CN113121463A - Amide compound with bicyclic structure and application thereof in medicines - Google Patents

Abstract

The invention belongs to the technical field of medicines, and relates to an amide compound with ROR gamma t activity and a bicyclic structure, application of the amide compound in medicines, a pharmaceutical composition containing the compound and application of the compound in medicines. Specifically, the invention provides a compound shown as a formula (I), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a salt or a prodrug of the compound shown as the formula (I), a pharmaceutical composition containing the compound and application of the compound in medicines.

Description

Amide compound with bicyclic structure and application thereof in medicines

Technical Field

The invention belongs to the field of medicaments, and discloses an amide compound with ROR gamma t activity and a bicyclic structure, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in medicaments.

Background

Retinoic acid receptor-Related Orphan Receptors (RORs) are members of the steroid hormone nuclear receptor superfamily (receptor superfamily). The family includes ROR α, ROR β and ROR γ, ROR γ t, RORs comprise 4 major regions shared by most nuclear receptors, the N-terminal a/B domain, the DNA-binding domain, the hinge domain and the ligand binding domain. Each ROR gene produces a separate subtype, differing only in its N-terminal A/B domain. ROR γ has two subtypes, ROR γ l and ROR γ t. ROR γ 1 is expressed in various tissues such as thymus, muscle and kidney, while ROR γ t is expressed only in a part of immune cells (e.g., Th17 cells) and acts as a transcription factor for IL-17A and IL-17F, and a major regulator of Th17 cell differentiation. Thl7 cells are a subset of T helper cells that preferentially produce the proinflammatory cytokines IL-17A, IL-17F, IL-21 and IL-22. Thl7 cells and their effector molecules (e.g. IL-17, IL-21, IL-22, GM-CSF and CCL20) are involved in the pathogenesis of several autoimmune diseases and inflammatory diseases, and studies have also demonstrated that Th17 cells are involved in the pathogenesis of several autoimmune diseases and inflammatory diseases such as multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, autoimmune diseases and graft-versus-host disease (Jetten et al, nucl. recept. signal,2009,7: e 003; Manel et al, nat. immunol,2008,9, 641-one 649), as well as in the development of inflammation-associated tumors, Th17 cells are activated during the disease process and are responsible for the recruitment of other inflammatory cell types, such as neutrophils, to mediate the pathology of the target tissue (Korn et al, annu. rev. immunol. 2009,27: 485-517). Therefore, drugs having ROR γ t-modulating action are expected to exhibit therapeutic effects on various immune diseases by modulating differentiation and activation of Th17 cells.

The ROR gamma t agonist can promote the differentiation of Th17 cell and enhance the level of proinflammatory cytokines, so as to raise the cytotoxicity of lymphocyte. At the same time, ROR γ T agonists are able to inhibit the production of regulatory T cells which suppress the immune response, and therefore agonists are able to push the balance of the immune response in the direction of activation. ROR γ T agonists are also capable of promoting expression of a range of Co-Stimulatory molecules (Co-Stimulatory molecules) such as CD226, CD27 and 4-1BB (CD137) and inhibiting expression of Co-Inhibitory molecules (Co-Inhibitory molecules) such as PD-1, TIGIT, TIM3, CD73 and LAG3, thereby promoting T cell activation. Studies have shown that ROR γ t agonists are able to inhibit Tumor growth and prolong animal survival by an immune response in a variety of homologous Tumor Models (Syngeneic Tumor Models).

The company Lycera first reported the development of small molecule agonists of ROR γ t, and in 2017, the company Lycera declared the initiation of a phase 1/2a clinical trial to examine the efficacy of the developed ROR γ t agonist LYC-55716 in treating patients with advanced, recurrent, or refractory solid tumors. At present, ROR gamma t agonist has been concerned about anti-tumor, a great deal of research is carried out in the industry, and the IL-17 family provides good target points for tumor treatment in the future is very possible; therefore, ROR gamma t is considered as a new target for developing anti-tumor, anti-inflammatory and autoimmune disease drugs, and can be used as a new way for treating cancers and autoimmune inflammatory diseases.

Disclosure of Invention

The invention provides an amide compound with a bicyclic structure and ROR gamma t activity, which is a compound shown as a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound shown as the formula (I), a pharmaceutical composition containing the compound and application thereof in medicines,

the invention provides a compound which has a structure shown as a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof of the structure shown as the formula (I),

wherein, A, B, C, L, R¹、R²、R³、R⁴M and n have the meanings given in the description.

In some embodiments, ring a of the present invention is

Denotes a connection to L; represents a linkage to a carbonyl group; wherein X¹、X²And X³Each independently selected from CH₂、NH、S(O)_tOr O; x⁴、X⁵、X⁶And X⁷Each is independently selected from CH or N; wherein t has the meaning described in the present invention.

In some embodiments, ring a of the present invention is preferably

Denotes a connection to L; represents a linkage to a carbonyl group; wherein X¹、X²And X³Each independently selected from CH₂NH or O; x⁴、X⁵、X⁶And X⁷Each independently selected from CH or N.

In some embodiments, ring B is C_6-10Aryl or heteroaryl of 5 to 6 atoms.

In some embodiments, ring B of the present invention is preferably phenyl, naphthyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, or 1,3, 5-triazinyl.

In some embodiments, ring C is C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms; wherein ring C is independently unsubstituted or substituted with 1,2,3 or 4R^ySubstituted; wherein said R^yHave the meaning as described in the present invention.

In some embodiments, ring C of the present invention is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, cyclohexyl, and the like,Imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3, 5-triazinyl; wherein each ring C is independently unsubstituted or substituted with 1,2,3 or 4R^ySubstituted; wherein said R^yHave the meaning as described in the present invention.

In some embodiments, ring C of the present invention is preferably phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl or pyridazin-3-yl; wherein each ring C is independently unsubstituted or substituted with 1,2,3 or 4R^ySubstituted; wherein said R^yHave the meaning as described in the present invention.

In some embodiments, each R described herein^yIndependently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted; wherein said R^dHave the meaning as described in the present invention.

In some embodiments, each R described herein^yIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolylAn azole group, an oxadiazolyl group, a pyrazinyl group, a pyridazinyl group or a 1,3, 5-triazinyl group; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted; wherein said R^dHave the meaning as described in the present invention.

In some embodiments, each R described herein^yIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, methylamino, ethylamino, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidyl, phenyl, naphthyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, or 1,3, 5-triazinyl; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted; wherein said R^dHave the meaning as described in the present invention.

In some embodiments, each R described herein^dIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-S(＝O)₂R^a、-S(＝O)₂NR^aR^b、C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein R is^aAnd R^bHave the meaning as described in the present invention.

In some embodiments, each R described herein^dIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-S(＝O)₂R^a、-S(＝O)₂NR^aR^b、C_1-4Haloalkyl, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein R is^aAnd R^bHave the meaning as described in the present invention.

In some embodiments, each R described herein^dIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-S(＝O)₂R^a、-S(＝O)₂NR^aR^bMethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, ethylamino, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, aziridinyl, phenyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, or pyrimidinyl; wherein R is^aAnd R^bHave the meaning as described in the present invention.

In some embodiments, L is selected from the group consisting of a bond, -NR^x-、-O-、*-(CH₂)_r-C(O)-(CH₂)_r-、*-(CH₂)_r-S(O)_t-(CH₂)_r-or C_1-6An alkylene group; indicates attachment to ring a; wherein said R^xR and tHave the meaning as described in the present invention.

In some embodiments, L according to the present invention is preferably selected from the group consisting of a bond, -NR^x-、-O-、-C(O)-、*-C(O)-CH₂-、*-CH₂-C(O)-、-S(O)₂-、*-S(O)₂-CH₂-、*-CH₂-S(O)₂-、-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-or-CH₂CH₂CH₂CH₂-; indicates attachment to ring a.

In some embodiments, R is as described herein^xSelected from H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkylene, heterocyclic group of 3-6 atoms-C_1-6Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-6Alkylene, heteroaryl of 5 to 10 atoms or heteroaryl-C of 5 to 10 atoms_1-6An alkylene group.

In some embodiments, each R described herein⁴Independently selected from H, deuterium, F, Cl, Br, I, -CN, -OH, -NR^aR^b、-C(＝O)OR^f、-C(＝O)R^f、-C(＝O)NR^aR^b、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-6An alkylamino group; wherein each R⁴Independently unsubstituted or substituted by 1,2,3 or 4R^cSubstituted; wherein said R^a、R^b、R^fAnd R^cHave the meaning as described in the present invention.

In some embodiments, each R described herein⁴Independently preferably selected from H, deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、-NHCH₃N' N-dimethylamino, -C (═ O) OH, -C (═ O) OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)H、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, methylamino, ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, C_2-4Alkenyl or C_2-4An alkynyl group; wherein each R⁴Independently unsubstituted or substituted by 1,2,3 or 4R^cSubstituted; wherein said R^cHave the meaning as described in the present invention.

In some embodiments, each R described herein^cIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OR^f、-C(＝O)NR^aR^b、-S(＝O)₂R^f、-S(＝O)₂NR^aR^b、C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein said R^a、R^bAnd R^fHave the meaning as described in the present invention.

In some embodiments, each R described herein^cIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)OCH₃、-C(＝O)OCH₂CH₃、-C(＝O)H、-C(＝O)NH₂、-C(＝O)NHCH₃、-C(＝O)N(CH₃)₂、-S(＝O)₂CH₃、-S(＝O)₂CH₂CH₃、-S(＝O)₂NH₂、C_1-4Haloalkyl, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms.

In some embodiments, R is as described herein¹Selected from H, deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano-substituted C_1-6Alkyl, carboxy substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R¹Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some embodiments, R is as described herein¹Preferably selected from H, deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-CH₂OH、-CH₂CN、-CH₂COOH, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, methylamino, ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl or tetrahydrofuranyl, wherein each R¹Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some embodiments, R is as described herein²Selected from F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano-substituted C_1-6Alkyl, carboxy substituted C_1-6Alkyl, hydroxy substituted C_1-6Alkyl radical, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R²Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some embodiments, R is as described herein²Preferably selected from F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-CH₂OH、-CH₂CN、-CH₂COOH, methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, methylamino, ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl or tetrahydrofuranyl, wherein each R²Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some casesIn embodiments, each R described herein³Independently selected from H, -NO₂Or C_3-6A cycloalkyl group.

In some embodiments, each R described herein³Independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -SH, -NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -S (═ O) -C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, heterocyclic radical composed of 3-6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R³Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some embodiments, each R described herein³Independently preferably selected from deuterium, F, Cl, Br, I, -CN, -OH, -SH, -NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-CH₃、-S(＝O)-CH₃、-S(＝O)₂-CH₂CH₃or-S (═ O)₂-CH₂CH₂CH₃(ii) a Wherein each R³Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted; wherein said R^eHave the meaning as described in the present invention.

In some embodiments, each R described herein^eIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OR^a、-S(＝O)₂R^a、-C(＝O)NR^aR^b、-S(＝O)₂NR^aR^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, 3-10Heterocyclic radical of an atom, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein said R^aAnd R^bHave the meaning as described in the present invention.

In some embodiments, each R described herein^eIndependently preferably selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)OCH₃、-S(＝O)₂CH₃、-S(＝O)₂CH₂CH₃、-C(＝O)NH₂、-S(＝O)₂NH₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms.

In some embodiments, each R described herein^aIndependently selected from H, deuterium, C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-3Alkylene, heterocyclic group consisting of 3 to 10 atoms, (heterocyclic group consisting of 3 to 10 atoms) -C_1-3Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-3Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-3An alkylene group.

In some embodiments, each R described herein^bIndependently selected from H, deuterium, C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-3Alkylene, heterocyclic group consisting of 3 to 10 atoms, (heterocyclic group consisting of 3 to 10 atoms) -C_1-3Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-3Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-3An alkylene group.

Each R^fIndependently selected from H, deuterium, F, Cl,Br、I、-CN、-NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-3Alkyl, heterocyclic group consisting of 3 to 10 atoms, (heterocyclic group consisting of 3 to 10 atoms) -C_1-3Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-3Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-3An alkylene group.

In some embodiments, each t is independently 0, 1, or 2.

In some embodiments, each r described herein is independently 0, 1,2,3, or 4.

In some embodiments, n is 0, 1,2,3, or 4.

In some embodiments, m is 0, 1,2,3, or 4.

In some embodiments, the compounds of the present invention are not any of the following:

in some embodiments, the compounds of the present invention are of the structure shown in formula (II) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of the structure shown in formula (II),

wherein Z is¹Is CH or N; s is 0, 1,2,3 or 4; r¹、R²、R³、R⁴、R^yA, L and m have the meanings given in the description of the invention.

In some embodiments, the compounds of the present invention are stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts, or prodrugs thereof, of the structure shown as formula (III) or formula (IV) or of the structure shown as formula (III) or formula (IV),

wherein Z is¹Is CH or N; s is 0, 1,2,3 or 4; r^e、R³、R⁴、R^yA, L and m have the meanings given in the description of the invention.

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

in one aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III) or formula (IV) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle or combination thereof.

In one aspect, the invention relates to the use of a compound of formula (I), formula (II), formula (III) or formula (IV), or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing, treating or ameliorating a disease mediated by roryt in a patient.

In some embodiments, the diseases mediated by roryt according to the present invention include cancer, multiple sclerosis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune diseases, graft-versus-host disease, autoimmune ocular diseases, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infections, fungal infections, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.

The tumor or cancer of the invention is selected from non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical 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, fallopian tube tumor, ovarian tumor, peritoneal tumor, melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

In another aspect, the invention relates to methods of preparation, isolation and purification of compounds encompassed by formula (I), formula (II), formula (III) or formula (IV).

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. Other aspects will be more fully described in detail below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

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

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereoisomers" are stereoisomers whose pairs or multiple chiral centers are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., by subjectingHigh Performance Liquid Chromatography (HPLC) with chiral adsorbents. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)^nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (also known as proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers (valenctautomers) include interconversion by recombination of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of the pentan-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the tautomerism of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The terms "optional," "optionally," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, i.e., that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with 1,2,3, or 4 …" includes the case where the group is substituted with 1, or 2, or 3, or 4 of the substituents described, as well as the case where the group is not substituted with the substituents described. Further, when the group is substituted with 1 or more of the substituents, the substituents are independent of each other, that is, the 1 or more substituents may be different from each other or the same; or "optionally salified with a suitable acid" includes salification of the compound with a suitable acid or without any acid, and may optionally salify in a ratio of 1:1, or 1:1.5, or 1:2, or 1:3, or 2:1, or 3: 1.

The compounds of the invention may be independently optionally substituted with one or more substituents, as described herein, in the general formula above, or as specified in the examples, subclasses, and classes of compounds encompassed by the invention. It will be understood that the term "optionally substituted", "optionally substituted with … …", or "optionally including" is used interchangeably with the term "substituted or unsubstituted". The term "independently optionally" is used interchangeably with the term "optionally independently", and generally speaking, the term "independently optionally" whether or not preceded by the term "substituted" indicates that one or more hydrogen atoms in a given structure may be substituted or unsubstituted with the particular substituent 1. Unless otherwise indicated, an optional substituent group may be substituted with a substituent 1 at each substitutable, reasonable position of the group. When more than one position in a given formula can be substituted with one or more substituents 1 selected from a particular group, the substituents can be substituted identically or differently at each of the possible positions in the formula. Wherein said substituent 1 may be, but is not limited to: hydrogen, deuterium, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl-S (═ O)_z-, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde group, aminoacyl, alkoxy, alkylamino, alkylthio, alkanoyl, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C ═ O) -, benzyl, cycloalkyl, alkylamino-C (═ O) -, CN-alkyl-C (═ O) -, alkyl-O-C (═ O) -alkyl, ester group, hydroxyalkanoyl, or alkoxyalkyl, and the like. Where appropriate, substituents 1 can further independentlyOptionally mono-substituted by a substituent 2 or poly-substituted by a plurality of substituents 2 which may be the same or different. Wherein said substituent 2 may be, but is not limited to: hydrogen, oxo, fluoro, chloro, bromo, iodo, hydroxy, amino, carboxy, alkyl-S (═ O)_z-, haloalkyl, hydroxyalkyl, aminoalkyl, aldehyde group, aminoacyl, alkoxy, alkylamino, alkylthio, haloalkoxy, cyano, aryl, heteroaryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxyalkoxy, alkyl- (C ═ O) -, benzyl, alkylamino-C (═ O) -, CN-alkyl-C (═ O) -, alkyl-O-C (═ O) -alkyl, ester group, hydroxyalkanoyl, or alkoxyalkyl, and the like. Wherein z is 0, 1, or 2.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" as used herein includes saturated straight or branched chain monovalent hydrocarbon groups of 1 to 20 carbon atoms, wherein the alkyl groups may independently be optionally substituted with one or more substituents described herein. In some of these embodiments, the alkyl group contains 1 to 10 carbon atoms; in other embodiments, the alkyl group contains 1 to 8 carbon atoms; in other embodiments, the alkyl group contains 1 to 6 carbon atoms, and in other embodiments, the alkyl group contains 1 to 4 carbon atoms; in other embodiments, the alkyl group contains 1 to 3 carbon atomsAnd (4) adding the active ingredients. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) 2-methylpropyl or isobutyl (i-Bu, -CH)₂CH(CH₃)₂) 1-methylpropyl or sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" as used herein, both include straight and branched saturated carbon chains.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) Propenyl (-CH ═ CH-CH)₃) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, which has a structureThe alkynyl group may be optionally substituted with one or more substituents as described herein. In some embodiments, alkynyl groups contain 2-8 carbon atoms; in other embodiments, alkynyl groups contain 2-6 carbon atoms; in still other embodiments, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "haloalkyl" denotes a situation where an alkyl group may be substituted by one or more of the same or different halogen atoms. Wherein the alkyl group has the meaning as described herein, and such examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 2, 2-difluoroethyl, 3,3, 3-trifluoropropyl, and the like. Haloalkyl groups may be substituted with one or more substituents described herein.

