WO2018214862A1 - Spiroformamide derivative, preparation method therefor, and application thereof for use in pharmaceuticals - Google Patents

Abstract

A spiroformamide derivative, a preparation method therefor, and an application thereof for use in pharmaceuticals. In particular, a spiroformamide derivative represented by general formula (AI), a preparation method therefor, and a pharmaceutical composition containing the derivative, a use thereof as an ROR modulator, and a use thereof for the prevention and/or treatment of diseases such as inflammation, autoimmune diseases, and cancers, substituents in general formula (AI) being the same as those defined in the description.

Description

Spirocyclic formamide derivatives, preparation method thereof and application thereof in medicine Technical field

The invention belongs to the field of medicine, and relates to a spirocyclic formamide derivative, a preparation method thereof and application thereof in medicine. In particular, the present invention relates to a spiroformamide derivative represented by the formula (AI), a process for producing the same, a pharmaceutical composition containing the same, which is used as a ROR modulator and for preventing and/or treating inflammation Use in drugs for autoimmune diseases, tumors or cancer.

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, WO2015171558, 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), the compound represented by the formula (I) is an inhibitor, and when the ring A ortho group is a haloalkyl group (for example, a trifluoromethyl group), the steric hindrance is large. When the group is a compound represented by the formula (I), it is a ROR agonist, whereby the present invention has developed a new generation of ROR modulators, and further studies have found that structural changes of the compounds can modulate different mechanisms.

Summary of the invention

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

Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

among them:

W ¹ , W ² and W ^{3 are the} same or different and are each independently CH 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;

Ring C is a cycloalkyl or heterocyclic group;

R ^{1 is the} same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, haloalkyl, Substituted with one or more substituents of alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{2 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. a cyclic group, an aryl group, a heteroaryl group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ ;

R ^{3 is} selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl a group wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from the group consisting of a hydroxyl group, a halogen, an alkyl group, a halogenated alkyl group, a cyano group, an amino group, and a nitrate Substituted by one or more substituents of a group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ^{4 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, wherein the alkyl group, the cycloalkyl group, the halogenated alkyl group, The heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of a hydroxyl group, a halogen, an alkyl group, a halogenated alkyl group, a cyano group, an amino group, a nitro group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkane group. Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

m is 0, 1 or 2;

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

t is 0, 1, 2, 3 or 4.

In a preferred embodiment of the invention, the compound of the formula (AI), wherein the ring C is a C _3-6 cycloalkyl group or a 3 to 6 membered heterocyclic group, wherein the hetero The cyclic group contains 1 to 3 hetero atoms selected from N, O or S; preferably selected from cyclopropyl, cyclobutyl, cyclopentyl or tetrahydropyranyl.

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

n is 1, 2 or 3;

Ring A, Ring B, R ¹ to R ³ , s and t are as defined in the formula (AI).

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

among them:

Ring A, Ring B, R ¹ to R ³ , s and t are as defined in the general formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) wherein ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.

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

among them:

G ¹ and G ^{2 are the} same or different and are each independently CH or N;

Ring B, R ¹ to R ³ and t are as defined in the formula (I).

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

among them:

R ^{b is} selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

p is 0, 1, 2 or 3;

Ring B, R ¹ to R ³ and t are as defined in the formula (I).

In a preferred embodiment of the invention, the compound of the formula (I) wherein ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ² is -S(O) _m R ⁴ ; m is 2; and R ⁴ is an alkyl group, preferably B base.

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

among them:

R ¹ and R ³ to R ⁴ are as defined in the formula (III).

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

among them:

R ^{b is} selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

p is 0, 1, 2 or 3;

R ¹ , R ³ and R ⁴ are as defined in the formula (IV).

In a preferred embodiment of the invention, the compound of the formula (III-A) or the formula (IV-A) wherein R ⁴ is an alkyl group, preferably an ethyl group.

In a preferred embodiment of the invention, the compound of the formula (IV) or (IV-A), wherein R ^b is haloalkyl, preferably trifluoromethyl.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ¹ is haloalkyl, preferably trifluoromethyl.

In a preferred embodiment of the invention, the compound of the formula (I), wherein R ³ is a hydrogen atom, an alkyl group or a hydroxyalkyl group.

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.

In another aspect, the present invention provides a compound of the formula (AI-A) which is prepared according to the compound of the formula (AI) or a tautomer thereof, a mesogen, a racemate, an enantiomer An intermediate of an isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

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

among them:

Ring A, Ring C, W ¹ , W ² , W ³ , R ¹ and s are as defined in the general formula (AI).

In a further preferred embodiment, the present invention provides a compound of the formula (IA) which is a compound according to formula (I) or a tautomer thereof, a mesogen, a racemate thereof. An intermediate of an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

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

among them:

Ring A, R ¹ , s and n are as defined in formula (I).

Typical compounds of the general formula (AI-A) include, but are not limited to:

In another aspect, the invention provides a method of preparing the compound of formula (AI), the method comprising:

a compound of the formula (AI-A) is condensed with a compound of the formula (I-B) to give a compound of the formula (AI);

among them:

Ring A, Ring B, Ring C, W ¹ , W ² , W ³ , R ¹ to R ³ , s and t are as defined in the formula (AI).

In another aspect, the invention provides a process for the preparation of a compound of formula (I), which process comprises:

a compound of the formula (I-A) is subjected to a condensation reaction with a compound of the formula (I-B) to give a compound of the formula (I);

among them:

Ring A, Ring B, R ¹ to R ³ , n, s and t are as defined in the general formula (I).

In another aspect, the invention provides a method of preparing the compound of formula (II), the method comprising:

a compound of the formula (II-A) is subjected to a condensation reaction with a compound of the formula (I-B) to give a compound of the formula (II);

among them:

Ring A, Ring B, R ¹ to R ³ , s and t are as defined in the formula (II).

Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer a form, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer, a non- The enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed 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 Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the preparation of a ROR modulator.

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 inflammation, autoimmune diseases, tumors 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 Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the prevention and/or treatment of inflammation, an autoimmune disease, a tumor or a cancer selected from the group consisting of asthma, Atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, allograft rejection, Hugh's syndrome , uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, systemic lupus erythematosus (SLE), scleroderma, pancreatitis, psoriasis, Psilosargic arthritis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease, said tumor or cancer selected from non-Hodgkin's lymphoma Diffuse large B-cell lymphoma, follicular drenching Tumor, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer , fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma, bone marrow Tumor and non-small cell lung 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 as a ROR inhibitor for the preparation of a medicament for the prevention and/or treatment of an inflammatory and autoimmune disease selected from the group consisting of asthma, Atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, allograft rejection, Hugh's syndrome , uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, systemic lupus erythematosus (SLE), scleroderma, pancreatitis, psoriasis, Psoriatic arthritis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease.

.

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, said tumor or cancer being selected from the group consisting of non-Hodgkin's lymphoma, Diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast, cervical, colon, lung, stomach, rectal, pancreatic, brain, skin, oral, prostate, bone cancer , kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, Head and neck cancer, leukemia, lymphoma, myeloma and non-small cell lung cancer.

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

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, which is used as a ROR modulator.

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 inflammation, autoimmune diseases, tumors or cancer.

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 selected from the group consisting of asthma, atopic dermatitis, contact dermatitis, acne , bronchitis, Crohn's disease, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, allograft rejection, Hugh's syndrome, uveitis, Behcet's disease, Dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, systemic lupus erythematosus (SLE), scleroderma, pancreatitis, psoriasis, psoriatic arthritis (PsA), rheumatoid Arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes and autoimmune thyroid disease.

