CN109963845B - Spirocyclic formamide derivative, preparation method and medical application thereof - Google Patents

Spirocyclic formamide derivative, preparation method and medical application thereof Download PDF

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CN109963845B
CN109963845B CN201880004348.4A CN201880004348A CN109963845B CN 109963845 B CN109963845 B CN 109963845B CN 201880004348 A CN201880004348 A CN 201880004348A CN 109963845 B CN109963845 B CN 109963845B
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general formula
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CN109963845A (en
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钱文建
李心
蒋宏健
刘�东
刘苏星
张儒民
贺峰
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

Discloses a spiro carboxamide derivative, a preparation method thereof and application thereof in medicine. In particular, spiro carboxamide derivatives represented by general formula (AI), wherein each substituent is as defined in the specification, their preparation method, pharmaceutical compositions containing the derivatives, their use as ROR modulators, and their use for preventing and/or treating diseases such as inflammation, autoimmune diseases and cancer are disclosed.

Description

Spirocyclic formamide derivative, preparation method and medical application thereof
Technical Field
The invention belongs to the field of medicines, and relates to a spiro carboxamide derivative, a preparation method thereof and application thereof in medicines. In particular, the present invention relates to spirocyclic carboxamide derivatives represented by general formula (AI), a method for preparing the same, a pharmaceutical composition comprising the same, a use thereof as ROR modulators and a medicament for preventing and/or treating inflammation, autoimmune diseases, tumors or cancer.
Background
Retinoic acid-related orphan nuclear receptors (RORs) are members of the nuclear receptor family, which are capable of modulating a variety of physiological and life processes. The ROR family contains three types of ROR α, ROR β, and ROR γ. Three different RORs can be expressed in different tissues and control different physiological processes, ROR α is mainly distributed in liver, skeletal muscle, skin, lung, adipose tissue, kidney, thymus and brain, ROR β has a small range of action and mainly acts on the central nervous system, and ROR γ can be expressed in many tissues including liver, animal fat and skeletal muscle. The lack of ROR γ in mammals shows a phenomenon of blood glucose lowering.
There are two subtypes of ROR γ: ROR γ 1 and ROR γ 2. ROR γ 1 is found in many tissues, such as: thymus, muscle, kidney and liver, while ROR γ 2 is expressed only in immune cells, ROR γ 2 is thought to control T cell helper T17 (Th17) differentiation. Th17 is a kind of T helper cell, which can produce interleukin 17(IL-17) and other cytokines, and it has been found that Th-17 has been associated with human inflammatory diseases and immune disorders, such as multiple sclerosis, rheumatoid arthritis, psoriasis, Crohn's disease and asthma, and now it is reported that ROR gamma may be associated with the occurrence and development of prostate cancer.
ROR gamma t is a subtype of ROR gamma specifically expressed on immune cells, is a main transcription factor of human and mouse Th17 cells, can promote the differentiation of Th17 cells, and can regulate the expression and secretion of a specific effector IL-17 of Th17 cells, and ROR gamma t is closely related to the occurrence and development of various immune diseases, infectious diseases, tumors and the like.
ROR γ, particularly ROR γ t type, has been identified as an important transcriptional regulator of the differentiation of Th17 cells. In 2006, Vanov et al found that ROR γ t is an important transcription factor for Th17 cell differentiation in mouse experiments. Their studies showed that mice are difficult to induce to form EAE models in the absence of ROR γ t. In the process of human Th17 cell differentiation, ROR gamma t is also quickly proved to have similar important function, and the pioneering discovery causes people to pay high attention to ROR gamma t.
Currently, ROR has been highly regarded as an inhibitor in the medical field and has become a hot problem in research, and patent applications disclosed in these days include WO2015171610, WO2015171558, WO2015131035, WO2013169864, WO2014179564, WO2015116904, and the like.
In the process of researching ROR regulators, the inventors found that in the compound shown in the general formula (I) described in the invention, the regulation effect can be changed by the change of the ring A ortho-position group, the compound shown in the general formula (I) is an inhibitor when the ring A ortho-position group is a group with smaller steric hindrance (such as H), and the compound shown in the general formula (I) is an ROR agonist when the ring A ortho-position group is a group with larger steric hindrance in a halogenated alkyl group (such as trifluoromethyl), so that the invention develops a new generation of ROR regulators, and further research finds that the change of the compound structure can regulate different mechanisms.
Disclosure of Invention
The object of the present invention is to provide a compound represented by the general formula (AI):
Figure GPA0000266393270000041
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
W1、W2and W3Are 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 cycloalkyl, heterocyclyl, aryl and heteroaryl;
ring C is cycloalkyl or heterocyclyl;
R1the same or different, and each is independently selected from the group consisting of hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups, wherein the alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;
R2the same OR different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4；
R3Selected from the group consisting of hydrogen atoms, halogens, alkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more groups selected from the group consisting of hydroxyl groups, halogens, alkyl groups, haloalkyl groups, cyano groups, amino groups, nitro groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groupsSubstituted by a group;
R4selected from the group consisting of hydrogen atoms, alkyl groups, cycloalkyl groups, haloalkyl groups, alkoxy groups, haloalkoxy groups, heterocyclyl groups, aryl groups, and heteroaryl groups, wherein said alkyl groups, cycloalkyl groups, haloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy groups, halogen groups, alkyl groups, haloalkyl groups, cyano groups, amino groups, nitro groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;
m is 0, 1 or 2;
s is 0, 1, 2, 3 or 4; and is
t is 0, 1, 2, 3 or 4.
In a preferred embodiment of the invention, the compounds of the formula (AI) in which ring C is C3-6The cycloalkyl group or the heterocyclic group of 3 to 6 members, wherein the heterocyclic 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 present invention, the compound represented by the general formula (AI) is a compound represented by the general formula (I):
Figure GPA0000266393270000051
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
n is 1, 2 or 3;
ring A, ring B, R1～R3S and t are as defined in the general formula (AI).
In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (II):
Figure GPA0000266393270000052
wherein:
ring A, ring B, R1～R3S and t are as defined in formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein ring a is selected from the group consisting of phenyl, pyridyl, pyrimidyl, cyclohexyl and piperidyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (III):
Figure GPA0000266393270000061
wherein:
G1and G2Identical or different, each independently CH or N;
ring B, R1～R3And t is as defined in formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (IV):
Figure GPA0000266393270000062
wherein:
Rbselected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p is 0, 1, 2 or 3;
ring B, R1～R3And t is as defined in formula (I).
In a preferred embodiment of the present invention, the compound represented by the general formula (I), wherein ring B is selected from the group consisting of phenyl, pyridyl, pyrimidyl, cyclohexyl and piperidyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) wherein R is2is-S (O)mR4(ii) a m is 2; and R is4Is an alkyl group, preferably an ethyl group.
In a preferred embodiment of the present invention, the compound represented by the general formula (III) is a compound represented by the general formula (III-A):
Figure GPA0000266393270000063
wherein:
R1and R3～R4As defined in formula (III).
In a preferred embodiment of the present invention, the compound represented by the general formula (IV) is a compound represented by the general formula (IV-A):
Figure GPA0000266393270000071
wherein:
Rbselected from the group consisting of alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, alkyl, haloalkyl, cyano, amino, nitro, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
p is 0, 1, 2 or 3;
R1、R3and R4As defined in formula (IV).
In a preferred embodiment of the present invention, the compound represented by the formula (III-A) or the formula (IV-A), wherein R is4Is an alkyl group, preferablyAnd (4) ethyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (IV) or the general formula (IV-A) wherein R isbIs a haloalkyl group, preferably trifluoromethyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) wherein R is1Is a haloalkyl group, preferably trifluoromethyl.
In a preferred embodiment of the present invention, the compound represented by the general formula (I) wherein R is3Is a hydrogen atom, an alkyl group or a hydroxyalkyl group.
