CN110511213A - A kind of immunomodulator - Google Patents

A kind of immunomodulator Download PDF

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CN110511213A
CN110511213A CN201910429679.9A CN201910429679A CN110511213A CN 110511213 A CN110511213 A CN 110511213A CN 201910429679 A CN201910429679 A CN 201910429679A CN 110511213 A CN110511213 A CN 110511213A
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yuan
compound
alkyl
naphthenic base
preparation
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CN110511213B (en
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李进
张登友
白晓光
张维熙
尚巳耘
钟猛
潘垒昌
陈伟
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Chengdu Pioneer Drug Development Co Ltd
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Abstract

The invention discloses a kind of immunomodulators, and in particular to one kind inhibits the compound of IL-17A and its purposes as immunomodulator in medicine preparation.The invention discloses Formulas I compounds represented or its stereoisomer or its pharmaceutically acceptable salt to inhibit the purposes in IL-17A class drug in preparation, provides a kind of new selection clinically to screen and/or preparing the drug of disease relevant to IL-17A activity.

Description

A kind of immunomodulator
Technical field
Purposes the present invention relates to a kind of immunomodulator and its in medicine preparation.
Background technique
IL-17 (Interleukin-17) is pro-inflammatory cytokine, in induction other inflammatory cytokines, chemotactic factor (CF) It plays a role in adhesion factor.IL-17 family is made of the cell factor that participation acute and chronic inflammation reacts, including IL- 17A (CTLA-8), IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F.IL-17A is expressed by TH17 cell, It participates in inflammation and the pathology of autoimmune disease occurs.Mankind IL-17A is the sugared egg that molecular weight is about 17000 dalton It is white.IL-17A transmits signals to intracellular (Wright, et by IL-17 receptor complex (IL-17RA and IL-17RC) al.Journal of immunology,2008,181:2799-2805).The major function of IL-17A is by proinflammatory and thermophilic The property granulocyte migrating cell factor and chemotactic factor (CF) (including IL-6, G-CSF, TNF-α, IL-1, CXCL1, CCL2, CXCL2) On transfer Coordinating Bureau's portion's tissue inflammation and matrix metalloproteinase to allow the T cell penetrating cell epimatrix activated.It grinds Study carefully and show that IL-17A plays a significant role in Severe Asthma and Chronic Obstructive Pulmonary Disease (COPD), those patients are usually to mesh Preceding available drug without respond or respond it is bad (Al-Ramli et al.J Allergy Clin Immunol, 2009,123: 1185-1187).The up-regulation of IL-17A level is related to purulence in many diseases, including rheumatoid arthritis (RA), bone erosion, peritonaeum Swollen, inflammatory bowel disease, allograft rejection reaction, psoriasis, atherosclerosis, asthma and multiple sclerosis (Gaffen,SL et al.Arthritis Research&Therapy,2004,6:240-247)。
The combination of targeting IL-17A and IL-17RA is to treat the effective plan for the autoimmune inflammatory disease that IL-17A is mediated Slightly.Treat animal by IL-17A neutralizing antibody reduces disease incidence and seriousness in Autoimmune Encephalomyelitis (Komiyama Y et al.J.Immunol.,2006,177:566-573).The clinical test of existing IL-17A antibody is in IL- In the inflammatory disease (including asthma, psoriasis, rheumatoid arthritis, ankylosing spondylitis and multiple sclerosis) that 7A is mediated Show good result.IL-17A antibody (Cosentyx/secukinumab of Novartis) is in January, 2015 by FDA Approval is used for psoriasis treatment.
Despite the presence of a variety of IL-17A antibody, but few small molecules to the IL-17 with oral administration biaavailability are special Specific inhibitor is studied.In view of the limitation for the cost consideration and administration route for generating antibody, exploitation IL-17A small molecule suppression Preparation medicine has good Prospect of R & D.
Summary of the invention
The present invention provides Formulas I compound represented or its stereoisomers or its pharmaceutically acceptable salt:
Wherein,
X is selected from O, S, NR1’；
R1、R2It is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 yuan it is miscellaneous Naphthenic base, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics ,-S (O)2R6、-S(O)R6、-S(O)2NR6R7、-S(O)NR6R7、-C(O) R6、-C(O)OR6、-C(O)NR6R7、-P(O)(OR7)R6、-P(O)R6R7、-P(O)R6(NR6R7)、-P(O)(NR6R7)(NR6R7)、- P(O)(OR7)(NR6R7)、P(O)(OR7)(OR7)；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic By m RcReplace；
R6、R7It is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 yuan it is miscellaneous Naphthenic base, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, virtue are miscellaneous Ring is by m RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd、-SRd、-NRdRd, halogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3 ~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings；Wherein Rd, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle alkane Base, aromatic ring are by m RcReplace；Alternatively, R3And R3’Connect into 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；
RdSelected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~ 10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；
B ring is selected from 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Its middle ring Alkyl, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R1’Selected from hydrogen, C1~10Alkyl；
L1It is selected from
R is 0,1,2,3；
R8And R9It is independently chosen from hydrogen, halogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3 ~10 yuan of Heterocyclylalkyl；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl are by m RcReplace；
Alternatively, R8And R9Be connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan it is miscellaneous Aromatic ring；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace；
L2Selected from-C (O) NR10-、-NR10C(O)-、-C(O)-、-C(O)O-、-S(O)2NR10-、-S(O)NR10-、-NR10S (O)2-、-NR10S(O)-、-P(O)NR10-、-NR10P (O)-or nothing；
R10Selected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, Middle alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl are by m RcReplace；
R4And R5It is independently chosen from hydrogen, halogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~ 10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics ,-CN ,-NO2、-ORa、-OC(O)Ra、-OC(O)NRaRb、-OS (O)2Ra、-SRa、-S(O)2Ra、-S(O)2NRaRb、-OS(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、- NRaC(O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-NRaS(O)2Rb、-NRaS(O)2NRaRb；Wherein Ra、Rb, alkyl, alkene Base, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；Wherein naphthenic base, Heterocyclylalkyl quilt M RcReplace；
X1Selected from CR11Or N；
X2Selected from NR12, O, S or-(CR13=CR14)-；
X4Selected from N or CH；
R11Selected from hydrogen, halogen ,-CN ,-NO2、C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, C1~10Halogenalkyl, 3~10 The naphthenic base of member, 3~10 yuan of Heterocyclylalkyl ,-ORa、-NRaRb；
R12Selected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 yuan of heterocycle alkane Base ,-S (O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb；
R13、R14It is independently chosen from hydrogen, halogen ,-CN ,-NO respectively2、C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, C1~10Halogen Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl ,-ORa、-NRaRb；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl is by m RcReplace；
M is 0,1,2,3,4；
Ra、RbIt is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl ,-S (O)2Rd、-S(O)Rd、-P(O)2Rd、-P(O)Rd, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Wherein, alkyl, Alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace；
RcIt is independently chosen from C respectively1~10Alkyl ,=S ,=O, halogen ,-CN ,-NO2、-ORa、-OC(O)Ra、-OS(O)2Ra、- SRa、-S(O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb、 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics, wherein alkyl, 3~10 yuan of cycloalkanes Base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics are by 0~3 C1~10Alkyl, halogen ,-NRaRb、- ORd、-C(O)NRaRb, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics replace.
Further,
R1、R2It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of virtues Ring, 5~10 yuan of heteroaromatics ,-S (O)2R6、-S(O)R6、-S(O)2NR6R7、-C(O)R6、-C(O)OR6、-C(O)NR6R7；Wherein alkane Base, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R6、R7It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of virtues Ring, 5~10 yuan of heteroaromatics；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd, halogen, C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5 ~10 yuan of aromatic rings；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring are by m RcReplace；Alternatively, R3And R3’Connect into 3~10 yuan Naphthenic base；
RdSelected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~ 10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；
R8And R9It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl； Wherein alkyl, naphthenic base, Heterocyclylalkyl are by m RcReplace；
Alternatively, R8And R9Be connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan it is miscellaneous Aromatic ring；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring can be further by m RcReplace；
R10Selected from hydrogen, C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, wherein alkyl, naphthenic base, heterocycle Alkyl is by m RcReplace；；
R4And R5It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl, 6 ~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics ,-CN ,-NO2、-ORa、-OC(O)Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、- NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaS(O)2Rb、-NRaS(O)2NRaRb、-S(O)2Ra、-S(O)2NRaRb；Wherein Alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl；Wherein naphthenic base, heterocycle alkane Base is by m RcReplace；
R11Selected from hydrogen, halogen, C1~6Alkyl；
R12Selected from hydrogen, C1~6Alkyl；
R13、R14It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, C2~6Alkenyl；Wherein alkyl, alkenyl are by m RcReplace；
M is 0,1,2,3；
Ra、RbIt is independently chosen from hydrogen, C respectively1~6Alkyl, C2~6Alkenyl, C2~6Alkynyl ,-S (O)2Rd、-S(O)Rd、-P(O)2Rd、-P(O)Rd3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Wherein, alkyl, Alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace.
Further,
R1、R2It is independently chosen from hydrogen ,-S (O) respectively2R6、-S(O)R6、-S(O)2NR6R7、-C(O)R6、-C(O)OR6、-C(O) NR6R7；
R6、R7It is independently chosen from hydrogen, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan respectively Heteroaromatic；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd、C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 First aromatic ring；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring are by m RcReplace；Alternatively, R3And R3’Connect into 3~8 yuan of cycloalkanes Base；
R8And R9It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl；
Alternatively, R8And R9Be connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan it is miscellaneous Aromatic ring；
R4And R5It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of virtues Ring, 5~10 yuan of heteroaromatics ,-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、-NRaC(O)Rb、-NRaC(O) NRaRb、-NRaS(O)2Rb、-NRaS(O)2NRaRb、-S(O)2Ra、-S(O)2NRaRb,；Wherein alkyl-cycloalkyl, Heterocyclylalkyl, virtue Ring, heteroaromatic can be further by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；Wherein naphthenic base, Heterocyclylalkyl can Further by m RcReplace；
R11Selected from hydrogen, C1~6Alkyl；
R12Selected from hydrogen, C1~6Alkyl；
R13、R14It is independently chosen from hydrogen, C respectively1~6Alkyl, C2~6Alkenyl；Wherein alkyl, alkenyl are by m RcReplace；
M is 0,1,2.
Further, compound shown in Formulas I is as shown in Formula II a:
Wherein,
Ra’Selected from C1~6Alkyl.
Further, compound shown in Formula II a is as shown in Formula II a-1 or IIa-2:
Wherein,
Ra’Selected from C1~6Alkyl.
Further, compound shown in Formula II a-1 is as shown in formula III a-1 or IIIa-2:
Further, R5’For halogen, CN；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C(O)-、-C(O)-、-C(O) O- or nothing.
Further, compound shown in formula III a-1 or formula III a-2 specifically:
Further, R5’For halogen and 5~10 yuan of hetero-aromatic rings, wherein 5~10 yuan of heteroaromatics can be further by 0~3 C1~10Alkyl substitution, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics replace；
N is selected from 0,1,2,3；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
Further, compound shown in formula III a-1 or formula III a-2 specifically:
Further, R5’For halogen and-ORa；N is selected from 0,1,2,3；L2For nothing.
Further, compound shown in formula III a-1 or formula III a-2 specifically:
Further, compound shown in Formula II a-1 is as shown in formula III b-1 or IIIb-2:
Wherein,
Ra’Selected from substituted or unsubstituted C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、- NR10C (O)-,-C (O)-,-C (O) O- or nothing.
Further, compound shown in formula III b-1 or IIIb-2 specifically:
Further, compound shown in Formula II a-1 is as shown in formula III c:
Ra’、RcIt is respectively selected from C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
Further, compound shown in formula III c specifically:
Further, compound shown in Formula II a-2 is as shown in formula III d:
Wherein,
Ra’Selected from substituted or unsubstituted C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、- NR10C (O)-,-C (O)-,-C (O) O- or nothing.
Further, compound shown in formula III d specifically:
Further, compound shown in Formulas I is as shown in Formula II b:
Wherein,
Ra’Selected from C1~6Alkyl.
