WO2017157332A1 - Aromatic amide derivative, preparation method therefor, and pharmaceutical applications thereof - Google Patents

Abstract

An aromatic amide derivative represented by formula (I), a preparation method therefor, a pharmaceutical composition comprising the derivative, uses thereof as an ROR regulator, and users thereof in preventing or treating inflammatory disease, autoimmune diseases, cancers and other diseases. The aromatic amide derivative has an agitation or anti-agitation activity on ROR. The combined medication of the aromatic amide derivative and a PD-1 antibody can be used in treatment of tumors or cancers.

Description

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

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 amide derivative represented by the formula (I), a process for producing the same, and a pharmaceutical composition containing the same, which are useful as ROR modulators and for preventing and/or treating autoimmune diseases and the like the use of.

Background technique

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 RORα, RORβ, and RORγ. Three different RORs can be expressed in different tissues and control different physiological processes. RORα is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain. RORβ has a small range of action, mainly acting on In the central nervous system, RORγ can be expressed in many tissues, including liver, animal fat, and skeletal muscle. The lack of RORγ in mammals shows a decrease in blood glucose.

There are two subtypes of RORγ: RORγ1 and RORγ2. RORγ1 is expressed in many tissues such as thymus, muscle, kidney and liver, while RORγ2 is expressed only in immune cells, and RORγ2 is thought to control T cell-assisted T cell 17 (Th17) differentiation. Th17 is a class of helper T cells that produce 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, Rheumatoid arthritis, psoriasis, clonal diseases and asthma are related. Now, it is reported in the literature that RORγ may be related to the occurrence and development of prostate cancer.

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

RORγ, particularly the RORγt type, has been identified as an important transcriptional regulator of the differentiation of Th17 cells. In 2006, Vanov et al. found that RORγt 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 RORγt. In the process of human Th17 cell differentiation, RORγt was also confirmed to have a similar important role. The groundbreaking discovery caused people to attach great importance to RORγt.

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.

In the process of studying the ROR regulator, the inventors found that in the compound of the formula (I) of the present invention, the change of the ortho group of the ring A changes its regulation effect, when the ring A is ortho When the group is a group having a small steric hindrance (for example, H and F), the compound represented by the formula (I) is an inverse agonist, and when the ring A ortho group is halogenated A compound represented by the general formula (I) is a compound having a sterically hindered group such as an alkyl group (for example, a trifluoromethyl group), an alkyl group (for example, an ethyl group), and a halogenated alkoxy group (for example, a trifluoromethoxy group). Thus, the present invention has developed a new generation of ROR modulators, and further studies have found that structural changes in compounds can modulate different mechanisms.

Summary of the invention

It is an object of the present invention to provide 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,

among them:

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 the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

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 halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. a base, 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 said Alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, Substituted with one or more substituents of alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ³ and R ^{4 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 halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. 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 said alkyl group, cycloalkyl group, halogenated alkane The radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

Or R ³ and R ⁴ form an oxo group;

R ^{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino 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 said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, One or more of haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;

R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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)OR ⁸ and —S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituting one or more substituents in the heteroaryl;

R ^{7 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{9 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;

m is 0, 1 or 2;

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

y is 0, 1, 2 or 3;

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):

among them:

X is CR ⁹ or N;

Y is CH or N;

R ⁹ is a hydrogen atom or an alkyl group;

Ring A, Ring B, R ¹ to R ⁷ , x, y and z are as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) wherein A ring and The B rings 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):

among them:

X is CR ⁹ or N; R ⁹ is a hydrogen atom or an alkyl group;

G is CH or N;

R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, amino, 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 said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, The heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane. Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

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):

among them:

X is CR ⁹ or N;

Y is CH or N;

R ⁹ is a hydrogen atom or an alkyl group;

Ring A, R ¹ to R ⁷ , x, y and z are as defined in the general formula (I).

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

among them:

X is CR ⁹ or N;

Y is CH or N;

R ⁹ is a hydrogen atom or an alkyl group;

R ¹ to R ⁷ , x, y and z are as defined in the formula (I).

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

among them:

X is CR ⁹ or N;

Y is CH or N;

R ⁹ is a hydrogen atom or an alkyl group;

R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, 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 said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic ring The aryl group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{b is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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 said alkyl group, cycloalkyl group, alkoxy group, Haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;

p is 0, 1, 2 or 3;

q is 0, 1, or 2;

R ¹ to R ⁸ , m, y and z are as defined in the 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):

among them:

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 halogenated alkyl group, a halogenated alkoxy group, a halogen And a cyano group, a heterocyclic group, and -C(O)NHR ⁸ , wherein each of the alkyl group, the cycloalkyl group, the alkoxy group and the heterocyclic group is independently selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group, and an amino group. 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 halogenated alkyl group, an alkoxy group, and a halogenated alkoxy 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 each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group and a hydroxyl group, Or R ³ and R ⁴ together form an oxo 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 group The cycloalkyl and aryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkenyl and hydroxy; preferably R ⁵ is isopropyl or cyclopropyl.

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 optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl and hydroxy Alkyl; 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 mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, Or an intermediate thereof, or 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,

among them:

X, Y and Z are the same or different and are each independently 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;

R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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 said alkyl group, cycloalkyl group, alkoxy group, Haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, 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 the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. 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 said alkyl group, cycloalkyl group, halogenated alkane The radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

Or R ³ and R ⁴ form an oxo group;

R ^{5 is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ ,- C(O)OR ⁸ and -S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, One or more of halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;

R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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)OR ⁸ and —S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituting one or more substituents in the heteroaryl;

R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{9 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;

m is 0, 1 or 2;

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

y is 0, 1, 2 or 3.

The invention further provides a preparation of a compound according to formula (II-A) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof An intermediate of the form, or a pharmaceutically acceptable salt thereof, is 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 , 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 said compound of formula (I), which process comprises:

a compound of the formula (V) is condensed with a compound of the formula (VI) to give a compound of the formula (I);

among them:

Ring A, Ring B, X, Y, Z, R ¹ to R ⁷ , x, y and z are as defined in the general formula (I).

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

a compound of the formula (II-A-1) is condensed with a compound of the formula (II-A-2) to give a compound of the formula (II-A);

among them:

Rings 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 formula (I), (II), (III), (IV), (IV-A), (IV-B), a compound represented by IV-C) or (V) or a tautomer, a mesophil, 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 invention further relates to a process for the preparation of 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 form thereof The salt is mixed with a pharmaceutically acceptable carrier, diluent or excipient.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, 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 modulator in the manufacture of a medicament for the prevention and/or treatment of inflammation, autoimmune diseases, tumors or cancer.

The present invention further relates to a compound represented by the formula (I) or a tautomer thereof, a mesogen, and an external 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 as a ROR inverse agonist in the preparation for prophylaxis and/or treatment Use in medicines for inflammation and autoimmune diseases.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, 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 agonist in the manufacture of a medicament for the prevention and/or treatment of a tumor or cancer.

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 prevention and/or treatment of a tumor or cancer.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, 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 an 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 mesomer, 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 the modulation of ROR.

The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, 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 mesomer, 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 the present 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 , glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, allergic skin Inflammation, 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 mesomer, 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 the prevention and/or treatment of a tumor or cancer.

In the present 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, rectum 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, nerve glue Tumor, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer, especially non-Hodgkin's lymphoma, diffuse large B-cell lymph Tumor, 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 In the form of a mixture, or a pharmaceutically acceptable salt thereof.

