CN115724802A - Thiazolidine compound and application thereof - Google Patents
Thiazolidine compound and application thereof Download PDFInfo
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- CN115724802A CN115724802A CN202111020993.5A CN202111020993A CN115724802A CN 115724802 A CN115724802 A CN 115724802A CN 202111020993 A CN202111020993 A CN 202111020993A CN 115724802 A CN115724802 A CN 115724802A
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- -1 Thiazolidine compound Chemical class 0.000 title claims description 94
- 108010052167 Dihydroorotate Dehydrogenase Proteins 0.000 claims abstract description 38
- 102100032823 Dihydroorotate dehydrogenase (quinone), mitochondrial Human genes 0.000 claims abstract description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 201000010099 disease Diseases 0.000 claims abstract description 21
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- 150000001875 compounds Chemical class 0.000 claims description 176
- 238000002360 preparation method Methods 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
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- 201000006417 multiple sclerosis Diseases 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000004423 acyloxy group Chemical group 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
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- RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 abstract description 15
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 106
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Images
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Abstract
The invention relates to a thiazole amine derivative and application thereof, wherein the thiazole amine derivative has ROR gamma t regulation activity and/or DHODH regulation activity, especially inhibition activity, and is used for preparing a medicament for preventing or treating ROR gamma t and/or DHODH related diseases.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a thiazolamine compound and application thereof.
Background
Retinoic acid receptor-Related Orphan Receptors (RORs), which are members of the nuclear receptor superfamily, can be divided into three subtypes: ROR α (NR 1F 1), ROR β (NR 1F 2) and ROR γ (NR 1F 3). Each ROR subtype has an individual tissue distribution and regulates a variety of physiological processes. Among them, ROR α is widely distributed in adipose tissue, liver, skin, kidney, skeletal muscle, lung, thymus and brain; the distribution of ROR β is relatively limited and is mainly expressed in the central nervous system; ROR γ has two subtypes: ROR γ 1 and ROR γ 2 (also referred to as ROR γ t), ROR γ 1 is mainly expressed in liver, skeletal muscle, adipose tissue and kidney, while ROR γ t is only highly expressed in immune tissues such as thymus. ROR γ T is a key regulator of the cell differentiation and secretion of the inflammatory cytokine interleukin-17 (interleukin-17, IL-17) by helper T cells 17 (T helper 17cells, th17). Th17 cells play a key role in many mouse autoimmune disease models, such as Experimental Allergic Encephalomyelitis (EAE) and collagen-induced arthritis (CIA) animal models. In addition, increased levels of IL-17 can be detected in a number of human autoimmune diseases including Rheumatoid Arthritis (RA), multiple Sclerosis (MS), psoriasis (Psoriasisis) and Inflammatory Bowel Disease (IBD). The number of Th17 cells found in tissues and peripheral blood samples from patients with autoimmune diseases is increased. Therefore, th17 cells or the cytokine IL-17 produced by them are closely linked to the pathogenesis of inflammatory and autoimmune diseases.
The monoclonal antibody Cosentyx (Secukinumab/AIN 457) developed by Nowa, which is used to treat psoriasis by specifically blocking IL-17, was approved by the FDA to be marketed in 1 month 2015, and is the first drug acting on IL-17 in the psoriasis-treating drug market. This also underscores the importance of the IL-17 signaling pathway in inflammatory diseases and demonstrates the potential for treating inflammatory diseases by affecting the IL-17 signaling pathway through ROR γ t inhibitors. Therefore, ROR gamma t can be used as a novel target of medicaments for treating autoimmune diseases, and ROR gamma t small molecule modulators, especially inhibitors, can be used for treating ROR gamma t mediated inflammation and autoimmune diseases. CN107257791A, CN108026039A, CN108026050A, CN108064224A, CN108863850A and the like disclose ROR gamma t small molecule modulators and uses thereof.
Recent studies found that ROR γ acts as a key driver upstream of Androgen Receptor (AR), directly regulating the expression of AR receptor. The ROR γ gene is highly expressed in metastatic castration resistant prostate cancer (mCRPC) patient tumors and drives transcription of AR receptors, including AR-V7 mutants, in tumors, closely associated with aberrant tumor signaling pathways in mCRPC. ROR gamma inhibitors can greatly reduce the expression of AR in tumor cells, show an inhibitory effect on tumor growth in a variety of AR-dependent prostate cancer transplant tumor models, and can resist resistance to hormone therapy. Therefore, ROR γ is a new target for drug resistance treatment of mCRPC and prostate cancer (Nature Medicine,2016,22 (5), 488-496), and there is a patent disclosing the use of ROR γ inhibitors in tumor therapy (WO 2017127442). ROR γ t has the same sequence as ROR γ in the Ligand Binding Domain (LBD) and only the N-terminal residue is different, so ROR γ t inhibitors also have ROR γ inhibitory activity and can be used for mCRPC and the treatment of drug-resistant prostate cancer.
Dihydroorotate dehydrogenase (DHODH) is a key rate-limiting enzyme in the de novo pyrimidine synthesis pathway, and inhibition of DHODH causes the de novo pyrimidine nucleotide synthesis pathway in cells to be blocked, thereby affecting the over-proliferation of immune cells and cancer cells. DHODH inhibitors have immunomodulatory activity, most pronounced on T cells, while helper T cells 1 (Th 1) and Th17 cells are important contributors in the development of autoimmune diseases. Therefore, DHODH is considered to be an ideal therapeutic target for autoimmune diseases and cancer, etc. For most organisms, pyrimidine bases are available both by de novo synthesis and by salvage synthesis. For resting lymphocytes in the human body, pyrimidine obtained from salvage synthetic pathways is sufficient to meet their metabolic needs, but pyrimidine base needs of immune activated lymphocytes and cancer cells are not sufficiently met by salvage synthetic pathways and de novo synthetic pathways must be initiated to meet their physiological needs. The metabolic stress caused by DHODH inhibition in immune-activated lymphocytes further leads to a reduction in the release of proinflammatory cytokines, including IL-17 (IL-17A and IL-17F) and Interferon (IFN) - γ, and to increased lymphocyte apoptosis. Therefore, the DHODH inhibitor can inhibit DNA or RNA synthesis of immune activated lymphocytes and tumor cells, and play a role in resisting tumors and treating autoimmune diseases; inhibition of proinflammatory cytokine release by DHODH can also be used to treat autoimmune diseases. In addition, pyrimidine synthesis inhibitors represented by DHODH inhibitors have a broad-spectrum inhibitory effect on airway RNA viruses and are involved in host antiviral reactions. In virus-infected cells, rapid viral replication requires large amounts of intracellular nucleotides, and the de novo nucleotide synthesis pathway is critical for viral replication. In contrast to DNA viruses, RNA viruses require unique UMP in their genome, but no TMP. UMP is a specific nucleoside produced by DHODH, which means that RNA viruses may be more sensitive to DHODH activity. Thus, DHODH inhibitors can inhibit viral activity and limit cytokine storm produced in the middle and late stages of viral infection, and are a new direction for the study against novel coronaviruses (COVID-19) (Protein Cell,2020,11 (10), 723-739).
Several DHODH inhibitors have been approved for marketing or are in clinical research. Leflunomide (Leflunomide) has been approved for the treatment of Rheumatoid Arthritis (RA) which is refractory to treatment with methotrexate; the active metabolite teriflunomide (Teriflunomid) of leflunomide has been approved for the treatment of relapsing Multiple Sclerosis (MS). Brequinar (Brequinar) is in clinical secondary studies of relapsed/refractory Acute Myeloid Leukemia (AML) and resistance to the novel coronavirus (COVID-19). Several patents disclose the use of various DHODH inhibitors for the treatment or prevention of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumor diseases, angiogenesis-related diseases, viral diseases and infectious diseases. For example W02009137081, W02009133379, W02009021696, W02009082691, W02009029473, W02009153043, US2009209557, US2009062318, US2009082374, W02008097180, W02008077639, US 27079, US2007299114, US 2008027193, US2007224672, W02007149211, JP 2007015915952, W02006044741, W02006001961, W02006051937, W02038383838606, W02006022442, US2006 199060060060199856, W2007005075410, US7074831, W02004004004056856.
ROR gamma t is a key regulator of Th17 cells, inhibits ROR gamma t, prevents Th17 cells from differentiating, and reduces the production of proinflammatory cytokines IL-17 (IL-17A and IL-17F); DHODH is a rate-limiting enzyme for de novo pyrimidine synthesis, inhibits DHODH, can reduce pyrimidine nucleotide stock, triggers the metabolic inhibition of lymphocytes, and reduces the production of cytokines such as IL-17, IL-6, IL-1 beta, IFN-gamma, TNF alpha and the like. Dual target inhibition of ROR γ t and DHODH may result in stronger or even synergistic anti-inflammatory, anti-infective or anti-tumor effects, thus yielding greater benefit to treatment. Meanwhile, the dual-target inhibition of ROR gamma t and DHODH can also reduce thymic aberration caused by too strong inhibition of ROR gamma t and can reduce side effects caused by too strong inhibition of DHODH. Therefore, the search for small molecule modulators (especially inhibitors) of ROR γ t and/or DHODH and their use in the prevention or treatment of autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, hematologic cancers, malignant diseases, angiogenesis-related diseases, viral diseases and infectious diseases, as well as diseases associated with the death of cellular iron is of great importance.
Disclosure of Invention
In view of the above, the present invention aims to provide a thiazolamine derivative and an application thereof, wherein the thiazolamine derivative has ROR γ t regulation activity and/or DHODH regulation activity, especially inhibition activity, and is used for preparing a medicament for preventing or treating ROR γ t and/or DHODH related diseases.
In a first aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein, the first and the second end of the pipe are connected with each other,
R 1 、R 2 independently selected from H, or substituted or unsubstituted C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 1 -C 8 Alkoxy radical, C 1 -C 8 Hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, or R 1 And R 2 Substituted or unsubstituted ring formed by linking together, the substituents being selected from halogen, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acylAcyloxy or substituted acyloxy, acylamino or substituted acylamino, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, = N-OH, = N-O-C 1 -C 8 Alkyl or-O-C 1 -C 8 An alkyl group;
R 3 selected from H, C 1 -C 8 Alkyl, halogen substituted C 1 -C 8 Alkyl, halogen, cyano, C 1 -C 8 Alkoxy or halogen substituted C 1 -C 8 An alkoxy group;
R 4 selected from H, C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, aryl, aralkyl, haloaryl, or haloaralkyl;
x is selected from CH 2 NH, O; y is selected from N and CH; x and Y are not hetero atoms at the same time;
R 5 、R 6 independently selected from H, C 1 -C 8 Alkyl, or R 5 And R 6 A substituted or unsubstituted three to seven membered ring linked together to form a ring; the three-to seven-membered ring optionally comprising a N, O or S heteroatom, the substituent being selected from C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acyl, acyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
Preferably, R 4 Is H.