Typical compounds of formula (I) include, but are not limited to:
Figure GPA0000266393270000072
Figure GPA0000266393270000081
Figure GPA0000266393270000091
Figure GPA0000266393270000101
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a compound represented by the general formula (AI-a), which is an intermediate for preparing a compound according to the general formula (AI) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000266393270000102
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A, ring C, W1、W2、W3、R1And s is as defined in formula (AI).
In a further preferred embodiment, the present invention provides a compound of formula (I-a) which is an intermediate for the preparation of a compound according to formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000266393270000103
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A, R1S and n are as defined in formula (I).
Typical compounds of formula (AI-A) include, but are not limited to:
Figure GPA0000266393270000104
Figure GPA0000266393270000111
Figure GPA0000266393270000121
in another aspect, the present invention provides a process for preparing said compound of formula (AI), which process comprises:
Figure GPA0000266393270000122
carrying out condensation reaction on the compound with the general formula (AI-A) and the compound with the general formula (I-B) to obtain a compound with the general formula (AI);
wherein:
ring A, ring B, ring C, W1、W2、W3、R1～R3S and t are as defined in the general formula (AI).
In another aspect, the present invention provides a process for preparing said compound of formula (I), which process comprises:
Figure GPA0000266393270000123
carrying out condensation reaction on the compound with the general formula (I-A) and the compound with the general formula (I-B) to obtain a compound with the general formula (I);
wherein:
ring A, ring B, R1～R3N, s and t are as defined in formula (I).
In another aspect, the present invention provides a process for preparing said compound of formula (II), which process comprises:
Figure GPA0000266393270000131
carrying out condensation reaction on the compound with the general formula (II-A) and the compound with the general formula (I-B) to obtain a compound with the general formula (II);
wherein:
ring A, ring B, R1～R3S and t are as defined in formula (II).
Another aspect of the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The invention also relates to a method for preparing the composition, which comprises the step of mixing the compound shown in the general formula (I) or the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.
The invention further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of ROR modulators.
The invention further relates to application of the compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound in preparation of medicines for preventing and/or treating inflammation, autoimmune diseases, tumors or cancers.
The invention further relates to the use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, for the preparation of a medicament for the prophylaxis and/or treatment of an inflammatory or autoimmune disease, selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren's syndrome, uveitis, behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, Systemic Lupus Erythematosus (SLE), scleroderma, pancreatitis, psoriasis, psoriatic arthritis (PsA), psoriasis, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, Rheumatoid arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease, said tumor or cancer 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, renal cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The invention further relates to the use of a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, as a ROR inhibitor, for the preparation of a medicament for the prevention and/or treatment of inflammatory and autoimmune diseases selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren's syndrome, uveitis, behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, Systemic Lupus Erythematosus (SLE), scleroderma, pancreatitis, psoriasis, psoriatic arthritis (PsA), Rheumatoid arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease.
The invention further relates to the use of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as a ROR agonist, for the preparation of a medicament for the prophylaxis and/or treatment of tumors or cancers 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, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, colon cancer, renal tumor, renal carcinoma, melanoma, neuroblastoma, colorectal carcinoma, renal carcinoma, neuroblastoma, renal carcinoma, melanoma, renal carcinoma, melanoma, neuroblastoma, renal carcinoma, melanoma, renal carcinoma, melanoma, renal carcinoma, melanoma, and tumor cell carcinoma of the same, and tumor cell carcinoma of the same, or a patient's, Head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
The invention further relates to a compound of general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for use as a medicament.
The invention also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound, which is used as an ROR regulator.
The invention also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound, which is used for preventing and/or treating inflammation, autoimmune diseases, tumors or cancers.
The present invention also relates to a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of inflammatory or autoimmune diseases selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren'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 also relates to a compound shown in the general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the prevention and/or treatment of tumors or cancers, the tumor or cancer is selected from 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, glioma, glioblastoma, hepatocellular carcinoma, papillary 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 inflammation, autoimmune diseases, tumors or cancers, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof, or pharmaceutical composition comprising the same, to a patient in need thereof, wherein the inflammatory or autoimmune diseases are selected from the group consisting of asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren's syndrome, uveitis, behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, Systemic Lupus Erythematosus (SLE), scleroderma, Pancreatic inflammation, psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease, said tumor or cancer 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, glioma, glioblastomas, hepatocellular carcinoma, mastoid nephroma, 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 inflammatory or autoimmune diseases selected from asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren's syndrome, uveitis, behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, Systemic Lupus Erythematosus (SLE), scleroderma, or a mixture thereof, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as a ROR inhibitor, Pancreatitis, psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis, osteoarthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease.
The present invention also relates to a method for the treatment, prevention and/or treatment of tumors or cancers selected from the group consisting of non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, synovial sarcoma, breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, neuroblastoma, or a pharmaceutically acceptable salt thereof, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, 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 of modulating ROR comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a pleasant to the eye and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. 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.
Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present 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 an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.
The compounds of the present invention may be administered in the form of suppositories 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 therefore will melt in the rectum to release the drug.
As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as the mode of treatment, the daily amount of compound (I) of the formula or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, isopropyl, 2-methylbutyl, and the like,1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted OR unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one OR more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, carboxylate, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4。
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. Alkoxy may be optionally substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, carboxylate, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4。
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:
Figure GPA0000266393270000181
the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure GPA0000266393270000191
the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure GPA0000266393270000192
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, carboxylate, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4。
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably 3 to 6 ring atoms, of which 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, preferably piperidinyl, piperazinyl, or morpholinyl. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. According to the number of spiro atoms shared between ringsThe spiro heterocyclic group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi spiro heterocyclic group, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferred is a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic group. Non-limiting examples of spiro heterocyclic groups include:
Figure GPA0000266393270000201
the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure GPA0000266393270000202
the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure GPA0000266393270000203
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure GPA0000266393270000211
and the like.
The heterocyclyl group may be optionally substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, carboxylate, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4。
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
Figure GPA0000266393270000212
the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably imidazolyl, tetrazolyl, pyridyl, thienyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferred is a pyridyl group. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure GPA0000266393270000213
Figure GPA0000266393270000221
heteroaryl groups may be optionally substituted OR unsubstituted, and when substituted, the substituents are preferably one OR more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, carboxylate, -OR4、-C(O)R4、-C(O)OR4and-S (O)mR4。
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group 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" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to the group-NH2。
The term "cyano" refers to — CN.
The term "nitro" means-NO2。
The term "oxo" refers to ═ O.
The term "carbonyl" refers to C ═ O.
The term "carboxy" refers to-C (O) OH.
The term "carboxylate" 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 group that is-C (O) -halogen.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
R4And m is as defined in formula (I).
Synthesis of the Compounds of the invention
In order to achieve the purpose of the invention, the invention adopts the following technical scheme:
the invention relates to a method for preparing a compound shown as a general formula (AI) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GPA0000266393270000231
firstly, under the acidic condition, a compound of a general formula (AI-1) and paraformaldehyde close a ring to obtain a general formula (AI-2);
in a second step, the compound of formula (AI-2) is reacted with CO and R in the presence of a catalyst under basic conditionscOH to obtain a general formula (AI-3);
thirdly, under the alkaline condition, the compound of the general formula (AI-3) is subjected to trifluoroacetyl removal to obtain a general formula (AI-4);
fourthly, the compound of the general formula (AI-4) and the compound of the general formula (I-5) are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain the compound of the general formula (AI-5); or the compound of the general formula (I-4) and the compound of the general formula (I-6) are subjected to reductive amination under an acidic condition and in the presence of a reducing agent to obtain a compound of the general formula (AI-5);
fifthly, hydrolyzing the compound with the general formula (AI-5) under alkaline conditions to obtain a (AI-A) compound;
a sixth step of subjecting the compound of the formula (AI-A) and the compound of the formula (I-B) to an alkaline condition in the presence of a condensing agent
Then condensation reaction is carried out to obtain a compound with a general formula (AI);
the reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate;
reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf；
Catalysts include, but are not limited to, palladium on carbon, raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl, [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1 ' -bis (dibenzylphosphine) dichloropentairon palladium, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl, preferably [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl.