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 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 said 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 mesomer, 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 use in the prevention and/or treatment of 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 prophylaxis and/or treatment of 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 meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same. The inflammatory and autoimmune diseases described therein 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, internal elimination A form of a polar body, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. The tumors and cancers described therein 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). The tumors and cancers described therein 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 (IV-A) and an anti-PD-1 antibody composition. . The tumors and cancers described therein 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 of 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 thereof, An enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, lozenges, aqueous or oily 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, 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 and tasty pharmaceutical preparation. 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 packaged by a known technique that 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. clothes. 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.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. 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. Flavoring agents such as sucrose, saccharin or aspartame.

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. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the 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 may 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 circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. This type of equipment An example of this is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical composition may 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. The sterile injectable preparation may also be a sterile injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a parenterally acceptable non-toxic diluent or solvent. 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 a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, 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 patient's behavior. The dosage, 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 mode such as the mode of treatment, the daily dosage of the compound of formula (I) or a 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 containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 carbons. The alkyl group of the atom. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 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-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. 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, sec-butyl Base, 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-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 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 the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo 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, heterocycle Alkylthio group.

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 6 carbon atoms. One carbon atom. 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 have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 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 rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares 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. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered 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 the rings have 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, tetrahydronaphthalene Base, 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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo 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 comprising from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; most preferably from 3 to 8 ring atoms, wherein from 1 to 3 are heteroatoms; most preferably from 3 to 6 ring atoms, wherein from 1 to 2 It 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 monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares 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-membered/5-membered or 5-membered/6-membered 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:

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, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo 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 (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. 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, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.

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, and has 1 to 3 hetero atoms; more preferably 5 or 6 members, and 1 to 2 hetero atoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridyl Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl , thiazolyl; more selective 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 the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio 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 the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted by 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" means -NH _2.

The term "cyano" refers to -CN.

The term "nitro" refers to -NO ₂ .

The term "oxo" 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 "acyl halide" 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" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.

"Optional" or "optionally" 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" It is meant that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the 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 amino 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, which facilitates the absorption of the active ingredient and thereby exerts 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.

Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

a compound of the formula (I) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a drug thereof The preparation method of the salt used includes the following steps:

Dissolving a compound of the formula (IA), a compound of the formula (IB), bis(cyanium dichloride) and norbornene in a polar solvent, and heating the reaction under basic conditions to obtain a compound of the formula (IC), The alkaline reagent of this condition 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 chlorinated compound under heating and basic conditions to obtain a pass. a compound of the formula (ID), wherein 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). The alkaline reagent of this condition is preferably 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 general formula. (I) a compound.

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

among them:

R ^{x is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each is optionally independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;

Ring A, Ring B, X, Y, Z, R ¹ to R ⁷ , x, y and z are as defined in the general formula (I).

a compound of the formula (II-A) of the present invention or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A method for preparing a pharmaceutically acceptable 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 the condition is preferably sodium hydrogencarbonate, the polar solvent is preferably N,N-dimethylacetamide; and the obtained compound of the formula (II-3) is heated under alkaline conditions with iodine. Methane and a chlorinated product are reacted to obtain a compound of the formula (II-4). The alkaline reagent of the condition is preferably sodium hydride; the obtained compound of the formula (II-4) is hydrolyzed under basic conditions to give the formula (II-A). -1) a compound, the alkaline reagent of this 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, Reaction with N-diisopropylethylamine gives the compound of the formula (II-A).

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

among them:

R ^{x is} selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each is optionally independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by one or more substituents;

Rings A, G, X, R ^a , R ¹ to R ⁷ , p, y and z are as defined in the formula (II-A).

DRAWINGS

Effect of Compound Example 30 of Figure 1 on MC38 colorectal tumor growth in C57BL/6 mice.

detailed description

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). NMR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), internal standard was four. Methyl silane (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 column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

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

Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for thin layer chromatography separation and purification is 0.4mm. ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel 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, 韶远 Companies such as Accela ChemBio Inc., Dary 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. Purification compounds using column chromatography eluent systems and thin layer chromatography developer systems include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: dichloromethane and acetone In the system, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and a small amount of an alkaline or acidic reagent such as triethylamine or acetic acid may be added for adjustment.

Example 1

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

first step

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

1H-indole-5-carboxylic acid methyl ester 1a (50 mg, 0.28 mmol), 1-(bromomethyl)-2-trifluoromethoxybenzene 1b (71 mg, 0.28 mmol), diacetonitrile palladium dichloride (7 mg, 0.03 mmol), norbornene (54 mg, 0.57 mmol), sodium bicarbonate (72 mg, 0.86 mmol) dissolved in N,N-dimethylacetamide The reaction 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)-1H-indole-5-carboxylate 1d

1c (60mg, 0.17mmol) was dissolved in N,N-dimethylformamide, a catalytic amount of potassium iodide was added, sodium hydride (10mg, 0.26mmol, 60% in oil) was added, and the reaction was stirred for 30 minutes, then added 2- 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)-1H-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)-1H-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-) Methylaminopropyl)-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 reaction was 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 saturated sodium chloride solution, dry over anhydrous sodium sulfate, The residue was purified by EtOAc EtOAc EtOAc:

MS m/z (ESI): 559.4 [M+1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.06 (s, 1H), 7.87 (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)-1H-indole-5-carboxamide 2

first step

2-(2-methoxybenzyl)-1H-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) Methyl), the reaction was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to room temperature, and the mixture was combined with EtOAc EtOAc. The residue was purified with EtOAc EtOAc (EtOAc)

Second step

1-isopropyl-2-(2-methoxybenzyl)-1H-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, then sodium hydride (30 mg, 0.74 mmol, 60% in oil) was added, and the reaction was stirred for 30 minutes, then 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)-1H-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)-1H-indole-5-carboxamide 2

2d (23 mg, 0.08 mmol), (4-(ethylsulfonyl)phenyl)methanamine (24 mg, 0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Acid salt (21 mg, 0.12 mmol), 1-hydroxybenzotriazole (17 mg, 0.12 mmol), N,N-diisopropylethylamine (53 mg, 0.41 mmol) dissolved in dichloromethane. . Add water, extract with a mixed solvent of dichloromethane and methanol (V: V = 8:1) (20 mL × 3), combine the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, The residue was purified by EtOAc EtOAc EtOAc.

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)-1H-indole-5-carboxamide 3

first step

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

3b (4.4g, 13.2mmol) was dissolved in N,N-dimethylformamide, sodium hydride (1.06g, 26.4mmol, 60% in oil) and ethyl iodide (10.29g, 66.01mmol) were added and stirred. Reaction 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)-1H-indole-5-carboxylic acid 3d

3c (1.4 g, 3.87 mmol) was dissolved in 15 mL of methanol, 5 mL of 2M 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 3d (1.1 g, pale yellow solid).

the fourth step

1-ethyl-N-(4-(ethylsulfonyl)benzyl)-2-(2-(trifluoromethyl)benzyl)-1H-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-ethylcarbazide Amine hydrochloride (1.21 g, 6.33 mmol), 1-hydroxybenzotriazole (856 g, 6.33 mmol), triethylamine (641 mg, 6.33 mmol). The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj

MS m/z (ESI): 529.9 [M + 1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.11 (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-1H-indole-5-carboxamide 4

first step

Methyl 2-(4-fluoro-2-(trifluoromethyl)benzyl)-1H-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 m.