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 selected from the group consisting of non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymph Tumor, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer , fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck cancer, leukemia, lymphoma, bone marrow Tumor and non-small cell lung cancer. .

The invention also relates to a method of preventing and/or treating inflammation, an autoimmune disease, a tumor or a cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a mutual mutation thereof a form, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, said inflammation or Autoimmune diseases are selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, allograft rejection Response, Hugh's syndrome, uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, systemic lupus erythematosus (SLE), scleroderma, Pancreatitis, psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease, said tumor or cancer From non-Hodgkin's lymphoma, diffuse B cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney Cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid renal tumor, head and neck Tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.

The present invention also relates to a method for preventing and/or treating an inflammatory or autoimmune disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) as an ROR inhibitor or a tautomer thereof. An isomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, said inflammation Or autoimmune disease selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, Crohn's disease, inflammatory bowel disease (IBD), ulcerative colitis, allograft Rejection, Hugh's syndrome, uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, systemic lupus erythematosus (SLE), scleroderma , pancreatitis, psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease.

The present invention also relates to a method for the treatment of preventing and/or treating a tumor 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 as an ROR agonist. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, said tumor or cancer Selected from non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer , oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, liver Cell carcinoma, mastoid renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.

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 can be inert excipients, granulating agents, disintegrating agents, binders, and lubricants. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.

Oral formulations can also be provided in soft gelatine capsules in which the active ingredient is mixed with an inert solid diluent or the active ingredient in admixture with a water-soluble vehicle or an oil vehicle.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending, dispersing or wetting agents. The aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

The oil suspension can be formulated by suspending the active ingredient in vegetable oil, or mineral oil. The oil suspension may contain a thickening agent. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, and emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical compositions of the invention 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 oil phase, and the injection or microemulsion may 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. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

The pharmaceutical compositions of the invention 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 prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension medium. Any blended fixed oil can be used for this purpose. In addition, fatty acids can also be prepared as injections.

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.

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, the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of formula (I) or the pharmaceutically acceptable salt The type can be verified according to traditional treatment options.

Detailed description of the invention

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group 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 Base, 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 Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, carboxylate, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ And -S(O) _m R ⁴ .

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are 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, a carboxylate group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ .

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, a carboxylate group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ .

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 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiro heterocyclic 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, a carboxylate group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ .

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, a carboxylate group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ .

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 "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.

"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" means that an alkyl group may be, but not necessarily, 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.

R ⁴ and m are as defined in the formula (I).

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 (AI) 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:

In the first step, the compound of the formula (AI-1) and paraformaldehyde are under acidic conditions, and the ring is closed to obtain the formula (AI-2);

In the second step, the compound of the formula (AI-2) is reacted with CO and R ^c OH in the presence of a catalyst under basic conditions to obtain the formula (AI-3);

In the third step, the compound of the formula (AI-3) is subjected to dehydration of the trifluoroacetyl group under basic conditions to obtain the formula (AI-4);

In the fourth step, a compound of the formula (AI-4) is subjected to a coupling reaction with a compound of the formula (I-5) in the presence of a catalyst under basic conditions to obtain a compound of the formula (AI-5); or a formula ( I-4) a compound which is reductively aminated with a compound of the formula (I-6) in the presence of a reducing agent under acidic conditions to give a compound of the formula (AI-5);

In the fifth step, the compound of the formula (AI-5) is hydrolyzed under basic conditions to obtain a compound of (AI-A);

In the sixth step, the compound of the formula (AI-A) and the compound of the formula (I-B) are present in a condensing agent under basic conditions.

a condensation reaction occurs to obtain a compound of the formula (AI);

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

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOT _f ;

Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylideneacetone) Palladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-dicyclohexyl Phosphine-2',6'-dimethoxybiphenyl.

The reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) ₃ , AlH ₃ , NaCNBH ₃ , Na(AcO) ₃ BH, BH ₃ in tetrahydrofuran solution (1N), B. ₂ H ₅ , Li(Et) ₃ BH, Pd/C/H ₂ and Raney nickel/H ₂ ;

Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate, benzene And triazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate, preferably 2-(7 -azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;

among them:

R ^c is an alkyl group, preferably an ethyl group;

X is a halogen, preferably bromine;

Ring A, Ring B, Ring C, W ¹ , W ² , W ³ , R ¹ to R ³ , n, s and t are as defined in the general formula (I).

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:

In the first step, the compound of the formula (I-1) and paraformaldehyde are under acidic conditions, and the ring is closed to obtain the formula (I-2);

In the second step, the compound of the formula (I-2) is reacted with CO and R ^c OH in the presence of a catalyst under basic conditions to obtain the formula (I-3);

In the third step, the compound of the formula (I-3) is subjected to the removal of the trifluoroacetyl group under basic conditions to obtain the formula (I-4);

In the fourth step, the compound of the formula (I-4) is subjected to a coupling reaction with a compound of the formula (I-5) in the presence of a catalyst under basic conditions to obtain a compound of the formula (I-7); or a formula ( I-4) a compound is reductively aminated with a compound of the formula (I-6) in the presence of a reducing agent under acidic conditions to give a compound of the formula (I-7);

In the fifth step, the compound of the formula (I-7) is hydrolyzed under basic conditions to give a compound (I-A);

In the sixth step, the compound of the formula (I-A) and the compound of the formula (I-B) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (I);

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

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOT _f ;

Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylideneacetone) Palladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-dicyclohexyl Phosphine-2',6'-dimethoxybiphenyl.

The reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) ₃ , AlH ₃ , NaCNBH ₃ , Na(AcO) ₃ BH, BH ₃ in tetrahydrofuran solution (1N), B. ₂ H ₅ , Li(Et) ₃ BH, Pd/C/H ₂ and Raney nickel/H ₂ ;

Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate, benzene And triazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate, preferably 2-(7 -azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;

among them:

R ^c is an alkyl group, preferably an ethyl group;

X is a halogen, preferably bromine;

Ring A, Ring B, R ¹ to R ³ , n, s and t are as defined in the general formula (I).

a compound of the formula (II) 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:

In the first step, the compound of the formula (II-1) and paraformaldehyde are under acidic conditions, and the ring is closed to obtain the formula (II-2);

In the second step, the compound of the formula (II-2) is reacted with CO and R ^c OH in the presence of a catalyst under basic conditions to obtain a formula (II-3);

In the third step, the compound of the formula (II-3) is subjected to dehydration of the trifluoroacetyl group under basic conditions to obtain the formula (II-4);

In the fourth step, the compound of the formula (II-4) is subjected to a coupling reaction with a compound of the formula (I-5) in the presence of a catalyst under basic conditions to obtain a compound of the formula (II-7); or a formula ( II-4) compound is reductively aminated with a compound of the formula (I-6) in the presence of a reducing agent under acidic conditions to give a compound of the formula (II-7);

In the fifth step, the compound of the formula (II-7) is hydrolyzed under basic conditions to obtain a compound of (II-A);

In the sixth step, the compound of the formula (II-A) and the compound of the formula (I-B) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (II);

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

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, hydrogen chloride in 1,4-dioxane solution, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me ₃ SiCl and TMSOT _f ;

Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylideneacetone) Palladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-dicyclohexyl Phosphine-2',6'-dimethoxybiphenyl;

The reducing reagents include, but are not limited to, lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH(Ot-Bu) ₃ , AlH ₃ , NaCNBH ₃ , Na(AcO) ₃ BH, BH ₃ in tetrahydrofuran solution (1N), B. ₂ H ₅ , Li(Et) ₃ BH, Pd/C/H ₂ and Raney nickel/H ₂ ;

Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate, benzene And triazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate, preferably 2-(7 -azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;

among them:

R ^c is an alkyl group, preferably an ethyl group;

X is a halogen, preferably bromine;

Ring A, Ring B, R ¹ to R ³ , s and t are as defined in the formula (II).

a compound of the formula (III) 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:

In the first step, the compound of the formula (II-4) is subjected to a coupling reaction with a compound of the formula (III-1) in the presence of a catalyst under basic conditions to obtain a compound of the formula (III-2);

In the second step, the compound of the formula (III-2) is hydrolyzed under basic conditions to give a compound of (III-3);

In the third step, the compound of the formula (III-3) and the compound of the formula (I-B) are subjected to a condensation reaction under basic conditions in the presence of a condensing agent to obtain a compound of the formula (III);

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

Catalysts include, but are not limited to, palladium on carbon, Raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadium iron palladium, tris(dibenzylideneacetone) Palladium or 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or 2-dicyclohexyl Phosphine-2',6'-dimethoxybiphenyl;

Condensing agents include, but are not limited to, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N'-dicyclohexylcarbodiimide, N,N'-di Propylcarbodiimide, O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7- Azobenzotriazole, O-benzotriazole-N,N,N',N'-tetramethyluron hexafluorophosphate, 2-(7-azobenzotriazole)-N, N,N',N'-tetramethylurea hexafluorophosphate, 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate, benzene And triazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphonium phosphate, preferably 2-(7 -azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

The above reaction is preferably carried out in a solvent including, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-two. Oxy hexacyclohexane, water, N,N-dimethylformamide and mixtures thereof;

among them:

R ^c is an alkyl group, preferably an ethyl group;

X is a halogen, preferably bromine;

Rings B, G ¹ , G ² , R ¹ to R ³ and t are as defined in the formula (III).

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, Accela ChemBio Inc, Dari Companies such as 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 developing agent used for the reaction, the column chromatography eluent system used for the purification of the compound, and the thin layer chromatography developing solvent system including: A: Methylene chloride/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate / dichloromethane / n-hexane, H: ethyl acetate / dichloromethane / acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, a small amount of triethylamine and acetic acid may also be added. Adjust with alkaline or acidic reagents.

Example 1

N-(4-(ethylsulfonyl)benzyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1, 4'-isoquinoline]-7'-carboxamide 1

first step

1-(7'-bromo-1'H-spiro[cyclopropane-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethanone 1b

Preparation of N-((1-(4-bromophenyl)cyclopropyl)methyl)-2,2,2-trifluoroacetamide 1a (22 g, 68.3 mmol, prepared by the method disclosed in PCT patent application "WO2011124093" In a mixed solvent of 150 mL of pre-formed acetic acid and sulfuric acid (V/V = 2:3), paraformaldehyde (7.96 g, 264.99 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was poured into 500 mL of ice water, and extracted with ethyl acetate (500 mL×2). The organic phase was combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the crude title compound 1b (4.5 g).

Second step

2'-(2,2,2-Trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid B Ester 1c

The crude compound 1b (4 g, 11.97 mmol) was dissolved in a mixed solvent of 40 mL of ethanol and dimethyl sulfoxide (V/V = 1:1), and 1,3-bis(diphenylphosphino)propane (987.5 mg, 2.39 mmol), triethylamine (1.21 g, 11.97 mmol) and palladium acetate (537.53 mg, 2.39 mmol) were heated to 60 ° C under a carbon monoxide atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, Chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

third step

2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid ethyl ester 1d

1c (2.5 g, 7.64 mmol) was dissolved in a mixed solvent of 100 mL of ethanol and water (V/V = 1:1), potassium carbonate (1.58 g, 11.46 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc) ), the product was directly subjected to the next reaction without purification.

the fourth step

2'-(4-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid B Ester 1f

The crude compound 1d (2 g, 8.65 mmol) and 1-bromo-4-(trifluoromethyl)benzene 1e (2.33 g, 10.38 mmol, using the known method "Organic Letters, 2014, 16 (16), 4268-4271 "Prepared" was dissolved in 50 mL of 1,4-dioxane, and cesium carbonate (8.45 g, 25.94 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (412.22 mg) was added. , 864.72 umol) and tris(dibenzylideneacetone) dipalladium (791.83 mg, 864.72 umol), and the mixture was heated to 90 ° C and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue obtained was purified by EtOAc EtOAc (EtOAc)

the fifth step

2'-(4-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid 1g

Compound 1f (1.5 g, 4 mmol) was dissolved in a mixed solvent of 60 mL of ethanol and water (V/V = 5:1), and sodium hydroxide (799.12 mg, 19.98 mmol) was added thereto, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The organic layer was dried, filtered, and evaporated, mjjjjjj

Step 6

N-(4-(ethylsulfonyl)benzyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1, 4'-isoquinoline]-7'-carboxamide 1

The crude compound 1 g (1.4 g, 4.03 mmol) and (4-(ethylsulfonyl)phenyl)methanamine 1 h (1.2 g, 6.05 mmol, prepared by the method disclosed in PCT patent application "WO2015017335") were dissolved in 30 mL To N,N-dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.06 g, 8.06 mmol) And triethylamine (1.22 g, 12.09 mmol), and the reaction was stirred for 12 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 1 (1.1 g, yield: 51.63%).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (s, 1H), 7.80-7.85 (m, 3H), 7.69-7.71 (m, 1H), 7.55-7.57 (m, 2H), 7.49-7. (m, 2H), 7.11 - 7.13 (m, 2H), 6.93 - 6.95 (m, 1H), 4.65 (s, 2H), 4.56 - 4.57 (m, 2H), 3.54 (s, 2H), 3.23 - 3.28 (m, 2H), 1.05-1.09 (m, 7H).

Example 2

N-(1-4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1' H-spiro [cyclopropane-1,4'-isoquinoline]-7'-carboxamide 2

The crude compound 1 g (200 mg, 575.82 umol) and 2-amino-2-(4-(ethylsulfonyl)phenyl)ethanol 2a (198.05 mg, 863.73 umol, prepared by the method disclosed in PCT patent application "WO2016061160". Dissolved in 10 mL of N,N-dimethylformamide, adding 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate (328.22) Mg, 863.73 umol) and triethylamine (174.8 mg, 1.73 mmol) were stirred for 12 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 2 ( 120 mg, yield: 37.31%).

MS m/z (ESI): 559.1 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.75-8.77 (m, 1H), 7.80-7.84 (m, 3H), 7.70-7.72 (m, 1H), 7.64-7.66 (m, 2H), 7.49 -7.51 (m, 2H), 7.12-7.14 (m, 2H), 6.92-6.95 (m, 1H), 5.11-5.17 (m, 1H), 4.66 (s, 2H), 4.23 (s, 1H), 3.69 - 3.75 (m, 2H), 3.54 (s, 2H), 3.24 - 3.29 (m, 2H), 1.03-1.11 (m, 7H).

Example 3, 4

(R)-N-(1-4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-di Hydrogen-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxamide 3

(S)-N-(1-4-(ethylsulfonyl)phenyl)-2-hydroxyethyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-di Hydrogen-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxamide 4

Chiral preparation of 2 (120 mg, 0.215 mmol) (separation conditions: chiral preparative column Lux Cellulose-1 OD 4.6*150 mm 5 μm (with guard column); mobile phase: n-hexane:ethanol:trifluoroacetic acid=50:50: 0.01, flow rate: 1.0 mL/min), the corresponding fractions were collected, concentrated under reduced pressure, and the residue obtained was purified by high-purity chromatography to give the title compound 3 (10 mg) and 4 (20 mg).