Further, compound shown in Formula II b specifically:
The present invention also provides compounds above-mentioned or its stereoisomer or its pharmaceutically acceptable salt to prepare Treat the purposes in the drug of the disease of IL-17A mediation.
The disease that IL-17A defined in the present invention is mediated is that IL-17A plays an important role in the pathology of the disease occurs Disease.The major function of IL-17A is to coordinate local tissue inflammation, to work in various diseases.What IL-17A was mediated Disease include one of inflammation, autoimmune disease, infectious diseases, cancer, the relevant disease of precancer syndrome or It is several.
" cancer " or " malignant tumour " refers to appointing in a variety of diseases characterized by uncontrolled abnormal cell proliferation What is a kind of, and impacted cell (turns in part or by the body that blood flow and lymphatic system are diffused into the ability at other positions Move) and any one of many features structure and/or characterization of molecules." cancer cell " refers to experience multi-step tumour progression In early days, the cell of mid-term or late stage.Cancer includes sarcoma, breast cancer, lung cancer, the cancer of the brain, osteocarcinoma, liver cancer, kidney, colon cancer And prostate cancer.In some embodiments, the compound of Formulas I is selected from colon cancer, the cancer of the brain, breast cancer, fiber meat for treating The cancer of tumor and squamous cell carcinoma.In some embodiments, cancer is selected from melanoma, breast cancer, colon cancer, lung cancer and ovary Cancer.In some embodiments, the cancer treated is metastatic cancer.
Caused by autoimmune disease is the immune response as body to the substance and tissue of internal normal presence.Itself The example of immunological diseases includes myocarditis, lupus nephritis, primary biliary cirrhosis, psoriasis, type 1 diabetes, Gray Fu Shi disease, celiaca, Crohn disease, autoimmune neutropenia, juvenile arthritis, rheumatoid joint Inflammation, fibromyalgia, lucky blue Barre syndrome, multiple sclerosis and autoimmune retinopathy become.Some realities of the invention The scheme of applying is related to treating autoimmune disease such as psoriasis or multiple sclerosis.
Inflammation disease includes the various diseases characterized by Histopathologic inflammation.The example of inflammatory disease includes common Acne, asthma, celiaca, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, class Airway inflammation caused by rheumatic arthritis, sarcoidosis, vasculitis, house dust mite and interstitial cystitis.Inflammatory disease and itself There are significant overlappings between immunity disease.Some embodiments of the invention are related to the treatment of inflammatory disease asthma.Siberian crabapple System is usually directed to diseases associated with inflammation, has performance in allergic reaction and some myopathies, many disease of immune system lead to exception Inflammation.The disease that IL-17A is mediated also includes auto-immune inflammatory disease.
The present invention also provides a kind of drug, it be with compound above-mentioned or its stereoisomer or its pharmaceutically may be used The salt of receiving, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
Compound and derivative provided in the present invention can according to IUPAC (International Union of Pure and Applied Chemistry) or The name of CAS (chemical abstracts service, Columbus, OH) naming system.
About the definition of the invention using term: unless otherwise indicated, group or term herein provide initial Definition is suitable for group or term of entire description；For the term being not specifically defined herein, it should according to open Content and context, their meaning can be given by providing those skilled in the art.
" substitution " refers to that the hydrogen atom in molecule is replaced by other different atoms or molecule.
The minimum value and maximum value of carbon content are indicated by prefix in hydrocarbon group, for example, prefix CA~bAlkyl shows Any alkyl containing " a " to " b " a carbon atom.Thus, for example, " C1~4Alkyl " refers to the alkyl comprising 1~4 carbon atom.
" alkyl " refers to the saturated hydrocarbon chain with the member atoms specified number.For example, C1~C6Alkyl refers to 1 to 6 A member atoms, such as the alkyl group of 1 to 4 member atoms.Alkyl group can be linear chain or branched chain.Representative branch Alkyl group has one, two or three branch.Alkyl group is optionally by one or more as herein defined Substituent group replaces.Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (normal-butyl, isobutyl group and tertiary fourth Base), amyl (n-pentyl, isopentyl and neopentyl) and hexyl.Alkyl group is also possible to a part of other groups, it is described its His group is such as C1~C6Alkoxy.
" naphthenic base " refer to 3 to 14 carbon atoms and without ring hetero atom and have single ring or multiple rings (including Condensed, bridging and spiro ring system) saturation or fractional saturation cyclic group.For having without the aromatics of ring hetero atom and non- The polycyclic system of aromatic ring, when tie point is located at non-aromatic carbon atom, applicable term " naphthenic base " (such as 5,6,7,8 ,-four Hydrogenated naphthalene -5- base).Term " naphthenic base " includes cycloalkenyl groups, such as cyclohexenyl group.The example of group of naphthene base includes example Such as, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopenta, cyclooctyl, cyclopentenyl and cyclohexenyl group.Including how bicyclic The example of the group of naphthene base of alkyl ring systems is dicyclohexyl, Bicvclopentyl, bicyclooctyl etc..It enumerates below and names two kinds Such bicyclic alkyl multiring structure:Dicyclohexyl andDicyclohexyl.
" alkenyl " refers to 2 to 10 carbon atoms and 2 to 6 carbon atoms or 2 to 4 carbon originals in some embodiments Son and the linear chain or branched chain hydrocarbyl group at least one vinyl unsaturated sites (>C=C<).For example, (Ca-Cb) alkenyl Refer to the alkenyl group with a to b carbon atom and is intended to include such as vinyl, acrylic, isopropenyl, 1,3- fourth two Alkenyl etc..
" alkynyl " refers to straight chain monovalent hydrocarbon or branch monovalent hydrocarbon containing at least one three key.Term " alkynyl " is also anticipated It is including that there is those of three keys and double bond hydrocarbyl group.For example, (C2-C6) alkynyl is intended to include acetenyl, third Alkynyl etc..
" halogen " is fluorine, chlorine, bromine or iodine.
" halogenalkyl " refers to that the hydrogen atom in alkyl can be replaced by one or more halogen atoms.Such as C1~4Halogenalkyl Refer to the alkyl comprising 1~4 carbon atom that hydrogen atom is replaced by one or more halogen atoms.
" heterocycle ", " Heterocyclylalkyl " refer to comprising at least one heteroatomic saturated rings or nonaromatic unsaturated ring；Its Middle hetero atom refers to nitrogen-atoms, oxygen atom, sulphur atom；
" heteroaromatic " refers to comprising at least one heteroatomic armaticity unsaturated ring；Wherein hetero atom refers to that nitrogen-atoms, oxygen are former Son, sulphur atom；
" stereoisomer " includes enantiomter and diastereoisomer；
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or to be formed by salt usual In chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " salt " and " pharmaceutical salt " refer to above compound or its stereoisomer, with inorganic and/or organic acid The acid and/or basic salt formed with alkali also includes amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.This A little salt can be to be directly obtained in being finally separating and purify of compound.It is also possible to by by above compound or it is vertical Body isomers is obtained by mixing with a certain number of acid or alkali appropriate (such as equivalent).These salt may be in the solution It forms precipitating and is collected with filter method, or recycle obtain after the solvent evaporates, or be freeze-dried after reacting in an aqueous medium It is made.Heretofore described salt can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, the hydrogen of compound Fluorate, phosphate, acetate, propionate, succinate, oxalates, malate, succinate, fumarate, maleic acid Salt, tartrate or trifluoroacetate.
Noval chemical compound shown in Formulas I disclosed by the invention shows good IL-17A inhibitory activity, is clinical treatment A kind of new medicinal possibility is provided to the abnormal relevant disease of IL-17A activity.
In some embodiments, one or more compounds of the invention can be used in conjunction with one another.Also may be selected will The compound of the present invention is used in combination with any other active agent, is used to prepare regulating cell function or treats the medicine of disease Object or pharmaceutical composition.If using one group of compound, can by these compounds simultaneously, respectively or in an orderly manner to tested Object is administered.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific embodiment of form by the following examples remakes further specifically above content of the invention It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention The technology realized all belongs to the scope of the present invention.
Specific embodiment
The structure of compound is by nuclear magnetic resonance (NMR) and mass spectrum (MS) come what is determined.NMR is displaced (δ) with 10-6 (ppm) unit provides.The measurement of NMR is to use (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic resonance spectrometer, Measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) is inside designated as tetramethyl Base silane (TMS).
The measurement of LC-MS uses Shimadzu LC-MS instrument (Shimadzu LC-MS 2020 (ESI)).
The measurement of HPLC uses Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A).
MPLC (middle to suppress standby chromatography) uses Gilson GX-281 reversed-phase preparative chromatography instrument.
Tlc silica gel plate isolates and purifies product with Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plate, thin-layer chromatography The specification of use is 0.4mm~0.5mm.
Column chromatography is generally carrier using 200~300 mesh silica gel of Yantai Huanghai Sea silica gel.
Known starting material of the invention can be used or be synthesized according to methods known in the art, or can purchase in Pacify the companies such as resistance to Jilin Chemical, Chengdu section Long Huagong, splendid remote chemical science and technology, lark prestige science and technology.
Without specified otherwise in embodiment, reaction carries out under nitrogen atmosphere.
Without specified otherwise in embodiment, solution refers to aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature.
Without specified otherwise in embodiment, M is mole every liter.
Room temperature is optimum reaction temperature, is 20 DEG C~30 DEG C.
DMF: refer to N,N-dimethylformamide.
DMSO: refer to dimethyl sulfoxide.
DIPEA: refer to diisopropyl ethyl amine.
Boc: refer to tertiary butyl oxycarbonyl.
TFA: refer to trifluoroacetic acid.
11 carbon -7- alkene of DBU:1,8- diazabicylo.
HATU:2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester.
HBTU:O- benzotriazole-tetramethylurea hexafluorophosphate.
EDCI:1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate.
HOAT:1- hydroxyl -7- azo benzotriazole.
The preparation of 1 intermediate 1 of embodiment
The preparation of step 1 intermediate 1-1
Ethyl nitroacetate (28.5g, 130mmol) and the bromo- 2- chlorobenzaldehyde (17.3g, 130mmol) of 5- are dissolved in anhydrous Tetrahydrofuran (400mL) titanium tetrachloride (28.5mL, 260.0mmol) is slowly added dropwise at 0 DEG C under nitrogen protection, after being added dropwise Continuation is stirred to react 1 hour at 0 DEG C.N-methylmorpholine (57.8mL, 520.0mmol) is slowly added dropwise into reaction solution, is dripped Finish and be slowly increased to room temperature, continues to be stirred to react 2 hours.Distilled water quenching reaction is added, is extracted with ethyl acetate, merges organic Phase, anhydrous sodium sulfate dry, filter, evaporating solvent under reduced pressure, through column chromatographic purifying (eluant, eluent: petroleum ether: ethyl acetate=20: 1) intermediate 1-1 (23.6g, 71mmol, yield 54%) is obtained after.MS m/z 335(M+1)+。
The preparation of step 2 intermediate 1-2
Anhydrous zinc chloride (14.4g, 106.0mmol) is dissolved in anhydrous tetrahydro furan (100mL), at 0 DEG C under nitrogen protection The isopropylmagnesium chloride tetrahydrofuran solution (53mL, 106.0mmol) of 2M is slowly added dropwise, it is anti-in 0 DEG C of stirring that continuation is added dropwise It answers 1 hour.By obtained isopropyl magnesium bromide zinc be slowly added dropwise under 0 DEG C of nitrogen protection to intermediate 1-1 (23.6g, In anhydrous tetrahydro furan (100mL) solution 70.5mmol), continue to be stirred to react at 0 DEG C 2 hours after being added dropwise.It is added full It with ammonium chloride solution quenching reaction, is extracted with ethyl acetate, merges organic phase, anhydrous sodium sulfate is dried, filtered, removed under reduced pressure molten Agent, intermediate 1-2 is obtained after column chromatographic purifying (eluant, eluent: petroleum ether: ethyl acetate=20:1), and (18.6g, 49.1mmol are produced Rate 70%).MS m/z 379(M+1)+。
The preparation of step 3 intermediate 1-3
Intermediate 1-2 (18.6g, 49.1mmol) is dissolved in glacial acetic acid (300mL), zinc powder is added in batches at 0 DEG C (16.0g, 245.5mmol) is warming up to and reaction 12 hours is stirred at room temperature.It is filtered to remove zinc powder, evaporating solvent under reduced pressure is chromatographed through column Intermediate 1-3 (7.6g, 21.8mmol, yield 44%) is obtained after purifying (eluant, eluent: petroleum ether: ethyl acetate=10:1).MS m/ z 350(M+1)+.