Second step

2-(4-Fluoro-2-(trifluoromethyl)benzyl)-1-isopropyl-1H-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°C The reaction was stirred for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc m. Chromatography of the residue obtained from EtOAc (EtOAc)

third step

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

4c (34 mg, 0.09 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M 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-1H-indole-5-carboxamide 4

Crude 4d (26 mg, 0.068 mmol), 4-(ethylsulfonyl)phenyl)methanamine (16.4 mg, 0.082 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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 (400MHz, CDCl 3}} ) δ8.10 (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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 5

first step

Methyl 2-(4-chloro-2-(trifluoromethyl)benzyl)-1H-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 m.

Second step

Methyl 2-(4-chloro-2-(trifluoromethyl)benzyl)-1-isopropyl-1H-indole-5-carboxylate 5c

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

third step

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

5c (28 mg, 0.071 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M 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 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

Crude 5d (28 mg, 0.07 mmol), 4-(ethylsulfonyl)phenyl)methanamine (16.92 mg, 0.085 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (27.12 mg, 0.141 mmol), 1-hydroxybenzotriazole (19.12 mg, 0.101 mmol), triethylamine (14.32 mg, 0.141 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuo. EtOAcjjjjjjj

MS m/z (ESI): 577.4 [M+1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.08 (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)-1H-indole-5-carboxamide 6

first step

Methyl 2-(2-(trifluoromethyl)benzyl)-1H-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 m.

Second step

Methyl 1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1H-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 m. Chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

third step

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

6b (1.5 g, 4 mmol) was dissolved in 15 mL of methanol, 5 mL of 2M potassium hydroxide solution was added, and the mixture was heated to reflux and stirred for 2 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 6c (1.33 g, pale yellow solid).

the fourth step

N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-2-(2-(trifluoromethyl)benzyl)-1H-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-ethylcarbazide Amine 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 Should be 12 hours. The reaction mixture was concentrated under reduced vacuo.

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

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.11 (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)-1H-indole-5-carboxamide 7

first step

Sodium 4-cyanobenzenesulfinate 7b

4-Cyanobenzenesulfonyl 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, EtOAc (EtOAc (EtOAc) The residue was obtained to give the title compound (jjjjjjj

third step

(4-((cyclopropylmethyl)sulfonyl)phenyl)methanamine 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)-1H-indole-5-carboxamide 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 (400MHz, CDCl 3}} ) δ8.13 (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)-1H-indole-5-carboxamide 8

first step

4-(ethylsulfonyl)-2-fluorobenzylcarbamic acid tert-butyl ester 8b

4-Bromo-2-fluorobenzylcarbamic 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), carbonic acid The hydrazine (642.7 mg, 1.97 mmol) was dissolved in dimethyl sulfoxide, and a catalytic amount of cuprous iodide and L-valine 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 the mixture was filtered and evaporated. The residue was obtained to give the title compound (jjjjjjj

Second step

(4-(ethylsulfonyl)-2-fluorophenyl)methanamine 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)-1H-indole-5-carboxamide 8

The crude product 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 (400MHz, CDCl 3}} ) δ8.10 (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)-1H-indole-5-carboxamide 9

first step

Methyl 1-cyclopropyl-2-(2-(trifluoromethyl)benzyl)-1H-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)-1H-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 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)-1H-indole-5-carboxamide 9

Crude 9b (55 mg, 0.15 mmol), 4-(ethylsulfonyl)phenyl)methanamine (40 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt Acid salt (44 mg, 0.23 mmol), 1-hydroxybenzotriazole (31 mg, 0.23 mmol), N,N-diisopropylethylamine (59 mg, 0.46 mmol) dissolved in dichloromethane. . Add water and a small amount of methanol, and extract with a mixed solvent of dichloromethane and methanol (V: V = 8:1) (20 mL × 2), the organic phase is combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. 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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 10

first step

2-(2-(ethylbenzyl)-1H-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 hydrogencarbonate (143.86 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-(ethylbenzyl)-1-isopropyl-1H-indole-5-carboxylic acid methyl ester 10c

10b (67 mg, 0.23 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (18.27mg, 0.46mmol, 60% in oil), 2-bromopropane (140.45mg, 1.14mmol), The reaction was stirred at 50 ° C for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc (EtOAc) Chromatography The residue was purified with EtOAc EtOAc (EtOAc)

third step

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

10c (46 mg, 0.137 mmol) was dissolved in 5 mL of methanol, 2 mL of 2M 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 solution was washed with EtOAc EtOAc (EtOAc m.

the fourth step

2-(2-(ethylbenzyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 10

Crude 10d (42 mg, 0.13 mmol), (4-(ethylsulfonyl)phenyl)methanamine (31.25 mg, 0.16 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine hydrochloride (50.01 mg, 0.26 mmol), 1-hydroxybenzotriazole (35.31 mg, 0.26 mmol), triethylamine (26.45 mg, 0.26 mmol) was dissolved in dichloromethane. The reaction mixture was concentrated under reduced vacuolululululululululululululululu

MS m/z (ESI): 503.5 [M + 1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.04 (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)-1H-indole-5- Amide 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 mmol) 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)-1H-indole-5-carboxamide 12

first step

2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-cyclopropyl-1H-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 mixture was cooled to room temperature and then evaporated. The residue was purified with EtOAc EtOAc (EtOAc)

Second step

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

12a (21 mg, 0.05 mmol) was dissolved in 2 mL of methanol, 2 mL of 2M 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 solution was washed with EtOAc EtOAc (EtOAc m.

third step

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

Crude 12b (16 mg, 0.04 mmol), (4-(ethylsulfonyl)phenyl)methanamine (12.2 mg, 0.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine 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 (400MHz, CDCl 3}} ) δ8.02 (s, 1H), 7.87 (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)-1H-indole-5-carboxamide 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 mixture was cooled to room temperature, EtOAc was evaporated, evaporated, evaporated, evaporated. Light yellow oil), Yield: 64%.

Second step

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

13a (71 mg, 0.174 mmol) was dissolved in 3 mL of methanol, and 3 mL of 2M 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 solution was washed with EtOAc EtOAc (EtOAc m.

third step

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

Crude 13b (56 mg, 0.148 mmol), (4-(ethylsulfonyl)phenyl)methanamine (44.36 mg, 0.222 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine 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 EtOAc.

MS m/z (ESI): 557.1 [M-1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.05 (s, 1H), 7.91 (d, 2H), 7.72 (dd, 1H), 7.59-7.65 (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)-1H-indole-5-carboxamide 14

first step

2-(4-(Trifluoromethyl)benzyl)-1H-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, EtOAc (EtOAc (EtOAc) The resulting residue was purified with EtOAc EtOAcjjjjj

Second step

Methyl 2-(4-(trifluoromethyl)benzyl)-1-isopropyl-1H-indole-5-carboxylate 14c

14b (94mg, 0.28mmol) was dissolved in 3mL of N,N-dimethylformamide, sodium hydride (27mg, 0.56mmol, 60% in oil), 2-bromopropane (70mg, 0.56mmol), 80°C The reaction was stirred 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-1H-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 2M 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, and water was added to the residue, and concentrated hydrochloric acid was added dropwise to pH 5-6, extracted with ethyl acetate (20 mL×3), and the organic phase was combined with water and saturated sodium chloride solution The mixture was washed with EtOAc EtOAc EtOAc.

the fourth step

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

Crude 14d (54 mg, 0.15 mmol), (4-(ethylsulfonyl)phenyl)methanamine (36 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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 (400MHz, CDCl 3}} ) δ8.08 (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-1H-indole-5-carboxamide 15

first step

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-1H-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), 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.

