TW201733982A - Aromatic amide derivatives, preparation process thereof and pharmaceutical use thereof - Google Patents

Abstract

The present invention relates to aromatic amide derivatives, preparation process thereof and pharmaceutical use thereof. In particular, the present invention relates to aromatic amide derivatives as shown in the formula (I), a preparation method thereof and a pharmaceutical composition containing the derivative, a use as a ROR modifier and a use for the prevention and / or treatment of diseases such as inflammation, autoimmune diseases and cancer, wherein each substitute of general formula (I) is defined as the specification.

Description

Aromatic amide derivatives, preparation method thereof and application thereof in medicine

The invention belongs to the field of medicine, and relates to an aromatic amide derivative, a preparation method thereof and application thereof in medicine. In particular, the present invention relates to an aromatic guanamine derivative represented by the formula (I), a process for producing the same, a pharmaceutical composition containing the same, as a ROR modulator, and a prophylactic and/or therapeutic autoimmune property thereof The use of the disease.

Retinoic acid-related orphan nuclear receptors (RORs) are members of the nuclear receptor family that regulate a variety of physiological and life processes. The ROR family contains three types of ROR α, ROR β, and ROR γ. Three different RORs can be expressed in different tissues and control different physiological processes. ROR α is mainly distributed in the liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain. ROR β has a small range of action, the main role In the central nervous system, ROR γ can be expressed in many tissues, including liver, animal fat, and skeletal muscle. Lack of ROR γ in mammals shows a decrease in blood glucose.

There are two subtypes of ROR γ: ROR γ 1 and ROR γ 2 . ROR γ 1 is expressed in many tissues such as thymus, muscle, kidney and liver, while ROR γ 2 Only in immune cells, ROR γ 2 is thought to control the differentiation of T cell helper T cell 17 (Th17). Th17 is a type of helper T cell that produces interleukin-17 (IL-17) and other cytokines. Th-17 has been found to be associated with human inflammatory diseases and immune disorders such as multiple sclerosis and rheumatism. Sexual arthritis, psoriasis, clonal diseases, and asthma are related. It is now reported in the literature that ROR γ may be associated with the development and progression of prostate cancer.

ROR γ t is a subtype of ROR γ specifically expressed on immune cells. It is the major transcription factor of human and murine Th17 cells, which not only promotes the differentiation of Th17 cells, but also regulates the expression of IL-17, a specific effector of Th17 cells. And secretion, ROR γ t is closely related to the occurrence and development of various immune diseases, infectious diseases and tumors.

ROR γ, particularly the ROR γ t type, has been identified as an important transcriptional regulator of the differentiation of Th17 cells. In 2006, Vanov et al. found that ROR γ t is an important transcription factor for Th17 cell differentiation in mouse experiments. Their study showed that mice were difficult to induce the formation of an EAE model in the absence of ROR γ t. In the process of human Th17 cell differentiation, ROR γ t was also confirmed to have a similar important role, and the groundbreaking discovery caused people to attach great importance to ROR γ t.

At present, ROR has been highly regarded as an inhibitor in the medical field and has become a hot issue of research. The patent applications that have been published include WO2015171610, WO22015171558, WO2015131035, WO2013169864, WO2014179564, WO2015116904 and the like.

The inventors discovered in the process of studying ROR regulators in the present invention In the compound of the formula (I), a change in the ortho group of the ring A changes its regulation effect, and when the ortho group of the ring A is a group having a small steric hindrance (for example, H and F) The compound of the formula (I) is an inverse agonist when the ring A ortho group is a haloalkyl group (e.g., a trifluoromethyl group), an alkyl group (e.g., an ethyl group), and a haloalkoxy group (e.g., trifluoromethyl). The compound represented by the formula (I) is a ROR agonist when the oxy) sterically hindered group is large, whereby the present invention has developed a new ROR regulator, and further studies have revealed changes in the structure of the compound. Different mechanisms can be adjusted.

It is an object of the present invention to provide a compound of the formula (I):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are the same Or different, and each independently is CR ⁹ or N; ring A and ring B are the same or different and are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R ¹ and R ^{2 are the} same or Different, and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amine group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group , heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, cycloalkyl group And alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy. Substituting one or more substituents of a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R ³ and R ^{4 are the} same or different and are each independently selected from Hydrogen atom, alkyl group, cycloalkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen , amine, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ wherein the alkyl group, cycloalkyl group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of an alkyl group, a haloalkyl group, a halogen group, an amine group, a nitro group, and a cyano group. Substituted by one or more substituents of a group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R ³ and R ⁴ form a ketone R ^{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an amine group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, -OR ⁸ , C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl groups are each independently as desired Selected from alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and a heteroaryl group one or more substituents; R ⁶ is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy Halogen, amino, nitro, hydroxyl, cyano, heterocyclyl, aryl, ^{heteroaryl, -OR 8, -C (O)} R 8, -C (O) OR 8 and -S (O) _m R ⁸ wherein the alkyl group, cycloalkyl group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of an alkyl group, a haloalkyl group, a halogen group, an amine group, a nitro group, and a cyano group. Substituted by one or more substituents of a group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{7 is} selected from a hydrogen atom, an alkane a group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{8 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkane group a base, a hydroxyl group, an amine group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the amine group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently desired One or more selected from the group consisting of alkyl, halogen, hydroxy, amine, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl a substituents; R ⁹ is selected from hydrogen, alkyl, cycloalkyl, haloalkyl, Oxyl, haloalkoxy, amine, alkenyl, alkynyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently selected as desired From alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group; m is 0, 1 or 2; x is 0, 1, 2, 3 or 4; y is 0, 1, 2 or 3; and z is 0, 1, 2 , 3 or 4.

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II):

Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and Ring A, Ring B, R ¹ to R ⁷ , x, y and z are as in the formula (I) definition.

In a preferred embodiment of the invention, the compound of the formula (I) wherein the ring A and the ring B are the same or different and are each independently selected from the group consisting of a heterocyclic group, an aryl group and a heteroaryl group.

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II-A):

Wherein: X is CR ⁹ or N; R ⁹ is a hydrogen atom or an alkyl group; G is CH or N; and R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, Amino, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from an alkyl group, a haloalkyl group, as needed One or more substituents of halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted; p is 0, 1, 2 or 3; Ring A, R ¹ to R ⁸ , m, y and z are as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (II-A), wherein Selected from

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (III):

Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and Ring A, R ¹ to R ⁷ , x, y and z are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (IV):

Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and R ¹ to R ⁷ , x, y and z are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (IV-A), the formula (IV-B) or the formula (IV-C):

Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and R ^{a is} selected from an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an amine group. , nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S (O) _m R ⁸ , wherein the alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from an alkyl group, a haloalkyl group, a halogen Substituting one or more substituents of an amine group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R ^{b is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amine group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group, a heteroaryl group. , -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, cycloalkyl group, alkoxy group , haloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy base Hydroxyalkyl group, one or more cycloalkyl, heterocyclyl, aryl and heteroaryl groups substituted with a substituent; p is 1, 2 or 3; q is 0, 1 or 2; and R ¹ To R ⁸ , m, y and z are as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (IV-A) is a compound of the formula (IV-A-1):

Wherein: R ¹ to R ⁷ , p, y and z are as defined in the formula (IV-A).

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, Halogen, cyano, heterocyclic and -C(O)NHR ⁸ , wherein the alkyl, cycloalkyl, alkoxy and heterocyclic groups are each independently selected from alkyl, halogen, hydroxy, amine groups, as desired And one or more substituents in the cyano group are substituted; preferably, R ^{1 is} selected from the group consisting of an alkyl group, a halogen, a haloalkyl group, an alkoxy group, and a haloalkoxy group; and R ^{8 is} selected from a hydrogen atom or an alkyl group.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ² is halogen; preferably fluorine or chlorine.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ³ or R ^{4 are the} same or different, and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group and a hydroxyl group, Or R ³ and R ⁴ together form a keto group.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ^{5 is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl and aryl, wherein the alkyl, ring The alkyl group and the aryl group are each independently substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen, an alkenyl group and a hydroxyl group; preferably, R ⁵ is an isopropyl group or a cyclopropyl group.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ⁶ is halogen; preferably fluorine.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ⁷ is an alkane optionally substituted with one or more substituents selected from the group consisting of halogen, cycloalkyl and hydroxy; Preferably, R ⁷ is ethyl.

Typical compounds of formula (I) include, but are not limited to:

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.

The invention further provides a preparation according to the compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or An intermediate of a pharmaceutically acceptable salt, that is, a compound of the formula (V):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are the same or Different, and each independently is CR ⁹ or N; ring A is selected from cycloalkyl, heterocyclic, aryl and heteroaryl; R ^{1 is} selected from hydrogen, alkyl, cycloalkyl, haloalkyl, alkane Oxy, haloalkoxy, halogen, amine, nitro, hydroxy, cyano, heterocyclyl, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , —C(O)OR ⁸ and —S(O) _m R ⁸ , wherein the alkyl group, the cycloalkyl group, the alkoxy group, the haloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently regarded Need to be selected from alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents in the group; R ³ and R ^{4 are the} same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, Halogen, amine, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O) R ⁸ , —C(O)OR ⁸ and —S(O) _m R ⁸ , wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected as desired From alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents; or R ³ and R ⁴ form a keto group; R ^{5 is} selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amine, alkenyl, alkyne a base, an aryl group, a heteroaryl group, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, the cycloalkyl group, the haloalkyl group And the aryl and heteroaryl are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents of a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{6 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group , haloalkoxy, halogen, amine, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ And -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, cycloalkyl group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from an alkane as needed One of a group, a haloalkyl group, a halogen, an amine group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Substituted by a plurality of substituents; R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amine group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl group, the amine group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from an alkyl group, a halogen group, a hydroxyl group, an amine group, a carboxylate group, a nitro group, a cyano group, and the like. Substituted by one or more substituents in the alkoxy group, hydroxyalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group; R ^{9 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group , alkoxy, haloalkoxy, amine, alkenyl, alkynyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently as desired Selected from alkyl, haloalkyl, halogen, amine, nitro Substituted by one or more substituents of cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m is 0, 1 or 2; x is 0, 1, 2, 3 or 4; and y is 0, 1, 2 or 3.

The invention further provides a preparation according to the compound of the formula (II-A) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or an intermediate thereof, or a compound of the formula (II-A-1):

Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: ring A, X, R ^a And R ¹ , R ³ to R ⁶ , p and y are as defined in the formula (II-A).

The invention further provides a process for the preparation of a compound of formula (I), the process comprising:

A condensation reaction of a compound of the formula (V) with a compound of the formula (VI) to give a compound of the formula (I); wherein: ring A, ring B, X, Y, Z, R ¹ to R ⁷ , x, y and z As defined in the general formula (I).

The invention further provides a process for the preparation of a compound of the formula (II-A), the process comprising:

A condensation reaction of a compound of the formula (II-A-1) with a compound of the formula (II-A-2) to give a compound of the formula (II-A); wherein: ring A, G, X, R ^a , R ¹ to R ⁷ , p, y and z are as defined in the formula (II-A).

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the formulae (I), (II), (III), (IV), (IV-A), (IV-B), (IV) a compound represented by -C) or (V) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present invention also relates to a method of preparing the above composition comprising the general formulae (I), (II), (III), (IV), (IV-A), (IV-B), (IV-C) Or a compound represented by (V) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Mix with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or The use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as a ROR modulator in the manufacture of a medicament for the prevention and/or treatment of inflammation, autoimmune diseases, tumors or cancer.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use as a ROR inverse agonist in the manufacture of a medicament for the prevention and/or treatment of inflammatory and autoimmune diseases.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or The use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, as a ROR agonist in the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.

The present invention further relates to a compound represented by the general formula (IV-A) as a ROR agonist for the preparation of a medicament for preventing and/or treating a tumor or cancer Use in.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of a tumor or cancer with a combination of a ROR agonist and an anti-PD-1 antibody.

The invention further relates to the use of a compound of the formula (IV-A) as an ROR agonist for the preparation of a medicament for the treatment of a tumor or cancer in combination with an anti-PD-1 antibody.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for modulating ROR.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for an ROR agonist.

The invention further relates to the use of a compound of the formula (IV-A) for the manufacture of a medicament for an ROR agonist.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of inflammatory and autoimmune diseases.

In this context, the inflammatory and autoimmune diseases are selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, ankylosing spondylitis, chronic obstructive pulmonary disease, blood vessels Spheric nephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, allergic dermatitis, acne, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis And dermatomyositis allergic rhinitis.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.

In this context, the cancer and tumor are selected from the group consisting of 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, stage IV melanoma, solid tumor, glioma , glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer, especially non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, filtration Follicular lymphoma, synovial sarcoma.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof for use as a medicament Form, or a pharmaceutically acceptable salt thereof.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or A mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of an inflammatory or autoimmune disease, wherein the inflammatory and autoimmune diseases are as defined above.

The present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a tumor or cancer, wherein the tumor and cancer are as defined above.

The present invention also relates to a compound represented by the formula (IV-A) for use in the prevention and/or treatment of a tumor or a cancer, wherein the tumor and the cancer are as defined above.

The invention further relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, is for use in a ROR agonist and an anti-PD-1 antibody composition for preventing and/or treating a tumor or cancer, wherein the tumor and cancer are as defined above.

The present invention also relates to a compound represented by the formula (IV-A) and an anti-PD-1 antibody composition for preventing and/or treating a tumor or a cancer, wherein the tumor and the cancer are as defined above.

The present invention also relates to a method for the treatment of preventing and/or treating a prophylactic or autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the inflammatory and autoimmune diseases are as defined above.

The present invention also relates to a method for the prophylactic and/or therapeutic treatment of preventing tumors or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof or a mesogen thereof. , a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the tumor and cancer are as defined above.

The present invention also relates to a method of treating prevention and/or treatment for preventing tumor or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A). Wherein the tumor and cancer are as defined above.

The present invention also relates to a method of treating prevention and/or treatment for preventing tumor or cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (IV-A) and an anti-PD-1 antibody composition. Wherein the tumor and cancer are as defined above.

The present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in modulating ROR.

The invention further relates to compounds of the general formula (IV-A) for use in ROR agonists.

The present invention also relates to a compound represented by the formula (IV-A) and an anti-PD-1 antibody composition for use in an ROR agonist.

The invention also relates to a method of modulating ROR comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof Isomer, diastereomeric A form or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pleasing appearance. And delicious pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of a tablet for admixture. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.

It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules provide oral preparations.

Aqueous suspensions containing active substances and suitable preparations for mixing An excipient for the float. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and acacia; dispersing or wetting agents may be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose, saccharin or arsenic. Spartan.

The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

The dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents may also be added. Save these by adding an antioxidant such as ascorbic acid Composition.

The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, for example Polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition can be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oily phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the bloodstream of the patient by a local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant loop concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile in the preparation of a non-toxic diluent or solvent Injection solutions or suspensions, such as solutions prepared in 1,3-butanediol. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include mixtures of cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug to be administered depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt The type can be verified according to traditional treatment options.

(Detailed description of the invention)

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 carbon atoms, more preferably 1 to 6 An alkyl group of a carbon atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, third Butyl, t-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2 -methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl , 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3- Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-Octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4 , 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, N-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2 , 2-diethylhexyl, and various branches thereof Isomers. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl A pentyl group, a 2,3-dimethylbutyl group, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently Selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl A group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a ketone group, a carboxyl group or a carboxylate group.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" means -(CH ₂ ) ₄ - and the like.

The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 3 carbon atoms. 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings are fully conjugated π electronic system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a complete Conjugate π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane A thio group, a heterocycloalkylthio group, a ketone group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably, it contains from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; preferably from 3 to 6 ring atoms, of which 1 to 2 is a hetero atom. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably piperidinyl, piperazinyl or morpholinyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. . More preferably 4 members / 4 members, 4 members / 5 members, 4 members / 6 members, 5 members / 5 members or 5 members / 6 members of the monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic group. . Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include: with Wait.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane A thio group, a heterocycloalkylthio group, a ketone group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably from 6 to 10 members, for example, Phenyl and naphthyl. More preferably, it is a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, preferably 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl , pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl Or pyrimidinyl, thiazolyl; more preferably pyridyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, decyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkane A thio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio group, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, hetero A cycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo.

The term "amino" refers to -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "keto" refers to =0.

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "isocyanato" refers to -NCO.

The term "mercapto" refers to =N-OH.

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

The term "halohalide" refers to a compound containing a -C(O)-halogen group.

"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" are expressed in different terms. The same meaning means that X can be any one or several of A, B, and C.

"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, and to facilitate the absorption of the active ingredient to exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

(Synthesis method of the compound of the present invention)

In order to accomplish the object of the present invention, the present invention adopts the following technical scheme: the compound of the formula (I) of the present invention or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair thereof A method for preparing a conjugate or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

Dissolving the compound of the formula (IA), and the compound of the formula (IB), bis-cyanide palladium dichloride and norbornene in a polar solvent, and heating the reaction under basic conditions to obtain a compound of the formula (IC), which The alkaline reagent is preferably sodium hydrogencarbonate, and the polar solvent is preferably N,N-dimethylacetamide; the obtained compound of the general formula (IC) is reacted with methyl iodide and chloride under heating and basic conditions. To obtain a compound of the formula (ID), the alkaline reagent of the condition is preferably sodium hydride; the obtained compound of the formula (ID) is hydrolyzed under basic conditions to give a compound of the formula (V), an alkaline reagent of the condition Preferred is sodium hydroxide; the obtained compound of the formula (V) is reacted with a compound of the formula (VI), 1-hydroxybenzotriazole and N,N-diisopropylethylamine to give a compound of the formula (I) .

The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. Potassium acetate, sodium butoxide or potassium butoxide, including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, carbonic acid Sodium, sodium bicarbonate, potassium carbonate or cesium carbonate.