Reducing agents include, but are not limited to: lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu)3、AlH3、NaCNBH3、Na(AcO)3BH、BH3Tetrahydrofuran solution (1N), B2H5、Li(Et)3BH、Pd/C/H2And Raney nickel/H2；
Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 2- (7-azobenzotriazol) -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-dioxane, water, N-dimethylformamide and a mixture thereof;
wherein:
Rcis an alkyl group, preferably an ethyl group;
x is halogen, preferably bromine;
ring A, ring B, ring C, W1、W2、W3、R1～R3N, s and t are as defined in formula (I).
The invention relates to a method for preparing a compound shown as a general formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereoisomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GPA0000266393270000251
firstly, a compound of a general formula (I-1) and paraformaldehyde are subjected to ring closure under an acidic condition to obtain a general formula (I-2);
in the second step, the compound of the formula (I-2) is reacted with CO and R in the presence of a catalyst under basic conditionscOH to obtain a general formula (I-3);
thirdly, under the alkaline condition, the compound of the general formula (I-3) is subjected to trifluoroacetyl removal to obtain a general formula (I-4);
fourthly, the compound of the general formula (I-4) and the compound of the general formula (I-5) are subjected to coupling reaction under alkaline conditions and in the presence of a catalyst to obtain a compound of the general formula (I-7); or the compound of the general formula (I-4) and the compound of the general formula (I-6) are subjected to reductive amination under an acidic condition and in the presence of a reducing agent to obtain the compound of the general formula (I-7);
fifthly, hydrolyzing the compound in the general formula (I-7) under alkaline condition to obtain a compound (I-A);
sixthly, carrying out condensation reaction on the compound with the general formula (I-A) and the compound with the general formula (I-B) under an alkaline condition in the presence of a condensing agent to obtain a compound with the general formula (I);
the reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate;
reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf；
Catalysts include, but are not limited to, palladium on carbon, raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl, [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1 ' -bis (dibenzylphosphine) dichloropentairon palladium, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl, preferably [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl.
Reducing agents include, but are not limited to: lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu)3、AlH3、NaCNBH3、Na(AcO)3BH、BH3Tetrahydrofuran solution (1N), B2H5、Li(Et)3BH、Pd/C/H2And Raney nickel/H2；
Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 2- (7-azobenzotriazol) -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-dioxane, water, N-dimethylformamide and a mixture thereof;
wherein:
Rcis an alkyl group, preferably an ethyl group;
x is halogen, preferably bromine;
ring A, ring B, R1～R3N, s and t are as defined in formula (I).
The invention relates to a method for preparing a compound shown as a general formula (II) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GPA0000266393270000261
firstly, under the acidic condition, a compound of a general formula (II-1) and paraformaldehyde are subjected to ring closing to obtain a general formula (II-2);
in the second step, the compound of the formula (II-2) is reacted with CO and R in the presence of a catalyst under basic conditionscOH to obtain a general formula (II-3);
thirdly, under the alkaline condition, the compound of the general formula (II-3) is subjected to trifluoroacetyl removal to obtain a general formula (II-4);
fourthly, the compound of the general formula (II-4) and the compound of the general formula (I-5) are subjected to coupling reaction under the alkaline condition and in the presence of a catalyst to obtain a compound of the general formula (II-7); or the compound of the general formula (II-4) and the compound of the general formula (I-6) are subjected to reductive amination under an acidic condition and in the presence of a reducing agent to obtain a compound of the general formula (II-7);
fifthly, hydrolyzing the compound in the general formula (II-7) under alkaline condition to obtain a compound (II-A);
sixthly, performing condensation reaction on the compound with the general formula (II-A) and the compound with the general formula (I-B) under alkaline conditions in the presence of a condensing agent to obtain a compound with a general formula (II);
the reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate;
reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf；
Catalysts include, but are not limited to, palladium on carbon, raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl, [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1 ' -bis (dibenzylphosphine) dichlorodipentaerythritol palladium, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl, preferably [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl;
reducing agents include, but are not limited to: lithium aluminum hydride, sodium borohydride, DIBAL-H, NaAlH (O-t-Bu)3、AlH3、NaCNBH3、Na(AcO)3BH、BH3Tetrahydrofuran solution (1N), B2H5、Li(Et)3BH、Pd/C/H2And Raney nickel/H2；
Condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 2- (7-azobenzotriazol) -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-dioxane, water, N-dimethylformamide and a mixture thereof;
wherein:
Rcis an alkyl group, preferably an ethyl group;
x is halogen, preferably bromine;
ring A, ring B, R1～R3S and t are as defined in formula (II).
The invention relates to a method for preparing a compound shown as a general formula (III) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt form thereof, which comprises the following steps:
Figure GPA0000266393270000281
firstly, carrying out coupling reaction on a compound of a general formula (II-4) and a compound of a general formula (III-1) under an alkaline condition and in the presence of a catalyst to obtain a compound of a general formula (III-2);
secondly, hydrolyzing the compound in the general formula (III-2) under an alkaline condition to obtain a compound (III-3);
thirdly, carrying out condensation reaction on the compound of the general formula (III-3) and the compound of the general formula (I-B) under an alkaline condition in the presence of a condensing agent to obtain a compound of the general formula (III);
the reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, or potassium tert-butoxide, and inorganic bases including, but not limited to, sodium hydride, sodium hydroxide, potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate;
catalysts include, but are not limited to, palladium on carbon, raney nickel, tetrakis-triphenylphosphine palladium, palladium dichloride, palladium acetate, 2-dicyclohexylphosphine-2, 4, 6-triisopropylbiphenyl, [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1 ' -bis (dibenzylphosphine) dichlorodipentaerythritol palladium, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl, preferably [1, 1 ' -bis (diphenylphosphino) ferrocene ] palladium dichloride or 2-dicyclohexylphosphine-2 ', 6 ' -dimethoxybiphenyl;
condensing agents include, but are not limited to, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N '-dicyclohexylcarbodiimide, N, N' -diisopropylcarbodiimide, O-benzotriazol-N, N, N ', N' -tetramethyluronium tetrafluoroborate, 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazol, O-benzotriazol-N, N, N ', N' -tetramethyluronium hexafluorophosphate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, Benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, preferably 2- (7-azobenzotriazol) -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-dioxane, water, N-dimethylformamide and a mixture thereof;
wherein:
Rcis an alkyl group, preferably an ethyl group；
X is halogen, preferably bromine;
ring B, G1、G2、R1～R3And t is as defined in formula (III).
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Brukeravence-400 nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS).
MS was determined using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150X 4.6mm column).
Chiral HPLC analytical determination using LC-10A vp (Shimadzu) or SFC-analytical (Berger Instruments Inc.).
The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Chiral preparative column chromatography used Prep Star SD-1(Varian Instruments Inc.) or SFC-multigram (Berger Instruments Inc.).
Average inhibition rate of kinase and IC50The values were determined with a NovoStar microplate reader (BMG, Germany).
Known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/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, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.
Example 1
N- (4- (ethylsulfonyl) benzyl) -2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 1
Figure GPA0000266393270000301
First step of
1- (7 ' -bromo-1 ' H-spiro [ cyclopropane-1, 4 ' -isoquinoline ] -2 ' (3 ' H) -yl) -2, 2, 2-trifluoroacetone 1b
N- ((1- (4-bromophenyl) cyclopropyl) methyl) -2, 2, 2-trifluoroacetamide 1a (22g, 68.3mmol, prepared as disclosed in PCT patent application "WO 2011124093") was dissolved in 150mL of a pre-prepared mixed solvent of acetic acid and sulfuric acid (V/V ═ 2: 3), paraformaldehyde (7.96g, 264.99mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 500mL of ice water, extracted with ethyl acetate (500mL × 2), and the organic phases were combined, washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1b (4.5g), which was directly subjected to the next reaction without purification.
