example 11 Synthesis of (R)-3-(2-amino-2-phenylethyl)-5-(3-((1-(cyclopropanoyl)piperidin-4-yl)oxy)-2-fluorophenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1: Synthesis of (R)-tert-butyl (2-(5-(3-((1-cyclopropanoylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6- dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl) carbamate

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.3 g, 0.475 mmol), (1-cyclopropanoyl-4-piperidinyl) 4-methylbenzenesulfonate (230 mg, 0.71 mmol) and cesium carbonate (154 mg, 0.47 mmol) in N,N-dimethylformamide (6 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (312 mg, 83.9%).

MS(ESI,pos.ion)m/z:783.3[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.62–7.51 (m, 2H), 7.30–7.20 (m, 7H), 7.15 (dd, J ＝15.2,7.6Hz,1H),5.32(s,2H),4.93(dt,J＝14.9,7.3Hz,1H),4.65(td,J＝7.1,3.7Hz,1H),4.11–3.80(m, 5H),3.55(s,1H),2.11(s,3H),2.05–1.89(m,4H),1.33(s,9H),0.75–0.69(m,4H).

Step 2) (R)-3-(2-amino-2-phenylethyl)-5-(3-((1-(cyclopropanoyl)piperidin-4-yl)oxy)-2-fluoro Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl (2-(5-(3-((1-cyclopropanoylpiperidin-4-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.312 g, 0.4 mmol) and methanesulfonic acid (117 mg, 1.19 mmol) in dichloromethane (6 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (237 mg, 87.1%).

MS(ESI,pos.ion)m/z:683.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 6.9 Hz, 1H), 7.59–7.53 (m, 2H), 7.30–7.22 (m, 6H), 7.19 (dd, J ＝9.5,4.0Hz,1H),7.16–7.10(m,1H),5.35(s,2H),4.64(s,1H),4.13(dd,J＝12.3,6.2Hz, 1H),4.06–3.83(m,5H),3.59–3.49(m,1H),2.10(s,3H),2.00(dd,J＝6.7,5.0Hz,2H),1.61(ddd,J＝11.2, 7.8,4.1Hz,2H),1.26–1.21(m,1H),0.71(dd,J＝9.5,6.5Hz,4H).

Example 12 Synthesis of (R)-5-(3-((1-acetylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) Synthesis of (R)-tert-butyl (2-(5-(3-((1-acetylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl -2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl) carbamate

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.4 g, 0.63 mmol), (1-acetylazetidin-3-yl) 4-methylbenzenesulfonate (255 mg, 0.95 mmol) and cesium carbonate (207 mg, 0.63 mmol) in N,N-dimethylformamide (8 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (411 mg, 89.1%).

MS(ESI,pos.ion)m/z:729.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.7 Hz, 1H), 7.61–7.50 (m, 2H), 7.29–7.20 (m, 6H), 7.15 (dd, J ＝15.4,7.8Hz,1H),6.95(t,J＝7.9Hz,1H),5.32(s,2H),5.09(ddd,J＝10.1,6.6,3.9Hz,1H),4. 94(dt,J＝15.8,7.8Hz,1H),4.57(dd,J＝15.7,6.5Hz,1H),4.34–4.26(m,1H),4.18–4.12(m,1H),4.05–4.00( m,2H),3.86–3.78(m,1H),2.10(s,3H),1.80(s,3H),1.33(s,9H).

Step 2) (R)-5-(3-((1-acetylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenyl Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl (2-(5-(3-((1-acetylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.4 g, 0.55 mmol) and phosphoric acid (2 mL) in dichloromethane (6 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (316 mg, 91.6%).

MS(ESI,pos.ion)m/z:629.2[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 6.6 Hz, 1H), 7.61–7.53 (m, 2H), 7.28–7.25 (m, 5H), 7.19 (dd, J ＝7.9,4.0Hz,1H),7.17–7.12(m,1H),6.95(t,J＝8.1Hz,1H),5.35(s,2H),5.12–5.0 7(m,1H),4.57(dd,J＝15.7,6.5Hz,1H),4.34–4.27(m,1H),4.15(dt,J＝14.0,4.8Hz,2H),3.97–3.89(m, 2H),3.82(dd,J=10.5,2.9Hz,1H),2.11(s,3H),1.81(s,3H).

