RU2804127C2 - 1,2,3,4-tetrahydroquinoxaline derivative, method for its obtaining and its application - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: compound of Formula (IIb), its stereoisomer or a pharmaceutically acceptable salt.

also relates to a method for preparing a compound of Formula (IIb), a stereoisomer or a pharmaceutically acceptable salt thereof, also relates to the use of a compound of Formula (IIb), a stereoisomer or a pharmaceutically acceptable salt thereof for the manufacture of preparations for the treatment of one or more types of tumors, malignancies, metabolic diseases, autoimmune diseases or disorders associated with RORγt.

EFFECT: ensuring the development of a low molecular weight RORγt agonist having the structure of Formula (IIb).

12 cl, 1 tbl, 122 ex

Description

TECHNICAL FIELD

The present invention relates to the field of pharmaceutical synthesis and, in particular, to a 1,2,3,4-tetrahydroquinoxaline derivative, a method for its preparation and its use.

BACKGROUND OF THE ART

The retinoic acid-related orphan receptor (ROR) family consists of three members: RORα, RORβ, and RORγ. The RORα receptor is critical for cerebellar development, and the RORβ receptor is expressed primarily in the brain and retina. Both receptors play an important role in normal retinal development. Depending on the splice sites during transcription, the RORγ receptor can be one of two subtypes, RORγ1 and RORγ2 (RORγt), the former of which is expressed primarily in the liver, skeletal muscle, and kidney. RORγt is expressed mainly in organs of the immune system. RORγt-deficient mice lack lymph nodes, Peyer's patches, and other lymphoid organs. In addition, such deficiency negatively affects the development and maturation of T cells, and the number of different T cells is reduced compared to those in normal mice.

Helper T cells play a critical role in the human immune system. Under the influence of various cytokines induced during the developmental stage of the organism, CD4-positive T helper cells can differentiate to form a number of regulatory helper cells, such as Th1, Th2, Th17 and Tregs. Th1 and Th2 play important roles in antigen recognition, antigen presentation, and T effector cell activation. Tregs are a class of regulatory cells that help suppress the immune response. Th17 are a relatively new type of T helper cell discovered in recent years that are characterized by the secretion of the cytokine interleukin 17 (IL-17). Th17 cells were initially thought to exert their immune functions by primarily participating in the fight against bacterial and fungal infections through the mobilization of neutrophils. The results of later studies showed that these cells are closely associated with the development of autoimmune diseases and malignancies. Therefore, the treatment of autoimmune diseases by suppressing the differentiation of Th17 cells and the treatment of malignancies by activating the differentiation of Th17 cells have attracted increased interest both in terms of basic and translational research in immune diseases and from specialists in the field of oncology.

RORγt is a key transcription factor in the differentiation of CD4+ Th17 cells, and modulation of RORγt activity by small molecules can directly influence the number and activity of Th17 cells. Following activation of RORγt, the levels of cytokines secreted by Th17 cells (such as IL-17A) are significantly increased, and Th17 cell survival and ability to undergo immune activation are significantly increased. However, increased activation of Th17 cells may lead to a decrease in the number of immunosuppressive Treg cells and the expression of immunosuppressive receptors (such as PD-1) in tumor-infiltrating lymphocytes. Based on the mechanism of action, the oral small molecule RORγt agonist can enhance the immune system's ability to recognize and destroy tumor cells through Th17 cell activation, making it a potential new small molecule anticancer drug following the success of anti-PD-1/PD-L1 antibodies .

DISCLOSURE OF INVENTION

The objective of the present invention is to create a small molecule RORγt agonist.

The first aspect of the present invention relates to a compound of formula (I), stereoisomer, prodrug or pharmaceutically acceptable salt:

Where

L is selected from the group consisting of the bond, -C(R ₇ )=C(R ₈ )-, -(CR ₉ R ₁₀ ) _m1 -, -(CR ₁₁ R ₁₂ ) _m2 -O-, -O-(CR ₁₃ R ₁₄ ) _m3 -, -N(R ₁₅ )-C(O)-, -C(O)-N(R ₁₆ )-, -(CR ₁₇ R ₁₈ ) _m4 -N(R ₁₉ )-, - N(R ₂₀ )-(CR ₂₁ R ₂₂ ) _m5 -, -(CR ₂₃ R ₂₄ ) _m6 -S(O) _r - and -S(O) _r -(CR ₂₅ R ₂₆ ) _m7 -;

cycle A is

cycle B represents where Y represents -O- or -N(R ₂₇ )-;

R ₁ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl , C _5-10 aryl, 5-10-membered heteroaryl, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _{1- 10} alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10- member heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C( O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 - N(R ₃₁ )-C(O)R ₃₀ ;

R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C( O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C( O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ , or R ₂ and R ₃ , together with the carbon atom directly attached to them form C(O), 3 -10-membered cycloalkyl or 3-10 membered heterocyclyl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl , C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _{0 -8} -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C( O)R ₃₀ ;

R ₄ is selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, vinyl, propenyl, allyl, ethynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, benzyl, diazole, triazole, methylsulfonyl , isopropylsulfonyl, aminosulfonyl, carboxyl, methoxycarbonyl, ethoxycarbonyl and acetyl, said _C1-4 alkyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, benzyl, diazole and triazole are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, cyclopropyl, oxacyclobutyl, =O, methoxy, carboxyl, methoxycarbonyl, acetyl, amino, dimethylamino and acetylamino,

or R ₄ and R ₃ , together with the carbon atom directly attached thereto, form a 5-10 membered heterocyclyl, the 5-10 membered heterocyclyl is optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano , nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _{5 -10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -C(S)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ , the above groups in turn optionally substituted with one or more substituents selected from the group, consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3- 10-membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 - C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -C(S)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _{0- 8} -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ ;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10- membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -SF ₅ , -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C (O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C (O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro , azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ ;

each R ₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10- membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 - C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _{0- 8} -N(R ₃₁ )-C(O)R ₃₀ ;

R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, deuterium, fluorine, C _1-4 alkyl, C _1-4 deuteroalkyl and C _1-4 fluoroalkyl;

R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₇ , R ₁₈ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ and R ₂₆ are each independently selected from the group consisting of hydrogen , deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O )R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N (R ₃₁ )-C(O)R ₃₀ , or R ₉ and R ₁₀ , R ₁₁ and R ₁₂ , R ₁₃ and R ₁₄ , R ₁₇ and R ₁₈ , R ₂₁ and R ₂₂ , R ₂₃ and R ₂₄ , R ₂₅ and R ₂₆ , together with the carbon atom directly attached thereto, each independently form C(O), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, the above groups optionally substituted with one or more additional substituents selected from the group , consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3 -10-membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ ;

R ₁₅ , R ₁₆ , R ₁₉ , R ₂₀ and R ₂₇ are each independently selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -C(O)OR ₂₉ and -C _{0 -8} -C(O)R ₃₀ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _2-10 alkenyl, C _{2 -10} alkynyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 - OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ ;

each R ₂₈ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10- membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₃₁ R ₃₂ , the above groups optionally substituted by one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3- 10-membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₃₁ R ₃₂ ;

each R ₂₉ is independently selected from the group consisting of hydrogen, deuterium, C _1-10 alkyl, C _2-10 alkenyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl and 5-10 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, cyano, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _{3- 10} cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₃₁ R ₃₂ ;

each R ₃₀ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₃₁ R ₃₂ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, _C1-10 alkyl, _C1-10 alkoxy, _C3-10 cycloalkyl, _C3-10 cycloalkyloxy, 3-10- membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and -NR ₃₁ R ₃₂ ;

R ₃₁ and R ₃₂ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, _C5-10 aryl, 5-10 membered heteroaryl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino, monoalkylamino, dialkylamino and _C1-10 alkanoyl, the above groups optionally substituted with one or more additional substituents selected from the group , consisting of deuterium, halogen, hydroxy, carboxyl, C _1-8 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl;

or R ₃₁ and R ₃₂ together with the nitrogen atom directly attached thereto form a 4-10 membered heterocyclyl, the above groups being optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, C _1-10 alkyl, C _1-10 alkoxy, C _3-10 cycloalkyl, C _3-10 cycloalkyloxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C _5-10 aryl, C _5-10 aryloxy, 5-10- membered heteroaryl, 5-10 membered heteroaryloxy, amino, monoalkylamino, dialkylamino and C _1-10 alkanoyl;

m is an integer from 0 to 5; n is an integer from 0 to 3; p is an integer from 0 to 5;

m1, m3, m5 and m7 each independently take the values 1 or 2;

m2, m4 and m6 each independently take the values 0, 1 or 2;

each r independently takes on the values 0, 1, or 2.

In a preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, each R ₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , - C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C(O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ , the above groups optionally substituted by one or several additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C(O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ ; R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ and R ₃₂ correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, each _R6 is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, vinyl, allyl, ethynyl, cyclopropyl, 3-oxacyclobutyl, 3-azacyclobutyl, phenyl, pyridyl, diazole, triazole, methylsulfonyl, aminosulfonyl, methoxy, methoxyacyl, carboxyl, acetyl, acetoxy, amino, dimethylamino, aminoacyl and acetylamino, the above groups are optionally substituted one or several additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, cyclopropyl, phenyl, pyridyl, methylsulfonyl, hydroxy, methoxy, carboxyl and amino.

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (IIa):

where R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C (O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C (O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ , or R ₂ and R ₃ , together with the carbon atom directly attached to them form C(O), 3-10 membered cycloalkyl or 3-10 membered heterocyclyl;

R ₄ is selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, methylsulfonyl, isopropylsulfonyl, aminosulfonyl, carboxy, methoxycarbonyl, ethoxycarbonyl and acetyl, and said C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and phenyl are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl , difluoromethyl, trideuteromethyl, cyclopropyl, oxacyclobutyl, methoxy, carboxy, methoxycarbonyl, acetyl, amino, dimethylamino and acetylamino;

cycle A, cycle B, L, R ₁ , R ₅ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , r, m and p correspond to those of the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound with formula (IIIa1), formula (IIIa2), formula (IIIa3) or formula (IIIa4 ) as described below:

or
where R ₂ and R ₃ are each independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -C _0-4 -OR ₂₉ , -C _{0- 4} -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ and -C _0-4 -OC(O)R ₃₀ , or R ₂ and R ₃ , together with the carbon atom directly attached to them, form C(O), 3-6-membered cycloalkyl or 3-6-membered heterocyclyl;

R ₄ is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, said C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, cyclopropyl, oxacyclobutyl, methoxy, carboxy, methoxycarbonyl, acetyl, amino, dimethylamino and acetylamino;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR ₂₉ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, oxacyclobutyl, =O, methoxy and carboxy;

R ₇ is selected from the group consisting of hydrogen, deuterium, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;

ring A, R ₁ , R ₂₉ , R ₃₀ and m correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (IIb):

where Z is selected from the group consisting of bonds, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ₃₃ )- and -(CR ₃₅ R ₃₆ )-;

R ₃₃ is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 -membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O) OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S)R ₃₀ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C( O)NR ₃₁ R ₃₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S( O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S )R ₃₀ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ ;

each R ₃₄ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C(O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ , the above groups are optionally substituted by one or more additional substituents selected from the group consisting from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 -membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C (O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C (O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ ;

R ₃₅ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C (O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S)R ₃₀ and -C _0-4 -OC(O)R ₃₀ , the above groups are optionally replaced by one or several additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl , C _3-6 cycloalkyl, 3-6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, =O, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 - OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C(O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ ;

R ₃₆ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3 -6-membered heterocyclyl, C _5-8 aryl, 5-8-membered heteroaryl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C( O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S)R ₃₀ and -C _0-4 -OC(O)R ₃₀ , the above groups are optionally substituted by one or several additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl, =O, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ , -C _0-4 -NR ₃₁ R ₃₂ , -C _0-4 -C(O)NR ₃₁ R ₃₂ and -C _0-4 -N(R ₃₁ )-C(O)R ₃₀ ;

q is an integer from 0 to 4; cycle A, cycle B, L, R ₁ , R ₂ , R ₅ , R ₆ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , m, r and p correspond to those of the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, the compound of formula (I) is a compound of formula (IIIb1), formula (IIIb2), formula (IIIb3), formula (IIIb4 ) or formula (IIIb5) as described below:

or
where Z is selected from the group consisting of bonds, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ₃₃ )- and -(CR ₃₅ R ₃₆ )-;

each R ₅ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR ₂₉ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, oxacyclobutyl, =O, methoxy and carboxy;

R ₇ is selected from the group consisting of hydrogen, deuterium, fluorine, methyl, ethyl, trifluoromethyl, difluoromethyl, trideuteromethyl and dideuteromethyl;

R ₃₃ is selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 -membered heterocyclyl, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O) R ₃₀ , -C _0-4 -C(S)R ₃₀ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ , the above groups optionally substituted with one or several additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ ;

R ₃₅ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -OR ₂₉ , -C (O)OR ₂₉ , -OC(O)R ₃₀ and -C(O)NR ₃₁ R ₃₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, =O, -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C(O)OR ₂₉ , -C(O)R ₃₀ and -C(O)NR ₃₁ R ₃₂ ;

R ₃₆ is selected from the group consisting of hydrogen, deuterium, halogen, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 haloalkyl, C _1-4 deuteroalkyl and C _3-6 cycloalkyl, above the groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, hydroxy, methoxy and carboxy;

ring A, R ₁ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ and m correspond to those in the compound of formula (I).

In yet another preferred embodiment of the invention, in a compound of formula (I), its stereoisomer, prodrug or pharmaceutically acceptable salt, ring A together with -(R ₁ ) _m - form the following structures:

wherein each R ₁ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR ₂₉ , the above groups being optionally substituted by one or more additional substituents selected from the group consisting of deuterium, fluorine, chlorine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, trideuteromethyl, dideuteromethyl, cyclopropyl, oxacyclobutyl, =O, methoxy, carboxy, methoxycarbonyl, acetyl, amino, dimethylamino and acetylamino ;

each R ₂₈ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl, 5-8 membered heteroaryl and -NR ₃₁ R ₃₂ , the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _{3- 8} cycloalkyl, C _3-8 cycloalkoxy and 3-8 membered heterocyclyl;

each R ₂₉ is independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-8 aryl and 5-8 membered heteroaryl, the above groups are optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, C _{3- 8} cycloalkoxy and 3-8 membered heterocyclyl;

each R ₃₀ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, C _3-8 cycloalkyloxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₃₁ R ₃₂ , the above groups optionally substituted with one or more additional substituents selected from the group consisting of deuterium, halogen, hydroxy, cyano, _C1-4 alkyl, _C1-4 alkoxy, _C3-8 cycloalkyl, _C3-8 cycloalkyloxy, 3-8- membered heterocyclyl, 3-8 membered heterocyclyloxy, C _5-8 aryl, C _5-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₃₁ R ₃₂ ;

R ₃₁ and R ₃₂ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, amino, monoalkylamino and dialkylamino.

In the most preferred embodiment of the invention, the compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof includes, but is not limited to, the following compounds:

or .

A second aspect of the present invention is a method for preparing the above compound of formula (I), a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, comprising the following steps:

;

or,

;

optionally, the compound of formula (I) can be prepared by a subsequent substitution reaction in accordance with the definitions of the substituents R ₂ , R ₃ and R ₄ ;

where ring A, ring B, L, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , m, n and p correspond to those in the compound of formula (I).

A third aspect of the present invention is a pharmaceutical composition containing a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A fourth aspect of the present invention is the use of the above compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof for the manufacture of preparations for the treatment of one or more types of tumors, malignancies, metabolic diseases and autoimmune diseases or disorders.

In a preferred embodiment of the invention, the metabolic disease and the autoimmune disease or disorder are selected from the group consisting of atopic dermatitis, contact dermatitis, allergic dermatitis, comedones, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, systemic lupus erythematosus (SLE), psoriasis, chronic lymphocytic thyroiditis, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis (PsA), autoimmune diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus, obesity, fatty liver degeneration, fatty tissue-related inflammation, pancreatitis, thyroiditis, autoimmune thyroid disease, biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease ( IBD), inflammatory bowel syndrome (IBS), Stevens-Johnson syndrome (SJS), primary sclerosing cholangitis, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, celiac disease, neuritis, systemic sclerosis, endometriosis, Behçet's syndrome, myocarditis, dermatomyositis, polymyositis, graft-versus-host disease, sarcoidosis, myocardial infarction, pulmonary hypertension, cutaneous leishmaniasis, Crohn's disease, autoimmune eye disease, optic neuritis, optic neuromyelitis, xerophthalmia, uveitis, insulin resistance, myasthenia gravis, age-related macular degeneration , Guillain-Barré syndrome, glomerulonephritis, scleritis, major depressive disorder, seasonal affective disorder, post-traumatic stress disorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's disease, bronchial asthma, chronic obstructive pulmonary disease (COPD), bronchitis, hay fever , allergic rhinitis, steroid-resistant bronchial asthma, toxic diffuse goiter, obstructive sleep apnea syndrome (OSA), sinus polyps and nervous system disorders associated with changes in sleep and/or circadian rhythm.

In a preferred embodiment of the invention, the tumor or malignancy is selected from the group consisting of fallopian tube tumors, ovarian tumors, peritoneal tumors, stage 4 melanoma, solid tumors, glioma, glioblastoma, papillary renal carcinoma, head and neck tumors, lymphoma , myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, hepatocellular carcinoma, breast cancer, uterine cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer , skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, leukemia and non-small cell lung cancer.

A fifth aspect of the present invention is the use of the above compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof as drugs for the treatment of one or more types of tumors, malignancies, metabolic diseases, autoimmune diseases or disorders.

DETAILED DESCRIPTION OF THE INVENTION

After conducting comprehensive and in-depth research, the inventors of the present invention have first developed a 1,2,3,4-tetrahydroquinoxaline derivative with the structure described by formula (I), as well as a method for its preparation and its use. The compound of the present invention has a strong ability to inhibit the activity of RORγt kinase, can be widely used for drug production and is expected to serve as the basis for the development of new generation RORγt agonists. The present invention is made on this basis.

Detailed Description: Unless otherwise specified, the following terms as used in the specification and claims have the following meanings.

"Alkyl" refers to linear or branched saturated aliphatic alkyl groups, for example "C _1-8 alkyl" refers to linear or branched alkyl containing from 1 to 8 carbon atoms, which includes, but is not limited to, methyl, ethyl, n -propyl , isopropyl, n -butyl, isobutyl, tert -butyl, sec -butyl, n -pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl , n -hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2 -methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n -heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2 ,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n -octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3 -dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers , etc.

Alkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 - C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _{0- 8} -N(R ₃₁ )-C(O)R ₃₀ .

"Cycloalkyl" refers to monocyclic or polycyclic hydrocarbon substituents that are saturated or partially unsaturated, for example, "C _3-10 cycloalkyl" refers to a cycloalkyl containing from 3 to 10 carbon atoms, which may be monocyclic cycloalkyl and polycyclic cycloalkyl, where

monocyclic cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl , etc. ;

polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl. "Spirocycloalkyl" refers to a polycyclic group in which a carbon atom (called spiroatom) is shared by monocyclic rings, these rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of them have a fully conjugated π-electron system. According to the number of spiro atoms common to the rings, spirocycloalkyl may be monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl, including but not limited to:

.

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring shares two adjacent carbon atoms with other rings in the system, wherein one or more (preferably 1 or 2) rings may contain one or more (preferably 1, 2 or 3 ) double bonds, but none of them have a fully conjugated π-electron system. Depending on the number of rings formed, the fused cycloakyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings have two carbon atoms that are not directly bonded to each other, which rings may contain one or more (preferably 1, 2 or 3) double bonds, but none one of them does not have a fully conjugated π-electron system. Depending on the number of rings formed, the bridged cycloalkyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

A cycloalkyl ring may be fused to an aryl, heteroaryl , or heterocycloalkyl ring, where the ring attached to the parent structure is a cycloalkyl, which includes, but is not limited to, indanyl, tetrahydronaphthyl, benzocycloheptyl , etc.

Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 - C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _{0- 8} -N(R ₃₁ )-C(O)R ₃₀ .

"Heterocyclyl" refers to a monocyclic or polycyclic hydrocarbon substituent that is saturated or partially unsaturated, where one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _r ( where r is an integer 0, 1 or 2), excluding the ring portions -OO-, -OS- or -SS-, and the remaining ring atoms are carbon atoms. For example, "5-10 membered heterocyclyl" refers to a cyclic group containing from 5 to 10 ring atoms, and "3-10 membered heterocyclyl" refers to a cyclic group containing from 3 to 10 ring atoms.

Monocyclic heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl , etc.

Polycyclic heterocyclyl includes spiroheterocyclyl, fused heterocyclyl and bridged heterocyclyl. "Spiroheterocyclyl" refers to a polycyclic heterocyclyl group in which an atom (called spiroate) is common to monocyclic rings, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _r (where r is an integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. These rings may contain one or more (preferably 1, 2, 3 or 4) double bonds, but none have a fully conjugated π electron system. According to the number of spiroatoms common to the rings, the spiroheterocyclyl may be a monospiroheterocyclyl, a bispiroheterocyclyl, or a polyspiroheterocyclyl. Spiroheterocyclyl includes, but is not limited to:

.

"Fused heterocyclyl" refers to a polycyclic heterocyclyl in which each ring shares two adjacent atoms with other rings in the system, wherein one or more (preferably 1 or 2) rings may contain one or more (preferably 1, 2 or 3) double bonds , but none of them have a fully conjugated π electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _r (where r represents the integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings formed, the fused heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

"Bridged heterocyclyl" refers to a polycyclic heterocyclyl in which any two rings have two carbon atoms that are not directly bonded to each other, which rings may contain one or more (preferably 1, 2 or 3) double bonds, but none none of these are fully conjugated π electron systems where one or more (preferably 1, 2, 3 or 4) ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _r (where r is the integer 0, 1 or 2), and the remaining ring atoms are carbon atoms. Depending on the number of rings formed, the linked heterocyclyl may be bicyclic, tricyclic, tetracyclic or polycyclic, including but not limited to:

.

A heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring attached to the parent structure is a heterocyclyl, including but not limited to:

.

The heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 - C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _{0- 8} -N(R ₃₁ )-C(O)R ₃₀ .

"Aryl" refers to an all-carbon monocyclic or fused polycyclic group (i.e., rings sharing two adjacent carbon atoms) and a polycyclic group having a conjugated π electron system (i.e., rings sharing two adjacent carbon atoms), e.g., " C _5-10 aryl" refers to an all-carbon aryl containing from 5 to 10 carbon atoms, and "5-10-membered aryl" refers to an all-carbon aryl containing from 5 to 10 carbon atoms, including, but not limited to, phenyl and naphthyl. An aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, including but not limited to:

.

Aryl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _{1 -10} alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C (O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, and heteroatoms include heteroatoms selected from nitrogen, oxygen or S(O)r (where r is an integer of 0, 1 or 2), for example 5-8 -membered heteroaryl refers to a heteroaromatic system containing from 5 to 8 ring atoms, and 5 to 10-membered heteroaryl refers to a heteroaromatic system containing from 5 to 10 ring atoms, including, but not limited to, furyl, thiophenyl, pyridyl, pyrrolyl, N -alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. A heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, including but not limited to:

.

Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl , C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _{0 -8} -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C( O)R ₃₀ .

"Alkenyl" refers to an alkyl, as defined above, containing at least two carbon atoms and at least one carbon-carbon double bond, for example, "C _2-8 alkenyl" refers to a linear or branched alkenyl containing from 2 to 8 carbon atoms. Alkenyl includes, but is not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl , etc.

Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _{1 -10} alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C (O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"Alkynyl" refers to an alkyl, as defined above, containing at least two carbon atoms and at least one carbon-carbon triple bond, for example, "C _2-8 alkynyl" refers to a linear or branched alkynyl containing from 2 to 8 carbon atoms. Alkynyl includes, but is not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl , etc.

The alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _{1 -10} alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C (O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"Alkoxy" refers to -O-(alkyl), where alkyl is as defined above, for example, "C _1-8 alkoxy" refers to an alkoxy radical containing from 1 to 8 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy -, butoxyradical , etc.

Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5- 10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 - C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _{0- 8} -N(R ₃₁ )-C(O)R ₃₀ .

"Cycloalkyloxy" refers to -O- (unsubstituted cycloalkyl), where cycloalkyl is as defined above, for example, "C _3-10 cycloalkyloxy" refers to a cycloalkyloxy radical containing from 3 to 10 carbon atoms, including, but not limited to, cyclopropyloxy-, cyclobutyloxy-, cyclopentyloxy, cyclohexyloxy radical , etc.

Cycloalkyloxy may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _{1 -10} alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 -membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C (O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"3-10 membered heterocyclyloxy" refers to -O-(unsubstituted 3-10 membered heterocyclyl), wherein 3-10 membered heterocyclyl is as defined above. The 3-10 membered heterocyclyloxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10-membered heterocyclyl, C _{5- 10} aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , - C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

" _C5-10 aryloxy" refers to -O-(unsubstituted _C5-10 aryl), where _C5-10 aryl is as defined above. The _C5-10 aryloxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from the group consisting of deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, = O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"5-10 membered heteroaryloxy" refers to -O-(unsubstituted 5-10 membered heteroaryl), wherein 5-10 membered heteroaryl is as defined above. The 5-10 membered heteroaryloxy may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from the group consisting of deuterium, halogen, cyano, nitro , azido, C _1-10 alkyl, C _1-10 haloalkyl, C _1-10 deuteroalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _5-10 aryl, 5-10-membered heteroaryl, =O, -C _0-8 -S(O) _r R ₂₈ , -C _0-8 -OR ₂₉ , -C _0-8 -C(O)OR ₂₉ , -C _0-8 -C(O)R ₃₀ , -C _0-8 -OC(O)R ₃₀ , -C _0-8 -NR ₃₁ R ₃₂ , -C _0-8 -C(O)NR ₃₁ R ₃₂ and -C _0-8 -N(R ₃₁ )-C(O)R ₃₀ .

"C _1-8 alkanoyl" refers to the monovalent atomic group that results from the removal of the hydroxy group from a C _1-8 alkyl acid, and is also commonly referred to as "C _0-7 -C(O)-", e.g. "C ₁ -C (O)-" refers to acetyl; “C ₂ -C(O)-” “refers to propionyl; and "C ₃ -C(O)-" refers to butyryl or isobutyryl.

"-C _0-8 -S(O) _r R ₂₈ " means that the sulfur atom in -S(O) _r R ₂₈ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to the bond and C _1-8 alkyl corresponds to the above definition.

"-C _0-8 -OR ₂₉ " means that the oxygen atom in -OR ₂₉ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to a bond and C _1-8 alkyl is as defined above.

" _-C0-8 -C(O)OR ₂₉ " means that the carbonyl group in -C(O)OR ₂₉ is attached to a _C0-8 alkyl, where _C0 alkyl refers to the bond and _C1-8 alkyl corresponds to the above definition.

"-C _0-8 -C(O)OR ₃₀ " means that the carbonyl group in -C(O)R ₃₀ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to the bond and C _1-8 alkyl corresponds to the above definition.

"-C _0-8 -OC(O)R ₃₀ " means that the oxygen atom in -OC(O)R ₃₀ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to the bond and C _1-8 alkyl corresponds to the above definition.

"-C _0-8 -NR ₃₁ R ₃₂ " means that the nitrogen atom in -NR ₃₁ R ₃₂ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to a bond and C _1-8 alkyl is as defined above.

"-C _0-8 -C(O)NR ₃₁ R ₃₂ " means that the carbonyl group in -C(O)NR ₃₁ R ₃₂ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to the bond and C _{1 -8} alkyl corresponds to the above definition.

“-C _0-8 -N(R ₃₁ )-C(O)R ₃₀ ” means that the nitrogen atom in -N(R ₃₁ )-C(O)R ₃₀ is attached to a C _0-8 alkyl, where C ₀ alkyl refers to a bond, and C _1-8 alkyl is as defined above.

"C _1-8 haloalkyl" refers to an alkyl containing from 1 to 8 carbon atoms, in which the alkyl hydrogen atoms are optionally replaced by a fluorine, chlorine, bromine or iodine atom, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl , etc.

"C _1-8 haloalkoxy" refers to an alkoxy radical containing from 1 to 8 carbon atoms, in which the alkyl hydrogen atoms are optionally replaced by a fluorine, chlorine, bromine or iodine atom, including, but not limited to, difluoromethoxy-, dichloromethoxy-, dibromomethoxy-, trifluoromethoxy -, trichloromethoxy-, tribromomethoxy radical , etc.

"Halogen" refers to fluorine, chlorine, bromine or iodine. "DCM" refers to dichloromethane. "PE" refers to petroleum ether. "EA/EtAc" refers to ethyl acetate. "THF" refers to tetrahydrofuran. "PE" refers to petroleum ether. "DMSO" refers to dimethyl sulfoxide. "MeCN" refers to acetonitrile. "DME" refers to dimethyl ether. "Pd(dppf)Cl ₂ " refers to palladium[1,1'-dikis(diphenylphosphorus)ferrocene]chloride.

The term “optional” or “optional” means that the event or circumstance described below may occur, but does not necessarily occur, and that the description includes cases in which the event or circumstance does or does not occur. For example, “heterocyclyl group optionally substituted with alkyl” means that alkyl may, but is not required to, be present and that the description includes cases where the heterocyclyl group is or is not substituted with alkyl.

The term "substituted" means that one or more hydrogen atoms in a group are independently substituted with an appropriate number of substituents. It goes without saying that the substituent is only in its possible chemical position, and those skilled in the art will be able to determine (experimentally or theoretically) the possible or impossible substitution without undue effort. For example, instability may occur if an amino group or hydroxy group having a free hydrogen is bonded to a carbon atom having an unsaturated bond (eg, an olefin).

“Pharmaceutical composition” refers to a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, as well as other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of this pharmaceutical composition is to facilitate the administration of the drug into the body, improving the absorption of the active substance and thereby facilitating the manifestation of its biological activity.

The following is a detailed explanation of the present invention with reference to embodiments thereof, which are not intended to limit the present invention; however, the present invention is not limited to the embodiments presented.

The structure of the compound of the present invention is determined using nuclear magnetic resonance (NMR) and/or liquid chromatography coupled with mass spectrometry (LC-MS). Chemical shifts of NMR spectra (δ) are given in parts per million (ppm). Determination by NMR spectrum is carried out using a Bruker AVANCE-400 or Bruker AVANCE-500 nuclear magnetic resonance unit with deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ) as solvents and tetramethylsilane (TMS) as internal standard.

LC-MS determinations are performed using an Agilent 6120 mass spectrometer. HPLC determinations are performed using an Agilent 1200 DAD HPLC (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 HPLC (chromatographic column Gimini C18 150×4.6 mm).

The thin layer chromatography (TLC) plate used is Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification for TLC is set to 0.15-0.20 mm, and the specification for thin layer chromatography for separation and purification of products is set to 0.4-0.5 mm. Yantai Yellow Sea silica gel with a particle size of 200-300 mesh is usually used as a carrier for column chromatography.

The starting materials in the exemplary embodiments of the present invention are known and commercially available or can be synthesized by or in accordance with methods known in the art.

Unless otherwise specified, all reactions of the present invention are carried out under an atmosphere of dry nitrogen or argon with continuous stirring on a magnetic stirrer, where the solvent is a dry solvent and the reaction temperature is in degrees Celsius (°C).

I. Preparation of intermediate substances

1. Preparation of 6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline

Step 1. Synthesis of 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethan-1-ol

4-bromo-1-fluoro-2-nitrobenzene (2.50 g, 11.4 mmol), 2-(methylamino)ethan-1-ol (2.13 g, 28.4 mmol), potassium carbonate (4, 70 g, 34.1 mmol) and N , N -dimethylformamide (10 ml) were added to a 250 ml one-neck flask, the reaction mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled and then diluted with water (50 ml) and extracted with ethyl acetate (50 ml x 2). The organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate and then filtered and concentrated to give 2-((4-bromo-2-nitrophenyl)(methyl)amino)ethan-1-ol (3.20 g , output: 100%). Electrospray ionization mass spectrometry (ESI-MS): 275.0 [M+1] ⁺ .