The preparation of step 4 intermediate 1-4
Intermediate 1-3 (3.8g, 10.9mmol) is dissolved in methylene chloride (60mL), triethylamine is successively added dropwise at 0 DEG C (4.6mL, 32.7mmol) and di-tert-butyl dicarbonate (3.8mL, 16.4mmol) is added dropwise and is warmed to room temperature that be stirred to react 1 small When.Evaporating solvent under reduced pressure, after column chromatographic purifying (eluant, eluent: petroleum ether: ethyl acetate=20:1) intermediate 1-4 (4.5g, Yield 92%).MS m/z 350(M-99)+, 394 (M-55)+。
The preparation of step 5 intermediate 1
Intermediate 1-4 (4.5g, 10.0mmol) is dissolved in the mixed of tetrahydrofuran (15mL), water (15mL) and methanol (5mL) In bonding solvent, 0 DEG C is added portionwise sodium hydroxide (2.0g, 50.0mmol), is warmed to room temperature and is stirred to react 4 hours after adding.Decompression Solvent is evaporated off, 1N HCl is added dropwise under ice bath and is adjusted to pH~4, solid is precipitated, obtains crude product after filtering vacuum is dry, crude product is through SFC hand Property split post separation preparation and respectively obtain four single chiral isomers 1-a, 1-b, 1-c, the 1-d of intermediate 1,0.8g respectively, Yield 19%.MS m/z 322(M-99)+, 366 (M-55)+。
The preparation of 2 intermediate 2 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using o-chlorobenzaldehyde as starting material, through condensation, grignard reaction, Nitro reduction, Boc protection amino, hydrolysis, most can respectively obtain four of intermediate 2 through the preparation of SFC chiral resolution post separation afterwards Single chiral isomers 2-a, 2-b, 2-c, 2-d.MS m/z:242[M-99]+, 286 [M-55]+。
The preparation of 3 intermediate 3 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using m chlorobenzaldehyde as starting material, through condensation, grignard reaction, Nitro reduction, Boc protection amino, hydrolysis, most can respectively obtain four of intermediate 3 through the preparation of SFC chiral resolution post separation afterwards Single chiral isomers 3-a, 3-b, 3-c, 3-d.MS m/z:242[M-99]+, 286 [M-55]+。
The preparation of 4 intermediate 4 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using the chloro- 5- fluorobenzaldehyde of 2- as starting material, through condensation, grignard Reaction, nitro reduction, Boc protection amino, hydrolysis, most can respectively obtain intermediate 4 through the preparation of SFC chiral resolution post separation afterwards Four single chiral isomers 4-a, 4-b, 4-c, 4-d.MS m/z:257[M-99]+, 304 [M-55]+。
The preparation of 5 intermediate 5 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using 2- chloro-5-methoxyl benzaldehyde as starting material, through condensation, Grignard reaction, nitro reduction, Boc protection amino, hydrolysis, most can respectively obtain centre through the preparation of SFC chiral resolution post separation afterwards Four single chiral isomers 5-a, 5-b, 5-c, 5-d of body 5.MS m/z:257[M-99]+, 316 [M-55]+。
The preparation of 6 intermediate 6 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using the chloro- 5- cyanobenzaldehyde of 2- as starting material, through condensation, lattice Family name's reaction, nitro reduction, Boc protection amino, hydrolysis, most can respectively obtain intermediate 6 through the preparation of SFC chiral resolution post separation afterwards Four single chiral isomers 6-a, 6-b, 6-c, 6-d.MS m/z:267[M-99]+, 311 [M-55]+。
The preparation of 7 intermediate 7 of embodiment
The preparation of step 1 intermediate 7-1
Centre can be obtained by o-chlorobenzaldehyde and ethyl nitroacetate reaction in the preparation method of 1 intermediate 1-2 of reference implementation Intermediate 2-1 (5g, 19.56mmol) is dissolved in methanol (50mL) by body 2-1 at room temperature, addition sodium methoxide (4.23g, 78.23mmol), it is stirred to react at room temperature 2 hours, TLC shows that raw material disappears, and is concentrated under reduced pressure and removes solvent, and saturation chlorination is added Aqueous ammonium 20mL, ethyl acetate (20mL × 2) extraction, merges organic phase, through washing, saturated sodium-chloride is washed, anhydrous sodium sulfate Dry, filter, be concentrated to dryness, crude product through silica gel post separation (petrol ether/ethyl acetate 4:1) obtain intermediate 7-1 (3g, 10.43mmol, 53.32%yield), weak yellow liquid, Rf=0.5 (Hexanes/EtOAc=8:1).
The preparation of step 2 intermediate 7-2
Intermediate 7-1 (1.58g, 5.48mmol) is dissolved in 10mL glacial acetic acid, addition zinc powder (1.79g, 27.41mmol), reaction is stirred to react 2 hours at room temperature, is filtered, and a small amount of ethyl acetate washing, filtrate decompression is concentrated to dryness, Crude product obtains intermediate 7-2 (0.83g, 3.22mmol, 58.76% through silica gel post separation (petrol ether/ethyl acetate 2:1) Yield), faint yellow solid, MS m/z:258 [M+1]
The preparation of step 3 intermediate 7-3
Intermediate 7-2 (0.83g, 3.22mmol) is dissolved in the mixed solution of THF (3mL) and water (1mL), is separately added into NaHCO3(541.11mg, 6.44mmol) and (Boc)2O (737.20mg, 3.38mmol) is stirred to react 12 hours at room temperature, adds Entering ethyl acetate (15mL) and water (15mL) washing, organic phase through washing, wash by saturated sodium-chloride, and anhydrous sodium sulfate dries, filters, Be concentrated to dryness, crude product through silica gel post separation (petrol ether/ethyl acetate 4:1) obtain intermediate 7-3 (1.1g, 3.07mmol, 95.45%yield), weak yellow liquid, MS m/z:302 [M-55]
The preparation of step 4 intermediate 7
Intermediate 7-3 (1.23g, 3.44mmol) is dissolved in the mixed solution of methanol (15mL), water (15mL), hydrogen is added Reaction 4 hours is stirred at room temperature in lithia monohydrate (1.20g, 28.53mmol).Evaporating solvent under reduced pressure is added dropwise under ice bath 0.5N HCl is adjusted to pH~4, ethyl acetate extraction-tetrahydrofuran 5:1 extraction, organic phase be concentrated under reduced pressure among weak yellow liquid Body 7 (1.1g, 3.34mmol, 97.04%yield).MS m/z 274[M-55].
The preparation of 8 intermediate 8 of embodiment
Referring to the method that embodiment 7 prepares intermediate 7, intermediate 2-1 is reacted with sodium ethoxide, again through nitro reduction, Boc guarantor Intermediate 8 can be obtained in shield amino, hydrolysis.MS m/z:288[M-55]+。
The preparation of 9 intermediate 9 of embodiment
Referring to the method that embodiment 7 prepares intermediate 7, intermediate 2-1 is reacted with sodium isopropylate, again through nitro reduction, Boc Intermediate 9 can be obtained in protection amino, hydrolysis.MS m/z:302[M-55]+。
The preparation of 10 intermediate 10 of embodiment
Referring to the method that embodiment 7 prepares intermediate 7, intermediate 2-1 reacts in the presence of potassium tert-butoxide, again with cyclopropyl alcohol Intermediate 10 can be obtained through nitro reduction, Boc protection amino, hydrolysis.MS m/z:300[M-55]+。
The preparation of 11 intermediate 11 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using propionic aldehyde as starting material, be condensed with ethyl nitroacetate, with Chloro-O-Phenyl magnesium bromide carries out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis, most afterwards through SFC chiral resolution Post separation prepares four single chiral the isomers 11-a, 11-b, 11-c, 11-d that can respectively obtain intermediate 11.MS m/z: 228[M-99]+, 272 [M-55]+。
The preparation of 12 intermediate 12 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using cyclopropyl formaldehyde as starting material, through contracting with ethyl nitroacetate It closes, carry out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis with Chloro-O-Phenyl magnesium bromide, most afterwards through SFC chirality Four single chiral isomers 12-a, 12-b, 12-c, 12-d of intermediate 12 can be respectively obtained by splitting post separation preparation.MS m/ z:228[M-99]+, 272 [M-55]+。
The preparation of 13 intermediate 13 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using ring fourth formaldehyde as starting material, through contracting with ethyl nitroacetate It closes, carry out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis with Chloro-O-Phenyl magnesium bromide, most afterwards through SFC chirality Four single chiral isomers 13-a, 13-b, 13-c, 13-d of intermediate 13 can be respectively obtained by splitting post separation preparation.MS m/ z:254[M-99]+, 298 [M-55]+。
The preparation of 14 intermediate 14 of embodiment
Referring to the method that embodiment 1 prepares intermediate 1, using hexahydrobenzaldehyde as starting material, warp and ethyl nitroacetate Condensation carries out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis with Chloro-O-Phenyl magnesium bromide, most afterwards through SFC hand Property split post separation preparation and can respectively obtain the four single chiral isomers 14a, 14-b, 14-c, 14-d of intermediate 14.MS m/z:282[M-99]+, 326 [M-55]+。
The preparation of 15 intermediate 15 of embodiment
The resin that methylene chloride was activated add to FMOC-D-CHA-OH (2.00g, 5.08mmol) and DIPEA (1.97g, 15.24mmol, 2.66mL) DMF (40.00mL) solution in, after concussion reaction 12 hours, filter, by DCM/MeOH/DIPEA (85/10/5) it adds in resin, vibrates 30min, filtering, DCM (50*10ml), DMF (50*10ml), DCM (50*10ml) is successively Washing, HFIP (20%in DCM) (913.89mg, 5.08mmol, 40.00mL) is added in resin, in concussion a moment, is filtered, then HFIP (20%in DCM) (913.89mg, 5.08mmol, 40.00mL) is added into resin, concussion filters, and merging filtrate is dense Contracting obtains cyclohexyl-D- glycine (870.00mg, 5.08mmol, 100.00%yield), takes its 500mg (2.92mmol), adds Enter THF- water (1:1,20ml) and sodium carbonate (618.98mg, 5.84mmol) and Boc2O (954.84mg, 4.38mmol), room temperature It is stirred to react overnight, most of organic solvent, 6N HCl tune pH~4 is removed under reduced pressure, ethyl acetate extracts (3*10ml), is associated with Machine phase is concentrated under reduced pressure, obtains crude product 0.78g, the MS m/z:272 [M+1] of intermediate 15+。
The preparation of 16 intermediate 16 of embodiment
Referring to the method that embodiment 7 prepares intermediate 7, using hexahydrobenzaldehyde as starting material, warp and ethyl nitroacetate Condensation is reacted with sodium methoxide, again through nitro reduction, Boc protection amino, hydrolysis, most afterwards can through the preparation of SFC chiral resolution post separation Respectively obtain four single chiral isomers 16-a, 16-b, 16-c, 16-d of intermediate 16.MS m/z:302[M+1]+。
The preparation of 17 intermediate 17 of embodiment
Referring to the method that embodiment 7 prepares intermediate 7, intermediate 2-1 and 4-methylpyrazole are under potassium carbonate-DMF system It reacts, again through nitro zinc powder reduction, Boc protection amino, hydrolysis, can most be respectively obtained through the preparation of SFC chiral resolution post separation afterwards Four single chiral isomers 17-a, 17-b, 17-c, 17-d of intermediate 17.MS m/z:324[M-55]+。
The preparation of 18 intermediate 18 of embodiment
The preparation of step 1 intermediate 18-1
Under ice bath and nitrogen protection, by 4- pyrazoles pinacol borate (5g, 25.8mmol) and cesium carbonate (16.9g, It 51.5mmol) is added in the there-necked flask equipped with DMF (100mL), is added iodomethane (5.68g, 40mmol), is warmed to room temperature.Room temperature Stirring is filtered after 8 hours, removes most of solvent under reduced pressure, is then extracted with water and ethyl acetate, then by water phase ethyl acetate Be extracted twice, merge organic phase, evaporating solvent under reduced pressure to get intermediate 18-1 crude product (4.85g, 23.3mmol, yield 90%), MS m/z:209[M+1]+。