Preferably, when X is CH 2 When, Y is N; or when X is O, Y is CH.
Preferably, when R is 5 And R 6 When taken together to form a substituted or unsubstituted six-membered ring, the six-membered ring includes a N, O or S heteroatom, and the N, O or S heteroatom is para to Y, and the substituent is attached to the N, O or S heteroatom and is selected from C 1 -C 8 Alkyl orWherein R is 7 Is selected from C l -C 8 Alkyl, halogen substituted C l -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, halogen substituted C 3 -C 8 Cycloalkyl, or C 3 -C 8 A heterocycloalkyl group.
Preferably, the compound is selected from:
in a second aspect, the present invention also provides a process for the preparation of a compound as described above, characterised in that it can be prepared by the following three synthetic schemes and procedures:
synthesis scheme 1:
reaction conditions are as follows: (a) tert-butyl piperidine-1-carboxylate, acOH, naBH (AcO) 3 ,0℃ to rt,overnight;(b)4N HCl in dioxane,rt,5h;(c)cyclopentanecarbonyl chloride,Et 3 N,DCM,5h;(d)Pd 2 (dba) 3 ,K 3 PO 4 ,various 2-aminothiazol,tBuBrettPhos,tBuOH,120℃,5h。
1) The aldehyde compound shown in the formula 1-1 and amine are subjected to reductive amination reaction under the action of sodium triacetoxyborohydride to obtain a Boc-protected piperazine compound shown in the formula 1-2;
2) Removing a protecting group from the compound shown in the formula 1-2 in a dioxane system of hydrochloric acid, and then reacting with acyl chloride in an alkaline environment to obtain a nitro compound shown in the formula 1-3;
3) The compound represented by the formula 1-3 is represented by Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain the target compound.
Synthesis scheme 2:
the reaction conditions are as follows: (a) NaNO 2 ,H 2 SO 4 ,H 2 O,0℃ to 100℃,2h;(b)tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate,K 2 CO 3 ,DMF,90℃,overnight;(c)4N HCl in dioxane,rt,5h;(d)T3P,4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid,Et 3 N,DCM,rt,overnight;;(e)Pd 2 (dba) 3 ,K 2 CO 3 ,various 2-aminothiazol,tBuBrettPhos,tBuOH,HOAc,110℃,3-5h。
1) Diazotizing and hydroxylating an amine compound shown as a formula 2-1, and carrying out nucleophilic substitution to obtain a Boc-protected piperazine compound shown as a formula 2-2;
2) Removing a protecting group from the compound shown in the formula 2-2 in a dioxane hydrochloride system, and then reacting with acid in a T3P/triethylamine system to obtain a bromobenzene compound shown in the formula 2-3;
3) The compound of formula 2-3 is in Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain the target compound.
Synthesis scheme 3:
reaction conditions are as follows: (a) Pd 2 (dba) 3 ,K 2 CO 3 ,2-amino-6,7-dihydrobenzo[d]thiazol-4(5H)-one,tBuBrettPhos,tBuOH,HOAc,110℃,3-5h;(b)various fatty AmineAcOH,NaBH(OAc) 3 ,0℃ to rt,overnight;
1) The compound represented by the formula 3-1 is in Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain a compound shown as a formula 2-2;
2) The aldehyde compound shown in the formula 3-2 and amine are subjected to reductive amination reaction under the action of sodium triacetoxyborohydride to obtain the target compound.
In a third aspect, the present invention also provides a pharmaceutical composition comprising a compound as described above, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention also provides the use of a pharmaceutical composition as described above in the preparation of a medicament for the prevention or treatment of a disease associated with roryt and/or DHODH, including autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumor diseases, angiogenesis-related diseases, viral diseases and infectious diseases.
Preferably, the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, psoriasis or inflammatory bowel disease; the immune and inflammatory disorders are selected from encephalomyelitis, crohn's disease, or asthma; the malignant tumor disease is selected from prostate cancer, triple negative breast cancer, acute Myelogenous Leukemia (AML) or lung cancer; the viral and infectious diseases are selected from the group consisting of novel coronavirus pneumonia (COVID-19) and infectious atypical pneumonia (SARS).
Drawings
FIG. 1 is a graph showing the activity of the compounds I-29 provided by the present invention in a DSS-induced acute enteritis model.
Detailed Description
The invention provides a compound shown as a formula (I), or pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein the content of the first and second substances,
R 1 、R 2 independently selected from H, substituted or unsubstituted C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl radical, C 1 -C8 alkoxy, C 1 -C 8 Hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, or R 1 And R 2 A substituted or unsubstituted ring formed by linking together, the substituents being selected from halogen, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acyl, acyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, = N-OH, = N-O-C 1 -C 8 Alkyl or-O-C 1 -C 8 An alkyl group;
R 3 selected from H, C 1 -C 8 Alkyl, halogen substituted C 1 -C 8 Alkyl, halogen, cyano, C 1 -C 8 Alkoxy or halogen substituted C 1 -C 8 An alkoxy group;
R 4 selected from H, C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, aryl, haloaryl, or haloaralkyl;
x is selected from CH 2 NH, O; y is selected from N and CH; x and Y are not hetero atoms at the same time;
R 5 、R 6 independently selected from H, C 1 -C 8 Alkyl, or R 5 And R 6 A substituted or unsubstituted three-to seven-membered ring taken together; what is needed isThe three-to seven-membered ring optionally includes a heteroatom of N or O, when the three-to seven-membered ring includes a heteroatom of N or O, the heteroatom of N or O is located para to Y, the substituent is attached to the heteroatom of N or O, and the substituent is selected from C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acyl, acyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
Preferably, R 4 Is H.
Preferably, when X is CH 2 When, Y is N; or when X is O, Y is CH.
Preferably, when R is 5 And R 6 When taken together to form a substituted or unsubstituted six-membered ring, the six-membered ring includes a N or O heteroatom, and the N or O heteroatom is para to Y, and the substituent is attached to the N or O heteroatom and is selected from C 1 -C8 alkyl orWherein R is 7 Is selected from C l -C 8 Alkyl, halogen substituted C l -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, halogen substituted C 3 -C 8 Cycloalkyl, or C 3 -C 8 A heterocycloalkyl group.
The compounds provided by the present invention can be synthesized by the following synthesis scheme 1,2 or 3:
synthesis scheme 1:
reaction conditions are as follows: (a) tert-butyl piperidine-1-carboxylate, acOH, naBH (AcO) 3 ,0℃ to rt,overnight;(b)4N HCl in dioxane,rt,5h;(c)cyclopentanecarbonyl chloride,Et 3 N,DCM,5h;(d)Pd 2 (dba) 3 ,K 3 PO 4 ,various 2-aminothiazol,tBuBrettPhos,tBuOH,120℃,5h。
1) The aldehyde compound shown in the formula 1-1 and amine are subjected to reductive amination reaction under the action of sodium triacetoxyborohydride to obtain a Boc-protected piperazine compound shown in the formula 1-2;
2) Removing a protecting group from the compound shown in the formula 1-2 in a dioxane system of hydrochloric acid, and then reacting with acyl chloride in an alkaline environment to obtain a nitro compound shown in the formula 1-3;
3) The compound represented by the formula 1-3 is represented by Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain the target compound.
Synthesis scheme 2:
reaction conditions are as follows: (a) NaNO 2 ,H 2 SO 4 ,H 2 O,0℃ to 100℃,2h;(b)tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate,K 2 CO 3 ,DMF,90℃,overnight;(c)4N HCl in dioxane,rt,5h;(d)T3P,4,4,4-trifluoro-3-(trifluoromethyl)butanoic acid,Et 3 N,DCM,rt,overnight;;(e)Pd 2 (dba) 3 ,K 2 CO 3 ,various 2-aminothiazol,tBuBrettPhos,tBuOH,HOAc,110℃,3-5h。
1) Diazotizing, hydroxylating and nucleophilic substituting the amine compound shown as the formula 2-1 to obtain a Boc-protected piperazine compound shown as the formula 2-2;
2) Removing a protecting group from the compound shown in the formula 2-2 in a dioxane system of hydrochloric acid, and then reacting with acid in a T3P/triethylamine system to obtain a bromobenzene compound shown in the formula 2-3;
3) The compound represented by the formula 2-3 is represented by Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain the target compound.
Synthesis scheme 3:
reaction conditions are as follows: (a) Pd 2 (dba) 3 ,K 2 CO 3 ,2-amino-6,7-dihydrobenzo[d]thiazol-4(5H)-one,tBuBrettPhos,tBuOH,HOAc,110℃,3-5h;(b)various fatty AmineAcOH,NaBH(OAc) 3 ,0℃ to rt,overnight;
1) The compound represented by the formula 3-1 is represented by Pd 2 (dba) 3 /K 3 PO 4 Buchwald reaction is carried out under the system to obtain a compound shown as a formula 2-2;
2) The aldehyde compound shown in the formula 3-2 and amine are subjected to reductive amination reaction under the action of sodium triacetoxyborohydride to obtain the target compound.
Unless otherwise indicated, the groups, terms, and meanings described in the above synthetic schemes are the same as those in the compounds of formula I. The above synthetic schemes are only examples of the preparation methods of some compounds of the present invention, and those skilled in the art can synthesize the compounds of the present invention by similar methods based on the above synthetic schemes with reference to the means commonly used in the art and the prior art.
The term "compound" as used herein includes all stereoisomers, geometric isomers, tautomers and isotopes.
The "compounds" of the present invention may be asymmetric, e.g., having one or more stereoisomers. Unless otherwise indicated, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the invention containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form; the optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The "compounds" of the present invention also include tautomeric forms; tautomeric forms result from the exchange of one single bond with an adjacent double bond and the concomitant migration of one proton.