The term "amino" refers to a compound having the formula-NH₂A group of (1).

The term "carboxy", whether used alone or in combination with other terms, means-C (═ O) OH; the term "carbonyl", whether used alone or in combination with other terms, means- (C ═ O) -.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" wherein the hydrogens on the amino groups are each independently replaced by one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some of these examples, the alkylamino group is one or two C_1-6The alkyl group is attached to the nitrogen atom to form a lower alkylamino group. In other embodiments, the alkylamino group is one or two C_1-4To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, N-methyl-N-ethylamino, and the like.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl groupHave the meaning as described in the present invention. In some embodiments, alkoxy groups contain 1 to 6 carbon atoms; in other embodiments, the alkoxy group contains 1 to 4 carbon atoms; in still other embodiments, alkoxy groups contain 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) N-propoxy (n-PrO, n-propoxy, 1-propoxy, -OCH₂CH₂CH₃) Isopropoxy (-OCH (CH)₃)₂) And so on.

The term "alkanoyl", "alkanoyl" or "alkylcarboxyl" means that an alkyl group is attached to the rest of the molecule through a carbonyl group (-C (═ O) -), wherein the alkyl group has the meaning described herein. The alkanoyl group can be optionally substituted with one or more substituents described herein. Examples of alkanoyl groups include, but are not limited to, acetyl (-C (═ O) CH₃) Propionyl (-C (═ O) CH₂CH₃) Butyryl (-C (═ O) CH₂CH₂CH₃) And the like; among them, particularly, a formyl group (-C (═ O) H) is also included in the range of alkanoyl groups.

The term "cycloalkyl" refers to a monovalent or polyvalent, nonaromatic, saturated monocyclic, bicyclic, or tricyclic ring system containing from 3 to 12 ring carbon atoms, wherein the bicyclic, tricyclic, or tetracyclic ring system forms a ring in a fused, bridged, or spiro fashion. In some embodiments, cycloalkyl groups contain from 3 to 10 ring carbon atoms; in other embodiments, cycloalkyl groups contain from 3 to 8 ring carbon atoms; in still other embodiments, cycloalkyl groups contain 3 to 6 ring carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group may be optionally substituted with one or more substituents described herein.

The term "aryl" may be monocyclic, bicyclic, and tricyclic carbocyclic ring systems in which at least one ring system is aromatic, each of whichThe ring system contains 6 to 10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl and anthracenyl. The aryl group may be substituted with one or more substituents described herein. The term "C_6-10Aryl "means an aryl group having 6 to 10 carbon atoms, the aryl group being as defined above.

The terms "heteroaryl", "heteroaryl ring" and "heteroaromatic ring" are used interchangeably herein and all refer to monocyclic, bicyclic, tricyclic or polycyclic ring systems in which the bicyclic, tricyclic or tetracyclic heteroaromatic ring systems form a ring in fused form. Wherein the heteroaromatic ring system is aromatic in its entirety and one or more of the atoms in the ring is independently optionally substituted with a heteroatom (heteroatom selected from N, O, P, S, where S or P is independently optionally substituted with one or more oxygen atoms to yield a compound like SO, SO₂、PO、PO₂The group of (1). The heteroaryl ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. The heteroaryl group may be a monocyclic ring of 3 to 6 atoms, or a bicyclic ring of 7 to 10 atoms, or a tricyclic ring of 10 to 15 atoms. The bicyclic ring having 7 to 10 atoms may be bicyclo [4,5 ]]，[5,5]，[5,6]Or [6,6 ]]The tricyclic ring having 10 to 15 atoms may be a tricyclic [5,5,6 ]]、[5,7,6]Or [6,5,6 ]]And (4) preparing the system. The term "heteroaryl of 5 to 6 atoms" refers to a heteroaryl having 5 to 6 atoms in atoms, at least one heteroatom selected from N, O, S or P, the heteroaryl having the above definition.

In other embodiments, heteroaryl systems (including heteroaryl, heteroaryl rings) include, but are not limited to, the following examples: furyl (e.g., furan-2-yl, furan-3-yl, etc.), imidazolyl (e.g., N-imidazolyl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, etc.), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, etc.), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, etc.), 4-methylisoxazol-5-yl, pyrrolyl (e.g., N-pyrrolyl, pyrrol-2-yl, pyrrol-3-yl, etc.), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, etc.), pyrimidinyl (pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, etc.), pyridazinyl (e.g., pyridazin-3-yl),thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, etc.), tetrazolyl (e.g., tetrazol-5-yl, etc.), triazolyl (e.g., 1,2, 3-triazol-2-yl, etc.), thienyl (e.g., thiophen-2-yl, thiophen-3-yl, etc.), pyrazolyl (e.g., pyrazol-2-yl), isothiazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, etc.), 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazol-2-yl, pyrazinyl (e.g., pyrazin-2-yl, etc.), 1,3, 5-triazinyl, benzo [ d ] carbonyl]Thiazol-2-yl, imidazo [1,5-a ]]Pyridin-6-yl, benzimidazolyl, benzoxazolyl, dibenzofuranyl, imidazopyridinyl, indazolyl, indolizinyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl, naphthyridinyl, oxazolidinedionyl, oxazolidinyl, oxazolopyridyl, oxazolyl, catechinylphenyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, pyridopyridinyl, quinazolinyl, quinoxalinyl, thiophenyl, triazinyl, 2H-pyrrolo [3,4-c ] group]Pyridyl, imidazo [2',1':2, 3)]Thiazolo [4,5-b]Pyrazinyl, imidazo [2',1':2, 3)]Thiazolo [5,4-b ]]Pyridyl, imidazo [2',1':2, 3)]Thiazolo [4,5-c ]]Pyridyl, 1H-benzo [ f ]]Imidazo [4,5-b ]][1,4]Sulfoazazepine

And the like. Heteroaryl groups may be substituted with one or more substituents described herein.

The terms "heterocyclyl", "heterocycle", "heterocyclic" or "heterocycloalkyl" are used interchangeably herein and all refer to a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein the bicyclic, tricyclic or tetracyclic ring system is fused or bridged or spiro-connected to form a ring, wherein one or more carbon atoms in the ring are independently optionally substituted with a heteroatom selected from the group consisting of a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S) or a phosphorus atom (P). and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. The phosphorus atom of the ring may optionally be oxidized to a P-oxygen compound. The heterocyclic ring may beAre fully saturated or contain one or more unsaturations, but have no aromaticity overall. For example, in some embodiments, bicyclic heterocyclic groups, wherein one ring has aromatic character and the other ring does not have aromatic character throughout. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound. One or more of the ring hydrogen atoms are independently optionally substituted with one or more substituents described herein. Some examples of these are "heterocyclyl", "heterocycle", "heterocyclic" or "heterocycloalkyl" groups which are 3-6 membered monocyclic (2-5 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, only one of which is present when the ring is a three-membered ring), or 5-12 atoms bicyclic (4-11 carbon atoms and 1-3 heteroatoms selected from N, O, P, S). The term "5-12 membered heterocycloalkyl" refers to a heterocycloalkyl having 5 to 12 atoms in the ring system, wherein heterocyclyl is as defined above.

"Heterocyclyl" may be a carbon atom radical or a heteroatom radical. "Heterocyclyl" also includes groups formed by the fusion of heterocyclic groups with saturated or partially unsaturated rings or heterocycles. Examples of heterocycles include, but are not limited to, ethylene oxide, pyrrolidinyl, tetrahydrofuranyl (e.g., tetrahydrofuran-3-yl, etc.), dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl (e.g., N-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, etc.), thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, azepinyl, oxepanyl, thiepinyl, morpholinyl (e.g., N-morpholinyl, 2-morpholinyl, 3-morpholinyl, etc.), thiomorpholinyl, piperazinyl (e.g., N-piperazinyl, 2-piperazinyl, 3-piperazinyl, etc.), 1,2,3, 6-tetrahydropyridin-1-yl, oxazepin.

Radical, diaza

Radical, S-N-aza

1, 3-dioxopentyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, hexahydro-2H- [1, 4-dioxopentyl, pyrazolinyl, dithianyl, dithienoalkyl, dihydrothienyl, imidazolidinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2, 6-thiadiazinane 1, 1-dioxo-2-yl, hexahydro]Dioxin [2,3-c ]]Pyrrolyl, quinolizinyl, 1, 1-thiomorpholinyl dioxide, 2,3,3a,7 a-tetrahydro-1H-isoindolyl, isoindolinyl, 1,2,3, 4-tetrahydroquinolyl, dibenzofuranyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, isobenzotetrahydrofuryl, isobenzotetrahydrothienyl, isobenzothienyl, isobenzodihydropyranyl, isocoumarinyl, isoindolinyl, 1,3, 5-trithianyl, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidonyl, 3, 5-dioxopiperidyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [ 2.2.1.1 ] azabicyclo [2.2.1 ] 2]Hept-5-yl, 4-oxomorpholinyl and pyrimidinedionyl.

In heterocyclic radicals of-CH₂Examples of-groups substituted with-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1, 1-dioxide, and the like.

The term "cycloalkyl-C_1-6Alkyl group, heterocyclic group-C_1-6Alkyl group, aryl group-C_1-6Alkyl "," heteroaryl-C_1-6Alkyl represents cycloalkyl, heterocyclyl, aryl and heteroaryl through-C_1-6Alkyl groups attached to the rest of the molecule, wherein-C_1-6Alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups all have the meaning as indicated in the present invention. Said "cycloalkyl-C_1-6Alkyl group, heterocyclic group-C_1-6Alkyl group, aryl group-C_1-6Alkyl "," heteroaryl-C_1-6An "alkyl" group is optionally substituted with one or more substituents described herein.

The terms "k-member" or "k-member" are used interchangeably herein, where k is an integer typically describing the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is k. For example, 5-12 membered heteroaryl means heteroaryl consisting of 5,6, 7, 8,9, 10, 11 or 12 ring atoms. As another example, piperidinyl is heterocyclyl or 6-membered heterocyclyl consisting of 6 ring atoms, and pyridinyl is heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

As described herein, the substituent is attached to the ring through a bond to form a ring system, which means that the substituent can be substituted at any substitutable position on the ring. For example, formula (a) represents that y substituents R may be substituted at any possible substituted position on the pyridine ring, and when y is greater than 1, each R may be independently selected from the same or different substituent groups.

As described herein, the linkage is attached to the ring system formed by the rings, meaning that the linkage can be attached to the rest of the molecule at any attachable position on the ring system. For example, as shown in formula b, the A end is fixedly connected to U₁On the A' end can be arbitrarily connected to U₂-U₇The possible positions of the above.

As described herein, two points of attachment on ring Ar in formula c can be attached to the rest of the molecule, for example, as shown in formula c, where either the E or E' terminus in formula c is attached to the rest of the molecule, i.e., the attachment of the two ends can be interchanged, unless explicitly stated otherwise.

If it is stated otherwise, for example, as shown in formula d, the F-terminal in formula d can only be connected to the end marked with an "x" in the molecule, and the F' terminal can only be connected to the end marked with an "x" in the molecule, i.e. the connection of the two ends is not interchangeable.

In addition, unless otherwise expressly indicated, the descriptions "each … independently is," "each … independently is selected from," "each independently is selected from," and "each independently is" used throughout this document are interchangeable and should be broadly understood to mean that particular items expressed between the same symbols in different groups do not interfere with each other, or that particular items expressed between the same symbols in the same groups do not interfere with each other. For example, R1 "R" in formula f represent identical or different groups and do not influence each other; "r 1" and "r 2" represent the same or different values and do not affect each other.

The term "pharmaceutically acceptable" means physiologically tolerable and generally not producing an allergic or similar untoward reaction, such as gastrointestinal upset, vertigo and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by a federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Suitable Pharmaceutical carriers are described in e.w. martin, "Remington's Pharmaceutical Sciences".

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, MeOH, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol.

The "ester" of the present invention means that the compounds represented by the formulae (I) to (IV) having a hydroxyl group can form an in vivo hydrolysable ester. Such esters are, for example, pharmaceutically acceptable esters which are hydrolysed in the human or animal body to yield the parent alcohol. The group of the in vivo hydrolysable ester of the compounds of formula (I) -formula (IV) containing a hydroxyl group includes, but is not limited to, phosphate, acetoxymethoxy, 2, 2-dimethylpropionyloxymethoxy, alkanoyl, benzoyl, benzoylacetyl, alkoxycarbonyl, dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl, etc.

"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form a nitroxide. Specific examples of nitroxides are those of tertiary amines or nitrogen containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acids) to form nitrogen oxides (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the nitroxides can be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as DCM.

The compounds may exist in a number of different geometric isomers and tautomers and the compounds of formula (I), formula (II), formula (III) or formula (IV) include all such forms. For the avoidance of doubt, when a compound exists as one of several geometric isomers or tautomers and only one is specifically described or shown, it is clear that all other forms are encompassed in formula (I), formula (II), formula (III) or formula (IV).

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I) -formula (IV).Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)_1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S.Symphostem series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery,2008,7, 255-.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms. The invention includes isotopically-labeled compounds, which are identical to those recited in formula (I) -formula (IV), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹³C、¹¹C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms, prodrugs thereof, and the compoundsPharmaceutically acceptable salts of the compounds or of the prodrugs are within the scope of the invention. Certain isotopically-labelled compounds of the invention, e.g. by incorporation of radioactive isotopes (e.g. by introducing³H and¹⁴C) can be used in drug and/or substrate tissue distribution assays. Isotopically labeled compounds of formula (I) -formula (IV) of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in carrying out the procedures disclosed in the schemes and/or in the examples and preparations below.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

Various pharmaceutically acceptable salt forms of the compounds of the present invention are useful. The term "pharmaceutically acceptable salts" means those salt forms that are readily apparent to the pharmaceutical chemist as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion. Other factors, more practical in nature, are also important for selection, these are: cost of raw materials, ease of crystallization, yield, stability, hygroscopicity and, as a result, flowability of the drug substance.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the descriptive pharmaceutical acceptable salts in detail in J. pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, nitrate and the like, and organic acid salts such as acetate, propionate, glycolate, oxalate, maleate, malonate, succinate, fumarate, tartrate, citrate, benzoate, mandelate, methanesulfonate, ethanesulfonate, toluenesulfonate, sulfosalicylate and the like, or those obtained by other methods described in the literature such as ion exchange.

Other pharmaceutically acceptable salts include adipates, malates, 2-hydroxypropionic acid, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodiates, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurylsulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, picrates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, glucarates, half sulfates, heptanates, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. The alkali metal or alkaline earth metal salt includes sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, aluminum salt and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates. Amine salts such as, but not limited to, N-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines,ethylenediamine, N-methyl reduced glucamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidin-1' -ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazine and tris (hydroxymethyl) aminomethane; alkaline earth metal salts such as, but not limited to, barium, calcium and magnesium; a transition metal salt such as, but not limited to, zinc.

The term "protecting group" or "PG" refers to a substituent that, when reacted with another functional group, is generally used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

"room temperature" in the present invention means a temperature of from 10 ℃ to 40 ℃. In some embodiments, "room temperature" refers to a temperature from 20 ℃ to 30 ℃; in other embodiments, "room temperature" refers to 25 ℃.

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.

Abbreviations for any protecting groups, amino acids and other compounds used in the present invention shall be based on their commonly used, accepted abbreviations unless otherwise indicated, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see biochem.1972, 11: 942-944).

Pharmaceutical compositions, formulations and administration of the compounds of the invention

As described herein, the pharmaceutical composition of the present invention comprises any one of the compounds of formula (I), formula (II), formula (III) or formula (IV) of the present invention, and further comprises pharmaceutically acceptable excipients, such as any solvent, solid excipient, diluent, binder, disintegrant, or other liquid excipient, dispersant, flavoring or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as used herein, suitable for the particular target dosage form. Different excipients can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.

Substances described in the present invention as pharmaceutically acceptable excipients include, but are not limited to, ion exchangers; aluminum; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; polyacrylate esters; a wax; polyethylene-polyoxypropylene-blocking polymers; lanolin; sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc powder; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salt; ringer's solution; ethanol; phosphoric acid buffer solution; and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate; a colorant; a release agent; coating the coating material; a sweetener; a flavoring agent; a fragrance; preservatives and antioxidants. When the compound of the present invention is administered in the form of a medicament to a mammal such as a human, it may be administered in the form of the compound itself or may be administered in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of an active ingredient and a pharmaceutically acceptable carrier. By "therapeutically effective amount" or "effective amount" is meant a sufficient amount of one or more compounds of the invention to treat, prevent, alleviate, ameliorate, or eliminate one or more symptoms of a particular disease, disorder, or syndrome, or to prevent or delay the onset of one or more symptoms of a particular disease, disorder, or syndrome described herein. In the case of treating cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; inhibit (i.e., slow to some extent or stop) cancer cell infiltration into peripheral organs; inhibiting tumor metastasis; inhibit tumor growth to some extent; and/or relieve to some extent one or more symptoms associated with cancer. In the case of infectious disease states, a therapeutically effective amount is an amount sufficient to reduce or alleviate infectious disease (symptoms of infection caused by bacteria, viruses, and fungi). One of ordinary skill in the art will be able to study the factors contained herein and determine, without undue experimentation, an effective amount of a compound of the invention.