Compound 3:

MS m/z (ESI): 559.0 [M+1];

Chiral HPLC analysis: retention time 4.411 minutes, chiral purity: 93% (column: Lux Cellulose-1 OD 4.6*150mm 5um (with guard column)); mobile phase: n-hexane / ethanol / trifluoroacetic acid = 50 / 50/0.01 (v/v/v)).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 - 8.76 (m, 1H), 7.79-7.84 (m, 3H), 7.64-7.72 (m, 3H), 7.49-7.51 (m, 2H), 7.12 7.1. - 3.29 (m, 2H), 0.85-1.11 (m, 7H).

Compound 4:

MS m/z (ESI): 559.1 [M+1];

Chiral HPLC analysis: retention time 6.9148 min, chiral purity: 90%. % (column: Superchiral S-AD (Chiralway), 0.46 cm I.D.*25 cm, 5 um; mobile phase: n-hexane/ethanol/trifluoroacetic acid = 50/50/0.01 (v/v/v)).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.74 - 8.75 (m, 1H), 7.79-7.84 (m, 3H), 7.64-7.71 (m, 3H), 7.49-7.51 (m, 2H), 7.12 -7.14(m,2H),6.92-6.94(m,1H),5.13-5.15(m,1H),4.66(s,2H),3.67-3.77(m,2H),3.54(s,2H),3.23 - 3.29 (m, 2H), 0.84-1.11 (m, 7H).

Example 5

N-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H- Spirulina [cyclopropane-1,4'-isoquinoline]-7'-carboxamide

The crude compound 1 g (50 mg, 0.14 mmol) and 5-(ethylsulfonyl)pyridin-2-yl)methylamine 5a (43.24 mg, 0.22 mmol, obtained by the method disclosed in PCT patent application "WO2015017335") were dissolved. In 10 mL of N,N-dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.41 mg, 0.29) was added. Methyl) and triethylamine (43.62 mg, 0.43 mmol) were stirred for 12 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 5 (20mg, yield: 24.92%).

MS m/z (ESI): 530.1 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.22 (s, 1H), 8.95-8.96 (m, 1H), 8.24 - 8.26 (m, 1H), 7.83 (s, 1H), 7.74 - 7.75 (m) , 1H), 7.57-7.59 (m, 1H), 7.50-7.52 (m, 2H), 7.13-7.15 (m, 2H), 6.95-6.97 (m, 1H), 4.67 (s, 4H), 3.67-3.70 (m, 2H), 3.37-3.40 (m, 2H), 1.07-1.14 (m, 7H).

Example 6

N-((1-(ethylsulfonyl)piperidin-4-yl)methyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H - Spiro [cyclopropane-1,4'-isoquinoline]-7'-carboxamide 6

The crude compound 1 g (100 mg, 0.287 mmol) and (1-(ethylsulfonyl)piperidin-4-yl)methylamine 6a (89.1 mg, 0.432 mmol, obtained by the method disclosed in US Patent Application No. US20160122318)) Dissolved in 20mL N,N-dimethylformamide, added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluron hexafluorophosphate (164.11mg 0.432 mmol) and triethylamine (87.4 mg, 0.864 mmol) were stirred for 3 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 6 (50 mg, yield: 34.42%).

MS m/z (ESI): 536.5 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ8.46 (s, 1H), 7.74 (s, 1H), 7.63-7.65 (m, 1H), 7.49-7.52 (m, 2H), 7.12-7.14 (m , 2H), 6.90-6.92 (m, 1H), 4.65 (s, 2H), 3.53-3.56 (m, 3H), 3.16-3.19 (m, 3H), 2.99-3.05 (m, 2H), 2.73-2.78 (m, 2H), 1.73-1.76 (m, 3H), 1.02-1.23 (m, 9H).

Example 7

N-(4-(ethylsulfonyl)benzyl)-2'-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-2',3'-dihydro-1'H- snail [Cyclopropane-1,4'-isoquinoline]-7'-carboxamide 7

first step

2'-(4-(Trifluoromethyl)cyclohexyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid B Ester 7b

The crude compound 1d (300 mg, 1, 3 mmol) was dissolved in 10 mL of methanol, and acetic acid (15.58 mg, 0.259 mmol) and sodium triacetoxyborohydride (549.81 mg, 2.59 mmol) were added, and the reaction was stirred for 2 hours, then added 4 -(Trifluoromethyl)cyclohexane-1-one 7a (430.99 mg, 2.59 mmol, prepared by the method disclosed in PCT patent application "WO2008007930"), and the reaction was stirred for 12 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The obtained residue was purified to give the title compound 7b (100 mg, yield: 20.21.%).

Second step

2'-(4-(Trifluoromethyl)cyclohexyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid 7c

Compound 7b (100 mg, 0.262 mmol) was dissolved in a mixed solvent of 13 mL of ethanol and water (V/V = 10:3), sodium hydroxide (52.43 mg, 1.31 mmol) was added, and the mixture was heated to 70 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. EtOAc (EtOAc m. The organic layer was dried under reduced pressure to give crystals crystals crystals crystals

third step

N-(4-(ethylsulfonyl)benzyl)-2'-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-2',3'-dihydro-1'H- snail [Cyclopropane-1,4'-isoquinoline]-7'-carboxamide 7

The crude compound 7c (50 mg, 0.141 mmol) and compound 1h (33.83 mg, 0.17 mmol) were dissolved in 5 mL of N,N-dimethylformamide and 2-(7-azobenzotriazole)-N was added. , N, N', N'-tetramethylurea hexafluorophosphate (80.65 mg, 0.212 mmol) and triethylamine (42.95 mg, 0.424 mmol) were stirred for 12 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The obtained residue was purified to crystal crystal crystal crystal crystal crystal

MS m/z (ESI): 535.2 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 7.83-7.85 (m, 2H), 7.55-7.64 (m, 4H), 6.79-6.81 (m, 1H), 4.55-4.57 (m, 2H), 3.84 (s, 2H), 3.23 - 3.27 (m, 2H), 2.61 (s, 2H), 1.94 (s, 3H), 1.24-1.36 (m, 7H), 0.90-1.11 (m , 7H).

Example 8

N-(4-(ethylsulfonyl)benzyl)-2'-(2-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1, 4'-isoquinoline]-7'-carboxamide 8

first step

2'-(2-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid B Ester 8b

The crude compound 1d (200 mg, 0.864 mmol) and 1-bromo-2-(trifluoromethyl)benzene 8a (233.48 mg, 1.04 mmol, using a known method "European Journal, 2013, 19 (52), 17692-17697 "Prepared" was dissolved in 3 mL of 1,4-dioxane, sodium tert-butoxide (249.31 mg, 2.59 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl ( 82.44 mg, 172.74 umol) and tris(dibenzylideneacetone)dipalladium (158.37 mg, 172.74 umol), and the mixture was heated to 105 ° C and stirred for 18 hours. The reaction mixture was cooled to room temperature, poured into 10 mL of water, EtOAc (EtOAc (EtOAc) The resulting residue was purified to give the title compound 8b (130 mg, yield: 40.05%).