The invention also includes all isotopic atoms, whether in the intermediate or final compound; isotopic atoms include those having the same number of atoms but different mass numbers, for example, isotopes of hydrogen include deuterium and tritium. Also, if desired, the compounds of the invention may incorporate isotopes or radioisotopes known in the art, for example for the purpose of particular therapeutic or diagnostic treatment 3 H、 15 O、 13 C or 13 An N isotope.
The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt which improves physicochemical properties or metabolic properties while maintaining the pharmacological activity of the parent compound. Such salts include acid addition salts and base addition salts prepared from pharmaceutically acceptable acids or bases, including organic acids, inorganic acids, organic bases, inorganic bases, or mixtures of both. In the present invention, suitable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; suitable organic acids are, for example, acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, salicylic acid, stearic acid, muconic acid, or the like.
The compounds according to the invention may also be present in the form of their solvates. Such as hydrates (hemihydrate, monohydrate, dihydrate, trihydrate, etc.).
In the present invention, the terms used have the following meanings unless otherwise specified.
The term "halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
The term "amino" refers to the group-NH 2 。
The term "cyano" refers to — CN.
The term "nitro" refers to-NO 2 。
The term "hydroxy" refers to-OH.
The term "mercapto", refers to-SH.
The term "carbonyl" refers to C = O.
The term "carboxy" refers to-C (= O) OH.
The term "carboxylate group" means-C (= O) O (alkyl) or-C (= O) O (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "sulfonyl" refers to-S (= O) 2 (alkyl) or-S (= O) 2 (cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
The term "sulfinyl" refers to-S (= O) (alkyl) or-S (= O) (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
The term "phosphoryl" refers to-P (= O) (OH) 2 。
The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group consisting of carbon atoms and hydrogen atoms, and is a straight or branched chain alkyl (C) group containing 1 to 20 carbon atoms 1 -C 20 Alkyl), preferably C 1 -C 8 Alkyl, more preferably C 1 -C 6 Alkyl groups such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl or tert-butyl), pentyl (including n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl), hexyl (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) and the like; the alkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl, for example to form a haloalkyl group, preferably C 1 -C 6 A haloalkyl group.
The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like; the alkenyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl.
The term "alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., ethynyl, 1-propynyl, 2-propynyl, and the like; the alkynyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl.
The term "alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined above.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro or bridged) cyclic hydrocarbon substituent, and cycloalkyl contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. For example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, spiro [3.4 ]]Octyl, bicyclo [3.1.1]Hexyl and the like. The cycloalkyl group may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl, e.g. to form a halocycloalkyl group, preferably C 3 -C 8 Halogenocycloalkyl, more preferably C 3 -C 6 A halocycloalkyl group.
The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic (fused, spiro, or bridged) cyclic hydrocarbon substituent containing 1 or more heteroatoms of N, O, or S, the heterocycloalkyl containing from 3 to 8 ring atoms of which 1-3 are heteroatoms; preferably containing 3 to 6 ring atoms of which 1-2 are heteroatoms. Typically a 3-6 membered heterocyclic group containing 1 or more heteroatoms of N, O or S, for example, aziridin-1-yl, oxetan-3-yl, azetidin-1-yl, pyrrolidinyl, tetrahydrofuranyl, piperidino, piperazino, morpholino, and derivatives thereof. The heterocycloalkyl group can be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxyl, carboxylate, sulfonyl, sulfinyl, phosphoryl, for example to form a haloheterocycloalkyl group, preferably a haloheterocycloalkyl group containing 3 to 8 ring atoms.
The term "aryl" refers to an all-carbon monocyclic or fused ring having a completely conjugated pi-electron system, typically having 6 to 14 carbon atoms, preferably having 6 to 12 carbon atoms, most preferably having 6 carbon atoms. Aryl groups may be unsubstituted or substituted with one or more substituents including, but not limited to, alkyl, alkoxy, alkylthio, alkylamino, halo, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl. Examples of unsubstituted aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
The term "heteroaryl" refers to a monocyclic or fused ring containing 5-12 ring atoms containing 1-4 ring atoms selected from N, O, S, the remaining ring atoms being C, and having a fully conjugated pi-electron system, including but not limited to pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, triazolyl, tetrazolyl. Heteroaryl groups may be unsubstituted or substituted, and the substituents include, but are not limited to, alkyl, alkoxy, alkylthio, alkylamino, halogen, amino, cyano, nitro, hydroxy, mercapto, aryl, heteroaryl, carbonyl, carboxy, carboxylate, sulfonyl, sulfinyl, phosphoryl.
The term "aralkyl" refers to- (alkyl) - (aryl), wherein alkyl and aryl are as defined above.
The term "heteroaralkyl" refers to- (alkyl) - (heteroaryl), wherein alkyl, heteroaryl are as defined above.
The term "chemical bond" refers to a single, double or triple bond.
The term "heteroatom" refers to an atom other than carbon.
Administration and pharmaceutical compositions
In general, the compounds of the present invention may be administered in an effective amount by any acceptable mode of administration for other similar uses. For example, the compounds of the present invention may be administered orally, parenterally, transdermally, topically, rectally, or intranasally.
When used as a medicament, the compounds of the invention are typically administered in the form of a pharmaceutical composition. These compositions may be prepared by methods well known in the art of pharmacy and comprise at least one active compound. In formulating the compositions provided herein, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed in a container in the form of a capsule, sachet, paper or other form. When used as a diluent, the excipient may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or vehicle for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, sprays (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some typical excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. Additionally, lubricating agents (such as talc, magnesium stearate and mineral oil), wetting agents, emulsifying and suspending agents, preservatives (such as methyl and propyl parabens), sweetening agents and flavoring agents may be included. The pharmaceutical composition of the present invention can achieve rapid, sustained or delayed release of the pharmaceutically active ingredient after administration to a patient by a specific vehicle, which is also a widely used method in the art.
The amount of active ingredient, i.e., a compound of the present invention, in a pharmaceutical composition and unit dosage form may be varied or greatly modified depending upon the particular application, the activity of the particular compound, and the desired concentration.
By "treatment" is meant any treatment of a disease in a mammal, including: (1) Preventing disease, i.e., the symptoms that cause clinical disease do not develop; (2) inhibiting disease, i.e., arresting the development of clinical symptoms; (3) relieving the disease, i.e., causing regression of clinical symptoms.
Examples
The technical solutions of the present invention are further described below with reference to specific examples, but the scope of the present invention is not limited to these examples. All changes, substitutions and equivalents that do not depart from the spirit and scope of the invention are intended to be included within the scope thereof.
In the preparation method of the target compound, the column chromatography adopts silica gel (200-300 meshes) produced by Ningshan Sun drying agent GmbH; thin layer chromatography using GF254; nuclear magnetic resonance chromatography (NMR) was measured using a Varian-400 nuclear magnetic resonance instrument; LC/MS an Agilent technology ESI 6120 LC/MS instrument was used. In addition, all operations involving easily oxidizable or hydrolyzable raw materials were carried out under nitrogen protection. Unless otherwise indicated, the starting materials used in the present invention are all commercially available starting materials and can be used without further purification.
The first embodiment is as follows: general Synthesis of Compounds I-1 to I-26, I-33 to I-34 (FIG. 1, supra)
substituted benzaldehyde 1-1 (1 equivalent), 1-tert-butyloxycarbonyl piperazine (1.1 equivalent), and acetic acid (1.1 equivalent) were dissolved in dichloromethane and reacted with stirring at room temperature for 1 hour. Sodium triacetoxyborohydride (3 equivalents) was then added and the reaction was allowed to proceed overnight at room temperature. After TLC detection reaction is completed, saturated NaHCO is added 3 Quenching the solution for reaction, washing an organic phase by using water and a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure to obtain a crude product 1-2.
the crude product 1-2 is dissolved in dichloromethane, dioxane hydrochloride solution is added, and the reaction is carried out at room temperature overnight. The reaction liquid supernatant was discarded, and the residue was concentrated under reduced pressure. The residue obtained by concentration was dissolved in methylene chloride and triethylamine (3 equivalents), and cyclopentylcarbonyl chloride (1.2 equivalents) was slowly added dropwise and reacted at room temperature overnight. After TLC detection reaction is complete, saturated NaHCO is added 3 Quenching the solution for reaction, washing an organic phase with water and a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain a crude product 1-3.
dissolving the crude product 1-3 in tert-butanol, adding Pd 2 (dba) 3 (0.1 equiv.), tBuBrettPhos (0.3 equiv.), K 3 PO 4 (1.4 equiv.) of the corresponding 2-aminothiazole (1 equiv.) under nitrogen at 110 ℃ overnight, after completion of the TLC detection, the reaction was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography and reverse phase medium pressure preparation system to obtain compounds I-1 to I-26, I-33 to I-34.
The second embodiment:
compound I-1 cyclopentyl (4- (2-methyl-3- (thiazol-2-ylamino) benzyl) piperazin-1-yl) Preparation of ketones
Compound I-1. 1 H NMR(400MHz,DMSO-d6)δ9.19(s,1H),7.63(d,J=7.8Hz,1H),7.16–7.09(m,2H),7.02(d,J=7.3Hz,1H),6.77(d,J=3.6Hz,1H),3.46(s,2H),3.48–3.40(m,4H),3.00–2.90(m,1H),2.39–2.28(m,4H),2.24(s,3H),1.79–1.47(m,8H). 13 C NMR(151MHz,DMSO-d6)δ173.24,166.92,139.98,138.69,137.02,129.82,125.95,125.38,121.55,107.93,60.66,53.16,52.60,44.96,41.32,40.05,39.99,29.57,25.64,13.31.HRMS(ESI + )m/z calcd for C 21 H 28 N 4 OS[M+H] + :385.2057;found:385.2060.
Example three:
preparation of the Compound I-2 cyclopentyl (4- (2-methyl-3- ((5-methylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-2. 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.62(d,J=8.0Hz,1H),7.09(d,J=7.8Hz,1H),6.98(d,J=7.1Hz,1H),6.79(d,J=1.3Hz,1H),3.45(brs,6H),2.93(dd,J=15.5,7.2Hz,1H),2.42–2.27(m,4H),2.27–2.19(m,6H),1.80–1.43(m,8H).HRMS(ESI + )m/z calcd for C 22 H 30 N 4 OS[M+H] + :399.2;found:399.2.