Second step

2-(2-Fluoro-4-(trifluoromethyl)benzyl)-1-isopropyl-1H-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), stirred at 50 °C Reaction for 12 hours. The reaction mixture was cooled to room temperature, poured into water, EtOAc (EtOAc (EtOAc) The residue was purified by EtOAc EtOAc (EtOAc)

third step

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

15c (72 mg, 0.183 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M 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, and water was added to the residue, and concentrated hydrochloric acid was added dropwise to pH 5-6, extracted with ethyl acetate (20 mL×3), and the organic phase was combined with water and saturated sodium chloride solution The mixture was washed with EtOAc EtOAc EtOAc.

the fourth step

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

Crude 15d (47 mg, 0.12 mmol), (4-(ethylsulfonyl)phenyl)methanamine (30 mg, 0.15 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 16

first step

2-(2-chloro-4-(trifluoromethyl)benzyl)-1H-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-1H-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), stirred at 50 ° C Reaction 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-1H-indole-5-carboxylic acid 16d

The crude 16c (41 mg, 0.1 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M 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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 16

Crude 16d (34 mg, 0.086 mmol), (4-(ethylsulfonyl)phenyl)methanamine (26 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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)-1H-indole-5-carboxamide 17

first step

Methyl 2-(3-(trifluoromethyl)benzyl)-1H-indole-5-carboxylate 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 m.

Second step

2-(3-(Trifluoromethyl)benzyl)-1-isopropyl-1H-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), and stirred at 70 ° C Reaction for 12 hours. The reaction mixture was cooled to EtOAc.

third step

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

17c (30 mg, 0.08 mmol), (4-(ethylsulfonyl)phenyl)methanamine (20 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The acid salt (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 HNMR (400MHz, CDCl 3)}} δ8.08 (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)-1H-indole-5-carboxamide 18

first step

Methyl 2-(4-(trifluoromethoxy)benzyl)-1H-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) , 5.7mmol), sodium bicarbonate (360 The mg, 4.28 mmol) was dissolved in N,N-dimethylacetamide, and the reaction was stirred at 70 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc m.

Second step

1-isopropyl-2-(4-(trifluoromethoxy)benzyl)-1H-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 ° C for 12 hours. The reaction mixture was cooled to EtOAc EtOAc m.

third step

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

18c (30 mg, 0.08 mmol), (4-(ethylsulfonyl)phenyl)methanamine (20 mg, 0.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The acid salt (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 HNMR (400MHz, CDCl 3)}} δ8.08 (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)-1H-indole-5-carboxamide 19

first step

Methyl 2-(4-(trifluoromethyl)benzyl)-1H-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 the reaction was 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)-1H-indole-5-carboxylate 19b

The crude product 19a (0.2 g, 0.6 mmol) was dissolved in 5 mL of N,N-dimethylformamide, sodium hydride (48 mg, 1.2 mmol, 60% in oil) was added, and the reaction was stirred at 0 ° C for 1 hour. The alkane (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)-1H-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 mixture was cooled to room temperature, EtOAc EtOAc (EtOAc m. 67%.

the fourth step

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

19c (10 mg, 0.029 mmol), (4-(ethylsulfonyl)phenyl)methanamine (11.6 mg, 0.058 mmol), 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.044 mmol), N,N-diisopropylethylamine ( 18.7 mg, 0.044 mmol) was dissolved in 5 mL of N,N-dimethylformamide and the reaction was stirred for 16 hours. 50 ml of water was added to the reaction solution, 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 residue was purified with EtOAc EtOAc (EtOAc)

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

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.88 (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)-1H-indole-5-carboxamide 20

first step

Methyl 1-cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1H-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 The residue was purified by EtOAc EtOAcjjjjjjj

Second step

1-cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1H-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 4M 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)-1H-indole-5-carboxamide 20

Crude 20b (60 mg, 0.17 mmol), (4-(ethylsulfonyl)phenyl)methanamine (50 mg, 0.25 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), N,N-diisopropylethylamine (65 mg, 0.50 mmol) dissolved in dichloromethane. hour. Add water, extract with a mixed solvent of dichloromethane and methanol (V: V = 8:1) (20 mL × 3), combine the organic phase, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, The residue was purified by EtOAc EtOAc EtOAc:

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)-1H-indole-5-carboxamide 21

first step

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

18c (50mg, 0.14mmol) was dissolved in 5mL of tetrahydrofuran, sodium hydride (12mg, 0.28) Methanol, 60% in oil), the reaction was stirred for 5 minutes, methyl iodide (30.5 mg, 0.21 mmol) was added, and the reaction was stirred for 30 minutes. The reaction mixture was poured into EtOAc (3 mL, EtOAc (EtOAc) Light yellow oil), the product was directly subjected to the next reaction without purification.

Second step

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

The crude product 21a (28 mg, 0.07 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M 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)-1H-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-ethylcarbazide The amine 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)}} δ8.07 (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)-1H-indole-5-carboxamide 22

first step

Methyl 1-ethyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1H-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) was added, and the reaction 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)-1H-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 2M 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, and water was added to the residue, and concentrated hydrochloric acid was added dropwise to pH 5-6, extracted with ethyl acetate (20 mL×3), and the organic phase was combined with water and saturated sodium chloride solution The mixture was washed with EtOAc EtOAc EtOAc.

third step

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

Crude 22b (24 mg, 0.066 mmol), (4-(ethylsulfonyl)phenyl)methanamine (26.2 mg, 0.131 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine 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)-1H-indole-5-carboxamide 23

first step

Methyl 1-ethyl-2-(4-(trifluoromethoxy)benzyl)-1H-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), 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)-1H-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 2M 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-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethoxy)benzyl)-1H-indole-5-carboxamide 23

Crude 23b (21 mg, 0.057 mmol), (4-(ethylsulfonyl)phenyl)methanamine (23 mg, 0.115 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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)-1H-indole-5-carboxamide 24

first step

Methyl 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-(trifluoromethyl)benzyl)-1H-indole-5-carboxylate 24a

14c (60 mg, 0.18 mmol), cesium carbonate (117 mg, 0.36 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (86 mg, 0.36 mmol) and a catalytic amount of potassium iodide dissolved in 3 mL of 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)-1H-indole-5-carboxylic acid 24b

24a (38 mg, 0.077 mmol) was dissolved in 6 mL of methanol, and 1 mL of a 2M sodium hydroxide solution was added thereto, and the reaction was stirred at 65 ° C for 12 hours. The reaction mixture was cooled to room temperature, and then concentrated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. Carry out the next reaction.

third step

N-(4-(ethylsulfonyl)benzyl)-1-(2-hydroxyethyl)-2-(4-(trifluoromethyl)benzyl)-1H-indole-5-carboxamide 24

Crude 24b (14 mg, 0.038 mmol), (4-(ethylsulfonyl)phenyl)methanamine (10 mg, 0.046 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (11 mg, 0.057 mmol), 1-hydroxybenzotriazole (8 mg, 0.057 mmol), triethylamine (19 mg, 0.19 mmol) dissolved in dichloromethane. Time. After adding 40 mL of ethyl acetate, it was washed with water (20 mL), EtOAc (EtOAc) Title 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)-1H-indole-5-carboxamide 25

first step

2-((6-(Trifluoromethyl)pyridin-3-yl)methyl)-1H-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 m.