Second step of
2 '- (2, 2, 2-trifluoroacetyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid ethyl ester 1c
The crude compound 1b (4g, 11.97mmol) was dissolved in 40mL of a mixed solvent of ethanol and dimethylsulfoxide (V/V ═ 1: 1), and 1, 3-bis (diphenylphosphino) propane (987.5mg, 2.39mmol), triethylamine (1.21g, 11.97mmol) and palladium acetate (537.53mg, 2.39mmol) were added, and the reaction was stirred at 60 ℃ for 12 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (2.5g, yield: 63.8%).
The third step
2 ', 3 ' -dihydro-1 ' H-spiro [ cyclopropane-1, 4 ' -isoquinoline ] -7 ' -carboxylic acid ethyl ester 1d
1c (2.5g, 7.64mmol) was dissolved in 100mL of a mixed solvent of ethanol and water (V/V ═ 1: 1), and potassium carbonate (1.58g, 11.46mmol) was added to stir the reaction at room temperature for 12 hours. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 1d (2g), which 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 ethyl ester 1f
The crude compound 1d (2g, 8.65mmol) and 1-bromo-4- (trifluoromethyl) benzene 1e (2.33g, 10.38mmol, prepared by the well-known method "Organic Letters, 2014, 16(16), 4268-propan 4271") were dissolved in 50mL1, 4-dioxane, cesium carbonate (8.45g, 25.94mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (412.22mg, 864.72umol) and tris (dibenzylideneacetone) dipalladium (791.83mg, 864.72umol) were added, and the reaction was stirred at 90 ℃ for 3 hours. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 1f (1.7g, yield: 52.37%).
The fifth step
2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid 1g
Compound 1f (1.5g, 4mmol) was dissolved in 60mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (799.12mg, 19.98mmol) was added, followed by heating to reflux and stirring for reaction for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1g (1.5g) of the crude title compound, which was directly subjected to the next reaction without purification.
The sixth step
N- (4- (ethylsulfonyl) benzyl) -2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 1
1g (1.4g, 4.03mmol) of the crude compound and (4- (ethylsulfonyl) phenyl) methylamine were dissolved in 30mL of N, N-dimethylformamide for 1h (1.2g, 6.05mmol, prepared as disclosed in PCT patent application "WO 2015017335"), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (3.06g, 8.06mmol) and triethylamine (1.22g, 12.09mmol) were added and the reaction was stirred for 12 h. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 1(11g, yield: 51.63%).
MS m/z(ESI)：529.5[M+1]
1H NMR(400MHz，DMSO-d6)δ9.11(s，1H)，7.80-7.85(m，3H)，7.69-7.71(m，1H)，7.55-7.57(m，2H)，7.49-7.50(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
Figure GPA0000266393270000321
1g (200mg, 575.82umol) of the crude compound and 2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol 2a (198.05mg, 863.73umol, prepared by the method disclosed in PCT patent application "WO 2016061160") were dissolved in 10mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (328.22mg, 863.73umol) and triethylamine (174.8mg, 1.73mmol) were added and reacted with stirring for 12 hours. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 2(120mg, yield: 37.31%).
MS m/z(ESI)：559.1[M+1]
1H NMR(400MHz，DMSO-d6)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)。
Examples 3 and 4
(R) -N- (1-4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 3
(S) -N- (1-4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 4
Figure GPA0000266393270000331
Chiral preparation (separation conditions: chiral preparative column Lux Cellulose-1OD 4.6. mu.m 150mm 5 μm (protected column); mobile phase: n-hexane: ethanol: trifluoroacetic acid 50: 0.01, flow rate: 1.0mL/min) was performed on 2(120mg, 0.215mmol), and the corresponding fractions were collected, concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compounds 3(10mg) 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% (chromatographic column: Lux Cellulose-1OD 4.6. about.150 mm 5um (with guard column)); mobile phase: n-hexane/ethanol/trifluoroacetic acid-50/50/0.01 (v/v/v)).
1H NMR(400MHz，DMSO-d6)δ8.74-8.76(m，1H)，7.79-7.84(m，3H)，7.64-7.72(m，3H)，7.49-7.51(m，2H)，7.12-7.14(m，2H)，6.92-6.95(m，1H)，5.13-5.15(m，1H)，4.66(s，2H)，3.70-3.75(s，2H)，3.54(s，2H)，3.24-3.29(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 minutes, chiral purity: 90 percent. % (chromatographic column: Superchiral S-AD (Chiralway), 0.46em I.D. 25em, 5 um; mobile phase: n-hexane/ethanol/trifluoroacetic acid 50/50/0.01 (v/v/v)).
1H NMR(400MHz，DMSO-d6)δ8.74-8.75(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-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide
Figure GPA0000266393270000341
1g (50mg, 0.14mmol) of the crude compound and 5- (ethylsulfonyl) pyridin-2-yl) methylamine 5a (43.24mg, 0.22mmol, prepared by the method disclosed in PCT patent application "WO 2015017335") were dissolved in 10mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (109.41mg, 0.29mmol) and triethylamine (43.62mg, 043mmol) were added and the reaction was stirred for 12 hours. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 5(20mg, yield: 24.92%).
MS m/z(ESI)：530.1[M+1]
1H NMR(400MHz，DMSO-d6)δ9.22(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
Figure GPA0000266393270000342
1g (100mg, 0.287mmol) of the crude compound and (1- (ethylsulfonyl) piperidin-4-yl) methylamine 6a (89.1mg, 0.432mmol, prepared by the method disclosed in U.S. patent application Ser. No. ' US 20160122318) were dissolved in 20mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethyluronium hexafluorophosphate (164.11mg, 0.432mmol) and triethylamine (87.4mg, 0.864mmol) were added and the reaction was stirred for 3 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 6(50mg, yield: 34.42%).
MS m/z(ESI)：536.5[M+1]
1H NMR(400MHz，DMSO-d6)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-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 7
Figure GPA0000266393270000351
First step of
2 '- (4- (trifluoromethyl) cyclohexyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid ethyl ester 7b
Crude compound 1d (300mg, 1,3mmol) was dissolved in 10mL of methanol, acetic acid (15.58mg, 0.259mmol) and sodium triacetoxyborohydride (549.81mg, 2.59mmol) were added, and after stirring for 2 hours, 4- (trifluoromethyl) cyclohexan-1-one 7a (430.99mg, 2.59mmol, prepared by the method disclosed in PCT application "WO 2008007930") was added, and stirring for 12 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 7B (100mg, yield: 20.21%).
Second step of
2 '- (4- (trifluoromethyl) cyclohexyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid 7c compound 7b (100mg, 0.262mmol) was dissolved in 13mL of a mixed solvent of ethanol and water (V/V ═ 10: 3), and sodium hydroxide (52.43mg, 1.31mmol) was added, and the reaction was stirred at 70 ℃ for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (30mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 7c (92mg), which was directly subjected to the next reaction without purification.
The third step
N- (4- (ethylsulfonyl) benzyl) -2 '- ((1r, 4r) -4- (trifluoromethyl) cyclohexyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 7
The crude compound 7c (50mg, 0.141mmol) and compound 1h (33.83mg, 0.17mmol) were dissolved in 5mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (80.65mg, 0.212mmol) and triethylamine (42.95mg, 0.424mmol) were added and the reaction was stirred for 12 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 7(20mg, yield: 26.5%).