Example 13 Synthesis of (R)-5-(3-((1-methylsulfonylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenylethyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

Step 1) Synthesis of (R)-tert-butyl (2-(5-(3-((1-methylsulfonylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl -2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl) carbamate

The title compound of this step was prepared by the method described in Step 8 of Example 1, i.e., (R)-tert-butyl (2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.35 g, 0.55 mmol), (1-methylsulfonylazetidin-3-yl) 4-methylbenzenesulfonate (253 mg, 0.83 mmol) and cesium carbonate (181 mg, 0.56 mmol) in N,N-dimethylformamide (6 mL), and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3/1) to give the title compound as a white solid (256 mg, 60.4%).

MS(ESI,pos.ion)m/z:665.1[M+H-100] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 7.6Hz, 1H), 7.61–7.51 (m, 2H), 7.29–7.20 (m, 6H), 7.18–7.12 (m ,1H),7.00(t,J＝8.1Hz,1H),5.33(s,2H),5.14–5.07(m,1H),4.99–4.89(m,1H),4.34(dd,J＝15.4,7.8 Hz,2H),4.06–3.96(m,4H),3.09(s,3H),2.11(s,3H),1.34(s,9H).

Step 2) (R)-5-(3-((1-methylsulfonylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-amino-2-phenyl)- Synthesis of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione

The title compound of this step was prepared by referring to the method described in Step 11 of Example 1, i.e., (R)-tert-butyl(2-(5-(3-((1-methylsulfonylazetidin-3-yl)oxy)-2-fluorophenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl)carbamate (0.24 g, 0.32 mmol) and phosphoric acid (2 mL) in dichloromethane (5 mL), and the crude product was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) to give the title compound as a white solid (159 mg, 76.2%).

MS(ESI,pos.ion)m/z:665.1[M+H] ⁺ ;

¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.66 (d, J = 5.5Hz, 1H), 7.62–7.52 (m, 2H), 7.30–7.22 (m, 4H), 7.21–7.10 (m ,2H),7.00(d,J＝6.9Hz,1H),6.87–6.65(m,1H),5.35(s,2H),5.10(d,J＝4.7Hz,1H),4.33(dd,J＝ 14.2,6.9Hz,2H),4.16–4.09(m,1H),4.02–3.85(m,4H),3.08(s,3H),2.10(s,3H).

Biological tests

Example A: Antagonistic effect of the compounds of the present invention on humanized GnRH receptor

Purpose

The antagonistic effect of the compounds of the present invention on humanized GnRH receptors transfected in RBL-1 cells (rat basophilic leukemia cells) was evaluated by fluorescence detection of cytoplasmic calcium flux.

Experimental Procedure

The cells were suspended in HBSS buffer (Invitrogen, USA), 20mM HEPES buffer (Invitrogen, USA) was added, and then added to the microwell reaction plate at an average density of 1.186×10 ⁴ cells/well. The fluorescent probe (Fluo8 Direct, AAT Bioquest) and HBSS buffer (20mM HEPES buffer, pH=7.4) were mixed and added to each well, and the cells were incubated at 30°C for 60min. The reaction plate was then placed in an ELISA reader (FlipR Tetra, Molecular Device) for testing, and the test compound or HBSS buffer (blank control) was added. 8nM LH-RH (agonist ligand) was added 5min later, and the change in fluorescence intensity proportional to the intracytoplasmic calcium ion concentration was measured. The fluorescence intensity of the blank control group without the addition of the compound was taken as 100% (inhibition rate was 0%), and the inhibition rate of the compound was calculated. The inhibition rate of the compound at different concentrations was determined, and its _IC50 value was calculated. The corresponding Ki value was calculated by the following equation:

Ki=IC ₅₀ /[1+(A/EC _50A )], wherein A represents the concentration of the agonist ligand; EC _50A represents the EC ₅₀ value of the agonist ligand.

The experimental results are shown in Table A below.

Table A Antagonistic effect of the compounds of the present invention on humanized GnRH receptor

Example No. IC ₅₀ (nM) Ki(nM) Example No. IC ₅₀ (nM) Ki(nM) Example 1 1.187 0.326 Example 5 5.101 1.402 Example 2 2.329 0.640 Example 8 1.907 0.524 Example 3 1.36 0.374 Example 12 4.414 1.213 Example 4 4.589 1.262 Example 13 3.644 1.002

The experimental results show that the compound of the present invention has a good antagonistic effect on humanized GnRH receptors.

Example B: Pharmacokinetic evaluation of the compound of the present invention after intravenous injection or oral gavage in rats and dogs

The present invention has evaluated the pharmacokinetic study of the compound of the present invention in rats and/or dogs. The animal information is shown in Table B.