The administration regimen may affect the constitution of the effective amount. The compounds of the invention may be administered to an individual prior to or after the onset of a disease mediated by roryt. In addition, multiple divided doses and staggered doses may be administered daily or sequentially, or may be administered as a continuous infusion, or may be administered as a bolus. Furthermore, the dosage of the compounds of the invention may be increased or decreased as appropriate, depending on the exigencies of the condition being treated or prevented.

The compounds of the invention are useful for treating the conditions, disorders or diseases described herein, or for the preparation of pharmaceutical compositions for treating such diseases. The present invention relates to methods of use of the compounds of the class described herein in the treatment of such diseases or pharmaceutical formulations containing the compounds of the invention for use in the treatment of such diseases.

"pharmaceutically acceptable carriers" are art-recognized and include pharmaceutically acceptable materials, compositions or vehicles suitable for administration of the compounds of the invention to a mammal. The carrier comprises a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transferring the active pharmaceutical ingredient from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; phosphate buffer; and other non-toxic compatible materials used in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; oil-soluble antioxidants such as ascorbyl palmitate, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral, nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form is generally that amount of the compound which produces a therapeutic effect. Generally, the amount is from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10 to about 30%, in units of one percent.

The methods of making these formulations or compositions include the step of bringing into association a compound of the invention with a carrier, optionally and independently one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compounds of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, typically sucrose and acacia or tragacanth), powders, granules, or solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions, or elixirs or syrups, or pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or mouthwashes and the like, each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the invention may also be administered in the form of a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicic acids and sodium carbonate; solution retarding agents (solution retaring agents), such as paraffin; absorption promoters, such as quaternary ammonium compounds; wetting agents, for example, cetyl alcohol and glycerol monostearate; adsorbents such as kaolin and bentonite; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and a colorant. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared with binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agents. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the invention, such as dragees, capsules, pills and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical art. They may also be formulated with, for example, hydroxypropylmethyl cellulose in various proportions to provide the desired release properties, other polymer matrices, liposomes and/or microspheres to provide slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other injectable sterile vehicle immediately prior to use. These compositions may also optionally contain opacifying agents and may be of a composition that it releases the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, if appropriate with the use of one or more of the above-mentioned excipients.

Liquid dosage forms of the compounds of the invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

In addition to inert diluents, the oral compositions can also include adjuvants (adjuvants) such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain co-excipients, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or salicylate, and which is solid at room temperature but liquid at body temperature and will therefore melt in the rectum or vaginal cavity and release the active compound.

Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to an active compound of the invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of the invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. Sprays can also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable vehicle. Absorption enhancers may also be used to increase the flux of compounds through the skin. The rate of flow of such compounds can be controlled by providing a rate controlling membrane or dispersing the active compound in a polymer matrix or gel.

Also included within the scope of the present invention are ophthalmic formulations, ophthalmic ointments, powders, solutions, and the like.

Pharmaceutical compositions of the invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that can be used in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Suitable fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. Prevention of the action of microorganisms can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. Thus, the rate of absorption of the drug will depend on its rate of dissolution, which in turn may depend on crystal size and crystal form. Alternatively, prolonged absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oily matrix.

Injectable depot forms are prepared by forming a microencapsulated matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular compound used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations can also be prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.

The formulations of the present invention may be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for the respective route of administration. For example, they are administered in the form of tablets or capsules, by injection, inhalation, ophthalmic lotion, ointment, suppository and the like, by injection, infusion or inhalation; topically applied by lotion or ointment; administered rectally by means of suppositories. Oral and/or intravenous administration is preferred.

The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, typically by injection, including, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

The terms "systemic administration" and "peripheral administration" as used herein mean administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and is thus subject to metabolism and other similar processes, e.g., subcutaneous administration.

These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including oral, nasal (e.g., in spray form), rectal, intravaginal, parenteral, intracisternal, and topical (in powder, ointment, or drop form) administration, including buccal and sublingual administration.

Regardless of the route of administration chosen, the compounds of the invention and/or the pharmaceutical compositions of the invention, which may be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms using conventional methods known to those skilled in the art.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the invention can be varied to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, and which is non-toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the invention or ester, salt or amide thereof employed, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, body weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start a dose of a compound of the invention employed in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase its dose until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such effective dosages will generally depend on the factors described above. In general, the compounds of the invention are administered to a patient in a dosage of about 0.001 to about 500mg/kg body weight/day.

If desired, an effective daily dose of the active compound may be administered at suitable intervals throughout the day in two, three, four, five, six or more sub-doses administered separately, optionally in unit dosage forms.

For an individual of about 50-70kg, the pharmaceutical composition or combination of the invention may be in a unit dose of about 1-1000mg of the active ingredient. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient which is required to prevent, treat or inhibit the progression of the disorder or disease.

The above dosage properties are illustrated for mammals, such as mice, rats, dogs, monkeys or their related organs, tissues or preparations, which are advantageous for use in vitro and in vivo assays. The compounds of the invention can be applied in vitro in the form of solutions, for example aqueous solutions, and in vivo enterally, parenterally, advantageously intravenously, for example as suspensions or aqueous solutions. The in vitro dosage may range between about 10-3 molar and 10-9 molar. The therapeutically effective amount in vivo can range from about 0.1 to 500mg/kg or between about 1 to 100mg/kg, depending on the route of administration.

The term "individual" as used herein means an animal. Typically, the animal is a mammal. A subject also means, for example, a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the individual is a human.

Although the compounds of the present invention may be administered alone, it is preferred to administer the compounds in the form of a pharmaceutical composition.

Pharmaceutical combination

Combination therapy using one or more compounds or compositions provided herein, or pharmaceutically acceptable derivatives thereof, in combination with other pharmaceutically active agents, is useful for treating the diseases and conditions described herein.

An effective amount of a compound or composition comprising a therapeutically effective concentration of a compound formulated for oral, systemic delivery, including parenteral or intravenous delivery or for topical or topical administration, is administered to an individual in need of treatment exhibiting symptoms of a disease or disorder. The amount is effective to treat, control or alleviate one or more symptoms of the disease or disorder.

One of ordinary skill in the art will appreciate that the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein, including pharmaceutical compositions and formulations comprising such compounds, have broad application in combination therapy to treat the disorders and diseases described herein. Thus, the present invention contemplates the use of the compounds, isomers, prodrugs and pharmaceutically acceptable derivatives provided herein in combination with other active agents for the treatment of the diseases/disorders described herein.

Use of the Compounds and compositions of the invention

The compound or the pharmaceutical composition disclosed by the invention can be used for preparing medicaments for preventing, treating or relieving ROR gamma t mediated diseases of patients, mammals including human beings, and related to ROR gamma t mediated diseases.

Such diseases include, but are in no way limited to, cancer, multiple sclerosis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune diseases, graft-versus-host disease, autoimmune ocular diseases, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infections, fungal infections, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.

The compounds or compositions of the present invention can be used in, but are in no way limited to, the administration of an effective amount of a compound or composition of the present invention to a patient for the treatment, prevention, amelioration, control or alleviation of cancer, infectious diseases and autoimmune diseases in mammals, including humans.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic methods

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined for the compounds of formulae (I) - (IV), unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.

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

In the examples described below, all temperatures are set at C unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.

The anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous toluene and anhydrous ether are obtained by refluxing and drying the metal sodium. The anhydrous dichloromethane and anhydrous chloroform are obtained by refluxing and drying calcium hydride. The anhydrous ethyl acetate, anhydrous petroleum ether, anhydrous N-hexane, anhydrous N, N-dimethylacetamide and anhydrous N, N-dimethylformamide were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. Nuclear magnetic resonance spectroscopy with CDC1₃、d₆-DMSO、CD₃OD or d₆Acetone as solvent (in ppm) and TMS (0ppm) or chloroform (7.25ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets, quartet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).

Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311B quaternary pump and a G1316ATCC (column temperature maintained at 30 ℃), a G1329B autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.

The spectrometer was equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in table 1:

TABLE 1

Time (min)	A(CH3CN，0.1％HCOOH)	B(H2O，0.1％HCOOH)
			0-3	5-100	95-0
3-6	100	0
			6-6.1	100-5	0-95
6.1-8	5	95

Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10 min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.

The following acronyms are used throughout the invention:

the following synthetic schemes describe the steps for preparing the presently disclosed compounds, unless otherwise indicated, wherein each X is¹、X²、X³X⁴、X⁵Ring B, ring C, R¹、R²、R³、R^yL, r and n have the meanings as described in the invention.

Synthesis scheme I

In the formula, X represents a leaving group including, but not limited to, a halogen atom, methanesulfonyloxy group, p-methylbenzenesulfonyloxy group, and the like;

compound (f) can be obtained by the synthetic method of synthesis scheme one: the compound (a) and the compound (b) are subjected to nucleophilic reaction to obtain a compound (c), the compound (c) hydrolyzes an ester group to obtain a compound (d), and the compound (d) and the compound (e) are subjected to condensation reaction to obtain a final product.

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Synthesis of intermediate 1: (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol

Prepared using the method disclosed in patent application WO 2017132432.

Synthesis of intermediate 2: (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride

The method comprises the following steps: synthesis of (S) -3- ((tert-butoxycarbonyl) amino) -3- (4-ethylsulfonylphenyl) propionic acid

LiOH (10g,459.10mmol) was dissolved in water (50mL) at room temperature, and a solution of methyl (S) -3- ((tert-butoxycarbonyl) amino) -3- (4-ethylsulfonylphenyl) propionate (18.00g,41.91mmol) in methanol (50mL) was added and reacted at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, concentrated hydrochloric acid (12mol/L) was added to the remaining aqueous phase to adjust pH to 5, and the mixture was extracted with EtOAc (100 mL. times.2), washed with saturated brine (80mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 14g of a white solid, yield: 93 percent.

MS(ESI,pos.ion)m/z:302.1[M-56+H]⁺.

Step two: synthesis of tert-butyl (S) - (3-amino-1- (4- (ethylsulfonyl) phenyl) -3-oxopropyl) carbamate

Ammonium chloride (6.28g,117.41mmol), HATU (20.00g,52.60mmol), and triethylamine (16.3mL,117.27mmol) were added sequentially to a solution of (S) -3- ((tert-butoxycarbonyl) amino) -3- (4-ethylsulfonylphenyl) propionic acid (14g,39.17mmol) in dichloromethane (160mL) and reacted at room temperature for 16 h. After the reaction solution was concentrated under reduced pressure, methanol (100mL) was added and dissolved, insoluble materials were removed by filtration, the filtrate was concentrated under reduced pressure, dichloromethane (300mL) was added and dissolved, washed with dilute hydrochloric acid (0.5mol/L,100 mL. times.2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was slurried with dichloromethane (20mL) overnight and filtered to give 12.5g of a white solid, yield: 89 percent.

MS(ESI,pos.ion)m/z:301.1[M-56+H]⁺.

Step three: synthesis of tert-butyl (S) - (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate

Trifluoroacetic anhydride (33mL,237.4mmol) was slowly added dropwise to a solution of (S) - (3-amino-1- (4- (ethylsulfonyl) phenyl) -3-oxopropyl) carbamic acid tert-butyl ester (48g,134.70mmol) and pyridine (40.00mL,497.00mmol) in THF (600mL) at-10 deg.C under nitrogen (taking about 30min), stirred for 1h after addition, and then transferred to room temperature for further reaction for 12 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate (200mL) to the reaction mixture, concentrated under reduced pressure until a white solid precipitated, filtered and the filter cake was washed with water, the filter cake was dissolved with dichloromethane (100mL) and washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product 43.0g as a white solid, yield: 94 percent. MS (ESI, pos. ion) M/z 361.1[ M + Na ]]⁺.

Step four: synthesis of (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride

Dioxane hydrochloride solution (100mL,4mol/L) was added dropwise to a solution of tert-butyl (S) - (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate (45.00g,133.00mmol) in dichloromethane (300mL) at 0 deg.C, after addition, the reaction was shifted to room temperature overnight, and filtered to give 34.2g of a white solid, yield: 94 percent.

MS(ESI,pos.ion)m/z:239.1[M+H]⁺；

¹H NMR(400MHz,CD₃OD)δ(ppm):8.09(d,J＝8.4Hz,2H),7.87(d,J＝8.3Hz,2H),4.96(t,J＝7.0Hz,1H),3.37(d,J＝6.9Hz,2H),3.29(q,J＝7.4Hz,2H),1.25(t,J＝7.4Hz,3H)。

Synthesis of intermediate 3: (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionic acid methyl ester hydrochloride

To a solution of methyl (S) -3- ((tert-butoxycarbonyl) amino) -3- (4- (ethylsulfonyl) phenyl) propanoate (467mg,1.26mmol) in dichloromethane (6mL,93.61mmol) at room temperature was added dioxane hydrochloride solution (1mL,4M) and reacted at room temperature for 24 hours and concentrated directly to give the product as a white solid 398mg, yield: 99 percent.

MS(ESI,pos.ion)m/z:272.1[M+H]⁺

Example 1

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 3- (2-ethoxy-2-oxoethoxy) -4-nitrobenzoate

To a mixture of methyl 3-hydroxy-4-nitro-benzoate (5.0g,25mmol) and potassium carbonate (7.1g,51mmol) was added acetone (210mL) followed by ethyl 2-bromoacetate (3.2mL,30mmol) and the reaction was stopped after 12h of reflux. Water dilution (60mL), ethyl acetate extraction (50mL × 3), organic phases combined, washed with brine (30mL), dried over anhydrous sodium sulfate, column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) afforded the product 5.8g as a pale yellow solid, yield: 81 percent.

MS(ESI,pos.ion)m/z:284.20[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.78(d,J＝8.4Hz,1H),7.66(dd,J＝8.4,1.1Hz,1H),7.59(s,1H),4.79(s,2H),4.20(q,J＝7.1Hz,2H),3.88(s,3H),1.22(t,J＝7.1Hz,3H).

Step two: synthesis of methyl 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To a mixture of methyl 3- (2-ethoxy-2-oxoethoxy) -4-nitrobenzoate (5.6g,20mmol) and Pd/C (560mg) were added tetrahydrofuran (32mL) and methanol (90mL), and after hydrogen gas had been replaced, the mixture was stirred at room temperature for 24 hours. After filtering with celite, the reaction solution was concentrated to give a crude product as a white solid, then acetic acid (50mL) was added, after heating at 100 ℃ for 1 hour, the acetic acid was concentrated, and the mixture was slurried with petroleum ether and filtered to give 4g of an off-white solid product, yield: 97.8 percent.

MS(ESI,pos.ion)m/z:209.10[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.06(s,1H),7.58(dd,J＝8.2,1.5Hz,1H),6.98(d,J＝8.2Hz,1H),4.64(s,2H),3.81(s,3H).

Step three: synthesis of methyl 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

At 0 ℃, anhydrous tetrahydrofuran (80mL) is added into methyl 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (4.15g,20.0mmol), boron trifluoride diethyl ether (3.3mL,42mmol) is added under the protection of nitrogen, after the addition is finished, the room temperature is recovered, the stirring is carried out for 30 minutes, the temperature is reduced to 0 ℃, sodium borohydride (1.6g,42mmol) is slowly added, after the addition is finished, the room temperature is recovered, and the reaction is continued for 5 hours. Quenching with diluted hydrochloric acid (20mL,1.0M), neutralization to pH 7 with saturated sodium bicarbonate solution, extraction with ethyl acetate (50mL × 3), combination of organic layers, washing with saturated brine (30mL), drying over anhydrous sodium sulfate, silica gel dressing, column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) gave the desired product 3.2g, yield: 83 percent.

MS(ESI,pos.ion)m/z:194.2[M+H]⁺

Step four: synthesis of methyl 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To a mixture of methyl 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (300mg,1.55mmol), 4- (trifluoromethyl) benzyl bromide (570mg,2.34mmol), potassium carbonate (429mg,3.10mmol) was added N, N-dimethylformamide (5mL) and reacted at 100 ℃ for 16H under nitrogen. After dilution with water, extraction with ethyl acetate (20mL × 3), combination of the organic phases and washing with saturated brine (15mL), drying over anhydrous sodium sulfate, concentration and column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) gave 490mg of the product as a pale yellow solid, yield: 89.83 percent.

MS(ESI,pos.ion)m/z:352.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.62(d,J＝8.1Hz,2H),7.47–7.37(m,4H),6.86(d,J＝8.2Hz,1H),4.56(s,2H),4.38–4.30(m,2H),3.84(s,3H),3.41–3.33(m,2H).

¹³C NMR(101MHz,CDCl₃)δ167.11,148.20,141.76,134.90,129.76(q,J＝32.5Hz),127.53,125.72(q,J＝3.8Hz),124.13(q,J＝272.0Hz),123.47,120.63,116.31,113.64,64.83,54.51,51.77,46.75.

Step five: synthesis of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To a solution of methyl 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (490mg,1.40mmol) in methanol (12mL,297mmol) was added a solution of sodium hydroxide (223mg,5.58mmol) in water (3mL) and the reaction was heated at 65 ℃ for 10 hours. Dilute hydrochloric acid (1M) was adjusted to pH 5-6, extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, and concentrated to give 450mg of the product as a pale yellow solid, yield: 95.6 percent.