Second step

2'-(2-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxylic acid 8c

Compound 8b (130 mg, 0.346 mmol) was dissolved in a mixed solvent of 12 mL of ethanol and water (V/V = 5:1), sodium hydroxide (138.51 mg, 3.46 mmol) was added, and the mixture was heated to 60 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated, evaporated, evaporated.

third step

N-(4-(ethylsulfonyl)benzyl)-2'-(2-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1, 4'-isoquinoline]-7'-carboxamide 8

The crude compound 8c (100 mg, 0.288 mmol) and compound 1h (114.74 mg, 0.576 mmol) were dissolved in 2 mL of N,N-dimethylformamide and 2-(7-azobenzotriazole)-N was added. N,N', N'-tetramethyluronium hexafluorophosphate (218 mg, 0.576 mmol) and N,N-diisopropylethylamine (111.63 mg, 0.864 mmol) were stirred for 1 hour. The reaction mixture was added with 10 mL of water, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue gave the title compound 8 (40 mg, yield: 26.26%).

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

^{1 H NMR (400MHz, CDCl3)} δ7.85-7.87 (m, 2H), 7.66-7.68 (m, 1H), 7.59-7.61 (m, 1H), 7.52-7.54 (m, 4H), 7.38-7.40 ( m,1H), 6.80-6.82 (m, 1H), 6.60-6.63 (m, 1H), 4.74-4.75 (m, 2H), 4.29 (s, 2H), 3.08-3.13 (m, 4H), 1.25- 1.29 (m, 3H), 1.07-1.10 (m, 2H), 0.95-0.98 (m, 2H).

Example 9

N-(4-(ethylsulfonyl)benzyl)-2'-(5-(trifluoromethyl)pyrimidin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane -1,4'-isoquinoline]-7'-carboxamide 9

first step

2'-(5-(Trifluoromethyl)pyrimidin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'- Ethyl carboxylate

9b

The crude compound 1d (100 mg, 0.432 mmol) and 2-chloro-5-(trifluoromethyl)pyrimidine 9a (118 mg, 0.646 mmol) were dissolved in 2 mL DMSO, and 1,8-diazabicyclo[5. ] undob-7-ene (326 mg, 1.294 mmol), and the mixture was heated to 90 ° C and stirred for 18 hours. The reaction mixture was cooled to room temperature, poured into 10 mL of water, EtOAc (EtOAc (EtOAc) Chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

Second step

2'-(5-(Trifluoromethyl)pyrimidin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'- Carboxylic acid 9c

Compound 9b (50 mg, 0.132 mmol) was dissolved in a mixed solvent of 12 mL of ethanol and water (V/V = 5:1), and sodium hydroxide (53 mg, 1.32 mmol) was added thereto, and the mixture was heated to 60 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and then evaporated, evaporated, evaporated,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

third step

N-(4-(ethylsulfonyl)benzyl)-2'-(5-(trifluoromethyl)pyrimidin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane -1,4'-isoquinoline]-7'-carboxamide 9

The crude compound 9c (50 mg, 0.143 mmol) and compound 1h (28 mg, 0.140 mmol) were dissolved in 2 mL of N,N-dimethylformamide, and 2-(7-azobenzotriazole)-N was added. N,N',N'-tetramethyluronium hexafluorophosphate (82 mg, 0.216 mmol) and N,N-diisopropylethylamine (37 mg, 0.286 mmol) were stirred for 1 hour. The reaction mixture was added with 10 mL of water, and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated The residue gave the title compound 9 (50 mg, yield: 65.84%).

MS m/z (ESI): 531.4 [M+1]

_{^{1 H NMR (400MHz, CDCl 3}} ) δ8.49-8.51 (m, 2H), 7.65-7.75 (m, 4H), 7.44-7.46 (m, 2H), 7.03-7.06 (m, 1H), 6.85-6.87 (m, 1H), 5.13-5.16 (m, 2H), 4.71-4.73 (m, 2H), 3.96-3.98 (m, 2H), 3.06-3.11 (m, 2H), 1.24-1.27 (m, 3H) , 1.07-1.12 (m, 4H).

Example 10

N-(4-(ethylsulfonyl)benzyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1 ,4'-isoquinoline]-7'-carboxamide 10

first step

1-(7'-bromo-1'H-spiro[cyclobutane-1,4'-isoquinoline]-2'(3'H)-yl)-2,2,2-trifluoroethanone 10b

Preparation of N-((1-(4-bromophenyl)cyclobutyl)methyl)-2,2,2-trifluoroacetamide 10a (1.2 g, 3.57 mmol, prepared by the method disclosed in patent application "WO2011124093" In a mixed solvent of 27 mL of pre-formed acetic acid and sulfuric acid (V/V = 2:3), paraformaldehyde (321 mg, 10.69 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 100 mL of ice water, and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate Concentration gave the crude title compound 10b (1 g).

Second step

2'-(2,2,2-Trifluoroacetyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-7'-carboxylic acid Ethyl ester 10c

The crude compound 10b (1 g, 2.87 mmol) was dissolved in a mixed solvent of 20 mL of ethanol and dimethyl sulfoxide (V/V = 1:1), and 1,3-bis(diphenylphosphino)propane (118 mg, 0.28) was added. Methyl acetate (290 mg, 2.86 mmol) and palladium acetate (64 mg, 0.28 mmol) were heated to 60 ° C under a carbon monoxide atmosphere for 12 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, Chromatography The residue obtained was purified with EtOAc (EtOAc)

third step

2',3'-Dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-7'-carboxylic acid ethyl ester 10d

10c (400 mg, 1.17 mmol) was dissolved in 50 mL of a mixed solvent of ethanol and water (V/V = 1:1), potassium carbonate (485 mg, 3.51 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into water (100 mL), EtOAc (EtOAc m. ), the product was directly subjected to the next reaction without purification.

the fourth step

2'-(4-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-7'-carboxylic acid Ethyl ester 10f crude compound 10d (350 mg, 1.42 mmol) and 1-bromo-4-(trifluoromethyl)benzene 10e (481 mg, 2.13 mmol, using known methods "Organic Letters, 2014, 16 (16), 4268 -4271"prepared" dissolved in 30 mL of 1,4-dioxane, cesium carbonate (1.4 g, 4.29 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl ( 68 mg, 142.64 μmol) and tris(dibenzylideneacetone)dipalladium (130 mg, 141.96 μmol) were heated to 90 ° C under a helium atmosphere and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into 50 mL of water, EtOAc (50 mL EtOAc) Chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

the fifth step

2'-(4-(Trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-7'-carboxylic acid 10g

Compound 10f (400 mg, 1.03 mmol) was dissolved in a mixed solvent of 30 mL of ethanol and water (V/V = 5:1), sodium hydroxide (164 mg, 4.10 mmol) was added, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The mixture was dried, filtered, and evaporated, evaporated, evaporated

Step 6

N-(4-(ethylsulfonyl)benzyl)-2'-(4-(trifluoromethyl)phenyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1 ,4'-isoquinoline]-7'-carboxamide 10

The crude compound 10 g (300 mg, 0.83 mmol) and (4-(ethylsulfonyl)phenyl)methanamine 10 h (198 mg, 0.99 mmol, obtained by the method disclosed in the patent application "WO2015017335") were dissolved in 10 mL of N, N 2-Dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (630 mg, 1.66 mmol) and triethyl Amine (252 mg, 2.49 mmol) was stirred for 12 h. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 10 (200 mg, yield: 44.39%).

MS m/z (ESI): 543.2 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 - 9.15 (m, 1H), 7.83 - 7.85 (m, 3H), 7.74 - 7.79 (m, 2H), 7.53 - 7.58 (m, 4H), 7.16 -7.18(m,2H),4.58-4.59(m,2H),4.49(s,2H),3.67(s,2H),3.23-3.28(m,2H),2.22-2.35(m,3H),2.01 -2.10 (m, 3H), 1.06-1.09 (m, 3H).