Wherein: R ^{x is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently selected from the group consisting of alkyl, halogen, hydroxy, amine, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Substituted by one or more substituents in the aryl group; ring A, ring B, X, Y, Z, R ¹ to R ⁷ , x, y and z are as defined in formula (I).

a compound of the formula (II-A) of the present invention or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A method for preparing a medicinal salt, comprising the steps of:

Dissolving the compound of the formula (II-1), and the compound of the formula (II-2), bis-cyanide palladium dichloride and norbornene in a polar solvent, and heating the reaction under basic conditions to obtain a formula (II) -3) a compound, the alkaline reagent of this condition is preferably sodium hydrogencarbonate, and the polar solvent is preferably N,N-dimethylacetamide; The compound of the formula (II-3) is reacted with methyl iodide and chloride under heating and basic conditions to obtain a compound of the formula (II-4), and the alkaline reagent of the condition is preferably sodium hydride; II-4) The compound is hydrolyzed under basic conditions to give a compound of the formula (II-A-1), and the alkaline reagent of the condition is preferably sodium hydroxide; the obtained compound of the formula (II-A-1) and The compound of the formula (II-A-2), 1-hydroxybenzotriazole and N,N-diisopropylethylamine are reacted to give a compound of the formula (II-A).

The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, and inorganic bases. Potassium acetate, sodium butoxide or potassium butoxide, including but not limited to sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate or cesium carbonate.

Wherein: R ^{x is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently selected from the group consisting of alkyl, halogen, hydroxy, amine, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and hetero Substituted by one or more substituents in the aryl group; the rings A, G, X, R ^a , R ¹ to R ⁷ , p, y and z are as defined in the formula (II-A).

Figure 1 is a graph showing the effect of Compound Example 30 on the growth of MC38 colorectal tumors in C57BL/6 mice.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

(Example)

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl hydrazine (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four. Methyl decane (TMS).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

Chiral HPLC analysis assays were performed using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).

The thin layer chromatography gelatin plate uses Yantai Huanghai HSGF254 or Qingdao GF254 gelatin plate. The specification of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm to 0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. Up to 0.5mm.

Column chromatography generally uses Yantai Huanghai Silicone 200 to 300 mesh silicone as a carrier.

Chiral preparative column chromatography was performed using Prep Star SD-1 (Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.

Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.

Unless otherwise stated in the examples, the solution means an aqueous solution.

There is no particular description in the examples, and the reaction temperature is room temperature and is 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound. The system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: n-hexane and Ethyl acetate system, C: dichloromethane and acetone system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid.

Example 1 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 1

first step Methyl 2-(2-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylate 1c

1 H -indole-5-carboxylic acid methyl ester 1a (50 mg, 0.28 mmol), 1-(bromomethyl)-2-trifluoromethoxybenzene 1b (71 mg, 0.28 mmol), bis acetonitrile palladium dichloride (7 mg, 0.03 mmol), norbornene (54 mg, o. 57 mmol), sodium hydrogencarbonate (72 mg, 0.86 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to room temperature, and water was added, and the mixture was applied to ethyl acetate (20 mL × 3), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified to give titled product 1c (yield: 70 mg, yellow solid).

Second step Methyl 1-isopropyl-2-(2-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylate 1d

1c (60mg, 0.17mmol) was dissolved in N,N -dimethylformamide, a catalytic amount of potassium iodide was added, then sodium hydride (10 mg, 0.26 mmol, 60% in oil) was added, and the reaction was stirred for 30 minutes and then added. Bromopropane (103 mg, 0.86 mmol) was stirred at 60 ° C for 12 hours. The reaction mixture was cooled to room temperature, and water was added, and the mixture was combined with ethyl acetate (20 mL×3). The resulting residue was purified with EtOAc EtOAcjjjjj

third step 1-isopropyl-2-(2-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylic acid 1e

1 d (25 mg, 0.064 mmol) was dissolved in 7 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 5:2), 2 mL of a 4 M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated EtOAc EtOAc (EtOAc m. The resulting residue was purified by EtOAc EtOAcjjjjj

the fourth step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 1

1e (20 mg, 0.053 mmol), (4-(ethylsulfonyl)phenyl)methanamine (16 mg, 0.08 mmol, prepared by the method disclosed in the patent application "WO2015/17335"), 1-(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (15 mg, 0.08 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), N,N -diisopropylethylamine (21 mg, 0.16 mmol) was dissolved in dichloromethane, and the mixture was stirred for 12 hr. Water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The resulting residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (ESI): 559.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.78 (d, 2H), 7.64 (d, 1H), 7.53 - 7.57 ( m, 3H), 7.31 (d, 2H), 7.17-7.21 (m, 1H), 7.03 (d, 1H), 6.64 (t, 1H), 6.34 (s, 1H), 4.79 (d, 2H), 4.41 -4.48 (m, 1H), 4.20 (s, 2H), 3.11 (q, 2H), 1.49 (d, 6H), 1.28 (t, 3H).

Example 2 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-methoxybenzyl)-1 H -indole-5-carbenamide 2

first step 2-(2-methoxybenzyl)-1 H -indole-5-carboxylic acid methyl ester 2b

1a (250 mg, 1.43 mmol), 1-(bromomethyl)-2-methoxybenzene 2a (301 mg, 1.5 mmol, using a known method " Journal of the American Chemical Society 2013, 135 (30), 10934- Prepared by 10937", diacetonitrile palladium dichloride (37 mg, 0.14 mmol), norbornene (268 mg, 2.86 mmol) dissolved in N,N -dimethylacetamide, sodium bicarbonate (240 mg, 2.86 mmol), the reaction was stirred at 70 ° C for 12 hours. The reaction solution was cooled to room temperature, and then added with aq. EtOAc (EtOAc) Chromatography of the residue obtained from EtOAc (EtOAc)

Second step 1-isopropyl-2-(2-methoxybenzyl)-1 H -indole-5-carboxylic acid methyl ester 2c

2b (110mg, 0.37mmol) was dissolved in N,N -dimethylformamide, a catalytic amount of potassium iodide was added, sodium hydride (30mg, 0.74mmol, 60% in oil) was added, and the reaction was stirred for 30 minutes and then added 2 Bromopropane (183 mg, 1.49 mmol) was stirred at 55 ° C for 12 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Chromatography of the residue obtained from EtOAc (EtOAc)

third step 1-isopropyl-2-(2-methoxybenzyl)-1 H -indole-5-carboxylic acid 2d

2c (25 mg, 0.085 mmol) was dissolved in 6 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 4:2), 2 mL of a 4 M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 1 hour. The reaction mixture was cooled to room temperature. EtOAc was evaporated. The residue obtained was purified by EtOAc (EtOAc) eluting

the fourth step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-methoxybenzyl)-1 H -indole-5-carbenamide 2

2d (23mg, 0.08mmol), (4-(ethylsulfonyl)phenyl)methanamine (24mg, 0.12mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiam Amine hydrochloride (21 mg, 0.12 mmol), 1-hydroxybenzotriazole (17 mg, 0.12 mmol), N,N -diisopropylethylamine (53 mg, 0.41 mmol) 12 hours. Water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The residue obtained was purified by EtOAc (EtOAc) eluting

MS m/z (ESI): 505.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.78 (d, 2H), 7.62 (d, 1H), 7.53 - 7.57 ( m,3H), 7.23(t,1H), 6.91(t,2H), 6.85(t,1H), 6.64(t,1H),6.30(s,1H),4.79(d,2H),4.50-4.56 (m, 1H), 4.12 (s, 2H), 3.88 (s, 3H), 3.11 (q, 2H), 1.51 (d, 6H), 1.27 (t, 3H).

Example 3 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 3

first step Methyl 2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 3b

1a (2.7 g, 15.41 mmol), 1-(bromomethyl)-2-(trifluoromethyl)benzene 3a (3.87 g, 16.18 mmol), diacetonitrile palladium dichloride (399 mg, 1.54 mmol) The borneol (2.9 g, 30.82 mmol), sodium hydrogencarbonate (2.59 g, 30.82 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated.

Second step Methyl 1-ethyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 3c

3b (4.4 g, 13.2 mmol) was dissolved in N,N -dimethylformamide, sodium hydride (1.06 g, 26.4 mmol, 60% in oil) and ethyl iodide (10.29 g, 66.01 mmol). The reaction was stirred for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL×3). The residue obtained was purified to afford titled product 3c (4.2 g, pale yellow solid).

third step 1-ethyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 3d

3c (1.4 g, 3.87 mmol) was dissolved in 15 mL of methanol, and 5 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux for 12 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and ethyl acetate (50 mL×3), and the organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the crude title product 3d (1.1 g, pale yellow solid).

the fourth step 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 3

3d (1.1 g, 3.17 mmol), 4-(ethylsulfonyl)phenyl)methanamine (757.31 mg, 3.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarb Diimine hydrochloride (1.21 g, 6.33 mmol), 1-hydroxybenzotriazole (856 g, 6.33 mmol), triethylamine (641 mg, 6.33 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjj .

MS m/z (ESI): 529.9 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.91 (d, 2H), 7.72-7.77 (m, 2H), 7.61 ( d, 2H), 7.37-7.49 (m, 3H), 7.16 (d, 1H), 6.67 (t, 1H), 6.34 (s, 1H), 4.83 (d, 2H), 4.37 (d, 2H), 4.05 -4.10 (m, 2H), 3.14 (q, 2H), 1.25-1.33 (m, 6H).

Example 4 N- (4-(ethylsulfonyl)benzyl)-2-(4-fluoro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5- formazan Amine 4

first step Methyl 2-(4-fluoro-2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 4b

1a (200 mg, 1.14 mmol), 1-(bromomethyl)-4-fluoro-2-(trifluoromethyl)benzene 4a (308.1 mg, 1.2 mmol), diacetonitrile palladium dichloride (29.6 mg, 0.14 Methyl), norbornene (215 mg, 2.28 mmol), sodium hydrogencarbonate (191.8 mg, 2.28 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 4c

4b (50mg, 0.142mmol) was dissolved in N,N -dimethylformamide, sodium hydride (12mg, 0.285mmol, 60% in oil), 2-bromopropane (87.53mg, 0.711mmol), 50 The reaction was stirred at ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc) (EtOAc) The residue obtained was purified by EtOAc EtOAcjjjjjj

third step 2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 4d

4c (34 mg, 0.09 mmol) was dissolved in 3 mL of methanol, 1 mL of 2 M potassium hydroxide solution was added, and the mixture was warmed to reflux for 12 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and ethyl acetate (50 mL×3), and the organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the crude title product 4d (26 mg, pale yellow solid).

the fourth step N- (4-(ethylsulfonyl)benzyl)-2-(4-fluoro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5- formazan Amine 4

Crude 4d (26 mg, 0.068 mmol), 4-(ethylsulfonyl)phenyl)methanamine (16.4 mg, 0.082 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The imine hydrochloride (26.28 mg, 0.137 mmol), 1-hydroxybenzotriazole (18.52 mg, 0.137 mmol), triethylamine (13.87 mg, 0.137 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 561.3 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.91 (d, 2H), 7.69 (dd, 1H), 7.58-7.61 ( m,3H), 7.48 (dd, 1H), 7.16 (dt, 1H), 7.08 (d, 1H), 6.67 (t, 1H), 6.34 (s, 1H), 4.83 (d, 2H), 4.40-4.47 (m, 1H), 4.33 (s, 2H), 3.14 (q, 2H), 1.53 (d, 6H), 1.31 (t, 3H).

Example 5 2- (4-chloro-2- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl Amine 5

first step Methyl 2-(4-chloro-2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 5b

1a (200 mg, 1.14 mmol), 1-(bromomethyl)-4-chloro-2-(trifluoromethyl)benzene 5a (327.83 mg, 1.2 mmol), diacetonitrile palladium dichloride (29.6 mg, 0.14 Methyl), norbornene (215 mg, 2.28 mmol), sodium hydrogencarbonate (191.8 mg, 2.28 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 5c

5b (50mg, 0.136mmol) was dissolved in N,N -dimethylformamide, sodium hydride (11mg, 0.272mmol, 60% in oil), 2-bromopropane (84mg, 0.68mmol), 50°C The reaction was stirred for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc) (EtOAc) The residue obtained was purified by EtOAc EtOAcjjjjjj

third step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 5d

5c (28 mg, 0.071 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux for 12 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and ethyl acetate (50 mL×3), and the organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the crude title product 5d (14 mg, pale yellow solid).

the fourth step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 5

The crude product 5d (28mg, 0.07mmol), 4-(ethylsulfonyl)phenyl) Amine (16.92 mg, 0.085 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.12 mg, 0.141 mmol), 1-hydroxybenzotriazole (19.12) Methyl, 0.101 mmol), triethylamine (14.32 mg, 0.141 mmol) was dissolved in dichloromethane and stirred for 12 hr. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 577.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.81 (d, 2H), 7.65-7.71 (m, 2H), 7.53 7.56 (m, 3H), 7.39 (dd, 1H), 7.00 (d, 1H), 6.78 (t, 1H), 6.30 (s, 1H), 4.78 (d, 2H), 4.35-4.42 (m, 1H) ), 4.29 (s, 2H), 3.10 (q, 2H), 1.50 (d, 6H), 1.28 (t, 3H).

Example 6 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 6

first step Methyl 2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 6a

1a (3g, 17.12mmol), 1-(bromomethyl)-2-(trifluoromethyl)benzene 3b (4.3g, 17.98mmol), diacetonitrile palladium dichloride (444mg, 1.71mmol), borneol The olefin (3.22 g, 34.25 mmol), sodium hydrogencarbonate (2.88 g, 34.25 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step Methyl 1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 6b

6a (4.6 g, 13.8 mmol) was dissolved in 20 mL of N,N -dimethylformamide, sodium hydride (1.1 g, 27.6 mmol, 60% in oil), 2-bromopropane (84 mg, 0.68 mmol) The reaction was stirred at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc) (EtOAc) Column chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

third step 1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 6c

6b (1.5 g, 4 mmol) was dissolved in 15 mL of methanol, and 5 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated hydrochloric acid was added dropwise to pH 4, and extracted with ethyl acetate (50 mL×3). The organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration by pressure gave the crude title product 6c (1.33 g, pale yellow solid).

the fourth step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 6

Crude 6c (1.33 g, 3.68 mmol), 4-(ethylsulfonyl)phenyl)methanamine (880.11 mg, 0.42 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (1.41 g, 7.36 mmol), 1-hydroxybenzotriazole (994.66 mg, 7.36 mmol), triethylamine (744.87 mg, 7.36 mmol) dissolved in dichloromethane. . The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 544.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.89 (d, 2H), 7.76 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 2H), 7.38-7.46 (m, 2H), 7.10 (d, 1H), 6.74 (t, 1H), 6.35 (s, 1H), 4.83 (d, 2H), 4.42-4.49 (m, 1H), 4.38 (s, 2H), 3.14 (q, 2H), 1.52 (d, 6H), 1.31 (t, 3H).

Example 7 N- (4-((cyclopropylmethyl)sulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- Formamide 7

first step Sodium 4-cyanobenzenesulfinate 7b

4-cyanobenzenesulfonium chloride 7a (1.01 g, 5 mmol), sodium sulfite (1.26 g, 10 mmol), sodium hydrogencarbonate (0.84 g, 10 mmol) was added to 20 mL of water, and the mixture was stirred at 75 ° C for 5 hours. The reaction mixture was cooled to room temperature and then evaporated, evaporated, evaporated

Second step 4-((cyclopropylmethyl)sulfonyl)benzonitrile 7c

The crude 7b (946 mg, 5 mmol), (bromomethyl)cyclopropane (2.03 g, 15 mmol) and a catalytic amount of methyl iodide were added to 30 mL of N,N -dimethylformamide, and the reaction was stirred at 75 ° C for 12 hours. The reaction solution was cooled to room temperature, and then added with 100 mL of water, and ethyl acetate (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to eluent. The obtained residue was purified to purified crystal crystal crystal crystal crystal crystal

third step (4-((cyclopropylmethyl)sulfonyl)phenyl)methylamine 7d

7c (670 mg, 3 mmol) was dissolved in 30 mL of methanol, 5 mL of aqueous ammonia was added, and a catalytic amount of Raney nickel was added thereto, and the hydrogen was replaced three times, and the reaction was stirred for 12 hours. The reaction solution was filtered, and the filtrate was evaporated. mjjjjjjjjj

the fourth step N- (4-((cyclopropylmethyl)sulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- Formamide 7

Crude 7d (28.06 mg, 0.12 mmol), crude 6e (30 mg, 0.083 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (32 mg, 0.166 mmol) 1-Hydroxybenzotriazole (23 mg, 0.166 mmol), N,N -diisopropylethylamine (22 mg, 0.166 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 569.2 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.89 (d, 2H), 7.76 (d, 1H), 7.71 (d, 1H), 7.57 (t, 3H), 7.38-7.47 (m, 2H), 7.10 (d, 1H), 6.86 (t, 1H), 6.34 (s, 1H), 4.82 (d, 2H), 4.42-4.49 (m,1H), 4.37(s,2H), 3.03(d,2H), 1.52(d,6H),0.99-1.02(m,1H),0.57-0.62(m,2H),0.17-0.21(m , 2H).

Example 8 N -(4-(ethylsulfonyl)-2-fluorobenzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 8

first step 4-(ethanesulfonyl)-2-fluorobenzylaminocarboxylic acid tert-butyl ester 8b

4-Bromo-2-fluorobenzylaminocarboxylic acid tert-butyl ester 8a (400 mg, 1.32 mmol, prepared by the method disclosed in the patent application "EP991638"), sodium ethyl sulfinate (229 mg, 1.97 mmol) Cesium carbonate (642.7 mg, 1.97 mmol) was dissolved in dimethyl hydrazine, and a catalytic amount of cuprous iodide and L -proline was added thereto, and the mixture was heated to 120 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, and an appropriate amount of ethyl acetate was added and filtered, and the filtrate was washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified to crystal crystal crystal crystal crystal crystal crystal

Second step (4-(ethylsulfonyl)-2-fluorophenyl)methylamine trifluoroacetate 8c

8b (340 mg, 1.12 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 3 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals

third step N -(4-(ethylsulfonyl)-2-fluorobenzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 8

Crude 8c (21.64 mg, 0.1 mmol), 6e (30 mg, 0.083 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.83 mg, 0.166 mmol) 1-Hydroxybenzotriazole (22.44 mg, 0.166 mmol), N,N -diisopropylethylamine (21.46 mg, 0.166 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 561.1 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.95 (s, 1H), 7.75-7.78 (m, 2H), 7.67- 7.71 (m, 2H), 7.59 (d, 1H), 7.38-7.48 (m, 2H), 7.10 (d, 1H), 6.89 (t, 1H), 6.35 (s, 1H), 4.85 (d, 2H) , 4.42-4.49 (m, 1H), 4.38 (s, 2H), 3.15 (q, 2H), 1.52 (d, 6H), 1.31 (t, 3H).