The preparation of step 2 intermediate 18
By under nitrogen protection, embodiment 1 intermediate 1-4 (710mg, 1.63mmol), intermediate 18-1 (509.69mg, 2.45mmol), Pd (PPh3) 4 (94.31mg, 81.66umol) and Na2CO3 (519.33mg, 4.90mmol) are suspended in Isosorbide-5-Nitrae- The in the mixed solvent of dioxane (3mL) and H2O (0.3mL), and ultrasonic degassing 15min, reaction solution are heated to 80 DEG C and reacted Night is concentrated to dryness, and residue obtains coupled product (0.45g, 1.03mmol, 63.21% through silica gel column separating purification Yield), MS m/z:435 [M+1]+.Coupled product can most be distinguished through the preparation of SFC chiral resolution post separation afterwards again through basic hydrolysis Obtain four single chiral isomers 18-a, 18-b, 18-c, 18-d, MS m/z:422 [M+1] of intermediate 18+。
The preparation of 19 intermediate 19 of embodiment
The preparation of step 1 intermediate 19-1
Under ice bath and nitrogen protection, by 4- pyrazoles pinacol borate (5g, 25.8mmol) and cesium carbonate (16.9g, It 51.5mmol) is added into DMF (100mL), is added 2- iodopropane (6.1g, 36mmol), is warmed to room temperature.It is stirred at room temperature 8 hours After filter, remove most of solvent under reduced pressure, then extracted with water and ethyl acetate, then water phase is extracted with ethyl acetate twice, Merge organic phase, evaporating solvent under reduced pressure is to get intermediate 19-1 crude product (5.5g, 23.3mmol, yield 90%).MS m/z:237 [M+1]+。
The preparation of step 2 intermediate 19
Referring to the method for 18 step 2 of embodiment, again through basic hydrolysis after intermediate 1-4 and 19-1 coupling, most afterwards through SFC chirality Four single chiral isomers 19-a, 19-b, 19-c, 19-d of intermediate 19 can be respectively obtained by splitting post separation preparation.MS m/ z:450[M+1]+。
The preparation of 20 intermediate 20 of embodiment
Referring to 18 step 1 of embodiment, N- substitution reaction is occurred with 4- pyrazoles pinacol borate and N-Boc-4- iodine piperidines Obtain intermediate 20, MS m/z:378 [M+1]+。
The preparation of 21 intermediate 21 of embodiment
Referring to the method for 18 step 2 of embodiment, alkali again after intermediate 1-4 and the coupling of 2- methoxypyridine -4- valeryl boric acid Hydrolysis most can respectively obtain intermediate 21 4 single chiral isomers 21-a, 21- through the preparation of SFC chiral resolution post separation afterwards b,21-c,21-d。MS m/z:449[M+1]+。
The preparation of 22 intermediate 22 of embodiment
Referring to 1 preparation method of embodiment, using the chloro- 4- bromobenzaldehyde of 2- as starting material, through being condensed with ethyl nitroacetate, Cyclopropyl magnesium bromide carries out grignard reaction, nitro reduction, and amino Boc protection refers again to 19 coupling method of embodiment, with intermediate 19-1 coupling, then basic hydrolysis again most can respectively obtain 22 4 single hands of intermediate through the preparation of SFC chiral resolution post separation afterwards Property isomers 22-a, 22-b, 22-c, 22-d.MS m/z:448[M+1]+。
The preparation of 23 intermediate 23 of embodiment
The preparation of step 1 intermediate 23-1
At nitrogen protection and 0 DEG C, to the DMF (700mL) of the drying of paranitrophenylacetic acid ethyl ester (156g, 745.71mmol) Cs2CO3 (290.82g, 894.85mmol) is added in solution, is warmed to room temperature and stirs 1 hour, be subsequently reduced to 0 DEG C and slowly drip Add iodomethane (116.43g, 820.28mmol), drop finishes, and reaction overnight, filters, and filtrate is diluted with 2L ethyl acetate, saturated common salt Water washing (3*1.5L), organic phase anhydrous sodium sulfate dry, filter, concentration, can be obtained intermediate 23-1 (165g, 739.16mmol, 99.12%yield), MS m/z:224 [M+1]+, crude product be directly used in next step.
The preparation of step 2 intermediate 23-2
Intermediate 23-1 (2.30g, 10.30mmol) is dissolved in EtOH (20mL), after nitrogen displacement, 10%Pd/C is added (0.5g) is stirred to react under atmospheric hydrogen atmosphere overnight, after raw material disappears, through suction filtered through kieselguhr, ethanol washing, filtrate decompression concentration To doing, silica gel column separating purification is obtained intermediate 23-2 (1.30g, 6.73mmol, 65.31%yield), MS m/z:194 [M+ 1]+。
The preparation of step 3 intermediate 23-3
Intermediate 23-2 (2.70g, 13.97mmol) is dissolved in aceticanhydride (10mL), is cooled to 0 DEG C, and stir 15min, It is slowly added dropwise HNO3 (1.76g, 27.94mmol, 68% mass fraction), drop finishes, and reaction continues to stir 30min, and raw material disappears, will Reaction solution is poured into ice water, and ethyl acetate (2*30mL) extraction merges organic phase, washs through saturated sodium carbonate, anhydrous sodium sulfate It dries, filters, is concentrated to dryness to obtain intermediate 23-3 crude product (3.45g, 12.32mmol, 88%yield), MS m/z: 281[M+1]+。
The preparation of step 4 intermediate 23-4
Intermediate 23-3 (3.45g, 12.32mmol) is dissolved in 20ml ethyl alcohol, SOCl is added2(4.40g, 36.96mmol, 2.68mL), it is heated to 50 DEG C and stirs 1 hour, LC-MS shows that raw material disappears, and reaction solution is concentrated to dryness, adds Enter CH2Cl2(150mL) and H2O (150mL), with saturation NaHCO3PH value~8 are adjusted, water phase is again through CH2Cl2(2*150mL) extraction, Merge organic phase, anhydrous sodium sulfate dries, filters, is concentrated to dryness, obtain intermediate 23-4 crude product (2.89g, 12.07mmol, 98%yield), MS m/z:239 [M+1]+, product is not purified to be directly used in reaction in next step.
The preparation of step 5 intermediate 23
Intermediate 23-4 (2.89g, 12.07mmol) is dissolved in 10ml to be dissolved in ethyl alcohol, Pd/C is added under nitrogen atmosphere (0.5g), overnight, after raw material disappears, through suction filtered through kieselguhr, filtrate decompression is concentrated to dryness, MPLC C18 reverse phase for normal pressure hydrogenation reaction Column purification obtains intermediate 23 (2.13g, 10.26mmol, 85%yield), MS m/z:209 [M+1]+.
The preparation of 24 intermediate 24 of embodiment
Referring to the method for 23 step 1~5 of embodiment, using paranitrophenylacetic acid ethyl ester as raw material, warp and iodoethane are in DMF- Cesium carbonate catalysis is lower to occur the alkylation of benzyl position, aligns nitro reduction, and nitrated in position simultaneously aligns acetylated then deacetylated simultaneously Intermediate 24, MS m/z:223 [M+1] can be obtained in base, hydro-reduction+.
The preparation of 25 intermediate 25 of embodiment
Referring to the method for 23 step 1~5 of embodiment, using paranitrophenylacetic acid ethyl ester as raw material, through existing with 2- N-Propyl Bromide The catalysis of DMF- potassium carbonate is lower to occur the alkylation of benzyl position, contraposition nitro reduction, and nitrated in position simultaneously aligns acetylated simultaneously, then takes off Intermediate 25, MS m/z:237 [M+1] can be obtained in acetyl group, hydro-reduction+.
The preparation of 26 intermediate 26 of embodiment
The preparation of step 1 intermediate 26-1
At nitrogen protection and 0 DEG C, to DMF (2L) solution of the drying of paranitrophenylacetic acid ethyl ester (350g, 1.67mol l) Middle addition Cs2CO3 (2.73kg, 8.37mol) is warmed to room temperature and stirs 1 hour, be then slowly added dropwise iodomethane (1.19kg, 8.37mol), drop finishes, and room temperature reaction overnight, filters, and filtrate is diluted with 10L ethyl acetate, saturated common salt water washing (3*10L), Organic phase anhydrous sodium sulfate dries, filters, and intermediate 26-1 (320g, 1.24mol, 74.17%yield) can be obtained in concentration, MS m/z:238[M+1]+, crude product be directly used in next step.
The preparation of step 2~5 intermediates 26
Referring to the method for 23 step 2~5 of embodiment, with step 1 intermediate 26-1 raw material, through contraposition nitro reduction, meta position It nitrifies and aligns simultaneously acetylated, then intermediate 26, MS m/z:223 [M+1] can be obtained in deacetylation, hydro-reduction+.
The preparation of 27 intermediate 27 of embodiment
Referring to the method for embodiment 23, using 2-F-4- nitrophenyl-acetic acid ethyl ester as starting material, warp and iodomethane are in DMF- Cesium carbonate catalysis is lower to occur the double methylations in benzyl position, contraposition nitro reduction, and nitrated in position simultaneously aligns acetylated, then de- second simultaneously Intermediate 27, MS m/z:241 [M+1] can be obtained in acyl group, hydro-reduction+.
The preparation of 28 intermediate 28 of embodiment
Referring to the method for embodiment 23, using the fluoro- 4- nitrophenyl-acetic acid ethyl ester of 2- as starting material, warp and iodomethane are in DMF- Cesium carbonate catalysis is lower to occur the double methylations in benzyl position, contraposition nitro reduction, meta position (3-) nitrifications and while align it is acetylated, Intermediate 28, MS m/z:241 [M+1] can be obtained in deacetylation again, hydro-reduction+.
The preparation of 29 intermediate 29 of embodiment
Referring to the method for embodiment 23, using the fluoro- 4- nitro -5- bromo-acid ethyl ester of 2- as starting material, warp and iodomethane The double methylations in generation benzyl position under the catalysis of DMF- cesium carbonate, the reduction of 4- nitro, meta position (3-) nitrifications are simultaneously simultaneously to bit amino second It is acylated, then deacetylation, simultaneously intermediate 29, MS m/z:241 [M+1] can be obtained in de- 5- bromines to hydro-reduction simultaneously+.
The preparation of 30 intermediate 30 of embodiment
The preparation of step 1 intermediate 30-1
Cumidine (15.6g, 115.38mmol) is dissolved in aceticanhydride (100mL), is cooled to 0 DEG C, and stir HNO is slowly added dropwise in 15min3(21.81g, 346.14mmol, 68% mass fraction), drop finish, and reaction continues to stir 12h, raw material It disappears, reaction solution is poured into ice water, ethyl acetate (2*300mL) extraction merges organic phase, washs through saturated sodium carbonate, nothing Aqueous sodium persulfate dries, filters, and is concentrated to dryness to obtain intermediate 30-1 crude product (16g, 64.79mmol, 56.16%yield), MS m/z:223[M+1]+。
The preparation of step 2 intermediate 30-2
Intermediate 30-1 (15g, 67.49mmol) is dissolved in ethyl alcohol (150mL), addition NaOH (4.05g, 101.24mmol), it is heated to 80 DEG C to react 2 hours, LC-MS shows that raw material has reacted, and reaction solution is poured into water, DCM (100ml*3) extraction, merges organic phase, and organic phase is washed through saturated common salt again, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure Intermediate 30-2 crude product (10g, 49.94mmol, 74.00%yield) is obtained to dry, is directly used in next step, MS m/z:181 [M+1]+。
The preparation of step 3 intermediate 30
Referring to step 23 nitro restoring method, intermediate 30-2 is purified through Pd/C hydro-reduction, then through MPLC reverse phase Obtain intermediate 30, MS m/z:151 [M+1]+。
The preparation of 31 intermediate 31 of embodiment
Referring to 23 step 1~5 of embodiment method, using paranitrophenylacetic acid ethyl ester as raw material, through with 1,2- Bromofume Occur benzyl position ciprofloxacin eye drops under DMF- sodium hydrogen condition, contraposition nitro reduction, nitrated in position simultaneously aligns acetylated simultaneously, then takes off Intermediate 31, MS m/z:221 [M+1] can be obtained in acetyl group, hydro-reduction+.