Example 11

N-(4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)phenyl)-2,2',3,3',5',6'-hexahydro-1H- Spirulina [isoquinoline-4,4'-pyran]-7-carboxamide 11

first step

4-(4-bromophenyl)tetrahydro-2H-pyran-4-carbonitrile 11b

2-(4-Bromophenyl)acetonitrile 11a (2.5 g, 12.75 mmol) was dissolved in 30 mL of dimethyl sulfoxide, cooled to 0 ° C, sodium hydrogen (1.02 g, 25.50 mmol) was slowly added, and stirred for 30 minutes. 1-Bromo-2-(2-bromoethoxy)ethane (3.22 g, 14.03 mmol) was added and stirred at room temperature for 12 h. The reaction mixture was poured into 100 mL of ice water, and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed sequentially with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The obtained residue was purified to purified crystalljjjjjjjjj

Second step

(4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)methylamine 11c

The crude compound 11b (2.5 g, 9.39 mmol) was dissolved in 100 mL of tetrahydrofuran, 1M borane tetrahydrofuran solution (28.18 ml, 28.18 mmol) was added, and the mixture was warmed to reflux and stirred for 12 hr. The temperature was raised to reflux for 1 hour, and the mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The residue was poured into water (200 ml), and the mixture was adjusted to pH>9 with 1M sodium hydroxide solution and extracted with ethyl acetate (200 mL×2). The organic phase was combined, washed with EtOAc EtOAc m.

The third step N-((4-(4-bromophenyl)tetrahydro-2H-pyran-4-yl)methyl)-2,2,2-trifluoroacetamide 11d

11c (2g, 7.40mmol) was dissolved in 100ml of dichloromethane, cooled to 0 ° C, added triethylamine (2.25g, 22.21mmol), slowly added trifluoroacetic anhydride (2.02g, 9.02mmol), The reaction was stirred at room temperature for 12 hours. The reaction solution was poured into 100 mL of water and the layers were separated. The organic phase was washed with saturated sodium bicarbonate and sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography with eluent system B The residue was obtained to give the title compound 11d (2 g,j.

the fourth step

1-(7-Bromo-2',3',5',6'-tetrahydro-1H-spiro[isoquinoline-4,4'-pyran]-2(3H)-yl)-2,2 , 2-trifluoroethyl ketone 11e

11d (2g, 5.46mmol) was dissolved in a mixed solvent of 50 mL of pre-formed acetic acid and sulfuric acid (V/V = 2:3), paraformaldehyde (492 mg, 16.39 mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 300 mL of ice water, and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate The residue was purified by silica gel column chromatography elut elut elut elut elut elut

the fifth step

2-(2,2,2-Trifluoroacetyl)-2,2',3,3',5',6'-hexahydro-1H-spiro[isoquinoline-4,4'-pyran] -7-carboxylate ethyl ester 11f

Compound 11e (600 mg, 1.59 mmol) was dissolved in a mixed solvent of 20 mL of ethanol and dimethyl sulfoxide (V/V = 1:1), and 1,3-bis(diphenylphosphino)propane (130 mg, 317.31 μmol) was added. Triethylamine (481 mg, 4.76 mmol) and palladium acetate (71 mg, 317.71 μmol) were heated to 60 ° C under a carbon monoxide atmosphere and stirred for 12 hours. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The resulting residue was purified to give the title compound 11j (l.

Step 6

2,2',3,3',5',6'-hexahydro-1H-spiro[isoquinoline-4,4'-pyran]-7-carboxylic acid ethyl ester 11g

11f (100 mg, 269.29 μmol) was dissolved in 50 mL of a mixed solvent of ethanol and water (V/V = 1:1), and potassium carbonate (111 mg, 807.86 μmol) was added thereto, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was poured into water (30 mL), EtOAc (EtOAc) ), the product was directly subjected to the next reaction without purification.

Seventh step

2-(4-(Trifluoromethyl)phenyl)-2,2',3,3',5',6'-hexahydro-1H-spiro[isoquinoline-4,4'-pyran] -7-carboxylate ethyl ester 11h

The crude compound 11 g (50 mg, 181.59 μmol) and 1-bromo-4-(trifluoromethyl)benzene 1e (61 mg, 272 μmol, were prepared by a known method "Organic Letters, 2014, 16 (16), 4268-4271". And dissolved in 30 mL of 1,4-dioxane, adding cesium carbonate (177 mg, 544.78 μmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (8 mg, 18.16 μmol) And tris(dibenzylideneacetone)dipalladium (16 mg, 18.16 μmol), and the mixture was heated to 90 ° C under a helium atmosphere and stirred for 3 hours. The reaction solution was cooled to room temperature, poured into 50 mL of water, EtOAc (50 mL EtOAc) Chromatography The residue obtained was purified with EtOAc EtOAc (EtOAc)

Eighth step

2-(4-(Trifluoromethyl)phenyl)-2,2',3,3',5',6'-hexahydro-1H-spiro[isoquinoline-4,4'-pyran] -7-carboxylic acid 11i

The compound 11h (30 mg, 71.52 μmol) was dissolved in a mixed solvent of 30 mL of ethanol and water (V/V = 5:1), sodium hydroxide (14 mg, 357.62 μmol) was added, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The title compound (11i (30 mg)) was obtained.

Step 9

N-(4-(ethylsulfonyl)benzyl)-2-(4-(trifluoromethyl)phenyl)-2,2',3,3',5',6'-hexahydro-1H - Spiro[isoquinoline-4,4'-pyran]-7-carboxamide 11

The crude compound 11i (30 mg, 76.65 μmol) and (4-(ethylsulfonyl)phenyl)methanamine 1 h (18 mg, 91.98 μmol, prepared by the method disclosed in the patent application "WO2015017335") were dissolved in 10 mL of N, N 2-Dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (43 mg, 114.98 μmol) and triethyl Amine (23 mg, 229.95 μmol) was stirred for 12 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 11 (15 mg, yield: 34.17%).

MS m/z (ESI): 573.6 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ9.11 (s, 1H), 7.78-7.80 (m, 4H), 7.53-7.62 (m, 5H), 7.15-7.16 (m, 2H), 4.53 (s , 4H), 3.73-7.75 (m, 6H), 2.04 (m, 2H), 1.49-1.52 (m, 2H), 1.20 (m, 2H), 1.05 (m, 3H).

Example 12

N-(4-(ethylsulfonyl)benzyl)-2'-(5-(trifluoromethyl)pyridin-2-yl)-2',3'-dihydro-1'H-spiro[ring Propane-1,4'-isoquinoline]-7'-carboxamide 12

first step

2'-(5-(Trifluoromethyl)pyridin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'- Ethyl carboxylate 12b

The crude compound 1d (500 mg, 2.16 mmol) and 2-chloro-5-(trifluoromethyl)pyridine 12a (732 mg, 3.24 mmol) were dissolved in 50 mL of 1,4-dioxane, and cesium carbonate (2.11 g, 6.49 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (103 mg, 216.82 μmol) and tris(dibenzylideneacetone)dipalladium (197 mg, 216.18 μmol), warmed to 90 The reaction was stirred for 3 hours under a helium atmosphere. The reaction solution was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (100 mL×2), and the organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The resulting residue was purified to give the title compound 12b (450 mg, yield: 55.31%).