MS m/z(ESI)：535.2[M+1]
1H NMR(400MHz，DMSO-d6)δ9.03(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
Figure GPA0000266393270000361
First step of
2 '- (2- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid ethyl ester 8b
The crude compound 1d (200mg, 0.864mmol) and 1-bromo-2- (trifluoromethyl) benzene 8a (233.48mg, 1.04mmol, prepared by the well-known method "European Journal, 2013, 19(52), 17692-17697") were dissolved in 3mL of 1, 4-dioxane, sodium tert-butoxide (249.31mg, 2.59mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (82.44mg, 172.94umol) and tris (dibenzylideneacetone) dipalladium (158.37mg, 172.94umol) were added, and the reaction was stirred at 105 ℃ for 18 hours. The reaction solution was cooled to room temperature, poured into 10mL of water, extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 8B (130mg, yield: 40.05%).
Second step of
2 '- (2- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid 8c
Compound 8b (130mg, 0.346mmol) was dissolved in 12mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (138.51mg, 3.46mmol) was added to the solution, and the reaction was stirred at 60 ℃ for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 1M hydrochloric acid was added dropwise to the obtained residue to a pH of 3-4, and concentrated under reduced pressure to obtain a crude title compound 8c (120mg), which was directly subjected to the next reaction without purification.
The 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 (100mg, 0.288mmol) and compound 1h (114.74mg, 0.576mmol) were dissolved in 2mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (218mg, 0.576mmol) and N, N-diisopropylethylamine (111.63mg, 0.864mmol) were added and the reaction was stirred for 1 hour. The reaction solution was added with 10mL of water, extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 8(40mg, yield: 26.28%).
MS m/z(ESI)：529.5[M+1]
1H 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
Figure GPA0000266393270000371
Figure GPA0000266393270000381
First step of
2 '- (5- (trifluoromethyl) pyrimidin-2-yl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid ethyl ester 9b
The crude compound 1d (100mg, 0.432mmol) and 2-chloro-5- (trifluoromethyl) pyrimidine 9a (118mg, 0.646mmol) were dissolved in 2mL of DMSO, 1, 8-diazabicyclo [5.4.0] undec-7-ene 326mg, 1.294mmol were added, and the reaction was stirred at 90 ℃ for 18 hours. The reaction solution was cooled to room temperature, poured into 10mL of water, extracted with ethyl acetate (20 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 9B (100mg, yield: 61.29%).
Second step of
2 '- (5- (trifluoromethyl) pyrimidin-2-yl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid 9c
Compound 9b (50mg, 0.132mmol) was dissolved in 12mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (53mg, 1.32mmol) was added to the solution, and the reaction was stirred at 60 ℃ for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 1M hydrochloric acid was added dropwise to the obtained residue to a pH of 3 to 4, and concentrated under reduced pressure to obtain a crude title compound 9c (50mg), which was directly subjected to the next reaction without purification.
The 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 (50mg, 0.143mmol) and compound 1h (28mg, 0.140mmol) were dissolved in 2mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (82mg, 0.216mmol) and N, N-diisopropylethylamine (37mg, 0.286mmol) were added and the reaction was stirred for 1 hour. The reaction solution was added with 10mL of water, extracted with ethyl acetate (10 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 9(50mg, yield: 65.84%).
MS m/z(ESI)：531.4[M+1]
1H NMR(400MHz，CDCl3)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
Figure GPA0000266393270000391
First step of
1- (7 ' -bromo-1 ' H-spiro [ cyclobutane-1, 4 ' -isoquinoline ] -2 ' (3 ' H) -yl) -2, 2, 2-trifluoroacetone 10b
N- ((1- (4-bromophenyl) cyclobutyl) methyl) -2, 2, 2-trifluoroacetamide 10a (1.2g, 3.57mmol, prepared by the method disclosed in patent application "WO 2011124093") was dissolved in 27mL of a prepared mixed solvent of acetic acid and sulfuric acid (V/V ═ 2: 3), paraformaldehyde (321mg, 10.69mmol) was added, and the reaction was stirred for 12 hours. The reaction solution was poured into 100mL of ice water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 10b (1g), which was directly subjected to the next reaction without purification.
Second step of
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 (1g, 2.87mmol) was dissolved in 20mL of a mixed solvent of ethanol and dimethylsulfoxide (V/V ═ 1: 1), and 1, 3-bis (diphenylphosphino) propane (118mg, 0.28mmol), triethylamine (290mg, 2.86mmol) and palladium acetate (64mg, 0.28mmol) were added, and the reaction was stirred at 60 ℃ for 12 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (100mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 10c (400mg, yield: 40.8%).
The third step
2 ', 3 ' -dihydro-1 ' H-spiro [ cyclobutane-1, 4 ' -isoquinoline ] -7 ' -carboxylic acid ethyl ester 10d
10c (400mg, 1.17mmol) was dissolved in 50mL of a mixed solvent of ethanol and water (V/V ═ 1: 1), and potassium carbonate (485mg, 3.51mmol) was added to stir the reaction at room temperature for 12 hours. The reaction was poured into 100mL of water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude title compound 10d (350mg) which 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 the crude compound 10d (350mg, 1.42mmol) and 1-bromo-4- (trifluoromethyl) benzene 10e (481mg, 2.13mmol, prepared by the well-known method "Organic Letters, 2014, 16(16), 4268-. The reaction solution was cooled to room temperature, poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 10f (400mg, yield: 71.99%).
The fifth step
2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -7' -carboxylic acid 10g
Compound 10f (400mg, 1.03mmol) was dissolved in 30mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (164mg, 4.10mmol) was added, followed by heating to reflux and stirring for reaction for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 10g (300mg) of the crude title compound, which was subjected to the next reaction without purification.
The sixth step
N- (4- (ethylsulfonyl) benzyl) -2 '- (4- (trifluoromethyl) phenyl) -2', 3 '-dihydro-1' H-spiro [ cyclobutane-1, 4 '-isoquinoline ] -7' -carboxamide 10
10g (300mg, 0.83mmol) of the crude compound and (4- (ethylsulfonyl) phenyl) methylamine for 10h (198mg, 0.99mmol, prepared by the method disclosed in the patent application "WO 2015017335") were dissolved in 10mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (630mg, 1.66mmol) and triethylamine (252mg, 2.49mmol) were added and the reaction was stirred for 12 h. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 10(200mg, yield: 44.39%).
MS m/z(ESI)：543.2[M+1]
1H NMR(400MHz，DMSO-d6)δ9.13-9.15(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-spiro [ isoquinoline-4, 4 ' -pyran ] -7-carboxamide 11
Figure GPA0000266393270000411
First step of
4- (4-bromophenyl) tetrahydro-2H-pyran-4-carbonitrile 11b
2- (4-bromophenyl) acetonitrile 11a (2.5g, 12.75mmol) was dissolved in 30mL of dimethyl sulfoxide, cooled to 0 ℃ and sodium hydride (1.02g, 25.50mmol) was added slowly, and the mixture was stirred for 30 minutes, followed by addition of 1-bromo-2- (2-bromoethoxy) ethane (3.22g, 14.03mmol) and stirring at room temperature for 12 hours. The reaction solution was poured into 100mL of ice water, extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed successively with water, a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 11B (2.5g, yield: 73.75%).
Second step of
(4- (4-bromophenyl) tetrahydro-2H-pyran-4-yl) methylamine 11c
Crude compound 11b (2.5g, 9.39mmol) was dissolved in 100mL tetrahydrofuran, 1M borane tetrahydrofuran solution (28.18mL, 28.18mmol) was added, the reaction was stirred under reflux for 12 hours, the reaction was cooled to room temperature, adjusted to pH < 2 with 1M hydrochloric acid, heated to reflux for 1 hour, cooled to room temperature, the reaction was concentrated under reduced pressure, the residue was poured into 200mL water, adjusted to pH > 9 with 1M sodium hydroxide solution, extracted with ethyl acetate (200 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 11c (2g, yield: 78.81%).