The preparation of 32 intermediate 32 of embodiment
Referring to 23 step 1~5 of embodiment method, using paranitrophenylacetic acid ethyl ester as raw material, through with 1,3- diiodo propane DMF- cesium carbonate catalysis under occur benzyl position ring fourth, contraposition nitro reduction, nitrated in position and simultaneously align it is acetylated, then Intermediate 32, MS m/z:235 [M+1] can be obtained in deacetylation, hydro-reduction+.
The preparation of 33 intermediate 33 of embodiment
Referring to the method for 23 step 1~5 of embodiment, using paranitrophenylacetic acid ethyl ester as raw material, warp and bromocyclopentane exist The catalysis of DMF- cesium carbonate is lower to be occurred benzyl position and introduces cyclopenta, contraposition nitro reduction, nitrated in position and align simultaneously it is acetylated, Intermediate 33, MS m/z:263 [M+1] can be obtained in deacetylation again, hydro-reduction+.
The preparation of 34 intermediate 34 of embodiment
The preparation of step 1 intermediate 34-1
By 2- nitro -4- bromaniline (5.00g, 23.04mmol), ethyl acrylate (4.61g, 46.08mmol) and DIPEA (8.94g, 23.04mmol, 12.50mL) is successively added in 100ml acetonitrile, and nitrogen is bubbled lower ultrasonic degassing 5min, is then added Pd (PPh3) 4 (2.60g, 23.04mmol) is heated to 90 DEG C of reactions under nitrogen protection overnight, after completion of the reaction, is cooled to room Temperature is diluted with water, and ethyl acetate extracts (3x200mL), merges organic phase, and anhydrous sodium sulfate is dry to be filtered, and filtrate is concentrated to dryness, Crude product obtains intermediate 34-1 (2.20g, 9.31mmol, 40.42%yield) through silica gel column chromatography separating purification, MS m/z: 237[M+1]+.
The preparation of step 2 intermediate 34-2
Intermediate 34-1 (3.20g, 13.55mmol) is dissolved in 30ml to be dissolved in ethyl alcohol, Pd/C is added under nitrogen atmosphere (0.2g), overnight, after raw material disappears, through suction filtered through kieselguhr, filtrate decompression is concentrated to dryness, MPLC C18 reverse phase for normal pressure hydrogenation reaction Column purification obtains intermediate 34-2 (1.76g, 8.53mmol, 62.95%yield), MS m/z:207 [M+1]+.
The preparation of step 3 intermediate 34
Intermediate 34-2 (640.00mg, 3.10mmol) is dissolved in 30ml to be dissolved in methanol, PtO2 is added under nitrogen atmosphere (60.00mg), overnight, after raw material disappears, through suction filtered through kieselguhr, filtrate decompression is concentrated to dryness, MPLC C18 for normal pressure hydrogenation reaction Reverse phase column purification obtains intermediate 34 (620.00mg, 2.98mmol, 96.13%yield), MS m/z:209 [M+1]+.
The preparation of 35 intermediate 35 of embodiment
Referring to the method for 18 step 2 of embodiment, firstly, 2- nitro -4- bromaniline and 3,5- dimethyl pyrazole -4- boric acid frequency After the coupling of that alcohol ester, intermediate 35, MS m/z:203 [M+1] can be obtained referring again to 23 nitro palladium carbon restoring method of embodiment+.
The preparation of 36 intermediate 36 of embodiment
Referring to the method for 18 step 2 of embodiment, firstly, 2- nitro -4- bromaniline and 3,5- dimethyl isoxazole -4- boric acid After pinacol ester coupling, intermediate 36, MS m/z:204 [M+1] can be obtained referring again to 23 nitro palladium carbon restoring method of embodiment+.
The preparation of 37 intermediate 37 of embodiment
The preparation of step 1 intermediate 37-1
By 3,5- dimethyl isoxazole -4- pinacol borate (1g, 4.50mmol) and the bromo- 2- Ethyl Methyl Ether of 1- (688.41mg, 4.95mmol) and cesium carbonate (2.93g, 9.01mmol) add in the DMF of 10mL, and it is small to be stirred to react 24 at room temperature When, water 100ml is added, ethyl acetate (100ml*3) extraction merges organic phase, and saturated common salt washing, anhydrous sodium sulfate is dry, Filtering, concentration, crude product obtain yellow green intermediate 37-1 through silica gel column separating purification (petrol ether/ethyl acetate 3:1~1:1), (1.12g, 4.0mmol, 89%yield), MS m/z:281 [M+1]+.
The preparation of step 2 intermediate 37
Referring to the method for 18 step 2 of embodiment, firstly, after 2- nitro -4- bromaniline and pinacol borate 37-1 coupling, Intermediate 37, MS m/z:261 [M+1] can be obtained referring again to 23 nitro palladium carbon restoring method of embodiment+.
The preparation of 38 intermediate 38 of embodiment
The preparation of step 1 intermediate 38-1
By 4- bromine o-phenylenediamine (5.00g, 26.73mmol), connection boric acid pinacol ester (20.37g, 80.20mmol) and KOAc (10.48g, 106.93mmol) is successively added in 100ml dioxane, and nitrogen is bubbled lower ultrasonic degassing 5min, is then added Enter Pd (dppf) Cl2(586.25mg, 801.98umol) is heated to 100 DEG C under nitrogen protection and reacts 20 hours, end of reaction Afterwards, it is cooled to room temperature, is filtered through short silicagel column, filtrate decompression concentration, crude product is through silica gel column chromatography separating purification (petroleum ether/second Acetoacetic ester 2:1) intermediate 38-1 (86mg, 367.36umol, 6.87%yield) is arrived, MS m/z:235 [M+1]+.
The preparation of step 2 intermediate 38-2
2- (bromo- 1, the 3- dimethyl -1H- pyrazoles -5- base of 4-) methyl acetate (660mg, 2,83mmol) is dissolved in 15ml's In 7M ammonium hydroxide-ethanol solution, be stirred at room temperature 20 hours, be concentrated to dryness can be obtained intermediate 38-2 (574mg, 2, 63mmol, 93%yield), MS m/z:232 [M+1]+.
The preparation of step 3 intermediate 38
Referring to the method for 18 step 2 of embodiment, step 1 gained pinacol borate 38-1 and step 2 gained 38-2 are coupled Intermediate 38, MS m/z:246 [M+1] can be obtained+.
The preparation of 39 intermediate 39 of embodiment
Referring to the method for 18 step 2 of embodiment, by 38 step 1 gained pinacol borate 38-1 and 2- of embodiment, (4- is bromo- 1,3- dimethyl -1H- pyrazoles -5- base) ethamine coupling intermediate 39, MS m/z:218 [M+1] can be obtained+.
The preparation of 40 intermediate 40 of embodiment
The preparation of step 1 intermediate 40-1
At room temperature by O- methylsulphur acidic group ethyl lactate (1.24g, 6.30mmol) and cesium carbonate (3.08g, 9.46mmol) It adds in the 10ml acetonitrile solution of 3,5- dimethyl pyrazole -4- boric acid pinacol ester (0.7g, 3.15mmol), reacts on 60 DEG C and stir Mix 10 hours, be concentrated under reduced pressure, water and ethyl acetate is added to extract, after organic phase concentration through silica gel column chromatography separating purification (petroleum ether/ Methyl tertiary butyl ether(MTBE) 1:1) it obtains intermediate 40-1 (700mg, 2.17mmol, 68.93%yield), MS m/z:323 [M+1]+.
The preparation of step 2 intermediate 40-2
Intermediate 40-1 (0.7g, 2.17mmol) is dissolved in THF/EtOH/H2O=4/1/1 (10mL), LiOH mono- is added Hydrate (260.16mg, 10.86mmol) is stirred at room temperature 3 hours, and through 1N HCl tune pH~5, ethyl acetate extraction is organic Mutually be concentrated, obtain the crude product (500mg, 1.70mmol, 78.24%yield) of intermediate 40-2, it is not purified be directly used in it is next Step, MS m/z:295 [M+1]+.
The preparation of step 3 intermediate 40-3
Intermediate 40-2 (0.5g, 1.70mmol) is dissolved in the DCM of 10ml, sequentially adds HBTU at room temperature (647.29mg, 2.55mmol), DIEA (1.10g, 8.50mmol) and methylamine (105.58mg, 3.40mmol), reaction solution is in 50 It is stirred to react 10 hours, is concentrated under reduced pressure at DEG C, water and ethyl acetate is added to extract, be concentrated under reduced pressure after organic phase is dry, silica gel column layer Analysis isolates and purifies (DCM/MeOH:20/1) and intermediate 40-3 (80mg, 260.42umol, 15.32%yield), MS can be obtained m/z:308[M+1]+.
The preparation of step 4 intermediate 40
Referring to the method for 18 step 2 of embodiment, firstly, after 2- nitro -4- bromaniline and pinacol borate 40-3 coupling, Intermediate 40, MS m/z:288 [M+1] can be obtained referring again to 23 nitro palladium carbon restoring method of embodiment+.
The preparation of 41 compound 41 of embodiment
The preparation of step 1 intermediate 41-1
Referring to the method for 23 step 1~5 of embodiment, using paranitrophenylacetic acid ethyl ester as raw material, restored through contraposition nitro, Nitrated in position simultaneously aligns acetylated simultaneously, then intermediate 41-1, MS m/z:195 [M can be obtained in deacetylation, hydro-reduction +1]+.
The preparation of step 2 intermediate 41-2
By 1- ethyl -1H- pyrazoles -5- carboxylic acid, (1.40g, 9.99mmol are dissolved in 5ml DMF, sequentially add HOAt at 0 DEG C After (2.27g, 9.99mmol), DIPEA (1.29g, 9.99mmol, 1.74mL) and EDCI (2.23g, 9.99mmol), 5min, It is added (S)-(-)-Cyclohexylalanine methyl esters (2.22g, 11.99mmol), goes to and be stirred at room temperature 2 hours, end of reaction adds water It is extracted with ethyl acetate, organic phase is washed through saturated ammonium chloride, and anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, crude product is through silica gel Column chromatographic analysis purifies to obtain intermediate 41-2 (1.70g, 5.53mmol, 55.36%yield), MS m/z:308 [M+1]+.
The preparation of step 3 intermediate 41-3
Intermediate 41-2 (1.40g, 4.55mmol) and LiOH (218.16mg, 9.11mmol) are added to the THF- water of 10ml It in (1:1), stirs 4 hours at room temperature, after reduced pressure, is extracted, merged organic with 1N HCl tune pH~4, DCM (2 × 20ml) Phase, anhydrous sodium sulfate dry, filter, and filtrate decompression is concentrated to dryness to obtain intermediate 41-3 (700.00mg, 2.39mmol, 52.44% Yield), not purified be directly used in of crude product is reacted in next step, MS m/z:294 [M+1]+.
The preparation of step 4 intermediate 41-4 constitutional isomer mixture
Under ice bath, by intermediate 41-3 (280.92mg, 957.60umol), HATU (1.31g, 3.46mmol) is dissolved in 5mL DCM in, stirring in a moment, sequentially add diamines 41-1 (194mg, 1.0mmol) and DIPEA (1.03g, 7.98mmol), room Temperature reaction 3 hours, adds water quenching to go out, and most of organic solvent is removed under reduced pressure, and ethyl acetate (20ml*3) extraction merges organic phase, Saturated common salt washing is distinguished again, and anhydrous sodium sulfate is dry, and decompression is spin-dried for, and crude product is purified by silica gel column chromatography separation (petroleum ether/second Acetoacetic ester 1:1) constitutional isomer mixture (992.00mg, 2.11mmol, 79.22% of intermediate 41-4 can be obtained Yield), MS m/z:470 (M+1)+, the two is without separating and in next step.