Second step

2'-(5-(Trifluoromethyl)pyridin-2-yl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'- Carboxylic acid 12c

Compound 12b (1.5 g, 3.99 mmol) was dissolved in a mixed solvent of 60 mL of ethanol and water (V/V = 5:1), sodium hydroxide (797.12 mg, 19.93 mmol) was added, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The title compound 12c (1.3 g) was obtained.

third step

N-(4-(ethylsulfonyl)benzyl)-2'-(5-(trifluoromethyl)pyridin-2-yl)-2',3'-dihydro-1'H-spiro[ring Propane-1,4'-isoquinoline]-7'-carboxamide 12

The crude compound 12c (1 g, 2.87 mmol) and (4-(ethylsulfonyl)phenyl)methanamine 1 h (858 mg, 4.31 mmol, obtained by the method disclosed in the patent application "WO2015017335") were dissolved in 30 mL of N, N 2-Dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.64 g, 4.31 mmol) and three Ethylamine (871 mg, 8.61 mmol) was stirred for 12 hours. The reaction mixture was poured into 100 mL of water and extracted with ethyl acetate (100 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The residue was obtained to give the title compound 12 (1 g, yield: 65.77%).

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 - 9.15 (m, 1H), 8.43 (s, 1H), 7.81-7.86 (m, 4H), 7.71-7.73 (m, 1H), 7.57-7.59 (m, 2H), 7.07-7.09 (m, 1H), 6.97-6.99 (m, 1H), 4.99 (s, 2H), 4.58-4.59 (m, 2H), 3.83 (s, 2H), 3.24-3.30 (m, 2H), 1.07-1.11 (m, 7H).

Example 13

(R)-N-(1-(5-(ethylsulfonyl)pyridin-2-yl)-2-hydroxyethyl)-2'-(4-(trifluoromethyl)phenyl)-2' ,3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-carboxamide 13

The crude compound 1 g (50 mg, 143.96 μmol) and (R)-2-amino-2-(5-(ethylsulfonyl)pyridin-2-yl)ethanol 13a (39 mg, 172.75 μmol, using the patent application "WO2016061160" Prepared by the disclosed method) dissolved in 10 mL of N,N-dimethylformamide, added with 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea Hexafluorophosphate (82 mg, 215.93 μmol) and triethylamine (43 mg, 431.87 μmol) were stirred for 12 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The obtained residue obtained the title compound 13 (20 mg, yield:

MS m/z (ESI): 560.6 [M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.43 (s, 1H), 8.73 - 8.75 (m, 1H), 8.23 - 8.24 (m, 1H), 7.83 (s, 1H) ), 7.67-7.72 (m, 2H), 7.50-7.51 (m, 2H), 7.13-7.14 (m, 1H), 6.94-6.96 (m, 1H), 5.21 (s, 1H), 4.67 (s, 2H) ), 3.85-3.87 (m, 3H), 3.55 (s, 2H), 3.39-3.40 (m, 2H), 1.05-1.13 (m, 7H).

Example 14

N-(4-(ethylsulfonyl)benzyl)-6'-(4-(trifluoromethyl)phenyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1 ,8'-[1,6]naphthyridine]-3'-carboxamide 14

first step

3'-Nitro-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-6'(7'H)-carboxylic acid tert-butyl ester 14b

Compound 14a (600 mg, 2.66 mmol, prepared by the method disclosed in the patent application "WO2010114957") was dissolved in 30 ml of a 7 M ammonia methanol solution, and compound 14b (530 mg, 2.66 mmol) was added to warm to 60 ° C, and the reaction was stirred overnight. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj

Second step

3'-Amino-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-6'(7'H)-carboxylic acid tert-butyl ester 14d

Compound 14c (300 mg, 982.54 μmol) was dissolved in 50 ml of a mixed solvent of ethanol and water (V/V = 2:1), and iron powder (274 mg, 4.90 mmol), ammonium chloride (106 mg, 1.96 mmol) was added, and the temperature was raised. The reaction mixture was stirred at reflux for 3 hours, and the reaction mixture was cooled to room temperature. The mixture was poured into 50 ml of water and extracted with dichloromethane (100 mL×2). 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 to give the title compound 14d (270mg).

third step

3'-Bromo-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-6'(7'H)-carboxylic acid tert-butyl ester 14e

14d (250mg, 907.95μmol) was dissolved in 30ml acetonitrile, cooled to 0 ° C, isoamyl nitrite (212mg, 1.81mmol) was slowly added dropwise, stirred for 30 minutes, added copper bromide, and stirred to room temperature. Reaction for 12 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL×2). The organic phase was combined, washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate The obtained residue was purified to silica gel elution eluting

the fourth step

6'-(tert-butyl) 3'-ethyl 5'H-spiro [cyclopropane-1,8'-[1,6]naphthyridine]-3',6'(7'H)-dicarboxylic acid Ester 14f

Compound 14e (100 mg, 294.78 μmol) was dissolved in a mixed solvent of 20 mL of ethanol and dimethyl sulfoxide (V/V = 1:1), and 1,3-bis(diphenylphosphino)propane (25 mg, 57.25 μmol) was added. Potassium carbonate (61 mg, 442.03 μmol) and palladium acetate (6 mg, 26.72 μmol) were heated to 60 ° C under a carbon monoxide atmosphere and stirred for 12 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), EtOAc (EtOAc (EtOAc) The resulting residue was purified to purified crystalljjjjjjjjjj

the fifth step

6',7'-Dihydro-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-3'-carboxylic acid ethyl ester 14g

14f (80 mg, 240.68 μmol) was dissolved in a mixed solvent of 20 mL of ethanol and water (V/V = 1:1), 5 ml of a 4 M hydrochloric acid methanol solution was added, and the reaction was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc (EtOAc m. The filtrate was concentrated under reduced pressure to give the title compound md.

Step 6

6'-(4-(Trifluoromethyl)phenyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-3' -Carboxylic acid ethyl ester 14h

The crude compound was 14 g (70 mg, 301.36 μmol) and 1-bromo-4-(trifluoromethyl)benzene 1e (101 mg, 448.87 μmol, using a known method "Organic Letters, 2014, 16 (16), 4268-4271" Prepared) dissolved in 20 mL of 1,4-dioxane, added with cesium carbonate (294 mg, 902.34 μmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (14 mg, 29.37 Molmol) and tris(dibenzylideneacetone)dipalladium (27 mg, 29.48 μmol) were heated to 90 ° C under a helium atmosphere and stirred for 3 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), EtOAc (EtOAc (EtOAc) Chromatography of the residue obtained from EtOAc (EtOAc)

Seventh step

6'-(4-(Trifluoromethyl)phenyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1,8'-[1,6]naphthyridine]-3' -carboxylic acid 14i

The compound 14h (100 mg, 265.69 μmol) was dissolved in a mixed solvent of 20 mL of ethanol and water (V/V = 5:1), and sodium hydroxide (53 mg, 1.32 mmol) was added thereto, and the mixture was heated to reflux and stirred for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. The organic layer was dried under reduced pressure to give crystall

Eighth step

N-(4-(ethylsulfonyl)benzyl)-6'-(4-(trifluoromethyl)phenyl)-6',7'-dihydro-5'H-spiro[cyclopropane-1 ,8'-[1,6]naphthyridine]-3'-carboxamide 14

The crude compound 14i (80 mg, 229.67 μmol) and (4-(ethylsulfonyl)phenyl)methanamine 1 h (68 mg, 341.24 μmol, prepared by the method disclosed in the patent application "WO2015017335") were dissolved in 10 mL of N, N 2-Dimethylformamide, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (130 mg, 342.10 μmol) and triethyl Amine (69 mg, 681.88 μmol) was stirred for 12 hours. The reaction mixture was poured into 30 mL of water and extracted with ethyl acetate (30 mL×2). The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, The obtained residue obtained the title compound 14 (30 mg, yield:

MS m/z (ESI): 530.2 [M+1]

^{1 H NMR (400MHz, DMSO-} d 6) δ9.27-9.29 (m, 1H), 8.81-8.82 (m, 1H), 8.09-8.10 (m, 1H), 7.84-7.86 (m, 2H), 7.58 - 7.60 (m, 2H), 7.51 - 7.53 (m, 2H), 7.18 - 7.21 (m, 2H), 4.73 (s, 2H) 4.60 - 4.61 (m, 2H), 3.74 (s, 2H), 3.25- 3.30 (m, 2H), 1.26-1.28 (m, 2H), 1.07-1.09 (m, 5H).