MS(ESI,pos.ion)m/z:338.1[M+H]⁺

Step six: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (34mg,0.10mmol) in dichloromethane (2mL) were added HATU (58mg,0.15mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (30mg,0.11mmol) and triethylamine (55. mu.L, 0.40mmol) in that order, and the mixture was stirred at room temperature for 16 hours. The reaction was stopped, quenched by addition of saturated ammonium chloride solution (20mL), extracted with dichloromethane (20mL × 3), the organic phases combined and washed with saturated brine (15mL), dried over anhydrous sulfuric acid, stirred on silica gel and column chromatographed (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product 37mg as a white solid, yield: 59.1%, purity: 89.74 percent.

MS(ESI,pos.ion)m/z:558.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.93(d,J＝8.1Hz,1H),7.87(d,J＝8.3Hz,2H),7.69(dd,J＝16.1,8.1Hz,4H),7.54(d,J＝7.9Hz,2H),7.20(d,J＝8.2Hz,1H),7.14(s,1H),6.83(d,J＝8.2Hz,1H),5.43(dd,J＝14.9,8.3Hz,1H),4.63(s,2H),4.30(s,2H),3.44(s,2H),3.27(dd,J＝14.7,7.3Hz,1H),3.14–3.10(m,1H),2.69(s,2H),1.08(t,J＝7.3Hz,3H).

Example 2

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To 3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (150mg,0.77mmol), Pd (OAc)₂To a mixture of (17mg,0.08mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (50mg,0.08mmol) and cesium carbonate (1.3g,4.0mmol) was added toluene (5mL), 4-trifluoromethyliodobenzene (320mg,1.17mmol) under nitrogen protection at 95 ℃ for 12 hours. After the reaction was completed, filtration and column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) were concentrated and mixed to obtain 259mg of the product as a white solid, yield: 98.90 percent.

MS(ESI,pos.ion)m/z:338.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.79(d,J＝1.9Hz,1H),7.61(d,J＝8.5Hz,2H),7.58(dd,J＝8.5,2.0Hz,1H),7.30(d,J＝8.5Hz,2H),6.96(d,J＝8.5Hz,1H),4.39–4.32(m,2H),3.85(s,3H),3.81–3.75(m,2H).

Step two: synthesis of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To a solution of methyl 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (259mg,0.77mmol) in methanol (5mL) was added sodium hydroxide solution (1mL,4M) and the reaction was heated at 65 ℃ for 12 hours. The reaction was stopped, neutralized to pH between 5-6 with dilute hydrochloric acid (1M), extracted with dichloromethane (30mL × 3), the organic phases combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, and concentrated to give the product 230mg as a pale yellow solid, yield: 92.65 percent.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (100mg,0.31mmol) in dichloromethane (5mL) were added HATU (180mg,0.47mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (85mg,0.31mmol) and triethylamine (180. mu.L, 1.29mmol) in that order, and the mixture was stirred at room temperature for 24 hours. The reaction was stopped, quenched by addition of saturated ammonium chloride solution (15mL), extracted with dichloromethane (25mL × 3), the organic phases combined and concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product 110mg as a white solid, yield: 63.41%, purity: 96.92 percent.

MS(ESI,pos.ion)m/z:544.15[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.89(d,J＝8.3Hz,2H),7.64(dd,J＝8.4,3.2Hz,4H),7.42(d,J＝1.7Hz,1H),7.34(d,J＝8.3Hz,2H),7.30–7.26(m,1H),7.00(t,J＝9.6Hz,2H),5.60(dd,J＝13.2,6.3Hz,1H),4.34(s,2H),3.79(s,2H),3.13(d,J＝7.2Hz,4H),1.29(t,J＝7.3Hz,3H).

Example 3

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

The method comprises the following steps: synthesis of methyl 4- (2-ethoxy-2-oxoethoxy) -3-nitrobenzoate

To a mixture of methyl 4-hydroxy-3-nitro-benzoate (5.0g,25mmol) and sodium carbonate (4.0g,37.74mmol) was added acetone (210mL) followed by methyl 2-bromoacetate (4.2g,27mmol) at room temperature and the reaction was refluxed at 60 ℃ for 20 hours. Water dilution, ethyl acetate extraction (20mL × 2), organic phase combination, washing with saturated brine (15mL), drying over anhydrous sodium sulfate, silica gel pad chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) afforded 2.5g of a pale yellow solid, yield: 37 percent.

MS(ESI,pos.ion)m/z:270.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.46(d,J＝2.1Hz,1H),8.14(dd,J＝8.8,2.1Hz,1H),7.01(d,J＝8.8Hz,1H),4.85(s,2H),3.90(s,3H),3.78(s,3H).

Step two: synthesis of methyl 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate

To a mixture of methyl 4- (2-ethoxy-2-oxoethoxy) -3-nitrobenzoate (2.5g,9.3mmol) and Pd/C (250mg) were added tetrahydrofuran (40mL) and methanol (16mL), and after hydrogen substitution, the mixture was stirred at room temperature for 12 hours. TLC detection raw material disappearance, filtration and concentration to obtain a white solid crude product, adding acetic acid (20mL) for dissolution, heating at 115 ℃ for reaction for 1 hour, concentrating the solvent to obtain a brown solid, pulping with petroleum ether, and filtering to obtain a brown powder product 1.6g, yield: 84 percent.

MS(ESI,pos.ion)m/z:208.05[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ10.88(s,1H),7.54(dd,J＝11.2,2.8Hz,2H),7.03(d,J＝8.3Hz,1H),4.68(s,2H),3.82(s,3H).

Step three: synthesis of methyl 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate

To methyl 3-oxo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate (900mg,4.34mmol) was added anhydrous tetrahydrofuran (20mL), then boron trifluoride diethyl ether (720 μ L,9.21mmol) was added under nitrogen protection, after stirring at room temperature for 30 minutes, sodium borohydride (340mg,8.99mmol) was slowly added, the reaction was continued at room temperature overnight, ethyl acetate was diluted (30mL), diluted hydrochloric acid (1.0M) was quenched, and after neutralization to neutrality by addition of a saturated sodium bicarbonate solution, ethyl acetate was extracted (20mL × 2), the organic layers were combined, washed with brine (15mL), dried over anhydrous sodium sulfate, stirred with silica gel, and column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) gave 630mg of the target product, yield: 75.1 percent.

MS(ESI,pos.ion)m/z:194.2[M+H]⁺

Step four: synthesis of methyl 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate

To a mixture of methyl 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate (300mg,1.55mmol), 4- (trifluoromethyl) benzyl bromide (570mg,2.34mmol), potassium carbonate (429mg,3.10mmol) was added N, N-dimethylformamide (5mL) at room temperature under nitrogen protection and reacted at 100 ℃ overnight. After cooling to room temperature, water was added to dilute (35mL), ethyl acetate was extracted (20mL × 2), the organic phases were combined and washed with saturated brine (25mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) gave 490mg of the product as a pale yellow solid, yield: 89.8 percent.

MS(ESI,pos.ion)m/z:352.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.62(d,J＝8.1Hz,2H),7.47–7.37(m,4H),6.86(d,J＝8.2Hz,1H),4.56(s,2H),4.38–4.30(m,2H),3.84(s,3H),3.41–3.33(m,2H).

Step five: synthesis of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid

To a solution of methyl 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate (490mg,1.40mmol) in methanol (12mL) was added sodium hydroxide solution (2M,2mL) and the reaction was heated at 65 ℃ for 5 hours. After the reaction was stopped, it was cooled to room temperature, diluted hydrochloric acid (1M) was adjusted to pH 5-6, dichloromethane was extracted (25mL × 2), dried over anhydrous sodium sulfate, and concentrated to give 450mg of a pale yellow solid product, yield: 95.65 percent.

MS(ESI,pos.ion)m/z:338.1[M+H]⁺

Step six: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

To a solution of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid (34mg,0.10mmol) in dichloromethane (2mL) were added HATU (58mg,0.15254mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (30mg,0.11mmol) and triethylamine (55 μ L,0.40mmol) in this order, the mixture was stirred at room temperature for 24 hours, the reaction was stopped, a saturated ammonium chloride solution (30mL) was added thereto and quenched, dichloromethane-extracted (25mL × 3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sulfuric acid, and silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave 37mg of a white solid product, yield: 59.07%, purity: 89.74 percent.

MS(ESI,pos.ion)m/z:588.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.93(d,J＝8.1Hz,1H),7.87(d,J＝8.3Hz,2H),7.69(dd,J＝16.1,8.1Hz,4H),7.54(d,J＝7.9Hz,2H),7.20(d,J＝8.2Hz,1H),7.14(s,1H),6.83(d,J＝8.2Hz,1H),5.43(dd,J＝14.9,8.3Hz,1H),4.63(s,2H),4.30(s,2H),3.44(s,2H),3.27(dd,J＝14.7,7.3Hz,1H),3.14–3.10(m,1H),2.69(s,2H),1.08(t,J＝7.3Hz,3H).

Example 4

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

The method comprises the following steps: synthesis of methyl 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate

To 3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-6-carboxylic acid methyl ester (390mg,2.01mmol), Pd (OAc)₂To a mixture of (40mg,0.18mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (120mg,0.18mmol) and cesium carbonate (3.1g,9.5mmol) was added toluene (16mL), 1-iodo-4- (trifluoromethyl) benzene (780mg,2.86mmol) under nitrogen protection at 95 ℃ for 12 hours. After the reaction was stopped, it was cooled to room temperature, filtered through celite, and concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product 590mg as a white solid, yield: 86.65 percent.

MS(ESI,pos.ion)m/z:338.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.79(d,J＝1.9Hz,1H),7.61(d,J＝8.5Hz,2H),7.58(dd,J＝8.5,2.0Hz,1H),7.30(d,J＝8.5Hz,2H),6.96(d,J＝8.5Hz,1H),4.39–4.32(m,2H),3.85(s,3H),3.81–3.75(m,2H).

Step two: synthesis of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid

To a solution of methyl 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylate (590mg,1.75mmol) in methanol (15mL) was added sodium hydroxide solution (2mL,2M) and reacted at 65 ℃ for 10 hours. After the reaction was stopped, it was cooled to room temperature, adjusted to pH 5-6 with dilute hydrochloric acid (1M), extracted with dichloromethane (25mL × 3), dried, and concentrated to give 520mg of a pale yellow solid product, yield: 91.95 percent.

MS(ESI,pos.ion)m/z:324.1[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

To a mixture of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid (32mg,0.10mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (30mg,0.11mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (28mg,0.14mmol), 1-hydroxybenzotriazole (20mg,0.14mmol) was added N, N-dimethylformamide (1.5mL), triethylamine (55. mu.L, 0.40mmol) and stirred at room temperature for 24 hours, the reaction was stopped, a saturated ammonium chloride solution (20mL) was added for dilution, dichloromethane was extracted (25 mL. times.3), the organic phases were combined, washed with brine (15mL), concentration by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave the product as a white solid, 16mg, yield: 28.69%, purity: 96.47 percent.

MS(ESI,pos.ion)m/z:544.15[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.2Hz,2H),7.67–7.58(m,4H),7.31(d,J＝8.3Hz,2H),7.26–7.20(m,1H),6.95(d,J＝8.4Hz,1H),6.71(d,J＝7.3Hz,1H),5.53(dd,J＝12.7,6.3Hz,1H),4.45–4.27(m,2H),3.87–3.71(m,2H),3.22–2.95(m,4H),1.31–1.27(m,3H).

¹³C NMR(101MHz,CDCl₃)δ166.65,149.08,148.80,144.37,138.96,131.09,129.14,127.49,126.93(dd,J＝7.5,3.7Hz),125.69,124.63(dd,J＝152.0,119.3Hz),121.81,119.81,117.48,117.43,116.50,64.72,50.59,49.65,47.59,24.04,7.32.

Example 5

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzoyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine

To a mixture of 2-amino-5-bromo-phenol (500mg,2.66mmol) and potassium carbonate (1.85g,13.4mmol) was added N, N-dimethylformamide (8mL), 1, 2-dibromoethane (350 μ L,4.02mmol), and after heating at 125 ℃ for 12 hours, the reaction was stopped and cooled to room temperature, and diluted with saturated ammonium chloride (25mL), extracted with ethyl acetate (20mL × 3), the organic phases were combined and washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) gave 180mg of a brown solid product, yield: 31.6 percent.

MS(ESI,pos.ion)m/z:214.0[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ6.93(d,J＝1.7Hz,1H),6.86(dd,J＝8.4,1.6Hz,1H),6.46(d,J＝8.4Hz,1H),4.27–4.20(m,2H),3.78(s,1H),3.46–3.37(m,2H).

¹³C NMR(101MHz,CDCl₃)δ144.80,132.90,123.97,119.66,116.49,109.66,65.18,40.71.

Step two: synthesis of (7-bromo-2, 3-dihydro-4H-benzo [ b ] [1,4] oxazin-4-yl) (4- (trifluoromethyl) phenyl) methanone

To a solution of 4- (trifluoromethyl) benzoic acid (540mg,2.84mmol) in dichloromethane (10mL) at 0 deg.C was added oxalyl chloride (550. mu.L, 7.10mmol), N, N-dimethylformamide (16. mu.L) in that order, then allowed to return to room temperature, stirred for 1 hour, concentrated to dryness, the solvent and oxalyl chloride were evaporated under reduced pressure, dichloromethane (4mL) was added to dissolve, the temperature was again lowered to 0 deg.C, the reaction was slowly added dropwise to a solution of 7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (300mg,1.40mmol) and diisopropylethylamine (750. mu.L, 4.29mmol) in dichloromethane (10mL), allowed to return to room temperature after addition, and stirred overnight. To the reaction solution was added a saturated ammonium chloride solution (20mL) to dilute, dichloromethane extracted (20mL × 3), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and column-stirred (eluent: PE/EtOAc (v/v) ═ 4/1) to give 290mg of a brown solid product, yield: 53.58 percent.

MS(ESI,pos.ion)m/z:386.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.66(dd,J＝23.1,8.2Hz,4H),7.12(s,1H),6.84(d,J＝6.1Hz,2H),4.46–4.34(m,2H),4.01(s,2H).

Step three: synthesis of 4- (4- (trifluoromethyl) benzoyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

At room temperature, to Pd (OAc)₂(8mg,0.035mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (21mg,0.035mmol) to a mixture was added formic acid (190. mu.L, 5.04mmol), (7-bromo-2, 3-dihydro-4H-benzo [ b ] in this order][1,4]Oxazin-4-yl) (4- (trifluoromethyl) phenyl) methanone (270mg,0.70mmol) in N, N-dimethylformamide (5mL), dicyclohexylcarbodiimide (30mg,0.14mmol) and triethylamine (200. mu.L, 1.43mmol) in N, N-dimethylformamide (5mL) were reacted by heating at 100 ℃ for 36 hours. After the reaction was stopped, it was cooled to room temperature, the solvent was concentrated, diluted with saturated ammonium chloride (20mL), extracted with dichloromethane (20mL × 3), the organic phases were combined, washed with a saturated ammonium chloride solution (15mL), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, and concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 230mg of a pale yellow solid product, yield: 93.65 percent.

MS(ESI,pos.ion)m/z:352.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.89(s,1H),7.96(s,1H),7.85(d,J＝8.3Hz,2H),7.80(d,J＝8.2Hz,2H),7.43(d,J＝1.7Hz,1H),7.35(d,J＝8.1Hz,1H),4.42–4.31(m,2H),3.93–3.83(m,2H).

Step four: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) benzoyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (4- (trifluoromethyl) benzoyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (110mg,0.31mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (95mg,0.34mmol), 1-hydroxybenzotriazole (86mg,0.63mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (122mg,0.63mmol), dichloromethane (8mL,124.8mmol), triethylamine (180 μ L,1.29mmol) was added, the reaction was stopped after stirring at room temperature for 24 hours, dichloromethane was added for dilution (25mL), a saturated ammonium chloride solution was washed (15mL × 2), anhydrous sodium sulfate was dried, and a concentrated pad-mix (eluent: PE/EtOAc (v/v) ═ 1/2) was concentrated to obtain a mesh The standard product 93mg, yield: 51.96%, purity: 96.07 percent.

MS(ESI,pos.ion)m/z:572.10[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.17(d,J＝8.1Hz,1H),7.90(d,J＝8.2Hz,2H),7.86(d,J＝8.2Hz,2H),7.80(d,J＝7.9Hz,2H),7.72(d,J＝8.2Hz,2H),7.51(s,1H),7.30(d,J＝7.1Hz,2H),5.50(dd,J＝15.0,8.2Hz,1H),4.40(s,2H),3.89(s,2H),3.28(t,J＝7.2Hz,2H),3.15(dd,J＝7.4,4.1Hz,2H),1.10(t,J＝7.3Hz,3H).

Example 6

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 7-bromo-4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine

To a solution of 7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (300mg,1.40mmol) in dichloromethane (8mL,124.8mmol) were added successively diisopropylethylamine (750 μ L,4.29mmol), 3- (trifluoromethyl) benzenesulfonyl chloride (350 μ L,2.18mmol) and 4-dimethylaminopyridine (35mg,0.28mmol), and after stirring at room temperature for 18 hours, silica gel pad chromatography was directly added (eluent: PE/EtOAc (v/v) ═ 5/1) to give 530mg of product as a brown oil, yield: 89.57 percent.

¹H NMR(400MHz,CDCl₃)δ7.83–7.70(m,5H),7.10(dd,J＝8.9,2.2Hz,1H),7.02(d,J＝2.2Hz,1H),3.97–3.87(m,2H),3.81–3.70(m,2H).