The preparation of step 5 intermediate 41-5
Step 4 gained intermediate 41-4 mixture (992.00mg, 2.11mmol) is added in AcOH (10mL), 55 DEG C anti- 12h is answered, reduced pressure is spin-dried for, and silica gel column chromatography separating purification (petrol ether/ethyl acetate 1:1) obtains intermediate 41-5 (800mg, 1.82mmol, 86.3%yield), MS m/z:452 (M+1)+。
The preparation of step 6 intermediate 41-6
Intermediate 41-5 (800mg, 1.82mmol) is dissolved in the THF-H2O (1:1) of 10mL, addition LiOH (438mg, 18.3mmol), it is stirred at room temperature 3 hours, through 1N HCl tune pH~5, ethyl acetate extraction, organic phase concentration obtains intermediate The crude product (500mg, 1.18mmol, 64.5%yield) of 41-6, not purified to be directly used in next step, MS m/z:424 [M+1]+.
It is prepared by step 7 intermediate 41
Under ice bath, the crude product (500mg, 1.18mmol) of intermediate 41-6 and HOAt (293.42mg, 2.16mmol) and The 10mL of EDCI (412.08mg, 2.16mmol) DCM mixed liquor stirring in a moment, sequentially add methylamine hydrochloride (239mg, 3.54mmol) with DIPEA (697.08mg, 5.39mmol, 939.46uL), room temperature reaction 3 hours is gone to, water quenching is added to go out, depressurized Most of organic solvent is removed, ethyl acetate (20ml*3) extraction merges organic phase, then saturated ammonium chloride and saturated common salt respectively Washing, anhydrous sodium sulfate is dry, and decompression is spin-dried for, and crude product is purified by silica gel column chromatography separation (petrol ether/ethyl acetate 3:1) It obtains compound 41 (0.44g, 0.1mmol, 85%yield), MS m/z:437 (M+1)+.
The preparation of 42 compound 42 of embodiment
The preparation of step 1 intermediate 42-1
During reference 41 step 7 method of embodiment, intermediate 41-6 and the condensation of D-Leu t-butyl ester hydrochloride can be obtained Mesosome 42-1, MS m/z:593 (M+1)+.
The preparation of step 2 compound 42
Intermediate 42-1 (600mg, 1.01mmol) is dissolved in 4ml methylene chloride, and 4mL trifluoroacetic acid is added under ice bath, and drop finishes, It stirs 3 hours, end of reaction, is concentrated under reduced pressure under ice bath, crude product can obtain compound 42 through MPLC reverse phase C18 column purification (26.85mg, 47.03umol, 4.66%yield), MS m/z:537 (M+1)+.
The preparation of 43 compound 43 of embodiment
Referring to 41 step 7 method of embodiment, compound 43 is can be obtained in intermediate 41-6 and iso-amylamine condensation, MS m/z: 493(M+1)+.
The preparation of 44 compound 44 of embodiment
Referring to 41 step 2-7 of embodiment, through 1- ethyl -3- methyl-1 H- pyrazoles -5- carboxylic acid and (S)-(-)-cyclohexyl third Propylhomoserin methyl esters condensation, methyl esters hydrolysis, is condensed with o-phenylenediamine, closes imidazole ring, and ethyl ester hydrolysis is finally condensed can be obtained with amine Close object 44, MS m/z:451 [M+1]+。
The preparation of 45 compound 45 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 30 intermediate o-phenylenediamine 30 of embodiment, Closing imidazole ring can be obtained compound 45, MS m/z:408 [M+1]+。
The preparation of 46 compound 46 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 23 intermediate o-phenylenediamine 23 of embodiment, Imidazole ring is closed, finally compound 46, MS m/z:451 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 47 compound 47 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 24 intermediate o-phenylenediamine 24 of embodiment, Imidazole ring is closed, finally compound 47, MS m/z:465 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 48 compound 48 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 25 intermediate o-phenylenediamine 25 of embodiment, Imidazole ring is closed, finally compound 48, MS m/z:479 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 49 compound 49 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 33 intermediate o-phenylenediamine 33 of embodiment, Imidazole ring is closed, finally compound 49, MS m/z:505 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 50 compound 50 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 31 intermediate o-phenylenediamine 31 of embodiment, Imidazole ring is closed, finally compound 50, MS m/z:463 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 51 compound 51 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 32 intermediate o-phenylenediamine 32 of embodiment, Imidazole ring is closed, finally compound 51, MS m/z:477 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 52 compound 52 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 26 intermediate o-phenylenediamine 26 of embodiment, Imidazole ring is closed, finally compound 52, MS m/z:465 [M+1] can be obtained with methylamine condensation in ethyl ester hydrolysis+.
The preparation of 53 compound 53 of embodiment
Referring to 41 step 4-7 of embodiment, successively by intermediate 41-3 and bromo- 4, the 5- o-phenylenediamine acetic acid second of intermediate 2- Ester condensation (can be obtained by the bromo- 4- nitro phenyl acetic acid ethyl ester of 2- referring to the method for 23 step 2~5 of embodiment), close imidazole ring, second Finally compound 53, MS m/z:515 [M+1] can be obtained with methylamine condensation in ester hydrolysis+.
The preparation of 54 compound 54 of embodiment
At room temperature by 53 compound 53 (89mg, 0.173mmol) of embodiment, 2- phenylvinylboronic acid (33.5mg, 0.227mmol), K2CO3(71.6mg, 0.519mmol) successively adds to 1,4- dioxane (2ml) and the mixing of water (0.3ml) is molten In liquid, nitrogen is bubbled lower ultrasound 10min, and Pd (dppf) Cl is then added2(25mg, 35.00umol) is reacted at 80 DEG C and is stirred Overnight, end of reaction is cooled to room temperature, and water dilution is added, and ethyl acetate extraction, organic phase is through washing, saturated sodium-chloride washing, It is filtered after anhydrous sodium sulfate is dry, filtrate decompression is concentrated to dryness, and middle chemical combination can be obtained through silica gel column chromatography separating purification in crude product Object 54 (20.7mg, 38.4umol, 22.21%yield), MS m/z:539 [M+1]+.
The preparation of 55 compound 55 of embodiment
Compound 54 (10.00mg, 0.019mmol) is dissolved in 5ml to be dissolved in methanol, 10%Pd/C is added under nitrogen atmosphere (3.00mg), overnight, after raw material disappears, through suction filtered through kieselguhr, filtrate decompression is concentrated to dryness, and MPLC C18 is anti-for normal pressure hydrogenation reaction Phase column purification obtains compound 55 (9.85mg, 0.018mmol, 96%yield), MS m/z:541 [M+1]+.
The preparation of 56 compound 56 of embodiment
Step 1 intermediate 56-1 must be prepared
Under ice bath, 4- pyrazole carboxylic acid ethyl ester (1.00g, 7.14mmol) is dissolved in the anhydrous THF of 20ml, NaH is added portionwise Stirred under nitrogen atmosphere 1 hour, Bromoethyl methyl ether (1.20g, 8.64mmol) then was added in (430.00mg, 17.92mmol), Allow to react nature to be warmed to room temperature, after 2 hours, end of reaction, with 1N HCl tune pH~5, ethyl acetate extraction, saturated salt solution It washes, organic phase anhydrous sodium sulfate dries, filters, and is concentrated under reduced pressure, and intermediate can be obtained through silica gel column chromatography separating purification in crude product 56-1 (1.20g, 6.05mmol, 84.79%yield), MS m/z:199 [M+1]+.
Step 2 intermediate 56-2 must be prepared
Referring to 41 step 6 method of embodiment, intermediate 56-2, MS can be obtained through lithium hydrate by intermediate 56-1 m/z:171[M+1]+.
The preparation of step 3 compound 56
Referring to 41 step 2-7 of embodiment, similarly, contracted by (S)-(-)-Cyclohexylalanine methyl esters and intermediate 56-2 Conjunction, methyl esters hydrolysis are condensed with intermediate 26, close imidazole ring, and ethyl ester hydrolyzes, and compound 56 finally can be obtained with methylamine condensation, MS m/z:495[M+1]+.
The preparation of 57 compound 57 of embodiment
The preparation of step 1 intermediate 57-1 constitutional isomer mixture
Referring to 41 step 4 method of embodiment, being condensed by intermediate 15 and intermediate 26 can be obtained intermediate 57-1 (structure is different Structure body mixture), MS m/z:476 (M+1)+, the two is without separating and in next step.
The preparation of step 2 intermediate 57-2
Referring to 41 step 5 method of embodiment, miaow is heated into acetic acid by intermediate 57-1 (constitutional isomer mixture) Intermediate 57-2, MS m/z:458 (M+1) can be obtained in azoles ring+。
The preparation of step 3 intermediate 57-3
Intermediate 57-2 (1.2g, 2.62mmol) is dissolved in 5mL methylene chloride, and 5mL trifluoroacetic acid is added under ice bath, and drop finishes, It stirs 3 hours, end of reaction, is concentrated under reduced pressure under ice bath, crude product can obtain compound 42 through MPLC reverse phase C18 column purification (800mg, 2.24mol, 85%yield), MS m/z:358 (M+1)+.
The preparation of step 4 intermediate 57-4
Referring to 41 step 2 method of embodiment, it is condensed by intermediate 57-3 and 1- methyl-1 H- pyrazoles -5- carboxylic acid in can be obtained Mesosome 57-4, MS m/z:466 (M+1)+。
The preparation of step 5 intermediate 57-5
Referring to 41 step 6 method of embodiment, intermediate 57-5, MS m/z can be obtained through LiOH hydrolysis by intermediate 57-4: 438(M+1)+。
The preparation of step 6 compound 57
Referring to 41 step 7 method of embodiment, it is condensed by intermediate 57-5 and (2R) -2- amino-N, N- dimethvl-propionamide Compound 57, MS m/z:536 (M+1) can be obtained+, white solid,1H NMR(400MHz,DMSO-d6)δ7.70–7.57(m, 2H), 7.51 (d, J=2.1Hz, 1H), 7.35 (d, J=8.5Hz, 1H), 7.04 (d, J=2.1Hz, 1H), 5.44 (dd, J= 8.8,6.7Hz, 1H), 4.66 (q, J=6.8Hz, 1H), 4.03 (s, 3H), 2.95 (s, 3H), 2.78 (s, 3H), 2.00 (t, J= 7.1Hz,2H),1.84–1.56(m,6H),1.52(s,6H),1.32–1.21(m,2H),1.20–0.92(m,9H).
The preparation of 58 compound 58 of embodiment
Referring to 57 method of embodiment, compound 58 can be obtained by 57-5 and (2R) -2- Amino-N-methyl-propionamide condensation, MS m/z:522(M+1)+, white solid,1H NMR(400MHz,DMSO-d6) δ 7.70-7.60 (m, 2H), 7.52 (d, J= 2.1Hz, 1H), 7.40 (d, J=8.8Hz, 1H), 7.05 (d, J=2.1Hz, 1H), 5.45 (dd, J=9.5,5.9Hz, 1H), 4.23 (q, J=7.1Hz, 1H), 4.03 (s, 3H), 2.07-1.96 (m, 2H), 1.84-1.72 (m, 2H), 1.66 (s, 2H), 1.61 (s, 1H), 1.53 (s, 6H), 1.35-1.23 (m, 1H), 1.16 (dd, J=19.5,9.0Hz, 6H), 1.02 (dt, J= 17.4,7.8Hz,3H).