Example four:
preparation of Compound I-3 cyclopentyl (4- (2-methyl-3- ((4-methylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-3. 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.60(d,J=7.7Hz,1H),7.12(t,J=7.8Hz,1H),7.01(d,J=7.0Hz,1H),6.30(d,J=0.9Hz,1H),3.45(brs,6H),3.05–2.85(m,1H),2.41–2.27(m,4H),2.24(s,3H),2.14(s,3H),1.80–1.43(m,8H).HRMS(ESI + )m/z calcd for C 22 H 30 N 4 OS[M+H] + :399.2;found:399.2.
Example five:
preparation of the Compound I-4 cyclopentyl (4- (3- ((4, 5-dimethylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-4. 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.58(d,J=7.8Hz,1H),7.10(t,J=7.8Hz,1H),6.98(d,J=7.1Hz,1H),3.44(brs,6H),3.02–2.87(m,1H),2.33(d,J=17.3Hz,4H),2.22(s,3H),2.14(s,3H),2.05(s,3H),1.80–1.45(m,8H).HRMS(ESI + )m/z calcd for C 23 H 32 N 4 OS[M+H] + :412.2;found:412.3.
Example six:
preparation of the Compound I-5 cyclopentyl (4- (3- ((5-ethylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-5. 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.60(d,J=7.8Hz,1H),7.10(t,J=7.7Hz,1H),6.99(d,J=7.2Hz,1H),6.82(s,1H),3.45(s,6H),2.99–2.89(m,1H),2.64(tt,J=7.5,3.7Hz,2H),2.33(d,J=17.3Hz,4H),2.23(s,3H),1.80–1.46(m,8H),1.17(t,J=7.5Hz,3H).HRMS(ESI + )m/z calcd for C 23 H 32 N 4 OS[M+H] + :412.2;found:412.3.
Example seven:
preparation of the Compound I-6 cyclopentyl (4- (3- ((4-ethylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-6. 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.60(d,J=7.7Hz,1H),7.14(dd,J=16.6,8.9Hz,1H),7.02(d,J=7.0Hz,1H),6.30(s,1H),3.47(s,6H),3.00–2.86(m,1H),2.54–2.45(m,2H),2.35(d,J=16.8Hz,4H),2.24(s,3H),1.81–1.45(m,8H),1.16(t,J=7.5Hz,3H).HRMS(ESI + )m/z calcd for C 23 H 32 N 4 OS[M+H] + :412.2;found:412.3.
Example eight:
preparation of Compound I-7 cyclopentyl (4- (2-methyl-3- ((5-propylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-7. 1 H NMR(400MHz,DMSO-d6)δ9.00(s,1H),7.64(d,J=7.6Hz,1H),7.11(t,J=7.8Hz,1H),7.00(d,J=7.1Hz,1H),6.84(s,1H),3.46(brs,6H),3.01–2.87(m,1H),2.60(t,J=7.2Hz,2H),2.35(d,J=16.7Hz,4H),2.25(s,3H),1.84–1.45(m,10H),0.92(t,J=7.3Hz,3H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 OS[M+H] + :426.3;found:426.3.
Example nine:
preparation of the Compound I-8 cyclopentyl (4- (2-methyl-3- ((4-propylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-8. 1 H NMR(400MHz,DMSO-d6)δ9.12(s,1H),7.61(d,J=7.7Hz,1H),7.12(t,J=7.8Hz,1H),7.01(d,J=7.1Hz,1H),6.30(s,1H),3.46(brs,6H),3.02–2.81(m,1H),2.45(t,J=7.4Hz,2H),2.34(d,J=16.6Hz,4H),2.24(s,3H),1.78–1.47(m,10H),0.90(t,J=7.4Hz,3H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 OS[M+H] + :426.3;found:426.3.
Example ten:
preparation of the Compound I-9 cyclopentyl (4- (3- ((5-isopropylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-9. 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.59(d,J=7.6Hz,1H),7.10(t,J=7.8Hz,1H),6.99(d,J=7.1Hz,1H),6.82(d,J=1.0Hz,1H),3.45(brs,6H),2.98(ddd,J=22.1,14.0,7.5Hz,2H),2.33(d,J=17.1Hz,4H),2.23(s,3H),1.79–1.42(m,8H),1.22(t,J=7.7Hz,6H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 OS[M+H] + :426.3;found:426.3.
Example eleven:
preparation of Compound I-10 cyclopentyl (4- (3- ((4-isopropylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-10. 1 H NMR(400MHz,DMSO-d 6 )δ9.14(s,1H),7.64(d,J=7.8Hz,1H),7.14(t,J=7.8Hz,1H),7.02(d,J=7.2Hz,1H),6.29(d,J=0.5Hz,1H),3.47(brs,6H),2.94(dd,J=15.4,7.4Hz,1H),2.80(dt,J=13.7,6.9Hz,1H),2.36(d,J=16.6Hz,4H),2.26(s,3H),1.80–1.45(m,8H),1.20(d,J=6.9Hz,6H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 OS[M+H] + :426.3;found:426.3.
Example twelve:
preparation of the Compound I-11 cyclopentyl (4- (3- ((4-ethyl-5-methylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-11. 1 H NMR(400MHz,DMSO-d 6 ) 1 H NMR(400MHz,DMSO)δ8.89(s,1H),7.60(d,J=7.9Hz,1H),7.10(t,J=7.8Hz,1H),6.98(d,J=7.1Hz,1H),3.44(brs,6H),2.93(dd,J=15.5,7.3Hz,1H),2.41(q,J=7.5Hz,2H),2.33(d,J=17.7Hz,4H),2.23(s,3H),2.15(s,3H),1.78–1.46(m,8H),1.11(t,J=7.5Hz,3H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 OS[M+H] + :426.3;found:426.3.
Example thirteen:
preparation of the Compound I-12 cyclopentyl (4- (3- ((4- (1-hydroxyethyl) -5-methylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-12. 1 H NMR(400MHz,DMSO-d 6 )δ8.92(s,1H),7.62(d,J=7.9Hz,1H),7.10(t,J=7.8Hz,1H),6.98(d,J=7.1Hz,1H),4.73(d,J=4.5Hz,1H),4.71–4.64(m,1H),3.45(brs,6H),2.93(dd,J=15.5,7.4Hz,1H),2.33(d,J=17.5Hz,4H),2.23(s,6H),1.79–1.47(m,8H),1.33(d,J=6.3Hz,3H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 O 2 S[M+H] + :443.2;found:443.2.
Example fourteen:
preparation of the Compound I-13 cyclopentyl (4- (3- ((5- (1-hydroxyethyl) -4-methylthiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-13. 1 H NMR(400MHz,DMSO-d 6 )δ8.95(s,1H),7.54(d,J=7.9Hz,1H),7.14–7.09(m,1H),7.02(t,J=6.7Hz,1H),5.17(d,J=3.6Hz,1H),4.92–4.82(m,1H),3.41(brs,6H),3.00–2.89(m,1H),2.33(d,J=17.6Hz,6H),2.23(s,4H),1.80–1.46(m,8H),1.29(t,J=6.5Hz,3H).HRMS(ESI + )m/z calcd for C 24 H 34 N 4 O 2 S[M+H] + :443.2;found:443.2.
Example fifteen:
preparation of the Compound I-14 cyclopentyl (4- (2-methyl-3- ((4-phenylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-14. 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),7.89–7.81(m,2H),7.73(d,J=7.8Hz,1H),7.39(t,J=7.6Hz,2H),7.28(t,J=7.3Hz,1H),7.21(s,1H),7.18(t,J=7.8Hz,1H),7.05(d,J=7.2Hz,1H),3.48(s,2H),3.51–3.40(m,4H),3.03–2.89(m,1H),2.41–2.30(m,4H),2.29(s,3H),1.82–1.43(m,8H). 13 C NMR(101MHz,DMSO-d6)δ173.22,166.29,149.97,139.78,137.13,134.68,130.20,128.49,127.37,126.22,125.55,125.47,121.72,102.56,60.63,53.11,52.54,44.95,41.32,30.90,29.54,25.60,13.43.HRMS(ESI + )m/z calcd for C 27 H 32 N 4 OS[M+H] + :461.2370;found:461.2367。
Example sixteen:
preparation of the Compound I-15 cyclopentyl (4- (2-methyl-3- ((5-phenylthiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-15. 1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),7.64(d,J=7.6Hz,1H),7.59(s,1H),7.51–7.45(m,2H),7.36(t,J=7.7Hz,2H),7.23(t,J=7.4Hz,1H),7.17(t,J=7.7Hz,1H),7.08(d,J=7.1Hz,1H),3.48(s,2H),3.51–3.42(m,4H),3.00–2.90(m,1H),2.42–2.31(m,4H),2.29(s,3H),1.80–1.47(m,8H). 13 C NMR(101MHz,DMSO-d6)δ173.22,166.04,139.54,137.17,135.11,132.00,130.47,128.95,126.55,126.42,125.99,125.46,124.92,122.22,60.57,53.13,52.58,44.93,41.31,29.54,25.60,13.32.HRMS(ESI + )m/z calcd for C 27 H 32 N 4 OS[M+H] + :461.2370;found:461.2372。
Example seventeen:
preparation of Compound I-16 cyclopentyl (4- (2-methyl-3- ((4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-16. 1 H NMR(600MHz,DMSO-d6)δ8.95(s,1H),7.60(d,J=7.8Hz,1H),7.11(t,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),3.45(s,2H),3.53–3.37(m,4H),2.99–2.90(m,1H),2.55–2.52(m,2H),2.48–2.43(m,2H),2.39–2.28(m,4H),2.23(s,3H),1.78–1.70(m,6H),1.68–1.47(m,6H). 13 C NMR(151MHz,DMSO-d6)δ173.23,163.31,144.91,140.08,136.89,129.68,125.68,125.31,121.46,115.84,60.67,53.15,52.59,44.95,41.32,40.05,29.57,26.35,25.64,23.11,22.65,22.46,13.32.HRMS(ESI + )m/z calcd for C 25 H 34 N 4 OS[M+H] + :439.2526;found:439.2530。
Example eighteen:
preparation of Compound I-17 cyclopentyl (4- (2-methyl-3- ((5, 6,7, 8-tetrahydro-4H-cycloheptyl [ d ] thiazol-2-yl) amino) benzyl) piperazin-1-yl) methanone
Compound I-17. 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.58(d,J=7.8Hz,1H),7.09(t,J=7.8Hz,1H),6.97(d,J=7.8Hz,1H),3.44(s,2H),3.50–3.39(m,4H),3.00–2.89(m,1H),2.70–2.53(m,4H),2.39–2.27(m,4H),2.22(s,3H),1.81–1.44(m,14H). 13 C NMR(151MHz,DMSO-d6)δ173.24,161.25,149.57,140.28,136.91,129.47,125.53,125.32,121.06,118.96,79.18,60.68,53.15,52.58,44.95,41.31,40.05,39.99,31.43,30.75,29.57,27.93,26.31,25.64,25.13,13.30.HRMS(ESI + )m/z calcd for C 26 H 36 N 4 OS[M+H] + :453.2683;found:453.2693。
Example nineteenth:
preparation of the Compound I-18 cyclopentyl (4- (3- ((5, 6-dihydro-4H-cyclopentyl [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-18. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.62(d,J=7.7Hz,1H),7.11(t,J=7.7Hz,1H),6.99(d,J=7.7Hz,1H),3.45(s,2H),3.53–3.37(m,4H),3.01–2.91(m,1H),2.76–2.53(m,4H),2.42–2.26(m,6H),2.24(s,3H),1.80–1.46(m,8H). 13 C NMR(151MHz,DMSO-d6)δ173.08,169.59,155.66,139.63,136.75,129.39,125.56,125.16,121.29,119.99,79.02,60.52,53.00,52.44,44.80,41.17,39.90,29.41,27.42,26.15,25.81,25.48,13.17.HRMS(ESI + )m/z calcd for C 24 H 32 N 4 OS[M+H] + :425.2370;found:425.2374。