Second step

1-ethyl 2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-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 solution was cooled to room temperature. Filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjj

third step

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

25c (36 mg, 0.1 mmol) was dissolved in 3 mL of methanol, 1 mL of 2M sodium hydroxide solution was added, and the reaction 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. The solution was washed with EtOAc EtOAc (EtOAc m.

the fourth step

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

Crude 25d (27 mg, 0.077 mmol), (4-(ethylsulfonyl)phenyl)methanamine (23.17 mg, 0.116 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide The amine 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), 7.87 (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)benzoyl)-1H-indole-5-carboxamide 26

first step

Methyl 1-ethyl-2-(4-(trifluoromethyl)benzoyl)-1H-indole-5-carboxylate 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 m.) Yield: 27%.

Second step

1-ethyl-2-(4-(trifluoromethyl)benzoyl)-1H-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 mixture was cooled to room temperature, and the mixture was evaporated to dryness.mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The next reaction was carried out directly by purification.

third step

1-ethyl-N-(4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)benzoyl)-1H-indole-5-carboxamide 26

Crude 26b (14 mg, 0.04 mmol), (4-(ethylsulfonyl)phenyl)methanamine (10 mg, 0.048 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 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 EtOAc EtOAc EtOAc (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Light 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)-1H-indole-5-carboxamide 27

first step

Methyl 1-cyclopropyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1H-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, EtOAcjjjjjjjjjjjjjjjjjj 57%.

Second step

1-cyclopropyl-2-(2-fluoro-4-(trifluoromethyl)benzyl)-1H-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. The solution was washed with EtOAc EtOAc EtOAc.

third step

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

Crude 27b (31 mg, 0.082 mmol), (4-(ethylsulfonyl)phenyl)methanamine (19.6 mg, 0.099 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (31.5 mg, 0.164 mmol), 1-hydroxyl Benzotriazole (22.2 mg, 0.164 mmol), triethylamine (16.6 mg, 0.164 mmol) was dissolved in dichloromethane and stirred for 12 hr. 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)-1H-indole-5-carboxamide 28

first step

Methyl 1-cyclopropyl-2-(4-(trifluoromethoxy)benzyl)-1H-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 m.

Second step

1-cyclopropyl-2-(4-(trifluoromethoxy)benzyl)-1H-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 to give a residue. Add water, add concentrated hydrochloric acid to pH 5-6, extract with ethyl acetate (20 mL×3), combine the organic phase, wash with water, saturated sodium chloride solution, dry over anhydrous sodium sulfate, Concentration gave the crude title product 28b (56 mg, white solid).

third step

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

Crude 28b (56 mg, 0.149 mmol), (4-(ethylsulfonyl)phenyl)methanamine (44.6 mg, 0.223 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbazide Amine hydrochloride (57.2 mg, 0.298 mmol), 1-hydroxybenzotriazole (40.3 mg, 0.298 mmol), triethylamine (30.2 mg, 0.298 mmol) was dissolved in dichloromethane. 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), 7.87 (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)-1H-indole-5- Formamide 29

first step

4-((1-Cyclopropyl-2-(4-(trifluoromethyl)benzyl)-1H-indole-5-carboxamido)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 Ment, prepared by the well-known method "Bioorganic & Medicinal Chemistry, 2002, 10 (5), 1347-1359"), 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) dissolved in N,N-dimethylformamide, stirred Reaction for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of dichloromethane and methanol (V:V=8:1) (20 mL×3), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate The 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)-1H-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. It is extracted with a methanol mixed solvent (V: V = 8:1) (20 mL × 3), washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give crude title product 29c (25 mg) It was used in the next reaction without purification.

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

third step

1-cyclopropyl-N-((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2-(4-(trifluoromethyl)benzyl)-1H-indole-5- Formamide 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 known method "Journal of Organic Chemistry, 2007, 72 (15), 5847). -5850" was prepared) dissolved in 5 mL of dichloromethane and 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, filtered The filtrate was concentrated under reduced vacuo.

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-(ethylsulfonyl)benzyl)-1-(2-fluoroethyl)-1H-indole-5- Formamide 30

first step

Methyl 2-(4-chloro-2-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-1H-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) The microwave was reacted at 100 ° C for 1 hour. The reaction mixture was cooled to room temperature, then evaporated, evaporated, evaporated

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

Second step

2-(4-Chloro-2-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-1H-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. EtOAc (EtOAc m. 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-(ethylsulfonyl)benzyl)-1-(2-fluoroethyl)-1H-indole-5- Formamide 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'-Tetramethylurea hexafluorophosphate (2138.73 mg, 5.63 mmol), triethylamine (1136.9 mg, 11.26 mmol) was dissolved in 30 mL of N,N-dimethylformamide, and the reaction was stirred for 12 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2), and the organic phase was combined. The title compound (30 mg, yield: 49.45%) was obtained.

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

^{1 H NMR (400MHz, DMSO-} d 6) δ8.98-9.01 (m, 1H), 8.05 (s, 1H), 7.82-7.86 (m, 3H), 7.69-7.73 (m, 2H), 7.53-7.57 (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)-1H-pyrazol-1-yl)methyl) -1H-吲哚-5-carboxamide 31

first step

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

Under an argon atmosphere, ethyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate 31b (1.0 g, 2.58 mmol, by a known method "Journal of the Chemical Society, Perkin Transactions 1" :Organic and Bio-Organic Chemistry, 1997 (14), 2059-2063 "prepared", tert-butyl dimethyl (prop-2-yn-1-yloxy) silane 31a (660 mg, 3.88 mmol, using A well-known method "Prepared by 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 is cooled to the chamber The mixture was filtered with Celite (EtOAc) (EtOAc)EtOAc. The resulting residue was purified to silica gel elut elut elut elut elut elut elut

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

Second step

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

31c (460 mg, 1.4 mmol) was dissolved in 1,2-dichloroethane, respectively, 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, celite was filtered, filtered, evaporated, evaporated, evaporated, evaporated, evaporated The residue was dried over EtOAc (EtOAc m.)

third step

1-cyclopropyl-2-(hydroxymethyl)-1H-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)-1H-pyrazol-1-yl)methyl)-1H-indole-5-carboxylic acid ethyl ester 31 g

Under an argon atmosphere, 31f (120 mg, 0.46 mmol), 3-methyl-5-(trifluoromethyl)-1H-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, then added diethyl azodicarboxylate (120 mg, 0.69 mmol), added, stirred for 12 hours . The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjj ).

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

the fifth step

1-cyclopropyl-2-((3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-1H-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. Product 31 h (55 mg).

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

Step 6

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

31h (30mg, 0.083mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (24mg, 0.12mmol), 1-hydroxybenzotriazole (17mg, 0.12 mmol), N,N-diisopropylethylamine (53 mg, 0.41 mmol) was dissolved in dichloromethane, and <RTI ID=0.0>> 0.223 mmol was prepared by the method disclosed in the patent application "US20150291607A1", 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). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. EtOAcjjjjjjjj

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

^{1 H NMR (400MHz, DMSO-} d 6) δ9.05 (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)-1H-pyrazol-1-yl)methyl)-1H-indole -5-carboxamide 32

first step

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

Under an argon atmosphere, methyl 3-iodo-4-(2,2,2-trifluoroacetamido)benzoate 32a (13.0 g, 34.85 mmol, using a known method "Journal of Medicinal Chemistry, 2005, 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 warmed to 60 ° C and stirred for 3 hours. Water was added to the reaction mixture, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjjj The obtained residue was purified to give the titled product 32b (yield: (yield: 63%).