The preparation of 59 compound 59 of embodiment
Referring to 57 method of embodiment, compound 59 can be obtained by 57-5 and (2R) -2- amino-propionamide condensation, MS m/z: 508(M+1)+, white solid,1H NMR(400MHz,DMSO-d6) δ 7.57 (d, J=8.1Hz, 2H), 7.48 (d, J=2.0Hz, 1H), 7.37-7.16 (m, 1H), 7.05 (t, J=6.7Hz, 1H), 5.51-5.34 (m, 1H), 4.20 (d, J=7.1Hz, 1H), 4.02 (s, 3H), 1.97 (t, J=7.0Hz, 2H), 1.75 (t, J=14.3Hz, 2H), 1.64 (s, 2H), 1.53 (t, J= 16.2Hz,6H),1.37(s,1H),1.31–1.22(m,3H),1.22–0.89(m,7H).
The preparation of 60 compound 60 of embodiment
It referring to 41 step 4-7 of embodiment, is successively condensed by intermediate 41-3 and the intermediate 34 of embodiment 34, closes imidazoles Ring, ethyl ester hydrolysis, is condensed with D-Leu t-butyl ester hydrochloride, and compound can be obtained through trifluoroacetic acid hydrolysis in the last tert-butyl ester 60, MS m/z:551 [M+1]+.
The preparation of 61 compound 61 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 26 intermediate o-phenylenediamine 26 of embodiment, Imidazole ring is closed, ethyl ester hydrolysis is condensed with D-Leu t-butyl ester hydrochloride, and the last tert-butyl ester can be obtained through trifluoroacetic acid hydrolysis Compound 61, MS m/z:565 [M+1]+.1H NMR(400MHz,DMSO-d6) δ 9.11 (d, J=7.2Hz, 1H), 7.57~ 7.63 (m, 2H), 7.54 (d, J=2.4Hz, 1H), 7.41 (d, J=8Hz, 1H), 7.33 (d, J=8Hz), 7.03 (dd, J1= 1.6Hz, J2=2Hz, 1H), 5.45 (dd, J1=7.6Hz, J2=14.8Hz, 1H), 4.39~4.54 (m, 2H), 4.23~4.28 (m, 1H), 1.99 (t, J=7.2Hz, 2H), 1.72~1.84 (m, 2H), 1.65~1.71 (m, 2H), 1.57~1.62 (m, 2H), 1.52 (d, J=2.8Hz, 6H), 1.34~1.46 (m, 3H), 1.28 (t, J=6.8Hz, 3H), 1.11~1.21 (m, 3H), 0.92~1.06 (m, 2H), 0.78 (t, J=5.6Hz, 6H)
The preparation of 62 compound 62 of embodiment
Firstly, referring to 38 method of embodiment, by intermediate 38-1 and 2- (bromo- 1, the 3- dimethyl -1H- pyrazoles -5- base of 4-) Methyl acetate coupling refers again to 57 step 1-6 of embodiment, and coupled product and 15 intermediate 15 of embodiment are condensed, and closes imidazole ring, takes off Boc, introduces 2- methyl-1 H- Pyrazole Acyl, and finally compound 62, MS m/z:557 can be obtained with cyclopentamine condensation in ester hydrolysis [M+1]+.
The preparation of 63 compound 63 of embodiment
Firstly, referring to 38 method of embodiment, by intermediate 38-1 and 2- (bromo- 1, the 3- dimethyl -1H- pyrazoles -5- base of 4-) Methyl acetate coupling refers again to 57 step 1-6 of embodiment, and coupled product and 15 intermediate 15 of embodiment are condensed, and closes imidazole ring, takes off Boc, introduces 2- methyl-1 H- Pyrazole Acyl, and finally compound 63, MS m/z:531 can be obtained with the condensation of 2- propylamine in ester hydrolysis [M+1]+.
The preparation of 64 compound 64 of embodiment
Referring to 41 step 4-7 of embodiment, successively it is condensed by intermediate 41-3 and 35 intermediate o-phenylenediamine 35 of embodiment, Closing imidazole ring can be obtained compound 64, MS m/z:460 [M+1]+.
The preparation of 65 compound 65 of embodiment
The preparation of step 1 intermediate 65-1
By 2- methyl -6,7- pyrazoline [1,5-a], simultaneously pyrazine -5 (4H)-benzyloxycarbonyl group (110mg, 0.405mmol) is molten In the DMF of 1mL, it is added NBS (72mg, 0.405mmol), is stirred at room temperature 3 hours, silica gel column chromatography separating purification can obtain bromo Intermediate 65-1, MS m/z:350 [M+1]+.
The preparation of step 2 intermediate 65-2
Referring to 38 method of embodiment, it is coupled by pinacol borate 38-1 and 65 step 2 gained bromo-derivative 65-1 of embodiment Intermediate 65-2, MS m/z:378 [M+1] can be obtained+.
The preparation of step 3 compound 65
Referring to 57 step 1-6 of embodiment, successively it is condensed, closes through 15 intermediate 15 and 65 intermediate 65-2 of embodiment of embodiment Imidazole ring takes off Boc, introduces 2- methyl-1 H- Pyrazole Acyl, then hydrogenate de- Cbz protecting group and compound 65 can be obtained, MS m/z: 487[M+1]+.
The preparation of 66 compound 66 of embodiment
Embodiment compound 65 (20mg, 41.10umol) is dissolved in the DCM of 1ml, cyclopenta isocyanates (4.57mg, 1ml dichloromethane solution 41.10umol) is added dropwise wherein, and drop finishes, and reacts at room temperature 4 hours, and concentration, crude product is through MPLC reverse phase C18 Column separating purification can obtain compound 66, MS m/z:598 [M+1]+.
The preparation of 67 compound 67 of embodiment
Referring to 57 step 1-6 method of embodiment, four isomer mixtures (before fractionation) of 14 intermediate 14 of embodiment with 41 intermediate 41-1 of embodiment condensation, close imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ester hydrolysis, finally with Compound 67, MS m/z:548 [M+1] can be obtained in methylamine hydrochloride condensation+.
The preparation of 68 compound 68 of embodiment
Referring to 57 step 1-6 method of embodiment, the single stereoisomers 14a and embodiment 41 of 14 intermediate 14 of embodiment Intermediate 41-1 condensation, close imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ester hydrolysis, finally with methylamine hydrochloric acid Compound 68, MS m/z:548 [M+1] can be obtained in salt condensation+.
The preparation of 69 compound 69 of embodiment
Referring to 57 step 1-6 method of embodiment, the single stereoisomers 14d and embodiment 41 of 14 intermediate 14 of embodiment Intermediate 41-1 condensation, close imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ester hydrolysis, finally with methylamine hydrochloric acid Compound 69, MS m/z:548 [M+1] can be obtained in salt condensation+.
The preparation of 70 compound 70 of embodiment
Referring to 57 step 1-6 method of embodiment, the single stereoisomers 14b and embodiment 41 of 14 intermediate 14 of embodiment Intermediate 41-1 condensation, close imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ester hydrolysis, finally with methylamine hydrochloric acid Compound 70, MS m/z:548 [M+1] can be obtained in salt condensation+.
The preparation of 71 compound 71 of embodiment
Referring to 57 step 1-6 method of embodiment, the single stereoisomers 14c and embodiment 41 of 14 intermediate 14 of embodiment Intermediate 41-1 condensation, close imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ester hydrolysis, finally with methylamine hydrochloric acid Compound 71, MS m/z:548 [M+1] can be obtained in salt condensation+.
The preparation of 72 compound 72 of embodiment
Referring to 57 step 1-6 method of embodiment, four isomer mixtures (before fractionation) of the intermediate 16 of embodiment 16 It is condensed with 26 intermediate 26 of embodiment, closes imidazole ring, take off Boc, introduce 1- ethyl -1H- pyrazoles -5- acyl group, ethyl ester hydrolyzes, finally Compound 72, MS m/z:552 [M+1] can be obtained with (2R) -2- Amino-N-methyl-propionamide condensation+。
The preparation of 73 compound 73 of embodiment
The preparation of step 1 intermediate 73-1 constitutional isomer mixture
Referring to 41 step 4 method of embodiment, can be obtained by the adjacent chloro- D-Boc- phenylalanine of starting material with the condensation of intermediate 34 To intermediate 73-1 (constitutional isomer mixture), MS m/z:490 (M+1)+, the two is without separating and in next step.
The preparation of step 2 intermediate 73-2
Referring to 41 step 5 method of embodiment, miaow is heated into acetic acid by intermediate 73-2 (constitutional isomer mixture) Intermediate 73-2, MS m/z:472 (M+1) can be obtained in azoles ring+。
The preparation of step 3-6 compound 73
Referring to 57 step 3-6 of embodiment, Boc successively is taken off by intermediate 73-2, is contracted with 1- methyl-1 H- pyrazoles -5- carboxylic acid It closes, ethyl ester hydrolysis is condensed with D-Leu t-butyl ester hydrochloride, and compound can be obtained through trifluoroacetic acid hydrolysis in the last tert-butyl ester 73, MS m/z:579 [M+1]+.
The preparation of 74 compound 74 of embodiment
The preparation of step 1 intermediate 74-1
2- methyl -2- (4- nitrobenzophenone) ethyl propionate (40.0g, 168.6mmol) is dissolved in ethyl alcohol (600mL), room temperature Under sodium hydroxide (10.1g, 252.9mmol) is added portionwise, finish and be warming up to 80 DEG C and be stirred to react 2 hours.Evaporating solvent under reduced pressure, 1N HCl solution is added dropwise under ice bath and adjusts pH~4, ethyl acetate extracts 3 times, merges organic phase, and anhydrous sodium sulfate is dry, decompression Intermediate 74-1 (33.5g, 160.2mmol, yield 95%) is obtained after solvent is evaporated off.MS m/z:210[M+1]+.
The preparation of step 2 intermediate 74-2
Intermediate 74-1 (33.5g, 160.2mmol) is dissolved in DMF (500mL), under ice bath be added HBTU (72.9g, 192.2mmol), n,N-diisopropylethylamine (45.5g, 352.4mmol) and ammonium chloride (12.9g, 240.3mmol) finish liter It warms to room temperature and is stirred to react 2 hours.Then it is extracted with water and ethyl acetate, then water phase is extracted with ethyl acetate twice, merged Organic phase, anhydrous sodium sulfate is dry, and intermediate 74-2 crude product (29.0g, 139.3mmol, yield are obtained after evaporating solvent under reduced pressure 87%).MS m/z:209[M+1]+.
The preparation of step 3 intermediate 74-3
Intermediate 74-2 (29.0g, 139.3mmol) is dissolved in methanol (300mL), palladium carbon (2.9g, palladium content is added 10%), reaction system is replaced three times with hydrogen, and (1atm) is stirred 12 hours under an atmosphere of hydrogen.Reactant diatomite mistake Filter, evaporating solvent under reduced pressure is to get intermediate 74-3 (22.4g, 125.4mmol, yield 90%).MS m/z:179[M+1]+.
The preparation of step 4 intermediate 74-4
Intermediate 74-3 (22.4g, 125.4mmol) is dissolved in tetrahydrofuran (300mL), 1M borine tetrahydro is added dropwise under ice bath Tetrahydrofuran solution (627.0mL, 627.0mmol) is added dropwise lower 60 DEG C of nitrogen protection and is stirred to react 12 hours.Saturation chlorination is added Ammonium salt solution quenching reaction, ethyl acetate extraction merge organic phase, and anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure is purified through MPLC Intermediate 74-4 is obtained after (eluent gradient: acetonitrile: water=0:100 to 40:60 20 minutes, contains 0.005% formic acid in water) (12.4g, 75.2mmol, yield 60%).MS m/z:165[M+1]+.
The preparation of step 5 intermediate 74-5
Intermediate 74-4 (12.4g, 75.2mmol) is dissolved in tetrahydrofuran (500mL), 0 DEG C of addition triethylamine (30.4g, 300.8mmol) and benzene methoxy carbonyl acyl succinimide (39.4g, 157.9mmol).Then heat to that reaction is stirred at room temperature is 1 small When.Be purified by silica gel column chromatography (eluant, eluent: petroleum ether: ethyl acetate=5:1) afterwards up to intermediate 74-5 (30.6g, 70.7mmol, yield 94%).MS m/z:433[M+1]+.