Step two: synthesis of 4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

At room temperature, to Pd (OAc)₂(6mg,0.026mmol), 4, 5-bis-diphenylphosphine-To a mixture of 9, 9-dimethylxanthene (15mg,0.025mmol) was added successively formic acid (155mg,3.39mmol), 7-bromo-4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] b][1,4]A solution of oxazine (200mg,0.47mmol) in N, N-dimethylformamide (5mL,63.9mmol), dicyclohexylcarbodiimide (20mg,0.10mmol) and triethylamine (96mg,0.95mmol) in N, N-dimethylformamide (3mL) was heated at 100 ℃ for reaction. After 24 hours the reaction was stopped, cooled to room temperature and diluted with saturated ammonium chloride (25mL), extracted with dichloromethane (20mL × 3), the organic phases combined, washed successively with saturated ammonium chloride solution (20mL × 2) and saturated brine (15mL), dried over anhydrous sodium sulphate and concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 166mg of a brown solid, yield: 90.48 percent.

MS(ESI,pos.ion)m/z:388.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),8.13(d,J＝8.4Hz,1H),8.06(d,J＝7.9Hz,1H),8.02(s,1H),7.85(dd,J＝18.4,8.3Hz,2H),7.53(dd,J＝8.6,1.8Hz,1H),7.33(d,J＝1.7Hz,1H),4.12–4.00(m,2H),3.92–3.80(m,2H).

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- ((4- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (110mg,0.28mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (88mg,0.32mmol), 1-hydroxybenzotriazole (80mg,0.58mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (110mg,0.57mmol) was added dichloromethane (8mL,124.8mmol), triethylamine (160. mu.L, 1.15mmol), and after stirring at room temperature for 20 hours, the reaction was stopped, diluted with dichloromethane (25mL), washed with a saturated ammonium chloride solution (20 mL. times.2), dried over anhydrous sodium sulfate, concentration by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave the desired product 83mg, yield: 48.10%, purity: 92.79 percent.

MS(ESI,pos.ion)m/z:608.10[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.89(t,J＝11.1Hz,3H),7.82(d,J＝8.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.65(d,J＝8.2Hz,2H),7.41(d,J＝8.7Hz,1H),7.36(s,1H),7.25(d,J＝7.7Hz,1H),5.60(dd,J＝13.3,6.4Hz,1H),3.93(d,J＝4.3Hz,2H),3.85(d,J＝4.1Hz,2H),3.28–2.89(m,4H),1.27(t,J＝7.4Hz,3H).

¹³C NMR(101MHz,CDCl₃)δ166.17,146.49,144.47,141.81,138.67,135.30,130.97,129.00,127.68,126.99,126.72,123.62,127.40–118.50,119.80,117.34,116.70,63.23,50.60,49.80,44.45,23.87,7.29.

Example 7

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 2- (4- (trifluoromethyl) phenyl) acetaldehyde

Dess-Martin oxidant (1.9g,4.50mmol) was added to a solution of 2- (4- (trifluoromethyl) phenyl) ethanol (570mg,2.99mmol) in dichloromethane (12mL,187.2mmol) at room temperature and stirred at room temperature for 5 hours. The reaction was stopped, washed with saturated sodium bicarbonate solution (15mL × 2), dried over anhydrous sodium sulfate, concentrated, and column chromatographed (eluent: PE/EtOAc (v/v) ═ 3/1) to give the desired product 350mg, yield: 62.06 percent.

¹H NMR(400MHz,CDCl₃)δ9.81(d,J＝1.9Hz,1H),7.65(d,J＝8.0Hz,2H),7.36(d,J＝8.0Hz,2H),3.81(s,2H).

Step two: synthesis of 7-bromo-4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine

To a solution of 7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (200mg,0.93mmol) in methanol (2mL) was added a solution of 2- (4- (trifluoromethyl) phenyl) acetaldehyde (243mg,1.29mmol) in methanol (8mL), sodium cyanoborohydride (90mg,1.43mmol) and acetic acid (0.7mL) in that order at room temperature, and the mixture was stirred at room temperature for 14 hours. The reaction was stopped, quenched by addition of saturated sodium bicarbonate solution (20mL), extracted with ethyl acetate (25mL × 3), the organic phases combined, washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 320mg of a brown oil, yield: 88.68 percent.

MS(ESI,pos.ion)m/z:386.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝8.0Hz,2H),7.35(d,J＝8.0Hz,2H),7.01–6.94(m,2H),6.56(d,J＝8.3Hz,1H),4.21–4.07(m,2H),3.52(t,J＝7.4Hz,2H),3.28–3.19(m,2H),2.95(t,J＝7.4Hz,2H).

Step three: synthesis of 4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

Under the protection of nitrogen at room temperature to Pd (OAc)₂(10mg,0.04mmol) and 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene (24mg,0.04mmol) were added to a mixture of anhydrous formic acid (268mg,5.82mmol) and 7-bromo-4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] b][1,4]A solution of oxazine (320mg,0.83mmol) in N, N-dimethylformamide (8mL,102mmol), dicyclohexylcarbodiimide (34mg,0.16mmol) and triethylamine (240. mu.L, 1.72mmol) in N, N-dimethylformamide (3mL) was heated at 100 ℃ for reaction for 18 hours. The reaction was stopped, cooled to room temperature, the solvent was concentrated, diluted with saturated ammonium chloride (30mL), extracted with dichloromethane (25mL × 3), the organic phases were combined, washed with saturated ammonium chloride solution (15mL), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated, and column-chromatographed with a blender (eluent: PE/EtOAc (v/v) ═ 1/2) to give 110mg of a pale yellow solid, yield: 37.79 percent.

MS(ESI,pos.ion)m/z:352.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.16(s,1H),7.67(d,J＝7.9Hz,2H),7.54(d,J＝8.0Hz,2H),7.41(d,J＝7.1Hz,1H),7.18(d,J＝1.5Hz,1H),6.81(d,J＝8.5Hz,1H),4.20–4.04(m,2H),3.62(t,J＝7.3Hz,2H),3.40(s,2H),2.95(t,J＝7.4Hz,2H).

Step four: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (4- (trifluoromethyl) phenethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (110mg,0.31mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (95mg,0.34mmol), 1-hydroxybenzotriazole (86mg,0.63mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (122mg,0.63mmol) was added dichloromethane (8mL), triethylamine (180. mu.L, 1.29mmol), and the mixture was stirred at room temperature for 24 hours. The reaction was stopped, washed with saturated ammonium chloride solution (15mL × 2), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated, and column-chromatographed with a stirring column (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product as a white solid, 75mg, yield: 40.13%, purity: 95.77 percent.

MS(ESI,pos.ion)m/z:572.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.2Hz,2H),7.65(d,J＝8.2Hz,2H),7.58(d,J＝7.9Hz,2H),7.41(dd,J＝8.4,1.6Hz,1H),7.33(d,J＝7.9Hz,2H),7.29(d,J＝2.3Hz,1H),6.87(d,J＝7.7Hz,1H),6.67(d,J＝8.5Hz,1H),5.60(dd,J＝13.0,6.2Hz,1H),4.20–4.04(m,2H),3.60(t,J＝7.2Hz,2H),3.33–3.21(m,2H),3.20–3.03(m,4H),2.98(t,J＝7.1Hz,2H),1.29(t,J＝7.4Hz,3H).

Example 8

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To 3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (250mg,1.29mmol), Pd (OAc)₂(29mg,0.13mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (83mg,0.13mmol), cesium carbonate (2.1g,6.4mmol) were added to a mixture of toluene (10mL), 2-bromo-4-cyclopropyl-benzonitrile (300mg,1.35mmol), nitrogen protected, reacted at 95 ℃ for 14 hours, the reaction was stopped, cooled to room temperature, a saturated ammonium chloride solution (25mL) was added, ethyl acetate was extracted (25 mL. times.3), dried over anhydrous sodium sulfate,silica gel column chromatography gave 258mg of product as a yellow oil, yield: and 59.62 percent.

MS(ESI,pos.ion)m/z:335.1[M+H]⁺

¹H NMR(600MHz,CDCl₃)δ7.62(d,J＝8.1Hz,1H),7.60(d,J＝1.8Hz,1H),7.47(dd,J＝8.5,1.8Hz,1H),7.10(d,J＝1.1Hz,1H),6.99(dd,J＝8.1,1.4Hz,1H),6.57(d,J＝8.5Hz,1H),4.41–4.35(m,2H),3.89(s,3H),3.86–3.79(m,2H),1.92(ddd,J＝13.3,8.5,5.0Hz,1H),1.16–1.09(m,2H),0.80–0.73(m,2H).

Step two: synthesis of 4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To a solution of methyl 4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (258mg,0.77mmol) in methanol (2mL) and tetrahydrofuran (2mL) was added sodium hydroxide solution (1.5mL,2M), and after 24 hours at room temperature, the reaction was stopped, pH was adjusted to 6-7 with dilute hydrochloric acid (1M), dichloromethane was extracted (25mL × 3), dried over anhydrous sodium sulfate, and concentrated to give 238mg of a yellow solid product, yield: 96.31 percent.

MS(ESI,pos.ion)m/z:321.2[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (2-cyano-5-cyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (70mg,0.22mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (67mg,0.24mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (85mg,0.44mmol) and 1-hydroxybenzotriazole (60mg,0.44mmol) was added dichloromethane (5mL,78.01mmol), triethylamine (95 μ L,0.68mmol), and after 30 hours at room temperature, the reaction was stopped, diluted with dichloromethane (25mL), washed with saturated ammonium chloride (20mL), dried over anhydrous sodium sulfate, and concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave white solid Product 57mg as a colored solid, yield: 46.95%, purity: 97.31 percent.

MS(ESI,pos.ion)m/z:541.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝8.0Hz,2H),7.63(d,J＝8.2Hz,2H),7.59(d,J＝8.1Hz,1H),7.50–7.39(m,2H),7.27(d,J＝7.8Hz,1H),7.07(s,1H),6.97(d,J＝8.0Hz,1H),6.52(d,J＝8.5Hz,1H),5.56(dd,J＝13.9,6.7Hz,1H),4.32(s,2H),3.77(d,J＝3.3Hz,2H),3.19–3.07(m,2H),3.07–2.97(m,2H),1.90(ddd,J＝13.2,8.5,5.0Hz,1H),1.25(t,J＝7.4Hz,3H),1.10(d,J＝7.7Hz,2H),0.75(d,J＝4.7Hz,2H).

¹³C NMR(101MHz,CDCl₃)δ166.79,152.70,148.85,145.10,144.05,138.39,135.88,134.32,128.89,127.71,124.83,124.44,123.36,121.04,117.42,116.93,116.47,115.38,106.99,64.29,50.58,49.88,49.18,24.00,15.98,10.93,7.33.

Example 9

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 2, 6-dicyclopropylpyridin-4-ol

To 2, 6-dibromo-4-bromopyridine (1.0g,4.0mmol), cyclopropylboronic acid (710mg,8.27mmol), potassium phosphate (5.9g,28mmol), Pd (OAc)₂After a reaction of a mixture of (92mg,0.40mmol) and tris (cyclohexyl) phosphine (220mg,0.78mmol) in toluene (20mL) and water (2.5mL) at 110 ℃ under reflux for 12 hours, a saturated ammonium chloride solution (30mL) was added for dilution, ethyl acetate was extracted (15mL × 3), the organic phases were combined and washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) gave 320mg of the product as a pale yellow oil, yield: 46 percent.

MS(ESI,pos.ion)m/z:176.3[M+H]⁺

Step two: synthesis of 2, 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate

To a solution of 2, 6-dicyclopropylpyridin-4-ol (320mg,1.82mmol) in dichloromethane (8mL) at 0 ℃ was added triethylamine (390 μ L,2.80mmol), followed by dropwise addition of trifluoromethanesulfonic anhydride (470 μ L,2.74mmol), reacted at room temperature overnight, then the reaction was stopped, diluted with saturated ammonium chloride solution (25mL), extracted with ethyl acetate (25mL × 3), the organic phase was combined and washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) gave 318mg of the product as a pale yellow oil, yield: 56.67 percent.

MS(ESI,pos.ion)m/z:308.2[M+H]⁺

Step three: synthesis of methyl 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To 3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (100mg,0.52mmol), Pd (OAc)₂To a mixture of (12mg,0.05mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (34mg,0.05mmol) and cesium carbonate (850mg,2.61mmol) was added toluene (6mL), 2, 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (160mg,0.67mmol), under nitrogen, and reacted at 100 ℃ for 12 hours. After cooling to room temperature, it was quenched by addition of saturated ammonium chloride solution (25mL), extracted with ethyl acetate (25mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 23.5mg of the product as a brown oil, yield: 68.4 percent.

MS(ESI,pos.ion)m/z:352.2[M+H]⁺

Step four: synthesis of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To methyl 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (93mg,0.26mmol) were added methanol (2mL) and tetrahydrofuran (2mL) to dissolve, followed by addition of aqueous sodium hydroxide (1mL,4M), heating at 50 ℃ for 7 hours, stopping the reaction, cooling to room temperature, adjusting pH to 6-7 with dilute hydrochloric acid (1M), extraction with dichloromethane (25mL × 3), drying over anhydrous sodium sulfate, and concentration to give 85mg of a yellow solid, yield: 95.20 percent.

MS(ESI,pos.ion)m/z:337.2[M+H]⁺

Step five: (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (85mg,0.25mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (77mg,0.28mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100mg,0.51mmol) and 1-hydroxybenzotriazole (70mg,0.51mmol) was added dichloromethane (5mL), triethylamine (110. mu.L, 0.79mmol), reacted at room temperature for 18 hours, the reaction was stopped, diluted with dichloromethane (25mL), washed with saturated ammonium chloride (15 mL. times.2), dried over anhydrous sodium sulfate, concentrated, column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the product 25mg as a white solid, yield: 17.35%, purity: 97.63 percent.

MS(ESI,pos.ion)m/z:557.15[M+H]⁺

¹H NMR(400MHz,MeOD)δ7.88(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),7.40(d,J＝1.9Hz,1H),7.31–7.29(m,1H),7.16(d,J＝8.6Hz,1H),6.63(s,2H),5.54(t,J＝6.7Hz,1H),4.29–4.20(m,2H),3.77–3.69(m,2H),3.14–2.96(m,4H),1.92–1.77(m,2H),1.25(d,J＝7.4Hz,4H),0.88(t,J＝6.7Hz,7H).

Example 10

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 1-chloro-3, 5-dicyclopropylbenzene

To 1, 3-bromo-5-chlorobenzene (270mg,1.0mmol), cyclopropylboronic acid (180mg,2.1mmol), potassium phosphate (1.5g,7.1mmol), Pd (OAc)₂Adding toluene (10mL) and water (0.5mL) into a mixture of (23mg,0.10mmol) and tri (cyclohexyl) phosphine (56mg,0.20mmol), reacting for 5 hours at 100 ℃ under the protection of nitrogen, stopping the reaction, cooling to room temperature, adding a saturated ammonium chloride solution to quench (20mL), extracting with ethyl acetate (15mL multiplied by 3), combining organic phases, washing with saturated brine (15mL), drying with anhydrous sodium sulfate, concentrating, sample-mixing and column-chromatography (eluent: PE/EtOAc (v/v) ═ 1/0) to obtain 180mg of a colorless oily product, and obtaining the productRate: 93.54 percent.

¹H NMR(400MHz,CDCl₃)δ6.84(s,2H),6.74(d,J＝1.1Hz,1H),1.93–1.79(m,2H),1.06–0.92(m,4H),0.72(dd,J＝7.0,4.2Hz,4H).

Step two: synthesis of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To 3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (100mg,0.52mmol), 1-chloro-3, 5-dipropylbenzene (100mg,0.52mmol), sodium tert-butoxide (150mg,1.56mmol), Pd₂(dba)₃Xylene (8mL) was added to a mixture of (48mg,0.05mmol) and tri (tert-butyl) phosphine (10mg,0.05mmol), reacted at 155 ℃ for 30 hours, stopped, cooled to room temperature and quenched by addition of saturated ammonium chloride solution (25mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give 150mg of the product as a pale yellow solid, yield: 86.40 percent.

MS(ESI,pos.ion)m/z:336.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.61(d,J＝1.8Hz,1H),7.50(dd,J＝8.6,1.8Hz,1H),6.76(s,2H),6.74(s,1H),6.68(s,1H),4.42–4.28(m,2H),3.85–3.68(m,2H),1.88(ddd,J＝13.5,8.5,5.1Hz,2H),1.08–0.93(m,4H),0.70(q,J＝4.9Hz,4H).

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (85mg,0.25mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (77mg,0.28mmol), 1-hydroxybenzotriazole (70mg,0.51mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100mg,0.51mmol) was added dichloromethane (8mL), triethylamine (145 μ L,1.04mmol), and after stirring at room temperature for 24 hours, the reaction was stopped, diluted with dichloromethane (15mL), washed with a saturated ammonium chloride solution (15mL × 2), dried over anhydrous sodium sulfate, and concentrated column chromatography to give (eluent: PE/EtOAc (v/v) ═ 1/2) as a white solid product 102mg Yield, yield: 66.98%, purity: 92.48 percent.

MS(ESI,pos.ion)m/z:556.20[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.1Hz,2H),7.65(d,J＝8.1Hz,2H),7.36(s,1H),7.23(d,J＝8.6Hz,1H),6.84(d,J＝7.6Hz,1H),6.78(d,J＝8.5Hz,1H),6.73(s,2H),6.65(s,1H),5.59(dd,J＝12.9,6.3Hz,1H),4.50–4.23(m,2H),3.73(d,J＝3.8Hz,2H),3.23–3.02(m,4H),1.93–1.80(m,2H),1.38–1.24(m,4H),0.97(q,J＝5.2Hz,4H),0.69(q,J＝5.0Hz,3H).