Step 2. Synthesis of 2-((2-amino-4-bromophenyl)(methyl)amino)ethan-1-ol

2-((4-bromo-2-nitrophenyl)(methyl)amino)ethan-1-ol (3.20 g, 99%, 11.6 mmol), water (50 ml), iron powder (2.35 g , 41.9 mmol) and ammonium chloride (626 mg, 11.6 mmol) were added to a 100 ml one-neck flask. The reaction was carried out overnight at 105°C, the reaction mixture was cooled to 40-50°C and filtered through celite, and the filter cake was washed with ethyl acetate (20 ml x 4). The filtrate was separated into layers and the aqueous layer was further extracted with ethyl acetate (50 ml). The organic phases were combined and dried over anhydrous sodium sulfate and then filtered and concentrated. The crude product was separated by silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 2:1-1:3] to give 2-((2-amino-4-bromophenyl)(methyl)amino)ethan-1-ol ( 2.30 g, yield: 76.9%). Electrospray ionization mass spectrometry (ESI-MS): 245.0 [M+1] ⁺ .

Stage 3. Synthesis of 4-bromo- N ¹ -(2-chloroethyl)- N ¹ -methylbenzene-1,2-diamine

2-((2-amino-4-bromophenyl)(methyl)amino)ethan-1-ol (2.30 g, 95%, 8.91 mmol) and dichloromethane (50 ml) were added to a 250 ml one-neck flask, then thionyl chloride (1.27 g, 10.7 mmol) was added dropwise in an ice bath, followed by two drops of N , N -dimethylformamide. The reaction mixture was warmed to room temperature and stirred for 1 hour, and then heated to a temperature of 35°C and stirred for 2.5 hours. After concentration, an aqueous solution of sodium hydroxide (1N) was added to it, and the mixture solution was extracted with dichloromethane. The organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash chromatography on a silica gel column [eluent: petroleum ether: ethyl acetate = 0:100-15:85] to give 4-bromo- N ¹ -(2-chloroethyl) -N ¹ -methylbenzene-1,2-diamine (1.84 g, yield: 74.4%). Electrospray ionization mass spectrometry (ESI-MS): 263.0 [M+1] ⁺ .

Step 4. Synthesis of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline

4-bromo ^- N1- (2-chloroethyl) -N1 ^- methylbenzene-1,2-diamine (1.84 g, 95%, 6.63 mmol) was dissolved in N , N -dimethylformamide (20 ml) and added to a solution of potassium carbonate (1.83 g, 13.3 mmol). The reaction mixture was stirred at 80°C for 1 hour, then heated to 100°C and stirred for 1.5 hours. The mixture solution was cooled to room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic phases were washed once with saturated sodium chloride (80 ml). The organic phases were dried and filtered, the filtrate was concentrated; the residue was separated by flash silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 0:100-70:30] to give 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (750 mg, yield: 47.3%). Electrospray ionization mass spectrometry (ESI-MS): 227.0 [M+1] ⁺ .

Step 5. Synthesis of 6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline

6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxaline (375 mg, 95%, 1.57 mmol), 3-(trifluoromethyl)-benzenesulfonyl chloride (422 mg, 1.73 mmol) was dissolved in dichloromethane ( 15 ml) and 4-dimethylaminopyridine (375 mg, 95%, 1.57 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated to dryness and the residue was separated by flash chromatography on a silica gel column [eluent: EtAc: PE = 0-80%] to give 6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl) sulfonyl)-1,2,3,4-tetrahydroquinoxaline (480 mg, yield: 66.7%). Electrospray ionization mass spectrometry (ESI-MS): 435.0 [M+1] ⁺ .

2. Receipt rubs -butyl 6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1(2 H )-carboxylate

Step 1. Synthesis of methyl (4-bromo-2-nitrophenyl) glycinate

4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.09 mmol), glycine methyl ester hydrochloride (1.26 g, 10.0 mmol), diisopropylethylamine (2.5 ml, 14.5 mmol ) and acetonitrile (30 ml) were added to a 250 ml one-neck flask; the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled and then diluted with water (40 ml) and extracted with ethyl acetate (70 ml x 2). The organic phases were washed with brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl (4-bromo-2-nitrophenyl)glycinate (2.1 g, yield: 71.9%). Electrospray ionization mass spectrometry (ESI-MS): 289.0 [M+1] ⁺ .

Stage 2. Synthesis of 7-bromo-3,4-dihydroquinoxaline-2(1 H )-she

Methyl (4-bromo-2-nitrophenyl)glycinate (1.8 g, 90%, 5.6 mmol), acetic acid (20 ml) and iron powder (1.57 g, 28.0 mmol) were added to a one-neck flask capacity 100 ml. The reaction was then carried out at a temperature of 60°C for 2.5 hours. The mixture solution was cooled to a temperature of 40-50°C and filtered through celite, and the filtered precipitate was washed with ethyl acetate (20 ml x 4). The filtrate was separated into layers and the aqueous layer was further extracted with ethyl acetate (50 ml). The organic phases were combined, washed successively with brine (50 ml x 2) and saturated sodium bicarbonate solution (50 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 95:5-1:100] to give 7-bromo-3,4-dihydroquinoxalin-2( 1H )-one (1.0 g, yield : 74.7%). Electrospray ionization mass spectrometry (ESI-MS): 227.0 [M+1] ⁺ .

Stage 3. Synthesis rubs -butyl-6-bromo-3-oxo-3,4-dihydroquinoxaline-1(2 H )-carboxylate

7-bromo-3,4-dihydroquinoxalin-2( 1H )-one (500 mg, 95%, 2.1 mmol), dichloromethane (15 ml), di -tert- butyl dicarbonate (684 mg, 3.14 mmol) and 4-dimethylaminopyridine (684 mg, 3.14 mmol) was added to a 100 mL one-neck flask. The reaction mixture was heated to 40°C and stirred for 2 hours. The solution of the mixture was concentrated and the residue was separated by flash chromatography on a silica gel column [eluent: petroleum ether: ethyl acetate = 0:100-40:60] to obtain tert -butyl- 6-bromo-3-oxo-3,4-dihydroquinoxaline-1( 2H )-carboxylate (580 mg, yield: 80.0%). Electrospray ionization mass spectrometry (ESI-MS): 349.0 [M+23] ⁺ , 271.0 [M-56] ⁺ .

Stage 4. Synthesis rubs -butyl-6-bromo-3,4-dihydroquinoxaline-1(2 H )-carboxylate

Tert -butyl-6-bromo-3-oxo-3,4-dihydroquinoxaline-1( 2H )-carboxylate (260 mg, 95%, 0.75 mmol) was dissolved in anhydrous tetrahydrofuran (6 ml) and borane was added to the solution -dimethylsulfide complex (2M tetrahydrofuran solution, 1.13 ml, 2.26 mmol). The reaction mixture was stirred at 50°C for 1.5 hours. Completion of the reaction was confirmed by LC-MS; To stop the reaction, methanol (10 ml) was added and stirred at 40°C for 1 hour. The mixture was concentrated and the residue was separated by flash chromatography on a silica gel column [eluent: petroleum ether: ethyl acetate = 0:100-50:50] to give tert -butyl-6-bromo-3,4-dihydroquinoxaline-1( 2H )-carboxylate (210 mg, yield: 84.9%). Electrospray ionization mass spectrometry (ESI-MS): 313.0 [M+1] ⁺ .

Stage 5. Synthesis rubs -butyl 6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1(2 H )-carboxylate

Tert -butyl-6-bromo-3,4-dihydroquinoxaline-1( 2H )-carboxylate (210 mg, 95%, 0.64 mmol), 3-(trifluoromethyl)benzenesulfonyl chloride (171 mg, 0.70 mmol) dissolved in dichloromethane (10 ml) and 4-dimethylaminopyridine (78 mg, 0.64 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated to dryness and the residue was separated by flash silica gel column chromatography [eluent: EtAc:PE = 0-60%)] to give a pale yellow oily tert -butyl-6-bromo-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1( 2H )-carboxylate (277 mg, yield: 79.2%). Electrospray ionization mass spectrometry (ESI-MS): 421.0 [M+1] ⁺ .

3. Preparation of methyl-( S )-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Stage 1. Synthesis of dimethyl (4-bromo-2-nitrophenyl)- L -glutamate

4-bromo-1-fluoro-2-nitrobenzene (10.0 g, 45.4 mmol), dimethyl D -glutamate hydrochloride (11.5 g, 54.5 mmol), potassium carbonate (25.1 g, 182 mmol ), N , N -dimethylformamide (50 ml) was added to a 250 ml one-neck flask and the reaction mixture was stirred at 80°C for 18 hours. The reaction mixture was cooled and then diluted with water (100 ml) and extracted with ethyl acetate (150 ml × 2). The organic phases were washed with saline (200 ml x 2), separated, dried over anhydrous sodium sulfate and filtered, and the residue was separated by silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 100:0-20:80] to give dimethyl -(4-bromo-2-nitrophenyl) -L- glutamate (6.0 g, yield: 32.8%). Electrospray ionization mass spectrometry (ESI-MS): 375.0 [M+1] ⁺ .

Stage 2. Synthesis of methyl-( S )-3-(6-bromo-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl) propanoate and ( S )-7-bromo-3,3a-dihydropyrrolo[1,2- a ]quinoxaline-1,4(2 H ,5 H )-dione

Dimethyl (4-bromo-2-nitrobenzene) -L -glutamate (6.0 g, 93%, 14.9 mmol), acetic acid (30 ml) and iron powder (4.17 g, 74.5 mmol) were added into a 250 ml one-neck flask, then reacted at 60°C for 2 hours, cooled to 40-50°C and filtered through celite, and the filtered precipitate was washed with ethyl acetate (30 ml × 5). The filtrate was separated into layers and the aqueous layer was further extracted with ethyl acetate (50 ml). The combined organic phases were washed successively with water (100 ml), brine (100 ml) and saturated sodium bicarbonate solution (100 ml x 3), and then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 100:0-0:100] to give methyl ( S )-3-(6-bromo-3-oxo-1,2,3,4- tetrahydroquinoxalin-2-yl)propanoate (1.7 g) (ESI-MS: 313.0 [M+1] ⁺ ) and ( S )-7-bromo-3,3a-dihydropyrrolo[1,2- a ]quinoxaline -1,4( 2H , 5H )-dione (500 mg) (ESI-MS: 281.0 [M+1] ⁺ ).

Stage 3. Synthesis of methyl-( S )-3-(6-bromo-1-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (1.70 g, 5.16 mmol) and N , N -dimethylformamide ( 10 ml) was added to a 250 ml one-neck flask. Aqueous formaldehyde (3.9 g, 40%, 51.6 mmol) and a few drops of acetic acid were added to the solution, and the reaction mixture was stirred at room temperature for 1.5 hours. Sodium cyanoborohydride (1.62 g, 25.8 mmol) and stirred for 18 hours. After dilution with ethyl acetate (150 ml), the mixture solution was washed with brine (100 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 0:100-15:85] to give methyl-( S )-3-(6-bromo-1-methyl-3-oxo- 1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (660 mg, yield: 34.4%). Electrospray ionization mass spectrometry (ESI-MS): 263.0 [M+1] ⁺ .

Stage 4. Synthesis of methyl-( S )-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-1-methyl-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (660 mg, 1.78 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and borane-dimethylsulfide complex (2M tetrahydrofuran solution, 2.2 ml, 4.44 mmol) was added to the solution. The reaction mixture was stirred at 40°C for 3 hours; completion of the reaction was confirmed using LC-MS and TLC plates; Methanol (10 ml) was added to stop the reaction and the reaction mixture was heated to 50°C and stirred for 1 hour. The mixture was concentrated and the residue was separated by flash silica gel column chromatography [eluent: petroleum ether: ethyl acetate = 0:100 -40:60] to give methyl-( S )-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (360 mg, yield: 61.4%) . Electrospray ionization mass spectrometry (ESI-MS): 313.0 [M+1] ⁺ .

Stage 5. Synthesis of methyl-( S )-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (360 mg, 1.09 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride ( 538 mg, 2.19 mmol) was dissolved in pyridine (8 ml) and 4-dimethylaminopyridine (199 mg, 1.64 mmol) was added to the solution. The reaction mixture was stirred overnight at room temperature 50°C. Completion of the reaction was confirmed using LC-MS. The reaction mixture was concentrated to dryness and the residue was separated by flash silica gel column chromatography (0-80% EtAc:PE) to give ( S )-3-(6-bromo-1-methyl-4-((3-( trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (560 mg, yield: 93.6%). Electrospray ionization mass spectrometry (ESI-MS): 521.2 [M+1] ⁺ .

4. Receiving ( S )-7-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline

Stage 1. Synthesis ( S )-7-bromo-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline

( S )-7-bromo-3,3a-dihydropyrrolo[1,2- a ]quinoxaline-1,4( 2H , 5H )-dione (170 mg, 0.57 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml ) and borane-dimethylsulfide complex (2M tetrahydrofuran solution, 0.86 ml, 1.72 mmol) was added to the solution. The reaction mixture was stirred at 50°C for 2 hours. Completion of the reaction was confirmed by LC-MS; To stop the reaction, methanol (10 ml) was added and stirred at 50°C for 1 hour. The mixture was concentrated and the residue was separated by flash chromatography on a silica gel column [eluent: petroleum ether: ethyl acetate = 0:100-50:50] to give ( S )-7-bromo-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline (100 mg, yield: 65.9%). Electrospray ionization mass spectrometry (ESI-MS): 253.0 [M+1] ⁺ .

Stage 2. Synthesis ( S )-7-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline

( S )-7-bromo-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline (100 mg, 0.375 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (137 mg, 0.563 mmol ) was dissolved in dichloromethane (5 ml) and 4-dimethylaminopyridine (46 mg, 0.375 mmol) was added to the solution. The reaction mixture was stirred at room temperature overnight. LC-MS showed almost complete completion of the reaction. The reaction mixture was concentrated to dryness and the residue was separated by flash silica gel column chromatography (0-30% EtAc:PE) to give ( S )-7-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline (160 mg, 93%). Electrospray ionization mass spectrometry (ESI-MS): 461.0 [M+1] ⁺ .

5. Receipt rubs -butyl-( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Stage 1. Synthesis ( S )-1-(4-bromo-2-nitrophenyl)-4-( rubs -butoxycarbonyl)piperazine-2-carboxylic acid

4-bromo-1-fluoro-2-nitrobenzene (2.2 g, 10 mmol) was dissolved in N , N -dimethylformamide (20 ml) and cesium carbonate (9.75 g, 30 mmol) and 1-( tert -butyl)3-methyl-( S )-piperazine-1,3-dicarboxylate (2.44 mg, 10 mmol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( S )-1-(4-bromo-2-nitrophenyl)-4-( tert -butoxycarbonyl)piperazine-2-carboxylic acid (310 mg, 7.2%). Electrospray ionization mass spectrometry (ESI-MS): 374 [M-55] ⁺ .

Stage 2. Synthesis rubs -butyl-( S )-8-bromo-5-oxo-1,2,4,4a,5,6-hexahydro-3 H -pyrazino [1,2- a ]quinoxaline-3-carboxylate

( S )-1-(4-bromo-2-nitrophenyl)-4-( tert -butoxycarbonyl)piperazine-2-carboxylic acid (890 mg, 2.0 mmol) was dissolved in acetic acid (10 ml) and added to the solution iron powder (560 mg, 10 mmol). The mixture solution was stirred at 70°C for 2 hours, filtered and concentrated to remove the solvent. The residue was washed with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried, concentrated and then separated by flash silica gel column chromatography to give tert -butyl( S )-8-bromo-5-oxo-1,2,4,4a,5 ,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (325 mg, 43%). Electrospray ionization mass spectrometry (ESI-MS): 326 [M-55] ⁺ .

Stage 3. Synthesis rubs -butyl-( R )-8-bromo-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl-( S )-8-bromo-5-oxo-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (325 mg, 0.85 mmol) was dissolved in tetrahydrofuran (15 ml) and a solution of borane dimethyl sulfide in tetrahydrofuran (1.3 ml, 2M) was added to the resulting solution. The reaction mixture was stirred at 50°C for 16 hours, then cooled to 0°C, methanol was added to stop the reaction, and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl-( R )-8-bromo-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline- 3-carboxylate (250 mg, 80%). Electrospray ionization mass spectrometry (ESI-MS): 312 [M-55] ⁺ .

Stage 4. Synthesis rubs -butyl-( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl ( R )-8-bromo-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (250 mg, 0.68 mmol) was dissolved in pyridine (4 ml) and 3-(trifluoromethyl)benzenesulfonyl chloride (332 mg, 1.36 mmol) was added to the solution. The reaction mixture was stirred at 70°C for 5 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl-( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro -3H- pyrazino[1,2- a ]quinoxaline-3-carboxylate (340 mg, 96%). Electrospray ionization mass spectrometry (ESI-MS): 520 [M-55] ⁺ .

6. Preparation of 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1. Synthesis of 1-bromo-3-(difluoromethoxy)-5-fluorobenzene

3-fluoro-5-bromophenol (8.69 g, 45.5 mmol) was dissolved in N , N -dimethylformamide (30 ml); Potassium carbonate (16.00 g, 115.8 mmol) was added to the resulting solution, and the mixture solution was stirred at room temperature for 30 minutes. Water (8.2 mL) and sodium difluorochloroacetate (11.98 g, 78.6 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 100°C under a nitrogen atmosphere for 3 days; the reaction mixture was cooled to room temperature and then diluted with ethyl acetate (30 ml) and washed with brine (100 ml x 3). The organic phases were dried over anhydrous magnesium sulfate. The reaction mixture was filtered, concentrated and separated by column chromatography [eluent: EA: PE = 2%) to give 1-bromo-3-(difluoromethoxy)-5-fluorobenzene (4.624 g, 42%), which was used without further treatment next stage.

Step 2. Synthesis of 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-bromo-3-(difluoromethoxy)-5-fluorobenzene (4.62 g, 19.1 mmol), pinacol-diborone (9.79 g, 38.6 mmol), potassium acetate (7.56 g, 77. 0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium chloride (1.51 g, 2.1 mmol) were dissolved in dioxane (45 ml) and reacted under nitrogen at 80°C for 17 hours The reaction mixture was cooled to room temperature, immediately concentrated and separated by column chromatography [eluent: EA: PE = 0%-10%) to give 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4. 5,5-tetramethyl-1,3,2-dioxaborolane (3.63 g, 66%), which was used without further processing in the next step.

7. Receiving ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Stage 1. Synthesis of 1-chloro-2-ethynyl-3-fluorobenzene

2-Chloro-6-fluorobenzaldehyde (1.0 g, 6.3 mmol) was dissolved in methanol (40 ml) and added to the dimethyl (1-diazo-2-oxopropyl)phosphonate solution (1.2 ml, 7. 9 mmol) and potassium carbonate (2.16 g, 15.75 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, added methyl tert-butyl ether (50 ml), extracted with water (50 ml x 3) and washed with brine (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1-chloro-2-ethynyl-3-fluorobenzene (0.8 g, 82%), which was used without further treatment in the next step.

Stage 2. Synthesis ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Pinacol diborone (1.45 g, 5.7 mmol), CuCl (0.05 g, 0.5 mmol) and 4,5-bis(di -tert -butylphosphino)-9,9-dimethylxanthene (0.30 g, 0.5 mmol) was stirred in tetrahydrofuran (50 ml) and reacted under nitrogen atmosphere for 5 min. Sodium tert -butoxide (0.55 g, 5.7 mmol) was dissolved in tetrahydrofuran (5 ml), added to the reaction mixture and stirred for 5 minutes. 1-Chloro-2-ethynyl-3-fluorobenzene (0.80 g, 5.2 mmol) and iodomethane (2.96 g, 20.8 mmol) were added to the reaction mixture, reacted overnight at room temperature, and then concentrated and separated by column chromatography [eluent: petroleum ether-petroleum ether/ethyl acetate (98:2)] to give ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-ene- 1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.5 g, 33%), which was used without further processing in the next step.

8. Preparation of intermediate B3: ( E )-2-(2-chloro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step 1. Synthesis of 1-chloro-2-ethynyl-3-trifluoromethylbenzene

2-chloro-6-trifluoromethyl benzaldehyde (3.65 g, 17.4 mmol) and dimethyl (1-diazo-2-oxopropyl) phosphonate (2.85 g, 14.9 mmol) were dissolved in methanol (30 ml). Potassium carbonate (8.28 g, 59.9 mmol) was added to the solution and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with methyl tert -butyl ether (100 ml) and washed with saturated aqueous sodium chloride (30 ml x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude 1-chloro-2-ethynyl-3-trifluoromethylbenzene (3.471 g, 98%), which was used without further treatment in the next step.

Stage 2. Synthesis ( E )-2-(2-chloro-6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Crude product 1-chloro-2-ethynyl-3-trifluoromethylbenzene (3.47 g, 17.0 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.75 g, 52.0 mmol) 7 mmol) was dissolved in toluene (26 ml) and carbonyl chlorotris-(triphenylphosphine)-ruthenium (0.96 g, 1.0 mmol) was added to the solution, after which the mixture solution was stirred under a nitrogen atmosphere at 50°C overnight . The reaction mixture was cooled to room temperature, diluted with ethyl acetate (80 ml) and washed with brine (30 ml x 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated and separated by column chromatography [eluent: EA: PE = 0%-10%) to give ( E )-2-(2-chloro-6-(trifluoromethyl) styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.096 g, 55%), which was used without further processing in the next step.

9. Preparation of 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-1,3,2-dioxaborolane

Stage 1. Synthesis of 2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl-4,4,4,4,4,4,4,4,4-nonafluoro-4λ ¹² -but-1,3-diyne-1-sulfonate

LDA (4.1 g, 2N, 38.4 mmol) was added to the solution under nitrogen atmosphere. The solution was cooled to -78°C; a solution of 2,2,6,6-tetramethyltetrahydro- 4H- pyran-4-one (5.0 g, 32.0 mmol) in THF (80 ml) was slowly added dropwise to the cooled solution. The reaction mixture was stirred at -78°C for 1 hour; then 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride (11.6 g, 38.4 mmol) was added to the mixture. The reaction mixture was stirred at -78°C to approximately 0°C for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated NaHCO ₃ (100 ml). The mixture solution was extracted with ethyl acetate (3×50 ml). The organic phases were combined, washed with brine (50 ml), dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was separated by flash silica gel column chromatography (PE:EA = 0-20%) to give 2,2,6,6-tetramethyl-3,6-dihydro- 2H- pyran-4-yl 4 ,4,4,4,4,4,4,4,4-nonafluoro- 4λ ¹² -but-1,3-diyne-1-sulfonate (10 g, 71%), which was used without further processing in the next step.

Stage 2. Synthesis of 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-1,3,2-dioxaborolane

2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl-4,4,4,4,4,4,4,4,4-nonafluoro- 4λ ¹² -but- 1,3-diyne-1-sulfonate (10.0 g, 22.8 mmol), bis(pinacolato) diborone (6.3 g, 25.1 mmol), Pd(dppf)Cl ₂ (930 mg, 1. 14 mmol) and potassium acetate (6.7 g, 68.4 mmol) were stirred in DME (100 ml). The reaction mixture was stirred at 80°C under nitrogen atmosphere for 16 hours. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated and the residue was separated by flash silica gel column chromatography (eluent: PE:EA = 0-5%] to give the product 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl -3,6-dihydro- 2H -pyran-4-yl)-1,3,2-dioxaborolane (2.3 g, 38%), which was used without further processing in the next step.

10. Receipt rubs -butyl-( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a, 5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

A reference is given to the preparation of tert -butyl-( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1 ,2- a ]quinoxaline-3-carboxylate.

11. Receiving ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Stage 1. Synthesis rubs -butyl-( S )-8-bromo-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl ( R )-8-bromo-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (1.2 g, 3.2 mmol) was dissolved in pyridine (10 ml) and 3-(trifluoromethoxy)benzenesulfonyl chloride (1.3 g, 4.8 mmol) was added to the solution. The reaction mixture was stirred at 50°C for 20 hours. The solvent was removed by concentration to give crude tert -butyl( S )-8-bromo-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4 ,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate, which was used without additional treatment in the next step.

Stage 2. Synthesis rubs -butyl( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

The crude tert -butyl ( S )-8-bromo-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate, tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol), sodium carbonate (1.1 g, 16.8 mmol) and ( E )-2-(2-chloro- 6-(trifluoromethyl)styryl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.6 g, 5.0 mmol); added toluene (18 ml), ethanol (12 ml) and water (6 ml). Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 90°C and reacted for 20 hours. After completion of the reaction, the reaction mixture was concentrated, washed with brine (60 mg) and extracted with ethyl acetate (30 ml x 3) to remove the solvent. The organic phases were combined, dried, filtered and concentrated, and the residue was separated by flash silica gel column chromatography to give tert -butyl( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3 -(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (235 mg, 10%). Electrospray ionization mass spectrometry (ESI-MS): 618 [M-Boc+H] ⁺ .

Stage 3. Synthesis ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Tert -butyl ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H- pyrazino[1,2- a ]quinoxaline-3-carboxylate (235 mg, 0.33 mmol) was dissolved in a solution of HCl in dioxane (6 ml, 4M). The reaction mixture was stirred at room temperature for 5 hours. The solvent was removed by concentration to give ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl )-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (219 mg, 100%), which was used without further treatment in the next step.

12. Receipt rubs -butyl ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a, 5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Stage 1. Synthesis of 3-bromo-2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridine

2-( tert -Butyldimethylsilyl)oxy)ethanol (9.7 g, 55.0 mmol) was dissolved in anhydrous THF (60 mL) and NaH (3.0 g, 60% in oil, 75.0 mmol) was added portionwise. The reaction mixture was stirred at 24°C under nitrogen atmosphere for 30 min. A solution of 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (13.0 g, 50.0 mmol) in anhydrous THF (20 ml) was added and the reaction mixture was stirred at 80°C for 3 hours; completion of the reaction was confirmed by LC-MS. The reaction mixture was quenched with saturated ammonium chloride (100 ml). The mixture was extracted with ethyl acetate (3×100 ml). The organic phases were combined, dried over magnesium sulfate and filtered. The filtrate was concentrated and separated by flash silica gel column chromatography (eluent: PE:EA = 0-50%] to give 3-bromo-2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl) pyridine (9.8 g, 49%).

^1H NMR (500 MHz, CDCl ₃ ) δ 8.25 (dd, J =2.5, 1.3 Hz, 1H), 7.92 (d, J =2.4 Hz, 1H), 4.42 (t, J =5.8 Hz, 2H), 3.91 (t, J =5.8 Hz, 2H), 0.80 (s, 9H), 0.00 (s, 6H). Electrospray ionization mass spectrometry (ESI-MS): 400 [M+H] ⁺ .

Step 2. Synthesis of 3-(benzylthio)-2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridine

3-bromo-2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridine (3.0 g, 7.5 mmol), benzylthiol (930 mg, 7.5 mmol), Pd ₂ (dba) ₃ (300 mg), xanthos (300 mg) and diisopropylethylamine (1.9 g, 15.0 mmol) were stirred in 1,4-dioxane (50 ml). The reaction mixture was stirred at 100°C under nitrogen atmosphere for 16 hours; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated and the residue was separated by flash silica gel column chromatography to give 3-(benzylthio)-2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridine (2.8 g, 84%) (PE:EA = 0-5%). Electrospray ionization mass spectrometry (ESI-MS): 444 [M+H] ⁺ .

Step 3. Synthesis of 2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

3-(benzylthio)-2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridine (2.8 g, 6.32 mmol) and dichlorohydantoin (2.7 g, 13.9 mmol) was dissolved in acetic acid (50 ml) and H ₂ O (15 ml). The reaction mixture was stirred at room temperature for 16 hours; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated. The residue was dissolved in DCM (100 ml), washed successively with saturated NaHCO ₃ (50 ml), H ₂ O (50 ml) and brine (50 ml). The organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was separated by flash silica gel column chromatography to give 2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (930 mg, 48%) (DCM: MeOH = 0-5%).

^1H NMR (500 MHz, CDCl ₃ ) δ 8.68 (d, J =2.3 Hz, 1H), 8.40 (d, J =2.3 Hz, 1H), 4.70 (t, J =5.8 Hz, 2H), 4.00 (t, J =5.8 Hz, 2H), 2.14 (br, 1H). Electrospray ionization mass spectrometry (ESI-MS): 306 [M+H] ⁺ .

Stage 4. Synthesis rubs -butyl-( S )-8-bromo-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridine-3-sulfonyl chloride (170 mg, 0.56 mmol), tert -butyl-( R )-8-bromo-1,2,4,4a,5, 6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (205 mg, 0.56 mmol) and diisopropylethylamine (145 mg, 1.11 mmol) were dissolved in acetonitrile (10 ml). The reaction mixture was stirred at 50°C for 16 hours; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated and the residue was separated by flash silica gel column chromatography to give tert -butyl-( S )-8-bromo-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (350 mg, 90%) (PE: EA = 0-25% ). Electrospray ionization mass spectrometry (ESI-MS): 637 [M+H] ⁺ .

Stage 5. Synthesis rubs -butyl ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a, 5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl ( S )-8-bromo-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro -3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (350 mg, 0.55 mmol), pinacol 3-difluoromethoxy-5-fluorobenzene borate (237 mg, 0.82 mmol), Pd(dppf)Cl ₂ (50 mg) and potassium carbonate (228 mg, 1.65 mmol) were added to 1,4-dioxane (15 ml) and H ₂ O (5 ml). The reaction mixture was stirred at 100°C under nitrogen atmosphere for 16 hours; completion of the reaction was confirmed by LC-MS. The reaction mixture was concentrated. The residue was dissolved in DCM (50 ml) and H ₂ O (50 ml). The organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated, the residue was separated by flash chromatography on a silica gel column (eluent: PE:EA = 0-25%] to give tert -butyl( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-( (2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ]quinoxaline- 3-carboxylate (280 mg, 71%) Electrospray ionization mass spectrometry (ESI-MS): 719 [M+H] ⁺ .

13. Tret -butyl-( S )-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(2,2,6, 6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

A reference is given to the preparation of tert -butyl ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl) -1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate. Electrospray ionization mass spectrometry (ESI-MS): 697 [M+H] ⁺ .

14. Receipt (S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid

Stage 1. Synthesis ( S )-8-bromo-6-((3-(trifluoromethyl))phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Tert -butyl ( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ] Quinoxaline-3-carboxylate (350 ml, 0.6 mmol) was dissolved in dichloromethane (3 ml). Trifluoroacetic acid (1 ml) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration to give crude ( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5. 6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (360 mg, crude). Electrospray ionization mass spectrometry (ESI-MS): 476.0 [M+H] ⁺ .

Stage 2. Synthesis of methyl-( S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate

( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[1,2- a ]quinoxaline (300 mg, 0.52 mmol) was dissolved in dimethyl sulfoxide (3 ml). Potassium carbonate (215 mg, 1.56 mmol) and methyl bromoacetate (159 mg, 1.04 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, water (10 ml) was added to the reaction mixture and extracted with ethyl acetate (10 m × 3). The organic phases were combined, washed three times with water (20 ml x 3), dried over anhydrous sodium sulfate and concentrated. The residue was separated by flash chromatography on a silica gel column [eluent: EtAc:PE = 0-30%] to give methyl-( S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate (210 mg, 73%). Electrospray ionization mass spectrometry (ESI-MS): 548.2 [M+H] ⁺ .

Stage 3. Synthesis ( S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid

Methyl-( S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate (210 mg, 0.38 mmol) was dissolved in tetrahydrofuran (6 ml) and water (2 ml). Lithium hydroxide monohydrate (92 mg, 3.8 mmol) was added. The mixture solution was stirred at room temperature for 16 hours, concentrated to remove the solvent, and oxidized with dilute hydrochloric acid. The residue was separated by reverse phase column chromatography [eluent: H ₂ O : MeCN = 0-50%] to give ( S )-2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid (130 mg, 63%). Electrospray ionization mass spectrometry (ESI-MS): 534.2 [M+H] ⁺ .

15. Preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-bromo-2-fluorobenzonitrile (500 mg, 2.5 mmol), bis(pinacolato)borate (950 mg, 3.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (185 mg, 0.25 mmol) and potassium acetate (491 mg, 5.0 mmol) were stirred in 1,4-dioxane (6 ml). Nitrogen was introduced three times to replace air by pumping. The reaction in the mixture solution was carried out at a temperature of 100°C for 4 hours. After completion of the reaction, the reaction mixture was filtered through celite. The filtrate was concentrated and the residue was separated by flash chromatography on a silica gel column (eluent: EtAc:PE = 0-20%) to give 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzonitrile (450 mg, 73%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.98 (ddd, J =7.5, 5.6, 1.9 Hz, 1H), 7.71 (ddd, J =7.9, 6.3 , 1.9 Hz, 1H), 7.26 (d, J =7.6 Hz, 1H), 1.37 (s, 12H).