The third step is N- ((4- (4-bromophenyl) tetrahydro-2H-pyran-4-yl) methyl) -2, 2, 2-trifluoroacetamide 11d
11c (2g, 7.40mmol) was dissolved in 100ml dichloromethane, cooled to 0 deg.C, triethylamine (2.25g, 22.21mmol) was added, trifluoroacetic anhydride (2.02g, 9.02mmol) was slowly added dropwise, and the reaction was stirred at room temperature for 12 hours. The reaction solution was poured into 100mL of water, the layers were separated, the organic phase was washed with saturated sodium bicarbonate and sodium chloride solution, respectively, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B to give the title compound 11d (2g, yield: 73.78%).
The fourth step
1- (7-bromo-2 ', 3 ', 5 ', 6 ' -tetrahydro-1H-spiro [ isoquinoline-4, 4 ' -pyran ] -2(3H) -yl) -2, 2, 2-trifluoroacetone 11e
11d (2g, 5.46mmol) was dissolved in 50mL of a prepared mixed solvent of acetic acid and sulfuric acid (V/V2: 3), and paraformaldehyde (492mg, 16.39mmol) was added thereto, followed by stirring for 12 hours. The reaction solution was poured into 300mL of ice water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 11e (600mg, yield: 29.05%).
The fifth step
2- (2, 2, 2-trifluoroacetyl) -2, 2 ', 3, 3 ', 5 ', 6 ' -hexahydro-1H-spiro [ isoquinoline-4, 4 ' -pyran ] -7-carboxylic acid ethyl ester 11f
Compound 11e (600mg, 1.59mmol) was dissolved in 20mL of a mixed solvent of ethanol and dimethylsulfoxide (V/V ═ 1: 1), and 1, 3-bis (diphenylphosphino) propane (130mg, 31731 μmol), triethylamine (481mg, 4.76mmol) and palladium acetate (71mg, 317.71 μmol) were added, and the reaction was stirred at 60 ℃ under a carbon monoxide atmosphere for 12 hours. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (100mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11f (100mg, yield: 16.97%).
The sixth step
2, 2 ', 3, 3 ', 5 ', 6 ' -hexahydro-1H-spiro [ isoquinoline-4, 4 ' -pyran ] -7-carboxylic acid ethyl ester 11g
11f (100mg, 269.29. mu. mol) was dissolved in 50mL of a mixed solvent of ethanol and water (V/V. RTM.1: 1), and potassium carbonate (111mg, 807.86. mu. mol) was added thereto, and the reaction was stirred at room temperature for 12 hours. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 11g (70mg) of the crude title compound, which 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-carboxylic acid ethyl ester 11H
11g (50mg, 181.59. mu. mol) of the crude compound and 1-bromo-4- (trifluoromethyl) benzene 1e (61mg, 272. mu. mol, prepared by the well-known method "Organic Letters, 2014, 16(16), 4268-propan 4271") were dissolved in 30mL of 1, 4-dioxane, cesium carbonate (177mg, 544.78. mu. mol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (8mg, 18.16. mu. mol) and tris (dibenzylideneacetone) dipalladium (16mg, 18.16. mu. mol) were added, and the reaction was stirred at 90 ℃ for 3 hours under protection of helium gas. The reaction solution was cooled to room temperature, poured into 50mL of water, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11h (30mg, yield: 39.39%).
Eighth step
2- (4- (trifluoromethyl) phenyl) -2, 2 ', 3, 3 ', 5 ', 6 ' -hexahydro-1H-spiro [ isoquinoline-4, 4 ' -pyran ] -7-carboxylic acid 11i
Compound 11h (30mg, 71.52 μmol) was dissolved in 30mL of a mixed solvent of ethanol and water (V/V5: 1), and sodium hydroxide (14mg, 357.62 μmol) was added thereto, followed by heating to reflux and stirring for reaction for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 11i (30mg), which was directly subjected to the next reaction without purification.
The ninth step
N- (4- (ethylsulfonyl) benzyl) -2- (4- (trifluoromethyl) phenyl) -2, 2 ', 3, 3 ', 5 ', 6 ' -hexahydro-1H-spiro [ isoquinoline-4, 4 ' -pyran ] -7-carboxamide 11
Crude compound 11i (30mg, 76.65. mu. mol) and (4- (ethylsulfonyl) phenyl) methylamine were dissolved in 10mL of N, N-dimethylformamide for 1h (18mg, 91.98. mu. mol, prepared by the method disclosed in patent application "WO 2015017335"), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (43mg, 114.98. mu. mol) and triethylamine (23mg, 229.95. mu. mol) were added and reacted with stirring for 12 h. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 11(15mg, yield: 34.17%).
MS m/z(ESI)：573.6[M+1]
1H NMR(400MHz，DMSO-d6)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 [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 12
Figure GPA0000266393270000441
First step of
2 '- (5- (trifluoromethyl) pyridin-2-yl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid ethyl ester 12b
The crude compound 1d (500mg, 2.16mmol) and 2-chloro-5- (trifluoromethyl) pyridine 12a (732mg, 3.24mmol) were dissolved in 50mL1, 4-dioxane, cesium carbonate (2.11g, 6.49mmol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (103mg, 216.82. mu. mol) and tris (dibenzylideneacetone) dipalladium (197mg, 216.18. mu. mol) were added, and the reaction was stirred at 90 ℃ for 3 hours under protection of helium gas. The reaction solution was cooled to room temperature, poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 12B (450mg, yield: 55.31%).
Second step of
2 '- (5- (trifluoromethyl) pyridin-2-yl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxylic acid 12c
Compound 12b (1.5g, 3.99mmol) was dissolved in 60mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (797.12mg, 19.93mmol) was added, followed by heating to reflux and stirring for reaction for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 12c (1.3g), which was directly subjected to the next reaction without purification.
The third step
N- (4- (ethylsulfonyl) benzyl) -2 '- (5- (trifluoromethyl) pyridin-2-yl) -2', 3 '-dihydro-1' H-spiro [ cyclopropane-1, 4 '-isoquinoline ] -7' -carboxamide 12
Crude compound 12c (1g, 2.87mmol) and (4- (ethylsulfonyl) phenyl) methylamine were dissolved in 30mL of N, N-dimethylformamide for 1h (858mg, 4.31mmol, prepared as disclosed in the patent application WO 2015017335), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (1.64g, 4.31mmol) and triethylamine (871mg, 8.61mmol) were added and the reaction was stirred for 12 h. The reaction solution was poured into 100mL of water, extracted with ethyl acetate (100 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 12(1g, yield: 65.77%).
MS m/z(ESI)：530.4[M+1]
1H NMR(400MHz，DMSO-d6)δ9.12-9.15(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
Figure GPA0000266393270000451
1g (50mg, 143.96. mu. mol) of the crude compound and (R) -2-amino-2- (5- (ethylsulfonyl) pyridin-2-yl) ethanol 13a (39mg, 172.75. mu. mol, prepared by the method disclosed in the patent application WO 2016061160) were dissolved in 10mL of N, N-dimethylformamide, and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (82mg, 215.93. mu. mol) and triethylamine (43mg, 431.87. mu. mol) were added and reacted with stirring for 12 hours. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 13(20mg, yield: 24.83%).
MS m/z(ESI)：560.6[M+1]
1H NMR(400MHz，DMSO-d6)δ8.98(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
Figure GPA0000266393270000461
First step of
3 ' -Nitro-5 ' H-spiro [ cyclopropane-1, 8 ' - [1, 6] naphthyridine ] -6 ' (7 ' H) -carboxylic acid tert-butyl ester 14b
Compound 14a (600mg, 2.66mmol prepared as disclosed in the patent application "WO 2010114957") was dissolved in 30ml of 7M methanolic ammonia, compound 14b (530mg, 2.66mmol) was added and the temperature was raised to 60 ℃ and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 14c (300mg, yield: 36.89%).