Example 11

(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (76mg,0.22mmol) in dichloromethane (4mL) were added HATU (130mg,0.34mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (60mg,0.26mmol) and triethylamine (130. mu.L, 0.93mmol) in that order, and the mixture was stirred at room temperature for 22 hours, the reaction was stopped, diluted with saturated ammonium chloride (25mL), extracted with dichloromethane (15mL × 3), the organic phases combined and washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the product 80mg as a white solid, yield: 62.24%, purity: 96.17 percent.

MS(ESI,pos.ion)m/z:549.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.83(d,J＝8.1Hz,2H),7.61(d,J＝7.9Hz,2H),7.54(d,J＝8.1Hz,2H),7.38(d,J＝7.8Hz,2H),7.34(s,1H),7.31(d,J＝10.3Hz,1H),7.06(d,J＝6.7Hz,1H),6.56(d,J＝8.4Hz,1H),5.24(s,1H),4.60(s,2H),4.30(s,2H),4.05–3.88(m,2H),3.73(dd,J＝14.0,7.0Hz,2H),3.09(dd,J＝14.7,7.3Hz,2H),1.27–1.23(m,3H).

Example 12

(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

To a solution of 4- (4- (trifluoromethyl) benzyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid (34mg,0.10mmol) in dichloromethane (2mL) were added HATU (58mg,0.15mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (30mg,0.13mmol) and triethylamine (55. mu.L, 0.40mmol) in that order, and the mixture was stirred at room temperature for 23 hours. The reaction was stopped, quenched by addition of saturated ammonium chloride solution (15mL), extracted with dichloromethane (15mL × 3), the organic phases combined, washed with saturated brine (15mL), dried over anhydrous sulfuric acid, and column chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product 35mg as a white solid, yield: 57.35%, purity: 90.61 percent.

MS(ESI,pos.ion)m/z:549.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.50(d,J＝7.5Hz,1H),7.81(d,J＝8.0Hz,2H),7.71(d,J＝7.9Hz,2H),7.60(d,J＝8.0Hz,2H),7.54(d,J＝7.7Hz,2H),7.22(d,J＝8.1Hz,1H),7.17(s,1H),6.80(d,J＝8.2Hz,1H),5.07(d,J＝6.4Hz,1H),5.01(s,1H),4.64(s,2H),4.29(s,2H),3.80–3.60(m,2H),3.42(s,2H),3.25(dd,J＝14.4,7.1Hz,2H),1.09(t,J＝7.2Hz,3H).

Example 13

(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (trifluoromethyl) phenyl) -dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (120mg,0.37mmol) in dichloromethane (5mL) were added HATU (215mg,0.56mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (105mg,0.45mmol) and triethylamine (210. mu.L, 1.51mmol) in that order, and the mixture was stirred at room temperature for 24 hours. The reaction was stopped, quenched by addition of saturated ammonium chloride solution (15mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product as a white solid 150mg, yield: 70.41%, purity: 93.14 percent.

MS(ESI,pos.ion)m/z:535.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.87(d,J＝8.3Hz,2H),7.64(d,J＝8.5Hz,2H),7.58(d,J＝8.2Hz,2H),7.43(d,J＝1.8Hz,1H),7.35(d,J＝8.4Hz,2H),7.30(d,J＝1.9Hz,1H),7.09(d,J＝6.9Hz,1H),7.04(d,J＝8.5Hz,1H),5.34–5.21(m,1H),4.40–4.28(m,2H),4.05(dd,J＝11.3,3.5Hz,1H),3.97(dd,J＝11.1,4.8Hz,1H),3.84–3.76(m,2H),3.11(q,J＝7.4Hz,2H),1.29(t,J＝7.4Hz,3H).

Example 14

(R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -4- (4- (trifluoromethyl) phenyl) -dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxamide

To a solution of 4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-6-carboxylic acid (90mg,0.28mmol) in dichloromethane (5mL) were added HATU (158mg,0.41mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (80mg,0.35mmol) and triethylamine (120 μ L,0.86mmol) in this order, and after stirring at room temperature for 24 hours, the reaction was stopped, a saturated ammonium chloride solution (15mL) was added and quenched, dichloromethane-extracted (15mL × 3), the organic phases were combined, washed with saturated brine (15mL), dried over anhydrous sulfuric acid, silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 91mg of a white solid product, yield: 56.96%, purity: 93.15 percent.

MS(ESI,pos.ion)m/z:535.10[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ8.63(d,J＝7.1Hz,1H),7.82(d,J＝7.5Hz,2H),7.68(d,J＝8.8Hz,3H),7.61(d,J＝7.5Hz,2H),7.54(d,J＝7.7Hz,1H),7.40(d,J＝7.7Hz,2H),6.99(d,J＝8.1Hz,1H),5.08(d,J＝5.6Hz,1H),5.02(s,1H),4.32(d,J＝26.1Hz,2H),3.81(s,2H),3.68(s,2H),3.25(d,J＝7.0Hz,2H),1.15–1.06(m,3H).

Example 15

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To a solution of 2- (4- (trifluoromethyl) phenyl) acetic acid (260mg,1.27mmol) in dichloromethane (8mL) was added HATU (590mg,1.55mmol), methyl 3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (200mg,1.03mmol) and triethylamine (580. mu.L, 4.17mmol) in that order at room temperature, and the mixture was stirred at room temperature for 6 hours. Quenching with saturated ammonium chloride (30mL), extraction with ethyl acetate (30mL × 3), combination of organic phases, washing with saturated brine (20mL), drying over anhydrous sodium sulfate, concentration and column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) afforded the product 368mg as a white solid, yield: 93.72 percent.

MS(ESI,pos.ion)m/z:408.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.59(d,J＝6.9Hz,4H),7.37(d,J＝7.9Hz,2H),4.33–4.20(m,2H),4.02(s,2H),3.96(s,2H),3.91(s,3H).

Step two: synthesis of 4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To a solution of methyl 4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (38mg,0.10mmol) in tetrahydrofuran (2mL) was added lithium hydroxide monohydrate (9mg,0.21mmol) and water (0.2mL) in this order at room temperature, and the mixture was stirred at room temperature for 12 hours. TLC detected the starting material reacted completely, diluted with water, neutralized to pH 5-6 with dilute hydrochloric acid (1M), extracted with dichloromethane (15mL × 3), concentrated, sample-stirred and column chromatographed to give the desired product (eluent: PE/EtOAc (v/v) ═ 1/2) as a yellow-green solid 10mg, yield: 27.32 percent.

MS(ESI,pos.ion)m/z:366.1[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- (2- (4- (trifluoromethyl) phenyl) acetyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (30mg,0.08mmol) in dichloromethane (3mL) was added HATU (50mg,0.13mmol) and (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (28mg,0.10mmol) in this order at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction was stopped, quenched with saturated ammonium chloride (30mL), extracted with dichloromethane (25mL × 3), the organic phases combined and washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product 11mg as a pale yellow solid, yield: 22.87%, purity: 94.75 percent.

MS(ESI,pos.ion)m/z:587.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.90(d,J＝8.1Hz,2H),7.63(dd,J＝14.6,8.1Hz,4H),7.38(dd,J＝15.9,7.6Hz,4H),7.23(d,J＝7.1Hz,1H),5.59(dd,J＝12.9,6.3Hz,1H),4.26(s,2H),4.01(s,2H),3.94(s,2H),3.67(d,J＝5.5Hz,1H),3.17–3.04(m,4H),1.31(s,3H).

Example 16

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of 7-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine

To a solution of 7-bromo-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine (300mg,1.40mmol) in dichloromethane (8mL) was added N, N-diisopropylethylamine (750. mu.L, 4.29mmol), 3- (trifluoromethyl) benzenesulfonyl chloride (350. mu.L, 2.18mmol) and 4-dimethylaminopyridine (35mg,0.28mmol) in that order, and the mixture was stirred at room temperature overnight. Column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) by direct addition of silica gel to afford 530mg of product as a brown oil, yield: 89.57 percent.

¹H NMR(400MHz,CDCl₃)δ7.97(s,1H),7.87(d,J＝7.9Hz,1H),7.79(d,J＝7.9Hz,1H),7.72(d,J＝8.9Hz,1H),7.65(t,J＝7.9Hz,1H),7.10(dd,J＝8.9,2.2Hz,1H),7.00(d,J＝2.2Hz,1H),3.96–3.87(m,2H),3.82–3.68(m,2H).

Step two: synthesis of 4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

At room temperature, to Pd (OAc)₂(6mg,0.026mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (15mg,0.03mmol) to a mixture was added anhydrous formic acid (155mg,3.37mmol), 7-bromo-4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] b][1,4]A solution of oxazine (200mg,0.47mmol) in N, N-dimethylformamide (5mL), dicyclohexylcarbodiimide (20mg,0.10mmol) and triethylamine (96mg,0.95mmol) in N, N-dimethylformamide (5mL) was heated at 100 ℃ for 16 hours. The reaction was stopped, diluted with saturated ammonium chloride (20mL), extracted with dichloromethane (30mL × 3), the organic phases combined, washed with saturated ammonium chloride solution (20mL), washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated pad-batch column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 166mg of a brown solid, yield: 90.48 percent.

MS(ESI,pos.ion)m/z:388.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ12.95(s,1H),8.13(d,J＝8.4Hz,1H),8.06(d,J＝7.9Hz,1H),8.02(s,1H),7.85(dd,J＝18.4,8.3Hz,2H),7.53(dd,J＝8.6,1.8Hz,1H),7.33(d,J＝1.7Hz,1H),4.12–4.00(m,2H),3.92–3.80(m,2H).

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a solution of 4- ((3- (trifluoromethyl) phenyl) sulfonyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (20mg,0.05mmol) in dichloromethane (4mL) were added HATU (30mg,0.08mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (16mg,0.06mmol) and triethylamine (39 μ L,0.28mmol) in that order, and the mixture was stirred at room temperature overnight. The reaction was stopped, diluted with saturated ammonium chloride (20mL), extracted with dichloromethane (30mL × 2), the organic phases combined and washed with saturated brine (20mL), dried over anhydrous sodium sulfate, concentrated, and column-chromatographed with celite (eluent: PE/EtOAc (v/v) ═ 1/2) to give 20mg of a white solid, yield: 61.30%, purity: 96.17 percent.

MS(ESI,pos.ion)m/z:608.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.98(s,1H),7.83(dd,J＝17.3,8.4Hz,5H),7.72–7.58(m,4H),7.41(d,J＝8.6Hz,1H),7.36(s,1H),5.59(dd,J＝13.7,6.6Hz,1H),3.97–3.77(m,4H),3.10(q,J＝7.3Hz,4H),1.26(t,J＝7.3Hz,3H).

Example 17

N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 3- ((3-methyl-2-buten-1-yl) oxy) -4-nitrobenzoate

To a mixture of methyl 3-hydroxy-4-nitro-benzoate (1g,5.07mmol) and potassium carbonate (1.4g,10mmol) was added acetone (40mL,540mmol) followed by 1-bromo-3-methyl-2-butene (700. mu.L, 6.06mmol), and the reaction was refluxed for 7 hours, stopping the reaction. After cooling to room temperature, dilution with water (35mL), extraction with ethyl acetate (30 mL. times.3), combination of the organic phases, washing with saturated brine (25mL), drying over anhydrous sodium sulfate, concentration to give a yellow solid, beating with petroleum ether and filtration to give the product as a pale yellow solid, 1.12g, yield: 83.2 percent.

MS(ESI,pos.ion)m/z:266.0[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.81(d,J＝8.3Hz,1H),7.76(s,1H),7.67(d,J＝8.3Hz,1H),5.48(t,J＝6.6Hz,1H),4.74(d,J＝6.7Hz,2H),3.98(s,3H),1.80(d,J＝5.1Hz,6H).

Step two: synthesis of methyl 3- (prop-2-ylidene) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

Triethyl phosphite (1.78mL,10.2mmol) was added to methyl 3- ((3-methyl-2-buten-1-yl) oxy) -4-nitrobenzoate (450mg,1.70mmol), and the reaction was stopped after 6 hours at 160 ℃ with tube closure. After cooling to room temperature, water was added for dilution (25mL), extracted with ethyl acetate (20 mL. times.3), the organic phases were combined, washed with saturated brine (15mL), dried over anhydrous sodium sulfate, and concentrated to give a brown solid 230mg, yield: 58.12 percent.

MS(ESI,pos.ion)m/z:234.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.53(dd,J＝8.3,1.5Hz,1H),7.50(s,1H),6.61(d,J＝8.2Hz,1H),5.07(d,J＝19.1Hz,2H),4.28(d,J＝11.7Hz,2H),3.94(dt,J＝9.8,8.0Hz,2H),3.87(s,3H),1.84(s,3H).

Step three: synthesis of methyl 3-isopropyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To methyl 3- (prop-2-ylidene) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (150mg,0.64mmol), Pd/C (19mg) was added methanol (6mL) and the reaction was stopped after 24 hours at room temperature under a hydrogen atmosphere, filtered through celite and concentrated to give 150mg of a colorless oily product, yield: 99.15 percent.

MS(ESI,pos.ion)m/z:236.1[M+H]⁺

Step four: synthesis of methyl 3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To 3-isopropyl-3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (90mg,0.38mmol), Pd (OAc)₂To a mixture of (9mg,0.04mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (25mg,0.04mmol), cesium carbonate (625mg,1.92mmol), 4- (trifluoromethyl) iodobenzene (136mg,0.50mmol) was added toluene (6mL), nitrogen protected, reacted at 100 ℃ for 24 hours, cooled to room temperature and quenched with saturated ammonium chloride solution (20mL), extracted with ethyl acetate (30mL × 3), the organic phases combined, dried over anhydrous sodium sulfate, concentrated column chromatography (eluent: PE/v) ═ 4/1) to give 40mg of a brown oily product, yield: 27.56 percent.

MS(ESI,pos.ion)m/z:380.2[M+H]⁺

Step five: synthesis of 3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To methyl 3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (43mg,0.11mmol) was added methanol (1mL), tetrahydrofuran (1mL) and sodium hydroxide solution (1mL, 2M), reacted at 50 ℃ for 4 hours, cooled to room temperature, adjusted to pH 5-6 with dilute hydrochloric acid (1M), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, and concentrated to give 38mg of crude product, yield: 91.76 percent.

MS(ESI,pos.ion)m/z:366.1[M+H]⁺

Step six: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (38mg,0.10mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (32mg,0.12mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (41mg,0.21mmol) and 1-hydroxybenzotriazole (29mg,0.21mmol) was added dichloromethane (4mL,62.40mmol), triethylamine (45. mu.L, 0.32mmol), reacted at room temperature for 24 hours, the reaction was stopped, diluted with dichloromethane (20mL), washed with saturated ammonium chloride solution (15mL), washed with saturated brine (15mL), dried over anhydrous sodium sulfate, concentrated, sample-mixed column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the title product, 25mg, in light yellow color, yield: 39.15%, purity: 95.38 percent.

MS(ESI,pos.ion)m/z:586.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.90(d,J＝8.2Hz,2H),7.66(d,J＝8.2Hz,2H),7.56(d,J＝8.5Hz,2H),7.45(s,1H),7.33(d,J＝8.5Hz,1H),7.27(d,J＝6.7Hz,2H),7.10(d,J＝8.5Hz,1H),6.97(d,J＝7.1Hz,1H),5.62(dd,J＝13.2,6.3Hz,1H),4.48(d,J＝11.0Hz,1H),3.97(dd,J＝11.0,2.0Hz,1H),3.43(d,J＝9.7Hz,1H),3.24–3.02(m,4H),1.91(td,J＝13.6,6.8Hz,1H),1.31–1.27(m,3H),1.15(d,J＝6.8Hz,3H),1.08(d,J＝6.6Hz,3H).

Example 18

N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -3-isopropyl-4- (3- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

The method comprises the following steps: synthesis of methyl 3-isopropyl-4- (3- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate

To 3-isopropyl-3, 4-dihydro-2H-benzo [ b ]][1,4]Oxazine-7-carboxylic acid methyl ester (90mg,0.38mmol), Pd (OAc)₂To a mixture of (9mg,0.04mmol), (R) - (+) -1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine (25mg,0.04mmol), cesium carbonate (625mg,1.91mmol), 3- (trifluoromethyl) iodobenzene (136mg,0.50mmol) was added toluene (6mL), nitrogen protected, reacted at 100 ℃ for 22 hours, cooled to room temperature and quenched with saturated ammonium chloride solution (20mL), extracted with ethyl acetate (30mL × 3), the organic phases combined, dried over anhydrous sodium sulfate, concentrated column chromatography (eluent: PE/v) ═ 4/1) to give 31mg of a brown oily product, yield: 21.36 percent.

MS(ESI,pos.ion)m/z:380.2[M+H]⁺

Step two: synthesis of 3-isopropyl-4- (3- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

To methyl 3-isopropyl-4- (3- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylate (38mg,0.10mmol) was added methanol (1mL), tetrahydrofuran (1mL) and sodium hydroxide solution (1mL), reacted at 50 ℃ for 4 hours, cooled to room temperature, adjusted to pH 5-6 with dilute hydrochloric acid (1M), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, and concentrated to give 31mg of crude product, yield: 84.70 percent.

MS(ESI,pos.ion)m/z:366.3[M+H]⁺

Step three: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -3-isopropyl-4- (4- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 3-isopropyl-4- (3- (trifluoromethyl) phenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (38mg,0.10mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (32mg,0.11mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (41mg,0.21mmol) and 1-hydroxybenzotriazole (29mg,0.21mmol) was added dichloromethane (4mL), triethylamine (45. mu.L, 0.32mmol), and after reaction at room temperature for 24, the reaction was stopped, diluted with dichloromethane (20mL), washed with a saturated ammonium chloride solution (15mL), washed with a saturated saline solution (15mL), dried over anhydrous sodium sulfate, concentrated, stirred-layer column chromatographed (eluent: PE/EtOAc (v/v) ═ 1/2) to give the product 16mg as a pale yellow solid, yield: 23.39%, purity: 89.03 percent.