16. Preparation of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A reference is given to the preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.88 (t, J = 1.1 Hz, 1H), 7.71 (dd, J = 8.6, 2.7 Hz, 1H), 7.55 -7.45 (m, 1H), 1.35 (s, 12H).

17. Preparation of 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A reference is given to the preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (dd, J =5.3, 2.2 Hz, 1H), 7.35 (s, 1H), 7.14 (t, J =8, 6 Hz, 1H), 1.37 (s, 12H).

18. Preparation of 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A reference is given to the preparation of 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzonitrile.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (dt, J = 7.3, 1.1 Hz, 1H), 7.79-7.66 (m, 2H), 1.35 (s, 6H), 1.26 (s, 6H).

19. Receiving ( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a ]quinoxaline

Stage 1. Synthesis ( S )-4-(4-bromo-2-nitrophenyl)-morpholine-3-carboxylic acid

4-bromo-1-fluoro-2-nitrobenzene (2.2 g, 10.3 mmol) was dissolved in dimethyl sulfoxide (20 ml). Cesium carbonate (6.6 g, 20.4 mmol) and ( S )-morpholine-3-carboxylic acid (0.9 g, 6.8 mmol) were added. The reaction mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and then diluted with 40 ml ethyl acetate and washed with brine (20 ml x 3). The organic layer was dried and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to obtain ( S )-4-(4-bromo-2-nitrophenyl)-morpholine-3-carboxylic acid (2.0 g, yield: 88.8%). Electrospray ionization mass spectrometry (ESI-MS): 329, 331[MH] ^- .

Stage 2. Synthesis ( S )-8-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3- a ]quinoxaline-5(6 H )-she

( S )-4-(4-bromo-2-nitrophenyl)-morpholine-3-carboxylic acid (2.0 g, 6.0 mmol) was dissolved in ethanol (20 ml). Iron powder (1.7 g, 30 mmol) was added. The mixture solution was stirred at 80°C for 2 hours, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( S )-8-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3- a ]quinoxaline-5( 6H )- she (230 mg, yield: 13.5%). Electrospray ionization mass spectrometry (ESI-MS): 283, 285 [M+H] ⁺ .

Stage 3. Synthesis ( R )-8-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a ]quinoxaline

( S )-8-bromo-1,2,4,4a-tetrahydro-[1,4]oxazino[4,3- a ]quinoxalin-5( 6H )-one (230 mg, 0.81 mmol) was dissolved in tetrahydrofuran (15 ml). A solution of borane dimethyl sulfide in tetrahydrofuran (1.3 ml, 2M in THF) was added. The reaction mixture was stirred at 30°C for 2 hours, cooled to 0°C, methanol was added to stop the reaction and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( R )-8-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a ]quinoxaline (190 mg , yield: 87.6%). Electrospray ionization mass spectrometry (ESI-MS): 269, 271 [M+H] ⁺ .

Step 4. Synthesis of ( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4] oxazino [4,3 - a ]quinoxaline

( R )-8-bromo-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a ]quinoxaline (190 mg, 0.71 mmol) was dissolved in dichloromethane (5 ml). 0.5 ml of pyridine and 3-(trifluoromethyl)-benzenesulfonyl chloride (259 mg, 1.06 mmol) were added to the solution. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1, 4]oxazino[4,3- a ]quinoxaline (270 mg, yield: 79.5%). Electrospray ionization mass spectrometry (ESI-MS): 477, 479 [M+H] ⁺ .

20. Receiving ( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3- a ]quinoxaline

A reference is given to the preparation of ( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3 - a ]quinoxaline. Electrospray ionization mass spectrometry (ESI-MS): 477, 479 [M+H] ⁺ .

21. Preparation of 8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]thiazino[4,3- a ]quinoxaline

A reference is given to the preparation of ( R )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3 - a ]quinoxaline. Electrospray ionization mass spectrometry (ESI-MS): 493, 495 [M+H] ⁺ .

22. Receiving (6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2- a ]quinoxalin-8-ol

Stage 1. Synthesis ( S )-1-(4-bromo-2-nitrophenyl)-4-oxopiperidine-2-carboxylic acid

( S )-1-( tert -butoxycarbonyl)-4-oxopiperidine-2-carboxylic acid (5.0 g, 20.5 mmol) was dissolved in 4M hydrogen chloride in dioxane (20 ml) and stirred at 25°C for 1 hour. The solvent was removed by concentration. The residue was dissolved in dimethyl sulfoxide (20 ml). Cesium carbonate (16.7 g, 51.2 mmol) and 4-bromo-1-fluoro-2-nitrobenzene were added to the solution. The reaction was stopped after stirring the mixture solution at 100°C for 2 hours, cooled to room temperature, diluted with 40 ml of ethyl acetate, washed with water (20 ml × 2), saline (20 ml × 2), dried over anhydrous sodium sulfate and concentrated to remove solvent. The residue was separated by flash silica gel column chromatography to obtain ( S )-1-(4-bromo-2-nitrophenyl)-4-oxopiperidine-2-carboxylic acid (4.0 g, yield: 56.9%). Electrospray ionization mass spectrometry (ESI-MS): 341, 343 [MH] ^- .

Stage 2. Synthesis ( 2S )-1-(4-bromo-2-nitrophenyl)-4-hydroxypiperidine-2-carboxylic acid

( S )-1-(4-bromo-2-nitrophenyl)-4-oxopiperidine-2-carboxylic acid (4.0 g, 11.6 mmol) was dissolved in methanol (20 ml). Sodium borohydride (1.3 g, 34.8 mmol) was added. The mixture solution was stirred at 25°C for 2 hours and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to obtain ( 2S )-1-(4-bromo-2-nitrophenyl)-4-hydroxypiperidine-2-carboxylic acid (3.4 g, yield: 85.0%). Electrospray ionization mass spectrometry (ESI-MS): 343, 345 [MH] ^- .

Stage 3. Synthesis (6a S )-3-bromo-8-hydroxy-7,8,9,10-tetrahydro-5 H -pyrido[1,2- a ]quinoxaline-6(6a H )-she

( 2S )-1-(4-bromo-2-nitrophenyl)-4-hydroxypiperidine-2-carboxylic acid (3.4 g, 9.8 mmol) was dissolved in ethanol (20 ml). Iron powder (2.7 mg, 49.0 mmol) and ammonium chloride (2.6 mg, 49.0 mmol) were added. The mixture solution was stirred at 80°C for 2 hours, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-8-hydroxy-7,8,9,10-tetrahydro- 5H -pyrido[1,2- a ]quinoxaline-6(6a H )-she (2.0 g, yield: 68.9%). Electrospray ionization mass spectrometry (ESI-MS): 297, 299 [M+H] ⁺ .

Stage 4. Synthesis (6a S )-3-bromo-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2- a ]quinoxalin-8-ol

( 6aS )-3-bromo-8-hydroxy-7,8,9,10-tetrahydro- 5H -pyrido[1,2- a ]quinoxalin-6( 6aH )-one (2.0 g, 6 .7 mmol) was dissolved in 4M borane-tetrahydrofuran (20 ml). The reaction mixture was stirred at 30°C for 2 hours. Methanol was added dropwise to complete the reaction. To remove the solvent, the reaction mixture was concentrated. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2- a ]quinoxalin-8-ol (1.7 g, yield: 89.5%). Electrospray ionization mass spectrometry (ESI-MS): 283, 285 [M+H] ⁺ .

Stage 5. Synthesis (6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2- a ]quinoxalin-8-ol

( 6aS )-3-bromo-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2- a ]quinoxalin-8-ol (1.7 mg, 6.0 mmol) dissolved in dichloromethane (20 ml). Pyridine (1.0 ml), dimethylaminopyridine (0.15 g, 1.2 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (1.47 g, 6.0 mmol) were added. The reaction in the mixture solution was carried out at a temperature of 25°C for 4 hours. The solvent was removed by concentration. The residue was dissolved in ethyl acetate (30 ml), washed successively with water (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate, and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2- a ]quinoxalin-8-ol (1.6 g, yield: 54.2%). Electrospray ionization mass spectrometry (ESI-MS): 491, 493 [M+1] ⁺ .

23. Receiving ( S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrido[1,2- a ]quinoxalin-8-one

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2- a ]quinoxaline- 8-ol (250 mg, 0.5 mmol) was dissolved in dichloromethane (10 ml). Dess-Martin oxidizing agent (318 mg, 0.75 mmol) was added. The reaction in the solution mixture was carried out at 25°C for 4 hours. The reaction mixture was filtered to remove insoluble material. The solution was washed with sodium bicarbonate solution (15 ml) and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,6a,7,9,10-hexahydro- 8H- pyrido[1,2- a ]quinoxalin-8-one (240 mg, yield: 98.3%). Electrospray ionization mass spectrometry (ESI-MS): 489, 491 [M+1] ⁺ .

II. Getting Compounds as Examples

Example 1. Preparation of 6-(3-(difluoromethoxy)-5-fluorophenyl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline

6-Bromo-1-methyl-4-((3-(trifluoromethyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline (100 mg, 95%, 0.23 mmol) and 2-(3-(difluoromethoxy) -5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (90 mg, 95%, 0.30 mmol) was dissolved in a solvent mixture of toluene: ethanol: water = 3:2:2 (14 ml). Sodium carbonate (66 mg, 0.62 mmol) and tetrakis(triphenylphosphine) palladium (27 mg, 0.023 mmol) were added. The reaction mixture was heated to 90°C overnight; the reaction mixture was cooled and then diluted ethyl acetate and washed with brine (30 ml). The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash chromatography on a silica gel column [eluent: EA: PE = 0-50%] to give 6-(3- (difluoromethoxy)-5-fluorophenyl)-1-methyl-4-((3-(trifluorophenyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline (5.1 mg, 95%). Mass spectrometry with electrospray ionization (ESI-MS): 517.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81-7.78 (m, 3H), 7.73 (d, J =8.0 Hz, 1H), 7.56 (t, J =8, 0 Hz, 1H), 7.35 (dd, J =8.8, 2.0 Hz, 1H), 7.16-7.13 (m, 1H), 7.11 (s, 1H), 6, 79-6.76 (m, 1H), 6.63 (d, J =8.8 Hz, 1H), 6.57 (t, J =73.2 Hz, 1H), 3.90 (t, J =5.6 Hz, 1H), 2.92 (t, J =5.6 Hz, 1H), 2.66 (s, 3H).

Example 2. Preparation of 7-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline

Stage 1. Synthesis rubs -butyl 6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1(2 H )-carboxylate

Tert -butyl-6-bromo-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1( 2H )-carboxylate (277 mg, 95%, 0.50 mmol) and 2- (3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (229 mg, 95%, 0.75 mmol) was dissolved in a solvent mixture of toluene: ethanol: water = 3:2:2 (14 ml). Sodium carbonate (106 mg, 1.0 mmol) and tetrakis(triphenylphosphine)palladium (60 mg, 0.05 mmol) were added. The reaction mixture was heated to 90°C overnight; the reaction mixture was cooled and then diluted with ethyl acetate and washed with brine (30 ml). The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash chromatography on a silica gel column [eluent: EA: PE = 0-60%] to give tert -butyl 6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl )sulfonyl)-3,4-dihydroquinoxaline-1( 2H )-carboxylate (100 mg, 88%). Electrospray ionization mass spectrometry (ESI-MS): 503.2 [M-100] ⁺ .

Step 2. Synthesis of 7-(3-(difluoromethoxy)-5-fluorophenyl)-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline

Tert -butyl 6-(3-(difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydroquinoxaline-1( 2H )-carboxylate (100 mg, 88% , 0.146 mmol) was dissolved in dichloromethane (5 ml). A solution of hydrogen chloride (4N in 1,4-dioxane) (0.12 mL, 0.438 mmol) was added. The reaction was allowed to proceed overnight at room temperature. The reaction mixture was concentrated; ethyl acetate (30 ml) was added to it. The solution was washed with saturated sodium bicarbonate (10 ml x 2). The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by reverse phase column chromatography [C18, 45 g, 0-100% acetonitrile: 0.01 mM trifluoroacetic acid/water] to give 7-(3-(difluoromethoxy)-5-fluorophenyl)-1-(( 3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-dihydroquinoxaline (8.2 mg, 95%). Electrospray ionization mass spectrometry (ESI-MS): 503.2 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.92 (d, J =7.6 Hz, 1H) _, 7.84 (d, J =8.0 Hz, 1H), 7.82 (d , J =2.4 Hz, 1H), 7.76 (s, 1H), 7.71 (t, J =8.0 Hz, 1H), 7.30 (dd, J =8.4, 2, 0 Hz, 1H), 7.18-7.11 (m, 2H), 6.93 (t, J =74 Hz, 1H), 6.84-6.81 (m, 1H), 6.59 ( d, J =8.4 Hz, 1H), 3.83 (t, J =5.2 Hz, 2H), 2.93 (t, J =5.2 Hz, 2H).

Example 3: Getting ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid

Stage 1. Synthesis ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (60 mg, 95 %, 0.11 mmol) and ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3 ,2-dioxaborolane (52 mg, 95%, 0.16 mmol) was dissolved in a solvent mixture of toluene: ethanol: water = 3:2:2 (7 ml). Sodium carbonate (18 mg, 0.17 mmol) and tetrakis(triphenylphosphine)palladium (10 mg, 0.01 mmol) were added. The reaction mixture was heated to 90°C overnight. The reaction mixture was cooled. A few drops of dilute hydrochloric acid (1N) were added to bring the pH of the reaction mixture to approximately 7. The organic phases were separated and concentrated. The residue was separated by flash silica gel column chromatography [eluent: EA: PE = 0-80%] to give ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1- en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (15 mg, yield: 21.2% ). Electrospray ionization mass spectrometry (ESI-MS): 611.3 [M+1] ⁺ .

Stage 2. Synthesis ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid

Methyl ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl) sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (15 mg, 0.023 mmol) was dissolved in a solvent mixture of tetrahydrofuran - water (3:1, 2 ml). Lithium hydroxide monohydrate (10 mg, 0.23 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°C. A few drops of dilute hydrochloric acid (1N) were added to bring the pH of the reaction mixture to approximately 6. The organic phases were separated and concentrated. The residue was separated by preparative TLC [eluent: MeOH: DCM = 10%] to give ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl )-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid (5.1 mg, 35.3% yield). Electrospray ionization mass spectrometry (ESI-MS): 597.3 [M+1] ⁺ .

^1H NMR (400 MHz, DMSO- d6 ) δ 8.15-8.09 (m, _2H ), 7.91-7.87 (m, 2H), 7.37-7.32 (m, 2H ), 7.27-7.23 (m, 1H), 7.18 (d, J =1.6 Hz, 1H), 7.06 (dd, J =8.8, 1.6 Hz, 1H) , 6.66 (d, J =8.8 Hz, 1H), 6.23 (s, 1H), 4.01-3.96 (m, 1H), 3.81-3.77 (m, 1H ), 3.35-3.24 (m, 2H), 2.72 (s, 3H), 2.27-2.21 (m, 2H), 1.97 (s, 3H), 1.84- 1.81 (m, 1H), 1.58-1.53 (m, 1H).

Examples 4-6 were obtained by the synthesis method indicated in example 1 or 3.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 4 ( S )-7-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,3a,4,5-hexahydropyrrolo[1,2- a ]quinoxaline 543.2 5 ( S )-3-(6-(3-(difluoromethoxy)-5-fluorophenyl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxaline-2 -yl)propanoic acid 589.3 6 ( S , E )-3-(6-(2-chloro-6-(trifluoromethyl)styryl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4- tetrahydroquinoxalin-2-yl)propanoic acid 633.3

¹ Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 4-6:

Example 4. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.91-7.86 (m, 3H), 7.80 (s, 1H), 7.69 (t, J = 8.0 Hz , 1H), 7.42 (dd, J =8.0.2.0 Hz, 1H), 7.18-7.11 (m, 2H), 7.10-6.74 (m, 2H), 6.60 (d, J =8.8 Hz, 1H), 4.62-4.58 (m, 1H), 3.35-3.31 (m, 1H), 2.95-2.87 ( m, 1H), 2.72-2.66 (m, 1H), 2.07-1.99 (m, 2H), 1.81-1.68 (m, 1H), 1.38-1, 28 (m, 1H).

Example 5. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.11 (t, J =8.0 Hz, 2H), 7.87 (t, J =8.0 Hz, 2H), 7, 54-7.18 (m, 3H), 7.16-7.14 (m, 1H), 7.06 (s, 1H), 7.02-7.00 (m, 1H), 6.71 ( d, J =8.8 Hz, 1H), 3.95-3.89 (m, 1H), 3.84-3.79 (m, 1H), 3.25-3.21 (m, 2H) , 2.69 (s, 3H), 2.25-2.21 (m, 2H), 1.84-1.81 (m, 1H), 1.58-1.52 (m, 1H).

Example 6. ^1H NMR (400 MHz, DMSO- d6 ) _δ 8.17 (d, J =8.0 Hz, 1H), 8.09 (d, J =8.0 Hz, 1H), 7, 93 (s, 1H), 7.90-7.80 (m, 2H), 7.78-7.75 (m, 1H), 7.51-7.48 (m, 1H), 7.29 ( d, J =2.0 Hz, 1H), 7.23 (d, J =8.4 Hz, 1H), 6.70 (s, 2H), 6.63 (d, J =8.8 Hz, 1H), 4.03-3.99 (m, 1H), 3.32-3.30 (m, 1H), 2.74 (s, 3H), 2.21-2.15 (m, 2H) , 1.85-1.82 (m, 1H), 1.56-1.52 (m, 1H).

Example 7: Getting ( S )-1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one

Stage 1. Synthesis rubs -butyl-( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl ( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ] quinoxaline-3-carboxylate (340 mg, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (50 mg, 0.059 mmol), potassium carbonate (244 mg, 1.77 mmol) and 2 -(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (221 mg, 0.77 mmol) was placed in a microwave reaction tube; 1,4-dioxane (4 ml) and water (1 ml) were added. Nitrogen was introduced three times to replace air by pumping in a microwave reactor. The mixture solution was heated to a temperature of 100°C and the reaction was carried out for half an hour. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2. 4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (300 mg, 77%).

Stage 2. Synthesis ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Tert -butyl ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (300 mg, 0.46 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (1 ml) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the solvent. The residue was washed with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, dried and concentrated to give ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3 ,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (240 mg, 93%).

Stage 3. Synthesis ( S )-1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one

( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline (50 mg, 0.09 mmol) was dissolved in pyridine (1 ml), the mixture solution was cooled to 0°C. Acetyl chloride (0.2 ml) was added. The reaction mixture was stirred at 0°C for half an hour, methanol was added to stop the reaction and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( S )-1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2. 4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one (24 mg, 44%). Electrospray ionization mass spectrometry (ESI-MS): 600 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.92-7.56 (m, 5H), 7.38 (dd, J =8.8, 2.2 Hz, 1H), 7.16-7, 09 (m, 2H), 6.84-6.74 (m, 2H), 6.57 (t, J =73.3 Hz, 1H), 4.48 (s, 1H), 4.28 (dd , J =14.3, 4.4 Hz, 1H), 3.78-3.57 (m, 2H), 3.34 (m, 1H), 3.15 (m, 0.5H), 2, 72-2.82 (m, 1H), 2.59 (m, 1H), 2.08-2.38 (m, 1.5H), 2.08 (s, 3H).

Example 8: Getting ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-6- ((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1 H -pyrazino[1,2- a ]quinoxaline

( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline (50 mg, 0.09 mmol) was dissolved in pyridine (1 ml), the mixture solution was cooled to 0°C. Methanesulfonyl chloride (0.2 ml) was added. The reaction mixture was stirred at 0°C for half an hour, methanol was added to stop the reaction and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2 ,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (20 mg, 35%). Electrospray ionization mass spectrometry (ESI-MS): 636 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.89-7.77 (m, 3H), 7.70-7.61 (m, 2H), 7.38 (dd, J = 8.8, 2 ,2 Hz, 1H), 7.17-7.08 (m, 2H), 6.81 (dd, J =11.0, 8.9 Hz, 2H), 6.57 (t, J =73, 3 Hz, 1H), 4.26 (dd, J =14.4, 4.6 Hz, 1H), 3.76-3.59 (m, 3H), 3.39 (dd, J =14.4 , 9.8 Hz, 1H), 2.80-2.65 (m, 5H), 2.49 (td, J =12.4, 3.3 Hz, 1H), 2.37 (t, J = 10.8 Hz, 1H).

Example 9. Getting ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid

Stage 1. Synthesis of methyl ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate

( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline (50 mg, 0.09 mmol) was dissolved in N , N -dimethylformamide (2 ml). Cesium carbonate (88 mg, 0.27 mmol) and methyl bromoacetate (14 mg, 0.45 mmol) were added to the solution. The reaction mixture was stirred at 95°C for 5 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give crude methyl-( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1 ,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate.

Stage 2. Synthesis ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid

Crude methyl-( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate was dissolved in methanol (2 ml). Lithium hydroxide monohydrate (38 mg) and water (1 ml) were added to the solution. The mixture solution was stirred at room temperature for 4 hours. To remove the solvent, the reaction mixture was concentrated and oxidized with dilute hydrochloric acid. The residue was separated by flash silica gel column chromatography to give ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2. 4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid (5 mg, 9%). Electrospray ionization mass spectrometry (ESI-MS): 616 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.88 (s, 1H), 7.80 (d, J =9.1 Hz, 2H), 7.64 (s, 2H), 7.04 (d , J =13.5 Hz, 2H), 6.79 (d, J =10.1 Hz, 2H), 6.54 (m, 1H), 4.24 (s, 1H), 3.41 (m , 7H), 2.78 (m, 1H), 2.57 (s, 1H), 2.29 (s, 1H).

Example 10: Getting ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5 ,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Stage 1. Synthesis rubs -butyl ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5 ,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carboxylate

Tert -butyl ( S )-8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ] Quinoxaline-3-carboxylate (340 mg, 0.59 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (98 mg, 0.12 mmol), potassium carbonate (244 mg, 1.77 mmol) and ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (209 mg , 0.71 mmol) was placed in the reaction flask. Toluene (4 ml), ethanol (2 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 90°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3 -(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (285 mg, 73%).

Stage 2. Synthesis ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5 ,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

Tert -butyl ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxaline-3-carboxylate (250 mg, 0.38 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (1 ml) was added to the solution. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the solvent. The residue was washed with saturated sodium hydrogen carbonate, extracted with ethyl acetate, dried and concentrated to give ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-(( 3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (200 mg, 93%). Electrospray ionization mass spectrometry (ESI-MS): 566 [M+H] ⁺ .

^1H NMR (500 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 7.80-7.84 (m, 2H), 7.75 (s, 1H), 7.62-7.67 ( m, 2H), 7.17-7.26 (m, 3H), 7.02 (t, J =8.4 Hz, 1H), 6.71 (d, J =8.7 Hz, 1H), 6.35 (s, 1H), 4.21-4.23 (m, 1H), 3.61 (d, J =12.6 Hz, 1H), 3.36 (t, J =12.1 Hz, 1H), 3.06-3.15 (m, 2H), 2.78-2.81 (m, 2H), 2.46-2.54 (m, 2H), 2.19 (s , 3H).

Examples 11, 12 and 13 were prepared by the synthesis method indicated in example 10.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ eleven ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline 602 12 ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline 558 13 ( S )-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3 ,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline 536

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 11 to 13:

Example 11. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.873-7.82 (m, 4H), 7.63-7.61 (m, 3H), 7.33-7.26 (m, 2H) , 6.97 (d, J =16.6 Hz, 1H), 6.80 (d, J =16.6 Hz, 1H), 6.71 (d, J =8.5 Hz, 1H), 4 ,23 (dd, J =14.2, 4.3 Hz, 1H), 3.58 (d, J =12.6 Hz, 1H), 3.30-3.36 (m, 1H), 3, 08-3.00 (m, 2H), 2.75 (t, J =12.5 Hz, 2H), 2.55 - 2.32 (m, 2H).

Example 12. ^1H NMR (400 MHz, methanol- d4 ) δ 8.04 (d, J =7.9 Hz, 1H), 7.99 ₍ d, J =7.9 Hz, 1H), 7, 87-7.77 (m, 2H), 7.65 (s, 1H), 7.51 (dd, J =8.7, 2.2 Hz, 1H), 7.22-7.14 (m, 2H), 6.95 (t, 1H), 7.04 (d, J =8.7 Hz, 1H), 6.90 (dt, J =9.6, 2.3 Hz, 1H), 4, 44 (dd, J =14.5, 4.4 Hz, 1H), 4.03 (d, J =14.4 Hz, 1H), 3.49-3.34 (m, 3H), 3.05 (qd, J =14.8, 13.7, 3.5 Hz, 2H), 2.78 (t, J =11.9 Hz, 1H), 2.68-2.56 (m, 1H).

Example 13. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.81 (t, J = 7.4 Hz, 2H), 7.72 (s, 1H), 7.65-7.57 (m, 2H ), 7.20 (d, J =8.6 Hz, 1H), 6.67 (d, J =8.8 Hz, 1H), 5.96 (s, 1H), 4.19 (dd, J =14.2, 4.3 Hz, 1H), 3.53 (d, J =12.6 Hz, 1H), 3.32 (dd, J =14.2, 9.9 Hz, 1H), 3 .05 (d, J =12.5 Hz, 1H), 2.98 (d, J =12.0 Hz, 2H), 2.76-2.63 (m, 2H), 2.46-2, 35 (m, 2H), 2.31 (s, 2H), 1.32 (d, J =11.6 Hz, 12H).

Examples 14, 15 and 16 were prepared by the synthesis method indicated in example 7.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 14 ( S , E )-1-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one 644 15 ( S , E )-1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one 608 16 ( S )-1-(8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)ethan-1-one 578

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 14 to 16:

Example 14. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.92-7.71 (m, 4H), 7.68-7.59 (m, 3H), 7.39-7.30 (m, 2H), 7.02-6.98 (m, 1H), 6.89-6.67 (m, 2H), 4.59-4.41 (m, 1H), 4.30 (dd, J = 14.3, 4.5 Hz, 1H), 3.81-3.55 (m, 2H), 3.36 (dt, J =14.2, 10.3 Hz, 1H), 3.18-3 .12 (m, 0.5H), 2.88-2.83 (m, 0.5H), 2.81-2.58 (m, 1.5H), 2.49-2.25 (m, 1.5H), 2.11 (d, J =4.0 Hz, 3H).

Example 15. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83-7.69 (m, 2H), 7.68-7.59 (m, 2H), 7.56-7.52 (m, 1H), 7.18-7.08 (m, 3H), 6.99-6.90 (m, 1H), 6.66 (dd, J =22.1, 8.6 Hz, 1H), 6 .29 (d, J =1.7 Hz, 1H), 4.40 (t, J =14.3 Hz, 1H), 4.19 (dd, J =14.2, 4.5 Hz, 1H) , 3.69-3.45 (m, 2H), 3.28 (dt, J =14.4, 9.2 Hz, 1H), 3.06 (t, J =10.8 Hz, 0.5H ), 2.82-2.67 (m, 0.5H), 2.67-2.43 (m, 1.5H), 2.37-2.16 (m, 1.5H), 2.14 (d, J =1.6 Hz, 3H), 2.01 (d, J =5.0 Hz, 3H).

Example 16. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.92-7.78 (m, 2H), 7.76-7.67 (m, 1H), 7.67-7.58 (m, 2H), 7.24 (td, J =5.9, 2.9 Hz, 1H), 6.71 (dd, J =22.1, 8.7 Hz, 1H), 6.03-5.95 (m, 1H), 4.55-4.43 (m, 1H),4.32-4.20 (m, 1H), 3.76-3.54 (m, 2H), 3.36 (ddd , J =14.3, 9.9, 7.5 Hz, 1H), 3.19-3.05 (m, 0.5H), 2.82(dd, J =12.8, 10.9 Hz , 0.5H), 2.73-2.50 (m, 1.5H), 2.42-2.23 (m, 3.5H), 2.09 (d, J =4.7 Hz, 3H ), 1.35 (d, J =11.8 Hz, 12H).

Examples 17, 18 and 19 were prepared by the synthesis method indicated in example 8.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 17 ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-3-(methylsulfonyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5 ,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline 680 18 ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-3-(methylsulfonyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) -2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline 644 19 ( S )-3-(methylsulfonyl)-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl) sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline 614

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 17 to 19:

Example 17. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.90-7.81 (m, 2H), 7.80-7.72 (m, 2H), 7.69-7.61 (m, 3H), 7.39-7.30 (m, 2H), 7.05-6.96 (m, 1H), 6.85-6.73 (m, 2H), 4.27 (dd, J = 14.3, 4.7 Hz, 1H), 3.77-3.63 (m, 3H), 3.42 (dd, J =14.3, 9.5 Hz, 1H), 2.86-2 .81 (m, 1H), 2.80 (s, 3H), 2.70 (td, J =11.7, 3.2 Hz, 1H), 2.54 (td, J =12.3, 3 .3 Hz, 1H), 2.40 (t, J =10.9 Hz, 1H).

Example 18. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.87-7.79 (m, 2H), 7.75 (d, J = 1.8 Hz, 1H), 7.68 (d, J =2.1 Hz,1H), 7.63 (t, J =7.8 Hz, 1H), 7.25-7.15 (m, 3H), 7.04-7.02 (m, 1H) , 6.73 (d, J =8.7 Hz, 1H), 6.36 (d, J =1.9 Hz, 1H), 4.23 (dd, J =14.2, 4.7 Hz, 1H), 3.66 (dddd, J =19.2, 9.2, 4.9, 2.4 Hz, 3H), 3.41 (dd, J =14.3, 9.6 Hz, 1H) , 2.77 (s, 4H), 2.66 (td, J =11.6, 2.8 Hz, 1H), 2.49 (td, J =12.2, 3.0 Hz, 1H), 2.37 (dd, J =11.3, 10.4 Hz, 1H), 2.20 (d, J =1.5 Hz, 3H).

Example 19. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.09 (d, J = 7.7 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7, 86 (t, J =7.9 Hz, 1H), 7.66 (d, J =1.8 Hz, 1H), 7.42 (d, J =2.2 Hz, 1H), 7.26 ( dd, J =8.7, 2.2 Hz, 1H), 6.90 (d, J =8.8 Hz,1H), 6.02 (d, J =1.4 Hz, 1H), 4, 38 (dd, J =14.4, 4.6 Hz, 1H), 3.89-3.75 (m, 1H), 3.57 (dt, J =11.4, 2.5 Hz, 1H) , 3.34 (s, 1H), 3.32-3.28 (m, 1H), 2.85 (s, 3H), 2.65 (td, J =11.8, 3.1 Hz, 1H ), 2.60-2.52 (m,1H), 2.36 (t, J =10.9 Hz, 1H), 2.30-2.15 (m, 3H), 1.24 (d, J =16.2 Hz, 12H).

Examples 20, 21 and 22 were prepared by the synthesis method indicated in example 9.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 20 ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid 660 21 ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid 624 22 ( S )-2-(8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid 594

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 20 to 22:

Example 20. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.78 (d, J =8.0 Hz, 1H), 7.73 (s, 1H), 7.68 (d, J =8.0 Hz, 1H),7.55-7.47 (m, 4H), 7.22-7.14 (m, 2H), 6.80 (dd, J =16.7, 1.9 Hz, 1H) , 6.68-6.58 (m, 2H), 4.14 (dd, J =14.0, 4.2 Hz, 1H), 3.56 (d, J =12.9 Hz, 1H), 3.39-3.09 (m, 6H), 2.74 (q, J =15.1, 13.8 Hz, 1H), 2.51 (s, 1H), 2.25 (s, 1H) .

Example 21. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79-7.81 (m, 3H), 7.55-7.64 (m, 2H), 7.15-7.23 (m , 3H), 7.02-6.99 (m, 1H), 6.72 (s, 1H), 6.30 (s, 1H), 4.24 (s, 1H), 3.67 (s, 2H), 3.43 (s, 3H), 3.20 (s, 3H), 2.63 (s, 1H), 2.35 (s, 1H), 2.14 (s, 3H).