Second step

2-(((tert-Butyldimethylsilyl)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)-1H-indole-5-carboxylic acid methyl ester 32d

32c (500 mg, 1.39 mmol) was dissolved in 5 mL of tetrahydrofuran, and the mixture was cooled to 0 ° C. 2.8 mL of 1M 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 extracted with ethyl acetate (50 mL×3). Title product 32d (300 mg). The product was directly subjected to the next reaction without purification.

the fourth step

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

The crude product 32d (120mg, 0.53mmol), 3-methyl-1H-pyrazole 32e (104mg, 0.69mmol) and triphenylphosphine (208mg, 0.795mmol) were dissolved in 3mL of tetrahydrofuran under argon, then azo was 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)-1H-pyrazol-1-yl)methyl)-1H-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, and 1 M hydrochloric acid was added dropwise to pH 1-2, and extracted with dichloromethane (30 mL × 3). The organic phase was combined, and the organic phase was washed with water and saturated sodium chloride The filtrate was concentrated under reduced pressure to give the crude title compound (32 g)

Step 6

1-cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-2-((5-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-1H-indole -5-carboxamide 32

32 g (20 mg, 0.057 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg, 0.115 mmol), 1-hydroxybenzotriazole (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, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced vacuo.

MS m/z (ESI): 531.2 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.04 (s, 1H), 7.88-7.86 (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)-1H-indole-5- Formamide 33

first step

2-((4-(Trifluoromethyl)piperidin-1-yl)methyl)-1H-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 the addition of dimethylformamide, the mixture was heated to 60 ° C and stirred for 5 hours. The reaction mixture was cooled to room temperature, and the mixture was evaporated. EtOAcjjjjjjjjjjjjj Column chromatography The residue obtained was purified with EtOAc EtOAc.

Second step

1-isopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1H-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 (67 mg) was added. , 0.40 mmol), and the reaction was stirred for 12 hours under 60 ° C sealing conditions. 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)-1H-indole-5-carboxylic acid 33d

33c (105 mg, 0.26 mmol) was dissolved in 10 mL of ethanol, and 3 mL of a 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 the mixture was extracted with methylene chloride and methanol (V:V = 1:1) (20 mL × 3). Product 33d (95 mg) was taken directly to the next product 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)-1H-indole-5- Formamide 33

Crude 33d (55 mg, 0.15 mmol), (4-(ethylsulfonyl)phenyl)methanamine (45 mg, 0.22 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (43 mg, 0.22 mmol), N,N-diisopropylethylamine (97 mg, 0.75 mmol) was dissolved in N,N-dimethylformamide, and the reaction was 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 (400 MHz, DMSO-d ₆ ) δ 9.02 (t, 1 H), 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)-1H-indole-5- Formamide 34

first step

1-cyclopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1H-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 solution was cooled to room temperature, filtered over Celite, ethyl acetate. The filtrate was concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated, evaporated. The obtained residue was purified to silicagel elut elut elut elut elut elut elut

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

Second step

1-cyclopropyl-2-((4-(trifluoromethyl)piperidin-1-yl)methyl)-1H-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 4M 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 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)-1H-indole-5- Formamide 34

Crude 34b (80 mg, 0.22 mmol), (4-(ethylsulfonyl)phenyl)methanamine (65 mg, 0.32 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride (61 mg, 0.32 mmol), N,N-diisopropylethylamine (142 mg, 1.1 mmol) was dissolved in N,N-dimethylformamide, and the reaction was 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 saturated sodium chloride solution, dry over anhydrous sodium sulfate, The residue was purified by EtOAc EtOAc (EtOAc)

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

¹ H NMR (400 MHz, 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-difluoropiperidin-1-yl)methyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole -5-formamide 35

Starting from 2-ethyl-4-oxopiperidine-l-carboxylic acid tert-butyl ester 35a, the title compound 35 (4 mg)

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

_{^{1 H NMR (400MHz, CDCl 3}} ) δ9.07 (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)-1H-indole-5-carboxamide 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) δ9.00 (t, 1H), 7.99 (s, 1H), 7.82 (d, 2H), 7.70 (d, 1H), 7.52-7.5 8 (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)-1H-indole-5-carboxamide 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}} ) δ7.85-7.81 (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)-1H-indole-5-carboxamide 38

(S)-1-cyclopropyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) Methyl)-1H-indole-5-carboxamide 39

first step

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

5-bromo-1H-indole-2-carboxylic acid 38b (600 mg, 2.5 mmol, prepared by the well-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-phenylene oxide) And triazole)-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 was completed, the reaction was stirred for 18 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjj

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

Second step

5-bromo-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1H-indole 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)-1H-indole 38e

The crude product 38d (120 mg, 0.33 mmol) was dissolved in 5 mL of 1,2-dichloroethane, and cyclopropylboronic acid was added. (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), added, 70 ° C The reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj

the fourth step

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

38e (100mg, 0.25mmol) was dissolved in 2mL ethanol and dimethyl sulfoxide (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.

the fifth step

1-cyclopropyl-2-((2-(trifluoromethyl)piperidin-1-yl)methyl)-1H-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 mixture was concentrated under reduced pressure. EtOAc was evaporated.

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)-1H-indole-5-carboxamide 38

(S)-1-cyclopropyl-N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2-((2-(trifluoromethyl)piperidin-1-yl) Methyl)-1H-indole-5-carboxamide 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 vacuolululululululululululululululululululululululululululululululululululu

Compound 38:

MS m/z (ESI): 549.1 [M+1];

Chiral HPLC analysis: retention time 16.910 min, chiral purity: 98% (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}} ) δ9.06 (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];

Chiral HPLC analysis: retention time 11.940 minutes, chiral purity: 98% (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}} ) δ9.06 (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-Diethylpiperidin-1-yl)methyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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 (400MHz, CDCl 3}} ) δ8.08 (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)-1H-indole-5-A Amide 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 (400MHz, CDCl 3}} ) δ8.62-8.61 (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)-1H-benzo[d]imidazole-5-carboxamide 42

From 2-(2-(trifluoromethyl)phenyl)acetic acid 42a (prepared by the published method "Tetrahedron, 2002, 58(50), 9925-9932") and 3-amino-4-(isopropyl) Starting from the base amino 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)-1H-indole-5- Formamide 43

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

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)-1H-indole哚-5-formamide 44

Starting from tert-butyl 4-bromo-2-chlorobenzylcarbamate (prepared by the method disclosed in the patent application "WO2005082859A1"), a product of the same procedure as in 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) δ 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)-1H-indole-5-carboxamide 45

Using the synthetic route of Example 14, the fourth step starting material (4-(ethylsulfonyl)phenyl)methanamine was replaced by (4-(methylsulfonyl)phenyl)methanamine (disclosed by the patent application "US20160122318A1") The title compound was obtained by the method 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-1H-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 (400MHz, CDCl 3}} ) δ8.11 (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)-1H-indole-5-carboxamide 47

Using the synthetic route of Example 14, the second step starting material, 2-bromopropane, was replaced 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) δ 8.10 (s, 1H), 7.88 (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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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 under microwave Reaction for 30 minutes. The reaction mixture was cooled to EtOAc.