Example twenty:
preparation of Compound I-19 cyclopentyl (4- (3- ((6, 7-dihydro-4H-pyrano [4,3-d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-19. 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.60(d,J=7.8Hz,1H),7.12(t,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),4.55(s,2H),3.87(t,J=5.4Hz,2H),3.45(s,2H),3.53–3.37(m,4H),3.01–2.85(m,1H),2.59–2.53(m,2H),2.41–2.27(m,4H),2.24(s,3H),1.81–1.46(m,8H). 13 C NMR(151MHz,DMSO-d6)δ173.24,164.68,142.80,139.83,137.00,129.93,125.98,125.37,121.74,113.52,79.17,64.59,63.18,60.64,53.16,52.59,44.96,41.32,40.06,29.57,27.28,25.64,13.32.HRMS(ESI + )m/z calcd for C 24 H 32 N 4 O 2 S[M+H] + :441.2319;found:441.2323。
Example twenty one:
preparation of Compound I-20 cyclopentyl (4- (3- ((7-hydroxy-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-20. 1 H NMR(400MHz,DMSO)δ9.16(s,1H),7.54(d,J=7.6Hz,1H),7.14(t,J=7.6Hz,1H),7.05(d,J=7.6Hz,1H),4.29(s,1H),3.47(s,2H),3.51–3.41(m,4H),3.31–3.26(m,3H),3.02–2.88(m,1H),2.40–2.29(m,4H),2.25(s,3H),1.90–1.47(m,12H). 13 C NMR(101MHz,DMSO-d6)δ173.21,165.61,148.16,139.78,137.06,130.52,126.25,125.38,122.26,116.77,72.24,60.56,55.36,53.12,52.55,44.93,41.30,29.54,28.36,26.48,25.59,18.79,13.28.HRMS(ESI + )m/z calcd for C 25 H 34 N 4 O 2 S[M+Na] + :477.2295;found:477.2291。
Example twenty two:
preparation of the Compound I-21 cyclopentyl (4- (3- ((4-hydroxy-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-21. 1 H NMR(400MHz,DMSO-d6)δ8.95(s,1H),7.63(d,J=7.8Hz,1H),7.11(t,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),4.83(d,J=5.6Hz,1H),4.43–4.36(m,1H),3.45(s,2H),3.51–3.41(m,4H),2.99–2.89(m,1H),2.61–2.53(m,1H),2.48–2.40(m,1H),2.39–2.27(m,4H),2.24(s,3H),1.95–1.83(m,4H)(m,1H),1.81–1.44(m,11H). 13 C NMR(101MHz,DMSO-d6)δ173.21,163.40,147.94,140.08,136.86,129.64,125.65,125.28,121.52,119.30,63.12,60.63,53.12,52.56,44.93,41.30,32.13,29.54,25.59,22.73,18.72,13.28.HRMS(ESI + )m/z calcd for C 25 H 34 N 4 O 2 S[M+H] + :455.2475;found:455.2473。
Example twenty three:
preparation of Compound I-22 cyclopentyl (4- (3- ((4-hydroxy-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-22. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.59(d,J=7.7Hz,1H),7.11(t,J=7.7Hz,1H),7.00(d,J=7.7Hz,1H),4.08(t,J=3.6Hz,1H),3.45(s,2H),3.51–3.41(m,4H),3.37(s,3H),2.99–2.88(m,1H),2.63–2.55(m,1H),2.51–2.41(m,1H),2.39–2.27(m,4H),2.24(s,3H),1.99–1.89(m,1H),1.86–1.76(m,1H),1.76–1.44(m,10H). 13 C NMR(101MHz,DMSO-d6)δ173.21,163.53,145.45,139.99,136.98,129.89,125.83,125.32,121.45,120.75,72.59,60.61,56.36,53.11,52.54,44.93,41.30,29.53,28.11,25.59,22.59,18.73,13.30.
Example twenty-four:
preparation of the Compound I-23- ((3- ((4- (cyclopentanecarbonyl) piperazin-1-yl) methyl) -2-methylphenyl) amino) -6, 7-dihydrobenzothiazol-4 (5H) -one
Compound I-23. 1 H NMR(400MHz,DMSO-d6)δ9.38(s,1H),7.61(d,J=7.8Hz,1H),7.15(t,J=7.8Hz,1H),7.06(d,J=7.8Hz,1H),3.45(s,2H),3.51–3.41(m,4H),2.99–2.89(m,1H),2.90(t,J=6.0Hz,2H),2.45(t,J=6.3Hz,2H),2.39–2.27(m,4H),2.25(s,3H),2.12–2.03(m,2H),1.79–1.45(m,8H). 13 C NMR(101MHz,DMSO-d6)δ189.59,173.21,163.36,145.67,142.86,139.33,137.16,130.46,126.53,125.50,122.25,60.54,53.12,52.57,44.93,41.30,37.85,30.91,29.54,25.60,23.67,23.19,22.01,13.91,13.27.HRMS(ESI + )m/z calcd for C 25 H 32 N 4 O 2 S[M+H] + :453.2319;found:453.2321。
Example twenty-five:
preparation of compound I-24- ((3- ((4- (cyclopentanecarbonyl) piperazin-1-yl) methyl) -2-methylphenyl) amino) -5, 6-dihydrobenzothiazol-7 (4H) -one
Compound I-24. 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),7.41(dd,J=6.9,2.2Hz,1H),7.24–7.16(m,2H),3.48(s,2H),3.51–3.39(m,4H),2.99–2.89(m,1H),2.74(t,J=6.1Hz,2H),2.43–2.35(m,2H),2.39–2.27(m,4H),2.24(s,3H),2.07–1.98(m,2H),1.80–1.43(m,8H). 13 C NMR(101MHz,DMSO-d6)δ189.74,173.22,172.30,167.59,138.37,137.69,132.53,128.28,125.87,124.19,118.82,60.30,53.11,52.55,44.91,41.28,36.79,30.91,29.54,26.74,25.60,22.45,22.01,13.91,13.26.HRMS(ESI + )m/z calcd for C 25 H 32 N 4 O 2 S[M+H] + :453.2319;found:453.2323。
Example twenty-six:
preparation of the Compound I-25 (E) -cyclopentyl (4- (3- ((4- (hydroxyimino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-25. 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.16(s,1H),7.78(d,J=7.8Hz,1H),7.11(t,J=7.8Hz,1H),6.99(d,J=7.8Hz,1H),3.45(s,2H),3.51–3.38(m,4H),2.99–2.89(m,1H),2.68(t,J=5.9Hz,2H),2.60(t,J=6.4Hz,2H),2.40–2.28(m,4H),2.25(s,3H),1.90–1.79(m,2H),1.79–1.44(m,8H). 13 C NMR(101MHz,DMSO-d6)δ173.22,163.06,149.22,141.25,139.71,136.85,129.34,125.88,125.74,125.27,121.29,60.65,54.86,53.12,52.56,44.94,41.31,29.54,25.60,22.33,22.12,21.99,13.27.HRMS(ESI + )m/z calcd for C 25 H 33 N 5 O 2 S[M+H] + :468.2428;found:468.2429。
Example twenty-seven:
preparation of the Compound I-26 (E) -cyclopentyl (4- (3- ((4- (methoxyimino) -4,5,6, 7-tetrahydrobenzothiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) methanone
Compound I-26. 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),7.49(d,J=7.7Hz,1H),7.15(t,J=7.7Hz,1H),7.07(d,J=7.7Hz,1H),3.82(s,3H),3.46(s,2H),3.51–3.38(m,4H),3.00–2.87(m,1H),2.66(t,J=6.0Hz,2H),2.59(t,J=6.4Hz,2H),2.40–2.28(m,4H),2.25(s,3H),1.89–1.79(m,2H),1.78–1.45(m,8H). 13 C NMR(101MHz,DMSO-d6)δ173.23,164.24,150.06,140.38,139.74,137.30,131.07,127.42,126.68,125.57,122.51,61.27,60.55,53.14,52.58,44.96,41.33,30.92,29.56,25.61,22.66,22.29,22.03,21.93,13.92,13.29.HRMS(ESI + )m/z calcd for C 26 H 35 N 5 O 2 S[M+H] + :482.2584;found:482.2583。
Example twenty eight: general procedure for Synthesis of Compounds I-27 to I-32 (FIG. 2 above)
at room temperature, 2-methyl-3-bromo-5-chloroaniline (1.0 equivalent) is dissolved in 50% sulfuric acid, sodium nitrite (1.0 equivalent) is added under ice bath, ice bath reaction is carried out for 1 hour, the reaction mixed solution is dripped into boiling 20% sulfuric acid, reflux is carried out for half an hour, after complete reaction, the temperature is reduced to room temperature, ethyl acetate is used for extraction for three times, and spin drying is carried out for the next step. The crude product was taken up in DMF and ((methylsulfonyl) oxy) piperidine-1-carboxylate (2.0 equiv.), potassium carbonate (3.0 equiv.) was added to react overnight at 90 ℃. After the reaction is finished, extracting with ethyl acetate, washing with saturated salt water, filtering, concentrating the filtrate under reduced pressure, pulping the residue with petroleum ether, and filtering to obtain a crude product 2-2.
dissolving the crude product 2-2 in dichloromethane, adding dioxane hydrochloride solution, and reacting at room temperature overnight. The reaction supernatant was discarded, and the residue was concentrated under reduced pressure. The residue obtained by concentration was dissolved in methylene chloride and triethylamine (6 equivalents), and 4, 4-trifluoro-3- (trifluoromethyl) butanoic acid (1.2 equivalents) was slowly added dropwise, followed by dropwise addition of T3P (2.0 equivalents) under ice bath, and reaction at room temperature overnight. After TLC detection reaction is complete, saturated NaHCO is added 3 Quenching the solution for reaction, washing an organic phase by using water and a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, filtering, and concentrating a filtrate under reduced pressure to obtain a crude product 2-3.
dissolving the crude product 2-3 in tert-butanol, adding Pd 2 (dba) 3 (0.1 equiv.), tBuBrettPhos (0.3 equiv.), K 3 PO 4 (1.4 equiv.) of the corresponding 2-aminothiazole (1 equiv.) under nitrogen at 110 ℃ overnight, after completion of the TLC detection, the reaction was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography and reverse phase medium pressure preparation system to obtain compounds I-27 to I-32.