Example 22. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.80 (s, 3H), 7.62 (s, 2H), 7.18 (d, J =8.0 Hz, 1H), 6, 67 (s, 1H), 5.93 (s, 1H), 4.20 (s, 1H), 3.57 (s, 1H), 3.30 (d, J =62.0 Hz, 3H), 2.94 (s, 3H), 2.65-2.63 (m, 3H), 2.39 (s, 1H), 2.12 (s, 1H), 1.31 (d, J =12, 6 Hz, 12H).

Example 23. Preparation of methyl 2-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoate

( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (60 mg, 0.106 mmol), methyl ( S )-2-chloropropanoate (115 mg, 1.06 mmol) and potassium carbonate ( 44 mg, 0.318 mmol) was stirred in acetonitrile (2 ml) and then reacted under microwave irradiation at 60°C for 12 hours. The reaction mixture was separated by flash reverse phase column chromatography to give methyl 2-(( S )-8-(( E )-2-(2-chloro-6-frotphenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2, 4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoate (15 mg, 22%). Electrospray ionization mass spectrometry (ESI-MS): 652 [M+H] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ): δ 7.82-7.77 (m, 2H), 7.74 (d, J =7.9 Hz, 1H), 7.71 (d, J =2 ,1 Hz, 1H), 7.59 (t, J =7.7 Hz, 1H), 7.25-7.12 (m, 3H), 7.07-6.97 (m, 1H), 6 .69 (d, J =8.6 Hz, 1H), 6.35 (d, J =1.8 Hz, 1H), 4.20 (dd, J =14.1, 4.5 Hz, 1H) , 3.70 (s, 3H), 3.53-3.44 (m, 1H), 3.37-3.22 (m, 2H), 2.78-2.74 (m, 2H), 2 .44-2.40 (m, 1H), 2.37-2.26 (m, 2H), 2.21 (d, J =1.5 Hz, 3H), 1.99 (t, J =10 .6 Hz, 1H), 1.26 (d, J =6.8 Hz, 3H).

Example 24 was prepared by the synthesis method described in Example 23.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 24 methyl 2-(( S )-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) -1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoate 622

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.76 (t, J =11.7 Hz, 3H), 7.63 (d, J =2.2 Hz, 1H), 7.58 (t, J =7.8 Hz, 1H), 7.18 (dd, J =8.6, 2.2 Hz, 1H), 6.65 (d, J =8.8 Hz, 1H), 5.95 (d , J =1.4 Hz, 1H), 4.18 (dd, J =14.1, 4.4 Hz, 1H), 3.69 (s, 3H), 3.46 (d, J =11, 5 Hz, 1H), 3.36-3.30 (m, 1H), 3.28 (d, J =7.8 Hz, 1H), 2.75 (t, J =9.5 Hz, 2H) , 2.56 (s, 1H), 2.39 (dt, J =37.2, 10.5 Hz, 2H), 2.31 (d, J =1.6 Hz, 2H), 1.97 ( t, J =10.6 Hz, 1H), 1.32 (d, J =11.2 Hz, 12H), 1.27 (d, J =7.1 Hz, 3H).

Example 25. Getting 2-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoic acid

Methyl 2-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) -1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoate (13 mg, 0.02 mmol) and lithium hydroxide (5 mg, 0 .1 mmol) was stirred in methanol (2 ml). Water was added drop by drop. The reaction mixture was stirred at 40°C overnight. The pH of the reaction mixture was adjusted to approximately 5 with dilute hydrochloric acid. The resulting mixture was separated by flash reverse phase column chromatography to give 2-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6 -((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoic acid (7.5 mg, 58%). Electrospray ionization mass spectrometry (ESI-MS): 638 [M+H] ⁺ .

^1H NMR (500 MHz, CDCl ₃ ): δ 7.86-7.76 (m, 3H), 7.62-7.60 (m, 2H), 7.22-7.15 (m, 3H) , 7.01 (t, J =8.3 Hz, 1H), 6.71 (d, J =8.4 Hz, 1H), 6.32 (s, 1H), 4.19 (d, J = 13.3 Hz, 1H), 3.58 (d, J =10.5 Hz 1H), 3.44-3.18 (m, 2H), 2.80-2.20 (m, 5H), 2 .17 (s, 3H), 2.07 (brs, 1H), 1.39-1.18 (m, 3H).

Examples 26-27 were prepared by the synthesis method indicated in example 25.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 26 2-(( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoic acid 630 27 2-(( S )-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(triflutomethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanoic acid 608

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 26 to 27:

Example 26. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.02 (dd, J = 14.5, 7.8 Hz, 2H), 7.85-7.79 (m, 2H), 7 .69 (d, J =4.6 Hz, 1H), 7.51 (dd, J =8.7, 2.2 Hz, 1H), 7.22-7.15 (m, 2H), 6, 95 (t, 1H), 7.04 (dd, J =8.9, 2.5 Hz, 1H), 6.93-6.88 (m, 1H), 4.47 (ddd, J =14, 2, 8.5, 4.3 Hz, 1H), 4.10 (d, J =9.6 Hz, 2H), 3.66-3.51 (m, 2H), 3.42 (ddd, J =14.6, 9.9, 5.4 Hz, 1H), 3.24-3.05 (m, 2H), 3.00-2.70 (m, 2H), 1.61 (d, J =7.3 Hz, 3H).

Example 27. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J =15.2 Hz, 3H), 7.61 (d, J =8.1 Hz, 2H), 7.17 ( d, J =9.4 Hz, 1H), 6.65 (s, 1H), 5.93 (s, 1H), 4.27-4.12 (m, 1H), 3.56 (ddd, J =16.1, 8.2, 4.6 Hz, 1H), 3.44-3.27 (m, 2H), 2.97-2.68 (m, 3H), 2.49 (d, J =32.6 Hz, 2H), 2.31-2.22 (m, 3H), 2.19-2.03 (m, 3H), 1.32 (s, 6H), 1.30 (s, 6H).

Example 28: Getting ( S )-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)-3-oxopropanenitrile

( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline (50 mg, 0.09 mmol) was dissolved in acetonitrile (2 ml); 2-cyanoacetic acid (96 mg, 1.13 mmol), 2- (7-hydroxybenzotriazole)-N, N , N ', N' -tetramethyluronium hexafluorophosphate (108 mg, 0.28 mmol) and N , N- diisopropylethylamine (148 mg, 1.15 mmol). The reaction mixture was stirred at 50°C for 5 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by TLC [solvent: methanol: dichloromethane = 1:20], then separated by reverse phase column chromatography [eluent: acetonitrile: water (0.5% HCl) = 0%-60%] to give ( S )-3-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H - pyrazino[1,2- a ]quinoxalin-3-yl)-3-oxopropanenitrile (27.4 mg, 49%). Electrospray ionization mass spectrometry (ESI-MS): 625 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.92 (t, J =8.4 Hz, 2H), 7.83 (d, J = _2.3 Hz, 1H), 7.74 (t , J =7.9 Hz, 1H), 7.65 (d, J =6.2 Hz, 1H), 7.48 (dd, J =8.7, 2.3 Hz, 1H), 7.23 -7.15 (m, 2H), 6.94 (t, 1H), 6.94 (d, J =8.7 Hz, 1H), 6.88 (dt, J =9.5, 2.3 Hz, 1H), 4.47-4.24 (m, 2H), 3.91 (dd, J =18.6, 2.9 Hz, 1H), 3.81 (d, J =18.6 Hz , 1H), 3.78-3.65 (m, 2H), 3.37 (td, J =10.5, 5.1 Hz, 1H), 2.90-2.60 (m, 2H), 2.47-2.31 (m, 1H), 2.03 (s, 1H).

Examples 29, 30 and 31 were prepared by the synthesis method described in example 28.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 29 ( S , E )-3-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-3-oxopropanenitrile 669 thirty ( S , E )-3-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-3-oxopropanenitrile 633 31 ( S )-3-oxo-3-(8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(trifluoromethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propanenitrile 603

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 29 to 31:

Example 29. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79 (d, J =7.8 Hz, 1H), 7.75 (d, J =7.9 Hz, 1H), 7.70- 7.69 (m, 1H), 7.63-7.62(m, 1H), 7.55-7.58 (m, 3H), 7.30-7.21 (m, 2H), 6, 93-6.89 (m, 1H), 6.74-6.64 (m, 2H), 4.39-4.34 (m, 1H), 4.27-4.19 (m, 1H), 3.65-3.51 (m, 2H), 3.48-3.37 (m, 2H), 3.34-3.16 (m, 1.5H), 2.91-2.86 (m , 0.5H), 2.76-2.70 (m, 1H), 2.63-2.60 (m, 0.5H), 2.50-2.40 (m, 0.5H), 2 .39-2.28 (m, 1H).

Example 30 ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.85-7.75 (m, 2H), 7.68 (s, 1H), 7.64-7.52 (m, 2H), 7.18-7.08 (m, 3H), 7.01-6.91 (m, 1H), 6.67 (dd, J =16.5, 8.6 Hz, 1H), 6.29 ( s, 1H), 4.36 (d, J =13.0 Hz, 1H), 4.38-4.19 (m, 1H), 3.60-3.45 (m, 2H), 3.45 -3.23 (m, 3H), 3.19-3.14 (m, 0.5H), 2.95-2.84 (m, 0.5H), 2.76-2.52 (m, 1.5H), 2.46-2.23 (m, 1.5H), 2.13 (d, J =1.8 Hz, 3H).

Example 31. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J =6.8 Hz, 1H), 7.81 (d, J =7.8 Hz, 1H), 7.71 ( s, 1H), 7.63 (t, J =7.9 Hz, 1H), 7.60-7.56 (m, 1H), 7.24-7.19 (m, 1H), 6.70 (dd, J =16.0, 8.7 Hz, 1H), 5.97 (s, 1H), 4.42 (d, J =13.1 Hz, 1H), 4.27 (ddd, J = 19.3, 14.3, 4.4 Hz, 1H), 3.60 (dd, J =26.2, 12.3 Hz, 2H), 3.52-3.40 (m, 2H), 3 .39-3.31 (m, 1H), 3.24 (t, J =11.7 Hz, 1H), 2.97-2.89 (m, 1H), 2.80-2.69 (m , 1H), 2.61 (s, 1H), 2.47 (t, J =11.1 Hz, 1H), 2.40-2.34 (m, 1H), 2.30 (s, 2H) , 1.32 (d, J =12.1 Hz, 12H).

Example 32: Getting ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-3-(oxetan-3-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5 ,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline

( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline (50 mg, 0.083 mmol) was dissolved in N , N -dimethylformamide (2 ml). Oxetan-3-one (12 mg, 0.166 mmol) and one drop of acetic acid were added to the solution. The reaction mixture was stirred at room temperature for 0.5 h and then sodium cyanoborohydride (10 mg, 0.166 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The residue was separated by flash reverse phase column chromatography to give ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-3-(oxetane-3 -yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[1,2- a ]quinoxaline (14.7 mg, 27%). Electrospray ionization mass spectrometry (ESI-MS): 658 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83-7.77 (m, 3H), 7.75 (d, J =2.1 Hz, 1H), 7.65-7.59 (m, 3H), 7.34-7.28 (m, 2H), 6.97 (dd, J =16.7, 1.9 Hz, 1H), 6.80 (d, J =16.6 Hz, 1H ), 6.71 (d, J =8.6 Hz, 1H), 4.65 (q, J =6.2 Hz, 2H), 4.56 (td, J =6.0, 3.7 Hz , 2H), 4.21 (dd, J =14.1, 4.4 Hz, 1H), 3.59-3.49 (m,1H), 3.45 (q, J =6.3 Hz, 1H), 3.34 (dd, J =14.1, 9.9 Hz, 1H), 2.74 (dd, J =4.5, 2.8 Hz, 1H), 2.67 (d, J =11.1 Hz, 1H), 2.61 (dt, J =10.5, 2.5 Hz, 1H), 2.52 (td, J =12.0, 3.1 Hz, 1H), 1 .88 (td, J =11.5, 3.2 Hz, 1H), 1.60 (d, J =10.5 Hz, 1H).

Examples 33-34 were prepared by the synthesis method indicated in example 32.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 33 ( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-3-(oxetan-3-yl)-6-((3-(trifluoromethyl) phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline 622 34 ( S )-3-(oxetan-3-yl)-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-( trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H- pyrazino[1,2- a ]quinoxaline 592

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 33 to 34:

Example 33. ¹ H NMR (500 MHz, CDCl ₃ ): 7.83-7.73 (m, 3H), 7.72 (d, J =2.1 Hz, 1H), 7.60 (t, J =7.8 Hz, 1H), 7.24-7.14 (m, 3H), 7.07-6.97 (m, 1H), 6.71 (d, J =8.7 Hz, 1H) , 6.36 (d, J =1.6 Hz, 1H), 4.65 (q, J =6.3 Hz, 2H), 4.55 (q, J =5.9 Hz, 2H), 4 .18 (dd, J =14.2, 4.4 Hz, 1H), 3.52 (dt, J =12.2, 2.8 Hz, 1H), 3.47-3.38 (m, 1H ), 3.36 (dd, J =13.5, 10.0 Hz, 1H), 2.67-2.60 (m, 2H), 2.60 (dt, J =10.5, 2.5 Hz, 1H), 2.49 (td, J =12.0, 3.1 Hz, 1H), 2.21 (d, J =1.5 Hz, 3H), 1.86 (td, J =11.4 , 3.2 Hz, 1H), 1.62-1.50 (m, 1H).

Example 34. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.80 (d, J =7.8 Hz, 1H), 7.77 (d, J =9.3 Hz, 2H), 7.63 ( d, J =2.2 Hz, 1H), 7.60 (t, J =7.8 Hz, 1H), 7.19 (dd, J =8.7, 2.2 Hz, 1H), 6, 67 (d, J =8.8 Hz, 1H), 5.96 (t, J =1.4 Hz, 1H), 4.64 (q, J =6.2 Hz, 2H), 4.55 ( td, J =6.2, 4.3 Hz, 2H), 4.17 (dd, J =14.1, 4.5 Hz, 1H), 3.49 (d, J =12.1 Hz, 1H ), 3.42 (t, J =6.3 Hz, 1H), 3.34 (dd, J =14.1, 9.8 Hz, 1H), 2.72-2.62 (m, 2H) , 2.59 (d, J =10.6 Hz, 1H), 2.48 (td, J =11.9, 3.0 Hz, 1H), 2.31 (d, J =1.4 Hz, 2H), 1.85 (td, J =11.4, 3.2 Hz, 1H), 1.55 (d, J =10.4 Hz, 1H), 1.32 (d, J =11.4 Hz, 12H).

Example 35. Getting ( R )-3-(( S )-8-(( E )-2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol

( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2- a ]quinoxaline (40 mg, 0.067 mmol) was dissolved in acetonitrile (2 ml). Potassium carbonate (27 mg, 0.201 mmol) and sodium iodide (30 mg, 0.201 mmol) were added. The reaction mixture was stirred at 60°C for 0.5 h and ( S )-3-chloropropane-1,2-diol (15 mg, 0.133 mmol) was added. The reaction mixture was stirred at 60°C for an additional 16 hours. The residue was separated by flash column chromatography to give ( R )-3-(( S )-8-(( E )-2-chloro-6-(trifluoromethyl) styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ]quinoxalin-3-yl)propan- 1,2-diol (14.7 mg, 27%). Electrospray ionization mass spectrometry (ESI-MS): 676 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 7.73 (d, J =7.9 Hz, 1H), 7.70-7.64 (m, 2H), 7 .58 -7.48 (m, 3H), 7.25-7.20 (m, 2H), 6.90 (d, J =16.6 Hz, 1H), 6.73 (d, J =16 .6 Hz, 1H), 6.64 (d, J =8.7 Hz, 1H), 4.13 (dd, J =14.2, 4.2 Hz, 1H), 3.70 (d, J =11.9 Hz, 2H), 3.52-3.36 (m, 2H), 3.27 (dd, J =14.1, 10.0 Hz, 1H), 2.82 (d, J = 10.9 Hz, 1H), 2.71 (d, J =11.0 Hz, 1H), 2.60 (s, 1H), 2.51 (t, J =11.1 Hz, 1H), 2 .40 (t, J =11.9 Hz, 1H), 2.31-2.17 (m, 2H), 1.67 (t, J =10.7 Hz, 1H).

Examples 36-42 were prepared by the synthesis method indicated in example 35.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 36 ( S )-3-(( S )-8-(( E )-2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 676 37 ( R )-3-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 640 38 ( S )-3-(( S )-8-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 640 39 ( R )-3-(( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 632 40 ( S )-3-(( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 632 41 ( R )-3-(( S )-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(triflutomethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 610 42 ( S )-3-(( S )-8-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-6-((3-(triflutomethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)propan-1,2-diol 610

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 36 to 42:

Example 36. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.83 (d, J =7.9 Hz, 1H), 7.79-7.74 (m, 2H ), 7.67-7.58 (m, 3H), 7.36-7.29 (m, 2H), 7.00 (d, J =16.4 Hz, 1H), 6.83 (d, J =16.6 Hz, 1H), 6.73 (d, J =8.6 Hz, 1H), 4.23 (dd, J =14.2, 4.1 Hz, 1H), 3.84- 3.76 (m, 2H), 3.57 (d, J =12.2 Hz, 1H), 3.52 (dd, J =11.4, 4.2 Hz, 1H), 3.36 (dd , J =14.1, 10.1 Hz, 1H), 2.97 (d, J =11.3 Hz, 1H), 2.77 (d, J =11.6 Hz, 2H), 2.60 (t, J =11.1 Hz, 1H), 2.45 (t, J =11.4 Hz, 1H), 2.39-2.34 (m, 1H), 2.05 (dt, J = 21.2, 11.0 Hz, 2H).

Example 37. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.83 (s, 1H), 7.80 (d, J =8.0 Hz, 1H), 7.76-7.66 (m, 2H), 7.58 (t, J =7.8 Hz, 1H), 7.25-7.10 (m, 3H), 7.07-6.97 (m, 1H), 6.71 (d , J =8.5 Hz, 1H), 6.36 (d, J =1.6 Hz, 1H), 4.19 (dd, J =14.2, 4.3 Hz, 1H), 3.83 -3.71 (m, 2H), 3.61-3.44 (m, 2H), 3.35 (dd, J =14.2, 9.9 Hz, 1H), 2.94 (d, J =11.4 Hz, 1H), 2.78-2.60 (m, 2H), 2.57 (dd, J =12.5, 9.7 Hz, 1H), 2.45-2.26 ( m, 2H), 2.21 (d, J =1.5 Hz, 3H), 2.08-1.92 (m, 2H).

Example 38. ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.83 (s, 1H), 7.80 (d, J =8.0 Hz, 1H), 7.76-7.70 (m, 2H), 7.58 (t, J =7.8 Hz, 1H), 7.25-7.14 (m, 3H), 7.07-6.97 (m, 1H), 6.71 (d , J =8.9 Hz, 1H), 6.36 (d, J =1.7 Hz, 1H), 4.18 (dd, J =14.1, 4.4 Hz, 1H), 3.84 -3.68 (m, 2H), 3.57-3.43 (m, 2H), 3.35 (dd, J =14.2, 10.0 Hz, 1H), 2.85 (d, J =11.1 Hz,1H), 2.76 (d, J =11.1 Hz, 1H), 2.65-2.50 (m, 2H), 2.43 (td, J =12.0, 3.0 Hz, 1H), 2.36-2.23 (m, 2H), 2.21 (d, J =1.5 Hz, 3H), 1.72 (t, J =10.6 Hz, 1H).

Example 39. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.07 (d, J =7.9 Hz, 1H), 8.01 (d, J =7.9 Hz, 1H), 7, 89-7.80 (m, 2H), 7.69 (d, J =6.3 Hz, 1H), 7.52 (dd, J =8.7, 2.2 Hz, 1H), 7.21 (d, J =9.7 Hz, 1H), 7.17 (s, 1H), 6.97 (t, 1H), 7.06 (d, J =8.7 Hz, 1H), 6.93 (dt, J =9.5, 2.3 Hz, 1H), 4.48 (ddd, J =14.4, 6.9, 4.3 Hz, 1H), 4.09 (td, J =12 ,1, 10.8, 6.0 Hz, 2H), 3.74-3.63 (m, 2H), 3.58 (tt, J =11.3, 6.1 Hz, 2H), 3, 50-3.41 (m, 1H), 3.31-3.23 (m, 2H), 3.23-3.07 (m, 2H), 2.94-2.82 (m, 1H), 2.82-2.69 (m, 1H).

Example 40. ^1H NMR (400 MHz, methanol- d4 ) δ 8.06 (d, J =7.9 Hz, 1H) _, 7.99 (d, J =7.9 Hz, 1H), 7, 87-7.79 (m, 2H), 7.64 (d, J =5.3 Hz, 1H), 7.50 (dd, J =8.7, 2.3 Hz, 1H), 7.21 -7.14 (m, 2H), 7.05 (d, J =8.8 Hz, 1H), 6.95 (t, 1H), 6.90 (dt, J =9.5, 2.3 Hz, 1H), 4.47 (ddd, J =13.2, 8.4, 4.3 Hz, 1H), 4.13-4.02 (m, 2H), 3.69 (t, J = 14.1 Hz, 2H), 3.56 (qd, J =11.3, 5.0 Hz, 2H), 3.43 (ddd, J =13.2, 9.9, 2.9 Hz, 1H ), 3.24 (dd, J =13.6, 3.6 Hz, 2H), 3.20-3.06 (m, 2H), 2.93-2.69 (m, 2H).

Example 41. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.83-7.69 (m, 3H), 7.65-7.55 (m, 2H), 7.20 (dd, J =8, 7, 2.2 Hz, 1H), 6.67 (d, J =8.8 Hz, 1H), 5.96 (s, 1H), 4.16 (dd, J =14.2, 4.4 Hz, 1H), 3.84-3.73 (m, 2H), 3.53-3.45 (m, 2H), 3.34 (dd, J =14.2, 9.9 Hz, 1H) , 2.81 (dd, J =51.6, 10.9 Hz, 2H), 2.64-2.51 (m, 2H), 2.42 (d, J =12.2 Hz, 1H), 2.29 (d, J =19.8 Hz, 3H), 1.71 (t, J =10.5 Hz, 2H), 1.32 (d, J =11.6 Hz, 12H).

Example 42. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.79 (d, J =8.0 Hz, 1H), 7.74 (d, J =7.9 Hz, 1H), 7.68 ( s, 1H), 7.60 (t, J =7.9 Hz, 1H), 7.49 (d, J =2.2 Hz, 1H), 7.12 (dd, J =8.6, 2 .2 Hz, 1H), 6.60 (d, J =8.8 Hz, 1H), 5.88 (d, J =1.4 Hz, 1H), 4.13 (dd, J =14.1 , 4.2 Hz, 1H), 3.96 (s, 1H), 3.68 (dd, J =11.5, 4.1 Hz, 1H), 3.58-3.44 (m, 2H) , 3.35 (dd, J =14.2, 9.0 Hz, 1H), 3.23-2.93 (m, 3H), 2.84-2.48 (m, 3H), 2.33 -2.13 (m, 4H), 1.25 (d, J =12.0 Hz, 12H).

Example 43. Preparation of ethyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate

( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (40 mg, 0.71 mmol) was dissolved in acetonitrile (3 ml). Potassium carbonate (29 mg, 0.212 mmol) and ethyl bromoacetate (18 mg, 0.106 mmol) were added. The reaction was carried out in a microwave reactor at 60°C for 12 hours. The reaction mixture was concentrated and separated by flash column chromatography to give ethyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl )prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl) acetate (10.5 mg, 23%). Electrospray ionization mass spectrometry (ESI-MS): 652 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74-7.69 (m, 2H), 7.69-7.63 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.11 (ddd, J =13.7, 9.5, 5.5 Hz, 3H), 6.95 (t, J =8.2 Hz, 1H), 6.63 (d, J =8.6 Hz, 1H), 6.29 (s, 1H), 4.11(q, J =7.4 Hz, 3H), 3.42 (d, J =12.2 Hz, 1H), 3.29 (dd, J =14.2, 9.8 Hz, 1H), 3.11 (d, J =4.2 Hz, 2H), 2.75 (q, J =16.0, 13, 3 Hz, 3H), 2.53-2.42 (m, 1H), 2.18-2.14 (m, 4H), 1.86 (s, 1H), 1.20 (d, J =7 ,2 Hz, 3H).

Examples 44-48 were prepared by the synthesis method indicated in example 43.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 44 methyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1 ,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate 638 45 methyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate 674 46 ethyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate 688 47 isopropyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate 702 48 isopropyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1 ,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate 666

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 44 to 48:

Example 44. ¹ H NMR ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.76-7.62 (m, 4H), 7.52 (t, J = 7.8 Hz, 1H), 7.18- 7.06 (m, 3H), 6.99-6.89 (m, 1H), 6.63 (d, J =8.7 Hz, 1H), 6.29 (s, 1H), 4.12 (dd, J =14.1, 4.5 Hz, 1H), 3.65 (s, 3H), 3.42 (d, J =12.3 Hz, 1H), 3.29 (dd, J = 14.2, 9.7 Hz, 1H), 3.21-3.04 (m, 2H), 2.83-2.60 (m, 3H), 2.48 (td, J = 11.9, 2.8 Hz, 1H), 2.21-2.10 (m, 4H), 1.85 (t, J =10.3 Hz, 1H).

Example 45. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.75 (m, 4H), 7.67-7.57 (m, 3H), 7.35-7.29 (m, 2H), 6.99 (d, J =16.9 Hz, 1H), 6.82 (d, J =16.5 Hz, 1H), 6.71 (d, J =8.7 Hz, 1H) , 4.22 (dd, J =14.2, 4.4 Hz, 1H), 3.74 (s, 3H), 3.53 (d, J =12.2 Hz, 1H), 3.35 ( dd, J =14.1, 9.9 Hz, 1H), 3.29-3.14 (m, 2H), 2.85 (t, J =9.8 Hz, 3H), 2.64-2 .52 (m, 1H), 2.32-2.19 (m, 1H), 2.02-1.87 (m, 1H).

Example 46. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.73 (m, 4H), 7.65-7.56 (m, 3H), 7.34-7.28 (m, 2H), 7.02-6.92 (m, 1H), 6.80 (d, J =16.5 Hz, 1H), 6.70 (d, J =8.7 Hz, 1H), 4, 27-4.12 (m, 3H), 3.51 (d, J =12.4 Hz, 1H), 3.34 (dd, J =14.2, 9.9 Hz, 1H), 3.18 (d, J =3.6 Hz, 2H), 2.85 (dd, J =10.5, 8.1 Hz, 3H), 2.64-2.51 (m, 1H), 2.26 ( dd, J =11.5, 3.2 Hz, 1H), 2.02-1.87 (m, 1H), 1.28 (t, J =7.1 Hz, 3H).

Example 47. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85-7.72 (m, 4H), 7.64-7.56 (m, 3H), 7.31 (dd, J =10, 3, 3.0 Hz, 2H), 6.80 (d, J =16.5 Hz, 1H), 6.70 (d, J =8.6 Hz, 1H), 5.05 (m, 1H) , 4.21 (dd, J =14.2, 4.3 Hz, 1H), 3.51 (d, J =12.2 Hz, 1H), 3.34 (dd, J =14.2, 10 .0 Hz, 1H), 3.15 (d, J = 3.3 Hz, 2H), 2.84 (s, 3H), 2.64-2.50 (m, 1H), 2.24 (t , J =10.6 Hz, 1H), 1.94 (t, J =10.5 Hz, 1H), 1.25 (d, J =6.2 Hz, 6H).

Example 48. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (t, J =6.8 Hz, 2H), 7.66 (s, 2H), 7.52 (t, J =7.9 Hz, 1H), 7.17-7.07 (m, 3H), 6.95 (t, J =8.3 Hz, 1H), 6.63 (d, J =8.6 Hz, 1H), 6.29 (s, 1H), 4.98 (m, 1H), 4.12 (dd, J =14.2, 4.6 Hz, 1H), 3.41 (d, J =12.2 Hz , 1H), 3.28 (dd, J =14.2, 9.8 Hz, 1H), 3.15-3.00 (m, 2H), 2.81-2.65 (m, 3H), 2.53-2.42 (m, 1H), 2.18-2.14 (m, 4H), 1.85 (t, J =10.4 Hz, 1H), 1.18 (d, J = 6.2 Hz, 6H).

Example 49. Preparation of ((isopropoxycarbonyl)oxy)methyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate

( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)acetic acid (15 mg, 0.024 mmol) was dissolved in N , N -dimethylformamide (2 ml). Triethylamine (12 mg, 0.12 mmol) and chloromethyl isopropyl carbonate (18 mg, 0.12 mmol) were added. The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was separated by flash column chromatography to give ((isopropoxycarbonyl)oxy)methyl( S , E )-2-(8-(2-(2-chloro-6 -fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 - a ]quinoxalin-3-yl) acetate (39.2 mg, 56%). Electrospray ionization mass spectrometry (ESI-MS): 740 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.80 (m, 2H), 7.75 (d, J =5.2 Hz, 2H), 7.63-7.61 (m, 1H), 7.27-7.17 (m, 3H), 7.04 (t, J =8.3 Hz, 1H), 6.72 (d, J =8.6 Hz, 1H), 6, 38 (s, 1H), 5.80 (s, 2H), 4.98-4.92 (m, 2H), 4.20 (dd, J =14.2, 4.5 Hz, 1H), 3 .51 (d, J =12.2 Hz, 1H), 3.37 (dd, J =14.3, 9.9 Hz, 1H), 3.29 (s, 2H), 2.83 (t, J =11.4 Hz, 2H), 2.75 (s, 1H), 2.53 (t, J =11.5 Hz, 1H), 2.31 (dd, J =13.5, 10.5 Hz, 1H), 2.23 (s, 3H), 2.01 (t, J =10.3 Hz, 1H), 1.38-1.32 (d, J =10 Hz, 6H).

Example 50. Preparation of ((isopropoxycarbonyl)oxy)methyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)acetate

Example 50 was prepared by the synthesis method described in Example 49. Electrospray ionization mass spectrometry (ESI-MS): 776 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84-7.73 (m, 4H), 7.62 (dd, J =8.2, 3.0 Hz, 3H), 7.33-7, 28 (m, 2H), 7.02-6.93 (m, 1H), 6.80 (d, J =16.5 Hz, 1H), 6.69 (d, J =8.7 Hz, 1H ), 5.78 (s, 2H), 4.93 (m, 1H), 4.20 (dd, J =14.1, 4.4 Hz, 1H), 3.51 (d, J =12, 3 Hz, 1H), 3.33 (dd, J =14.1, 10.0 Hz, 1H), 3.30-3.27 (m, 2H), 2.82 (q, J =10.0 , 9.2 Hz, 3H), 2.54 (td, J =12.0, 3.0 Hz, 1H), 2.37-2.25 (m, 1H), 2.01 (t, J = 10.4 Hz, 1H), 1.33 (d, J =6.3 Hz, 6H).

Example 51: Receiving rubs -butyl ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoate

( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino [1,2- a ]quinoxaline (110 mg, 0.20 mmol) was dissolved in acetonitrile (5 ml). Sodium iodide (120 mg, 0.80 mmol), tert -butyl 2-bromo-2-methylpropanoate (362 mg, 1.6 mmol) and N , N -diisopropylethylamine (80.8 mg, 0.63 mmol) were added. The reaction was carried out in a microwave reactor at a temperature of 120°C for 2.5 hours. To remove the solvent, the reaction mixture was concentrated. The residue was separated by reverse phase column chromatography [eluent: acetonitrile: water (0.5% HCl) = 0%-49%] to give tert -butyl( S )-2-(8-(3-(difluoromethoxy)- 5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ]quinoxalin-3-yl) -2-methylpropanoate (26 mg, 83%). Electrospray ionization mass spectrometry (ESI-MS): 700 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 7.90 (s, 1H), 7.84 (d, J =7.4 Hz, 1H), 7.77 (s , 1H), 7.53 (d, J =10.2 Hz, 1H), 7.38-7.34 (m, 1H), 7.14-7.07 (m, 2H), 6.84 ( d, J =9.3 Hz, 1H), 6.77 (s, 1H), 6.59 (t, 1H), 4.29 (d, J =13.8 Hz, 1H), 4.08 ( s, 1H), 3.69 (d, J =10.0 Hz,1H), 3.50 (m, 5H), 3.23 (s, 1H), 1.85 (s, 6H), 1, 59 (d, J =16.7 Hz, 9H).