MS(ESI,pos.ion)m/z:586.2[M+H]⁺。

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.3Hz,2H),7.67(d,J＝8.2Hz,2H),7.45(dd,J＝8.0,6.3Hz,3H),7.34(dd,J＝16.6,9.6Hz,2H),7.09–6.91(m,2H),5.62(dd,J＝12.9,6.1Hz,1H),4.75(s,1H),4.47(d,J＝11.0Hz,1H),3.98(dd,J＝11.0,2.0Hz,1H),3.39(d,J＝9.2Hz,1H),3.23–3.04(m,4H),1.92(dd,J＝14.9,7.0Hz,1H),1.29(s,3H),1.15(d,J＝6.8Hz,3H),1.07(d,J＝6.6Hz,3H).

Example 19

(R) -4- (3, 5-Dicyclopropylphenyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamide

To a mixture of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (60mg,0.18mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (53mg,0.23mmol), 1-hydroxybenzotriazole (50mg,0.36mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (70mg,0.36mmol) was added dichloromethane (8mL), triethylamine (100 μ L,0.72mmol), and after stirring at room temperature for 36 hours, the reaction was stopped, dichloromethane was diluted (25mL), washed with a saturated ammonium chloride solution (15mL), dried over anhydrous sodium sulfate, concentrated and stirred, column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave 64mg of a white solid product, yield: 61.52%, purity: 94.01 percent.

MS(ESI,pos.ion)m/z:547.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.88(d,J＝7.8Hz,2H),7.58(d,J＝8.1Hz,2H),7.37(d,J＝1.6Hz,1H),7.24(d,J＝8.5Hz,1H),6.97(t,J＝6.3Hz,1H),6.81(d,J＝8.5Hz,1H),6.74(s,2H),6.64(s,1H),5.28(s,1H),4.33(d,J＝3.9Hz,2H),4.09–3.90(m,2H),3.74(d,J＝4.0Hz,2H),3.11(q,J＝7.4Hz,2H),1.87(ddd,J＝13.4,8.5,5.1Hz,2H),1.31–1.27(m,3H),1.03–0.92(m,4H),0.75–0.63(m,4H).

Example 20

(R) -4- (2, 6-Dicyclopropylpyridin-4-yl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -3, 4-dihydro-2H-benzo [ b][1,4]Oxazine-7-carboxamides

To a mixture of 4- (2, 6-dicyclopropyl-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (60mg,0.18mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (45mg,0.20mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (70mg,0.36mmol) and 1-hydroxybenzotriazole (50mg,0.37mmol) was added dichloromethane (5mL,78.01mmol), triethylamine (75. mu.L, 0.538mmol), reacted at room temperature for 36 hours, then the reaction was stopped, diluted with dichloromethane (25mL), washed with a saturated ammonium chloride solution (15mL), dried over anhydrous sodium sulfate, concentrated and stirred, column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the product 52mg as a white solid, yield: 52.30 percent.

MS(ESI,pos.ion)m/z:548.3[M+H]⁺

¹H NMR(600MHz,CDCl₃)δ7.77(t,J＝7.0Hz,3H),7.55(d,J＝7.7Hz,2H),7.48(s,1H),7.39(d,J＝8.5Hz,1H),7.17(t,J＝8.4Hz,1H),6.65(s,2H),5.21(d,J＝4.6Hz,1H),4.24(s,2H),3.98–3.88(m,2H),3.83(s,1H),3.76–3.67(m,2H),3.06(q,J＝7.3Hz,2H),1.92(dt,J＝12.9,6.6Hz,2H),1.25–1.19(m,4H),0.93(dd,J＝20.8,4.9Hz,7H).

Example 21

(R) -1- (2, 6-dicyclopropylpyridin-4-yl) -N- (1- (4- (ethanesulfonyl) phenyl) -2-hydroxyethyl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-6-carboxamide

To a mixture of 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-6-carboxylic acid (67mg,0.19mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (53mg,0.23mmol), 1-hydroxybenzotriazole (55mg,0.40mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (78mg,0.40mmol) was added dichloromethane (8mL), triethylamine (110. mu.L, 0.79mmol), and after stirring at room temperature for 30 hours, the reaction was stopped, diluted with dichloromethane (25mL), washed with a saturated ammonium chloride solution (15mL), dried over anhydrous sodium sulfate, concentrated and stirred, column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the product 11mg as a white solid, yield: 9.34%, purity: 88.41 percent.

MS(ESI,pos.ion)m/z:549.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.40(d,J＝7.6Hz,1H),7.90(d,J＝8.2Hz,2H),7.74(d,J＝8.2Hz,1H),7.63(d,J＝8.2Hz,2H),7.58(d,J＝8.2Hz,1H),6.74(s,2H),5.31(dd,J＝12.1,5.1Hz,1H),4.58–4.48(m,2H),4.05(t,J＝5.1Hz,2H),3.85–3.78(m,2H),3.11(q,J＝7.4Hz,2H),1.93–1.87(m,2H),1.32–1.30(m,3H),1.04–0.99(m,4H),0.93–0.90(m,4H).

Example 22

(S) -3- (4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propanoic acid

The method comprises the following steps: synthesis of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid

Pd is added₂(dba)₃(200mg,0.21mmol), sodium tert-butoxide (600mg,6.24mmol), and tri-tert-butylphosphine (43.0mg,0.21mmol) were added sequentially to a solution of methyl 3, 4-dihydro-2H-1, 4-benzoxazine-7-carboxylate (400mg,2.07mmol) and 1-chloro-3, 5-dicyclopropyl-benzene (400mg,2.08mmol) in xylene (12mL) and reacted at 155 ℃ for 12 hours under nitrogen. After the reaction was stopped, the reaction mixture was cooled to room temperature and quenched by addition of saturated aqueous sodium chloride (30 mL). It was extracted with methylene chloride (20 mL. times.3), and after the organic phases were combined, it was dried over anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 2/1) to give the product as a white solid 226mg, yield: 33 percent.

MS(ESI,pos.ion)m/z:336.2[M+H]⁺

Step two: synthesis of methyl (S) -3- (4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propionate

To a solution of (S) -methyl 3-amino-3- (4- (ethylsulfonyl) phenyl) propionate hydrochloride (61.0mg,0.20mmol), 4- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-1, 4-benzoxazine-7-carboxylic acid (60.0mg,0.18mmol) in dichloromethane (6.0mL) was added HATU (143mg,0.36mmol) and triethylamine (80. mu.L, 0.57mmol) and stirred at room temperature for 2 hours. After the reaction was stopped, dichloromethane (20mL) was added for dilution. The washing was quenched with a saturated ammonium chloride solution (10mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/2) to give 105mg of a pale yellow solid, yield: 99 percent.

MS(ESI,pos.ion)m/z:589.3[M+H]⁺

Step three: synthesis of (S) -3- (4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propionic acid

Potassium carbonate (215mg,1.56mmol) was added to a solution of methyl (S) -3- (4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) methylphenylphenyl) propionate (115mg,0.20mmol) in methanol (6mL) and the mixture was stirred at room temperature for 12 hours. After the reaction was stopped, the reaction mixture was diluted with dichloromethane (100mL) and filtered through celite. After the filtrate was concentrated under reduced pressure, the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give 100mg of the product as a pale brown white solid, yield: 89% and purity 85.47%.

MS(ESI,pos.ion)m/z:573.1[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.13(s,1H),7.80(d,J＝8.1Hz,2H),7.62(d,J＝8.1Hz,2H),7.34(s,1H),7.24(d,J＝8.3Hz,1H),6.75–6.67(m,3H),6.59(s,1H),5.38(d,J＝6.5Hz,1H),4.26(s,2H),3.68(s,2H),3.25(d,J＝7.4Hz,3H),2.89(s,1H),2.73(s,1H),1.86(ddd,J＝13.4,8.5,5.2Hz,2H),1.09(t,J＝7.3Hz,3H),0.91(dt,J＝5.8,4.2Hz,4H),0.66(d,J＝4.6Hz,4H).

Example 23

(S) -3- (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propanoic acid

The method comprises the following steps: synthesis of methyl (S) -3- (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propionate

To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxylic acid (60mg,0.18mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionic acid methyl ester hydrochloride (61mg,0.19mmol), HATU (136mg,0.35mmol) in dichloromethane (6mL,93.61mmol) was added triethylamine (80. mu.L, 0.57mmol), and the mixture was stirred at room temperature for 12 hours, the reaction was stopped, quenched by addition of saturated ammonium chloride solution (25mL), extracted with dichloromethane (25mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give 100mg of the product as a pale yellow oil, yield: 95.08 percent.

MS(ESI,pos.ion)m/z:590.2[M+H]⁺

Step two: synthesis of (S) -3- (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propanoic acid

To a solution of methyl (S) -3- (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-carboxamido) -3- (4- (ethylsulfonyl) phenyl) propanoate (100mg,0.17mmol) in methanol (5mL) was added potassium carbonate (118mg,0.85mmol), and the mixture was stirred at room temperature for 48 hours. Dilution with dichloromethane (20mL), filtration through celite, concentration on silica gel, column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) afforded the product 85mg, yield: 83.00%, purity: 95.33 percent.

MS(ESI,pos.ion)m/z:576.4[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ9.06(s,1H),7.83(d,J＝8.2Hz,2H),7.66(d,J＝8.3Hz,2H),7.43(d,J＝1.5Hz,1H),7.37(d,J＝8.5Hz,1H),7.22(d,J＝8.5Hz,1H),6.87(s,2H),5.44(dd,J＝14.3,7.4Hz,1H),4.25(s,2H),3.79(s,2H),3.26(dd,J＝14.8,7.4Hz,2H),2.88–2.74(m,2H),1.95–1.89(m,2H),1.09(t,J＝7.3Hz,3H),0.83(d,J＝7.8Hz,8H).

Example 24

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -1- (3, 5-dicyclopropylphenyl) indoline-5-carboxamide

The method comprises the following steps: synthesis of indoline-5-methyl formate

To a solution of methyl 1H-indole-5-carboxylate (500mg,2.85mmol) in acetic acid (6mL) at 0 ℃ was added sodium cyanoborohydride (540mg,8.59mmol), allowed to naturally warm to room temperature for overnight reaction, stopped, quenched with saturated sodium bicarbonate solution (30mL), extracted with ethyl acetate (30mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 250mg of the product as a pale yellow solid, yield: 49.43 percent.

MS(ESI,pos.ion)m/z:178.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.77(d,J＝4.1Hz,2H),6.56(d,J＝8.6Hz,1H),3.87(s,3H),3.67(t,J＝8.5Hz,2H),3.08(t,J＝8.5Hz,2H).

Step two: synthesis of 1- (3, 5-dicyclopropylphenyl) indoline-5-formic acid

To indoline-5-carboxylic acid methyl ester (240mg,1.35mmol), 1-chloro-3, 5-cyclopropylbenzene (274mg,1.42mmol), sodium tert-butoxide (390mg,4.06mmol), Pd₂(dba)₃Xylene (10mL) was added to a mixture of (125mg,0.13mmol) and tri (tert-butyl) phosphine (28mg,0.14mmol), the reaction was stopped after 12 hours at 155 ℃ under nitrogen, quenched by addition of saturated ammonium chloride solution after cooling to room temperature (30mL), extracted with dichloromethane (30mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give the product as a pale yellow solid, 40mg, yield: 9.25 percent.

MS(ESI,pos.ion)m/z:320.1[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -1- (3, 5-dicyclopropylphenyl) indoline-5-carboxamide

To a mixture of 1- (3, 5-dicyclopropylphenyl) indoline-5-carboxylic acid (36mg,0.11mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (33mg,0.12mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (44mg,0.23mmol), and 1-hydroxybenzotriazole (31mg,0.22mmol), dichloromethane (4mL) and triethylamine (50. mu.L, 0.36mmol) were added, and the mixture was reacted at room temperature for 12 hours. The reaction was stopped, quenched by addition of saturated ammonium chloride solution (25mL), extracted with dichloromethane (30mL × 3), dried over anhydrous sodium sulfate, concentrated, and column-chromatographed (eluent: PE/EtOAc (v/v) ═ 1/1) to give the product 23mg as a pale yellow solid, yield: 34.52%, purity: 91.29 percent.

MS(ESI,pos.ion)m/z:540.0[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ7.92(d,J＝8.3Hz,2H),7.67(d,J＝8.3Hz,2H),7.63(s,1H),7.58(d,J＝8.4Hz,1H),6.97(d,J＝8.4Hz,1H),6.80(d,J＝7.7Hz,1H),6.75(s,2H),6.52(s,1H),5.62(dd,J＝13.0,6.2Hz,1H),4.02(t,J＝8.6Hz,2H),3.28–2.98(m,6H),1.93–1.80(m,2H),1.31(d,J＝7.4Hz,3H),1.02–0.93(m,4H),0.79–0.64(m,4H).

Example 25

(S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxamide

The method comprises the following steps: synthesis of 1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxylic acid methyl ester

Adding 1H-indole-5-carboxylic acid methyl ester (200mg,1.14mmol), 1-chloro-3, 5-dipropylbenzene (241mg,1.25mmol), Pd₂(dba)₃(54mg,0.05mmol), 2-dicyclohexanylphosphino-2' - (N, N-dimethylamine) -biphenyl (70mg,0.17mmol) and sodium tert-butoxide (165mg,1.72mmol), xylene (8mL) were added in sequence to a sealed tube, the reaction was stopped after heating at 130 ℃ for 12 hours under nitrogen protection, the reaction was cooled to room temperature and quenched by addition of saturated ammonium chloride solution (15mL), extracted with ethyl acetate (25mL × 3), dried over anhydrous sodium sulfate, concentrated by column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 269mg of product, yield: 71.10 percent.

MS(ESI,pos.ion)m/z:332.1[M+H]⁺

Step two: synthesis of 1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxylic acid

To methyl 1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxylate (269mg,0.81mmol) were added methanol (2mL) and tetrahydrofuran (2mL), sodium hydroxide (0.6mL,2mmol), the reaction was stopped by heating at 55 ℃ for 12 hours, quenched after cooling to room temperature by adding saturated ammonium chloride solution (8mL), pH was adjusted to around 7 with dilute hydrochloric acid (1M), dichloromethane extracted (30mL × 3), dried over anhydrous sodium sulfate, concentrated column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 110mg of the product as a pale yellow solid: 42.70 percent.

MS(ESI,pos.ion)m/z:318.2[M+H]⁺

Step three: synthesis of (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxamide

To a solution of 1- (3, 5-dicyclopropylphenyl) -1H-indole-5-carboxylic acid (50mg,0.15mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (46mg,0.16mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (61mg,0.31mmol), 1-hydroxybenzotriazole (43mg,0.31mmol) in dichloromethane (5mL) was added triethylamine (70 μ L,0.50mmol), reacted at room temperature for 24 hours, the reaction was stopped, quenched with a saturated ammonium chloride solution (15mL), extracted with dichloromethane (20mL × 3), dried over anhydrous sodium sulfate, concentrated and sample-stirred column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 53mg of a pale yellow solid product, yield: 59.74%, purity: 95.48 percent.

MS(ESI,pos.ion)m/z:538.2[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.21(s,1H),7.89(d,J＝8.3Hz,2H),7.71(d,J＝8.7Hz,1H),7.67(d,J＝8.3Hz,2H),7.52(d,J＝8.7Hz,1H),7.38(d,J＝3.2Hz,1H),7.28–7.20(m,1H),6.93(d,J＝1.0Hz,2H),6.85(s,1H),6.70(d,J＝3.2Hz,1H),5.65(q,J＝6.3Hz,1H),3.18–3.04(m,4H),1.94(td,J＝8.4,4.2Hz,2H),1.32–1.27(m,3H),1.08–0.97(m,4H),0.79–0.70(m,4H).

Example 26

(R) -1- (3, 5-dicyclopropylphenyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2, 3-dihydro-1H-pyridine [2,3-b ] [1,4] oxazine-6-carboxamide

The method comprises the following steps: synthesis of 1-tert-butyl 6-methyl 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1, 6-dicarboxylate

To 6-bromo-2, 3-dihydro-1H-pyrido [2,3-b ] at room temperature][1,4]Oxazine-1-carboxylic acid tert-butyl ester (370mg,1.17mmol), Pd (OAc)₂To a mixture of (20mg,0.09mmol) and 1,1' -bis (diphenylphosphino) ferrocene (170mg,0.29mmol) were added triethylamine (330. mu.L, 2.36mmol) and methanol (10mL), and the mixture was reacted at 50 ℃ for 24 hours under an atmosphere of carbon monoxide. After the reaction was stopped, the reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the mixture was diluted with methylene chloride (50mL), washed with saturated ammonium chloride solution (20mL), and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give the product 262mg as a pale yellow solid, yield: 76 percent.

MS(ESI,pos.ion)m/z:295.3[M+H]⁺。

Step two: synthesis of methyl 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-6-carboxylate

To a solution of 1-tert-butyl 6-methyl 2, 3-dihydro-1H-pyrido [2,3-b ] [1,4] oxazine-1, 6-dicarboxylate (262mg,0.89mmol) in dichloromethane (6mL) was added a solution of 1, 4-dioxane hydrochloride (2mL,8mmol,4M) and the mixture was stirred at room temperature overnight. The reaction was stopped, the solvent was concentrated, neutralized to neutrality by addition of saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 157mg of a brown solid product, yield: 91 percent.