Example twenty-nine:
preparation of Compound I-27- (4- (5-chloro-2-methyl-3- ((4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) phenoxy) piperidin-1-yl) -4, 4-trifluoro-3- (trifluoromethyl) butanone
Compound I-27. 1 H NMR(400MHz,DMSO-d6)δ9.09(s,1H),7.69(s,1H),6.83(d,J=1.6Hz,1H),4.74–4.64(m,1H),4.44–4.29(m,1H),3.81–3.66(m,2H),3.53–3.40(m,2H),3.00(d,J=5.3Hz,2H),2.60–2.53(m,2H),2.07(s,3H),1.99–1.83c(m,2H),1.80–1.71(m,4H),1.70–1.51(m,2H). 13 C NMR(151MHz,DMSO-d6)δ165.20,161.33,155.63,144.95,141.60,130.47,123.99(d,J=281.8Hz),117.38,115.48,112.33,107.98,72.02,43.59(dt,J=55.4,27.6Hz),41.76,30.71,30.03,26.47,26.35,23.02,22.61,22.39,10.21.HRMS(ESI + )m/z calcd for C 24 H 26 ClF 6 N 3 O 2 S[M+H] + :570.1411;found:570.1412。
Example thirty:
preparation of Compound I-28- ((5-chloro-2-methyl-3- ((1- (4, 4-trifluoro-3- (trifluoromethyl) butyryl) piperidin-4-yl) oxy) phenyl) amino) -6, 7-dihydrobenzothiazol-4 (5H) -one
Compound I-28. 1 H NMR(600MHz,DMSO-d6)δ9.47(s,1H),7.74(s,1H),6.92(d,J=1.7Hz,1H),4.75–4.69(m,1H),4.41–4.33(m,1H),3.79–3.68(m,2H),3.51–3.42(m,2H),3.00(d,J=5.4Hz,2H),2.94(t,J=5.9Hz,2H),2.49–2.45(m,2H),2.13–2.06(m,5H),1.98–1.86(m,2H),1.70–1.56(m,2H). 13 C NMR(151MHz,DMSO-d6)δ189.61,165.21,161.41,155.72,145.42,144.12,140.81,130.63,124.02(d,J=279.0Hz),116.27,113.07,108.80,72.08,43.59(dt,J=56.0,28.2Hz),41.77,37.87,30.70,30.01,26.47,23.65,23.18,10.28.HRMS(ESI + )m/z calcd for C 24 H 24 ClF 6 N 3 O 3 S[M+H] + :584.1204;found:584.1209。
Example thirty one:
preparation of Compound I-29- (4- (5-chloro-3- ((4-hydroxy-4, 5,6, 7-tetrahydrobenzothiazol-2-yl) amino) -2-methylphenoxy) piperidin-1-yl) -4, 4-trifluoro-3- (trifluoromethyl) butanone
Compound I-29. 1 H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.71(s,1H),6.84(d,J=1.9Hz,1H),4.91(d,J=5.8Hz,1H),4.74–4.63(m,1H),4.44(dd,J=9.2,4.0Hz,1H),4.42–4.30(m,1H),3.83–3.65(m,2H),3.53–3.40(m,2H),3.00(d,J=5.4Hz,2H),2.66–2.57(m,1H),2.53–2.44(m,1H),2.08(s,3H),1.99–1.83(m,3H),1.81–1.53(m,5H). 13 C NMR(151MHz,DMSO-d6)δ165.20,161.42,155.62,147.85,141.57,130.51,124.00(d,J=279.6Hz),115.50,112.45,108.01,72.02,63.02,43.60(dt,J=56.4,28.2Hz),41.77,32.19,30.95,30.72,30.04,26.47,22.71,22.06,18.61,13.96,10.24.HRMS(ESI + )m/z calcd for C 24 H 26 ClF 6 N 3 O 3 S[M+H] + :586.1360;found:586.1362。
Example thirty-two:
preparation of Compound I-30 and Compound I-31
A pair of enantiomer compound I-30 and compound I-31 can be obtained by preparing compound I-29 through manual HPLC. The compound I-29 has a chiral center and is related to (S) -6, 6-dimethyl-2-phenyl-4, 5,6, 7-tetrahydrobenzo [ d]Oxazol-4-ol is structurally similar. The absolute configurations of the compound I-30 and the compound I-31 can be determined by optical rotation contrast. With reported (S) -6, 6-dimethyl-2-phenyl-4, 5,6, 7-tetrahydrobenzo [ d ]]Oxazol-4-ol ([ alpha ])] D 20.4 +22.4°(c=1.10,CHCl 3 ) Compounds I-31 ([ alpha ]) having the same optical rotation direction] D 20.4 +3.516°(c=1.10,CHCl 3 ) An enantiomer identified as the (S) -configuration; and compound I-30 ([ alpha ])] D 20.4 -3.455°(c=1.10,CHCl 3 ) In the opposite direction to the optical rotation of the above-mentioned reporter compound, should be an enantiomer in the (R) -configuration.
Example thirty-three:
preparation of Compound I-32- (4- (3- ((4-amino-4, 5,6, 7-tetrahydrobenzothiazol-2-yl) amino) -5-chloro-2-methylphenoxy) piperidin-1-yl) -4, 4-trifluoro-3- (trifluoromethyl) butanone
Compound I-32. 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),7.76(s,2H),7.61(s,1H),6.89(s,1H),4.71(s,1H),4.45–4.29(m,1H),4.16(s,1H),3.83–3.64(m,2H),3.46(d,J=8.7Hz,2H),3.00(d,J=5.2Hz,2H),2.63(t,J=10.9Hz,2H),2.08(s,3H),1.99–1.53(m,7H),1.24(s,1H).MS(ESI + )m/z calcd for C 24 H 27 ClF 6 N 4 O 2 S[M+H] + :585.1;found:585.1.
Example thirty-four:
preparation of the Compound I-33- ((4-chloro-3- ((4- (cyclopentylcarbonyl) piperazin-1-yl) methyl) -2-methylphenyl) amino) -6, 7-dihydrobenzothiazol-4 (5H) -one
Compound I-33. 1 H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.78(d,J=8.7Hz,1H),7.31(d,J=8.7Hz,1H),3.67(s,2H),3.43(s,4H),2.95(dd,J=14.0,8.2Hz,3H),2.50–2.45(m,2H),2.41(d,J=17.9Hz,4H),2.36(s,3H),2.15–2.05(m,2H),1.82–1.43(m,8H).MS(ESI + )m/z calcd for C 25 H 31 ClN 4 O 2 S[M+H] + :487.2;found:487.1.
Example thirty-five:
preparation of Compound I-34 (4- (6-chloro-3- ((4-hydroxy-4, 5,6, 7-tetrahydrobenzo [ d ] thiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) (cyclopentyl) methanone
Compound I-34. 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.80(d,J=8.7Hz,1H),7.24(d,J=8.8Hz,1H),4.84(d,J=5.6Hz,1H),4.41(d,J=5.1Hz,1H),3.65(s,2H),3.42(s,4H),3.00–2.89(m,1H),2.59(dt,J=16.1,4.5Hz,1H),2.46(d,J=6.6Hz,1H),2.39(d,J=18.7Hz,4H),2.33(s,3H),1.96–1.43(m,12H).MS(ESI + )m/z calcd for C 25 H 33 ClN 4 O 2 S[M+H] + :489.2;found:489.2.
Example thirty-six: general procedure for Synthesis of Compounds I-35 to I-43 (FIG. 3 above)
dissolving substituted benzaldehyde 1-1 (1 equivalent) in tert-butanol, adding Pd 2 (dba) 3 (0.1 equiv.), tBuBrettPhos (0.3 equiv.), K 3 PO 4 (1.4 equiv.), the corresponding 2-aminothiazole (1 equiv.), reacted at 110 ℃ overnight under nitrogen atmosphere, after TLC to check the reaction was complete, the reaction was diluted with ethyl acetate, the organic phase was washed with water and saturated sodium chloride solution, anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography to obtain crude product 3-2.
crude 3-2-tert-butoxycarbonylpiperazine (1.1 eq) and acetic acid (1.1 eq) were dissolved in dichloromethane and reacted with stirring at room temperature for 1 hour. Sodium triacetoxyborohydride (3 equivalents) was then added and the reaction was allowed to proceed overnight at room temperature. After TLC detection reaction is complete, saturated NaHCO is added 3 Quenching the solution, washing the organic phase with water and saturated sodium chloride solution, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying by silica gel column chromatography and reverse phase medium pressure preparation system to obtain compounds I-35 to I-43.