Example 9 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 9

first step Methyl 1-cyclopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 9a

6c (100 mg, 0.3 mmol) was dissolved in 1,2-dichloroethane, respectively, cyclopropylboronic acid (39 mg, 0.45 mmol), copper acetate monohydrate (90 mg, 0.45 mmol), 2,2'-linked Pyridine (70 mg, 0.45 mmol) and sodium carbonate (64 mg, 0.6 mmol) were warmed to 70 ° C and stirred for 24 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

Second step 1-cyclopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 9b

9a (65 mg, 0.17 mmol) was dissolved in 7 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 5:2), 2 mL of a 4 M sodium hydroxide solution was added, and the mixture was heated to 60 ° C and stirred for 1 hour. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and ethyl acetate was evaporated to ethyl acetate (20 mL, 3), and the organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the title product 9b (55 mg, white solid).

third step 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 9

Crude 9b (55 mg, 0.15 mmol), 4-(ethylsulfonyl)phenyl)methanamine (40 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (44 mg, 0.23 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol), N,N -diisopropylethylamine (59 mg, 0.46 mmol) 12 hours. Add water and a small amount of methanol, extract with a mixed solvent of dichloromethane and methanol (V: V = 8:1) (20 mL × 2), combine the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, filtrate The residue was purified by EtOAc EtOAcjjjjjjj

MS m/z (ESI): 541.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.03 (t, 1H), 8.06 (s, 1H), 7.83 (d, 2H), 7.79 ( d,1H), 7.72(d,1H), 7.63(t,1H),7.57(d,3H),7.51(t,1H), 7.26(d,1H),6.01(s,1H),4.58(d , 2H), 4.44 (s, 2H), 3.25 (q, 2H), 3.08-3.13 (m, 1H), 1.10-1.15 (m, 2H), 1.08 (t, 3H), 0.94-0.98 (m, 2H) ).

Example 10 2- (2- (ethylbenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 10

first step 2-(2-(ethylbenzyl)-1 H -indole-5-carboxylic acid methyl ester 10b

1a (150 mg, 0.856 mmol), 1-(bromomethyl)-2-ethylbenzene 10a (179 mg, 0.899 mmol), diacetonitrile palladium dichloride (22.2 mg, 0.086 mmol), norbornene (161.24 mg) , 1.71 mmol), sodium bicarbonate (143.86mg, 1.71mmol) was dissolved in N, N - dimethylacetamide, the reaction was raised to 70 deg.] C was stirred for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 2-(2-(ethylbenzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 10c

10b (67 mg, 0.23 mmol) was dissolved in 5 mL of N,N -dimethylformamide, sodium hydride (18.27 mg, 0.46 mmol, 60% in oil), 2-bromopropane (140.45 mg, 1.14 mmol) The reaction was stirred at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAcjjjjjj

third step 2-(2-(ethylbenzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 10d

10c (46 mg, 0.137 mmol) was dissolved in 5 mL of methanol, 2 mL of 2 M potassium hydroxide solution was added, and the mixture was heated to reflux and stirred for 3 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, evaporated. The sodium solution was washed with EtOAc (EtOAc m.

the fourth step 2- (2- (ethylbenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 10

Crude 10d (42 mg, 0.13 mmol), (4-(ethylsulfonyl)phenyl)methanamine (31.25 mg, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (50.01 mg, 0.26 mmol), 1-hydroxybenzotriazole (35.31 mg, 0.26 mmol), triethylamine (26.45 mg, 0.26 mmol) dissolved in dichloromethane The reaction was stirred for 12 hours in the alkane. The reaction mixture was concentrated under reduced vacuolululululululululululululululu

MS m/z (ESI): 503.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.91 (d, 2H), 7.67 (d, 1H), 7.58-7.61 ( m,3H), 7.27-7.31 (m, 2H), 7.16 (t, 1H), 6.99 (d, 1H), 6.62 (t, 1H), 6.18 (s, 1H), 4.83 (d, 2H), 4.54 -4.61 (m, 1H), 4.16 (s, 2H), 3.14 (q, 2H), 2.74 (q, 2H), 1.60 (d, 6H), 1.25-1.31 (m, 6H).

Example 11 N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5 -carbamamine 11

Crude 6e (42 mg, 0.11 mmol), 5-(ethylsulfonyl)pyridin-2-yl)methylamine 11a (26.47 mg, 0.13 mmol, obtained by the method disclosed in the patent application "WO201517335"), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (42.45 mg, 0.22 mmol), 1-hydroxybenzotriazole (29.92 mg, 0.22 mmol), triethylamine (22.41) Mg, 0.22 Methyl) was dissolved in dichloromethane and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 544.4 [M+1].

Example 12 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-1 H -indole-5- formazan Amine 12

first step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-cyclopropyl-1 H -indole-5-carboxylic acid methyl ester 12a

5c (150 mg, 0.408 mmol) was dissolved in 1,2-dichloroethane, respectively, cyclopropylboronic acid (180 mg, 2.04 mmol), copper acetate (14.9 mg, 0.08 mmol), 2,2'-bipyridine (318.5 mg, 2.04 mmol) and sodium carbonate (86.5 mg, 0.816 mmol) were heated to 70 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjj

Second step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-cyclopropyl-1 H -indole-5-carboxylic acid 12b

12a (21 mg, 0.05 mmol) was dissolved in 2 mL of methanol, 2 mL of 2 M potassium hydroxide solution was added, and the mixture was heated to reflux and stirred for 3 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The sodium solution was washed with EtOAc EtOAc (EtOAc m.

third step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-1 H -indole-5- formazan Amine 12

Crude 12b (16 mg, 0.04 mmol), (4-(ethylsulfonyl)phenyl)methanamine (12.2 mg, 0.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarb Diimine hydrochloride (15.6 mg, 0.08 mmol), 1-hydroxybenzotriazole (11 mg, 0.08 mmol), triethylamine (9 mg, 0.08 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced EtOAc.

MS m/z (ESI): 575.4 [M+1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.78 (d, 2H), 7.68-7.71 (m, 2H), 7.56- 7.61 (m, 3H), 7.41 (dd, 1H), 7.02 (d, 1H), 6.62 (t, 1H), 6.20 (s, 1H), 4.79 (d, 2H), 4.42 (s, 2H), 3.10 (q, 2H), 2.96-3.00 (m, 1H), 1.28 (t, 3H), 1.10-1.14 (m, 2H), 1.97-1.01 (m, 2H).

Example 13 2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-1 H -indole-5- formazan Amine 13

first step Methyl 2-(4-fluoro-2-(trifluoromethyl)benzyl)-1-cyclopropyl- 1H -indole-5-carboxylate 13a

4c (100 mg, 0.285 mmol) was dissolved in 1,2-dichloroethane, respectively, cyclopropylboronic acid (125.4 mg, 1.42 mmol), copper acetate (103.4 mg, 0.569 mmol), 2,2'-linked Pyridine (222.3 mg, 1.42 mmol) and sodium carbonate (60.4 mg, 0.569 mmol) were heated to 80 ° C and stirred for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and acetic acid was added to the residue. Ethyl acetate, EtOAc (EtOAc m.)

Second step 2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-cyclopropyl-1 H -indole-5-carboxylic acid 13b

13a (71 mg, 0.174 mmol) was dissolved in 3 mL of methanol, and 3 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 3 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The sodium solution was washed with EtOAc EtOAc (EtOAc m.

third step 2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-1 H -indole-5- formazan Amine 13

Crude 13b (56 mg, 0.148 mmol), (4-(ethylsulfonyl)phenyl)methanamine (44.36 mg, 0.222 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (56.9 mg, 0.297 mmol), 1-hydroxybenzotriazole (40.11 mg, 0.297 mmol), triethylamine (30 mg, 0.297 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced pressure. mjjjjjjjj

MS m/z (ESI): 557.1 [M-1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.91 (d, 2H), 7.72 (dd, 1H), 7.59-7. m, 3H), 7.48 (dd, 1H), 7.18 (dt, 1H), 6.64 (t, 1H), 6.21 (s, 1H), 4.82 (d, 2H), 4.45 (s, 2H), 3.14 (q) , 2H), 3.00-3.06 (m, 1H), 1.32 (t, 3H), 1.14-1.19 (m, 2H), 1.02-1.05 (m, 2H).

Example 14 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 14

first step 2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid methyl ester 14b

1a (200 mg, 1.14 mmol), 1-(bromomethyl)-4-trifluoromethyl)benzene 14a (286 mg, 1.97 mmol), diacetonitrile palladium dichloride (16 mg, 0.057 mmol), norbornene ( 214 mg, 2.28 mmol), sodium hydrogencarbonate (144 mg, 1.71 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAcjjjjj

Second step 2-(4-(Trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 14c

The 14b (94mg, 0.28mmol) was dissolved in 3mL N, N - dimethylformamide was added sodium hydride (27mg, 0.56mmol, 60% in oil), 2- bromopropane (70mg, 0.56mmol), 80 The reaction was stirred at ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAcjjjjjjjjjjjjjjjjjj Product 14c (67 mg, pale yellow solid).

third step 2-(4-(Trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 14d

The crude product 14c (67 mg, 0.18 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The solution was washed with EtOAc EtOAc (EtOAc m.

the fourth step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 14

Crude 14d (54 mg, 0.15 mmol), (4-(ethylsulfonyl)phenyl)methanamine (36 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbane The imine hydrochloride (57 mg, 0.3 mmol), 1-hydroxybenzotriazole (39 mg, 0.3 mmol), triethylamine (33 mg, 0.3 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. mjjjjjjjj

MS m/z (ESI): 543.9 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.84 (d, 2H), 7.65 (d, 1H), 7.52-7.58 ( m, 5H), 7.30 (d, 2H), 6.74 (t, 1H), 6.34 (s, 1H), 4.78 (d, 2H), 4.47-4.50 (m, 1H), 4.22 (s, 2H), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 15 N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5- formazan Amine 15

first step 2-(2-Fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid methyl ester 15b

1a (200 mg, 1.14 mmol), 1-(bromomethyl)-2-fluoro-4-trifluoromethyl)benzene 15a (322.8 mg, 1.26 mmol), bis acetonitrile palladium chloride (13 mg, 0.057 mmol) The norbornene (12 mg, 0.114 mmol) and sodium hydrogencarbonate (144 mg, 1.71 mmol) were dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 2-(2-Fluoro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 15c

15b (131mg, 0.37mmol) was dissolved in N,N -dimethylformamide, sodium hydride (30mg, 0.75mmol, 60% in oil), 2-bromopropane (92mg, 0.75mmol), 50°C The reaction was stirred for 12 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate (20 mL × 3). The organic phase was combined, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAcjjjjjj

third step 2-(2-Fluoro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 15d

15c (72 mg, 0.183 mmol) was dissolved in 3 mL of methanol, 1 mL of 2 M potassium hydroxide solution was added, and the mixture was heated to 70 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The solution was washed with EtOAc EtOAc (EtOAc m.

the fourth step N - (4- (ethanesulfonyl acyl) benzyl) -2- (2-fluoro-4- (trifluoromethyl) benzyl) -1-isopropyl--1 H - indole-5-acyl Amine 15

Crude 15d (47mg, 0.12mmol), (4-(ethylsulfonyl)phenyl)methanamine (30mg, 0.15mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbamate The imine hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), triethylamine (26 mg, 0.25 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 561.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (s, 1H), 7.90 (d, 2H), 7.69 (d, 1H), 7.57-7.61 (m) , 3H), 7.42 (d, 1H), 7.37 (d, 1H), 7.20 (t, 1H), 6.69 (t, 1H), 6.36 (s, 1H), 4.82 (d, 2H), 4.50-4.57 ( m, 1H), 4.25 (s, 2H), 3.14 (q, 2H), 1.57 (d, 6H), 1.31 (t, 3H).

Example 16 2- (2-chloro-4- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl Amine 16

first step 2-(2-chloro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid methyl ester 16b

1a (200 mg, 1.14 mmol), 1-(bromomethyl)-2-chloro-4-trifluoromethyl)benzene 16a (328 mg, 1.2 mmol), bis acetonitrile dichloride (28 mg, 0.11 mmol) Norbornene (215 mg, 2.28 mmol), sodium hydrogencarbonate (144 mg, 1.71 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc (EtOAc m.)

Second step 2-(2-chloro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid methyl ester 16c

16b (89mg, 0.24mmol) was dissolved in N,N -dimethylformamide, sodium hydride (20mg, 0.48mmol, 60% in oil), 2-bromopropane (60mg, 0.48mmol), 50°C The reaction was stirred for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAcjjjjjjjjjjjjjjjjjjjjj 16c (41 mg, colorless oil), product was taken to the next step without purification.

third step 2-(2-chloro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 16d

The crude product 16c (41 mg, 0.1 mmol) was dissolved in 3 mL of methanol, 1 mL of 2 M potassium hydroxide solution was added, and the reaction was stirred at 70 ° C for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The solution was washed with EtOAc EtOAc (EtOAc m.

the fourth step 2- (2-chloro-4- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl Amine 16

Crude 16d (34 mg, 0.086 mmol), (4-(ethylsulfonyl)phenyl)methanamine (26 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The imine hydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), triethylamine (17.4 mg, 0.17 mmol) was dissolved in dichloromethane. The residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (ESI): 576.9 [M-1].

Example 17 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(3-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 17

first step 2-(3-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid methyl ester 17b

1a (200 mg, 1.13 mmol), 1-(bromomethyl)-3-trifluoromethyl)benzene 17a (286 mg, 1.2 mmol), diacetonitrile palladium dichloride (16 mg, 0.06 mmol), norbornene ( 218 mg, 2.3 mmol), sodium hydrogencarbonate (134 mg, 1.71 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 2-(3-(Trifluoromethyl)benzyl)-1-isopropyl-1 H -indole-5-carboxylic acid 17c

17b (134mg, 0.4mmol) was dissolved in N,N -dimethylformamide, sodium hydride (32mg, 0.8mmol, 60% in oil), 2-bromopropane (99mg, 0.8mmol), 70°C The reaction was stirred for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

third step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(3-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 17

17c (30 mg, 0.08 mmol), (4-(ethylsulfonyl)phenyl)methanamine (20 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine hydrochloride (33 mg, 0.17 mmol), 1-hydroxybenzotriazole (23 mg, 0.17 mmol), triethylamine (17 mg, 0.17 mmol) was dissolved in dichloromethane. The residue was purified by EtOAc EtOAcjjjjjjj

MS m/z (ESI): 543.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.85 (d, 2H), 7.65 (d, 1H), 7.50-7.57 (m) , 3H), 7.41-7.47 (m, 2H), 7.36 (d, 1H), 6.75 (t, 1H), 6.33 (s, 1H), 4.78 (d, 2H), 4.45-4.53 (m, 1H), 4.22 (s, 2H), 4.10-4.16 (m, 1H), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 18 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 18

first step Methyl 2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylate 18b

1a (500 mg, 2.85 mmol), 1-(bromomethyl)-4-trifluoromethoxybenzene 18a (716 mg, 3 mmol), diacetonitrile palladium dichloride (39 mg, 0.14 mmol), norbornene (534 mg) 5.7 mmol), sodium hydrogencarbonate (360 mg, 4.28 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 1-isopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylic acid 18c

18b (200mg, 0.573mmol) was dissolved in N,N -dimethylformamide, sodium hydride (46mg, 0.15mmol, 60% in oil), 2-bromopropane (140.84mg, 1.15mmol) The reaction was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc. EtOAcjjjjjjjjj

third step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 18

18c (30 mg, 0.08 mmol), (4-(ethylsulfonyl)phenyl)methanamine (20 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine hydrochloride (31 mg, 0.16 mmol), 1-hydroxybenzotriazole (21 mg, 0.16 mmol), triethylamine (17 mg, 0.16 mmol) was dissolved in dichloromethane. The residue was purified by EtOAc EtOAcjjjjjjj

MS m/z (ESI): 559.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.85 (d, 2H), 7.65 (d, 1H), 7.50-7.57 (m) , 3H), 7.41-7.47 (m, 2H), 7.36 (d, 1H), 6.75 (t, 1H), 6.33 (s, 1H), 4.78 (d, 2H), 4.45-4.53 (m, 1H), 4.22 (s, 2H), 4.10-4.16 (m, 1H), 3.10 (q, 2H), 1.47 (d, 6H), 1.27 (t, 3H).

Example 19 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carbenamide 19

first step Methyl 2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 19a

1a (1g, 5.71mmol), 14b (1.43g, 5.99mmol), diacetonitrile palladium dichloride (150mg, 0.571mmol), norbornene (1.1g, 11.42mmol), sodium bicarbonate (0.63g, 7.42) Methyl) was dissolved in N,N -dimethylacetamide and stirred at 70 ° C for 16 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc) (EtOAc) The crude title product 19a (1.5 g, yellow solid) was obtained.

Second step Methyl 1-ethyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 19b

The crude product 19a (0.2 g, 0.6 mmol) was dissolved in 5 mL of N,N -dimethylmethionamine, sodium hydride (48 mg, 1.2 mmol, 60% in oil) was added, and the reaction was stirred at 0 ° C for 1 hour, and iodine was added. Ethane (0.19 g, 1.2 mmol) was heated to 50 ° C and stirred for 15 hours. The reaction mixture was cooled to room temperature, then added with 50 mL of EtOAc (EtOAc (EtOAc) The crude title product 19b (63 mg, yellow solid).

third step 1-ethyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 19c

The crude product 19b (63 mg, 0.74 mmol) was dissolved in a mixed solvent of 11 mL of methanol and water (V: V = 10:1), sodium hydroxide (35 mg, 0.872 mmol) was added, and the reaction was stirred at 60 ° C for 16 hours. The reaction was cooled to room temperature, 2 M hydrochloric acid was added dropwise to pH 3-4, and concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product 19c (40g, white solid), producing Rate: 67%.

the fourth step 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carbenamide 19

19c (10 mg, 0.029 mmol), (4-(ethylsulfonyl)phenyl)methanamine (11.6 mg, 0.058 mmol), 2-(7-azobenzotriazole) -N,N,N ',N '-Tetramethylurea hexafluorophosphate (16 mg, 0.044 mmol), N,N -diisopropylethylamine (18.7 mg, 0.044 mmol) dissolved in 5 mL of N,N -dimethylformamide The reaction was stirred for 16 hours. 50 ml of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was combined, washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate The resulting residue was purified with EtOAc EtOAcjjjjj

MS m/z (ESI): 529.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.78 (d, 2H), 7.69 (dd, 1H), 7.56-7.60 (m) , 4H), 7.32-7.35 (m, 3H), 6.64 (t, 1H), 6.34 (s, 1H), 4.80 (d, 2H), 4.21 (s, 2H), 4.08 (q, 2H), 3.11 ( q, 2H), 1.29 (t, 3H), 1.21 (t, 3H).