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

Example 50

2-(4-carbamoylbenzyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 50

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

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

Example 51

N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-1-isopropyl-2-(4-(trifluoromethyl)benzyl)-1H-indole-5- Amide 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)-1H-indole-5-carboxamide 52

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

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

Example 53

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

Using the procedure of Example 14, the second step of the starting material, 2-bromopropane, was replaced with the bromocyclopentane to give 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)-1H-indole-5-carboxamide 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 (400MHz, CDCl 3}} ) δ8.10 (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)-1H-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 ) δ 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)-1H-benzo[d]imidazole-5-carboxamide 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 (400MHz, CDCl 3}} ) δ8.18 (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-1H-benzo[d]imidazole-5- Formamide 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-1H-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 (400MHz, 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)-1H-indole-5-carboxamide 59

Using the procedure of Example 8, the first step starting material 8a was replaced with 4-bromo-2-chlorobenzylcarbamic acid tert-butyl ester, and the second step 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 (400MHz, CDCl 3}} ) δ8.08 (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)-1H-benzo[d]imidazole-5-carboxamide 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 (400MHz, 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-1H-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}} ) δ8.10 (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)-1H-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 (400 MHz, 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)-1H-indole- 5-formamide 63

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

MS m/z (ESI): 560.5 [M + 1];

¹ H NMR (400 MHz, CDCl ₃ ) δ 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)-1H-indole-5-carboxamide 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)- 1H-吲哚-5-carboxamide 65

Using the synthesis scheme 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)methanamine was replaced with 11a to give the title product 65 (38 mg). ).

MS m/z (ESI): 549.5 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ9.13 (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)-1H-indole-5-carboxamide 66

Starting from (prop-2-yn-1-yloxy)tetrahydro-2H-pyran (prepared by the known method "ChemCatChem, 2016, 8 (18), 2912-2915"), Example 33 was employed. A similar synthetic route gave 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)-1H-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 (400MHz, DMSO-} d 6) δ9.06 (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)-1H-indole-5-carboxamide 68

Starting from piperazine-1-carboxylic acid tert-butyl ester 68a (prepared by the known method "Chemical Communications (Cambridge, United Kingdom), 2013, 49 (61), 6867-6869"), similar synthesis was carried out using Example 33 Route, the title product 68 (11 mg) was obtained.

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)-1H-indole-5-carboxamide 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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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 (400MHz, CDCl 3}} ) δ8.03 (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-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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-Cyclopropylbenzyl)-N-(4-(ethylsulfonyl)benzyl)-1-isopropyl-1H-indole-5-carboxamide 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)-1H-indole-5-carboxamide 73

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

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

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.07 (d, 1H), 7.88 (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)-1H-吲哚-5-formamide 74

first step

1-cyclopropyl-2-((4,4-difluoropiperidin-1-yl)methyl)-1H-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)-1H-indole哚-5-formamide 75

Starting from 6-chloro-1H-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)benzoyl)-1H-indole-5-carboxamide 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, 3H), 0.80-0.84 (m, 2H)

Example 77

1-cyclopropyl-N-(4-(ethylsulfonyl)benzyl)-2-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-indole-5-carboxamide 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)-1H-indole哚-5-formamide 78

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

MS m/z (ESI): 548.6 [M+1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.07 (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)-1H-indole-5-carboxamide 79

Methyl 6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carboxylate 79a (prepared by a known method "European Journal of Organic Chemistry, 2006, (13), 2956-2969" Starting from the same procedure as in Example 6, the title product 79 (6 mg) was obtained.

MS m/z (ESI): 561.4 [M+1];

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.38 (d, 1H), 7.91 (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)-1H-indole-5 -formamide 80

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

MS m/z (ESI): 542.4 [M + 1];

^{1 H NMR (400MHz, DMSO-} d 6) δ9.09 (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-(ethylsulfonyl)benzyl)-6-fluoro-1-(2-fluoroethyl)-1H-indole哚-5-A Amide 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 (400MHz, DMSO-} d 6) δ8.76 (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)-1H-indole-5-A Amide 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)-1H-indole-5-A Amide 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)-1H-indole-5-carboxamide 84

Starting from methyl 4-amino-2-fluorobenzoate, a similar synthetic route of Example 33 was used to give 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)-1H-pyrazole- 1-yl)methyl)-1H-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 (400MHz, DMSO-} d 6) δ9.12 (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 RORγ by the compounds of the examples of the present invention

First, experimental materials and instruments

1.

TR-FRET RORγ co-activation system (Life Technologies)

2.RORγLBD(AB Vector)

3. DMSO (Sigma Aldrich)

4.384-well cell culture plate (Perkin Elmer)

5. Microplate reader (Tecan)

Second, the experimental steps

Modulation of RORy activity by the compounds of the invention was screened using a LanthaScreen TR-FRET (Time Resolved Fluorescence Energy Resonance Transfer) RORγ co-activation 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 was 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 RORγLBD (AB Vector). The ROR γLBD concentration 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 [mu]L of intact buffer D without ROR[gamma]LBD. A mixture of 0.6 μM fluorescein-D22 (4X) and 8 nM 铽 (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.

Fluorescence readings were detected using a Tecan Infinite M1000, and a logarithmic curve of the ratio of the emission wavelength of 520 nm / 495 nm to the concentration of the compound was plotted by GraphPad Prism 6.0 software to calculate the IC ₅₀ /EC ₅₀ value of the test compound.

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

Table 1 IC ₅₀ /EC ₅₀ values of the compounds of the invention for RORγ in vitro activity

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 RORγ. It is shown in the experimental results that the modification of the A ring substituent in the compound represented by the general formula (I) shows different mechanisms for the regulation of the activity of RORγ in vitro, in A. When the ortho position of the ring has a larger substituent (for example: trifluoromethyl, methoxy, ethyl, trifluoromethoxy), it exhibits an agonistic effect (see Examples 1, 2, 4, 6 and 10, etc., exhibits an inhibitory effect when there are smaller substituents (for example, hydrogen atom or 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 activation reagent cytostim (10 μl/ml) was added in proportion to the cell suspension, and then the cells were seeded in 96-well cell culture plates 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 the IL-17A enzyme-linked 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.

Table 2 IC ₅₀ /EC ₅₀ values for quantitative analysis of IL-17A by immunoassay of the compounds of the invention

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 alone with the anti-mouse-PD-1 antibody was evaluated by measuring 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. After 5 days, when the tumors 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, was injected intraperitoneally (ip) to mice bearing MC38 tumors on days 5, 8, 11, and 14 after tumor implantation in mice. Anti-mouse PD-1 (CD279) antibody (BioXcell) (5 mg/head).

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 is 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 1 represents the length of the tumor, w represents the width of the tumor, and h represents the height of the tumor in millimeters.

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%. When Example 30 (12.5 mg/kg) was administered in combination with an anti-mouse PD-1 monoclonal antibody (5 mg/mouse), a strong synergistic effect (TGI of 68%) was exhibited.

TGI%=100x (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 antitumor activity, while Example 30 showed a strong synergistic effect with the PD-1 antibody combination, which also indicates that Example 30 has RORγ. Activating (rather than inhibiting) consistent biological activity opens up new avenues for improving the efficacy of immunotherapy.