Example thirty-seven:
preparation of Compound I-35- (4- (6-chloro-3- ((4-hydroxy-4, 5,6, 7-tetrahydrobenzothiazol-2-yl) amino) -2-methylbenzyl) piperazin-1-yl) ethan-1-one
Compound I-35. 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.80(d,J=8.8Hz,1H),7.24(d,J=8.8Hz,1H),4.85(d,J=5.5Hz,1H),4.41(d,J=5.1Hz,1H),3.65(s,2H),3.36(d,J=9.0Hz,4H),2.59(dt,J=16.1,4.7Hz,1H),2.47(d,J=6.0Hz,1H),2.44–2.34(m,4H),1.97(s,3H),1.89(ddd,J=14.3,10.1,5.8Hz,1H),1.78–1.64(m,3H).MS(ESI + )m/z calcd for C 21 H 27 ClN 4 O 2 S[M+H] + :435.2;found:435.2.
Example thirty-eight:
preparation of Compound I-36- ((4-chloro-3- (isoindol-2-ylmethyl) -2-methylphenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-36. 1 H NMR(400MHz,DMSO-d6)δ9.04(s,1H),7.82(d,J=8.8Hz,1H),7.27(d,J=8.8Hz,1H),7.25–7.14(m,4H),4.85(d,J=5.6Hz,1H),4.41(dd,J=9.2,4.1Hz,1H),4.0 5(s,2H),3.89(s,4H),2.59(dt,J=16.1,4.7Hz,1H),2.49–2.41(m,1H),2.35(s,3H),1.96–1.62(m,4H).MS(ESI + )m/z calcd for C 23 H 24 ClN 3 OS[M+H] + :425.1;found:425.2.
Example thirty-nine:
preparation of Compound I-37- ((4-chloro-2-methyl-3- (piperidin-1-ylmethyl) phenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-37. 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),7.75(d,J=8.7Hz,1H),7.21(d,J=8.7Hz,1H),4.84(d,J=5.5Hz,1H),4.40(dd,J=9.2,4.2Hz,1H),3.57(s,2H),2.58(dt,J=16.1,4.6Hz,1H),2.49–2.33(m,5H),2.31(s,3H),1.88(ddd,J=14.4,9.8,5.7Hz,1H),1.80–1.63(m,3H),1.49–1.31(m,6H).MS(ESI + )m/z calcd for C 20 H 26 ClN 3 OS[M+H] + :392.2;found:392.2.
Example forty:
preparation of Compound I-38- ((4-chloro-2-methyl-3- (pyrrolidin-1-ylmethyl) phenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-38. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.77(d,J=8.7Hz,1H),7.23(d,J=8.7Hz,1H),4.86(d,J=5.5Hz,1H),4.41(dd,J=9.2,4.2Hz,1H),3.55(s,2H),2.57(dt,J=16.1,4.6Hz,1H),2.49–2.33(m,5H),2.32(s,3H),1.89(ddd,J=14.4,9.8,5.7Hz,1H),1.80–1.62(m,3H),1.49–1.31(m,4H).MS(ESI + )m/z calcd for C 19 H 24 ClN 3 OS[M+H] + :378.1;found:378.1.
Example forty one:
preparation of Compound I-39-2- ((4-chloro-3- ((dimethylamino) methyl) -2-methylphenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-39. 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.77(d,J=8.8Hz,1H),7.23(d,J=8.8Hz,1H),4.85(d,J=5.6Hz,1H),4.41(dd,J=9.2,4.2Hz,1H),3.54(s,2H),2.59(dt,J=16.0,4.6Hz,1H),2.49–2.41(m,1H),2.30(s,3H),2.17(s,6H),1.95–1.84(m,1H),1.79–1.72(m,2H),1.72–1.63(m,1H).MS(ESI + )m/z calcd for C 17 H 22 ClN 3 OS[M+H] + :352.1;found:352.1.
Example forty two:
preparation of Compound I-40- ((4-chloro-2-methyl-3- (morpholinomethyl) phenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-40. 1 H NMR(400MHz,DMSO-d6)δ9.03(s,1H),7.78(d,J=8.8Hz,1H),7.23(d,J=8.8Hz,1H),4.84(d,J=5.6Hz,1H),4.40(dd,J=9.2,4.2Hz,1H),3.63(s,2H),3.56–3.46(m,4H),2.59(dt,J=16.0,4.7Hz,1H),2.47(d,J=6.0Hz,1H),2.44–2.38(m,4H),2.32(s,3H),1.95–1.82(m,1H),1.75(dd,J=9.7,5.4Hz,2H),1.72–1.64(m,1H).MS(ESI + )m/z calcd for C 19 H 24 ClN 3 O 2 S[M+H] + :394.1;found:394.1.
Example forty-three:
preparation of Compound I-41- (4-chloro-2-methyl-3- (piperazin-1-ylmethyl) phenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-41. 1 H NMR(400MHz,DMSO-d6)δ9.02(brs,2H),7.77(d,J=8.8Hz,1H),7.22(d,J=8.8Hz,1H),4.84(d,J=5.6Hz,1H),4.40(d,J=5.0Hz,1H),3.61(s,2H),2.58(dt,J=16.2,4.7Hz,1H),2.49–2.36(m,5H),2.28(d,J=17.9Hz,7H),1.88(dt,J=19.3,7.5Hz,1H),1.78–1.64(m,3H).MS(ESI + )m/z calcd for C 19 H 25 ClN 4 OS[M+H] + :393.1;found:393.1.
Example forty-four:
preparation of Compound I-42- ((4-chloro-2-methyl-3- ((4-methylpiperazin-1-yl) methyl) phenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-42. 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.78(d,J=8.8Hz,1H),7.23(d,J=8.8Hz,1H),4.85(d,J=5.6Hz,1H),4.41(d,J=5.0Hz,1H),3.60(s,2H),2.57(dt,J=16.2,4.7Hz,1H),2.50–2.35(m,5H),2.27(d,J=17.9Hz,7H),2.12(s,3H),1.87(m,1H),1.78–1.64(m,3H).MS(ESI + )m/z calcd for C 20 H 27 ClN 4 OS[M+H] + :407.2;found:407.2.
Example forty-five:
preparation of Compound I-43- ((4-chloro-3- ((4-isopropylpiperazin-1-yl) methyl) -2-methylphenyl) amino) -4,5,6, 7-tetrahydrobenzo [ d ] thiazol-4-ol
Compound I-43. 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),7.76(d,J=8.8Hz,1H),7.22(d,J=8.7Hz,1H),4.84(d,J=5.5Hz,1H),4.40(dd,J=9.0,4.1Hz,1H),3.60(s,2H),2.58(dd,J=11.9,5.2Hz,2H),2.49–2.32(m,9H),2.30(s,3H),1.88(ddd,J=14.3,10.0,5.6Hz,1H),1.75(dd,J=9.7,5.3Hz,2H),1.71–1.62(m,1H),0.93(d,J=6.5Hz,6H).MS(ESI + )m/z calcd for C 22 H 31 ClN 4 OS[M+H] + :435.2;found:435.2.
Example forty-six: assay for determining the inhibitory Activity of Compounds on ROR Gamma t at cellular level
The compounds of the invention, I-1, I-11 to I-32, were tested for their inhibitory activity at the cellular level against ROR γ t using ROR γ t GAL 4. The inhibitory activity was expressed as half Inhibitory Concentration (IC) 50 ) To indicate.
The luciferase reporter system is a reporter system for detecting luciferase activity using luciferin as a substrate. The principle is that the coding sequence of the luciferin reporter gene and the gene expression regulating sequence are fused to form a chimeric gene, thereby the transcription and the expression are carried out under the control of the regulating sequence, and then the expression condition of the target gene is calibrated by utilizing the condition that the expressed luciferase decomposes the substrate.
The experimental method comprises the following steps:
(1) preparing cells: 293T cells were passaged on 6cm plates and cultured under DMEM +10% FBS.
(2) Plasmid transfection: ROR-GAL4 and pGL4.31 are 2 μ g and transfection reagent is 10 μ L, and the transfection reagent is diluted with 50 μ L DMEM, mixed uniformly, incubated for 30min, and then dropped into 6cm plates.
(3) Cell plating, cell counting after 4.5h, plating on a 96-well plate, 5 ten thousand cells per well, 100. Mu.L of culture medium.
(4) Cell dosing: after 20h, the test compounds were diluted with DMEM +15% FBS, and 100. Mu.L of the corresponding diluted compounds were added per well.
(5) Fluorescence detection: luciferase reporter gene was detected after 24 h. And (3) diluting the lysate: 50. Mu.L of each well, the total amount of lysis solution required was calculated to be 96X 50=4.8 mL-5 mL of commercially available Passive solutions buffer as 5X solution for 96 wells, and therefore 1mL of mother liquor was required, diluted with 4mL of ultrapure water, and the mixed solution tank was shaken gently and uniformly. The cells were removed from the cell chamber, the culture medium was discarded, the cells were rinsed 1 time with pre-cooled PBS, PBS was aspirated off, 50. Mu.L of lysate was added to each well and shaken well, and the cells were lysed on ice for 20 minutes. Preparing a kit, taking out cells on ice after 20 minutes, placing the cells on a micro-oscillator for oscillation, fully suspending the cells, adding 50 mu L of lysate into a 96-hole white plate, adding a firefly luminescent agent Dual-Glo into each hole in a dark place, incubating for 10min, and detecting the activity of the firefly luciferase by using a chemiluminescence system of a microplate reader (Synergy 2). mu.L of Dual-Glo stop & Glo reagent was added to each well in the dark, and the wells were read after incubation for 10min (with the current formulation of RLA: RLAbuffer = 1.
(6) Data processing:
luciferase activity calculations are the luciferase activity in each sample divided by the renilla luciferase activity used to correct for differences in transfection efficiency. Relative luciferase activity is the activity of the luciferase in the sample compared to the DMSO blank value, and inhibition ratio is calculated by the following formula:
to verify the transfection efficiency of this system, we tested the positive compound T0901317, the inhibitory IC of T0901317 in this system 50 It was 0.81. Mu.M. In some references, IC in full-length ROR gamma t luciferase reporter gene experiments 50 At 1.7. Mu.M. The determination result shows that the compound of the invention has better inhibitory activity to ROR gamma protein receptor (shown in Table 1).