Example 20 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 20

first step Methyl 1-cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 20a

19c (75 mg, 0.22 mmol) was dissolved in 1,2-dichloroethane, respectively, cyclopropylboronic acid (39 mg, 0.45 mmol), copper acetate monohydrate (45 mg, 0.22 mmol), 2,2'-linked Pyridine (35 mg, 0.22 mmol) and sodium carbonate (36 mg, 0.34 mmol) were warmed to 70 ° C and stirred for 24 hours. The reaction mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated Concentrated under reduced pressure, using thin layer chromatography The residue obtained was purified to give titled product 20a (yield:

Second step 1-cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 20b

20a (80 mg, 0.21 mmol) was dissolved in 8 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 1:1), 2 mL of 4 M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 2 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 5-6, and ethyl acetate (20 mL×3), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, filtrate reduced Concentration under pressure gave the crude title product 20b (60 mg, pale yellow oil solid).

third step 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 20

Crude 20b (60 mg, 0.17 mmol), (4-(ethylsulfonyl)phenyl)methanamine (50 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Imine hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), N,N -diisopropylethylamine (65 mg, 0.50 mmol) Reaction for 12 hours. Water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The residue obtained was purified by EtOAc (EtOAc) elute

MS m/z (ESI): 541.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.03 (t, 1H), 8.09 (s, 1H), 7.84 (d, 2H), 7.70 ( d, 3H), 7.58 (t, 2.5H), 7.52 (t, 2.5H), 6.24 (s, 1H), 4.58 (d, 2H), 4.37 (s, 2H), 3.25 (q, 2H), 2.94 -2.99 (m, 1H), 1.12-1.17 (m, 2H), 1.08 (t, 3H), 0.97-1.01 (m, 2H).

Example 21 N- (4-(ethylsulfonyl)benzyl)-1-methyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 21

first step Methyl 2-(4-(trifluoromethoxy)benzyl)-1-methyl-1 H -indole-5-carboxylate 21a

18c (50 mg, 0.14 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (12 mg, 0.28 mmol, 60% in oil) was added, and the reaction was stirred for 5 minutes, and iodomethane (30.5 mg, 0.21 mmol) was added, and the reaction was stirred for 30 minutes. The reaction mixture was poured into water, EtOAc (EtOAc m. Yellow oil), the product was directly subjected to the next reaction without purification.

Second step 1-methyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylic acid 21b

The crude product 21a (28 mg, 0.07 mmol) was dissolved in 3 mL of methanol, 1 mL of 2 M potassium hydroxide solution was added, and the reaction was stirred at 70 ° C for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated under reduced pressure to give the title compound (jjjjjjjjj

third step N- (4-(ethylsulfonyl)benzyl)-1-methyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 21

Crude 21b (22 mg, 0.063 mmol), (4-(ethylsulfonyl)phenyl)methanamine (25.1 mg, 0.126 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (24 mg, 0.126 mmol), 1-hydroxybenzotriazole (17 mg, 0.126 mmol), triethylamine (13 mg, 0.126 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m / z (ESI): 530.9 [M + 1]; 1 HNMR (400MHz, CDCl 3) δ 8.07 (s, 1H), 7.85 (d, 2H), 7.69 (d, 1H), 7.55 (d, 2H ), 7.30 (d, 1H), 7.16-7.23 (m, 4H), 6.72 (t, 1H), 6.35 (s, 1H), 4.78 (d, 2H), 4.16 (s, 2H), 3.60 (s, 3H), 3.10 (q, 2H), 1.27 (t, 3H).

Example 22 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide twenty two

first step Methyl 1-ethyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 22a

15c (50 mg, 0.14 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (12 mg, 0.28 mmol, 60% in oil), ethyl iodide (33.3 mg, 0.21 mmol), and the mixture was stirred at 50 ° C for 2 hours. The reaction mixture was cooled to room temperature and then evaporated.

Second step 1-ethyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 22b

The crude product 22a (28 mg, 0.07 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, The solution was washed with EtOAc EtOAc (EtOAc m.

third step 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide twenty two

Crude 22b (24 mg, 0.066 mmol), (4-(ethylsulfonyl)phenyl)methanamine (26.2 mg, 0.131 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (26 mg, 0.131 mmol), 1-hydroxybenzotriazole (18 mg, 0.131 mmol), triethylamine (13.3 mg, 0.131 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 547.9 [M+].

Example 23 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carbenamide 23

first step Methyl 1-ethyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylate 23a

18c (50 mg, 0.14 mmol) was dissolved in 5 mL of tetrahydrofuran, sodium hydride (12 mg, 0.28 mmol, 60% in oil), ethyl iodide (33.5 mg, 0.21 mmol) was added and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give crystal crystal crystal crystal crystal crystal crystal crystal

Second step 1-ethyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylic acid 23b

The crude product 23a (26 mg, 0.07 mmol) was dissolved in 3 mL of methanol, and 1 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was heated to reflux and stirred for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated, evaporated, evaporated, evaporated. The filtrate was concentrated under reduced pressure to give crystals crystals crystals crystals crystals

third step 1-ethyl - N - (4- (ethanesulfonyl acyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) -1 H - indole-5-acyl-amine 23

Crude 23b (21 mg, 0.057 mmol), (4-(ethylsulfonyl)phenyl)methanamine (23 mg, 0.115 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The imine hydrochloride (22 mg, 0.115 mmol), 1-hydroxybenzotriazole (15 mg, 0.115 mmol), triethylamine (12 mg, 0.115 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjjj

MS m/z (ESI): 545.9 [M+1].

Example 24 N- (4-(ethylsulfonyl)benzyl)-1-(2-hydroxyethyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 24

first step Methyl 1-(2-((t-butyldimethylmethyl)oxy)ethyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 24a

14c (60mg, 0.18mmol), cesium carbonate (117mg, 0.36mmol), (2-bromoethoxy)-t-butyldimethyl decane (86mg, 0.36mmol) and a catalytic amount of potassium iodide dissolved in 3mL N In N -dimethylformamide, microwave reaction was carried out at 80 ° C for 1 hour. The reaction solution was cooled to room temperature, and then added with ethyl acetate (60 mL). Title product 24a (38 mg, viscous), yield: 43%.

Second step 1-(2-hydroxyethyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 24b

24a (38 mg, 0.077 mmol) was dissolved in 6 mL of methanol, 1.1 mL of 2 M sodium hydroxide solution was added, and the reaction was stirred at 65 ° C for 12 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove most of the solvent was added 5mL of tetrahydrofuran was added dropwise 1 M hydrochloric acid at 0 ℃ pH 4, concentrated under reduced pressure to give the crude title product 24b (14mg, pink solid), the product was used without Purification proceeds directly to the next reaction.

third step N- (4-(ethylsulfonyl)benzyl)-1-(2-hydroxyethyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 24

Crude 24b (14 mg, 0.038 mmol), (4-(ethylsulfonyl)phenyl)methanamine (10 mg, 0.046 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Imine hydrochloride (11 mg, 0.057 mmol), 1-hydroxybenzotriazole (8 mg, 0.057 mmol), triethylamine (19 mg, 0.19 mmol) The reaction was stirred for 12 hours. After adding 40 mL of ethyl acetate, it was washed with water (20 mL), EtOAc (EtOAc) Product 24 (9 mg, white solid), yield: 43%.

MS m/z (ESI): 545.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.88-7.83 (m, 2H), 7.65 (d, 1H), 7.50-7.53 (m, 4H), 7.32-7.34 (m, 3H), 6.74 (brs, 1H), 6.30 (s, 1H), 4.77 (d, 2H), 4.29 (s, 2H), 4.19 (t, 2H), 3.92 (s, 2H), 3.85 (t, 2H), 3.10 (q, 2H), 1.27 (t, 3H).

Example 25 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5- Formamide 25

first step 2-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5-carboxylic acid methyl ester 25b

1a (300 mg, 1.71 mmol), 5-(bromomethyl)-2-(trifluoromethyl)pyridine 25a (431.58 mg, 1.8 mmol), diacetonitrile palladium dichloride (44.43 mg, 0.17 mmol) The borneol (322.48 mg, 3.42 mmol), sodium hydrogencarbonate (281.71 mg, 3.42 mmol) was dissolved in N,N -dimethylacetamide, and the mixture was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 1-ethyl 2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5-carboxylic acid methyl ester 25c

25b (50 mg, 2.149 mmol) was dissolved in 5 mL of acetonitrile, ethyl iodide (116.64 mg, 0.748 mmol) and potassium carbonate (41.34 mg, 0.3 mmol) were added, and the reaction was stirred at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, filtered, and then evaporated tolulululululululululululululululululululululululululululu

third step 1-ethyl 2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5-carboxylic acid 25d

25c (36 mg, 0.1 mmol) was dissolved in 3 mL of methanol, 1 mL of 2 M sodium hydroxide solution was added, and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, evaporated. The sodium solution was washed with EtOAc (EtOAc m.

the fourth step 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5- Formamide 25

Crude 25d (27 mg, 0.077 mmol), (4-(ethylsulfonyl)phenyl)methanamine (23.17 mg, 0.116 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (29.7 mg, 0.155 mmol), 1-hydroxybenzotriazole (21 mg, 0.155 mmol), triethylamine (15.69 mg, 0.155 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 530.3 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.68 (s, 1H), 8.07 (s, 1H), 7.78 (d, 2H), 7.64 - 7.72 (m) , 3H), 7.57 (d, 2H), 7.35 (d, 1H), 6.64 (t, 1H), 6.29 (s, 1H), 4.79 (d, 2H), 4.23 (s, 2H), 4.11 (q, 2H), 3.11 (q, 2H), 1.26-1.30 (m, 6H).

Example 26 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzylidenyl)-1 H -indole-5-carbenamide 26

first step 1-ethyl-2-(4-(trifluoromethyl)benzylidenyl)-1 H -indole-5-carboxylic acid methyl ester 26a

19d (180 mg, 0.5 mmol) was dissolved in 20 mL of 1,4-dioxane, manganese dioxide (2.18 g, 25 mmol) was added, and the reaction was stirred at 100 ° C for 12 hours, and manganese dioxide (2.18 g, 25 mmol) was added. The reaction was stirred at 100 ° C for 36 hours. The reaction mixture was cooled to room temperature, EtOAc (EtOAc)EtOAc. , Yield: 27%.

Second step 1-ethyl-2-(4-(trifluoromethyl)benzylidenyl)-1 H -indole-5-carboxylic acid 26b

26a (15 mg, 0.04 mmol) was dissolved in 5 mL of methanol, 0.6 mL of 1 M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 12 hours. The reaction was cooled to room temperature, concentrated to remove the methanol, 2mL of tetrahydrofuran was added to the resulting residue, was added dropwise 1 M hydrochloric acid to pH 4-5, and concentrated under reduced pressure to give the crude title product 26b (14mg, white solid) under reduced pressure, The product was directly subjected to the next reaction without purification.

third step 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzylidenyl)-1 H -indole-5-carbenamide 26

Crude 26b (14 mg, 0.04 mmol), (4-(ethylsulfonyl)phenyl)methanamine (10 mg, 0.048 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The imine hydrochloride (14 mg, 0.072 mmol), 1-hydroxybenzotriazole (10 mg, 0.072 mmol), triethylamine (16 mg, 0.16 mmol) was dissolved in dichloromethane. After adding 20 mL of ethyl acetate, the mixture was washed with H2HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Yellow solid), Yield: 73%.

MS m/z (ESI): 543.3 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 8.00 (d, 2H), 7.86-7.91 (m, 3H), 7.79-7.81 (d, 2H), 7.58-7.53 (m, 3H), 7.07 (s, 1H), 6.67-6.69 (m, 1H), 4.80 (d, 2H), 4.67 (q, 2H), 3.11 (q, 2H) ), 1.51 (t, 3H), 1.29 (t, 3H).

Example 27 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 27

first step Methyl 1-cyclopropyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylate 27a

15c (150 mg, 0.427 mmol) was dissolved in 1,2-dichloroethane, respectively, cyclopropylboronic acid (183.39 mg, 2.13 mmol), copper acetate monohydrate (15.51 mg, 0.085 mmol), 2, 2' Bipyridine (133.38 mg, 0.854 mmol) and sodium carbonate (90.51 mg, 0.853 mmol) were heated to 70 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature, dichloromethane was added, filtered, and the filtrate was evaporated. mjjjjjjjj Rate: 57%.

Second step 1-cyclopropyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxylic acid 27b

27a (96 mg, 0.254 mmol) was dissolved in 4 mL of a mixed solvent of methanol and water (V: V = 1:1), and lithium hydroxide (13 mg, 0.508 mmol) was added thereto, and the mixture was heated to 70 ° C and stirred for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, evaporated. Sodium solution The mixture was washed with EtOAc EtOAc EtOAc.

third step 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 27

Crude 27b (31 mg, 0.082 mmol), (4-(ethylsulfonyl)phenyl)methanamine (19.6 mg, 0.099 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (31.5 mg, 0.164 mmol), 1-hydroxybenzotriazole (22.2 mg, 0.164 mmol), triethylamine (16.6 mg, 0.164 mmol) dissolved in dichloromethane. . The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 559.4 [M+1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (s, 1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.56-7.62 (m) , 3H), 7.40 (t, 2H), 7.28 (t, 1H), 6.79 (t, 1H), 6.28 (s, 1H), 4.81 (d, 2H), 4.36 (s, 2H), 3.13 (q, 2H), 3.02-3.07 (m, 1H), 1.30 (t, 3H), 1.20-1.25 (m, 2H), 1.07-1.11 (m, 2H).

Example 28 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxamide 28

first step Methyl 1-cyclopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylate 28a

18c (100 mg, 0.286 mmol) was dissolved in dichloromethane and cyclopropylboronic acid (126.12 mg, 1.43 mmol), copper acetate (10.4 mg, 0.057 mmol), 2,2'-bipyridine (223.5 mg, 1.43 mmol) and sodium carbonate (60.7 mg, 1.572 mmol) were heated to 70 ° C and stirred for 12 hours. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m.

Second step 1-cyclopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -indole-5-carboxylic acid 28b

28a (71 mg, 0.182 mmol) was dissolved in 3 mL of methanol, 3 mL of water was added, and potassium hydroxide (35.5 mg, 0.91 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and water was added to the residue. Concentrated hydrochloric acid was added dropwise to a pH of 5-6, which was extracted with ethyl acetate (20 mL×3). Product 28b (56 mg, white solid).

third step 1-Cyclopropyl - N - (4- (ethanesulfonyl acyl) benzyl) -2- (4- (trifluoromethoxy) benzyl) -1 H - indole-5-acyl-amine 28

Crude 28b (56 mg, 0.149 mmol), (4-(ethylsulfonyl)phenyl)methanamine (44.6 mg, 0.223 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbon Diimine hydrochloride (57.2 mg, 0.298 mmol), 1-hydroxybenzotriazole (40.3 mg, 0.298 mmol), triethylamine (30.2 mg, 0.298 mmol) dissolved in dichloromethane and stirred for 12 hours . The reaction mixture was concentrated under reduced EtOAc.

MS m/z (ESI): 557.3 [M+1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (s, 1H), 7.78 (d, 2H), 7.67 (d, 1H), 7.56 (d, 3H) ), 7.25 (d, 2H), 7.16 (d, 2H), 6.64 (t, 1H), 6.26 (s, 1H), 4.79 (d, 2H), 4.25 (s, 2H), 3.10 (q, 2H) , 2.92 - 2.96 (m, 1H), 1.28 (t, 3H), 1.13-1.17 (m, 2H), 1.02-1.06 (m, 2H).

Example 29 1-cyclopropyl- N -((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2-(4-(trifluoromethyl)benzyl)-1 H -吲哚- 5-carbamide 29

first step 4-((1-cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carbamido)methyl)piperidine-1-carboxylic acid tert-butyl Ester 29b

20b (23 mg, 0.064 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate 29a (21 mg, 0.096 mmol, using a known method " Bioorganic & Medicinal Chemistry, 2002, 10(5) , 1347-1359 "prepared", 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (18 mg, 0.096 mmol), 1-hydroxybenzotriazole (13 mg) , 0.096 mmol) and N,N -diisopropylethylamine (42 mg, 0.32 mmol) were dissolved in N,N -dimethylformamide, and the reaction was stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixture of dichloromethane and methanol (V:V=8:1) (20 mL×3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The obtained residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (ESI): 554.2 [M-1];

Second step 1-cyclopropyl- N- (piperidin-4-ylmethyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 29c

29b (350mg, 0.063mmol) was dissolved in 5mL of dichloromethane, 1mL of trifluoroacetic acid was added to the reaction solution, and the reaction was stirred for 1 hour. Saturated sodium hydrogencarbonate was added to the reaction solution to neutral, and then dichloromethane was used. And methanol mixed solvent (V: V = 8:1) was extracted (20 mL × 3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title product 29c (25 mg). It was directly used for the next reaction by purification.

MS m/z (ESI): 456.3 [M + 1];

third step 1-cyclopropyl- N -((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2-(4-(trifluoromethyl)benzyl)-1 H -吲哚- 5-carbamide 29

The crude product 29c (25 mg, 0.055 mmol), triethylamine (8.5 mg, 0.082 mmol) and ethanesulfonyl chloride 29d (8 mg, 0.066 mmol, by the well-known method " Journal of Organic Chemistry , 2007, 72 (15), 5847-5850 "prepared" was dissolved in 5 mL of dichloromethane, and the reaction was stirred for 3 hours. Adding a saturated sodium hydrogencarbonate solution, and extracting with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3), and the organic phase is combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAc m.