Table B Information table of the test animals of the present invention

Test methods

The compound of the present invention was administered to the test animals in the form of 10% DMSO + 10% Kolliphor HS15 + 78% Saline + 2% (2% HCl) solution or 78% Saline + 2% (2% HCl) + 20% PEG400 solution. The animals were fasted for 12 hours before administration and had free access to water. For the intravenous administration group, the dosage was 1 mg/kg (rat) or 0.5 mg/kg (dog). After administration, blood was collected venously at the following time points (blood volume of about 0.2 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24h (dog) or 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h (rat), and EDTA-K ₂ was pre-added in the blood collection tube as an anticoagulant. For the oral administration group, the dosage was 5 mg/kg (rat) or 2.5 mg/kg (dog), and venous blood was collected at the following time points after administration (blood volume was about 0.2 mL): 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h (dog) or 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 h (rat), and EDTA-K ₂ was added in advance as an anticoagulant in the blood collection tube. The blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C.

The collected plasma samples were processed (frozen plasma was thawed at room temperature, vortexed for 15 seconds to mix, 10-20 μL of plasma was taken, 120-150 μL of acetonitrile solution containing internal standard was added, vortexed for 5 minutes to mix, centrifuged at 4,000 rpm for 5 minutes, 100 μL of supernatant was taken, 120-150 μL of methanol/water (v/v=1/1) was added to mix) and the concentration of the compound in the plasma was analyzed by LC/MS/MS.

The analysis results show that the compounds of the present invention have good pharmacokinetic properties in rats and/or dogs, indicating that the compounds of the present invention have good drugability and good clinical application prospects.

In the description of this specification, the description with reference to the terms "one embodiment", "an implementation", "some embodiments", "example", "specific example" or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment, implementation or example are included in at least one embodiment, implementation or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment, implementation or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments, implementations or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments, implementations or examples described in this specification and the features of different embodiments, implementations or examples, without contradiction.

Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims (9)

1. A compound which is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound of formula (II),

wherein:

each R ^2a And R ^2b Independently is H, D or C ₁ -C ₆ An alkyl group;

R ⁴ is H, D or C ₁ -C ₆ An alkyl group;

R ^5d is H, D, F, cl, br, I or C ₁ -C ₆ An alkyl group;

r is

X is-O-or-NR ⁿ -；

R ⁿ Is H, D, C _1-6 Alkyl, -C (= O) - (C) ₁ -C ₆ Alkyl), -C (= O) - (C) _3- C ₆ Cycloalkyl), -C (= O) - (heterocyclic group composed of 3 to 8 atoms), -S (= O) ₂ -(C ₁ -C ₆ Alkyl), -S (= O) ₂ -(C _3- C ₆ Cycloalkyl) or-S (= O) ₂ - (3-8 atom-constituting heterocyclic groups);

y is 0, 1,2 or 3; and

z is 1,2 or 3.

2. The compound of claim 1, wherein R is

X is-O-or-NR ⁿ -；

R ⁿ Is H, D, C _1-4 Alkyl, -C (= O) - (C) ₁ -C ₄ Alkyl), -C (= O) - (C) _3- C ₆ Cycloalkyl), -C (= O) - (heterocyclic group of 3-6 atoms), -S (= O) ₂ -(C ₁ -C ₄ Alkyl), -S (= O) ₂ -(C _3- C ₆ Cycloalkyl) or-S (= O) ₂ - (heterocyclic groups of 3 to 6 atoms).

3. A compound according to claim 1 or 2, wherein R is

4. The compound of claim 1, wherein each R ^2a And R ^2b Independently is H, D or C ₁ -C ₄ An alkyl group;

R ⁴ is H, D or C ₁ -C ₄ An alkyl group.

5. A compound according to claim 1 or 4, wherein each R is ^2a And R ^2b Independently H, D, methyl, ethyl, n-propyl or isopropyl;

R ⁴ h, D, methyl, ethyl, n-propyl or isopropyl.

6. The compound of claim 1, wherein R ^5d H, D, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl.

7. The compound of claim 1, which is a compound having one of the following structures or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of a compound having one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7; and

the pharmaceutical composition optionally further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or any combination thereof.

9. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the prevention or treatment of a sex hormone dependent disease;

wherein the sex hormone dependent disease is a sex hormone dependent cancer, bone metastasis of a sex hormone dependent cancer, prostatic hypertrophy, hysteromyoma, endometriosis, uterine fibroids, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, multi-atrial ovarian syndrome, polycystic ovarian syndrome, acne, alopecia, infertility or irritable bowel syndrome.