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 compound 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. 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 RORγ LBD (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 against RORγ in vitro

a: If it is an inhibitor, 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 a different mechanism for the regulation of the activity of RORγ in vitro. When the ortho position of A has a small substituent (for example, a hydrogen atom), it exhibits an inhibitory effect (see Examples 1 to 7 and Examples 9 to 14, etc.), and a large substitution is made in the ortho position of the ring A. The base (for example, trifluoromethyl) exhibits an agonistic effect (see Example 8).

Test Example 2: Quantitative Analysis of Activity of IL-17A Enzyme-Linked Immunosorbent Assay

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.

The quantitative analysis of the IL-17A enzyme-linked immunosorbent assay of the compound of the present invention was carried out by the above test, and the measured IC ₅₀ values are shown in Table 2.

Table 2 IC ₅₀ values of quantitative analysis of IL-17A enzyme-linked immunosorbent assay of the compounds of the present invention

Example number	IC 50 (nM)
1	twenty two
2	28
3	18
4	291
5	297
9	289
10	59
12	45
13	134

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

Claims (25)

1. A compound of the formula (AI):

   

   Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

   among them:

   W ¹ , W ² and W ^{3 are the} same or different and are each independently CH 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;

   Ring C is a cycloalkyl or heterocyclic group;

   R ^{1 is the} same or different and is each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a hetero group. a cycloalkyl, aryl and heteroaryl group, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halo, alkyl, haloalkyl, Substituted with one or more substituents of alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

   R ^{2 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. a cyclic group, an aryl group, a heteroaryl group, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ and -S(O) _m R ⁴ ;

   R ^{3 is} selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl a group wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are each independently optionally selected from the group consisting of a hydroxyl group, a halogen, an alkyl group, a halogenated alkyl group, a cyano group, an amino group, and a nitrate Substituted by one or more substituents of a group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   R ^{4 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, wherein the alkyl group, the cycloalkyl group, the halogenated alkyl group, The heterocyclic group, the aryl group and the heteroaryl group are each independently selected from the group consisting of a hydroxyl group, a halogen, an alkyl group, a halogenated alkyl group, a cyano group, an amino group, a nitro group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkane group. Substituted by one or more substituents in the group, heterocyclic group, aryl group and heteroaryl group;

   m is 0, 1 or 2;

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

   t is 0, 1, 2, 3 or 4.
2. The compound of the formula (AI) according to claim 1, wherein the ring C is a C _3-6 cycloalkyl group or a 3 to 6 membered heterocyclic group, wherein the heterocyclic group contains 1 to 3 a hetero atom selected from N, O or S; preferably selected from cyclopropyl, cyclobutyl, cyclopentyl or tetrahydropyranyl.
3. The compound of the formula (AI) according to claim 1, which is 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:

   n is 1, 2 or 3;

   Ring A, Ring B, R ¹ to R ³ , s and t are as defined in claim 1.
4. A compound of the formula (I) according to claim 3 which is a compound of the formula (II):

   

   among them:

   Ring A, Ring B, R ¹ to R ³ , s and t are as defined in claim 3.
5. The compound according to any one of claims 1 to 4, wherein ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.
6. The compound of the formula (I) according to claim 3 or 4, which is a compound of the formula (III):

   

   among them:

   G ¹ and G ^{2 are the} same or different and are each independently CH or N;

   Ring B, R ¹ to R ³ and t are as defined in claim 3.
7. The compound of the formula (I) according to claim 3 or 4, which is a compound of the formula (IV):

   

   among them:

   R ^{b is} selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

   p is 0, 1, 2 or 3;

   Ring B, R ¹ to R ³ and t are as defined in claim 3.
8. The compound according to any one of claims 1 to 7, wherein ring B is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.
9. The compound according to any one of claims 1 to 8, wherein R ² is -S(O) _m R ⁴ ; m is 2; and R ⁴ is an alkyl group.
10. The compound of the formula (III) according to claim 6, which is a compound of the formula (III-A):

    

    among them:

    R ⁴ is an alkyl group;

    R ¹ and R ^{3 are} as defined in claim 6.
11. The compound of the formula (IV) according to claim 7, which is a compound of the formula (IV-A):

    

    among them:

    R ^{b is} selected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl And a heterocyclic group, an aryl group and a heteroaryl group are each independently selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cyclo Substituted by one or more substituents of an alkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

    R ⁴ is an alkyl group;

    p is 0, 1, 2 or 3;

    R ¹ and R ^{3 are} as defined in claim 1.
12. The compound of the formula (I) according to any one of claims 7 or 11, wherein R ^b is a halogenated alkyl group.
13. The compound of the formula (AI) according to any one of claims 1 to 12, wherein R ¹ is a halogenated alkyl group.
14. The compound of the formula (AI) according to any one of claims 1 to 13, wherein R ³ is a hydrogen atom, an alkyl group or a hydroxyalkyl group.
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 (AI-A):

    

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

    among them:

    Ring A, Ring C, W ¹ , W ² , W ³ , R ¹ and s are as defined in claim 1.
17. The compound of the formula (AI-A) according to claim 16, which is a compound of the formula (I-A):

    

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

    among them:

    Rings A, R ¹ , s and n are as defined in claim 16.
18. The compound of the formula (AI-A) according to claim 16 or 17, which is selected from the group consisting of

    
19. A method of preparing a compound of the formula (AI) according to claim 1, the method comprising:

    

    a compound of the formula (AI-A) is condensed with a compound of the formula (I-B) to give a compound of the formula (AI);

    among them:

    Ring A, Ring B, Ring C, W ¹ , W ² , W ³ , R ¹ to R ³ , s and t are as defined in claim 1.
20. A method of preparing a compound of formula (I) according to claim 3, the method comprising:

    

    a compound of the formula (I-A) is subjected to a condensation reaction with a compound of the formula (I-B) to give a compound of the formula (I);

    among them:

    Ring A, Ring B, R ¹ to R ³ , n, s and t are as defined in claim 1.
21. 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.
22. Use of a compound of the formula (I) according to any one of claims 1 to 15 or a pharmaceutical composition according to claim 21 for the preparation of a ROR modulator.
23. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 21, which is useful for the prevention and/or treatment of inflammation, autoimmune diseases, tumors Or use in drugs for cancer.
24. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 21 as a ROR inhibitor for preparation for prevention and/or treatment of inflammation or autoimmunity The use of a drug for a sexual disease selected from the group consisting of asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, Crohn's disease, Crohn's disease, and inflammatory bowel disease ( IBD), ulcerative colitis, allograft rejection, Hugh's syndrome, uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, whole body Sexual lupus erythematosus (SLE), scleroderma, pancreatitis, psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis, arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes And autoimmune thyroid disease.
25. The compound of the formula (I) according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 21 as an ROR agonist for the preparation of a medicament for preventing and/or treating a tumor or cancer For use in medicine, 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, gastric cancer, Rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, nerve Glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.