MS m/z (ESI): 548.5 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.39 (s, 1H), 8.02 (s, 1H), 7.66-7.71 (m, 2H), 7.63-7.64 (d, 1H), 7.48-7.51 (m, 3H), 6.22 (s, 1H), 4.34 (s, 2H), 3.58 (d, 2H), 3.17 (t, 2H), 3.01 (q, 2H), 2.90-2.98 (m, 1H), 2.75 (t , 2H), 1.73 (m, 3H), 1.12-1.33 (m, 7H), 0.98 (t, 2H).

Example 30 2- (4-chloro-2- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1- (2-fluoroethyl) -1 H - indole - 5-carbamide 30

first step Methyl 2-(4-chloro-2-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-1 H -indole-5-carboxylate 30a

5b (1g, 2.72mmol) was dissolved in 5mL of N,N -dimethylformamide, then added 1-bromo-2-fluoroethane (345.23mg, 2.72mmol) and cesium carbonate (1782.95mg, 5.44mmol) ), microwave reaction at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, mjjjjjjjj

MS m/z (ESI): 412.1 [M-1]

Second step 2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-1 H -indole-5-carboxylic acid 30b

30a (2 g, 4.83 mmol) was dissolved in 110 mL of a mixed solution of ethanol and water (V: V = 3:8), and sodium hydroxide (580 mg, 14.5 mmol) was added thereto, and the mixture was reacted at 80 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure, was added 30mL of water, was added dropwise 1 M hydrochloric acid to pH 2, extracted with ethyl acetate (2 × 30mL) and the combined organic phases, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, Filtration and concentration of the filtrate under reduced pressure afforded crude title product 30b (1500 mg).

MS m/z (ESI): 400.4 [M-1]

third step 2- (4-chloro-2- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1- (2-fluoroethyl) -1 H - indole - 5-carbamide 30

Crude 30b (1.5 g, 3.75 mmol), (4-(ethylsulfonyl)phenyl)methanamine (44.6 mg, 0.223 mmol), 2-(7-benzobenzotriazole) -N,N, N',N '-tetramethyluronium hexafluorophosphate (2138.73 mg, 5.63 mmol), triethylamine (1136.9 mg, 11.26 mmol) dissolved in 30 mL of N,N -dimethylformamide, stirring reaction 12 hour. 50 ml of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title product 30 (1100 mg, yield: 49.45%).

MS m/z (ESI): 579.1 [M-1]

¹ H NMR (400 MHz, DMSO- d ₆ ) 鯋 8.98-9.01 (m, 1H), 8.05 (s, 1H), 7.82-7.86 (m, 3H), 7.69-7.73 (m, 2H), 7.53-7. m,3H),7.31-7.33(m,1H),5.99(s,1H),4.71-4.72(m,1H),4.57-4.61(m,3H),4.44-4.52(m,2H),4.33( s, 2H), 3.22-3.27 (m, 2H), 1.05-1.09 (m, 3H).

Example 31 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((3-methyl-5-(trifluoromethyl)-1 H -pyrazol-1-yl)- Base)-1 H -吲哚-5-carbamamine 31

first step 2-(((tert-butyldimethylmethyl)oxy)methyl)-1 H -indole-5-carboxylic acid ethyl ester 31c

Ethyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate 31b (1.0 g, 2.58 mmol) was used in an argon atmosphere by a known method " Journal of the Chemical Society, Perkin Transactions 1:Organic and Bio-Organic Chemistry , 1997 (14), 2059-2063 "prepared", tert-butyldimethyl(prop-2-yn-1-yloxy)decane 31a (660 mg, 3.88) Ment, prepared by a well-known method " Journal of the American Chemical Society , 2016, 138 (24), 7532-7535"), cuprous iodide (99 mg, 0.52 mmol), bistriphenylphosphine palladium dichloride (362 mg, 0.52 mmol) and triethylamine (1.3 g, 12.9 mmol) were dissolved in N,N -dimethylformamide, and the mixture was warmed to 60 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, and the celite was filtered. Water was added to the filtrate, and the mixture was combined with ethyl acetate (50mL×3). The organic phase was combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate The residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (ESI): 334.2 [M + 1];

Second step Ethyl 2-(((tert-butyldimethylmethyl)oxy)methyl)-1-cyclopropyl- 1H -indole-5-carboxylate 31d

31c (460 mg, 1.4 mmol) was dissolved in 1,2-dichloroethane, respectively, and cyclopropylboronic acid (178 mg, 2.1 mmol), copper acetate monohydrate (393 mg, 2.1 mmol), 2,2'-linked Pyridine (328 mg, 2.1 mmol) and sodium carbonate (223 mg, 2.1 mmol) were heated to 70 ° C and stirred for 12 hours. Further, cyclopropylboronic acid (178 mg, 2.1 mmol), copper acetate monohydrate (393 mg, 2.1 mmol), 2,2'-bipyridine (328 mg, 2.1 mmol) and sodium carbonate (223 mg, 2.1 mmol) were added and stirred. After 6 hours, the reaction solution was cooled to room temperature, and the mixture was filtered, evaporated, evaporated, evaporated, evaporated. The residue was dried over anhydrous sodium sulfate (MgSO4).

third step 1-cyclopropyl-2-(hydroxymethyl)-1 H -indole-5-carboxylic acid ethyl ester 31f

31 d (329 mg, 0.88 mmol) was dissolved in tetrahydrofuran, 1 mL of 1 M tetrabutylammonium fluoride was added dropwise, and the reaction was stirred for 1 hour. The ethyl acetate was extracted (10 mL × 3), EtOAc (EtOAc m.

the fourth step 1-cyclopropyl-2-((3-methyl-5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -indole-5-carboxylic acid ethyl ester 31 g

Under a argon atmosphere, 31f (120 mg, 0.46 mmol), 3-methyl-5-(trifluoromethyl)-1 H -pyrazole 31e (104 mg, 0.69 mmol, using a known method " Tetrahedron Letters , 2016, 57 (14), 1555-1559 "prepared" and triphenylphosphine (181 mg, 0.69 mmol) dissolved in 10 mL of tetrahydrofuran, and then added diethyl azodicarboxylate (120 mg, 0.69 mmol), added, stirred reaction 12 hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj %).

MS m/z (ESI): 390.1 [M-1];

the fifth step 1-cyclopropyl-2-((3-methyl-5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -indole-5-carboxylic acid 31h

31 g (60 mg, 0.15 mmol) was dissolved in 6 mL of a mixed solution of methanol and tetrahydrofuran (V: V = 5:1), and 2 mL of a 4 M sodium hydroxide solution was added thereto, and the mixture was reacted at 60 ° C for 3 hours. Concentrated hydrochloric acid was added dropwise to pH 3, which was extracted with ethyl acetate (30 mL×3). The organic phase was combined and evaporated. 31 h (55 mg), the product was used in the next step without purification.

MS m/z (ESI): 362.1 [M-1];

Step 6 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((3-methyl-5-(trifluoromethyl)-1 H -pyrazol-1-yl)- Base)-1 H -吲哚-5-carbamamine 31

31h (30mg, 0.083mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24mg, 0.12mmol), 1-hydroxybenzotriazole (17mg) , 0.12mmol), N, N - diisopropylethylamine (53 mg, 0.41 mmol) dissolved in dichloromethane was added dropwise 31i (4- (ethanesulfonyl acyl) phenyl) methanamine hydrochloride (44.6 Mg, 0.223 mmol, prepared by the method disclosed in the patent application "US20150291607A1"), after completion, the reaction was stirred for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixture of dichloromethane and methanol (V:V=8:1) (20mL×3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc (EtOAc)

MS m/z (ESI): 545.5 [M+1]

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.05 (t, 1H), 8.11 (s, 1H), 7.84 (d, 2H), 7.75 (d, 1H), 7.57-7.61 (t, 3H), 6.79 (s, 1H), 6.16 (s, 1H), 5.72 (s, 2H), 4.59 (d, 2H), 3.27 (q, 2H), 3.20-3.23 (m, 1H), 2.21 (s, 3H), 1.15-1.21 (m, 2H), 1.09 (t, 3H), 0.98-1.05 (m, 2H).

Example 32 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -吲哚-5-carbamamine 32

first step 2-(((tert-butyldimethylmethyl) oxy)methyl)-1 H -indole-5-carboxylic acid methyl ester 32b

Methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate 32a (13.0 g, 34.85 mmol, by a known method " Journal of Medicinal Chemistry, 2005, under argon atmosphere) 48 (5), 1314-1317 "prepared", 31a (8.9 g, 52.27 mmol), cuprous iodide (1.33 g, 6.97 mmol), bistriphenylphosphine palladium dichloride (4.89 g, 6.97 mmol) And triethylamine (17.63 g, 174.23 mmol) was dissolved in 150 mL of N,N -dimethylformamide, and the mixture was heated to 60 ° C and stirred for 3 hours. Water was added to the reaction mixture, and the mixture was combined with EtOAc EtOAc (EtOAc m. The obtained residue was purified to give the titled product 32b (yield: (yield: 63%).

Second step 2-(((tert-Butyldimethylmethyl)oxy)methyl)-1-cyclopropyl- 1H -indole-5-carboxylic acid methyl ester 32c

32b (956 mg, 2.99 mmol), cyclopropylboronic acid (1.3 g, 14.96 mmol), copper acetate (1.14 g, 6.28 mmol), 2,2'-bipyridine (1.03 g, 6.58 mmol) and sodium carbonate (698 mg) , 6.58 mmol) was dissolved in 1,2-dichloroethane, and the mixture was heated to 70 ° C and stirred for 12 hours. The reaction mixture was cooled to room temperature and then evaporated.

third step 1-cyclopropyl-2-(hydroxymethyl)-1 H -indole-5-carboxylic acid methyl ester 32d

32c (500 mg, 1.39 mmol) was dissolved in 5 mL of tetrahydrofuran, cooled to 0 ° C, and 2.8 mL of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added dropwise, and the mixture was stirred for 0.5 hour. Water was added to the reaction mixture, and the aqueous layer was combined with EtOAc (EtOAc m. Product 32d (300 mg). The product was directly subjected to the next reaction without purification.

the fourth step 1-cyclopropyl-2-((5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -indole-5-carboxylic acid methyl ester 32f

The crude product 32d (120 mg, 0.53 mmol), 3-methyl-1 H -pyrazole 32e (104 mg, 0.69 mmol) and triphenylphosphine (208 mg, 0.795 mmol) were dissolved in 3 mL of tetrahydrofuran under argon and then added. Diethyl dicarboxylate (138 mg, 0.795 mmol) was added and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj

the fifth step 1-cyclopropyl-2-((5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -indole-5-carboxylic acid 32g

32f (51 mg, 0.14 mmol) was dissolved in 2 mL of a methanol solution, and 1.4 mL of a 2 M potassium hydroxide solution was added thereto, and the mixture was reacted at 70 ° C for 3 hours. The reaction solution was cooled to room temperature, 1 M hydrochloric acid was added dropwise to pH 1-2, and extracted with dichloromethane (30 mL×3), and the organic phase was combined, and the organic phase was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure afforded crude title product (32 g, 45 mg).

Step 6 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((5-(trifluoromethyl)-1 H -pyrazol-1-yl)methyl)-1 H -吲哚-5-carbamamine 32

32 g of crude product (20 mg, 0.057 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg, 0.115 mmol), 1- benzobenzotriazole ( 16 mg, 0.118 mmol), triethylamine (23 mg, 0.227 mmol) was dissolved in dichloromethane, (4-(ethylsulfonyl)phenyl)methanamine (23 mg, 0.115 mmol) was added. hour. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 531.2 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) 臎鯋 8.04 (s, 1H), 7.78-7.86 (d, 2H), 7.75-7.72 (d, 1H) , 7.65-7.61 (m, 2H), 7.57-7.55 (d, 2H), 6.81-6.78 (m, 1H), 6.75 (s, 1H), 6.31 (s, 1H), 5.76 (s, 2H), 4.81 -4.79(d,2H), 3.29-3.24(m,1H),3.16-3.10(q,2H),1.32-1.28(t,3H)1.27-1.24(m,2H),1.12.40-1.08(m , 2H).

Example 33 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚- 5-carbamamine 33

first step 2-((4-(Trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid ethyl ester 33b

1-(Propan-2-yn-1-yl)-4-(trifluoromethyl)piperidine 33a (950 mg, 6.2 mmol, prepared by the method disclosed in WO2003093253), under the argon atmosphere, 31b (1.2 g, 3.1 mmol), cuprous iodide (118 mg, 0.62 mmol), bistriphenylphosphine palladium dichloride (217 mg, 0.31 mmol) and triethylamine (1.57 g, 15.5 mmol) dissolved in N, N After adding dimethylformamide, the mixture was heated to 60 ° C and stirred for 5 hours. The reaction mixture was cooled to room temperature, water was added to the mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Column chromatography The residue obtained was purified with EtOAc EtOAc.

Second step 1-isopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid ethyl ester 33c

The crude product 33b (140 mg, 0.40 mmol) was dissolved in 5 mL of N,N -dimethylformamide, sodium hydride (24 mg, 0.60 mmol, 60% in oil) was added, and the reaction was stirred for 5 minutes, and 2-iodopropane was added. 67 mg, 0.40 mmol), and the reaction was stirred for 12 hours under a sealed condition at 60 °C. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate (30 mL × 3) was evaporated. The obtained residue was purified to afford titled product (yield: 67%).

third step 1-isopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid 33d

33c (105 mg, 0.26 mmol) was dissolved in 10 mL of ethanol, and 3 mL of 4 M sodium hydroxide solution was added thereto, and the reaction was stirred at 60 ° C for 12 hours. The reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and extracted with a mixture of dichloromethane and methanol (V: V = 1:1) (20 mL × 3). The title product, 33d (95 mg), was taken to the next step without purification.

MS m/z (ESI): 367.2 [M-1];

the fourth step N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚- 5-carbamamine 33

Crude 33d (55 mg, 0.15 mmol), (4-(ethylsulfonyl)phenyl)methanamine (45 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The imine hydrochloride (43 mg, 0.22 mmol), N,N -diisopropylethylamine (97 mg, 0.75 mmol) was dissolved in N,N -dimethylformamide and stirred for 12 hours. Add water, extract with a mixed solvent of dichloromethane and methanol (V: V = 8:1) (20 mL × 3), combine the organic phase, wash with water, saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, filtrate The mixture was concentrated under reduced pressure.

MS m/z (ESI): 550.4 [M+1]

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.02 (t, 1H), 8.12 (s, 1H), 7.85-7.95 (m, 2H), 7.66 (s, 2H), 7.56-7.59 (m, 2H) , 6.42 (s, 1H), 4.91-4.95 (m, 1H), 4.59 (d, 2H), 6.65 (s, 2H), 3.25 (q, 2H), 2.88 (d, 2H), 2.26 (brs, 1H) ), 1.97 (t, 2H), 1.79 (d, 2H), 1.56 (d, 6H), 1.36-1.39 (m, 2H), 1.08 (t, 3H).

Example 34 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole- 5-carbamide 34

first step 1-cyclopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid ethyl ester 34a

The crude product 33b (220 mg, 0.62 mmol) was dissolved in 1,2-dichloroethane, followed by copper acetate monohydrate (178 mg, 0.93 mmol), 2,2'-bipyridine (145 mg, 0.93 mmol), sodium carbonate (99 mg, 0.93 mmol) and cyclopropylboronic acid (39 mg, 0.45 mmol), warmed to 70 ° C, and stirred for 12 hours. Further, cyclopropylboric acid (39 mg, 0.45 mmol), copper acetate monohydrate (178 mg, 0.93 mmol) and 2,2'-bipyridine (145 mg, 0.93 mmol) were added and reacted for 12 hours. The reaction mixture was cooled to room temperature, filtered over Celite, EtOAc EtOAc (EtOAc)EtOAc. The solution was washed with EtOAc (EtOAc m.

MS m/z (ESI): 395.2 [M + 1];

Second step 1-cyclopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid 34b

34a (175 mg, 0.44 mmol) was dissolved in 15 mL of a mixed solvent of methanol and tetrahydrofuran (V:V=2:1), 4 mL of 4 M sodium hydroxide solution was added, and the reaction was stirred at 60 ° C for 12 hours. The reaction mixture was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to pH 4, and washed with a mixture of dichloromethane and methanol (V: V = 1:1). ), the product was directly subjected to the next reaction without purification.

MS m/z (ESI): 367.0 [M+1];

third step 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole- 5-carbamide 34

Crude 34b (80 mg, 0.22 mmol), (4-(ethylsulfonyl)phenyl)methanamine (65 mg, 0.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbane The imine hydrochloride (61 mg, 0.32 mmol), N,N -diisopropylethylamine (142 mg, 1.1 mmol) was dissolved in N,N -dimethylformamide and stirred for 12 hours. Water was added, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The resulting residue was purified to EtOAc EtOAcjjjjj

MS m/z (ESI): 548.5 [M+1]

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.03 (t, 1H), 8.11 (s, 1H), 7.83-7.85 (m, 2H), 7.54-7.59 (m, 4H), 6.45 (s, 1H) , 4.59 (d, 2H), 3.71 (d, 2H), 3.25 (q, 2H), 3.01 (m, 1H), 2.28 (brs, 1H), 2.06 (t, 2H), 1.78 (d, 2H), 1.45 (q, 2H), 1.15 (t, 2H), 1.05-1.10 (m, 7H).

Example 35 2 - ((2-ethyl-4,4-difluoro-piperidin- 1-yl) methyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H -吲哚-5-carbamide 35

Starting from 2-butyl-4-ketopiperidine-1-carboxylic acid tert-butyl ester 35a, A similar synthetic route to Example 33 gave the title product 35 (4 mg).

MS m/z (ESI): 545.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.07 (s, 1H), 8.16-8.18 (m, 1H), 8.09 (s, 1H), 7.71 7.73 (m, 1H), 7.58-7.62 (m, 2H), 7.34-7.37 (m, 1H), 6.49 (s, 1H), 4.91-4.92 (m, 2H), 4.22-4.25 (m, 1H), 3.58-3.62 (m, 1H), 3.25-3.28 (m, 1H), 3.14-3.20 (m, 2H), 2.87-2.93 (m, 1H), 2.61-2.63 (m, 1H), 2.40-2.43 (m , 1H), 2.08-2.12 (m, 1H), 1.84-1.93 (m, 3H), 0.89-1.35 (m, 12H).