Claims (29)

1. 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,

   among them:

   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 the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   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 halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. a base, 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 said Alkyl, cycloalkyl, alkoxy, haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, Substituted with one or more substituents of alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ³ and R ^{4 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 halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. 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 said alkyl group, cycloalkyl group, halogenated alkane The radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

   Or R ³ and R ⁴ form an oxo group;

   R ^{5 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino 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 said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, One or more of haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;

   R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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)OR ⁸ and —S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituting one or more substituents in the heteroaryl;

   R ^{7 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{9 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;

   m is 0, 1 or 2;

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

   y is 0, 1, 2 or 3;

   z is 0, 1, 2, 3 or 4.
2. The compound of the formula (I) according to claim 1, which is a compound of the formula (II):

   

   among them:

   X is CR ⁹ or N;

   Y is CH or N;

   R ⁹ is a hydrogen atom or an alkyl group;

   Ring A, Ring B, R ¹ to R ⁷ , x, y and z are as defined in claim 1.
3. The compound of the formula (I) according to claim 1 or 2, wherein the A ring and the B ring are the same or different and each is independently selected from a heterocyclic group, an aryl group and a heteroaryl group.
4. The compound of the formula (I) according to any one of claims 1 to 3, which is a compound represented by the formula (II-A):

   

   among them:

   X is CR ⁹ or N; R ⁹ is a hydrogen atom or an alkyl group;

   G is CH or N;

   R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, bromo, amino, 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 said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, The heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkane. Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

   p is 0, 1, 2 or 3;

   Rings A, R ¹ to R ⁸ , m, y and z are as defined in claim 1.
5. a compound of the formula (II-A) according to claim 4, wherein

   

   Selected from

   
6. The compound of the formula (I) according to any one of claims 1 to 3, which is a compound represented by the formula (III):

   

   among them:

   X is CR ⁹ or N;

   Y is CH or N;

   R ⁹ is a hydrogen atom or an alkyl group;

   Ring A, R ¹ to R ⁷ , x, y and z are as defined in claim 1.
7. The compound of the formula (I) according to any one of claims 1 to 3 and 6, which is a compound represented by the formula (IV):

   

   among them

   X is CR ₉ or N;

   Y is CH or N;

   R ⁹ is a hydrogen atom or an alkyl group;

   R ¹ to R ⁷ , x, y and z are as defined in claim 1.
8. The compound of the formula (I) according to any one of claims 1 to 3 and 6 to 7, which is a compound represented by the formula (IV-A):

   

   among them:

   X is CR ⁹ or N;

   Y is CH or N;

   R ⁹ is a hydrogen atom or an alkyl group;

   R ^{a is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, 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 said alkyl group, cycloalkyl group, alkoxy group, haloalkyl group, heterocyclic ring The aryl group, the aryl group and the heteroaryl group are each independently selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, Substituting one or more substituents in a heterocyclic group, an aryl group, and a heteroaryl group;

   p is 0, 1, 2 or 3;

   R ¹ to R ⁸ , m, y and z are as defined in claim 1.
9. The compound of the formula (IV-A) according to claim 8, which is a compound represented by the formula (IV-A-1):

   

   among them:

   R ¹ to R ⁷ , p, y and z are as defined in claim 8.
10. The compound of the formula (I) according to any one of claims 1 to 9, wherein R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkoxy group, and a halogen. And a cyano group, a heterocyclic group, and -C(O)NHR ⁸ , wherein each of the alkyl group, the cycloalkyl group, the alkoxy group and the heterocyclic group is independently selected from the group consisting of an alkyl group, a halogen group, a hydroxyl group, and an amino group. 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 halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group; and R ^{8 is} selected from a hydrogen atom or an alkyl group.
11. The compound of the formula (I) according to any one of claims 1 to 10, wherein R ² is a halogen; preferably fluorine or chlorine.
12. The compound of the formula (I) according to any one of claims 1 to 11, wherein R ³ and R ^{4 are the} same or different and are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group and a hydroxyl group. Or R ³ and R ⁴ together form an oxo group.
13. The compound of the formula (I) according to any one of claims 1 to 12, wherein R ^{5 is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkenyl and aryl, wherein said alkyl group The cycloalkyl and aryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of alkyl, halogen, alkenyl and hydroxy; preferably R ⁵ is isopropyl or cyclopropyl.
14. The compound of the formula (I) according to any one of claims 1 to 13, wherein R ⁷ is optionally substituted by one or more substituents selected from the group consisting of halogen, cycloalkyl and hydroxy. Alkyl; preferably R ⁷ is ethyl.
15. A compound according to any one of claims 1 to 14 which is selected from the group consisting of:

    

    

    
16. 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,

    among them:

    X, Y and Z are the same or different and are each independently 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;

    R ^{1 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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 said alkyl group, cycloalkyl group, alkoxy group, Haloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, 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 the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a heterocyclic ring. 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 said alkyl group, cycloalkyl group, halogenated alkane The radical, heterocyclyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, Substituted by one or more substituents in the cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

    Or R ³ and R ⁴ form an oxo group;

    R ^{5 is} selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkenyl, alkynyl, aryl, heteroaryl, -OR ⁸ , -C(O)R ⁸ ,- C(O)OR ⁸ and -S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, aryl and heteroaryl are each independently optionally selected from alkyl, haloalkyl, One or more of halogen, amino, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Substituted by a substituent;

    R ^{6 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino 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)OR ⁸ and —S(O) _m R ⁸ , wherein said alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl and heteroaryl The groups are each independently optionally selected from the group consisting of alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and Substituting one or more substituents in the heteroaryl;

    R ^{8 is} selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a hydroxyalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the amino group, and the ring are The alkyl group, heterocyclic group, aryl group and heteroaryl group are each independently selected from the group consisting of alkyl, halogen, hydroxy, amino, carboxylate, nitro, cyano, alkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

    R ^{9 is} selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an amino group, an alkenyl group, an alkynyl group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group And haloalkyl, aryl and heteroaryl are each independently selected from alkyl, haloalkyl, halo, amino, nitro, cyano, hydroxy, alkenyl, alkoxy, haloalkoxy, hydroxyalkyl Substituting one or more substituents of a cycloalkyl, a heterocyclic group, an aryl group, and a heteroaryl group;

    m is 0, 1 or 2;

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

    y is 0, 1, 2 or 3.
17. A method of preparing a compound of formula (I) according to claim 1 comprising:

    

    a compound of the formula (V) is condensed with a compound of the formula (VI) to give a compound of the formula (I);

    among them:

    Ring A, Ring B, X, Y, Z, R ¹ to R ⁷ , x, y and z are as defined in claim 1.
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to any one of claims 1 to 15, together with one or more pharmaceutically acceptable carriers, diluents Or an excipient.
19. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 as a ROR regulator for the preparation of a prophylactic and/or therapeutic inflammatory, autoimmune Use in drugs for sexual diseases, tumors or cancer.
20. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 as an ROR inverse agonist for preparation for preventing and/or treating inflammation or itself Use in medicines for immune diseases.
21. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 as an ROR agonist for the preparation of a tumor or a cancer for preventing and/or treating Use in medicine.
22. Use of the compound of the formula (IV-A) according to any one of claims 8 to 9 as an ROR agonist for the preparation of a medicament for preventing and/or treating a tumor or cancer.
23. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 for the preparation of a tumor for the treatment of a tumor with a combination of an ROR agonist and an anti-PD-1 antibody Use in cancer drugs.
24. Use of the compound of the formula (IV-A) according to claims 8 to 9 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.
25. Use of the compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 for the preparation of a medicament for regulating ROR.
26. Use of the compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 18 for the preparation of a medicament for an ROR agonist;
27. Use of the compound of the formula (IV-A) according to claims 8 to 9 for the preparation of a medicament for an ROR agonist.
28. The use according to claim 20, wherein the inflammatory or autoimmune disease is selected from the group consisting of psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, inflammatory bowel disease, ankylosing spine Inflammation, chronic obstructive pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, uveitis, Behcet's disease, asthma, allergic dermatitis, acne, Crohn's disease, ulcerative colitis, systemic erythema Allergic rhinitis of lupus, scleroderma, bronchitis and dermatomyositis.
29. The use according to any one of claims 21 to 24, 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, peritoneum Tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

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