Second step of
3 ' -amino-5 ' H-spiro [ cyclopropane-1, 8 ' - [1, 6] naphthyridine ] -6 ' (7 ' H) -carboxylic acid tert-butyl ester 14d
Compound 14c (300mg, 982.54 μmol) was dissolved in a mixed solvent of 50mL ethanol and water (V/V ═ 2: 1), iron powder (274mg, 4.90mmol) and ammonium chloride (106mg, 1.96mmol) were added, the mixture was heated to reflux and stirred for reaction for 3 hours, the reaction solution was cooled to room temperature, the reaction solution was poured into 50mL water, extraction was performed with dichloromethane (100mL × 2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 14d (270 mg).
The third step
3 ' -bromo-5 ' H-spiro [ cyclopropane-1, 8 ' - [1, 6] naphthyridine ] -6 ' (7 ' H) -carboxylic acid tert-butyl ester 14e
Dissolving 14d (250mg, 907.95 mu mol) in 30ml of acetonitrile, cooling to 0 ℃, slowly adding isoamyl nitrite (212mg, 1.81mmol) dropwise, stirring for 30 minutes after the addition is finished, adding cuprous bromide, raising the temperature to room temperature and stirring for reaction for 12 hours. The reaction solution was poured into 50mL of water, extracted with ethyl acetate (50 mL. times.2), and the organic phases were combined, washed successively with water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 14e (100mg, yield: 32.46%).
The fourth step
6 ' - (Tert-butyl) 3 ' -ethyl 5 ' H-spiro [ cyclopropane-1, 8 ' - [1, 6] naphthyridine ] -3 ', 6 ' (7 ' H) -dicarboxylate 14f
Compound 14e (100mg, 294.78 μmol) was dissolved in 20mL of a mixed solvent of ethanol and dimethylsulfoxide (V/V ═ 1: 1), and 1, 3-bis (diphenylphosphino) propane (25mg, 57.25 μmol), potassium carbonate (61mg, 442.03 μmol) and palladium acetate (6mg, 26.72 μmol) were added, and the reaction was stirred at 60 ℃ for 12 hours under a carbon monoxide atmosphere. The reaction solution was cooled to room temperature, poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 14f (80mg, yield: 81.64%).
The fifth step
14g of ethyl 6 ', 7 ' -dihydro-5 ' H-spiro [ cyclopropane-1, 8 ' - [1, 6] naphthyridine ] -3 ' -carboxylate
14f (80mg, 240.68. mu. mol) was dissolved in 20mL of a mixed solvent of ethanol and water (V/V. RTM.1: 1), and 5mL of a 4M methanol hydrochloride solution was added to stir the mixture at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the residue was adjusted to pH > 8 with 1N NaOH solution, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 14g (70mg) of the crude title compound, which was directly subjected to the next reaction without purification.
The sixth step
6 '- (4- (trifluoromethyl) phenyl) -6', 7 '-dihydro-5' H-spiro [ cyclopropane-1, 8 '- [1, 6] naphthyridine ] -3' -carboxylic acid ethyl ester 14H
14g (70mg, 301.36. mu. mol) of the crude compound and 1-bromo-4- (trifluoromethyl) benzene 1e (101mg, 448.87. mu. mol, prepared by the well-known method "Organic Letters, 2014, 16(16), 4268-propan 4271") were dissolved in 20mL of 1, 4-dioxane, cesium carbonate (294mg, 902.34. mu. mol), 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (14mg, 29.37. mu. mol) and tris (dibenzylideneacetone) dipalladium (27mg, 29.48. mu. mol) were added, and the reaction was stirred at 90 ℃ for 3 hours under protection of helium gas. The reaction solution was cooled to room temperature, poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title compound 14h (100mg, yield: 88.16%).
Seventh step
6 '- (4- (trifluoromethyl) phenyl) -6', 7 '-dihydro-5' H-spiro [ cyclopropane-1, 8 '- [1, 6] naphthyridine ] -3' -carboxylic acid 14i
Compound 14h (100mg, 265.69 μmol) was dissolved in 20mL of a mixed solvent of ethanol and water (V/V ═ 5: 1), and sodium hydroxide (53mg, 1.32mmol) was added thereto, followed by heating to reflux and stirring for reaction for 2 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was added dropwise with 1M hydrochloric acid to a pH of < 2, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 14i (80mg), which was directly subjected to the next reaction without purification.
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
Crude compound 14i (80mg, 229.67 μmol) and (4- (ethylsulfonyl) phenyl) methylamine were dissolved in 10mL of N, N-dimethylformamide for 1h (68mg, 341.24 μmol, prepared as disclosed in the patent application "WO 2015017335"), and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (130mg, 342.10 μmol) and triethylamine (69mg, 681.88 μmol) were added and the reaction was stirred for 12 hours. The reaction solution was poured into 30mL of water, extracted with ethyl acetate (30 mL. times.2), the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography to give the title compound 14(30mg, yield: 24.66%).
MS m/z(ESI)：530.2[M+1]
1H NMR(400MHz，DMSO-d6)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 present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 determination of the in vitro Activity of the Compounds of the invention on ROR γ
First, experimental material and instrument
1.
Figure GPA0000266393270000481
TR-FRET ROR gamma coactivation system (Life Technologies)
2.RORγLBD(AB Vector)
3.DMSO(SigmaAldrich)
4. Enzyme mark instrument (Tecan)
Second, the experimental procedure
The compound of the invention is screened for regulation of ROR gamma activity by using a LanthaScreen TR-FRET (time-resolved fluorescence energy resonance transfer) ROR gamma co-activation system.
Complete buffer D (complete TR-FRET Coreglator) (Life Technologies) was first prepared containing a final concentration of 5mM DTT. The final concentration of DMSO was 2%. Test compounds were serially diluted to 2x final concentration in complete buffer D containing 2% DMSO, with the highest dose being 60 μm. Mu.l/well were added to the test wells of 384-well plates (PerkinElmer). Each test compound was placed in 2 parallel control wells at the same concentration. Prepare 4 XROR. gamma. LBD (AB vector). ROR γ LBD concentration was diluted to 1 ng/. mu.L using intact buffer D. 5 μ l/well was added to the test wells of a 384 well assay plate. Negative control wells were 5 μ L of intact buffer D, no ROR γ LBD. A mixture containing 0.6. mu.M fluorescein-D22 (4X) and 8nM terbium (Tb) -labeled anti-GST antibody (4X) (Life Technologies) was prepared using complete buffer D, and 5. mu.L of the mixture was added to a 384-well plate. The total reaction system was 20. mu.L. The 384 well plates were gently mixed on a shaker and incubated at room temperature for 2-4 hours in the dark.
The IC of the test compound was calculated by measuring the fluorescence reading using Tecan Infinite M1000, plotting the ratio of the emission wavelength 520nm/495nm against the log of the compound concentration using GraphPad Prism 6.0 software50/EC50The value is obtained.
In vitro ROR gamma activity of the compounds of the invention was determined by the above assay, and the IC determined50/EC50The values are shown in Table 1.
TABLE 1 IC of the in vitro activity of the compounds of the invention on ROR gamma50/EC50Value of
Figure GPA0000266393270000491
a: if an inhibitor, the value is indicated as IC50(ii) a If agonist, the values are indicated as EC50。
And (4) conclusion: the compound has obvious regulation effect on ROR gamma in-vitro activity, and experimental results show that the change of the substituent of the ring A in the compound shown in the general formula (I) shows different mechanisms on the regulation of the ROR gamma in-vitro activity, the compound shows an inhibiting effect when the ortho-position of the ring A has a small substituent (such as a hydrogen atom) (see examples 1-7, examples 9-14 and the like), and shows an exciting effect when the ortho-position of the ring A has a large substituent (such as trifluoromethyl) (see example 8).