Example 36 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-fluoro-2-(trifluoromethoxy)benzyl)-1 H -indole-5- Guanamine 36

Starting from 1-(bromomethyl)-4-fluoro-2-(trifluoromethoxy)benzene, the title compound 36 (35 mg) was obtained using the procedure

MS m/z (ESI): 575.3 [M + 1]. ^{1 H NMR (400MHz, DMSO- d} 6) δ 9.00 (t, 1H), 7.99 (s, 1H), 7.82 (d, 2H), 7.70 (d, 1H), 7.52-7.58 (m, 4H), 7.33 -7.39 (m, 2H), 5.78 (s, 1H), 4.56 (d, 2H), 4.31 (s, 2H), 3.22-3.30 (m, 3H), 1.26 (q, 2H), 1.05-1.09 (m , 5H).

Example 37 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(1-(4-(trifluoromethyl)phenyl)ethyl)-1 H -indole-5- Formamide 37

Starting from 1-(1-bromoethyl)-4-(trifluoromethyl)benzene, the title compound (37 mg, m. MS m/z (ESI): 555.3 [M+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) Sha 7.85-7.81 (m, 3H), 7.57-7.55 (m, 1H), 7.52-7.48 (m, 5H), 7.37 (d, 2H), 7.02 (s, 1H) , 6.62 (t, 1H), 4.72 (d, 2H), 4.42 (q, 1H), 3.37-3.35 (m, 1H), 3.09 (q, 2H), 1.68 (d, 3H), 1.26 (t, 3H) ), 1.11-1.09 (m, 2H), 1.04-1.03 (m, 2H).

Example 38, 39 ( R )-1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) )methyl)-1 H -吲哚-5-carbamamine 38 ( S )-1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) )methyl)-1 H -吲哚-5-carbamamine 39

first step (5-bromo-1 H -indol-2-yl)(2-(trifluoromethyl)piperidin-1-yl)methanone 38c

5-bromo-1 H -indole-2-carboxylic acid 38b (600 mg, 2.5 mmol, prepared by a known method " Journal of Medicinal Chemistry , 2009, 52 (23), 7512-7527") was dissolved in 15 mL of tetrahydrofuran. 2-(trifluoromethyl)piperidine 38a (382.8 mg, 2.5 mmol, prepared by a known method " Tetrahedron , 2011, 67(1), 69-74"), 2-(7-oxidation) Benzotriazole) -N,N,N',N '-tetramethyluronium hexafluorophosphate (1424.7 mg, 3.75 mmol) and N,N -diisopropylethylamine (967.3 mg, 7.5 mmol) After the addition, the reaction was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj

MS m/z (ESI): 375.3 [M + 1];

Second step 5-bromo-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚38d

38c (400 mg, 1.07 mmol) was dissolved in N,N -dimethylformamide, lithium aluminum hydride (121.38 mg, 3.2 mmol) was added, and the reaction was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to give titled md.

MS m/z (ESI): 361.4 [M+1];

third step 5-bromo-1-cyclopropyl-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚38e

The crude product 38d (120 mg, 0.33 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and cyclopropylboronic acid (42.81 mg, 0.50 mmol), 2,2'-bipyridine (77.83 mg, 0.50 mmol), Copper acetate (99.17 mg, 0.50 mmol) and sodium carbonate (52.82 mg, 0.50 mmol) were added, and the reaction was stirred at 70 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj

the fourth step 1-cyclopropyl-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid ethyl ester 38f

38e (100mg, 0.25mmol) was dissolved in 2mL ethanol and dimethyl hydrazine (V: V = 1:1) mixed solvent, palladium acetate (11.23mg, 0.05mmol), 1,3-bis(diphenyl) The phosphine)propane (25.7 mg, 0.06 mmol) and triethylamine (25.17 mg, 0.25 mmol) were added, and the reaction was stirred at 80 ° C for 16 hours under a carbon monoxide atmosphere. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, mjjjjjjjj

the fifth step 1-cyclopropyl-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -indole-5-carboxylic acid 38g

38f (30mg, 0.08mmol) was dissolved in a mixed solvent of 2.1mL methanol and tetrahydrofuran (V:V=20:1), sodium hydroxide (30.42mg, 0.76mmol) was added, and the reaction was stirred at 45 °C. 3 hours. The reaction solution was concentrated under reduced pressure, 1 M hydrochloric acid was added dropwise to the reaction solution to pH 3, and concentrated under reduced pressure to give the crude title product 38g (27mg), the product was used without purification in the next step.

MS m/z (ESI): 365.4 [M-1];

Step 6 ( R )-1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) )methyl)-1 H -吲哚-5-carbamamine 38 ( S )-1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) )methyl)-1 H -吲哚-5-carbamamine 39

The crude product 38 g (30 mg, 0.08 mmol) was dissolved in 1.5 mL of N,N -dimethylformamide, and 11a (32.8 mg, 0.16 mmol), 2-(7-benzotriazole) -N, N,N',N '-tetramethyluronium hexafluorophosphate (62.23 mg, 0.16 mmol) and N,N -diisopropylethylamine (31.69 mg, 0.25 mmol) were added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

Compound 38: MS m/z (ESI): 549.1 [M+1]; Chiral HPLC analysis: retention time 16.910 min, chiral purity: 98% (chromatographic column: Lux Amylose-3 (AD), 4.6 * 150 cm Length, 5 um; mobile phase: ethanol / n-hexane = 60/40 (v/) v)).

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.06 (s, 1H), 8.15-8.17 (m, 1H), 8.09 (s, 1H), 7.71-7.73 (m, 1H), 7.57-7.62 (m, 2H) , 7.35-7.39 (m, 1H), 6.47 (s, 1H), 4.91-4.92 (m, 2H), 4.07-4.15 (m, 2H), 3.28-3.30 (m, 2H), 3.14 - 3.19 (m, 2H), 2.86-2.92 (m, 1H), 2.63-2.66 (m, 1H), 1.90- 1.93 (m, 1H), 1.75-1.79 (m, 1H), 1.56-1.64 (m, 3H), 1.31 1.35 (m, 4H), 1.15 - 1.17 (m, 2H), 1.08-1.10 (m, 2H).

Compound 39: MS m/z (ESI): 549.1 [M + 1]; </ RTI> </ RTI> HPLC analysis: retention time 11.940 minutes, chiral purity: 98% (column column: Lux Amylose-3 (AD), 4.6 * 150 cm Length, 5 um; mobile phase: ethanol / n-hexane = 60 / 40 (v / v)).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ 9.06 (s, 1H), 8.15-8.18 (m, 1H), 8.09 (s, 1H), 7.71-7.74 (m, 1H), 7.58-7.62 (m, 2H) , 7.34-7.37(m,1H), 6.47(s,1H),4.91-4.92(m,2H),4.08-4.15(m,2H), 3.27-3.33(m,2H),3.14-3.19(m, 2H), 2.86-2.92 (m, 1H), 2.63-2.66 (m, 1H), 1.90- 1.94 (m, 1H), 1.75-1.79 (m, 1H), 1.56-1.61 (m, 3H), 1.31 1.35 (m, 4H), 1.15 - 1.18 (m, 2H), 1.08-1.10 (m, 2H).

Example 40 2 - ((2-ethyl-piperidin-1-yl) methyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5- Guanamine 40

Starting from 2-ethylpiperidine 40a, the title compound 40 (70 mg) was obtained using the procedure of Example 33.

MS m/z (ESI): 510.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ臎豴襎覱豴 (s, 1H), 7.90 (d, 2H), 7.65-7.66 (m, 1H) ), 7.59 (s, 2H), 6.67 (s, 1H), 6.40 (s, 1H), 5.14 - 5.16 (m, 1H), 4.82 (s, 2H), 4.09 (d, 1H), 3.42 (d, 1H), 3.14 (q, 2H), 2.61-2.63 (m, 1H), 2.27-2.29 (m, 1H), 2.09-2.11 (m, 1H), 1.62-1.71 (m, 10H), 1.39-1.49 ( m, 4H), 1.31 (t, 3H), 0.94 - 0.96 (m, 3H).

Example 41 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-((2-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5 -carbamamine 41

Using the procedure of Example 2, the first step starting material 2a was replaced with 3-(bromomethyl)-2-(trifluoromethyl)pyridine to give the title product 41 (10 mg).

MS m/z (ESI): 544.3 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) 鯋 8.62-8.61 (m, 1H), 8.07 (s, 1H), 7.87 (d, 2H), 7.68- 7.66 (m, 1H), 7.57-7.55 (m, 3H), 7.46-7.42 (m, 2H), 6.65 (t, 1H), 6.30 (s, 1H), 4.79 (d, 2H), 4.43-4.40 ( m, 1H), 4.37 (s, 2H), 3.10 (q, 2H), 1.51 (d, 6H), 1.28 (t, 3H).

Example 42 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -benzo[ d ]imidazole-5-formamidine Amine 42

From 2-(2-(trifluoromethyl)phenyl)acetic acid 42a (prepared by the method disclosed in " Tetrahedron , 2002, 58(50), 9925-9932") and 3-amino-4-(iso) Starting from the propylamino group, the title product 42 (15 mg) was obtained using a similar synthetic route from Example 1.

MS m/z (ESI): 544.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.13 (t, 1H), 8.17 (s, 1H), 7.77-7.85 (m, 5H), 7.59-7.62 (m, 3H), 7.51-7.57 (m, 1H), 7.22 (d, 1H), 4.68-4.72 (m, 1H), 4.59 (d, 2H), 4.49 (s, 2H), 3.25 ( q, 2H), 1.51 (d, 6H), 1.09 (t, 3H).

Example 43 6-Chloro-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-fluoro-2-(trifluoromethyl)benzyl)-1 H -indole- 5-carbamide 43

Starting from 6-chloro- 1H -indole-5-carboxylic acid methyl ester (prepared by the method disclosed in the patent application "WO2004022712A2"), a product 43 (2.8 mg) was obtained by a similar synthetic route of Example 4.

MS m/z (ESI): 593.2 [M+1]

Example 44 N- (2-Chloro-4-(ethylsulfonyl)phenyl)-1-cyclopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚-5-carbamamine 44

Starting from the third butyl 4-bromo-2-chlorobenzylcarbamate (prepared by the method disclosed in the patent application "WO2005082859A1"), a similar synthetic route of Example 8 was used to obtain the product 44 (10 mg).

MS m/z (ESI): 582.2 [M+1]; ¹ H NMR (400 MHz, CD ₃ OD) 鯋 8.11 (s, 1H), 7.95 (s, 1H), 7.83-7.81 (m, 1H), 7.74 -7.72 (m, 1H), 7.67-7.63 (m, 2H), 6.48 (s, 1H), 4.75 (s, 2H), 3.80 (s, 2H), 3.29-3.21 (m, 3H), 3.12-3.09 (m, 2H), 2.19-2.09 (m, 3H), 1.88-1.85 (m, 2H), 1.64-1.54 (m, 2H), 1.24-1.20 (m, 5H), 1.12-1.08 (m, 2H) .

Example 45 1-isopropyl- N- (4-(methylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 45

Using the synthetic route of Example 14, the fourth step of the starting material (4-(ethene) The phenyl)methylamine was replaced by (4-(methylsulfonyl)phenyl)methylamine (prepared by the method disclosed in the patent application "US20160122318A1") to give the title product 45 (17.1 mg).

MS m/z (ESI): 529.5 [M+1]

Example 46 N- (4-(ethylsulfonyl)benzyl)-2-(4-fluorobenzyl)-1-isopropyl-1 H -indole-5-carboxamide 46

Using the synthetic route of Example 14, the first step starting material 14a was replaced with 1-bromomethyl-4-fluorobenzene to give the product 46 (26 mg).

MS m/z (ESI): 493.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.85 (d, 2H), 7.67 (d, 1H), 7.53 - 7.57 ( m, 3H), 7.15-7.19 (m, 2H), 7.01-7.05 (m, 2H), 6.87 (t, 1H), 6.3 6 (s, 1H), 4.80 (d, 2H), 4.51-4.58 (m , 1H), 4.16 (s, 2H), 3.11 (q, 2H), 1.49 (d, 6H), 1.30 (t, 3H).

Example 47 N- (4-(ethylsulfonyl)benzyl)-1-methyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 47

Using the synthetic route of Example 14, the second step of the starting material 2-bromopropane Replace with methyl iodide to give the title product 47 (26 mg).

MS m/z (ESI): 515.5 [M + 1]; ¹ H NMR (400 MHz, CD ₃ OD) 鯋 8.10 (s, 1H), 7.78 (d, 2H), 7.71-7.61 (m, 5H), 7.44 - 7.39 (m, 3H), 6.35 (s, 1H), 4.70 (s, 2H), 4.31 (s, 2H), 3.63 (s, 3H), 3.19 (q, 2H), 0.90 (t, 3H).

Example 48 2- (4-bromobenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 48

Using the synthetic route of Example 2, the first step starting material 2a was replaced with 1-bromo-4-(bromomethyl)benzene to give the title product 48 (58 mg).

MS m/z (ESI): 552.9 [M+1]

Example 49 2- (4-cyanobenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 49

48 (50 mg, 0.09 mmol), cuprous cyanide (17 mg, 0.18 mmol) and cuprous iodide (17.1 mg, 0.09 mmol) were dissolved in 1 mL of N,N -dimethylacetamide at 200 ° C. The microwave was reacted for 30 minutes. The reaction mixture was cooled to EtOAc.

MS m/z (ESI): 500.5 [M+1]

Example 50 2- (4-amino acyl methyl benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 50

49 (20 mg, 0.04 mmol) was dissolved in methanol, and 0.1 mL of 2 M potassium hydroxide solution and 0.1 mL of hydrogen peroxide were added thereto, and the reaction was carried out for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL×3). The organic phase was combined and evaporated. 16mg).

MS m/z (ESI): 518.2 [M+1]

Example 51 N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5 -carbamamine 51

The title material 51 (11 mg) was obtained from the title compound (4-(ethylsulfonyl)phenyl)methylamine.

MS m/z (ESI): 544.5 [M+1]

Example 52 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-3-methyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5- Guanamine 52

Using the synthetic route of Example 14, the first step starting material 1a was replaced with methyl 3-methyl-1 H -indole-5-carboxylate (using a known method " RSC Advances , 2015, 5(86), 70329-70332 "Prepared" gave the title product 52 (9 mg).

MS m/z (ESI): 557.5 [M+1]

Example 53 1-cyclopentyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 53

Using the synthetic route of Example 14, the second step of the starting material, 2-bromopropane Conversion to bromocyclopentane gave the title product 53 (23 mg).

MS m/z (ESI): 569.5 [M+1]

Example 54 N- (4-(ethylsulfonyl)-2-fluorobenzyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 54

Using the procedure of Example 14, the fourth step starting material (4-(ethylsulfonyl)phenyl)methylamine was replaced by 8c to give the title product 54 (11 mg).

MS m/z (ESI): 561.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, 1H), 7.59-7.70 (m, 7H), 7.31-7.35 (m, 2H), 6.82(t,1H), 6.38(s,1H),4.83(d,2H),4.50-4.53(m,1H), 4.25(s,1H),3.15(q,2H),1.49(d,6H) , 1.32 (t, 3H).

Example 55 N- (4-(ethylsulfonyl)benzyl)-1-phenyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 55

Using the synthesis route of Example 20, the first step starting material of the example 20, cyclopropylboronic acid, was replaced with phenylboronic acid to give the title product 55 (2.7 mg).

MS m/z (ESI): 577.1 [M+1]

¹ H NMR (400 MHz, CDCl ₃ ) 鯋 8.76-8.74 (dd, 1H), 8.44-8.41 (dd, 1H), 8.12 (s, 1H), 7.89-7.87 (d, 2H), 7.61-7.53 (m, 3H), 7.49-7.43 (m, 4H), 7.19-7.17 (m, 2H), 7.11-7.06 (m, 2H), 6.64-6.61 (t, 1H), 6.62 (s, 1H), 6.48 (s, 1H), 4.80-4.78 (d, 2H), 2.25-2.18 (m, 2H), 0.91 - 0.87 (t, 3H).

Example 56 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(3-(trifluoromethyl)benzyl)-1 H -benzo[ d ]imidazole-5-formamidine Amine 56

Using the synthetic route of Example 42, the first step starting material 42a was replaced with 2-(3-(trifluoromethyl)phenyl)acetic acid (using a known method " Angewandte Chemie, International Edition , 2010, 49 (27), 4665-4668, S4665/1-S4665/60" prepared to give the title product 56 (4.6 mg)

MS m/z (ESI): 544.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.89-7.87 (dd, 1H), 7.83-7.81 (dd, 1H), 7.58-7.39(m,7H), 6.72(s,1H),4.81-4.79(d,2H),4.62-4.55(m,1H),4.42(s,2H),3.14-3.08(m,2H), 1.47-1.45 (d, 6H), 1.30-1.262 (t, 3H).

Example 57 N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1-isopropyl-1 H -benzo[ d ]imidazole- 5-carbamamine 57

The first step starting material 42a was replaced with 2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (Admas) to give the title product 57 (4.6 mg).

MS m/z (ESI): 562.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.84-7.81 (m, 3H), 7.59-7.52 (m, 3H), 7.39-7.27 (m, 3H), 6.87-6.85 (t, 1H), 4.78-4.76 (d, 2H), 4.66-4.59 (m, 1H), 4.39 (s, 2H), 3.12-3.06 (m, 2H) ), 1.55-1.53 (d, 6H), 2.28-1.24 (t, 3H).

Example 58 N- (4-(ethylsulfonyl)benzyl)-2-(4-fluorobenzyl)-1-isopropyl-1 H -benzo[ d ]imidazole-5-carboxamide 58

Using the synthesis route of Example 42, the first step starting material 42a was replaced with 4-fluorophenylacetic acid (prepared by the known method " RSC Advances, 2016 , 6(8), 6719-6723") to obtain the title product 58 ( 4.6mg).

MS m/z (ESI): 494.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.18-8.09 (d, 2H), 7.80-7.75 (dd, 3H), 7.54 (s, 2H), 7.24(s,2H),7.07-7.06(d,2H), 4.80-4.73(d,3H),4.61(s,2H),3.11-3.06(m,2H),1.55-1.53(d,6H), 1.31-1.23 (t, 3H).