Examples 52-53 were prepared by the synthesis method indicated in example 51.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 52 tert -butyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5 ,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoate 744 53 tert -butyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) -1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoate 708

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 52 to 53:

Example 52. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.83-7.74 (m, 3H), 7.67-7.57 (m, 3H), 7 .32 (dd, J =8.5, 2.3 Hz, 2H), 6.99 (d, J =16.6 Hz, 1H), 6.82 (d, J =16.6 Hz, 1H) , 6.71 (d, J =8.6 Hz, 1H), 4.24 (dd, J =14.0, 4.1 Hz, 1H), 3.54 (d, J =11.7 Hz, 1H), 3.32 (dd, J =14.0, 10.4 Hz, 1H), 2.99-2.87 (m, 2H), 2.66-2.56 (m, 1H), 2 .47-2.37 (m, 1H), 2.34-2.25 (m, 1H), 1.98 (t, J =10.5 Hz, 1H), 1.46 (s, 9H), 1.26(s,6H).

Example 53. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.81 (d, J =7.8 Hz, 1H), 7.76-7.71 (m, 2H ), 7.59 (t, J =7.9 Hz, 1H), 7.26-7.15 (m, 3H), 7.07-7.01 (m, 1H), 6.72 (d, J =8.6 Hz, 1H), 6.37 (s, 1H), 4.21 (dd, J =14.1, 4.2 Hz, 1H), 3.52 (d, J =11.5 Hz, 1H), 3.34 (dd, J =14.1, 10.3 Hz, 1H), 2.91 (dd, J =19.6, 11.1 Hz, 2H), 2.62-2 .50 (m, 1H), 2.39 (td, J =11.6, 2.8 Hz, 1H), 2.34-2.26 (m, 1H), 2.23 (d, J =1 .4 Hz, 3H), 1.97 (t, J =10.4 Hz, 1H), 1.46 (s, 9H), 1.25 (s, 6H).

Example 54: Getting ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoic acid

Tert -butyl ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoate (21 mg, 0.03 mmol) was dissolved in a solution of hydrogen chloride in dioxane (3 ml, 4 M). The reaction solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by reverse phase column chromatography [eluent: acetonitrile: water (0.5% HCl) = 0%-46%] to give ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl )-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2- a ]quinoxalin-3-yl)-2- methylpropanoic acid (10 mg, 52%). Electrospray ionization mass spectrometry (ESI-MS): 644 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 8.02 (dd, J =15.4, 7.9 Hz, 2H) _, 7.85-7.78 (m, 2H), 7.69 ( s, 1H), 7.51 (dd, J =8.7, 2.2 Hz, 1H), 7.22-7.15 (m, 2H), 6.95 (t, 1H), 7.04 (d, J =8.8 Hz, 1H), 6.91 (d, J =9.5 Hz, 1H), 4.47 (dd, J =14.4, 4.2 Hz, 1H), 4 .09 (d, J =13.9 Hz, 1H), 3.53 (t, J =9.7 Hz, 2H), 3.42 (dd, J =14.4, 10.0 Hz, 1H) , 3.15 (d, J =13.2 Hz, 2H), 2.90 (t, J =11.4 Hz, 1H), 2.82 (t, J =12.7 Hz, 1H), 1 .60 (s, 6H).

Examples 55-56 were prepared by the synthesis method indicated in example 54.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 55 ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoic acid 688 56 ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-methylpropanoic acid 652

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 55 to 56:

Example 55. ^1H NMR (400 MHz, methanol- d4 ) δ 7.92 (d, J =7.9 Hz, 1H), 7.86 (d, J =7.9 _Hz , 1H), 7, 72-7.68 (m, 1H), 7.67-7.59 (m, 3H), 7.56 (s, 1H), 7.35-7.31 (m, 1H), 7.25 ( dd, J =8.6, 2.0 Hz, 1H), 6.90 (dd, J =16.6, 2.1 Hz, 1H), 6.81 (d, J =8.7 Hz, 1H ), 6.67 (d, J =16.5 Hz, 1H), 4.32 (dd, J =14.3, 4.3 Hz, 1H), 3.81 (d, J =13.2 Hz , 1H), 3.29 (dd, J =14.3, 10.0 Hz, 2H), 3.12 (d, J =12.1 Hz, 1H), 2.95 (s, 1H), 2 .77-2.69 (m, 1H), 2.62-2.54 (m, 1H), 2.45 (t, J =11.1 Hz, 1H), 1.31 (s, 6H).

Example 56. ^1H NMR (400 MHz, methanol- d4 ) δ 7.96 (d, J =7.9 Hz, 1H), 7.90 (d, J =7.9 _Hz , 1H), 7, 73 (t, J =7.9 Hz, 1H), 7.62-7.55 (m, 2H), 7.19 (q, J =3.6 Hz, 2H), 7.11 (dd, J =8.6, 2.0 Hz, 1H), 7.02 (td, J =5.9, 3.0 Hz, 1H), 6.86 (d, J =8.7 Hz, 1H), 6 .23 (s, 1H), 4.37 (dd, J =14.3, 4.2 Hz, 1H), 3.96 (d, J =14.4 Hz, 1H), 3.43 (t, J =10.5 Hz, 2H), 3.34 (dd, J =14.4, 9.9 Hz, 1H), 3.14-3.01 (m, 2H), 2.85-2.66 (m, 2H), 2.06 (d, J =1.4 Hz, 3H), 1.51 (d, J =2.2 Hz, 6H).

Example 57. Preparation of ethyl ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin -3-yl)-2-oxoacetate

( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (40 mg, 0.071 mmol) was dissolved in dichloromethane (3 ml). Triethylamine (22 mg, 0.212 mmol) and oxalyl chloride monoethyl ester (15 mg, 0.106 mmol) were added to the solution at 0°C. The reaction mixture was stirred at room temperature and the reaction was carried out overnight. The mixture solution was concentrated and separated by reverse phase column chromatography to give ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6- ((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-oxoacetate (24, 6 mg, 52%). Electrospray ionization mass spectrometry (ESI-MS): 666.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92-7.58 (m, 5H), 7.24-7.15 (m, 3H), 7.02 (t, J = 8.6 Hz, 1H), 6.73 (dd, J =19.3, 8.6 Hz, 1H), 6.36 (s, 1H), 4.44-4.19 (m, 4H), 3.64 (dt , J =21.8, 11.8 Hz, 2H), 3.37 (td, J =13.9, 9.7 Hz, 1H), 3.17 (t, J =12.0 Hz, 1H) , 2.88-2.60 (m, 2H), 2.39 (dt, J =33.4, 11.4 Hz, 2H), 2.20 (s, 3H), 1.39 (dt, J =14.8, 7.0 Hz, 3H).

Example 58. Preparation of ethyl ( S , E )-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxalin-3-yl)-2-oxoacetate

Example 58 was prepared by the synthesis method described in Example 57. Electrospray ionization mass spectrometry (ESI-MS): 702.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (d, J =8.0 Hz, 0.5H), 7.86-7.79 (m, 2H), 7.77-7.70 ( m, 1.5H), 7.67-7.61 (m, 3H), 7.38-7.31 (m, 2H), 6.99 (d, J =13.7 Hz, 1H), 6 .85-6.70 (m, 2H), 4.46-4.24 (m, 4H), 3.73-3.60 (m, 2H), 3.43-3.30 (m, 1H) , 3.19 (d, J =11.1 Hz, 0.5H), 2.91-2.69 (m, 2H), 2.44 (dd, J =24.2, 11.7 Hz, 1 ,5H), 1.41 (dt, J =15.5, 7.2 Hz, 3H).

Example 59. Preparation of (S,E)-2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a, 5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetamide

Methyl- (S,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5, 6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (150 mg, 0.23 mmol) was dissolved in a solution of ammonia in methanol (3 ml, 7N). The reaction mixture was heated to a temperature of 85°C in a sealed vessel and stirred for 48 hours. The reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give (S,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1 ,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetamide (38.5 mg, 84%). Electrospray ionization mass spectrometry (ESI-MS): 659 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.95 (d, J =7.8 Hz, 1H) _, 7.92-7.87 (m, 1H), 7.79-7.70 ( m, 5H), 7.46-7.42 (m, 1H), 7.34 (dd, J =8.7, 2.1 Hz, 1H), 7.01 (dd, J =16.5, 2.0 Hz, 1H), 6.86 (d, J =8.7 Hz, 1H), 6.79 (d, J =16.7 Hz, 1H), 4.31 (dd, J =14, 3, 4.5 Hz, 1H), 3.64 (d, J =12.5 Hz, 1H), 3.41-3.34 (m, 1H), 3.01 (d, J =2.5 Hz, 2H), 2.85 (ddt, J =9.7, 5.1, 2.2 Hz, 2H), 2.77 (ddt, J =10.2, 5.7, 2.8 Hz, 1H), 2.46 (td, J =12.2, 3.0 Hz, 1H), 2.16 (td, J =11.6, 3.1 Hz, 1H), 1.87 (t, J =10.6 Hz, 1H).

Example 60. Receipt (S,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxaline-3-carboxamide

(S,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline (50 mg, 0.083 mmol) and isocyanatotrimethylsilane (50 mg, 0.083 mmol) were heated to 90°C and stirred for 2 hours. Methanol was added to stop the reaction. The mixture solution was separated by flash reverse phase column chromatography to give (S,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1. 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carboxamide (24.2 mg, 14%). Electrospray ionization mass spectrometry (ESI-MS): 645 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82-7.64 (m, 3H), 7.72 (d, J =2.0 Hz, 1H), 7.64 (dd, J =8, 1, 2.5 Hz, 3H), 7.37-7.28 (m, 2H), 7.03-6.94 (m, 1H), 6.81 (d, J = 16.5 Hz, 1H ), 6.72 (d, J =8.7 Hz, 1H), 4.50 (s, 2H), 4.28 (dd, J =14.2, 4.5 Hz, 1H), 3.79 (dd, J =27.1, 12.6 Hz, 2H), 3.64-3.53 (m,1H), 3.33 (dd, J =14.3, 10.0 Hz, 1H), 3.08-2.93 (m, 1H), 2.75 (dd, J =8.5, 5.1 Hz, 1H), 2.59 (dd, J =12.4, 10.7 Hz, 1H), 2.48 (td, J =11.8, 3.4 Hz, 1H).

Examples 61-62 were prepared by the synthesis method indicated in example 60.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 61 ( S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino [1,2- a ]quinoxaline-3-carboxamide 601 62 (S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4 ,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carboxamide 609

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 61 to 62:

Example 61. ^1H NMR (400 MHz, methanol- d4 ) δ 7.93 (d, J =7.9 Hz, 1H) _, 7.87 (d, J =8.0 Hz, 1H), 7, 83 (d, J =2.3 Hz, 1H), 7.74 (t, J =7.9 Hz, 1H), 7.64 (s, 1H), 7.48 (dd, J =8.7 , 2.3 Hz, 1H), 7.21 (dt, J =9.8, 1.9 Hz, 1H), 7.18 (d, J =1.9 Hz, 1H), 6.95 (t , 1H), 6.93 (d, J =8.8 Hz, 1H), 6.88 (dt, J =9.5, 2.3 Hz, 1H), 4.36 (dd, J =14, 5, 3.6 Hz, 1H), 3.92-3.82 (m, 2H), 3.68 (dt, J =12.6, 3.1 Hz, 1H), 3.38-3.32 (m, 1H), 2.89 (td, J =13.0, 12.4, 3.4 Hz, 1H), 2.60-2.49 (m, 2H), 2.26 (td, J =12.0, 3.3 Hz, 1H).

Example 62. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (t, J =6.2 Hz, 2H), 7.76 (s, 1H), 7.68 (d, J =1.9 Hz, 1H), 7.61 (t, J =7.9 Hz, 1H), 7.25-7.14 (m, 3H), 7.02 (t, J =8.5 Hz, 1H), 6.72 (d, J =8.6 Hz, 1H), 6.36 (s, 1H), 4.50 (s, 2H), 4.25 (dd, J =14.3, 4.5 Hz , 1H), 3.77 (dd, J =23.3, 12.6 Hz, 2H), 3.56 (dt, J =12.5, 3.3 Hz, 1H), 3.33 (dd, J =14.3, 9.8 Hz, 1H), 3.04-2.90 (m, 1H), 2.68 (d, J =10.0 Hz, 1H), 2.56 (t, J =11.5 Hz, 1H), 2.43 (td, J =11.8, 3.3 Hz, 1H), 2.20 (s, 3H).

Example 63. Receiving (S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5, 6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxaline-3-carbothioamide

(S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (50 mg, 0.088 mmol), isothiocyanatotrimethylsilane (0.5 ml) was heated to a temperature of 90°C and stirred for 2 hours; Methanol was added to stop the reaction. The mixture solution was separated by flash reverse phase column chromatography to give (S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3- (trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carbothioamide (10.3 mg, 18.7%) Mass -electrospray ionization spectrometry (ESI-MS): 625 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84 (dd, J =19.9, 7.9 Hz, 2H), 7.76 (s, 1H), 7.65-7.62 (m, 2H), 7.26-7.21 (m, 3H), 7.02 (t, J =8.5 Hz, 1H), 6.69 (d, J =8.6 Hz, 1H), 6, 36 (s, 1H), 5.75 (s, 2H), 4.38 (d, J =11.8 Hz, 1H), 4.29 (dd, J =14.2, 4.3 Hz, 1H ), 4.16 (d, J =13.3 Hz, 1H), 3.59 (dd, J =10.7, 6.2 Hz, 1H), 3.47 (t, J =12.2 Hz , 1H), 3.32 (dd, J =14.2, 9.5 Hz, 1H), 3.01-2.84 (m, 2H), 2.75-2.61 (m, 1H), 2.19(s,3H).

Examples 64-65 were prepared by the synthesis method indicated in example 63.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 64 (S) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino [1,2 -a ]quinoxaline-3-carbothioamide 617 65 ( S , E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2- a ]quinoxaline-3-carbothioamide 661

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 64 to 65:

Example 64. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.92 (t, J = 8.1 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7, 75 (t, J =7.9 Hz, 1H), 7.60 (s, 1H), 7.49 (dd, J =8.7, 2.3 Hz, 1H), 7.24-7.16 (m, 2H), 6.95 (t, 1H), 6.94-6.85 (m, 2H), 4.49 (d, J =20.2 Hz, 1H), 4.37 (dd, J =14.4, 4.3 Hz, 2H), 3.67 (dt, J =12.5, 3.7 Hz, 1H), 3.35 (d, J =10.3 Hz, 1H), 3.28-3.21 (m, 1H), 2.83-2.74 (m, 1H), 2.69 (tt, J =10.8, 3.7 Hz, 1H), 2.41 ( ddd, J =13.3, 10.6, 3.4 Hz, 1H).

Example 65. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.81 (d, J = 7.9 Hz, 1H), 7.78-7.69 (m, 2H), 7.63-7.52 (m, 4H), 7.31-7.21 (m, 2H), 6.94-6.84 (m, 1H), 6.73 (d, J =16.5 Hz, 1H), 6, 61 (d, J =8.6 Hz, 1H), 5.66 (s, 2H), 4.31 (d, J =12.4 Hz, 1H), 4.24 (dd, J =14.2 , 4.4 Hz, 1H), 4.08 (d, J =13.3 Hz, 1H), 3.54 (dt, J =12.3, 4.4 Hz, 1H), 3.45 (t , J =11.3 Hz, 1H), 3.23 (dd, J =14.2, 9.8 Hz, 1H), 3.01-2.90 (m, 1H), 2.84 (t, J =11.6 Hz, 1H), 2.71-2.59 (m, 1H).

Example 66: Receiving (R,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5, 6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxaline-3-sulfonamide

(S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (40 mg, 0.071 mmol) was dissolved in ethylene glycol dimethyl ether (3 ml). Sulfonamide (40 mg, 0.417 mmol) was added. The reaction mixture was heated to 85°C and stirred overnight and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give (R,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl )phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-sulfonamide (8.8 mg, 19%). Electrospray ionization mass spectrometry (ESI-MS): 645.2 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J =7.9 Hz, 2H), 7.75 (s, 1H), 7.69 (s, 1H), 7.63 (s , 1H), 7.20 (dd, J =12.3, 4.5 Hz, 3H), 7.02 (t, J =8.7 Hz, 1H), 6.74 (d, J =8, 6 Hz, 1H), 6.36 (s, 1H), 4.36 (s, 2H), 4.23 (dd, J =14.3, 4.6 Hz, 1H), 3.71-3, 50 (m, 3H), 3.40 (dd, J =14.3, 9.6 Hz, 1H), 2.80-2.70 (m, 1H), 2.65 (t, J =10, 7 Hz, 1H), 2.57-2.44 (m, 1H), 2.35 (t, J =10.8 Hz, 1H), 2.20 (s, 3H).

Examples 67-68 were prepared by the synthesis method indicated in example 66.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 67 (R) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino [1,2 -a ]quinoxaline-3-sulfonamide ND 68 (R,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxaline-3-sulfonamide 681

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 67 to 68:

Example 67. ^1H NMR (400 MHz, methanol- d4 ) δ 8.00 (s, 1H), 7.90-7.81 (m, 2H ₎ , 7.77-7.65 (m, 2H) , 7.49 (dd, J =8.7, 2.3 Hz, 1H), 7.24-7.16 (m, 2H), 6.95 (t, 1H), 6.98 (dd, J =8.8, 2.8 Hz, 1H), 6.89 (dt, J =9.4, 2.3 Hz, 1H), 4.42 (dt, J =14.7, 4.0 Hz, 1H), 4.22 (t, J =10.9 Hz, 1H), 3.80 (t, J =11.4 Hz, 1H), 3.67 (dd, J =21.4, 12.9 Hz, 1H), 3.43-3.34 (m, 3H), 2.86-2.67 (m, 1H), 2.47-2.36 (m, 1H).

Example 68. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.9 Hz, 2H), 7.79-7.70 (m, 2H), 7.66 -7.59 (m, 3H), 7.36-7.29 (m, 2H), 6.98 (dd, J =15.2, 3.0 Hz, 1H), 6.84-6.70 (m, 2H ), 4.36 (s, 2H), 4.25 (dd, J =14.3, 4.6 Hz, 1H), 3.72-3.53 (m, 3H), 3.39 (dd, J =14.3, 9.6 Hz, 1H), 2.82 (t, J =3.9 Hz, 1H), 2.74-2.62 (m, 1H), 2.59-2.49 (m, 1H), 2.36 (t, J =10.9 Hz, 1H).

Example 69. Receiving (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)propan-1,3-diol

Stage 1. Synthesis (S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-3-(2,2-dimethyl-1,3-dioxan-5-yl)-6-(( 3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline

(S,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline (56 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (2 ml); 2,2-dimethyl-1,3-dioxan-5-one (26 mg, 0.2 mmol) and one drop of acetic acid were added to the solution. The reaction mixture was stirred at room temperature for 3 hours and then sodium cyanoborohydride (7 mg, 0.12 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The residue was separated by flash reverse phase column chromatography to give (S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-ene-1 -yl)-3-(2,2-dimethyl-1,3-dioxan-5-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6- hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (30 mg, 44%), which was used without further processing in the next step.

Example 2: Receipt (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)propan-1,3-diol

(S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-3-(2,2-dimethyl-1,3-dioxan-5-yl) -6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (30 mg, 0.044 mmol) and solution trifluoroacetic acid (1 ml) in water (1 ml) was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 15% aqueous sodium hydroxide and separated by flash reverse phase column chromatography to give (S,E) - 2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a, 5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)propan-1,3-diol (4.5 mg, 16%). Electrospray ionization mass spectrometry (ESI-MS): 640 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.94 (d, J = 7.8 Hz, 1H), 7.92-7.86 (m, 1H ₎ , 7.76 (t, J = 7.9 Hz, 1H), 7.71-7.66 (m, 2H), 7.34-7.26 (m, 2H), 7.20-7.10 (m, 2H), 6.84 (d, J =8.7 Hz, 1H), 6.34 (d, J =1.7 Hz, 1H), 4.29 (dd, J =14.3, 4.4 Hz, 1H), 3 .71-3.57 (m, 5H), 3.41-3.36 (m, 1H), 2.87 (ddd, J =12.9, 6.3, 3.7 Hz, 2H), 2 .66-2.50 (m, 3H), 2.36 (dd, J =11.9, 3.1 Hz, 1H), 2.28-2.18 (m, 4H).

Example 70 was prepared by the synthesis method described in Example 69.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 70 (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)propan-1,3-diol 632

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in example 70:

Example 70. ^1H NMR (400 MHz, methanol- d4 ) δ 8.05 (d, J =7.9 Hz, 1H), 8.00 (d, J = _7.8 Hz, 1H), 7, 87-7.77 (m, 2H), 7.68 (s, 1H), 7.52 (dd, J =8.7, 2.3 Hz, 1H), 7.26-7.16 (m, 2H), 6.96 (t, 1H), 7.04 (d, J =8.7 Hz, 1H), 6.92 (dd, J =9.5, 2.3 Hz, 1H), 4, 45 (dd, J =14.4, 4.2 Hz, 1H), 4.02 (d, J =13.8 Hz, 1H), 3.91 (d, J =5.0 Hz, 4H), 3.60 (d, J =11.8 Hz, 2H), 3.46 (dd, J =14.4, 9.8 Hz, 1H), 3.37 (s, 1H), 3.28 (s , 1H), 3.21-3.10 (m, 1H), 3.03 (d, J =11.8 Hz, 1H), 2.77 (t, J =13.1 Hz, 1H).

Example 71: Receipt (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylpropan-1,3-diol

Stage 1. Synthesis of dimethyl (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylmalonate

(S,E) -8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (150 mg, 0.27 mmol) was dissolved in dimethyl sulfoxide (2 ml). Diisopropylethylamine (70 mg, 0.53 mmol) and dimethyl 2-bromo-2-methylmalonate (280 mg, 0.53 mmol) were added to the solution. The reaction mixture was stirred in a microwave reactor at 60°C for 8 hours and then separated by flash reverse phase column chromatography to give dimethyl- (S,E) -2-(8-(2-(2-chloro- 6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino [1, 2 -a ]quinoxalin-3-yl)-2-methylmalonate (120 mg, 60%), which was used without further processing in the next step.

Stage 2. Synthesis (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylpropan-1,3-diol

Dimethyl- (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylmalonate (120 mg, 0.16 mmol) was dissolved in tetrahydrofuran (4 ml ). Lithium borohydride (30 mg, 1.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, extracted with ethyl acetate, dried and concentrated. The residue was separated by flash reverse phase column chromatography to give (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-(( 3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylpropan-1,3- diol (10.8 mg, 10%). Electrospray ionization mass spectrometry (ESI-MS): 654 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 8.01-7.80 (m, 2H), _7.82-7.64 (m, 3H), 7.38-7.23 (m, 2H ), 7.23-7.08 (m, 2H), 6.83 (d, J =8.7 Hz, 1H), 6.34 (d, J =1.7 Hz, 1H), 4.28 (dd, J =14.2, 4.4 Hz, 1H), 3.63-3.50 (m, 5H), 3.44-3.35 (m, 1H), 3.00 (d, J =10.6 Hz, 2H), 2.58 (s, 1H), 2.52-2.29 (m, 2H), 2.21 (d, J =1.5 Hz, 3H), 2.11 (t, J =10.7 Hz, 1H), 0.98 (s, 3H).

Example 72 was prepared by the synthesis method described in Example 71.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 72 (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylpropan-1,3-diol 646

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in the example with 72:

Example 72. ^1H NMR (400 MHz, methanol- d4 ) δ 7.91 (dd, J =12.9, 7.9 Hz, 2H), 7.83 ₍ d, J =2.2 Hz, 1H ), 7.74 (t, J =7.9 Hz, 1H), 7.65 (s, 1H), 7.45 (dd, J =8.6, 2.3 Hz, 1H), 7.22 -7.14 (m, 2H), 6.94 (t, 1H), 6.92-6.84 (m, 2H), 4.31 (dd, J =14.3, 4.2 Hz, 1H ), 3.68 (d, J =11.9 Hz, 1H), 3.58 (qd, J =11.6, 2.3 Hz, 4H), 3.36 (dd, J =14.4, 10.1 Hz, 1H), 3.11 (d, J =11.2 Hz, 2H), 2.71 (t, J =9.7 Hz, 1H), 2.52 (dt, J =46, 4, 11.7 Hz, 2H), 2.26 (t, J =10.8 Hz, 1H), 1.01 (s, 3H).

Example 73. Receiving (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanenitrile

Stage 1. Synthesis ( S , E )-5-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2,2-dimethyl-1,3-dioxane-5-carbonitrile

(S,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline (100 mg, 0.18 mmol) was dissolved in acetic acid (5 ml) and the mixture solution was cooled to 0°C; 2,2-dimethyl-1,3-dioxan-5-one (69 mg, 0.53 mmol) and trimethylsilanecarbonitrile (52 mg, 0.53 mmol) were added and stirred at room temperature for 18 hours. The reaction mixture was neutralized to pH > 7 and then separated by flash reverse phase column chromatography to give (S,E) -5-(8-(2-(2-chloro-6-fluorophenyl)prop-1-ene)-1-yl )-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2, 2-dimethyl-1,3-dioxane-5-carbonitrile (90 mg, 71%), which was used without further processing in the next step.

Stage 2. Synthesis ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanenitrile

(S,E) -5-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ]quinoxalin-3-yl)-2,2-dimethyl-1,3-dioxane-5-carbonitrile (90 mg, 0.128 mmol) and a solution of trifluoroacetic acid (2 ml) in water (2 ml) were stirred at room temperature for 24 hours. The reaction mixture was neutralized with 15% aqueous sodium hydroxide solution and then separated by flash reverse phase column chromatography to obtain (S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanenitrile (50 mg, 58.8%). Electrospray ionization mass spectrometry (ESI-MS): 665 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 8.01-7.87 (m, 2H), _7.83-7.63 (m, 3H), 7.36-7.27 (m, 2H ), 7.24-7.09 (m, 2H), 6.86 (d, J =8.7 Hz, 1H), 6.35 (d, J =1.7 Hz, 1H), 4.31 (dd, J =14.3, 4.4 Hz, 1H), 3.93-3.75 (m, 4H), 3.65 (dt, J =11.6, 2.5 Hz, 1H), 3.41 (dd, J =14.4, 10.1 Hz, 1H), 3.07 (dd, J =10.7, 2.3 Hz, 2H), 2.63 (tdd, J =10, 1, 4.4, 2.5 Hz, 1H), 2.35 (dtd, J =38.3, 11.7, 2.7 Hz, 2H), 2.21 (d, J =1.5 Hz , 3H), 2.00 (t, J =10.6 Hz, 1H).

Example 74: Receiving (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanenitrile

Example 74 was prepared by the synthesis method described in Example 73. Electrospray ionization mass spectrometry (ESI-MS): 657 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.91 (t, J =8.1 Hz, 2H) _, 7.85 (d, J =2.2 Hz, 1H), 7.74 (t , J =7.9 Hz, 1H), 7.61 (s, 1H), 7.46 (dd, J =8.7, 2.2 Hz, 1H), 7.23-7.15 (m, 2H), 6.94 (t, 1H), 6.89 (dd, J =16.2, 9.0 Hz, 2H), 4.31 (dd, J =14.4, 4.5 Hz, 1H ), 3.84 (dd, J =11.5, 8.7 Hz, 2H), 3.76 (dd, J =11.5, 4.7 Hz, 2H), 3.67 (d, J = 11.9 Hz, 1H), 3.37 (dd, J =14.4, 10.2 Hz, 1H), 3.06 (d, J =10.8 Hz, 2H), 2.64 (d, J =11.2 Hz, 1H), 2.45-2.34 (m, 1H), 2.29 (dd, J =12.7, 9.9 Hz, 1H), 1.99 (q, J =11.3, 10.5 Hz, 1H).

Example 75: Getting ( S , E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanamide

(S,E) -2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanenitrile (30 mg, 0.045 mmol) was dissolved in dimethyl sulfoxide (2 ml); the mixture solution was cooled to a temperature of 0°C. Potassium carbonate (100 mg) and hydrogen peroxide (0.5 ml, 30% wt) were added to the solution and stirred at room temperature for 18 hours. The reaction mixture was separated using flash reverse phase column chromatography to obtain (S,E )-2-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)-3-hydroxy-2-(hydroxymethyl)propanamide (27.5 mg, 92%). Electrospray ionization mass spectrometry (ESI-MS): 683 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.95 (d, J = 7.8 Hz, 1H) _, 7.92-7.85 (m, 1H), 7.77 (t, J = 7.9 Hz, 1H), 7.73-7.66 (m, 2H), 7.34-7.26 (m, 2H), 7.21-7.09 (m, 2H), 6.84 (d, J =8.7 Hz, 1H), 6.34 (d, J =1.7 Hz, 1H), 4.28 (dd, J =14.2, 4.3 Hz, 1H), 3 .91 (dd, J =11.9, 6.4 Hz, 2H), 3.81 (d, J =11.8 Hz, 2H), 3.66-3.55 (m, 1H), 3, 42-3.34 (m, 1H), 2.95 (dt, J =9.0, 3.0 Hz, 2H), 2.74-2.64 (m, 1H), 2.58 (t, J =3.4 Hz, 1H), 2.44-2.30 (m, 2H), 2.21 (d, J =1.4 Hz, 3H).

Example 76: Getting ( S , E )-1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carbonitrile

( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2-a]quinoxaline (300 mg, 0.53 mmol) was dissolved in acetic acid (5 ml) and the mixture solution was cooled to 0°C. Cyclobutanone (186 mg, 2.65 mmol) and trimethylsilanecarbonitrile (262 mg, 2.65 mmol) were added to the solution and stirred at room temperature for 18 hours. The reaction mixture was neutralized to pH>7 and then separated by rapid reflux. phase column chromatography to obtain (S,E) -1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-ene)-1-yl)-6-((3-(trifluoromethyl)phenyl )sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carbonitrile (315 mg, 92%). Electrospray ionization mass spectrometry (ESI-MS): 645 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.94 (d, J =7.9 Hz, 1H), 7.86 (d, J = _7.9 Hz, 1H), 7.76-7 .74 (m, 1H), 7.70-7.68 (m, 2H), 7.29-7.27 (m, 2H), 7.18 (dd, J = 8.6, 2.1 Hz , 1H), 7.14-7.07 (m, 1H), 6.86 (d, J =8.6 Hz, 1H), 6.33 (s, 1H), 4.30 (dd, J = 14.5, 4.4 Hz, 1H), 3.69 (dt, J =12.1, 2.6 Hz, 1H), 3.43-3.34 (m, 1H), 2.82-2 .68 (m, 2H), 2.53-2.48 (m, 1H), 2.42-2.17 (m, 8H), 2.14-1.85 (m, 3H), 1.68 (t, J =10.4 Hz, 1H).

Examples 77-78 were prepared by the synthesis method indicated in example 76.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 77 (S) -1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carbonitrile 637 78 ( S , E )-1-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carbonitrile 681

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 77 to 78:

Example 77. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.94 (d, J = 7.8 Hz, 1H), 7.88-7.83 (m, 2H), 7.75 (t , J =7.8 Hz, 1H), 7.67 (d, J =1.8 Hz, 1H), 7.50-7.44 (m, 1H), 7.24-7.17 (m, 2H), 6.95 (t, 1H), 6.95-6.85 (m, 2H), 4.36-4.29 (m, 1H), 3.73 (d, J =12.2 Hz , 1H), 3.40-3.32 (m, 1H), 2.75 (t, J =10.3 Hz, 2H), 2.50 (ddt, J =10.3, 7.3, 3 .4 Hz, 1H), 2.42-2.32 (m, 2H), 2.32-1.86 (m, 6H), 1.67 (t, J = 10.5 Hz, 1H).

Example 78. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.84-7.82 (m, 3H), 7.74 (d, J = 2.1 Hz, 1H), 7.67-7.63 (m, 3H), 7.36-7.29 (m, 2H), 7.00 (dd, J =16.6, 2.0 Hz, 1H), 6.82 (d, J =16.5 Hz, 1H), 6.74 (d, J =8.7 Hz, 1H), 4.25 (dd, J =14.1, 4.3 Hz, 1H), 3.70-3.51 (m , 1H), 3.40-3.34 (m, 1H), 2.80-2.59 (m, 3H), 2.47-2.40 (m, 3H), 2.28-2.07 (m, 4H), 1.96 (d, J =2.4 Hz, 1H), 1.81 (t, J =10.4 Hz, 1H).