MS(ESI,pos.ion)m/z:195.1[M+H]⁺

Step three: synthesis of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-1H-pyridine [2,3-b ] [1,4] oxazine-6-carboxylic acid

Sodium tert-butoxide (186mg,1.93mmol), tri-tert-butylphosphine (15mg,0.07mmol) and Pd₂(dba)₃(62mg,0.06mmol) and 1-chloro-3, 5-dicyclopropyl-benzene (136mg,0.70mmol) were added in sequence with 2, 3-dihydro-1H-pyrido [2,3-b ]][1,4]Oxazine-6-carboxylic acid methyl ester (125mg,0.64mmol) in xylene (7mL) was reacted at 155 ℃ under nitrogen for 12 h. After the reaction was stopped, it was cooled to room temperature. The reaction was quenched with saturated ammonium chloride solution (30 mL). The mixture was extracted with methylene chloride (25 mL. times.3), dried over anhydrous sodium sulfate and filtered. Column chromatography (eluent: DCM/MeOH (v/v) ═ 4/1) gave 46mg of a brown solid, yield: 21 percent.

MS(ESI,pos.ion)m/z:337.1[M+H]⁺

Step four: synthesis of (R) -1- (3, 5-dicyclopropylphenyl) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2, 3-dihydro-1H-pyridine [2,3-b ] [1,4] oxazine-6-carboxamide

1- (3, 5-Dicyclopropylphenyl) -2, 3-dihydro-1H-pyridine [2,3-b ] [1,4] oxazine-6-carboxylic acid (58mg,0.17mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (62mg,0.34mmol), 1-hydroxybenzotriazole (50mg,0.37mmol) and (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (80mg,0.35mmol) were added to a stirred vial in sequence, followed by dichloromethane (6mL) and triethylamine (73. mu.L, 0.52 mmol). After stirring at room temperature for 12 hours, the reaction mixture was diluted with methylene chloride (40 mL). The organic phases were mixed and washed with saturated sodium chloride solution (50mL) and dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure and separation by column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) gave 14mg of a pale yellow solid, yield: 15%, purity: 92.69 percent.

MS(ESI,pos.ion)m/z:548.6[M+H]⁺

¹H NMR(400MHz,CDCl₃)δ8.31(d,J＝7.3Hz,1H),7.87(d,J＝8.2Hz,2H),7.61(t,J＝7.9Hz,3H),7.06(d,J＝8.2Hz,1H),6.70(s,2H),6.67(s,1H),5.28(dd,J＝11.5,5.1Hz,1H),4.56–4.46(m,2H),4.02(s,2H),3.77–3.68(m,2H),3.09(q,J＝7.3Hz,2H),2.72(s,1H),1.85(td,J＝8.5,4.3Hz,2H),1.29(d,J＝7.3Hz,3H),0.97(q,J＝6.0Hz,4H),0.67(q,J＝5.1Hz,4H).

Biological Activity assay for Compounds of the invention

ROR gamma t protein receptor binding assay

1. The experimental principle is as follows:

ROR-gamma t agonist activity screening ROR-gamma t protein receptor binding assays were used. In the experimental system, a ROR-gamma t-LBD protein band GST label (RORgt-LBD-GST), a SRC coactivated protein band biotin label (SRC-biotin), a Eu-labeled anti-GST antibody (Europium anti-GST) is used for binding RORgt-LBD-GST, and D2-labeled Streptavidin (Streptavidin-D2) is used for binding SRC-biotin. When the compound can effectively bind to ROR-gamma t-LBD and cause the change of configuration, thereby enhancing the recruitment of SRC, due to the close distance between ROR-gamma t-LBD and SRC, under the excitation condition of excitation light, energy can be transferred from donor Eu to acceptor D2, thereby generating stronger TR-FRET signal. Conversely, when the compound is not effective in promoting ROR-gamma t-LBD recruitment to SRC, energy is not transferred from the donor Eu to the acceptor D2, and the TR-FRET signal is detected to be weak. According to the experimental principle, the activation effect of the compound on ROR-gamma t can be indirectly judged through the strength of a TR-FRET signal, so that the aim of screening effective compounds is fulfilled.

2. Experimental methods

The compounds were dissolved in DMSO and made up as 10mM stock solution for use1 XBuffer (PBS containing 5mM DTT, 50mM KF, 100mM NaCl, 0.01% BSA and 0.01% Tween-20) was prepared for use. 4 Xcompound final concentration dilutions (10uM) were made in 1 Xbuffer, 3-fold gradient dilution, 5ul per well in 384 well plates; 4 XROR-. gamma.t-LBD (20nM), 4 Xursolic acid (0.4uM) mix was prepared with 1 XBuffer, 5ul per well in 384 well plates; a mixture of 2 XSCC (100n M), 2 XSEuropium anti-GST (1:200) and 2 XSstreptavidin-D2 (25nM) was prepared with 1 XBuffer, 10ul per well was added to 384 well plates, and centrifuged at 1000g for 1 min. Incubating for 4h at room temperature in a dark place, detecting the signal intensity under 665nm and 615nm dual-wavelength conditions on a plate reader of an Envision2104 microplate reader, calculating the binding rate, and calculating Emax and EC₅₀The value is obtained.

3. Experimental data

According to the signal intensity values detected by a plate reader of an Envision2104 microplate reader under 665nm and 615nm dual wavelengths, the binding rate is calculated, and E is calculated_maxAnd EC₅₀The value is obtained. E_maxI.e., the maximum binding rate of the test compound, the following is a calculation formula for the binding rate:

the binding rate (%) - (X-min)/(max-min) × 100%

X: refers to the value of the test compound measured under 665/615 conditions minus the background value; min: the average value of the measured value of the DMSO blank control under the condition of 665/615 minus the background value is indicated; max: refers to the average value of 10uM positive drug measured under 665/615 conditions minus the background value.

The EC of the compound is obtained by fitting the following nonlinear fitting formula according to the binding rate by using Graphpad 5.0₅₀：

Z＝Bottom+(Top-Bottom)/(1+10^((LogEC₅₀-Y)*HillSlope))

Z: binding rate (%); y: log of compound concentration.

The experimental results are as follows:

TABLE 2 ROR gamma t protein receptor binding assay results for compounds of the invention

Example numbering	EC50(nM)	Emax％	Example numbering	EC50(nM)	Emax％
						8	19.1	121.1	21	6	132.1
10	29.29	158	22	5	129.9
						19	2.7	127.4	23	37.7	120.3
20	5.4	126.6	26	0.3	126.6

And (4) experimental conclusion: the compound of the invention has better binding activity to ROR gamma t protein receptor.

Cell functional activity experiment for evaluating in vitro drug effect of ROR-gamma t agonist

1. The experimental principle is as follows:

constructing a fusion protein vector pBIND-ROR gamma t-LBD for expressing ROR gamma t-LBD and GAL4-DBD, and after co-transfecting HEK293T cells with pGL4.31 vector, the co-expressed fusion protein of ROR gamma t-LBD and GAL4-DBD can be combined with an upstream regulatory sequence GAL4UAS expressed by luciferase, thereby starting the expression of the luciferase. When the compound is effective to activate ROR γ t, luciferase expression will increase and the detected fluorescent signal will increase accordingly. Therefore, by detecting the expression amount of luciferase, the activation effect of the compound on ROR γ t can be determined. The experiment mainly utilizes a Lipo3000 liposome transfection method and a single luciferase detection system to detect the influence of a compound on the transcription activity of ROR gamma t, thereby achieving the aim of screening the targeted ROR gamma t agonist.

2. The experimental method comprises the following steps:

HEK293T cells were cultured to 80% -90%, 2. mu.g pBIND-ROR γ t-LBD and 5. mu.g pGL4.31 plasmid were transfected into 10cm2 plates HEK293T cells according to Lipo3000 Lipofectation instructions, and 12-24 hours later counted in plates. The transfected HEK293T cells were resuspended in phenol red-free DMEM containing 10% FCS and seeded at 20,000 cells/well in 96-well plates at 90. mu.l/well, and ursolic acid was added to give a final concentration of 1. mu.M. Adding 10 μ l diluted compound working solution (initial final concentration of compound is 5 μ M, 3 times concentration gradient dilution, setting 9 concentration points), reserving six holes as negative control holes, and adding 10 μ l diluted solution containing DMSO and no medicinal liquid; six wells were used as positive control wells and 10 μ l of the highest dosing concentration positive control compound was added. The peripheral holes around the 96-well plate are not used as test holes, and the test holes are sucked away after the incubator is incubated for 24 hoursAdding 50 mul volume of supernatant into 50 mul volume of lysate and luciferase substrate buffer 50 mul/well, reacting for 15min in a dark place, detecting fluorescence value, calculating the activation percentage of compound to the expressed fluorescence of transfected cells under each concentration and calculating EC₅₀And E_max。

The experimental results are as follows:

TABLE 3 in vitro potency test results for the compounds of the invention

Example numbering	EC50(nM)	Emax％	Example numbering	EC50(nM)	Emax％
						8	101	57.03	21	340	107.5
19	106	82.1	26	68	73.92
						20	196	100.3

And (4) experimental conclusion: the compound of the invention has better agonistic activity on ROR gamma t protein receptor.

In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (11)

1. A compound which is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein:

ring A is

Wherein denotes a link to L; represents a linkage to a carbonyl group;

wherein X¹、X²And X³Each independently selected from CH₂、NH、S(O)_tOr O; x⁴、X⁵、X⁶And X⁷Each is independently selected from CH or N;

ring B is selected from C_6-10Aryl or heteroaryl of 5 to 6 atoms;

each R⁴Independently selected from H, deuterium, F, Cl, Br, I, -CN, -OH, -NR^aR^b、-C(＝O)OR^f、-C(＝O)R^f、-C(＝O)NR^aR^b、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Alkylthio radical, C_1-6Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl or C_1-6An alkylamino group; wherein each R⁴Independently unsubstituted or substituted by 1,2,3 or 4R^cSubstituted;

l is selected from the group consisting of a bond, -NR^x-、-O-、*-(CH₂)_r-C(O)-(CH₂)_r-、*-(CH₂)_r-S(O)_t-(CH₂)_r-or C_1-6An alkylene group; wherein denotes the attachment to ring a;

R^xselected from H, deuterium, C_1-6Alkyl radical, C_1-6Haloalkyl, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-6Alkylene, heterocyclic group of 3-6 atoms-C_1-6Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-6Alkylene, or a mixture thereof,Heteroaryl of 5 to 10 atoms or heteroaryl-C of 5 to 10 atoms_1-6An alkylene group;

ring C is selected from C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 6 atoms; wherein ring C is independently unsubstituted or substituted with 1,2,3 or 4R^ySubstituted;

R¹selected from H, deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R¹Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted;

R²selected from F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R²Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted;

each R³Independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -SH, -NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-C_1-3Alkyl, -C (═ O) -C_1-3Alkyl, -C (═ O) O-C_1-3Alkyl, -C (═ O) NH-C_1-3Alkyl radical, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, heterocyclic radical composed of 3-6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms, wherein each R³Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted;

each R^yIndependently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, heterocyclic group consisting of 3 to 6 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted;

each R^cIndependently selected from deuterium, F, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OR^f、-C(＝O)NR^aR^b、-S(＝O)₂R^f、-S(＝O)₂NR^aR^b、C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms;

each R^dIndependently selected from deuterium, F, Cl, Br, Cl, I, -CN, -NO₂、-OH、-SH、-NH₂、S(＝O)₂R^f、C_1-6Haloalkyl, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkoxy, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms;

each R^aAnd R^bIndependently selected from H, deuterium, C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10cycloalkyl-C_1-3Alkylene, heterocyclic group consisting of 3 to 10 atoms, (heterocyclic group consisting of 3 to 10 atoms) -C_1-3Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-3Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-3An alkylene group;

each R^fIndependently selected from H, deuterium, -OH, -SH, -NH₂、C_1-6Haloalkyl, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-3Alkyl, heterocyclic group consisting of 3 to 10 atoms, (heterocyclic group consisting of 3 to 10 atoms) -C_1-3Alkylene radical, C_6-10Aryl radical, C_6-10aryl-C_1-3Alkylene, heteroaryl of 5 to 10 atoms or (heteroaryl of 5 to 10 atoms) -C_1-3An alkylene group;

each R^eIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OR^f、-S(＝O)₂R^f、-C(＝O)NR^aR^b、-S(＝O)₂NR^aR^b、C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms;

each t is independently 0, 1 or 2;

each r is independently 0, 1,2,3 or 4;

n is 1,2,3 or 4;

m is 0, 1,2,3 or 4;

wherein the compound is not any of the following:

2. the compound of claim 1, wherein:

the ring A is

Denotes a connection to L; represents a linkage to a carbonyl group;

wherein X¹、X²And X³Each independently selected from CH₂NH or O; x⁴、X⁵、X⁶And X⁷Each is independently selected from CH or N;

ring B is selected from phenyl, naphthyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1,3, 5-triazinyl;

ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, or 1,3, 5-triazinyl; whereinEach ring C is independently unsubstituted or substituted with 1,2,3 or 4R^yAnd (4) substituting.

3. The compound of claim 1 or 2, wherein:

each of said R^yIndependently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidinyl, piperazinyl, hexahydropyrimidinyl, phenyl, naphthyl, pyrrolyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, or 1,3, 5-triazinyl; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted;

each of said R^dIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-S(＝O)₂R^f、C_1-4Haloalkyl, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_3-10Cycloalkyl, heterocyclic group consisting of 3 to 10 atoms, C_6-10Aryl or heteroaryl of 5 to 10 atoms.

4. A compound according to any one of claims 1-3, wherein:

each of said R^yIndependently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH₂Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, n-propoxy and isopropoxyA group, trifluoromethyl group, N-methylamino group, N-ethylamino group, methylthio group, ethylthio group, vinyl group, propenyl group, allyl group, ethynyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxirane group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, tetrahydrothienyl group, tetrahydropyranyl group, dioxanyl group, morpholinyl group, piperidinyl group, piperazinyl group, hexahydropyrimidyl group, phenyl group, naphthyl group, pyrrolyl group, pyridyl group, pyrimidinyl group, thiazolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isoxazolyl group, oxadiazolyl group, pyrazinyl group, pyridazinyl group or 1,3, 5-triazinyl group; wherein each R^yIndependently unsubstituted or substituted by 1,2,3 or 4R^dSubstituted;

each of said R^dIndependently selected from deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-S(＝O)₂R^fMethyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, tert-butyl, sec-butyl, methoxy, ethoxy, N-propoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, N-methylamino, N-ethylamino, methylthio, ethylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, aziridinyl, phenyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridyl or pyrimidinyl.

5. The compound according to any one of claims 1-4, wherein:

l is selected from the group consisting of a bond, -NR^x-、-O-、-C(O)-、*-C(O)-CH₂-、*-CH₂-C(O)-、-S(O)₂-、*-S(O)₂-CH₂-、*-CH₂-S(O)₂-、-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-or-CH₂CH₂CH₂CH₂-; wherein denotes the attachment to ring a.

6. The compound according to any one of claims 1-5, wherein:

R¹selected from H, deuterium, F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, N-methylamino, N-ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl or tetrahydrofuranyl, wherein each R¹Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted;

R²selected from F, Cl, Br, I, -CN, -NO₂、-OH、-SH、-NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂Methyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, N-methylamino, N-ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxiranyl, oxetanyl or tetrahydrofuranyl, wherein each R²Independently unsubstituted or substituted by 1,2,3 or 4R^eSubstituted;

each R³Independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -SH, -NH₂、-C(＝O)OH、-C(＝O)NH₂、-S(＝O)₂NH₂、-S(＝O)₂-CH₃、-S(＝O)₂-CH₂CH₃or-S (═ O)₂-CH₂CH₂CH₃；

Each R⁴Independently selected from H, deuterium, F, Cl, Br, I, -CN, -OH, -NR^aR^b、-C(＝O)OR^f、-C(＝O)R^f、-C(＝O)NR^aR^bMethyl, ethyl, N-propyl, isopropyl, N-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2, 2-trifluoroethyl, 1-difluoroethyl, 2, 2-difluoroethyl, 1-fluoroethyl, 2-fluoroethyl, methoxy, ethoxy, propoxy, methylthio, ethylthio, N-methylamino, N-ethylamino, N' N-dimethylamino, C_1-4Haloalkoxy, C_2-4Alkenyl or C_2-4An alkynyl group; wherein each R⁴Independently unsubstituted or substituted by 1,2,3 or 4R^cAnd (4) substituting.

7. The compound of any one of claims 1-6, wherein the compound has a structure according to formula (II):

wherein Z is¹Is CH or N; s is 0, 1,2,3 or 4.

8. The compound of any one of claims 1-7, wherein the compound has a structure according to formula (III) or formula (IV):

wherein Z is¹Is CH or N; s is 0, 1,2,3 or 4.

9. The compound according to any one of claims 1-8, having the structure of one of:

or a stereoisomer, tautomer, nitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof.

10. A pharmaceutical composition comprising a compound of any one of claims 1-9, optionally further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.

11. Use of a compound of any one of claims 1-9 or a pharmaceutical composition of claim 10 in the manufacture of a medicament for preventing, treating or alleviating a disease mediated by ROR γ t in a patient, wherein the disease mediated by ROR γ t comprises cancer, multiple sclerosis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, asthma, autoimmune disease, graft-versus-host disease, autoimmune ocular disease, psoriasis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, colitis, bacterial infection, fungal infection, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.