Example 59 N- (2-chloro-4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1 H -indole-5-carboxamide 59

Using the procedure of Example 8, the first starting material 8a was replaced with 4-bromo-2-chlorobenzylcarbamic acid tert-butyl ester, and the second starting material 6e was replaced with 14d to give the title product 59 (16 mg).

MS m/z (ESI): 577.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08 (s, 1H), 7.52-7.74 (m, 7H), 7.29-7.31 (m, 2H), 6.93(t,1H), 6.34(s,1H), 4.81(d,2H), 4.22(s,2H), 3.48(m,1H),3.11(q,2H),1.47(d,6H),1.26 (t, 3H).

Example 60 N- (4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(4-(trifluoromethoxy)benzyl)-1 H -benzo[ d ]imidazole-5- Guanamine 60

The first step starting material 42a was replaced with 4-trifluoromethoxyphenylacetic acid using the procedure of Example 42 to give the title product 60 (15 mg).

MS m/z (ESI): 559.9 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (s, 2H), 8.20-8.18 (d, 1H), 8.00 (s, 1H), 7.83 7.76 (m, 3H), 7.57-7.55 (d, 2H), 7.35-7.33 (d, 2H), 7.26-7.24 (d, 2H), 4.84-4.81 (m, 2H), 4.68 (s, 2H), 3.16-3.09 (m, 2H), 1.58-1.57 (d, 6H), 1.30-1.26 (t, 3H).

Example 61 N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1-methyl-1 H -indole-5-carboxamide 61

Using the synthetic route of Example 15, the second step of the starting material, 2-bromopropane, was replaced with methyl iodide to give the title product 61 (15 mg).

MS m / z (ESI): 532.9 [M + 1]; 1 H NMR (400MHz, CDCl 3) δ 8.10 (s, 1H), 7.87 (m, 2H), 7.74 (d, 1H), 7.57 (m, 2H), 7.30-7.37 (m, 3H), 7.21 (t, 1H), 6.83 (t, 1H), 6.38 (s, 1H), 4.80 (d, 2H), 4.25 (s, 2H), 3.68 (s) , 3H), 3.12 (q, 2H), 1.32 (t, 3H).

Example 62 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzyl)-1 H -benzo[ d ]imidazole-5-carboxamide 62

Using the synthetic route of Example 42, the first step starting material 42a was replaced with 4-trifluoromethylphenylacetic acid, and 42b was replaced with methyl 3-amino-4-(ethylamino)benzoate (using a known method). Bioorganic & Medicinal Chemistry, 2005 , 13(5), 1587-1597 "Prepared to give the title product 62 (15 mg).

MS m/z (ESI): 530.4 [M+1]

^{1 H NMR (400MHz, DMSO- d} 6) δ 9.16 (t, 1H), 9.21 (s, 1H), 7.83-7.85 (m, 3H), 7.71 (d, 2H), 7.55-7.62 (m, 5H) , 4.60 (d, 2H), 4.47 (s, 2H), 4.27 (t, 2H), 3.26 (q, 2H), 1.23 (t, 3H), 1.09 (t, 3H).

Example 63 1-cyclopropyl- N -((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-2-(4-(trifluoromethyl)benzyl)-1 H -吲哚-5-carbamamine 63

Starting from the tert-butyl (piperidin-4-ylmethyl)carbamate (prepared by the method disclosed in the patent application "WO2001096303A1"), using the similar synthetic route of Example 19, the title product 63 (15 mg) was obtained. .

MS m/z (ESI): 560.5 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) 鯋 7.95 (m, 1H), 7.. 63-7.53 (m, 4H), 7.35-7.33 (m, 2H), 6.32-6.27 (m, 2H), 4.31 (s, 2H), 3.85-3.82 (m, 3H), 3.42-3.39 (t, 2H), 3.10-3.07 (t, 1H), 2.93-2.90 ( m, 1H), 2.85-2.78 (m, 3H), 2.29-2.23 (m, 1H), 1.28-1.25 (m, 2H), 1.18-1.16 (m, 4H), 1.06-1.00 (m, 2H), 0.98-0.96 (m, 2H).

Example 64 1-allyl- N- (4-(ethylsulfonyl)benzyl)-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 64

Using the synthetic route of Example 15, the second step starting material, 2-bromopropane, was replaced with allyl bromide to give the fourth step product 64 (13 mg).

MS m/z (ESI): 559.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (s, 1H), 7.89-7.91 (m, 2H), 7.58-7.63 (m, 3H), 7.37-7.41 (m, 2H), 7.30-7.34 (m, 2H), 6.70 (t, 1H), 5.99 (m, 1H), 5.01 (dd, 2H), 4.81 (d, 2H), 4.21 (s, 3H), 3.61 (d, 2H), 3.14 (q, 2H), 1.31 (t, 3H).

Example 65 1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((4-(trifluoromethyl)piperidin-1-yl)methyl) -1 H -吲哚-5-carbamide 65

Using the synthesis route of Example 20, the first step starting material 19c of Example 20 was replaced with 33b, and the third step starting material (4-(ethylsulfonyl)phenyl)methylamine was replaced with 11a to obtain the title product 65 ( 38mg).

MS m/z (ESI): 549.5 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.13 (brs, 1H), 8.97 (s, 1H), 8.27 (d, 1H), 8.15 ( s, 1H), 7.75 (d, 1H), 7.59 (d, 2H), 6.46 (s, 1H), 4.69 (d, 2H), 3.73 (s, 2H), 3.38 (q, 2H), 3.27 (brs) , 1H), 3.01 (d, 2H), 2.28 (brs, 1H), 2.07 (t, 2H), 1.78 (d, 2H), 1.47 (q, 2H), 1.06-1.17 (m, 7H).

Example 66 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(piperidin-1-methyl)-1 H -indole-5-carbenamide 66

Starting from (prop-2-yn-1-yloxy)tetrahydro- 2H -pyran (prepared by the known method " ChemCatChem , 2016, 8(18), 2912-2915"), using the examples A similar synthetic route was obtained to give the title product 66 (21 mg).

MS m/z (ESI): 468.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.06 (brs, 1H), 8.13 (s, 1H), 7.83 (d, 2H), 7.73 ( Brs, 1H), 7.58 (d, 2H), 7.49 (brs, 1H), 6.41 (s, 1H), 4.58 (d, 2H), 4.27 (brs, 2H), 3.58 (brs, 2H), 3.25 (q) , 2H), 2.36 (brs, 3H), 1.79 (brs, 2H), 1.48 (brs, 2H), 1.39 (brs, 2H), 1.31 (brs, 2H), 1.23 (brs, 2H), 1.08 (t, 3H).

Example 67 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-(morpholinylmethyl)-1 H -indole-5-carboxamide 67

The title product 67 (21 mg) was obtained by the procedure of the procedure of Example 66, which was obtained from the title compound.

MS m/z (ESI): 470.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.06 (brs, 1H), 8.16 (brs, 1H), 7.83 (d, 2H), 7.73 ( Brs,1H), 7.58 (d, 2H), 7.50 (brs, 1H), 6.47 (brs, 1H), 4.59 (d, 2H), 4.32 (brs, 2H), 3.57-3.64 (m, 4H), 3.36 (brs, 4H), 3.27 (q, 2H), 2.41 (brs, 2H), 1.30 (brs, 3H), 1.08 (t, 3H).

Example 68 1-ethyl- N- (4-(ethylsulfonyl)benzyl)-2-((4-methylpiperazin-1-yl)methyl)-1 H -indole-5-carboxamide 68

Starting from Piperazine-1-carboxylic acid tert-butyl ester 68a (prepared by the well-known method " Chemical Communications (Cambridge, United Kingdom) , 2013, 49 (61), 6867-6869"), similar to Example 33 Synthetic route to give the title product 68 (11 mg).

MS m/z (ESI): 483.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.06 (brs, 1H), 8.15 (s, 1H), 7.83-7.85 (m, 2H), 7.72(d,1H), 7.58(d,2H), 7.49(d,1H), 6.49(s,1H),4.589(d,2H), 4.28(q,2H),3.7(s,2H),3.42 (brs, 4H), 3.23 (q, 2H), 2.85 (brs, 4H), 2.60 (s, 3H), 1.31 (t, 3H), 1.09 (t, 3H)

Example 69 N- (4-(ethylsulfonyl)benzyl)-1-methyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5-carbenamide 69

Using the synthetic route of Example 3, the second step of the starting material iodoethane was replaced with methyl iodide to give the title product 69 (8 mg).

MS m/z (ESI): 515.4 [M+1];

Example 70 2- (2-bromobenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 70

Using the synthetic route of Example 1, the first starting material 1b was replaced with 1-bromo-2-(bromomethyl)benzene to give the title product 70 (21 mg).

MS m/z (ESI): 553.3 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.85 (d, 2H), 7.60-7.64 (m, 2H), 7.53 7.56 (m, 3H), 7.18-7.20 (m, 1H), 7.12-7.14 (m, 1H), 6.97-6.99 (m, 1H), 6.65 (t, 1H), 6.25 (s, 1H), 4.77 ( d, 2H), 4.44 - 4.49 (m, 1H), 4.23 (s, 2H), 3.09 (q, 2H), 1.53 (d, 6H), 1.28 (t, 3H).

Example 71 2- (2-cyanobenzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 71

Using the synthetic route of Example 1, the first step starting material 1b was replaced with 2-(bromomethyl)benzonitrile to give the title product 71 (15 mg).

MS m/z (ESI): 500.2 [M+1]

Example 72 2- (2-cyclopropyl-benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -1-isopropyl--1 H - indole-5-acyl-amine 72

Starting from 1-bromo-2-(bromomethyl)benzene, a similar synthetic route from Example 1 was used to afford the title product 72 (9 mg).

MS m/z (ESI): 515.3 [M + 1];

Example 73 N- (4-(ethylsulfonyl)-2-chlorobenzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 73

Using the synthetic route of Example 8, the first step starting material 8a was replaced with 4-bromo-2-chlorobenzylaminocarboxylic acid tert-butyl ester to give the title product 73 (11 mg).

MS m/z (ESI): 577.1 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (d, 1H), 7.78 (d, 1H), 7.53 - 7.73 (m, 6H), 7.35- 7.44 (m, 2H), 7.06 (d, 1H), 6.31 (s, 1H), 4.79 (d, 2H), 4.38-4.45 (m, 1H), 4.34 (s, 2H), 3.11 (q, 2H) , 1.48(d,6H), 1.27(t,3H)

Example 74 1-cyclopropyl-2-((4,4-difluoropiperidin-1-yl)methyl) -N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-1 H-吲哚-5-carbamide 74

first step 1-cyclopropyl-2-((4,4-difluoropiperidin-1-yl)methyl)-1 H -indole-5-carbonitrile 74b

Starting from 4,4-difluoropiperidine, the title compound 74 (10 mg) was obtained using the procedure of the procedure of Example 38. MS m/z (ESI): 517.5 [M + 1];

Example 75 6-Chloro-1-cyclopropyl- N -((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2-(4-(trifluoromethyl)benzyl)-1 H -吲哚-5-carbamamine 75

Starting from 6-chloro-1 H -indole-5-carboxylic acid methyl ester, the title compound (yield: 75 mg)

MS m/z (ESI): 582.2 [M+1]

Example 76 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzylidene)-1 H -indole-5-carbamidamine 76

Starting from 20a, a similar synthetic route to Example 1 was used to give the title product 76 (35 mg).

MS m/z (ESI): 555.3 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.21. (t, 1H), 8.33 (s, 1H), 8.11 (d, 2H), 7.96- 7.98 (m, 3H), 7.84 (d, 2H), 7.74 (d, 1H), 7.59 (d, 2H), 7.13 (s, 1H), 4.60 (d, 2H), 3.62-3.67 (m, 1H) , 3.25 (q, 2H), 1.15 (brs, 2H), 1.08 (t, 3 H), 0.80-0.84 (m, 2H)

Example 77 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1 H -indole-5-A Guanamine 77

76 (10 mg, 0.018 mmol) was dissolved in 4 mL of a mixed solvent of methanol and tetrahydrofuran (V: V = 3:1), sodium borohydride (1.5 mg, 0.036 mmol) was added, and the reaction was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj

MS m/z (ESI): 557.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.06 (brs, 1H), 8.11 (s, 1H), 7.83 (d, 2H), 7.73 7.75 (m, 3H), 7.67 (d, 2H), 7.56-7.58 (m, 3H), 6.27 (d, 1H), 6.24 (d, 1H), 6.18 (s, 1H), 4.57 (d, 2H) , 3.25 (q, 2H), 3.02-3.07 (m, 1H), 1.15 (brs, 2H), 1.07 (t, 3H), 0.84 (m, 2H).

Example 78 ( S )-1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1 H -吲哚-5-carbamamine 78

Using the synthetic route of Example 39, the sixth step starting material 11a was replaced with 4-(ethylsulfonyl)phenyl)methylamine to give the title product 78 (20 mg).

MS m/z (ESI): 548.6 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.85-7.87 (m, 2H), 7.70-7.73 (m, 1H), 7.62-7.64(m,1H),7.4-7.56(m,2H),6.82-6.85(m,1H),6.63(s,1H),4.79-4.80(m,2H),4.40-4.54(m,2H ), 3.83-3.86 (m, 1H), 3.33-3.40 (m, 3H), 3.08-3.14 (m, 2H), 2.85-2.89 (m, 1H), 2.01-2.04 (m, 2H), 1.63-1.80 (m, 5H), 1.42-1.43 (m, 1H), 1.03-1.08 (m, 2H), 0.87-0.90 (m, 2H).

Example 79 N- (4-(ethylsulfonyl)benzyl)-6-fluoro-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1 H -indole-5- formazan Amine 79

From 6-fluoro-1-(triisopropyldecyl)-1 H -indole-5-carboxylic acid methyl ester 79a (using a known method " European Journal of Organic Chemistry , 2006, (13), 2956-2969" Starting from the preparation, the title product 79 (6 mg) was obtained using a similar synthetic route from Example 6.

MS m/z (ESI): 561.4 [M + 1]; ¹ H NMR (400 MHz, CDCl ₃ ) δ臎豴襎謸豴臎蟰d, 1H 蟖襈臎謩襎贃1 (d, 2H), 7.76 ( d,1H), 7.61(d,2H), 7.47(t,1H), 7.42(s,1H), 7.30-7.35(m,1H), 7.24(d,1H),7.10(d,1H),6.35 (s, 1H), 4.85 (d, 2H), 4.39-4.42 (m, 1H), 4.34 (s, 2H), 1.34 (q, 2H), 1.49 (d, 6H), 1.32 (t, 3H).

Example 80 1-cyclopropyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-(4-(-(trifluoromethyl)benzyl)-1 H -吲哚-5-carbamamine 80

Using the procedure of Example 20, the third step starting material (4-(ethylsulfonyl)phenyl)methylamine was replaced by 11a to give the title product 80 (60 mg).

MS m/z (ESI): 542.4 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) 鯋臎 9.9 (t, 1H), 8.95 (d, 1H), 8.25 (dd, 1H), 8.11 (d, 1H), 7.70-7.73 (m, 3H), 7.57 (t, 2H), 7.51 (d, 2H), 6.25 (s, 1H), 4.68 (d, 2H), 4.38 (s, 2H), 3.39 (q, 2H), 2.97-2.99 (m, 1H), 1.11-1.16 (m, 5H), 1.00-1.02 (m, 2H).

Example 81 2- (4-chloro-2- (trifluoromethyl) benzyl) - N - (4- (ethanesulfonyl acyl) benzyl) -6-fluoro-1- (2-fluoroethyl) -1 H -吲哚-5-carbamamine 81

Using the procedure of Example 5, the first step starting material 5a was replaced with 79b, and the second step starting material 2-bromopropane was replaced with 1-bromo-2-fluoroethane to give the title product 81 (55 mg).

MS m/z (ESI): 599.4 [M-1]; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.76 (brs, 1H), 7.84-7.86 (m, 3H), 7.79 (d, 1H), 7.76(d,1H), 7.58-7.60(m,2H), 7.48(d,1H),7.34(d,1H),5.94(s,1H),4.73(brs,1H),4.57-4.61(m, 3H), 4.51 (brs, 1H), 4.44 (brs, 1H), 4.31 (s, 2H), 3.26 (q, 2H), 1.09 (t, 3H).

Example 82 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1 H -indole-5 -carbamamine 82

Starting from 5-(bromomethyl)-2-(trifluoromethyl)pyridine, the title compound 82 (55 mg) was obtained.

MS m/z (ESI): 542.2 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.03 (t, 1H), 8.77 (s, 1H), 8.08 (s, 1H), 7.94 ( d,1H),7.83-7.89(m,3H),7.71(d,1H),7.54-7.59(m,3H),6.18(s,1H),4.58(d,2H),4.42(s,2H) , 3.25 (q, 2H), 3.02-3.06 (m, 1H), 1.10-1.12 (m, 2H), 1.08 (t, 3H), 1.02-1.03 (m, 2H).

Example 83 1-cyclopropyl- N- (4-(ethylsulfonyl)benzyl)-2-((5-(trifluoromethyl)pyridin-2-yl)methyl)-1 H -indole-5 -carbamamine 83

Starting from 2-(bromomethyl)-5-(trifluoromethyl)pyridine (prepared by the method disclosed in the patent application "WO2009103478A1"), using the similar synthetic route of Example 1, the title product 83 (12 mg) was obtained. .

MS m/z (ESI): 542.2 [M+1]

Example 84 1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-6-fluoro-2-((4-(trifluoromethyl)piperidin-1-yl) )methyl)-1 H -吲哚-5-carbamamine 84

Starting from methyl 4-amino-2-fluorobenzoate, a similar synthetic route from Example 33 gave the title product 84 (27 mg).

MS m/z (ESI): 566.5 [M+1]

Example 85 1-cyclopropyl- N -((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((3-methyl-5-(trifluoromethyl)-1 H -pyridyl) Zin-1-yl)methyl)-1 H -indole-5-carboxamide 85

Using the synthesis route of Example 31, the sixth step starting material 31i was replaced with 11a to give the title product 85 (30 mg).