Test example 2 determination of IL-17A enzyme-linked immunosorbent assay Activity by Compounds of the present invention
First, experimental material and instrument
1. Human Peripheral Blood Mononuclear Cells (PBMC) (Zenbio)
2. Lymphocyte culture medium (Zenbio)
3.TexMACS(Miltenyi Biotec)
4. Human cytostim (Miltenyi Biotec)
5. Human IL-17 enzyme linked immunosorbent assay kit (R & D system)
6.CO2Incubator (Fisher Scientific)
7. Centrifuge (Fisher Scientific)
8.96 well cell culture plate (Fisher Scientific)
9. Enzyme mark instrument (Tecan)
Second, the experimental procedure
Frozen human Peripheral Blood Mononuclear Cells (PBMC) were thawed quickly in pre-warmed lymphocyte medium, centrifuged at 1000rpm for 10min, the cell culture supernatant was removed, the cells were gently suspended in TexMACS medium, and the cells were counted. T cell activating reagent cytostim (10. mu.l/ml) was added to the cell suspension in proportion, and the cells were seeded in 96-well cell culture plates at a density of 1X 105 peripheral blood mononuclear cells/well. Test compounds were diluted in gradient using TexMACS medium and added to each experimental well, 2-3 parallel wells per group. Negative control wells containing cells alone without cytostim were prepared to obtain background readings. The cell culture plates were incubated in a 5% carbon dioxide incubator at 37 ℃ for 3 days. Cell culture supernatant was collected after 3 days of drug treatment and centrifuged to remove suspended matter. IL-17A in the supernatant was then quantified using an IL-17A enzyme linked immunosorbent assay kit. IC of test Compounds was calculated using GraphPad Prism 6.050/EC50The value is obtained.
IL-17A ELISA quantitative analysis by the Compound of the present invention IC determined by the above assay50The values are shown in Table 2.
TABLE 2 IC of IL-17A enzyme-linked immunosorbent assay for the compounds of the invention50Value of
Example numbering IC50(nM)
1 22
2 28
3 18
4 291
5 297
9 289
10 59
12 45
13 134
And (4) conclusion: the compound of the invention has obvious regulation effect on IL-17A enzyme-linked immunosorbent assay activity.

Claims (28)

1. A compound of the general formula (AI):
Figure FDA0003093081810000011
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
W1、W2and W3Are 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 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl, 6-to 10-membered aryl, and 5-to 10-membered heteroaryl;
ring C is a 3-to 6-membered cycloalkyl group or a 3-to 6-membered heterocyclic group, wherein the 3-to 6-membered heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S;
R1are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, cyano, amino, nitro, hydroxy and C1-6A hydroxyalkyl group;
R2are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, cyano, amino, nitro, hydroxy, C1-6Hydroxyalkyl and-S (O)mR4；
R3Selected from hydrogen atoms, C1-6Alkyl and C1-6A hydroxyalkyl group;
R4is selected from C1-6Alkyl, 3 to 6 membered cycloalkyl and C1-6A haloalkyl group;
m is 1 or 2;
s is 0, 1, 2, 3 or 4; and is
t is 0, 1, 2, 3 or 4.
2. The compound of formula (AI) according to claim 1, wherein ring C is selected from cyclopropyl, cyclobutyl, cyclopentyl and tetrahydropyranyl.
3. The compound represented by the general formula (AI) according to claim 1, which is a compound represented by the general formula (I):
Figure FDA0003093081810000021
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
n is 1, 2 or 3;
ring A, ring B, R1～R3S and t are as defined in claim 1.
4. The compound of formula (I) according to claim 3, which is a compound of formula (II):
Figure FDA0003093081810000022
wherein:
ring A, ring B, R1～R3S and t are as defined in claim 3.
5. A compound according to any one of claims 1 to 4, wherein Ring A is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.
6. The compound represented by the general formula (I) according to claim 3 or 4, which is a compound represented by the general formula (III):
Figure FDA0003093081810000023
wherein:
G1and G2Are the same or different and are each independently CH or N;
ring B, R1～R3And t is as defined in claim 3.
7. The compound of formula (I) according to claim 3, which is a compound of formula (IV):
Figure FDA0003093081810000031
wherein:
Rbis selected from C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6A hydroxyalkyl group;
p is 0, 1, 2 or 3;
ring B, R1～R3And t is as defined in claim 3.
8. A compound according to any one of claims 1 to 4, wherein ring B is selected from phenyl, pyridyl, pyrimidinyl, cyclohexyl and piperidinyl.
9. A compound according to any one of claims 1 to 4, wherein R2is-S (O)mR4(ii) a m is 2; and R is4Is C1-6An alkyl group.
10. The compound represented by the general formula (III) according to claim 6, which is a compound represented by the general formula (III-A):
Figure FDA0003093081810000032
wherein:
R4is C1-6An alkyl group;
R1and R3As defined in claim 6.
11. The compound represented by the general formula (IV) according to claim 7, which is a compound represented by the general formula (IV-a):
Figure FDA0003093081810000041
wherein:
Rbis selected from C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy and C1-6A hydroxyalkyl group;
R4is C1-6An alkyl group;
p is 0, 1, 2 or 3;
R1and R3As defined in claim 1.
12. A compound of formula (I) according to any one of claims 7 or 11, wherein RbIs C1-6A haloalkyl group.
13. The compound of formula (AI) according to any one of claims 1 to 4, wherein R1Is C1-6A haloalkyl group.
14. A compound according to claim 1 or 2, selected from:
Figure FDA0003093081810000042
Figure FDA0003093081810000051
15. a compound represented by the general formula (AI-A):
Figure FDA0003093081810000052
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A, ring C, W1、W2、W3、R1And s is as defined in claim 1.
16. The compound represented by the general formula (AI-a) according to claim 15, which is a compound represented by the general formula (I-a):
Figure FDA0003093081810000053
or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A, R1S and n are as defined in claim 15.
17. The compound of the formula (AI-A) according to claim 15, selected from
Figure FDA0003093081810000054
Figure FDA0003093081810000061
18. A process for the preparation of a compound of general formula (AI) according to claim 1, which comprises:
Figure FDA0003093081810000062
carrying out condensation reaction on the compound with the general formula (AI-A) and the compound with the general formula (I-B) to obtain a compound with the general formula (AI);
wherein:
ring A, ring B, ring C, W1、W2、W3、R1～R3S and t are as defined in claim 1.
19. A process for the preparation of a compound of general formula (I) according to claim 3, which process comprises:
Figure FDA0003093081810000063
carrying out condensation reaction on the compound with the general formula (I-A) and the compound with the general formula (I-B) to obtain a compound with the general formula (I);
wherein:
ring A, ring B, R1～R3N, s and t are as defined in claim 3.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (AI) according to any one of claims 1 to 14, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
21. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 for the preparation of a ROR modulator.
22. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 for the preparation of a medicament for the prevention and/or treatment of inflammation, autoimmune diseases and tumors.
23. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or of a pharmaceutical composition according to claim 20 as ROR inhibitor for the preparation of a medicament for the prevention and/or treatment of an inflammatory or autoimmune disease, the inflammatory or autoimmune disease is selected from the group consisting of asthma, atopic dermatitis, contact dermatitis, acne, bronchitis, crohn's disease, regional enteritis, Inflammatory Bowel Disease (IBD), ulcerative colitis, allograft rejection, sjogren's syndrome, uveitis, behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, neuromyelitis, Systemic Lupus Erythematosus (SLE), scleroderma, pancreatitis, psoriasis, arthritis, allergic rhinitis, autoimmune diabetes, and autoimmune thyroid disease.
24. The use according to claim 23, wherein the arthritis is selected from the group consisting of psoriatic arthritis (PsA), rheumatoid arthritis and osteoarthritis.
25. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 as a ROR agonist in the preparation of a medicament for the prevention and/or treatment of cancer.
26. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 as ROR agonist in the preparation of a medicament for the prevention and/or treatment of solid tumors.
27. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 as a ROR agonist for the preparation of a medicament for the prevention and/or treatment of a tumor selected from 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, renal cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, glioma, glioblastoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma and myeloma.
28. Use of a compound of general formula (AI) according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 20 as ROR agonist in the preparation of a medicament for the prevention and/or treatment of a tumour selected from non-hodgkin's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, ovarian cancer, hepatocellular carcinoma and non-small cell lung cancer.
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