Example 79. Getting ( S , E )-1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carboxamide

(S,E) -1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carbonitrile (300 mg, 0.465 mmol) was dissolved in dimethyl sulfoxide (5 ml) and the solution the mixtures were cooled to 0°C. Potassium carbonate (12.8 mg, 0.093 mmol) and hydrogen peroxide (0.5 ml, 30 wt%) were added to the solution and stirred at room temperature for 72 hours. The reaction mixture was separated using fast reverse phase column chromatography to give (S,E) -1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)- 1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carboxamide (179.7 mg, 58%). Electrospray ionization mass spectrometry (ESI-MS): 663 [M+1] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.93 (d, J =7.8 Hz, 1H), 7.83 (d, J = _7.9 Hz, 1H), 7.79-7 .66 (m, 3H), 7.33-7.25 (m, 2H), 7.20-7.07 (m, 2H), 6.83 (d, J =8.6 Hz, 1H), 6.32 (s, 1H), 4.25 (dd, J =14.3, 4.4 Hz, 1H), 3.60 (d, J =12.0 Hz, 1H), 3.41-3 .33 (m, 1H), 2.76 (d, J =11.0 Hz, 2H), 2.55 - 2.47 (m, 1H), 2.34-2.03 (m, 9H), 1.83-1.72 (m, 3H).

Examples 80-81 were prepared by the synthesis method indicated in example 79.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 80 ( S )-1-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carboxamide 655 81 ( S , E )-1-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)cyclobutan-1-carboxamide 699

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 80 to 81:

Example 80. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.94 (d, J = 7.7 Hz, 1H), 7.86-7.80 (m, 2H), 7.74 (t , J =7.9 Hz, 1H), 7.68 (d, J =1.9 Hz, 1H), 7.45 (dd, J =8.7, 2.3 Hz, 1H), 7.23 -7.16 (m, 2H), 6.94 (t, 1H), 6.92-6.83 (m, 2H), 4.27 (dd, J =14.4, 4.4 Hz, 1H ), 3.67-3.59 (m, 1H), 3.39-3.32 (m, 1H), 2.81-2.74 (m, 2H), 2.54-2.44 (m , 1H), 2.32 (td, J =11.9, 2.9 Hz, 1H), 2.27-2.19 (m, 2H), 2.17-2.12 (m, 1H), 2.12-2.03 (m, 2H), 1.81-1.70 (m, 3H).

Example 81. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.95 (d, J = 7.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.79-7 .70 (m, 5H), 7.44 (t, J =8.0 Hz, 1H), 7.35 (dd, J =8.7, 2.1 Hz, 1H), 7.01 (dd, J =16.6, 2.0 Hz, 1H), 6.88-6.75 (m, 2H), 4.29 (dd, J =14.3, 4.4 Hz, 1H), 3.69 -3.61 (m, 1H), 3.40-3.35 (m, 1H), 2.85-2.75 (m, 2H), 2.56 (dd, J = 4.4, 2, 7 Hz, 1H), 2.39-2.31 (m, 1H), 2.30-2.21 (m, 2H), 2.20-2.08 (m, 3H), 1.84-1 .74 (m, 3H).

Example 82: Getting ( S , E )-1-(8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)-2-methylpropan-2-ol

( S , E )-8-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4 ,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (100 mg, 0.18 mmol) was dissolved in dimethyl sulfoxide (2 ml). Cesium carbonate (172 mg, 0.531 mmol), potassium iodide (88 mg, 0.531 mmol) and 1-bromo-2-methylpropan-2-ol (134 mg, 0.88 mmol) were added. The reaction mixture was stirred in a microwave reactor at 80°C for 15 h and separated by flash reverse phase column chromatography to give (S,E) -1-(8-(2-(2-chloro-6-fluorophenyl) prop-1-en-1-yl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ] quinoxalin-3-yl)-2-methylpropan-2-ol (20.5 mg, 18.2%). Electrospray ionization mass spectrometry (ESI-MS): 638 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.83 (d, J =7.9 Hz, 1H), 7.75 (d, J =2.0 Hz, 1H ), 7.71 (d, J =7.9 Hz, 1H), 7.59 (t, J =7.8 Hz, 1H), 7.25 (d, J =8.0 Hz, 1H), 7.29-7.17 (m, 2H), 7.04 (t, J =8.3 Hz, 1H), 6.72 (d, J =8.6 Hz, 1H), 6.38 (s , 1H), 4.17 (dd, J =14.2, 4.3 Hz, 1H), 3.48 (d, J =11.9 Hz, 1H), 3.35 (dd, J =14, 1, 10.1 Hz, 1H), 2.83 (dd, J =23.1, 11.3 Hz, 2H), 2.67-2.60 (m, 1H), 2.48-2.41 (m, 1H), 2.35 (dd, J =11.4, 2.8 Hz, 1H), 2.31 (s, 2H), 2.24 (d, J =1.4 Hz, 3H) , 2.04 (t, J =10.6 Hz, 1H), 1.17 (s, 6H).

Example 83. Receiving (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

Stage 1. Synthesis rubs -butyl (R,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxaline-3-carboxylate

Tert -butyl (R) -8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ] Quinoxaline-3-carboxylate (100 mg, 0.17 mmol), (E) -2-(3-chloro-5-(trifluoromethyl)styryl)-4,4,5-trimethyl-1,3,2-dioxaborolane ( 67 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (13 mg, 0.017 mmol) and potassium carbonate (47 mg, 0.34 mmol) were stirred in 1,4-dioxane ( 6 ml) and water (3 ml). Nitrogen was introduced three times to replace air by pumping. The reaction in the mixture solution was carried out at a temperature of 90°C for 2 hours. After completion of the reaction, water (20 ml) was added to the reaction mixture and extracted three times with ethyl acetate (20 ml × 3). The organic phases were combined, washed with brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash chromatography on a silica gel column [eluent: EtAc:PE = 0-20%] to give tert -butyl (R,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-( (3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carboxylate (105 mg, 86%). Electrospray ionization mass spectrometry (ESI-MS): 702.3 [M+H] ⁺ .

Stage 2. Synthesis (R, E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline

Tert -butyl (R,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6- hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carboxylate (210 mg, 0.3 mmol) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (2 ml) was added to the solution. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed by concentration to give crude ( R,E )-8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl) sulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2- a ]quinoxaline (300 mg, crude). Electrospray ionization mass spectrometry (ESI-MS): 602.2 [M+H] ⁺ .

Stage 3. Methyl synthesis (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate

(R,E) -8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,4a,5,6-hexahydro-1 H -pyrazino[1,2 -a ]quinoxaline (300 mg, 0.75 mmol) was dissolved in dimethyl sulfoxide (5 ml). Potassium carbonate (311 mg, 2.25 mmol) and methyl bromoacetate (230 mg, 1.5 mmol) were added. The reaction mixture was stirred at 50°C for 2 hours. After completion of the reaction, water (20 ml) was added to the reaction mixture and extracted three times with ethyl acetate (20 ml × 3), the organic phases were combined, washed three times with water (30 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash silica gel column chromatography [eluent: EtAc:PE = 0-20%] to give methyl (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6- ((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (250 mg, 86% ). Electrospray ionization mass spectrometry (ESI-MS): 674.2 [M+H] ⁺ .

Stage 4. Synthesis (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

Methyl (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -Hexahydro- 3H- pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (250 mg, 0.37 mmol) was dissolved in methanol (5 ml) and water (1 ml). Lithium hydroxide monohydrate (36 mg, 1.5 mmol) was added. The mixture solution was stirred at room temperature for 2 hours and then concentrated to remove the solvent and oxidized with dilute hydrochloric acid. The residue was separated by reverse phase column chromatography [eluent: H ₂ O : MeCN = 0-70%] to give (R,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6 -((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid (80 mg, 33%). Electrospray ionization mass spectrometry (ESI-MS): 660.3 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.92-7.74 (m, 3H), 7.70-7.55 (m, 4H), 7.29 (t, J = 7.8 Hz, 2H), 6.94 (d, J =16.5 Hz, 1H), 6.84-6.64 (m, 2H), 4.23 (d, J =14.3 Hz, 1H), 3, 63 (s, 1H), 3.35 (s, 3H), 3.09 (s, 3H), 2.73 (s, 1H), 2.49 (s, 1H).

Example 84: Receiving (S,E) -1-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)ethan-1-one

Example 84 was prepared by the synthesis method described in Example 7. Electrospray ionization mass spectrometry (ESI-MS): 660 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.75 (d, J = 2.1 Hz, 1H), 7.73-7.68 (m, 2H ₎ , 7.61 (t, J = 8.5 Hz, 1H), 7.55 (d, J =8.0 Hz, 1H), 7.46 (s, 1H), 7.44-7.32 (m, 2H), 7.20 ( d, J =14.7 Hz, 1H), 7.00 (d, J =16.7 Hz, 1H), 6.89 (d, J =8.9 Hz, 1H), 6.79-6, 72 (m, 1H), 4.45-4.36 (m, 1H), 4.28 (d, J =22.3 Hz, 1H), 3.76 (t, J =11.1 Hz, 1H ), 3.48 (s, 1H), 3.16 (d, J =21.2 Hz, 1H), 2.69 (s, 3H), 2.08 (d, J =6.4 Hz, 2H ), 2.04 (d, J =7.9 Hz, 2H).

Example 85 Preparation of methyl (S,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate

Example 85 was prepared by the synthesis method described in Example 44. Electrospray ionization mass spectrometry (ESI-MS): 690 [M+H] ⁺ .

^1H NMR (400 MHz, CDCl ₃ ) δ 7.78 (d, J =2.1 Hz, 1H), 7.63 (d, J =2.3 Hz, 1H), 7.61 (d, J =2.2 Hz, 1H), 7.57 (dt, J =7.9, 1.4 Hz, 1H), 7.53-7.49 (m, 1H), 7.40-7.36 ( m, 2H), 7.31 (d, J =2.0 Hz, 1H), 7.29 (d, J =1.6 Hz, 1H), 7.01-6.94 (m, 1H), 6.80 (d, J =16.5 Hz, 1H), 6.71 (d, J =8.7 Hz, 1H), 4.23 (dd, J =14.1, 4.1 Hz, 1H ), 3.73 (s, 3H), 3.56 (d, J =12.3 Hz, 1H), 3.33-3.26 (m, 1H), 3.22 (d, J =3, 1 Hz, 2H), 2.89-2.76 (m, 3H), 2.59 (td, J =12.1, 3.1 Hz, 1H), 2.29 (td, J =11.5 , 3.2 Hz, 1H), 2.01-1.91 (m, 1H).

Example 86: Receiving (S,E) -2-(8-(2-chloro-6-(trifluoromethyl)styryl)-6-((3-(trifluoromethoxy)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

Example 86 was prepared by the synthesis method described in Example 9. Electrospray ionization mass spectrometry (ESI-MS): 676 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.78-7.62 (m, 5H) _, 7.59 (d, J =8.7 Hz, 1H), 7.51-7.19 ( m, 3H), 7.15-6.92 (m, 2H), 6.76 (d, J =16.6 Hz, 1H), 4.53-4.36 (m, 1H), 4.00 (d, J =13.8 Hz, 1H), 3.74 (d, J =22.8 Hz, 2H), 3.50 (d, J =12.4 Hz, 2H), 3.41-3 .37 (m, 1H), 3.16-3.02 (m, 1H), 2.96 (t, J =12.2 Hz, 1H), 2.67 (q, J =11.2, 10 ,1 Hz, 2H).

Example 87. Receiving (S) -2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,3,4,4a,5-hexahydro-6 H -pyrazino[1,2 -a ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol

Tert -butyl (S) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2 ,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxaline-3-carboxylate (280 mg, 0.39 mmol) was dissolved in HCl/dioxane (10 ml, 4M). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product (230 mg, 82%), which was used without further processing in the next step. The crude product (30 mg) was separated by reverse phase column chromatography [eluent: H ₂ O : MeCN = 0-80%] to give (S) -2-((3-((8-(3-(difluoromethoxy) -5-fluorophenyl)-1,2,3,4,4a,5-hexahydro-6 H -pyrazino[1,2 -a ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl )oxy)ethan-1-ol (7.6 mg, 25%). Electrospray ionization mass spectrometry (ESI-MS): 619 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.63 (s, 1H), 8.53 (d, J =28.1 Hz, 2H), 7.27 (s, 1H), 7.14 (s , 1H), 6.88 (s, 2H), 6.78 (d, J =9.1 Hz, 1H), 6.51 (t, J =73.2 Hz, 1H), 4.66 (d , J =30.7 Hz, 3H), 4.02 (s, 4H), 3.80 (s, 2H), 3.49 (s, 2H), 3.03 (s, 2H).

Example 88. (S) -2-((3-((8-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-1,2,3,4,4a,5-hexahydro-6 H -pyrazino[1,2 -a ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol

Example 88 was prepared by the synthesis method described in Example 87.

^1H NMR (400 MHz, methanol- d4 ) δ 8.76 (d, J =2.3 Hz, 1H), 8.51 (d, J =2.3 Hz _, 1H), 7.17 (dd , J =8.7, 2.1 Hz, 1H), 7.12 (d, J =2.0 Hz, 1H), 6.99 (d, J =8.7 Hz, 1H), 5.86 (s, 1H), 4.68 (dt, J =10.4, 4.9 Hz, 1H), 4.57 (dt, J =11.7, 4.5 Hz, 1H), 4.43 ( dd, J =13.9, 3.5 Hz, 1H), 4.17 (d, J =13.5 Hz, 1H), 3.85 (t, J =4.8 Hz, 2H), 3, 77 (dd, J =13.9, 8.2 Hz, 1H), 3.58-3.44 (m, 3H), 3.20 (td, J =12.5, 3.0 Hz, 1H) , 3.15-3.04 (m, 1H), 2.97 (t, J =12.3 Hz, 1H), 2.17 (s, 2H), 1.27 (s, 6H), 1, 25 (s, 6H). Electrospray ionization mass spectrometry (ESI-MS): 597 [M+H] ⁺ .

Example 89. Receiving (S) -2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-1,2,3,4,4a,5-hexahydro-6 H -pyrazino[1,2 -A ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol

Stage 1. Synthesis (S) -6-((2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy))-5-fluorophenyl)-2,3,4,4a,5,6-hexahydro -1 H -pyrazino[1,2 -a ]quinoxaline

(S) -2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,3,4,4a,5-hexahydro- 6H -pyrazino[1,2 -a ] quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol (200 mg, 0.32 mmol), TBSCl (150 mg, 0.97 mmol), imidazole (220 mg, 3.23 mmol) was stirred with anhydrous dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 2 hours; after completion of the reaction, the reaction mixture was washed with saturated NaHCO ₃ (10 ml), H ₂ O (10 ml) and brine (10 ml). The organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was separated by flash silica gel column chromatography to give (S) -6-((2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3)-yl) sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (180 mg, 77%) (PE:EA = 0-30%). Electrospray ionization mass spectrometry (ESI-MS): 733 [M+H] ⁺ .

Stage 2. Synthesis (S) -6-((2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-2,3,4,4a, 5,6-hexahydro-1 H -pyrazino[1,2 -a ] quinoxaline

(S) -6-((2-(2-(( tert- butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl )-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2 -a ]quinoxaline (40 mg, 5.46×10 ^-2 mmol), diisopropylethylamine (71 mg, 0.55 mmol ) and methanesulfonyl chloride (31 mg, 0.27 mmol) were stirred with DCM (5 ml). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was washed with saturated NaHCO ₃ (5 ml), H ₂ O (5 ml) and brine (5 ml). The organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated to give crude (S) -6-((2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy )-5-fluorophenyl)-3-(methylsulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (45 mg, 95%). Electrospray ionization mass spectrometry (ESI-MS): 811 [M+H] ⁺ . The crude product without additional processing was used in the next step.

Stage 3. Synthesis (S) -2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-1,2, 3,4,4a,5-hexahydro-6 H -pyrazino[1,2 -a ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol

(S) -6-((2-(2-(( tert- butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl )-3-(methylsulfonyl)-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (45 mg, 5.46×10 ^-2 mmol) was dissolved in HCl /dioxane (5 ml, 4M). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was first separated by preparative TLC (DCM:MeOH = 15:1) and then by reverse phase column chromatography [ eluent: H ₂ O: MeCN = 0-80%] to obtain (S) -2-((3-((8-(3-(difluoromethoxy)-5-fluorophenyl)-3-(methylsulfonyl)-1,2 ,3,4,4a,5-hexahydro- 6H -pyrazino[1,2 -a ]quinoxalin-6-yl)sulfonyl)-5-(trifluoromethyl)pyridin-2-yl)oxy)ethan-1-ol ( 6.7 mg, 17%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.53 (s, 1H), 8.40 (d, J =2.3 Hz, 1H), 7.49 (d, J =1.9 Hz, 1H ), 7.22 (d, J =2.0 Hz, 1H), 6.93 (dd, J =8.2, 2.0 Hz, 2H), 6.82 (d, J =8.6 Hz , 1H), 6.73 (d, J =9.1 Hz, 1H), 6.47 (t, J =73.3 Hz, 1H), 4.51 (s, 2H), 4.23 (d , J =12.6 Hz, 1H), 3.79 (dd, J =17.8, 10.9 Hz, 5H), 3.57 (s, 1H), 3.18 (s, 1H), 2 .87 (q, J =13.3, 12.3 Hz, 2H), 2.76 (s, 3H), 2.50 (s, 1H). Electrospray ionization mass spectrometry (ESI-MS): 697 [M+H] ⁺ .

Example 90. Preparation of methyl (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate

Stage 1. Methyl synthesis (S) -2-(6-((2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,4,4a,5,6-hexahydro- 3 H -pyrazino [1,2 -a ]quinoxalin-3-yl)acetate

(S) -6-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl )-2,3,4,4a,5,6-hexahydro- 1H -pyrazino[1,2 -a ]quinoxaline (85 mg, 0.12 mmol), methyl bromoacetate (88 mg, 0.58 mmol) and carbonate potassium (80 mg 0.58 mmol) was stirred in 10 ml of acetonitrile. The reaction mixture was stirred at 80°C for 2 hours; completion of the reaction was confirmed by LC-MS; the reaction mixture was concentrated. The residue was dissolved in DCM (10 ml), washed with saturated NaHCO ₃ (5 ml), H ₂ O (5 ml) and brine (5 ml). The organic phases were dried over magnesium sulfate and filtered. The filtrate was concentrated to give crude methyl (S) -2-(6-((2-(2-(( tert- butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-( 3-(difluoromethoxy)-5-fluorophenyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (90 mg, 95%) . Electrospray ionization mass spectrometry (ESI-MS): 805 [M+H] ⁺ . The crude product without additional processing was used in the next step.

Stage 2. Methyl synthesis (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate

Methyl (S) -2-(6-((2-(2-(( tert -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy) -5-fluorophenyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (90 mg, 0.11 mmol) was dissolved in HCl /dioxane (5 ml, 4M). The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product (80 mg), the crude product (50 mg) was used without further processing in the next step, and the remaining crude product (30 mg) was first separated by preparative TLC [eluent: DCM: MeOH = 15:1] and then by reverse phase column chromatography [eluent: _H2O : MeCN = 0-80%] to give methyl (S) -2-( 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5, 6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (5.7 mg, 7%). Electrospray ionization mass spectrometry (ESI-MS): 691 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.44 (s, 1H), 7.66 (s, 1H), 7.22 (ddd, J =6.9, 4.5, 1.7 Hz, 1H), 6.97 (s, 2H), 6.81 (d, J =9.2 Hz, 2H), 6.54 (t, J =73.2 Hz, 1H), 4.82 (s, 1H), 4.66 (s, 2H), 4.19 (s, 1H), 4.02 (d, J =31.0 Hz, 5H), 3.87 ( s, 3H), 3.74-3.52 (m, 5H), 3.20 (s, 1H).

Example 91: Receipt (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4, 4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

Stage 1. Synthesis rubs -butyl (S) -2-(6-((2-(2-(( rubs -butyldimethylsilyl)oxy)ethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-8-(3-(difluoromethoxy)-5-fluorophenyl)-1,2,4,4a,5,6-hexahydro- 3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetate

The substance was prepared by the method specified in example 90. Electrospray ionization mass spectrometry (ESI-MS): 847 [M+H] ⁺ .

Stage 2. Synthesis ( S )-2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4 ,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

The substance was prepared by the method specified in example 90. Electrospray ionization mass spectrometry (ESI-MS): 677 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 8.76 (d, J =2.4 Hz, 1H) _, 8.55 (d, J =2.4 Hz, 1H), 7.48-7 .36 (m, 2H), 7.11 (d, J =8.8 Hz, 1H), 7.07-7.02 (m, 2H), 6.90 (t, J =73.2 Hz, 1H), 6.87 (d, J =9.5 Hz, 1H), 4.67 (dt, J =10.4, 4.9 Hz, 1H), 4.58-4.48 (m, 1H ), 4.45 (dd, J =14.0, 3.4 Hz, 1H), 4.25 (d, J =11.5 Hz, 1H), 4.11 (s, 2H), 3.80 (t, J =4.8 Hz, 2H), 3.79-3.67 (m, 3H), 3.59 (s, 1H), 3.23 (d, J =11.3 Hz, 2H) , 3.01 (t, J =11.7 Hz, 1H).

Examples 92 and 93. Preparation of 2-((4aS)-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-oxo-5-(trifluoromethyl)-2,3-dihydropyridin-3-yl )sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid and (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a,5, 6-hexahydro-3 H -pyrazino[1,2 -A ]quinoxalin-3-yl)acetic acid

Methyl (S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-(2-hydroxyethoxy)-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1, 2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ]quinoxalin-3-yl)acetate (50 mg, 0.07 mmol) and lithium hydroxide monohydrate (30 mg, 0.7 mmol) was stirred in methanol (5 ml) and H ₂ O (5 ml). The reaction mixture was stirred at 80°C for 1 hour; completion of the reaction was confirmed by LC-MS; the reaction mixture was concentrated to dryness and DCM (10 ml) and H ₂ O (10 ml) were added to the residue. The organic phases were separated and concentrated. The residue was first separated by preparative TLC [eluent: DCM: MeOH = 15:1] and then by reverse phase column chromatography [eluent: _H2O : MeCN = 0-70%] to give 2-((4a S )-8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-oxo-5-(trifluoromethyl)-2,3-dihydropyridin-3-yl)sulfonyl)-1,2,4, 4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid (1.8 mg, 4%).

(Example 92). ^1H NMR (400 MHz, methanol- d4 ) δ 8.44 (d, J =2.7 Hz, 1H), 8.21 (dd, J = _2.8 , 1.3 Hz, 1H), 7 .66 (d, J =2.2 Hz, 1H), 7.36 (dd, J =8.7, 2.2 Hz, 1H), 7.08 (dd, J =11.4, 3.0 Hz, 3H), 6.91 (t, J =73.2 Hz, 1H), 6.87 (d, J =9.5 Hz, 1H), 4.41 (dd, J =13.7, 3 .5 Hz, 1H), 4.23 (d, J =11.0 Hz, 1H), 4.14 (s, 2H), 3.77 (t, J =10.1 Hz, 3H), 3, 61 (dd, J =13.8, 8.3 Hz, 1H), 3.30-3.20 (m, 2H), 3.07 (t, J =11.6 Hz, 1H). Electrospray ionization mass spectrometry (ESI-MS): 633 [M+H] ⁺ , and

(S) -2-(8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,4,4a ,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid (3.5 mg, 8%).

(Example 93). ^1H NMR (400 MHz, methanol- d4 ) δ 8.80-8.72 (m, 1H) _, 8.56 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 7.42 (dd, J =8.7, 2.2 Hz, 1H), 7.13 (d, J =8.7 Hz, 1H), 7.10-7, 04 (m, 2H), 6.91 (t, J =73.2 Hz, 1H), 6.87 (d, J =9.5 Hz, 1H), 4.34 (dd, J =13.9 , 3.5 Hz, 1H), 4.25 (d, J =11.6 Hz, 1H), 4.05 (d, J =3.7 Hz, 2H), 3.97 (s, 3H), 3.70 (t, J =9.3 Hz, 2H), 3.58 (dd, J =13.9, 8.8 Hz, 1H), 3.50-3.41 (m, 1H), 3 ,24-3.11 (m, 2H), 2.94 (t, J =11.6 Hz, 1H). Electrospray ionization mass spectrometry (ESI-MS): 647 [M+H] ⁺ .

Example 94. Receiving (S) -2-(8-(3-cyano-2-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-3 H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid

(S) -2-(8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H- pyrazino[1,2 -a ] quinoxalin-3-yl)acetic acid (30 mg, 0.056 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17 mg, 0.067 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (4 mg, 0.0056 mmol) and potassium carbonate (15 mg, 0.112 mmol) were stirred in 1,4-dioxane (3 ml) and water (1 ml). Nitrogen was introduced three times to replace air by pumping. The reaction in the solution mixture was carried out at a temperature of 90°C for 2 hours. After completion of the reaction, water (20 ml) was added to the reaction mixture and extracted three times with ethyl acetate (20 ml × 3), the organic phases were combined, washed with saline (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by flash silica gel column chromatography [eluent: MeOH: DCM = 0-40%] to give (S) -2-(8-(3-cyano-2-fluorophenyl)-6-((3-(trifluoromethyl )phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid and then separated by reverse phase column chromatography [eluent: H ₂ O : MeCN = 0-60%, HCOOH] to give (S) -2-(8-(3-cyano-2-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl) -1,2,4,4a,5,6-hexahydro- 3H -pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid (3.5 mg, 11%). Electrospray ionization mass spectrometry (ESI-MS): 575.2 [M+H] ⁺ .

^1H NMR (400 MHz, methanol- d4 ) δ 7.98 (dd, J =19.5, 7.9 Hz, 2H) _, 7.85-7.76 (m, 3H), 7.70 ( td, J =6.7, 5.7, 1.6 Hz, 1H), 7.62 (s, 1H), 7.48-7.36 (m, 2H), 6.99 (d, J = 8.8 Hz, 1H), 4.39 (dd, J =14.4, 4.2 Hz, 1H), 3.86 (d, J =12.3 Hz, 1H), 3.41 (d, J =12.5 Hz, 2H), 3.36 (d, J =9.6 Hz, 3H), 2.97 (d, J =16.5 Hz, 1H), 2.70-2.56 ( m, 2H), 2.36 (t, J =11.2 Hz, 1H).

Examples 95, 96 and 97 were prepared by the synthesis method described in example 94.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 95 (S) -2-(8-(3-cyano-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H - pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid 575.2 96 (S) -2-(8-(5-cyano-2-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H - pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid 575.2 97 (S) -2-(8-(3-chloro-5-cyanophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro- 3H - pyrazino[1,2 -a ]quinoxalin-3-yl)acetic acid 591.2

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in examples 95, 96 and 97:

Example 95. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.97 (t, J = 7.2 Hz, 2H), 7.87 (d, J = 2.3 Hz, 1H), 7, 83-7.75 (m, 2H), 7.66 (dt, J =10.1, 2.0 Hz, 1H), 7.60 (s, 1H), 7.53 (dd, J =8, 7, 2.3 Hz, 1H), 7.47 (dt, J =8.1, 1.8 Hz, 1H), 6.99 (d, J =8.8 Hz, 1H), 4.36 ( dd, J =14.5, 4.4 Hz, 1H), 3.92-3.73 (m, 1H), 3.36 (s, 3H), 3.22 (d, J =10.0 Hz , 2H), 2.88 (s, 1H), 2.57 (d, J =9.3 Hz, 2H), 2.28 (t, J =11.1 Hz, 1H).

Example 96. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 8.00 (d, J =7.9 Hz, 1H), 7.95 (d, J =7.9 Hz, 1H), 7, 87 (dd, J =7.3, 2.1 Hz, 1H), 7.80 (d, J =8.8 Hz, 2H), 7.73 (ddd, J =8.6, 4.5, 2.1 Hz, 1H), 7.62 (s, 1H), 7.40 (dd, J =10.4, 8.4 Hz, 2H), 6.97 (d, J =8.8 Hz, 1H), 4.37 (dd, J =14.9, 4.0 Hz, 1H), 3.81 (d, J =9.4 Hz, 1H), 3.39-3.32 (m, 3H ), 3.22 (d, J =10.1 Hz, 2H), 2.94 (s, 1H), 2.57 (d, J =8.7 Hz, 2H), 2.28 (d, J =11.5 Hz, 1H).

Example 97. ¹ H NMR (400 MHz, methanol- d ₄ ) δ 7.99 (t, J = 6.9 Hz, 2H), 7.90-7.86 (m, 2H), 7.84 (d , J =2.3 Hz, 1H), 7.80 (t, J =7.9 Hz, 1H), 7.72 (t, J =1.6 Hz, 1H), 7.64 (s, 1H ), 7.53 (dd, J =8.7, 2.3 Hz, 1H), 7.02 (d, J =8.8 Hz, 1H), 4.39 (dd, J =14.5, 4.4 Hz, 1H), 3.92 (d, J =13.3 Hz, 1H), 3.59 (s, 2H), 3.40-3.33 (m, 3H), 2.96 ( s, 1H), 2.78 (dd, J =13.4, 10.2 Hz, 1H), 2.63 (t, J =12.5 Hz, 1H), 2.47 (t, J =11 ,2 Hz, 1H).

Example 98. Receiving (R) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[ 4.3 -a ]quinoxaline

(R) -8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3 -a ]quinoxaline (80 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (58 mg, 0.08 mmol), potassium carbonate (58 mg, 0.42 mmol) and 2-(3 - (difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-pinacolborane (221 mg, 0.77 mmol) was placed in a three-neck flask. 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 100°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography to give (R) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a ,5,6-hexahydro-[1,4]oxazino[4,3 -a ]quinoxaline (60 mg, yield: 64.5%). Electrospray ionization mass spectrometry (ESI-MS): 559.5 [M+H] ⁺ .

^1H NMR (500 MHz, methanol- d4 ) δ 7.95 (d, J =7.8 Hz, 1H) _, 7.88 (d, J =2.3 Hz, 1H), 7.86 (d , J =8.1 Hz, 1H), 7.75 (t, J =7.9 Hz, 1H), 7.65 (s, 1H), 7.47 (dd, J =8.7, 2, 3 Hz, 1H), 7.22 (dt, J =9.9, 1.9 Hz, 1H), 7.19 (d, J =2.0 Hz, 1H), 7.1-6.8 ( t, 1H), 6.91-6.86 (m, 2H), 4.25 (dd, J =14.4, 4.3 Hz, 1H), 3.77 (ddd, J =31.8, 11.3, 3.3 Hz, 2H), 3.55-3.37 (m, 2H), 3.29-3.24 (m, 1H), 3.08-2.98 (m, 1H) , 2.55-2.30 (m, 2H).

Example 99 was prepared by the synthesis method described in Example 98.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 99 (S) -8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4 ]oxazino[4,3 -a ]quinoxaline 559.5 [M+H] ⁺ .

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in example 99:

Example 99. ^1H NMR (500 MHz, methanol- d4 ) δ 7.95 (d, J =7.7 Hz, 1H), 7.88 (d, J =2.2 Hz, _1H ), 7, 86 (d, J =8.0 Hz, 1H), 7.75 (t, J =7.9 Hz, 1H), 7.65 (s, 1H), 7.47 (dd, J =8.7 , 2.3 Hz, 1H), 7.22 (dt, J =9.9, 1.9 Hz, 1H), 7.19 (d, J =2.0 Hz, 1H), 7.1-6 .81 (t, 1H), 6.91-6.85 (m, 2H), 4.25 (dd, J =14.4, 4.3 Hz, 1H), 3.77 (ddd, J =32 ,0, 11.3, 3.4 Hz, 2H), 3.55-3.37 (m, 2H), 3.28-3.24 (m, 1H), 3.03 (t, J =10 .7 Hz, 1H), 2.58-2.31 (m, 2H).