MS m/z (ESI): 546.5 [M + 1]; ¹ H NMR (400 MHz, DMSO - d ₆ ) δ 9.12 (brs, 1H), 8.95 (s, 1H), 8.23 - 8.25 (m, 1H), 8.13(s,1H), 7.78(d,1H), 7.57-7.62(m,2H), 6.79(s,1H), 6.17(s,1H), 5.72(s,2H),4.67(s,2H) , 3.39 (d, 2H), 3.21 (brs, 1H), 2.20 (s, 3H), 1.11-1.16 (m, 5H), 1.01 (brs, 2H).

(biological evaluation)

The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.

Test Example 1. Determination of in vitro activity of ROR γ by the compounds of the examples of the present invention

First, experimental materials and instruments

1. LanthaScreen® TR-FRET ROR γ Co-Starting System (Life Technologies)

2. ROR γ LBD (AB Vector)

3. DMSO (SigmaAldrich)

4. 384-well cell culture plate (Perkin Elmer)

5. Microplate reader (Tecan)

Second, the experimental steps

Modulation of ROR gamma activity by the compounds of the invention was screened using the LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) ROR gamma co-priming system.

The Complete TR-FRET Coregulator (Life Technologies) was first formulated to contain a final concentration of 5 mM DTT. The final concentration of DMSO is 2%. The test compound was serially diluted to 2 x final concentration in intact buffer D containing 2% DMSO at a maximum dose of 60 μm. 10 μl/well was added to the test well of a 384-well plate (PerkinElmer). Two parallel control wells were placed at the same concentration for each test compound. Prepare 4X ROR γ LBD (AB Vector). The concentration of ROR γ LBD was diluted to 1 ng/μL using intact buffer D. 5 μl/well was added to the test well of a 384-well assay plate. The negative control wells were 5 μL of complete buffer D without ROR γ LBD. A mixture of 0.6 μM luciferin-D22 (4X) and 8 nM 鋱 (Tb)-labeled anti-GST antibody (4X) (Life Technologies) was prepared using Complete Buffer D, and 5 μL of the mixture was added to a 384-well plate. The total reaction system was 20 μL. The 384-well plate was gently mixed on a shaker and incubated for 2-4 hours at room temperature in the dark.

Using Tecan Infinite M1000 detecting fluorescence readings by GraphPad Prism 6.0 software logarithmic curve plotted emitting compound concentration ratio wavelength 520nm / 495nm was calculated IC ₅₀ values of the test compounds ₅₀ / EC.

The in vitro activity of the compounds of the present invention against ROR γ was determined by the above test, and the IC ₅₀ /EC ₅₀ values measured are shown in Table 1.

a: If it is an inverse agonist, the value is indicated as IC ₅₀ ; if it is an agonist, the value is indicated as EC ₅₀ .

Conclusion: The compound of the present invention has a significant regulatory effect on the in vitro activity of ROR γ. It is shown in the experimental results that the change of the A ring substituent in the compound represented by the general formula (I) shows different mechanisms for the regulation of the in vitro activity of ROR γ. When there is a large substituent in the ortho position of the ring A (for example, trifluoromethyl, methoxy, ethyl, trifluoromethoxy), it exhibits an agonistic effect (see Examples 1, 2, 4, 6 and 10, etc., exhibit a suppressing effect when there are smaller substituents (for example, hydrogen atom, fluorine) in the ortho position of the ring A (see Examples 14, 15, 17, and 18, etc.).

Test Example 2: Quantitative Analysis of Activity of IL-17A Enzyme-Linked Immunosorbent by Compounds of the Present Invention

First, experimental materials and instruments

1. Human peripheral blood mononuclear cells (PBMC) (Zenbio)

2. Lymphocyte medium (Zenbio)

3.TexMACS (Miltenyi Biotec)

4. People Cytostim (Miltenyi Biotec)

5. Human IL-17 enzyme-linked immunoassay kit (R & D system)

6.CO ₂ incubator (Fisher Scientific)

7. Centrifuge (Fisher Scientific)

8.96-well cell culture plate (Fisher Scientific)

9. Microplate reader (Tecan)

Second, the experimental steps

Frozen human peripheral blood mononuclear cells (PBMC) were rapidly resuscitated in pre-warmed lymphocyte medium, centrifuged at 1000 rpm for 10 min, and the cell culture supernatant was removed, and the cells were gently suspended in TexMACS medium, and the cells were counted. The T cell starter reagent cytostim (10 μl/ml) was added in proportion to the cell suspension, and then the cells were seeded in a 96-well cell culture plate at a density of 1 × 105 peripheral blood mononuclear cells/well. The test compounds were diluted with TexMACS medium and added to each test well, with 2-3 parallel wells per group. Prepare a negative control well containing only cells without cytostim to obtain a background reading. The cell culture plates were placed in a 5% carbon dioxide incubator at 37 ° C for 3 days. The cell culture supernatant was collected 3 days after the drug treatment, and the suspension was removed by centrifugation. The supernatant was then used to quantify IL-17A in the supernatant using the IL-17A enzyme-linked immunosorbent assay kit. Calculated using GraphPad Prism 6.0 ₅₀ / EC ₅₀ value of the test compound IC.

Quantitative analysis of IL-17A by immunoassay of the compound of the present invention was carried out by the above test, and the measured IC ₅₀ /EC ₅₀ values are shown in Table 2.

a: If it is an inverse agonist, the value is indicated as IC ₅₀ ; if it is an agonist, the value is indicated as EC ₅₀ .

Conclusion: The compounds of the present invention have a significant regulatory effect on the activity of IL-17A enzyme-linked immunoassay.

Test Example 3: In vivo pharmacodynamic study of the compound of the present invention

First, experimental materials and instruments

1. Anti-mouse-PD-1 antibody (BioXcell)

2. Mouse IgG2a (BioXcell)

Second, the experimental steps

The in vivo antitumor activity of the combination of Example 30 or Example 30 with an anti-mouse-PD-1 antibody alone was evaluated by detecting the growth of MC38 mouse colon tumors on syngeneic C57BL/6 mice.

MC38 cells (5 × 10 ⁵ ) were implanted subcutaneously into the right abdomen of each mouse, and after 5 days, when the tumor grew to 40-80 mm ³ , the mice were randomly divided into 4 groups and administered separately. Grouped as follows:

Group 1: The blank group was administered in combination with the IgG2a isotype control antibody for the CMC-Na solvent formulation. The dosage regimen of the CMC-Na solvent formulation is the same as that of the second group drug monotherapy group, and the administration scheme of the IgG2a isotype control antibody is the same as the third group antibody monotherapy group.

Group 2: The drug alone group was administered twice a day (Example 30, 12.5 mg/kg) for 21 consecutive days.

Group 3: The antibody alone group, the "anti-PD-1 antibody" group in Figure 1, on the 5th, 8th, 11th, and 14th day after the tumor of the mouse, the abdominal cavity (ip) of the mouse carrying the MC38 tumor. Anti-mouse PD-1 (CD279) antibody (BioXcell) (5 mg/mouse) was injected.

Group 4: The antibody was administered in combination with the compound of Example 30, i.e., "anti-PD-1 antibody + Example 30" in Figure 1. The antibody administration is the same as the third group antibody single administration protocol, the compound of the third embodiment is the same as the second group drug single administration protocol.

The tumor volume was measured in three dimensions with a caliper and then calculated according to the following formula: tumor volume (mm ³ ) = l × w × h × 0.5236, where l represents the length of the tumor, w represents the width of the tumor, and h represents the height of the tumor. The unit is mm.

As shown in Fig. 1, when 12.5 mg/kg of Example 30 was administered alone, the TGI was 34%. When the anti-mouse PD-1 (CD279) antibody (5 mg/mouse) was injected alone, the TGI was 25%. Example 30 (12.5 mg/kg) and anti-mouse PD-1 monoclonal antibody (5) When mg/only), the combination showed a strong synergistic effect (TGI was 68%).

TGI%=100 x (TV _control- TV _tumor- TV _initial )/(TV _control- TV _initial ), where TGI=tumor growth inhibition rate; TV _control =control group tumor volume; TV _tumor =treatment group tumor volume; TV _initial = tumor volume at 5 days.

These data indicate that in the MC38 colon tumor model, Example 30 alone showed anti-tumor activity, while Example 30 showed a strong synergistic effect with the PD-1 antibody combination, which also indicates that Example 30 has ROR γ initiates (but does not inhibit) consistent biological activity, opening up new avenues for improving the efficacy of immunotherapy.

Claims (33)

a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable compound thereof salt, Wherein: X, Y and Z are the same or different and are each independently CR ⁹ or N; ring A and ring B are the same or different and are each independently selected from cycloalkyl, heterocyclic, aryl and heteroaryl R ¹ and R ^{2 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amine group, a nitro group, a hydroxyl group, and a cyano group. a base, a heterocyclic group, an aryl group, a heteroaryl group, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , Wherein the alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from an alkyl group, a haloalkyl group, a halogen group, an amine group, a nitro group, and optionally Substituted by one or more substituents of cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ³ and R ^{4 are the} same or Different, and each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amine group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, an aryl group , heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group And a cycloalkyl group, a haloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from an alkyl group, a haloalkyl group, a halogen group, an amine group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, and an alkoxy group. Substituting one or more substituents of a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; or R ³ and R ⁴ form a keto group; R ^{5 is} selected from hydrogen Atom, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amine, alkenyl, alkynyl, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, as desired One or more of halogen, amine, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent; R ^{6 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amine group, a nitro group, a hydroxyl group, a cyano group, a heterocyclic group, and an aromatic group. group, a heteroaryl ^{group, -OR 8, -C (O)} R 8, -C (O) OR 8 and -S (O) _m R ^8, wherein the alkyl group The cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, Substituted by one or more substituents of a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{7 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a halogen alkyl group Alkoxy, haloalkoxy, heterocyclyl, aryl and heteroaryl; R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amine group, a ring An alkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the amine group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from an alkyl group, a halogen group, and a hydroxyl group, as needed. Substituted by one or more substituents of an amine group, a carboxylate group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ⁹ Selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an amine group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, Haloalkyl, aryl and heteroaryl groups are each Optionally, it is selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, Substituting one or more substituents in the aryl and heteroaryl; m is 0, 1 or 2; x is 0, 1, 2, 3 or 4; y is 0, 1, 2 or 3; 0, 1, 2, 3 or 4. a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or the a mixture form, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (II), Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and the ring A, ring B, R ¹ to R ^7, x, y and z range as patent item 1 Defined. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 1 or 2 of the patent application. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the Ring A and the Ring B are the same or different and are each independently selected from the group consisting of a heterocyclic group, an aryl group and a heteroaryl group. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 3; a compound or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (II-A), Wherein: X is CR ⁹ or N; R ⁹ is a hydrogen atom or an alkyl group; G is CH or N; and R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, Amine, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from an alkyl group, a haloalkyl group, as needed One or more substituents of halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted; p is 0, 1, 2 or 3; Ring A, R ¹ to R ⁸ , m, y and z are as defined in the first item of the patent application. a compound of the formula (II-A) as described in the fourth paragraph of the patent application, or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 3; a compound of the formula (III), or a mixture thereof, or a pharmaceutically acceptable salt thereof, Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and Ring A, R ¹ to R ⁷ , x, y and z are as defined in the first item of the patent application. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof, or a compound represented by any one of the above claims 1 to 3 and 6 a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV), Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and R ¹ to R ⁷ , x, y and z are as defined in the first item of the patent application. The compound of the formula (I) or the tautomer, mesogen, racemate, enantiomer thereof as described in any one of claims 1 to 3 and 6 to 7 a compound, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the formula (IV-A), Wherein: X is CR ⁹ or N; Y is CH or N; R ⁹ is a hydrogen atom or an alkyl group; and R ^{a is} selected from the group consisting of an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, and an amine group. , nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)NHR ⁸ , -C(O)OR ⁸ and -S (O) _m R ^8, wherein the alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl, each optionally independently selected from alkyl, haloalkyl, halo Substituting one or more substituents of an amine group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; p is 0, 1, 2 or 3; and R ¹ to R ⁸ , m, y and z are as defined in the first item of the patent application. a compound of the formula (IV-A) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof as described in claim 8 of the patent application. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the formula (IV-A-1), Wherein: R ¹ to R ⁷ , p, y and z are as defined in item 8 of the scope of the patent application. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 9 Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a halogen, a cyano group, a heterocyclic group and -C(O)NHR ⁸ wherein the alkyl group, cycloalkyl group, alkoxy group and heterocyclic group are each independently selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group, an amine group and a cyano group. Substituted by one or more substituents; R ^{8 is} selected from a hydrogen atom or an alkyl group. a compound of the formula (I), or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, or a compound thereof, as described in claim 10 a mixture, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from the group consisting of alkyl, halogen, haloalkyl, alkoxy, and haloalkoxy. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 10; Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is halogen. a compound of the formula (I), or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, or a compound thereof, as described in claim 12 a mixture, or a pharmaceutically acceptable salt thereof, wherein R ² is fluorine or chlorine. A compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof, as described in any one of claims 1 to 13 Or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ and R ^{4 are the} same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyl group, or R ³ and R ⁴ together form a ketone group. The compound of the formula (I) according to any one of claims 1 to 14, wherein R ^{5 is} selected from the group consisting of an alkyl group, a cycloalkyl group, a haloalkyl group, an alkenyl group and an aryl group, wherein The alkyl group, the cycloalkyl group and the aryl group are each independently substituted with one or more substituents selected from the group consisting of an alkyl group, a halogen group, an alkenyl group and a hydroxyl group, as needed. a compound of the formula (I), or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, or the compound thereof, as described in claim 15 a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is isopropyl or cyclopropyl. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 16. enantiomeric form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is optionally selected from halogen, an alkyl group substituted with a cycloalkyl group and one or more hydroxyl substituents. a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a compound thereof, as described in claim 17 a mixture, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is ethyl. A compound according to any one of claims 1 to 17 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof Or a pharmaceutically acceptable salt thereof, selected from the group consisting of: a compound of the formula (V) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof , Wherein: X, Y and Z are the same or different and each independently is CR ⁹ or N; ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; and R ^{1 is} selected from a hydrogen atom, an alkyl group, Cycloalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amine, nitro, hydroxy, cyano, heterocyclyl, aryl, heteroaryl, -OR ⁸ , -C(O) R ⁸ , —C(O)NHR ⁸ , —C(O)OR ⁸ and —S(O) _m R ⁸ , wherein the alkyl group, the cycloalkyl group, the alkoxy group, the haloalkyl group, the heterocyclic group, the aromatic group The base and heteroaryl are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Substituting one or more substituents in the heterocyclic group, the aryl group and the heteroaryl group; R ³ and R ^{4 are the} same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, Alkoxy, haloalkoxy, halogen, amine, nitro, hydroxy, cyano, heterocyclic, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O) OR ⁸ and -S (O) _m R ^8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally be From alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents; or R ³ and R ⁴ form a keto group; R ^{5 is} selected from alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amine, alkenyl, alkyne a base, an aryl group, a heteroaryl group, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S(O) _m R ⁸ , wherein the alkyl group, the cycloalkyl group, the haloalkyl group And the aryl and heteroaryl are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, Substituted by one or more substituents of a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{6 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a haloalkyl group, an alkoxy group , haloalkoxy, halogen, amine, nitro, hydroxy, cyano, heterocyclyl, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ , -C(O)OR ⁸ and -S (O) _m R ^8, wherein the alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected to be One of alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Or substituted with a plurality of substituents; R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amine group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. Wherein the alkyl group, the amine group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amine group, a carboxylate group, a nitro group, and a cyano group. Substituted by one or more substituents of an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R ^{9 is} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a halogen alkyl group Alkoxy group, alkoxy group, haloalkoxy group, amine group, alkenyl group, alkynyl group, aryl group and heteroaryl group, wherein the alkyl group, cycloalkyl group, haloalkyl group, aryl group and heteroaryl group are each independently regarded Need to be selected from alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl And one or more of the heteroaryl groups Substituted with substituents; m is 0, 1 or 2; x is 2, 3 or 4; and y is 2 or 3. A compound of the formula (I), or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, as described in claim 1 of the scope of the patent application. A method of form, or a pharmaceutically acceptable salt thereof, the method comprising: Formula (V) with a compound of formula (VI) condensation reaction of a compound of general formula (I) compound; wherein: ring A, ring B, X, Y, Z, R 1 to R ^7, x, y and z As defined in item 1 of the patent application. A pharmaceutical composition comprising a compound represented by the formula (I) or a tautomer, a mesogen thereof, a foreign form as described in any one of claims 1 to 19 of the patent application. A form of the polar, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. The use of a conjugate or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, which is used as a ROR modulator for the preparation of a preventive and/or therapeutic inflammatory Drugs, autoimmune diseases, tumors or cancer. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. The use of a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for use as a ROR inverse agonist in the preparation of a medicament for the prevention and/or treatment of inflammation or A drug for autoimmune diseases. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as described in claim 22, as an ROR agonist for the preparation of a medicament for the prevention and/or treatment of a tumor or Cancer drugs. A compound of the formula (IV-A) according to any one of claims 8 to 9 or a tautomer, a mesogen, a racemate, an enantiomer thereof, Use of a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, as an ROR agonist for the preparation of a medicament for the prevention and/or treatment of a tumor or cancer. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition according to claim 22, for use in the preparation of a combination therapy for an ROR agonist and an anti-PD-1 antibody A drug for cancer or cancer. The compound of the formula (IV-A) or a tautomer, a mesogen, a racemate, an enantiomer thereof, or a compound represented by the formula (IV-A) according to any one of claims 8 to 9 Use of a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, as an ROR agonist for the preparation of a medicament for the treatment of a tumor or cancer in combination with an anti-PD-1 antibody. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. The use of the conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 22, for use in the preparation of a medicament for modulating ROR. A compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a non-pair thereof according to any one of claims 1 to 19. The use of a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 22, for use in the preparation of a medicament for the preparation of a ROR agonist. A compound of the formula (IV-A) according to any one of claims 8 to 9 or a tautomer, a mesogen, a racemate, an enantiomer thereof, Use of a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for a ROR agonist. The use according to claim 24, wherein the inflammatory or autoimmune disease is selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, and ankylosing spine Inflammation, chronic obstructive pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye syndrome, Uveitis, Behcet's disease, asthma, allergic dermatitis, acne, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, scleroderma, bronchitis and dermatomyositis allergic rhinitis. The use according to any one of claims 25 to 28, wherein the tumor or cancer is selected from the group consisting of 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, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.