TABLE 1 ROR gamma GAL4 cell Activity test results for example Compounds
The inhibition rate is the average value of at least two independent tests
Inhibition rate value: * Denotes 0.50. Mu.M.gtoreq.IC 50 (ii) a * Denotes 5.0. Mu.M.gtoreq.IC 50 >0.50 μ M; * Denotes 10.0. Mu.M ≧ IC 50 >5.0 mu M; * Presentation IC 50 >10.0μM
The above experimental results show that R 1 And R 2 Whether independently selected from alkyl or substituted alkyl, alkoxy, cycloalkyl, and the like, or linked together to form a substituted or unsubstituted ring, provided that R 5 And R 6 Are linked together to form a substituted six-membered ring containing the N atom, and the N atom is para to Y, said substituent being attached to said N heteroatom, said substituent being selected from the group consisting ofThe resulting compounds then have very good ROR γ t inhibitory activity, most of the compounds ROR γ GAL4IC 50 <0.5μM(****)。
Example forty-seven: assay for the inhibitory Activity of Compounds on DHODH in vitro
The DCIP method was used to determine the DHODH inhibitory activity of the compounds I-1, I-11 to I-43 of the present invention. The inhibitory activity was measured using half Inhibitory Concentration (IC) 50 ) To indicate.
The experimental method comprises the following steps: DCIP method
DCIP, 2, 6-dichloroindophenol sodium, has a specific absorbance at 600nm, coQ when the substrate dihydroorotic acid (DHO) is catalytically dehydrogenated by hDHODH 0 While being reduced, DCIP is oxidized as a final electron acceptor instead of the respiratory chain, and the amount of DCIP originally in the reaction system is reduced, so that the absorption value at 600nm is also reduced. Therefore, the change rate of the absorption value can reflect the magnitude of the enzyme activity and the strength of the inhibitory activity of the compound. The greater the rate of change, the more vigorous the redox reaction, the stronger the enzymatic activity, and the weaker the inhibitory activity of the opposite compound.
The purified HsDHODH protein was diluted to 10nM with an activity test solution of 50mM HEPES pH 8.0, 150mM KCl,0.1% Triton X-100. Adding CoQ 0 And DCIP to final concentrations of 100. Mu.M and 120. Mu.M, respectively. After mixing, the mixture is arranged in a gun and added into a 96-pore plate, after incubation for 5min at room temperature, a substrate DHO is added to start reaction, and the final concentration of DHO is 500 mu M. Absorbance at 600nm was measured using a BioTek microplate reader, and read every 30s for 6min. Calculating the initial velocity V0 of the enzymatic reaction, adding inhibitors with different concentrations into the reaction system for the activity test of the inhibitors, calculating the initial velocity Vi of the enzymatic reaction, and calculating the inhibition rate of the compound by the formula (1-Vi/V0) multiplied by 100%. In the calculation of the IC50 of the compounds, the inhibition was tested at least 8 concentrations, and the IC50 value was calculated using Origin 8.0. A77 1726 is used as a positive control during the experiment, and at least three replicates are set in each experiment. The test results show that the compound of the invention has better inhibitory activity on DHODH (shown in Table 2).
TABLE 2 DHODH inhibitory Activity test results for the example Compounds
The inhibition rate is the average value of at least two independent tests
Inhibition rate value: * 0.50. Mu.M.gtoreq.IC 50 (ii) a * Denotes 5.0. Mu.M.gtoreq.IC 50 >0.50 μ M; * Denotes 10.0. Mu.M.gtoreq.IC 50 >5.0 mu M; * Presentation IC 50 >10.0μM
The above experimental results show that when R is 1 And R 2 When taken together to form a substituted or unsubstituted ring, whether R is 5 、R 6 Independently selected from H, C 1 -C 8 Alkyl, or R 5 And R 6 A substituted or unsubstituted three to seven membered ring linked together to form a ring; the three-to seven-membered ring optionally comprising a N, O or S heteroatom, the substituent being selected from C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, hydroxy, amino or substituted amino, cyano, nitro, carboxyl, acyl or substituted acylAcyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl. The obtained compounds have good DHODH inhibitory activity, and most of the compounds have DHODH IC 50 <5.0μM(***)。
Combining the results of two experiments, part of the compounds provided by the invention have ROR gamma t and DHODH double-target inhibition activity, and ROR gamma GAL4IC 50 Less than or equal to 5.0 mu M and DHODH inhibitory activity IC 50 Less than or equal to 5.0 mu M is a standard of higher activity, and the high-activity ROR gamma t and DHODH double-target inhibitor comprises compounds I-11, I-16, I-17, I-18, I-21, I-22, I-23, I-24, I-27, I-28, I-29, I-30 and I-31.
Example forty-eight: in vivo assay of the Effect of Compounds in a model of DSS-induced acute enteritis
For compound I-29 of the present invention, the in vivo activity of the compound was determined using a Dextran Sodium Sulfate (DSS) induced acute enteritis model.
There is a large body of data demonstrating the etiology, clinical symptoms, and pathological changes of DSS-induced colitis modelsBoth variable and therapeutic responses are similar to human Ulcerative Colitis (UC). DSS is a polyanionic derivative of dextran formed by esterification of dextran and chlorosulfonic acid and has a molecular formula of (C) 6 H 7 Na 3 O 14 S3) n MW:36000 to 50000, and the sulfur content is generally 17 to 20 percent. DSS is often used to induce colitis models, although the mechanism of induction is not clear. The current research mainly considers that DSS increases intestinal permeability, destroys intestinal mucosal barrier, up-regulates certain cytokines (tumor necrosis factor, interleukin, interferon, IL-10 and IL-12), activates certain pathways (NF-kB pathway and TRPV1 pathway) or is related to the imbalance of intestinal flora and the like.
Acute colitis was induced in male C57BL/6 by oral administration of 2.5% (wt/vol) DSS in water (days 1-5). Compound I-29 was dissolved in an aqueous solution containing 0.5% sodium carboxymethylcellulose and administered orally from day 1 to day 10. The blank and IBD groups were also given an equal volume of solvent control. The blank group was given normal drinking water for 10 days until sacrifice.
After administration of 2.5% dss-containing drinking water, mice exhibited acute clinical symptoms including anorexia, weight loss, diarrhea, and severe bloody stools. Compared to the IBD group, oral compound I-29 dose-dependently reduced body weight loss and decreased Disease Activity Index (DAI) (fig. 1D). At the end of the treatment period, the administration of compound I-29 significantly attenuated the shortening of colon length in the acute colitis model, measured as the length of the colon (fig. 1B-C). Histopathological analysis, which indirectly reflects the degree of colonic inflammation, showed that severe pathological changes, mainly including crypt necrosis, significant inflammatory infiltration and mucosal injury, occurred in the DSS-induced colitis mouse model (fig. 1E), and compound I-29 significantly ameliorated the symptoms of acute enteritis.
In conclusion, the results of the ROR γ GAL4 cell assay show that the 2-aminothiazole derivatives of the present invention can effectively inhibit ROR γ t activity. The result of an experiment on the inhibition activity of DHODH shows that the 2-aminothiazole derivative can effectively inhibit the DHODH activity. The animal activity data of the compound I-29 indicate that the 2-aminothiazole derivatives of the invention can effectively relieve autoimmune diseases represented by inflammatory bowel diseases. The 2-aminothiazole derivative can effectively inhibit ROR gamma T activity and DHODH activity, thereby inhibiting the proliferation of lymphocytes, the differentiation of Th17 cells and the amplification and activation of T cells, and can be further used as a therapeutic drug for treating ROR gamma T and/or DHODH mediated inflammation, autoimmune diseases, cancer, virus infection and other related diseases.
Claims (9)
1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
R 1 、R 2 independently selected from H, or substituted or unsubstituted C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl radical, C 3 -C 8 Heterocycloalkyl, C 1 -C 8 Alkoxy radical, C 1 -C 8 Hydroxyalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, or R 1 And R 2 A substituted or unsubstituted ring formed by linking together, the substituents being selected from halogen, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acyl, acyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl, = N-OH, = N-O-C 1 -C 8 Alkyl or-O-C 1 -C 8 An alkyl group;
R 3 selected from H, C 1 -C 8 Alkyl, halogen substituted C 1 -C 8 Alkyl, halogen, cyano, C 1 -C 8 Alkoxy or halogen substituted C 1 -C 8 An alkoxy group;
R 4 selected from H, C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, aryl, aralkyl, haloaryl, or haloaralkyl;
x is selected from CH 2 NH, O; y is selected from N and CH; x and Y are not hetero atoms at the same time;
R 5 、R 6 independently selected from H, C 1 -C 8 Alkyl, or R 5 And R 6 A substituted or unsubstituted three-to seven-membered ring taken together; the three-to seven-membered ring optionally comprising a N, O or S heteroatom, the substituent being selected from C 1 -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, C 3 -C 8 Heterocycloalkyl, hydroxy, amino or substituted amino, cyano, nitro, carboxy, acyl or substituted acyl, acyloxy or substituted acyloxy, amido or substituted amido, aryl or substituted aryl, aryloxy or substituted aryloxy, heteroaryl or substituted heteroaryl, heterocyclyl or substituted heterocyclyl.
2. A compound of claim 1, wherein R is 4 Is H.
3. The compound of claim 1, wherein when X is CH 2 When, Y is N; or when X is O, Y is CH.
4. A compound according to claim 1 or 2, wherein when R is 5 And R 6 When taken together to form a substituted or unsubstituted six-membered ring, the six-membered ring includes a N, O or S heteroatom, and the N, O or S heteroatom is para to Y, and the substituent is attached to the N, O or S heteroatom and is selected from C 1 -C 8 Alkyl orWherein R is 7 Is selected from C l -C 8 Alkyl, halogen substituted C l -C 8 Alkyl radical, C 3 -C 8 Cycloalkyl, halogen substituted C 3 -C 8 Cycloalkyl, or C 3 -C 8 A heterocycloalkyl group.
7. a pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable carrier.
8. Use of the pharmaceutical composition of claim 7 for the preparation of a medicament for the prevention or treatment of diseases associated with roryt and/or DHODH, including autoimmune diseases, immune and inflammatory diseases, destructive bone diseases, malignant tumor diseases, angiogenesis-related diseases, viral diseases, and infectious diseases.
9. Use according to claim 8, wherein the autoimmune disease is selected from multiple sclerosis, rheumatoid arthritis, psoriasis or inflammatory bowel disease; the immunological and inflammatory diseases are selected from encephalomyelitis, clonal disease or asthma; the malignant tumor disease is selected from prostate cancer, triple negative breast cancer, acute Myelogenous Leukemia (AML) or lung cancer; the viral and infectious diseases are selected from the group consisting of novel coronavirus pneumonia (COVID-19) and infectious atypical pneumonia (SARS).
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