Example 100 Preparation of 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4 ]thiazino[4,3 -A ]quinoxaline

8-bromo-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]thiazino[4,3 -a ]quinoxaline (200 mg, 0.41 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (58 mg, 0.08 mmol), potassium carbonate (138 mg, 1.0 mmol) and 2-(3-(difluoromethoxy) -5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-pinacolborane (115 mg, 0.4 mmol) was placed in a three-neck flask; 1,4-dioxane (6 ml) and water (3 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 100°C for 2 hours; after completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography to give 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro-[1,4]thiazino[4,3 -a ]quinoxaline (230 mg, yield: 98.7%). Electrospray ionization mass spectrometry (ESI-MS): 575.2 [M+H] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84 (dd, J =12.1, 7.8 Hz, 2H), 7.74-7.69 (m, 2H), 7.64 (t, J =7.9 Hz, 1H), 7.36 (dd, J =8.7, 2.3 Hz, 1H), 7.12 (dt, J =9.5, 2.0 Hz, 1H), 7.09 (d, J =2.0 Hz, 1H), 6.80 (dt, J =9.2, 2.3 Hz, 1H), 6.78-6.71 (m, 1H), 6 .74-6.38 (t, 1H), 4.28 (dd, J =14.4, 5.3 Hz, 1H), 3.93-3.80 (m, 1H), 3.41 (dd , J =14.4, 10.0 Hz, 1H), 3.09-2.95 (m, 1H), 2.79-2.64 (m, 1H), 2.59-2.47 (m , 1H), 2.47-2.31 (m, 3H).

Example 101 Preparation of 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4 ]thiazino [4.3 -a ]quinoxaline-3-oxide

8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4]thiazino[4 .3 -a ]quinoxaline (60 mg, 0.1 mmol) was dissolved in dichloromethane (5 ml). 3-chloroperbenzoic acid (18 mg, 0.1 mmol) was added. The reaction solution was stirred at room temperature for 16 hours and washed with saturated aqueous sodium sulfite. The solvent was removed by concentration. The residue was separated by flash silica gel column chromatography to give 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6 -hexahydro-[1,4]thiazino[4,3 -a ]quinoxaline-3-oxide (40 mg, yield: 67.7%). Electrospray ionization mass spectrometry (ESI-MS): 591.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.94 (dd, J =55.9, 7.3 Hz, 2H), 7.80-7.58 (m, 3H), 7.42-7, 32 (m, 1H), 7.13-7.01 (m, 2H), 6.91-6.77 (m, 2H), 6.75-6.37 (t, J = 3.3 Hz, 1H), 4.14 (d, J =13.8 Hz, 1H), 3.97 (s, 1H), 3.75 (d, J =13.8 Hz, 1H), 3.52 (d, J =13.8 Hz, 1H), 3.34(s, 1H), 3.08(s, 1H), 2.80 (t, J =15.7 Hz, 1H), 2.73-2, 53 (m, 1H), 2.44 (s, 1H).

Example 102 Preparation of 8-(3-(difluoromethoxy)-5-fluorophenyl)-6-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,4,4a,5,6-hexahydro-[1,4 ]thiazino[4,3 -a ]quinoxaline 3,3-dioxide

The substance was obtained by the synthesis method specified in example 101. 3 equivalents of 3-chloroperbenzoic acid were used. Electrospray ionization mass spectrometry (ESI-MS): 591.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14-8.00 (m, 3H), 8.00-7.91 (m, 2H), 7.78 (t, J = 7.7 Hz, 1H), 7.50 (d, J =8.3 Hz, 1H), 7.12-7.02 (m, 2H), 6.96 (d, J =9.0 Hz, 1H), 6, 76-6.41(t, J =3.1 Hz, 1H), 4.99 (s, 1H), 4.68 (s, 1H), 4.47 (t, J =13.5 Hz, 1H ), 4.20 (d, J =21.0 Hz, 3H), 3.81 (t, J =12.4 Hz, 1H), 3.19 (d, J =14.5 Hz, 1H), 3.02 (d, J =13.6 Hz, 1H).

Example 103. Getting (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ] quinoxaline

Stage 1. Synthesis (6a S )-3-bromo-8-fluoro-7,8,9,10-tetrahydro-5 H -pyrido[1,2 -a ]quinoxaline -6(6a H )-she

( 6aS )-3-bromo-8-hydroxy-7,8,9,10-tetrahydro- 5H -pyrido[1,2 -a ]quinoxalin-6( 6aH )-one (60 mg, 0.2 mmol) was dissolved in dichloromethane (5 ml) and the mixture solution was cooled to -70°C. DAST (33 mg, 0.2 mmol) was added to the solution. The mixture solution was stirred at -30°C for 2 hours, then naturally warmed to room temperature and stirred for 16 hours. The mixture solution was diluted with 15 ml of ethyl acetate, washed with saline (15 ml × 3), dried over anhydrous sodium sulfate , filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-8-fluoro-7,8,9,10-tetrahydro- 5H- pyrido[1,2 -a ]quinoxaline-6(6a H )-one (40 mg, yield: 66.8%). Electrospray ionization mass spectrometry (ESI-MS): 299, 300 [M+H] ⁺ .

Stage 2. Synthesis (6a S )-3-bromo-8-fluoro-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ] quinoxaline

( 6aS )-3-bromo-8-fluoro-7,8,9,10-tetrahydro- 5H -pyrido[1,2 -a ]quinoxalin-6(6aH)-one (40 mg, 0.12 mmol ) was dissolved in 4M borane-tetrahydrofuran (5 ml). The reaction mixture was stirred at 30°C for 2 hours. Methanol was added dropwise to complete the reaction. To remove the solvent, the reaction mixture was concentrated. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-8-fluoro-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline (17 mg, yield: 49.7%). Electrospray ionization mass spectrometry (ESI-MS): 285, 287 [M+H] ⁺ .

Stage 3. Synthesis (6a S )-3-bromo-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline

( 6aS )-3-bromo-8-fluoro-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (17 mg, 0.059 mmol) was dissolved in dichloromethane ( 5 ml). Pyridine (0.2 ml), dimethylaminopyridine (1 mg, 0.005 mmol) and 3-(trifluoromethyl)benzenesulfonyl chloride (18 mg, 0.072 mmol) were added. The reaction in the mixture solution was carried out at a temperature of 25°C for 4 hours. The solvent was removed by concentration. The residue was dissolved in ethyl acetate (15 ml), washed successively with water (10 ml), saturated aqueous sodium hydrogen carbonate (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, filtered and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-8-fluoro-5((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro -5H -pyrido[1,2 -a ]quinoxaline (30 mg, yield: 100%). Electrospray ionization mass spectrometry (ESI-MS): 493, 495 [M+H] ⁺ .

Stage 4. Synthesis (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2-a]quinoxaline

( 6aS )-3-bromo-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 - a ]quinoxaline (30 mg, 0.059 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (29 mg, 0.04 mmol), potassium carbonate (21 mg, 0.15 mmol) and 2-( 3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (17 mg, 0.06 mmol) was placed in a three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-fluoro-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6. 6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (15 mg, yield: 44.3%). Electrospray ionization mass spectrometry (ESI-MS): 575.6 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86-7.73 (m, 4H), 7.61 (t, J =7.8 Hz, 1H), 7.35 (dd, J =8, 7, 2.3 Hz, 1H), 7.12 (dt, J =9.5, 1.9 Hz, 1H), 7.09 (d, J =2.1 Hz, 1H), 6.90 ( d, J =8.7 Hz, 1H), 6.81 (dt, J =9.3, 2.3 Hz, 1H), 6.75-6.38 (t, J =73.3 Hz, 1H ), 4.45 (ddt, J =48.6, 10.5, 5.6 Hz, 1H), 4.29 (dd, J =14.4, 4.3 Hz, 1H), 3.82- 3.70 (m, 1H), 3.41 (dd, J =14.4, 10.4 Hz, 1H), 2.62 (s, 1H), 2.30 (t, J =12.7 Hz , 1H), 2.14 (s, 2H), 1.65 (m, 1H), 1.37 (m, 1H).

Example 104. Getting (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -A ]quinoxalin-8-yl-carbamate

Stage 1. Synthesis (6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl-carbamate

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-ol (40 mg, 0.08 mmol) was dissolved in tetrahydrofuran (5 ml). Carbonyldiimidazole (20 mg, 0.12 mmol) was added. The mixture solution was stirred at 25°C for 16 hours. Ammonia solution (2 ml) was added to the solution. The reaction mixture was stirred for another 2 hours, diluted with 15 ml of ethyl acetate, washed with water (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl-carbamate (45 mg, yield: 100%). Electrospray ionization mass spectrometry (ESI-MS): 534, 536 [M+H] ⁺ .

Stage 2. Synthesis (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido [1,2 -A ]quinoxalin-8-yl-carbamate

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-yl-carbamate (45 mg, 0.08 mmol), [1,1'-bis(diphenylphosphino) ferrocene] palladium chloride (29 mg, 0.04 mmol), potassium carbonate (28 mg, 0.2 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (23 mg, 0.08 mmol) was placed in a three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7. 8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl-carbamate (20 mg, yield: 40.6%). Electrospray ionization mass spectrometry (ESI-MS): 616.6 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (t, J =7.0 Hz, 2H), 7.79 (d, J =2.2 Hz, 1H), 7.67 (s, 1H ), 7.63 (t, J =7.7 Hz, 1H), 7.38-7.31 (m, 1H), 7.13 (dd, J =9.6, 2.2 Hz, 1H) , 7.10 (s, 1H), 6.80 (d, J =9.1 Hz, 1H), 6.75-6.38 (t, 1H), 6.66 (d, J =73.3 Hz, 1H), 4.54 (d, J =15.3 Hz, 2H), 4.25 (dd, J =14.4, 4.3 Hz, 1H), 3.77 (d, J =13 .7 Hz, 1H), 3.37 (dd, J =14.4, 10.1 Hz, 2H), 2.59 (s, 1H), 2.28 (t, J =12.8 Hz, 1H ), 2.04 (s, 2H).

Example 105. Getting (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -A ]quinoxalin-8-ol

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-ol (50 mg, 0.1 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium chloride (29 mg, 0.04 mmol), potassium carbonate (35 mg, 0.25 mmol) and 2 -(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (29 mg, 0.1 mmol) was placed in a three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7. 8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-ol (50 mg, yield: 87.3%). Electrospray ionization mass spectrometry (ESI-MS): 573.5 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J =8.4 Hz, 3H), 7.76 (d, J =7.9 Hz, 1H), 7.60 (t, J =7.7 Hz, 1H), 7.35 (dd, J =8.7, 2.3 Hz, 1H), 7.15-7.06 (m, 2H), 6.96 (s, 1H) , 6.82 (d, J =9.1 Hz, 1H), 6.75-6.38 (t, 1H), 4.28 (dd, J =14.4, 4.2 Hz, 1H), 3.79-3.58 (m, 2H), 3.50 (s, 1H), 2.66 (s, 1H), 2.05 (s, 2H), 1.47 (d, J =12, 6 Hz, 2H), 1.23 (d, J =12.7 Hz, 1H).

Example 106. Obtaining 2-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetic acid

Stage 1. Synthesis rubs -butyl 2-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -A ]quinoxalin-8-yl)oxy)acetate

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-ol (40 mg, 0.08 mmol) was dissolved in toluene (5 ml) and 2M aqueous sodium hydroxide (5 ml), tetrabutylammonium bromide (129 mg, 0.4 mmol) and tert -butyl bromoacetate (78 mg, 0.4 mmol). The mixture solution was stirred at 25°C for 24 hours. The reaction mixture was diluted with 15 ml of ethyl acetate, washed with water (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl 2-((( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9 ,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetate (35 mg, yield: 72.3%). Electrospray ionization mass spectrometry (ESI-MS): 605, 607 [M+H] ⁺ .

Stage 2. Synthesis 2-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetic acid

Tert -butyl 2-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1 ,2 -a ]quinoxaline-8-)oxy)acetate (35 mg, 0.057 mmol) was dissolved in dichloromethane (3 ml). A 4M solution of HCl in dioxane (3 ml) was added to the solution. The mixture solution was stirred at 25°C for 1 hour and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give 2-((( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10- hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetic acid (30 mg, yield: 95.8%). Electrospray ionization mass spectrometry (ESI-MS): 547, 549 [MH] ^- .

Stage 3. Synthesis 2-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetic acid

2-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 - a ]quinoxalin-8-yl)oxy)acetic acid (30 mg, 0.054 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (15 mg, 0.02 mmol), potassium carbonate (18 mg, 0.14 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (16 mg, 0.054 mmol) were placed in a three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was first separated by flash silica gel column chromatography and then by reverse phase column chromatography to give 2-((( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(( 3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxalin-8-yl)oxy)acetic acid (9.8 mg , yield: 28.7%). Electrospray ionization mass spectrometry (ESI-MS): 631.6 [M+1] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (d, J =6.7 Hz, 2H), 7.79-7.73 (m, 2H), 7.60 (t, J =8, 0 Hz, 1H), 7.35 (dd, J =8.6, 2.3 Hz, 1H), 7.11 (d, J =9.5 Hz, 1H), 7.08 (s, 1H) , 6.87 (d, J =8.8 Hz, 1H), 6.80 (d, J =9.2 Hz, 1H), 6.74 (s, 1H), 6.74-6.38( t, 1H)4.28 (dd, J =14.4, 4.1 Hz, 1H), 4.15 (s, 2H), 3.79 (d, J =13.1 Hz, 1H), 3 .38 (d, J =10.4 Hz, 2H), 2.58 (s, 1H), 2.24 (d, J =13.2 Hz, 1H), 2.08 (s, 2H), 1 .25-1.15(d, J =11.24.1H), 1.21 (d, J =11.2 Hz, 1H).

Example 107. Getting (6a S ,8 R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline-8-ol

Stage 1. Synthesis (6a S ,8 R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7, 8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-ol

( S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,6a,7,9,10-hexahydro-8 H -pyrido[1,2 -a ]quinoxaline-8 -one (50 mg, 0.1 mmol) was dissolved in tetrahydrofuran (5 ml) and the mixture solution was cooled to -15°C. A 3M solution of methylmagnesium bromide in dimethyltetrahydrofuran (0.04 mL, 0.12 mmol) was added under nitrogen. The mixture solution was naturally heated to 25°C and stirred for 2 hours, ammonium chloride was added to stop the reaction, diluted with 15 ml ethyl acetate, washed with saline (15 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS , 8R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9 ,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-ol (25 mg, yield: 50.0%). Electrospray ionization mass spectrometry (ESI-MS): 505, 507 [M+H] ⁺ .

Stage 2. Synthesis (6a S ,8 R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-ol

( 6aS , 8R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1 ,2 -a ]quinoxalin-8-ol (25 mg, 0.049 mmol), [1,1'-bis(diphenylphosphino) ferrocene] palladium chloride (15 mg, 0.02 mmol), potassium carbonate (17 mg, 0. 12 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (14 mg, 0.049 mmol) were placed in a three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography followed by reverse phase column chromatography to give ( 6aS , 8R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5- ((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-ol (3.8 mg, yield: 13.2%). Electrospray ionization mass spectrometry (ESI-MS): 587 [M+H] ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82 (dd, J =7.7, 5.3 Hz, 3H), 7.67 (d, J =7.8 Hz, 1H), 7.58 (t, J =7.7 Hz, 1H), 7.35 (dd, J =8.7, 2.3 Hz, 1H), 7.14 (dt, J =9.6, 1.9 Hz, 1H), 7.11 (d, J =2.1 Hz, 1H), 6.81 (t, J =8.9 Hz, 2H), 6.75-6.38 (t, 1H), 4, 23 (dd, J =14.4, 4.0 Hz, 1H), 3.70 (dt, J =13.0, 4.1 Hz, 1H), 3.25 (dd, J =14.4, 10.4 Hz, 1H), 2.39 (t, J =11.2 Hz, 1H), 2.22 (td, J =12.6, 3.7 Hz, 1H), 1.27 (q, J =11.7, 11.1 Hz, 2H), 1.07 (s, 3H).

Example 108 was prepared by the synthesis method specified in example 107.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 108 ( 6aS , 8S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9, 10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-ol 587

Compound data obtained by nuclear NMR spectroscopy ¹ H obtained in example 108:

Example 108. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83-7.75 (m, 3H), 7.70 (d, J =7.9 Hz, 1H), 7.57 (t, J =8.1 Hz, 1H), 7.33 (dd, J =8.7, 2.3 Hz, 1H), 7.14 (dt, J =9.5, 1.9 Hz, 1H), 7 .11 (d, J =2.1 Hz, 1H), 6.79 (t, J =8.9 Hz, 2H), 6.75-6.38 (t, 1H), 4.20 (dd, J =14.3, 4.3 Hz, 1H), 3.72 (q, J =7.0 Hz, 1H), 3.49 (s, 1H), 3.27 (dd, J =14.3 , 10.4 Hz, 1H), 2.84 (td, J =11.5, 9.1, 5.4 Hz, 1H), 2.49 (td, J =12.0, 4.1 Hz, 1H), 1.3 (m, 1H), 1.23 (s, 3H), 1.15 (t, J =12.4 Hz, 1H).

Example 109. Obtaining 3-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid

Stage 1. Synthesis rubs -butyl-3-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-ol (150 mg, 0.3 mmol) was dissolved in toluene (5 ml). Potassium hydroxide (17 mg, 0.3 mmol) and tert -butyl acrylate (192 mg, 1.5 mmol) were added. The mixture solution was stirred at 110°C for 24 hours. The reaction mixture was cooled and then diluted with 15 ml of ethyl acetate, washed with water (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl-3-((( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8, 9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate (110 mg, yield: 59.2%). Electrospray ionization mass spectrometry (ESI-MS): 619, 621 [M+H] ⁺ .

Stage 2. Synthesis rubs -butyl 3-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate

Tert -butyl 3-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1 ,2 -a ] quinoxalin-8-yl)oxy)propanoate (110 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (22 mg, 0.03 mmol), potassium carbonate (59 mg, 0.43 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (51 mg, 0.17 mmol) were placed in three-neck flask; 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography followed by reverse phase column chromatography to give tert -butyl 3-((( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5- ((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate (100 mg, yield: 84.0%), which was used without additional processing in the next step.

Stage 3. Synthesis 3-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid

Tert -butyl 3-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9, 10-Hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate (100 mg, 0.14 mmol) was dissolved in dichloromethane (3 ml). Trifluoroacetic acid (3 ml) was added to the solution. The mixture solution was stirred at 25°C for 1 hour and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give 3-((( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6. 6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid (30 mg, yield: 33.3%). Electrospray ionization mass spectrometry (ESI-MS): 645.2 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.84-7.71 (m, 4H), 7.59 (t, J =7.8 Hz, 1H), 7.33 (dd, J =8, 7, 2.3 Hz, 1H), 7.12 (dt, J =9.5, 2.0 Hz, 1H), 7.09 (d, J =2.0 Hz, 1H), 6.85- 6.76 (m, 2H), 6.74-6.37 (t, 1H), 4.25 (dd, J =14.4, 4.3 Hz, 1H), 3.73 (t, J = 6.1 Hz, 3H), 3.31 (dd, J =14.4, 10.3 Hz, 1H), 3.21 (td, J =10.7, 5.2 Hz, 1H), 2, 61 (t, J =6.1 Hz, 2H), 2.50 (t, J =10.7 Hz, 1H), 2.18 (t, J =12.5 Hz, 1H), 1.99 ( d, J =12.2 Hz, 2H), 1.36 (qd, J =12.7, 4.5 Hz, 1H), 1.05 (q, J =11.5 Hz, 1H).

Example 110. Getting (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10 -hexahydro-5 H -pyrido[1,2 -a ]quinoxaline

Stage 1. Synthesis (6a S )-3-bromo-8-((methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline

( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline- 8-ol (60 mg, 0.12 mmol) was dissolved in dimethyl sulfoxide (3 ml). Acetic anhydride (3 ml) and acetic acid (1 ml) were added to the solution. The mixture solution was stirred at 25°C for 16 hours. The reaction mixture was diluted with 15 ml of ethyl acetate, washed with water (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-bromo-8-((methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8 ,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (60 mg, yield: 90.7%). Electrospray ionization mass spectrometry (ESI-MS): 551, 553 [M+H] ⁺ .

Stage 2. Synthesis (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10 -hexahydro-5 H -pyrido[1,2 -a ]quinoxaline

(6a S )-3-bromo-8-((methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido [1,2 -a ]quinoxaline (60 mg, 0.10 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (15 mg, 0.02 mmol), potassium carbonate (35 mg, 0. 25 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (29 mg, 0.10 mmol) were placed in a three-neck flask. 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was first separated by flash silica gel column chromatography and then by reverse phase column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylthio)methoxy) -5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (40 mg, yield: 63.3 %). Electrospray ionization mass spectrometry (ESI-MS): 633 [M+H] ⁺ .

Stage 3. Synthesis (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10 -hexahydro-5 H -pyrido[1,2 -a ]quinoxaline

(6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylthio)methoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8, 9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (40 mg, 0.06 mmol) was dissolved in dichloromethane (3 ml); 3-chloroperoxybenzoic acid (21 mg, 0.1 mmol) was added to the solution. The mixture solution was stirred at 25°C for 16 hours, saturated aqueous sodium sulfite solution (5 ml) was added and stirred for 30 minutes. The organic layer was dried, concentrated and separated by flash silica gel column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)methoxy)-5-((3- (trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (5.4 mg, yield: 13.5%). Electrospray ionization mass spectrometry (ESI-MS): 665.4 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.82 (d, J =7.9 Hz, 2H), 7.76 (d, J =2.3 Hz, 1H), 7.71 (s, 1H ), 7.62 (t, J =7.9 Hz, 1H), 7.34 (d, J =8.7 Hz, 1H), 7.12 (d, J =10.2 Hz, 1H), 7.09 (s, 1H), 6.84-6.76 (m, 2H), 6.74-638 (t, J =73.4 Hz, 1H), 4.41 (d, J =24, 4 Hz, 2H), 4.26 (dd, J =14.5, 4.5 Hz, 1H), 3.87-3.74 (m, 2H), 3.36 (dd, J =14.4 , 10.0 Hz, 1H), 2.89 (s, 3H), 2.54 (s, 1H), 2.30-2.14 (m, 1H), 2.09 (d, J =12, 9 Hz, 2H), 1.46-1.37 (m, 1H), 1.15 (q, J =11.6 Hz, 1H).

Example 111. Getting (6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)ethoxy)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10 -hexahydro-5 H -pyrido[1,2 -a ] quinoxaline

(6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H - pyrido[1,2 -a ]quinoxalin-8-ol (50 mg, 0.07 mmol) was dissolved in toluene. Methylsulfonylethylene (37 mg, 0.35 mmol) and sodium hydride (5 mg, 0.11 mmol) were added to the solution. The reaction in the mixture solution was carried out at 25°C for 16 h and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-((methylsulfonyl)ethoxy)-5-((3-(trifluoromethyl)phenyl) sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline (10 mg, yield: 21.1%). Electrospray ionization mass spectrometry (ESI-MS): 679.2 [M+1] ⁺ .

^1H NMR (500 MHz, CDCl ₃ ) δ 7.86-7.70 (m, 4H), 7.61(s, 1H), 7.34 (s, 1H), 7.11 (d, J = 9.5 Hz, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 6.80 (d, J =9.2 Hz, 1H), 6.74-6.38 ( t, 1H), 4.27 (d, J =14.4 Hz, 1H), 3.90 (s, 2H), 3.78 (s, 1H), 3.38 (s, 1H), 3, 28 (s, 1H), 3.21 (s, 2H), 2.97 (s, 3H), 2.56 (s, 1H), 2.24 (s, 1H), 2.04 (s, 2H ), 1.40 (s, 1H), 1.11 (s, 1H).

Example 112: Getting (2 R ,3 R ,4 S ,5 S ,6 R )-2-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-3,4,5-triol

Stage 1. Synthesis (2 R ,3 R ,4 S ,5 R )-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy) tetrahydro-2 H -pyran-3,4,5-triyl-triacetate.

( 2R , 3R , 4S , 5R )-2-(acetoxymethyl)-6-hydroxytetrahydro- 2H -pyran-3,4,5-triyl-triacetate (350 mg, 1.0 mmol) was dissolved in dichloromethane . One drop of DBU and trichloroacetonitrile (450 mg, 3.0 mmol) were added to the solution. The reaction in the mixture solution was carried out at 25°C for 6 h and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 2R , 3R , 4S , 5R )-2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro- 2H -pyran-3,4,5-triyl-triacetate (390 mg, yield: 79.1%), which was used without further processing in the next step.

Stage 2. Synthesis (2 R ,3 R ,4 S ,5 R ,6 R )-2-(acetoxymethyl)-6-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl) oxy)tetrahydro-2 H -pyran-3,4,5-triyl-triacetate

(2 R ,3 R ,4 S ,5 R )-2-(acetoxymethyl)-6-hydroxytetrahydro-2 H -pyran-3,4,5-triyltriacetate (2 R ,3 R ,4 S ,5 R )- 2-(acetoxymethyl)-6-(2,2,2-trichloro-1-iminoethoxy)tetrahydro- 2H -pyran-3,4,5-triyltriacetate (390 mg, 0.79 mmol) was dissolved in dichloromethane, TMSOTF ( 176 mg, 0.79 mmol) and ( 6aS )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido [1,2 -a ]quinoxalin-8-ole (387 mg, 0.79 mmol). The reaction in the mixture solution was carried out at 25°C for 6 h and then concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 2R , 3R , 4S , 5R , 6R )-2-acetoxymethyl)-6-((( 6aS )-3-bromo-5-(( 3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxalin-8-yl)oxy)tetrahydro- 2H- pyran- 3,4,5-triyl-triacetate (250 mg, yield: 38.5%). Electrospray ionization mass spectrometry (ESI-MS): 821, 823 [M+H] ⁺ .

Stage 3. Synthesis (2 R ,3 R ,4 S ,5 R ,6 R )-2-(acetoxymethyl)-6-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)tetrahydro-2 H -pyran-3,4,5-triyl-triacetate

(2 R ,3 R ,4 S ,5 R ,6 R )-2-(acetoxymethyl)-6-(((6a S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)- 6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxalin-8-yl)oxy)tetrahydro- 2H- pyran-3,4,5-triyltriacetate (250 mg , 0.3 mmol) was dissolved in a solvent mixture of 1,4-dioxane (4 ml) and water (2 ml). 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (87 mg, 0.3 mmol), [1,1'-bis( diphenylphosphino)ferrocene]palladium chloride (29 mg, 0.04 mmol) and potassium carbonate (105 mg, 0.75 mmol). The mixture solution was placed in a three-neck flask. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography to give ( 2R , 3R , 4S , 5R , 6R )-2-(acetoxymethyl)-6-((( 6aS )-3-(3-(difluoromethoxy )-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline-8- yl)oxy)tetrahydro- 2H -pyran-3,4,5-triyl-triacetate (60 mg, yield: 22.2%). Electrospray ionization mass spectrometry (ESI-MS): 903 [M+H] ⁺ .

Stage 4. Synthesis (2 R ,3 R ,4 S ,5 S ,6 R )-2-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)-6-(hydroxymethyl)tetrahydro-2 H -pyran-3,4,5-triol

(2 R ,3 R ,4 S ,5 R ,6 R )-2-(acetoxymethyl)-6-(((6a S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-(( 3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxalin-8-yl)oxy)tetrahydro- 2H- pyran- 3,4,5-triyl-triacetate (60 mg, 0.066 mmol) was dissolved in methanol (5 ml). Sodium methoxide (11 mg, 0.2 mmol) was added. The reaction in the mixture solution was carried out at a temperature of 25°C for 1 hour; Once the reaction was complete, hydrochloric acid was added dropwise to adjust the pH to ~7.0, and the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography to give ( 2R , 3R , 4S , 5S , 6R )-2-((( 6aS )-3-(3-(difluoromethoxy)-5-fluorophenyl) -5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)-6 -(hydroxymethyl)tetrahydro- 2H -pyran-3,4,5-triol (13.2 mg, yield: 27.2%). Electrospray ionization mass spectrometry (ESI-MS): 735.2 [M+1] ⁺ .

¹ H NMR (500 MHz, DMSO- d6 ) δ 8.09 (d, J =7.9 Hz, 1H), 7.97 (d, J =8.0 _Hz , 1H), 7.86 (t , J =7.9 Hz, 1H), 7.72-7.64 (m, 1H), 7.60 (d, J =6.3 Hz, 1H), 7.53 (dd, J =8, 7, 2.3 Hz, 1H), 7.41 (d, J =6.7 Hz, 1H), 7.30 (dd, J =11.6, 9.5 Hz, 1H), 7.21 ( s, 1H), 7.04 (dd, J =12.3, 9.1 Hz, 2H), 4.90 (dd, J =8.3, 4.9 Hz, 3H), 4.44 (dt , J =11.7, 5.9 Hz, 1H), 4.31-4.17 (m, 2H), 3.89 (d, J =13.0 Hz, 1H), 3.68 (dd, J =11.5, 5.8 Hz, 1H), 3.57-3.41 (m, 2H), 2.89 (s, 1H), 3.1(m, 4H), 2.52-2 .43(d, 1H), 2.02 (dt, J =29.3, 14.8 Hz, 3H), 1.31-1.10 (m, 1H), 1.03 (q, J =11 ,6 Hz, 1H).

Example 113. Obtaining 3-(((6a S ,8 R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid

Stage 1. Synthesis rubs -butyl-3-(((6a S ,8 R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate

( 6aS , 8R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1 ,2 -a ]quinoxalin-8-ol (40 mg, 0.13 mmol) was dissolved in toluene (5 ml). Potassium hydroxide (4 mg, 0.06 mmol) and tert -butyl acrylate (166 mg, 1.3 mmol) were added. The mixture solution was stirred at 110°C for 24 hours. The reaction mixture was cooled and then diluted with 15 ml of ethyl acetate, washed with water (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give tert -butyl 3-((( 6aS , 8R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6. 6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate (25 mg, yield: 30.3%). Electrospray ionization mass spectrometry (ESI-MS): 633, 635 [M+H] ⁺ .

Stage 2. Synthesis rubs -butyl 3-(((6a S ,8 R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate

Tert -butyl 3-((( 6aS , 8R )-3-bromo-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro -5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoate (25 mg, 0.039 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (22 mg, 0.03 mmol), potassium carbonate (14 mg, 0.1 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (12 mg, 0.039 mmol ) was placed in a three-neck flask. 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was separated by flash silica gel column chromatography followed by reverse phase column chromatography to give tert -butyl 3-((( 6aS , 8R )-3-(3-(difluoromethoxy)-5-fluorophenyl) -8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxalin-8-yl) hydroxy)propanoate (27.8 mg, yield: 100%). Electrospray ionization mass spectrometry (ESI-MS): 715 [M+H] ⁺ .

Stage 3. Synthesis 3-(((6a S ,8 R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid

Tert -butyl 3-(((6a R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9, 10-Hexahydro- 5H -pyrido[1,2 -a ]quinoxaline-8)oxy)propanoate (27.8 mg, 0.039 mmol) was dissolved in dichloromethane (3 ml). Trifluoroacetic acid (3 ml) was added to the solution. The mixture solution was stirred at 25°C for 1 hour and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give 3-((( 6aS , 8R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-8-methyl-5-((3-(trifluoromethyl) phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid (5.5 mg, yield: 21, 4%). Electrospray ionization mass spectrometry (ESI-MS): 659.5 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.86-7.77 (m, 3H), 7.65 (d, J =7.9 Hz, 1H), 7.58 (t, J =7, 8 Hz, 1H), 7.34 (dd, J =8.6, 2.3 Hz, 1H), 7.14 (dd, J =9.6, 1.9 Hz, 1H), 7.11 ( s, 1H), 6.80 (d, J =8.7 Hz, 2H), 6.75-6.38 (t, J =73.4 Hz, 1H), 4.22 (dd, J =14 ,4, 4.0 Hz, 1H), 3.69 (s, 1H), 3.64 (t, J =6.3 Hz, 2H), 3.23 (dd, J =14.4, 10, 4 Hz, 1H), 2.56 (t, J =6.1 Hz, 2H), 2.44-2.36 (m, 1H), 2.26-2.18 (m, 1H), 1, 61 (s, 3H), 1.25 (t, J =12.1 Hz, 1H), 1.03 (s, 3H).

Example 114 was prepared by the synthesis method described in Example 113.

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85-7.75 (m, 3H), 7.70 (s, 1H), 7.61 (t, J =7.8 Hz, 1H), 7 .32 (dd, J =8.6, 2.3 Hz, 1H), 7.12 (dt, J =9.6, 1.9 Hz, 1H), 7.09 (s, 1H), 6, 78 (d, J =8.9 Hz, 2H), 6.74-6.37 (t, 1H), 4.18 (dd, J =14.2, 4.3 Hz, 1H), 3.51 (t, J =6.2 Hz, 2H), 3.49-3.39 (m, 1H), 3.26 (dd, J =14.2, 10.2 Hz, 1H), 2.82 ( s, 1H), 2.50 (t, J =6.0 Hz, 3H), 1.81 (dd, J =13.9, 2.9 Hz, 1H), 1.73 (dt, J =13 ,3, 2.7 Hz, 1H), 1.36 (td, J =13.4, 4.7 Hz, 1H), 1.15 (s, 3H), 1.04 (dd, J =13, 4, 11.6 Hz, 1H).

Example 115 was prepared by the synthesis method described in Example 109.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 115 3-(((6aS, 8R)-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10- hexahydro- 5H -pyrido[1,2-a]quinoxalin-8-yl)oxy)propanoic acid 645

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.82-7.74 (m, 3H), 7.71 (s, 1H), 7.60 (t, J =7.9 Hz, 1H), 7 .32 (dd, J =8.7, 2.3 Hz, 1H), 7.13 (dt, J =9.8, 1.9 Hz, 1H), 7.09 (d, J =2.0 Hz, 1H), 6.78 (dd, J =9.1, 2.1 Hz, 2H), 6.74-6.38 (t, J =73.5 Hz, 1H), 4.19 (dd , J =14.3, 4.3 Hz, 1H), 3.74-3.57 (m, 3H), 3.43 (d, J =10.5 Hz, 1H), 3.25 (dd, J =14.3, 10.5 Hz, 1H), 2.83 (t, J =10.9 Hz, 1H), 2.58 (t, J =6.0 Hz, 2H), 2.51- 2.44 (m, 1H), 1.89-1.77 (m, 2H), 1.55 (t, J =13.8 Hz, 1H), 1.27-1.17 (m, 1H) .

Example 116. Getting (6a S ,8 S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid

Stage 1. Synthesis (6a S , 8 S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline-8-carbonitrile

( S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6a,7,9,10-tetrahydro- 5H- pyrido[1,2 -a ]quinoxaline-8( 6H )- it (100 mg, 0.2 mmol) was dissolved in tetrahydrofuran (10 ml). Potassium tert -butoxide (25 mg, 0.22 mmol) was added and the mixture solution was stirred at 25°C for 30 min, then 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (43 mg, 0.22 mmol) was added ) and the mixture solution was stirred at 25°C for 16 hours. The reaction mixture was diluted with 15 ml of ethyl acetate, washed with brine (15 ml x 3), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS , 8S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro -5 H -pyrido[1,2 -a ]quinoxaline-8-carbonitrile (35 mg, yield: 35%), which was used without further treatment in the next step.

Stage 2. Synthesis (6a S ,8 S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid

( 6aS , 8S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline-8-carbonitrile (35 mg, 0.07 mmol) was dissolved in methanol (10 ml). Thionyl chloride (25 mg, 0.22 mmol) was added in an ice bath. The mixture solution was heated to 65°C and stirred for 16 hours and then concentrated to remove the solvent. A 2M aqueous solution of potassium hydroxide (15 ml) was added to the residue, stirred at 80°C for 4 hours, cooled to room temperature, an aqueous solution of HCl was added to adjust the pH to 6, extracted with ethyl acetate, washed with saline (15 ml × 3 ), dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The residue was separated by flash silica gel column chromatography to give ( 6aS , 8S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro -5H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid (30 mg, yield: 82.5%). Electrospray ionization mass spectrometry (ESI-MS): 519, 521 [M+H] ⁺ .

Stage 3. Synthesis (6a S , 8 S )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid

( 6aS , 8S )-3-bromo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H- pyrido[1,2 -a ]quinoxaline-8-carboxylic acid (30 mg, 0.057 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (22 mg, 0.03 mmol), potassium carbonate (20 mg, 0.14 mmol) and 2-(3-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3-dioxalane (17 mg, 0.057 mmol) was placed in a three-neck flask. 1,4-dioxane (4 ml) and water (2 ml) were added. Nitrogen was introduced three times to replace air by pumping. The mixture solution was heated to 60°C for 2 hours. After completion of the reaction, the solvent was removed by concentration. The residue was first separated by flash silica gel column chromatography and then by reverse phase column chromatography to give ( 6aS , 8S )-3-(3-difluoromethoxy)-5-fluorophenyl)-5-((3- (trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid (15 mg, yield: 43.8%) . Electrospray ionization mass spectrometry (ESI-MS): 599.4 [M-1] ⁺ .

^1H NMR (500 MHz, DMSO- d6 ) δ 8.08 (d, J =7.7 Hz, 1H), 7.92 (d, J =8.0 _Hz , 1H), 7.84 (t , J =7.8 Hz, 1H), 7.71 (d, J =2.3 Hz, 1H), 7.64 (s, 1H), 7.59-7.22 (t,1H), 7 .53 (dd, J =8.8, 2.4 Hz, 1H), 7.32 (dt, J =10.2, 1.8 Hz, 1H), 7.22 (d, J =2.8 Hz, 1H), 7.05 (dt, J =9.6, 2.3 Hz, 1H), 6.99 (d, J =8.9 Hz, 1H), 4.26 (dd, J =14 ,5, 4.5 Hz, 1H), 3.85 (d, J =12.6 Hz, 1H), 2.36 (s, 2H), 2.11-1.95 (m, 2H), 1 .83 (dd, J =26.3, 13.3 Hz, 2H), 1.39-1.22 (m, 1H), 1.03 (q, J =12.1 Hz, 1H).

Example 117 was prepared by the synthesis method described in Example 116.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 117 ( 6aS , 8R )-3-(3-(difluoromethoxy)-5-fluorophenyl)-5-((3-(trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro- 5 H -pyrido[1,2 -a ]quinoxaline-8-carboxylic acid 599

^1H NMR (400 MHz, DMSO- d6 ) δ 8.08 (d, J =7.7 Hz, 1H), 7.92 (d, J =8.0 _Hz , 1H), 7.84 (t , J =7.8 Hz, 1H), 7.71 (d, J =2.3 Hz, 1H), 7.64 (s, 1H), 7.59-7.22(t, 1H), 7 .53 (dd, J =8.8, 2.4 Hz, 1H), 7.32 (dt, J =10.2, 1.8 Hz, 1H), 7.22 (d, J =2.8 Hz, 1H), 7.05 (dt, J =9.6, 2.3 Hz, 1H), 6.99 (d, J =8.9 Hz, 1H), 4.26 (dd, J =14 ,5, 4.5 Hz, 1H), 3.85 (d, J =12.6 Hz, 1H), 2.36 (s, 2H), 2.11-1.95 (m, 2H), 1 .83 (dd, J =26.3, 13.3 Hz, 2H), 1.39-1.22 (m, 1H), 1.03 (q, J =12.1 Hz, 1H).

Example 118: Getting ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid

Stage 1. Synthesis of methyl ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (160 mg, 0.307 mmol) was dissolved in a solvent mixture of toluene: ethanol: water = 2:1:1 (12 ml). Sodium carbonate (50 mg, 0.460 mmol), 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro- 2H- pyran-4-yl)-1 ,3,2-dioxaborolane (123 mg, 0.460 mmol) and tetrakis(triphenylphosphine) palladium (50 mg) were added under a nitrogen atmosphere, the mixture solution was heated to a temperature of 80°C and stirred for 5 hours, then cooled and the mixture solution was extracted twice : water and ethyl acetate. The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The crude product was separated by flash silica gel column chromatography to give methyl ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro- 2H- pyran-4- yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (85 mg, 48%).

Stage 2. Synthesis ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro-2 H -pyran-4-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid

Methyl ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-4-((3-(trifluoromethyl) Phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (85 mg, 0.146 mmol) was dissolved in a solvent mixture of tetrahydrofuran: methanol: water = 1:1:1 (10 ml). Lithium hydroxide monohydrate (31 mg) was added. The mixture solution was stirred overnight at room temperature. To remove the solvent, the reaction mixture was concentrated and acidified with dilute hydrochloric acid. The residue was separated by flash silica gel column chromatography to give ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro- 2H- pyran-4-yl) -4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid (45 mg, 54%). Electrospray ionization mass spectrometry (ESI-MS): 567.6 [M+H] ⁺ .

^1H NMR (500 MHz, DMSO- d6 ) δ 8.41 (s, 1H), 8.13 (dd, J =16.5, 7.9 _Hz , 2H), 7.90 (dd, J = 17.1, 9.2 Hz, 2H), 7.11 (dd, J = 8.6, 2.2 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 6, 60 (d, J =8.8 Hz, 1H), 5.80 (d, J =1.5 Hz, 1H), 4.00 (dd, J =13.6, 5.3 Hz, 1H), 3.70 (dd, J =13.6, 4.0 Hz, 1H), 3.26 (d, J =9.0 Hz, 1H), 2.71 (s, 3H), 2.23 (dt , J =14.3, 8.3 Hz, 2H), 2.15-2.03 (m, 2H), 1.82 (d, J =7.7 Hz, 1H), 1.60-1, 51 (m, 1H), 1.21 (d, J =4.3 Hz, 6H), 1.17 (s, 6H).

Example 119. Getting ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyltetrahydro-2 H -pyran-4-yl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid

(S)-3-(1-methyl-6-(2,2,6,6-tetramethyl-3,6-dihydro- 2H -pyran-4-yl)-4-((3-(trifluoromethyl)phenyl )sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid (30 mg, 0.053 mmol) was dissolved in methanol (10 ml) and 10% wet palladium on carbon (10 mg) was added. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction mixture was filtered, concentrated to remove solvent, and lyophilized to give ( S )-3-(1-methyl-6-(2,2,6,6-tetramethyltetrahydro- 2H- pyran-4-yl)-4-(( 3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoic acid (17.3 mg, 57%). Electrospray ionization mass spectrometry (ESI-MS): 569.5 [M+H] ⁺ .

¹ H NMR (500 MHz, DMSO- d6 ) δ 8.09 (t, J =8.5 Hz, 2H), 7.87 (t, J =7.8 _Hz , 1H), 7.77 (s , 1H), 6.99 (d, J =2.1 Hz, 1H), 6.92 (dd, J =8.5, 2.1 Hz, 1H), 6.53 (d, J =8, 5 Hz, 1H), 3.88-3.74(m, 2H), 3.15 (s, 1H), 2.96 -2.87 (m, 1H), 2.59 (s, 3H), 2.24-2.09 (m, 2H), 1.78 (d, J =11.5 Hz, 1H), 1.63-1.44 (m, 3H), 1.26 (s, 6H) , 1.18 (dd, J =18.5, 12.8 Hz, 2H), 1.12 (d, J =7.3 Hz, 6H).

Example 120: Getting ( S , E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1, 2,3,4-tetrahydroquinoxalin-2-yl)propanoate

Methyl ( S )-3-(6-bromo-1-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (1.4 g , 2.69 mmol) was dissolved in a solvent mixture of toluene: ethanol: water = 2:1:1 (30 ml). Sodium carbonate (286 mg, 2.69 mmol), ( E )-2-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-4,4,5,5- was added tetramethyl-1,3,2-dioxaborolane (1.6 g, 5.38 mmol) and tetrakis(triphenylphosphine) palladium (200 mg). The mixture solution was heated to a temperature of 80°C in a nitrogen atmosphere and stirred overnight, then cooled and extracted twice: with water and ethyl acetate. The organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to remove the solvent. The crude product was separated by flash silica gel column chromatography to give methyl ( S,E )-3-(6-(2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-1-methyl -4-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinoxalin-2-yl)propanoate (1.0 g, 61%). Electrospray ionization mass spectrometry (ESI-MS): 610.7 [M+1] ⁺ .

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.83 (d, J =8.0 Hz, 1H), 7.74 (d, J =8.0 Hz, 1H ), 7.55 (t, J =7.7 Hz, 1H), 7.35 (d, J =2.0 Hz, 1H), 7.16-7.08 (m, 2H), 7.04 (dd, J =8.6, 2.1 Hz, 1H), 6.97-6.91 (m, 1H), 6.52 (d, J =8.5 Hz, 1H), 6.22 ( d, J =1.6 Hz, 1H), 3.81 (dd, J =5.3, 2.5 Hz, 2H), 3.63 (s, 3H), 3.19-3.10 (m , 1H), 2.65 (d, J =3.8 Hz, 3H), 2.39-2.21 (m, 2H), 2.05 (d, J =1.5 Hz, 3H), 1 .92-1.89 (m, 1H), 1.73-1.66 (m, 1H).

Example 121 was prepared by the synthesis method described in Example 113.

Example number Structural formula Chemical name ESI-MS: [M+1] ⁺ 121 3-((6a S ,8 R )-3-(( E )-2-(2-chloro-6-fluorophenyl)prop-1-en-1-yl)-8-methyl-5-((3- (trifluoromethyl)phenyl)sulfonyl)-6,6a,7,8,9,10-hexahydro-5 H -pyrazino[1,2 -a ]quinoxalin-8-yl)oxy)propanoic acid 667

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.95-7.88 (s, 1H), 7.85-7.78 (d, J =7.7 Hz, 1H), 7.74-7, 70 (d, J =1.9 Hz, 1H), 7.70-7.64 (d, J =7.9 Hz, 1H), 7.62-7.55 (t, J =7.8 Hz , 1H), 7.23-7.20 (m, 1H), 7.20 -7.13 (ddd, J =9.1, 4.9, 2.4 Hz, 2H), 7.06-6 .97 (m, 1H), 6.90-6.76 (s, 1H), 6.38-6.32 (d, J =1.7 Hz, 1H), 4.28-4.16 (dd , J =14.4, 3.8 Hz, 1H), 3.69-3.60 (t, J =6.1 Hz, 3H), 3.47-3.29 (s, 1H), 2, 65-2.55 (t, J =6.1 Hz, 2H), 2.53-2.26 (d, J =77.6 Hz, 2H), 2.25-2.17 (d, J = 1.4 Hz, 3H), 1.75-1.66(m, 3H), 1.38-1.26 (s, 1H), 1.10-1.01 (s, 3H).

Example 122 was prepared by the synthesis method described in Example 59.

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.14-8.07 (d, J =7.9 Hz, 1H), 7.89-7.81 (t, J =7.8 Hz, 1H), 7.81-7.72 (dd, J =8.5, 6.3 Hz, 3H), 7.60-7.23 (t, 1H), 7.58-7.51 (dd, J =8.8, 2.3 Hz, 1H), 7.42-7.38 (s, 0H), 7.38-7.30 (dt, J =10.0, 1.9 Hz, 1H) , 7.28-7.17 (m, 2H), 7.09-6.98 (m, 2H), 6.77-6.69 (s, 1H), 4.29-4.18 (m, 1H), 3.88-3.75 (d, J =13.3 Hz, 1H), 3.54-3.45 (t, J =6.6 Hz, 2H), 3.3-3.2 (m, 1H), 2.24-2.13 (t, J =6.4 Hz, 3H), 2.12-2.00 (dd, J =13.9, 11.0 Hz, 1H), 1.74-1.64 (d, J =12.7 Hz, 1H), 1.64-1.52 (d, J =12.8 Hz, 1H), 1.49-1.36 (dt, J =15.2, 7.5 Hz, 1H), 1.14-1.04 (t, J =12.1 Hz, 1H), 0.94-0.86 (s, 3H).

Assessment during biological analysis

I. Time-resolved fluorescence resonance energy transfer (TR-FRET)

The present experiment was a screening experiment for RORγt nuclear receptor agonists based on TR-FRET technology. Binding of the His-tagged RORγt-LBD receptor to receptor agonists may increase the recruitment of biotin-tagged coactivator peptides. Europium-His-RORγt-LBD is indirectly labeled by the donor (Eu) by binding to the anti-Eu-His antibody. Upon activation of Eu by an energy source (eg, a flash of light or laser), energy is transferred to the allophycocyanin-labeled coactivator indirectly by binding of allophycocyanin-streptavidin and the biotin-labeled coactivator.

1. Prepare 10-fold (10X) buffer (500 mM Tris-HCl, 500 mM KCl and 10 mM Na-EDTA), pH adjusted to 7.0. The buffer was stored at 4°C for later use and brought to room temperature before the experiment.

2. 10X buffer was diluted with pure water to 1-fold (1X) concentration. To prepare the assay buffer, Triton X-100 was added to a final concentration of 0.01% and DTT (dithiothreitol) to a final concentration of 1 mM.

3. DMSO was used to prepare a 1000x (1000X) stock solution of the substance. The solution of the substance was serially diluted 5 times to obtain 7 concentration options from a maximum concentration of 1000 nM to 10,000 nM. After this, a 10-fold solution of the substance was prepared based on the assay buffer. An aliquot of 2 μL was added to the 20 μL system.

4. The 5X RORγt-LBD protein solution was thawed and a 5X solution was prepared using assay buffer to obtain a final concentration of 30 nM. The entire process was carried out on ice.

5. The 5X SRC peptide solution was thawed and a 5X solution was prepared using assay buffer to obtain a final concentration of 500 nM. The entire process was carried out on ice.

6. 4 μl of RORγt-LBD receptor per well was added to the test wells of a 384-well plate, and the same amount of assay buffer without RORγt-LBD was added to the control wells.

7. 2 μl of the substance was added to each well of a 384-well plate.

8. 4 μl of SRC peptide was added to each well of a 384-well plate.

9. 2X Eu-anti-6X His/APC-streptavidin was diluted with Lance detection buffer to a final concentration of 0.25 nM and 5 nM, respectively, and then 10 μl of 2X Eu-anti-6X His was added to each well of a 384-well plate / APC-streptavidin.

10. After mixing, the solution was incubated at 4°C overnight.

11. The next morning, the 384-well plate was incubated at room temperature for 1 hour. The corresponding signal values were then read using a PerkinElmer EnVision plate analyzer at 665/615 nM. The agonist activity of the corresponding substance was calculated using Graphpad Prism 7.0 software. The results of specific experiments are shown in Table 1.

II. Assay to detect the RORγt reporter gene in cells

In this experiment, the RORγt reporter gene detection method was used to evaluate the ability of various compounds to activate and specifically interact with RORγt in cells. Plasmids pFN26A-RORγt-LBD and pGl4.35 (Promega, cat. no. E1370) were used to cotransfect HEK 293 cells (cat. no. GNHu18). The efficacy of various compounds was assessed in the presence of the ursolic acid antagonist (Selleck, catalog no. S2370-100 mg). A detailed description of the experiment is given below.

1. Cells cotransfected with plasmids were inoculated into a 96-well plate (Corning, catalog no. 3610) in fresh DMEM (Gibco, catalog no. 1773536) containing 10% fetal calf serum (Gibco, catalog no. 10099- 141), in an amount of 30,000 cells / 40 µl / well.

2. Add 5 μl of medium containing ursolic acid at a concentration of 20 μM.

3. The dose effect was assessed by diluting the test substance 4-fold, starting at 50 µM.

4. Add 5 μl of medium containing a substance with a concentration 10 times higher than its final test concentration.

5. After incubating the cells at 37°C and 5% CO ₂ for 24 hours, 50 μl of developing reagent was added to detect firefly luciferase fluorescence using a PerkinElmer EnVision plate analyzer; 50 μl of a second developing reagent was also added to detect protein fluorescence from the Renilla reniformis organism.

6. To determine the concentration required to activate the receptor by 50% (EC ₅₀ ), as well as the upper limit of activation (Amax), a four-parameter curve modeled in the Graphpad Prism program was used for each substance. The results of specific experiments are shown in Table 1.

Table 1.
Test results Number
connections (example) Biochemical analysis by TR-FRET method Cellular assay using a reporter gene EC ₅₀ /(nM) Amax EC ₅₀ /(nM) Amax 1 18.40 1.61 517.6 3.3 2 18.12 1.85 163.3 3.1 3 29.11 1.20 1739.3 4.4 4 28.39 1.25 3550.5 4.9 5 9.68 1.39 1028.0 5.0 6 16.09 1.54 528.4 4.2 7 17.51 1.45 144.6 3.7 8 13.32 1.22 90.4 5.5 9 11.61 0.63 289.6 3.5 10 13.62 0.81 578.2 2.8 eleven 21.65 0.82 428.7 3.2 12 136.25 0.67 2387.2 4.3 13 35.76 0.74 1423.0 1.7 14 30.51 0.89 69.7 3.1 15 24.99 0.83 134.4 3.2 16 9.52 0.78 59.0 2.0 17 29.57 0.82 603.5 4.2 18 15.13 0.62 177.7 4.3 19 17.81 0.97 25.7 2.0 20 32.00 1.01 418.2 6.3 21 17.63 0.94 273.3 5.5 22 1.51 0.62 244.8 3.3 23 17.17 0.79 1075.0 3.8 24 31.48 0.92 48.5 2.4 25 6.35 0.84 441.1 4.4 26 29.56 0.64 403.7 2.3 27 5.25 0.61 228.4 3.9 28 14.69 0.86 354.0 2.6 29 17.33 0.84 1980.0 6.7 thirty 8.34 0.80 404.0 4.0 31 11.53 0.97 419.1 3.4 32 10.77 0.93 599.0 4.3 33 45.71 0.93 2041.0 5.2 34 3.91 1.11 156.1 1.7 35 23.97 1.15 467.5 4.2 36 24.92 1.23 500.8 4.1 37 37.49 1.21 366.0 3.7 38 40.69 1.23 289.6 3.7 39 33.59 0.58 1245.0 2.2 40 12.97 0.76 732.8 2.5 41 6.73 1.01 NI NI 42 0.84 1.28 123.1 1.4 43 17.21 0.87 161.6 3.0 44 23.54 1.04 256.4 4.2 45 10.49 1.06 375.2 3.9 46 5.29 0.72 924.2 4.0 47 3.51 0.77 750.2 2.1 48 10.67 0.67 282.6 1.9 49 5.47 0.61 238.3 5.2 50 8.13 0.64 676.5 6.3 51 48.71 0.77 3941.0 1.5 52 183.90 0.50 50000.0 NI 53 256.50 0.55 50000.0 NI 54 20.07 0.72 297.4 3.9 55 46.56 0.78 507.6 2.7 56 44.52 0.71 621.7 3.2 57 6.54 0.89 304.3 3.2 58 19.45 0.79 1396.0 4.0 59 100.30 1.10 601.7 3.5 60 61.43 0.98 248.7 2.8 61 85.99 0.69 468.6 3.0 62 25.19 0.69 296.7 3.8 63 23.51 0.89 308.1 5.0 64 47.81 0.80 562.9 2.7 65 8.40 0.89 391.3 2.8 66 33.57 0.99 522.5 5.6 67 19.69 0.87 157.6 3.3 68 30.47 1.03 151.4 2.5 69 44.36 1.05 599.5 5.8 70 64.19 0.99 530.8 4.2 71 40.45 0.97 497.5 3.5 72 42.29 0.65 238.1 2.6 73 39.98 0.96 725.4 4.6 74 45.12 1.20 1037.0 6.2 75 55.69 0.87 1194.7 3.7 76 6.54 0.99 1176.5 3.2 77 18.29 0.95 1466.0 3.7 78 5.20 0.67 821.5 2.4 79 28.23 1.15 266.9 2.8 80 39.33 1.04 209.2 3.4 81 21.17 1.19 354.8 4.0 82 28.06 1.09 393.6 4.5 83 28.90 0.98 978.9 7.0 84 206.60 0.76 1141.0 4.7 85 75.43 1.01 279.5 1.8 86 78.40 0.69 2344.0 12.6 87 384.00 0.96 50000.0 NI 88 191.00 0.72 50000.0 NI 89 0.53 0.40 1094.0 2.7 90 20.63 0.86 368.1 1.8 91 34.13 0.47 3755.0 4.1 92 848.00 NI 50000.0 NI 93 46.44 0.51 264.3 2.1 94 159.00 0.27 3553.0 1.8 95 41.86 0.40 648.7 1.4 96 31.39 0.43 2092.0 1.2 97 37.03 0.61 604.9 2.5 98 20.58 0.75 1543.0 5.4 99 40.26 0.74 4840.0 6.3 100 91.70 0.84 3453.5 4.3 101 40.93 0.45 913.3 3.9 102 808.72 0.81 2149.4 3.7 103 41.08 0.49 1305.0 2.7 104 46.31 0.81 344.3 2.3 105 170.10 0.69 955.3 4.8 106 72.53 0.48 704.1 4.1 107 98.28 1.31 643.0 3.0 108 55.42 0.99 1981.0 4.0 109 17.54 0.65 467.7 5.9 110 12.09 0.76 214.2 2.8 111 18.93 0.64 564.3 3.2 112 273.40 0.33 1939.0 5.6 113 21.85 0.71 149.5 2.8 114 113.40 0.51 969.3 5.3 115 67.88 0.71 177.9 5.4 116 43.44 0.65 301.3 5.4 117 148.50 0.61 627.3 5.5 118 204.13 0.36 223.0 1.0 119 31.54 0.41 294.9 1.1 120 64.90 1.07 157.1 5.7 121 12.14 0.98 377.7 2.4 122 98.44 0.68 446.8 1.1 Notes 1. NI - not studied, that is, the object has not yet been discovered.
2. The above values are average values based on one or more measurements.

Based on the biochemical and cellular activity data of the compounds in the specific examples, it can be concluded that some of the compounds of the present invention have significant agonistic activity and specificity for the nuclear receptor RORγt and are expected to provide the basis for the development of new generation RORγt agonists, which will meet the needs of medicine.

All documents mentioned in the present invention are incorporated by reference, and each document is cited individually by reference. In addition, it should be understood that various modifications or changes may be made by those skilled in the art, having become familiar with the foregoing teachings of the present invention, and these equivalent forms are also included within the scope of the claims.

Claims (44)

1. A compound of formula (IIb), a stereoisomer thereof or a pharmaceutically acceptable salt: where L represents a bond or -C(R ₇ )=C(R ₈ )-; Z is selected from the group consisting of bonds, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ₃₃ )- and -(CR ₃₅ R ₃₆ )-; cycle A, together with -(R ₁ ) _m , forms the following structure: or ; wherein each R ₁ is independently selected from C _1-4 alkyl and -OR ₂₉ , the above groups being unsubstituted or substituted with three fluorines; cycle B represents where Y represents -O-; R ₂ represents hydrogen; each R ₅ is independently selected from halogen, cyano, C _1-10 alkyl and -C _0-8 -OR ₂₉ , the above groups being unsubstituted or substituted by three halogens, R ₆ represents hydrogen; R ₇ and R ₈ are each independently selected from hydrogen and C _1-4 alkyl, R ₃₃ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, oxetane, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _{0- 4} -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ , the above groups are unsubstituted or substituted by one or more additional substituents selected from the group consisting of cyano, =O, -C _0-4 -OR ₂₉ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ ; each R ₃₄ represents hydrogen; R ₃₅ is selected from the group consisting of halogen, -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ and -C _0-4 -OC(O)R ₃₀ , the above groups being unsubstituted or substituted with one or more additional substituents selected from the group consisting of -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _0-4 -C(O)OR ₂₉ and - C _0-4 -C(O)NR ₃₁ R ₃₂ ; R ₃₆ represents hydrogen or C _1-4 alkyl; each R ₂₈ is independently C _1-4 alkyl or -NR ₃₁ R ₃₂ ; each R ₂₉ is independently selected from hydrogen, C _1-4 alkyl and 6-membered heterocyclyl, the above groups being unsubstituted or substituted by one or more additional substituents selected from halogen and hydroxy; each R ₃₀ is independently selected from C _1-4 alkyl, C _1-4 alkoxy and -NR ₃₁ R _32, the above groups being unsubstituted or substituted by one cyano group; each R ₃₁ and each R ₃₂ independently represents hydrogen; p represents an integer from 0 to 5 q is an integer from 0 to 4; each r independently takes the value 2; when not specifically defined, a "heterocyclyl" heteroatom in the substituents mentioned above represents 1 oxygen atom. 2. A compound of formula (IIb), a stereoisomer thereof, or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (IIb) is a compound with formula (IIIb1), formula (IIIb2), formula (IIIb3), formula (IIIb4) or formula (IIIb5) as described below:
or
, where Z is selected from the group consisting of bonds, -O-, -S-, -S(O)-, -S(O) ₂ -, -N(R ₃₃ )- and -(CR ₃₅ R ₃₆ )-; each R ₅ is independently selected from the group consisting of halogen, cyano, C _1-4 alkyl and -OR ₂₉ , the above groups being unsubstituted or substituted by three additional substituents selected from the group consisting of fluorine and chlorine; R ₇ is selected from the group consisting of hydrogen, methyl and ethyl; R ₃₃ is selected from the group consisting of hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl, oxetane, -C _0-4 -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C _{0- 4} -C(O)OR ₂₉ , -C _0-4 -C(O)R ₃₀ , -C _0-4 -C(S)R ₃₀ and -C _0-4 -C(O)NR ₃₁ R ₃₂ , the above groups are unsubstituted or substituted by one or more additional substituents selected from cyano, =O, -C _0-4 -OR ₂₉ , -C _0-4 -OC(O)R ₃₀ and -C _0-4 -C(O )NR ₃₁ R ₃₂ ; R ₃₅ is selected from the group consisting of halogen, -OR ₂₉ , -C(O)OR ₂₉ and -OC(O)R ₃₀ , the above groups being unsubstituted or substituted by one or more additional substituents selected from -S(O) _r R ₂₈ , -C _0-4 -OR ₂₉ , -C(O)OR ₂₉ and -C(O)NR ₃₁ R ₃₂ ; R ₃₆ represents hydrogen; cycle A, R ₁ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ , R ₃₂ , r and m correspond to the definitions in paragraph 1. 3. A compound of formula (IIb), its stereoisomer or pharmaceutically acceptable salt according to any one of claims. 1 or 2, where the connection is selected from the following connections: or 4. A method for producing a compound of formula (IIb), its stereoisomer or a pharmaceutically acceptable salt according to any one of claims. 1-3, including the following stages: ; where cycle A, cycle B, L, Z, R ₁ , R ₂ , R ₅ , R ₆ , R _34, m, p and q correspond to the definitions in paragraph 1. 5. Use of a compound of formula (IIb), its stereoisomer or a pharmaceutically acceptable salt according to any one of claims. 1-3 for the manufacture of drugs for the treatment of one or more types of tumors, malignancies, metabolic diseases, autoimmune diseases or disorders associated with RORγt. 6. Use according to claim 5, wherein the metabolic disease and the autoimmune disease or disorder are selected from the group consisting of atopic dermatitis, contact dermatitis, allergic dermatitis, comedones, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, systemic lupus erythematosus ( SLE), psoriasis, chronic lymphocytic thyroiditis, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriatic arthritis (PsA), autoimmune diabetes, type 1 diabetes mellitus, type 2 diabetes mellitus type, obesity, fatty liver degeneration, adipose tissue-related inflammation, pancreatitis, thyroiditis, autoimmune thyroid disease, biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), ulcerative colitis, Crohn's disease, regional enteritis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Stevens-Johnson syndrome (SJS), primary sclerosing cholangitis, autoimmune polyendocrine syndrome type 1, autoimmune polyendocrine syndrome type 2, celiac disease, neuritis, systemic sclerosis, endometriosis, Behcet's syndrome, myocarditis, dermatomyositis, polymyositis, graft-versus-host disease, sarcoidosis, myocardial infarction, pulmonary hypertension, cutaneous leishmaniasis, Crohn's disease, autoimmune eye disease, optic neuritis, optic neuromyelitis, xerophthalmia, uveitis, insulin resistance, myasthenia gravis , age-related macular degeneration, Guillain-Barré syndrome, glomerulonephritis, scleritis, major depressive disorder, seasonal affective disorder, post-traumatic stress disorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer's disease, bronchial asthma, chronic obstructive pulmonary disease (COPD), bronchitis , hay fever, allergic rhinitis, steroid-resistant asthma, toxic diffuse goiter, obstructive sleep apnea syndrome (OSA), sinus polyps and nervous system disorders associated with changes in sleep and/or circadian rhythm. 7. Use according to claim 5, wherein the tumor or malignancy is selected from the group consisting of fallopian tube tumors, ovarian tumors, peritoneal tumors, stage 4 melanoma, solid tumors, glioma, glioblastoma, papillary renal carcinoma, head tumors and neck, lymphoma, myeloma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, hepatocellular carcinoma, breast cancer, uterine cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, leukemia and non-small cell lung cancer. 8. Use of a compound of formula (IIb), its stereoisomer or a pharmaceutically acceptable salt according to any one of claims. 1-3 as drugs for the treatment of one or more types of tumors, malignancies, metabolic diseases, autoimmune diseases or disorders associated with RORγt.