The preparation of step 6 intermediate 74-6
Intermediate 74-5 (30.6g, 70.7mmol) is dissolved in acetic anhydride (300mL), 0 DEG C of dropwise addition nitric acid (6.3mL, 141.4mmol), continuation is added dropwise to be stirred to react at 0 DEG C 5 hours.It is purified by silica gel column chromatography (eluant, eluent: petroleum ether: second Acetoacetic ester=3:1), it is rear up to intermediate 74-6 (22.3g, 46.7mmol, yield 66%).MS m/z:478[M+1]+.
The preparation of step 7 intermediate 74-7
Intermediate 74-6 (22.3g, 46.7mmol) is dissolved in ethyl alcohol (400mL), sodium hydroxide is added portionwise at room temperature (1.9g, 46.7mmol) is finished and is warming up to 70 DEG C and is stirred to react 1 hour.Then it is extracted with water and ethyl acetate, then water phase is used Ethyl acetate is extracted twice, and merges organic phase, and anhydrous sodium sulfate is dry, and intermediate 74-7 crude product is obtained after evaporating solvent under reduced pressure (15.4g, 44.8mmol, yield 96%).MS m/z:344[M+1]+.
The preparation of step 8 intermediate 74-8
Intermediate 74-7 crude product (15.4g, 44.8mmol) is dissolved in methanol (600mL), under ice bath be added zinc powder (14.6g, 224.0mmol) and ammonium chloride (239.6g, 448.0mmol), it finishes to be warmed to room temperature and be stirred to react 1 hour.Zinc powder is filtered to remove, Evaporating solvent under reduced pressure, through MPLC purifying, (eluent gradient: acetonitrile: water=0:100 to 50:50 20 minutes, contains 0.005% in water Formic acid) after intermediate 74-8 (12.5g, 40mmol, yield 89%), MS m/z:314 [M+1]+.
The preparation of step 9 intermediate 74-9
Referring to 57 step 1-4 of embodiment, using the single stereoisomers 2-c of 2 intermediate 2 of embodiment as raw material, with implementation 74 intermediate o-phenylenediamine 74-8 of example condensation, closes imidazole ring, takes off Boc, can be obtained with the condensation of 1- methyl-1 H- pyrazoles -5- carboxylic acid Intermediate 74-9, MS m/z:627 [M+1]+.
The preparation of step 10 intermediate 74-10
Intermediate 74-9 (1.25g, 2.0mmol) is dissolved in methanol (20mL), palladium carbon is added at room temperature, and (140.0mg, palladium contain Amount is 10%).Reaction system is replaced three times with hydrogen, and (1atm) is stirred 12 hours under an atmosphere of hydrogen.Reactant diatomite Filtering, evaporating solvent under reduced pressure is to get intermediate 74-10 crude product (0.935g, 1.9mmol, yield 96%).MS m/z:493[M+ 1]+.
The preparation of step 11 compound 74
Referring to 41 step 7 method of embodiment, compound 74 can be obtained by intermediate 74-10 and chloroacetic chloride condensation, MS m/z: 535(M+1)+.
The preparation of 75 compound 75 of embodiment
Referring to 74 method of embodiment, with the single stereoisomers 2-d of 2 intermediate 2 of embodiment pass through in embodiment 74 Mesosome o-phenylenediamine 74-8 condensation, cyclization take off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, finally and acetyl Compound 75, MS m/z:535 (M+1) can be obtained in chlorine condensation+.
The preparation of 76 compound 76 of embodiment
Referring to 74 method of embodiment, with the single stereoisomers 2-b of 2 intermediate 2 of embodiment pass through in embodiment 74 Mesosome o-phenylenediamine 74-8 condensation, cyclization take off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, finally and acetyl Compound 76, MS m/z:535 (M+1) can be obtained in chlorine condensation+.
The preparation of 77 compound 77 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single stereoisomers 2-a of 2 intermediate 2 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, finally Compound 77, MS m/z:535 (M+1) can be obtained with chloroacetic chloride condensation+.
The preparation of 78 compound 78 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single stereoisomers 13-a of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 78, MS m/z:547 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.1HNMR(400MHz,DMSO-d6)δ12.67(s, 1H), 8.79 (s, 1H), 8.42 (s, 1H), 7.58 (t, J=4.0Hz, 1H), 7.52 (s, 2H), 7.42 (t, J=9.6,2H), 7.36-7.32 (m, 2H), 7.24-7.19 (m, 2H), 6.67 (d, J=2.0Hz, 1H), 5.59 (t, J=10.0Hz, 1H), 4.13 (t, J=10.0Hz, 1H), 3.83 (s, 3H), 2.69-2.63 (m, 1H), 2.36-2.33 (m, 1H), 1.78 (s, 3H), 1.56- 1.49(m,2H),1.46-1.39(m,2H),1.30(s,6H),1.25-1.15(m,2H).
The preparation of 79 compound 79 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single stereoisomers 13-d of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 79, MS m/z:547 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 80 compound 80 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single stereoisomers 13-b of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 80, MS m/z:547 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 81 compound 81 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single stereoisomers 13-c of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 81, MS m/z:547 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.1HNMR(400MHz,DMSO-d6)δ12.10(s, 1H), 8.93 (s, 1H), 7.54 (t, J=5.6Hz, 1H), 7.48 (d, J=2.0Hz, 1H), 7.45-7.41 (m, 1H), 7.35 (d, J=7.6Hz, 1H), 7.30 (d, J=7.6Hz, 2H), 7.23 (t, J=7.2Hz, 1H), 7.16-7.09 (m, 2H), 7.07 (d, J=2.0Hz, 1H), 5.73 (t, J=8.8Hz, 1H), 4.27 (t, J=8.8Hz, 1H), 4.01 (s, 3H), 3.27-3.25 (m,2H),2.97-2.87(m,1H),1.89-1.79(m,2H),1.76(s,3H),1.69(dd,J1=8.4, J2=18.0, 1H),1.59-1.46(m,3H),1.25(s,6H).
The preparation of 82 compound 82 of embodiment
The preparation of step 1 intermediate 82-1
Referring to the method that embodiment 1 prepares intermediate 1, using benzaldehyde as starting material through condensation, grignard reaction, nitro also Former, Boc protection amino, hydrolysis, most can respectively obtain intermediate 82-1 tetra- through the preparation of SFC chiral resolution post separation afterwards A single chiral isomers 82-1a, 82-1b, 82-1c, 82-1d.MS m/z:320[M+1]+。
The preparation of step 2 compound 82
Referring to 74 method of embodiment, pass through by raw material of the single chiral isomers 81-1b of 82 intermediate 82-1 of embodiment It is condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization, takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, hydrogenation takes off Finally compound 82, MS m/z:539 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in Cbz+.
The preparation of 83 compound 83 of embodiment
Referring to 74 method of embodiment, pass through by raw material of the single chiral isomers 81-1c of 82 intermediate 82-1 of embodiment It is condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization, takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, hydrogenation takes off Finally compound 83, MS m/z:539 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in Cbz+.
The preparation of 84 compound 84 of embodiment
Referring to 74 method of embodiment, pass through by raw material of the single chiral isomers 81-1a of 82 intermediate 82-1 of embodiment It is condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization, takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, hydrogenation takes off Finally compound 84, MS m/z:539 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in Cbz+.
The preparation of 85 compound 85 of embodiment
Referring to 74 method of embodiment, pass through by raw material of the single chiral isomers 81-1d of 82 intermediate 82-1 of embodiment It is condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization, takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, hydrogenation takes off Finally compound 85, MS m/z:539 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in Cbz+.
The preparation of 86 compound 86 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 13-b of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 86, MS m/z:573 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 87 compound 87 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 13-c of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 87, MS m/z:573 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1H NMR(400MHz,DMSO-d6)δ12.44 (s, 1H), 8.67 (d, J=10.0Hz, 1H), 7.79 (t, J=6.0Hz, 1H), 7.60-7.48 (m, 2H), 7.44-7.29 (m, 5H), 7.26-7.19 (m, 2H), 6.65 (d, J=2.0Hz, 1H), 5.58 (t, J=6.0Hz, 1H), 4.12 (t, J=5.6Hz, 1H),3.83(s,3H),2.71-2.63(m,1H),1.65-1.40(m,6H),1.31(s,6H),0.63-0.56(m,5H).
The preparation of 88 compound 88 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 13-a of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 88, MS m/z:573 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 89 compound 89 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 13-d of 13 intermediate 13 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 89, MS m/z:573 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 90 compound 90 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 19-b of 19 intermediate 19 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 90, MS m/z:643 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 91 compound 91 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 19-d of 19 intermediate 19 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 91, MS m/z:643 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 92 compound 92 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 19-a of 19 intermediate 19 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 92, MS m/z:643 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 93 compound 93 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 19-c of 19 intermediate 19 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 93, MS m/z:643 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.1HNMR(400MHz,CD3OD) δ=8.42 (br, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.61~7.69 (m, 2H), 7.56 (d, J=8.4Hz, 1H), 7.33~7.44 (m, 4H), 6.48 (s, 1H), 6.10 (d, J=10.0Hz, 1H), 4.17~4.24 (m, 1H), 3.87 (s, 3H), 3.47 (s, 2H), 1.92~2.03 (m, 1H), 1.88 (s, 3H), 1.55 (d, J=6.4Hz, 6H), 1.30~1.41 (m, 6H), 1.01 (d, J= 6.4Hz, 3H), 0.90 (d, J=6.8Hz, 3H)
The preparation of 94 compound 94 of embodiment
The preparation of step 1 intermediate 94-1
Referring to the method that embodiment 1 prepares intermediate 1, using benzaldehyde as starting material, through condensation, grignard reaction, nitro Reduction, Boc protection amino, hydrolysis, can most respectively obtain four lists of intermediate 94-1 through the preparation of SFC chiral resolution post separation afterwards One chiral isomer 94-1a, 94-1b, 94-1c, 94-1d.MS m/z:308[M+1]+。
The preparation of step 2 compound 94
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 94-1b of step 1 intermediate 94-1 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 94, MS m/z:527 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1H NMR(400MHz,MeOD):δ7.54(s, 1H), 7.48 (d, J=8.7Hz, 1H), 7.37 (d, J=7.6Hz, 1H), 7.27-7.12 (m, 7H), 6.33 (d, J=2.1Hz, 1H), 5.86 (d, J=9.8Hz, 1H), 4.97 (d, J=3.2Hz, 1H), 4.16 (t, J=6.1Hz, 1H), 3.52-3.44 (m, 1H), 3.42-3.33 (m, 3H), 3.13 (dd, J=11.5,6.9Hz, 1H), 1.78 (ddd, J=19.2,12.0,6.5Hz, 2H), 1.60 (dt, J=13.1,6.5Hz, 1H), 1.36-1.27 (m, 6H), 0.83 (d, J=6.7Hz, 3H), 0.77 (d, J= 6.7Hz, 3H), 0.64 (dt, J=5.8,3.8Hz, 2H), 0.56 (ddd, J=10.2,6.6,3.8Hz, 2H)
The preparation of 95 compound 95 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 94-1c of 94 step 1 intermediate 94-1 of embodiment as raw material By being condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, hydrogenation Finally compound 95, MS m/z:527 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in de- Cbz+.
The preparation of 96 compound 96 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 94-1a of step 1 intermediate 94-1 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 96, MS m/z:527 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 97 compound 97 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 94-1d of step 1 intermediate 94-1 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 97, MS m/z:527 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 98 compound 98 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-b of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Finally compound 98, MS m/z:579 (M+1) can be obtained with chloroacetic chloride condensation in Cbz+.
The preparation of 99 compound 99 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-c of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Finally compound 99, MS m/z:579 (M+1) can be obtained with chloroacetic chloride condensation in Cbz+.
The preparation of 100 compound 100 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-c of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Finally compound 100, MS m/z:627 (M+1) can be obtained with chloroacetic chloride condensation in Cbz+.
The preparation of 101 compound 101 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-a of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Cbz is finally condensed available 101, MS m/z:579 (M+1) with chloroacetic chloride+.
The preparation of 102 compound 102 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-d of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Finally compound 102, MS m/z:579 (M+1) can be obtained with chloroacetic chloride condensation in Cbz+.
The preparation of 103 compound 103 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 103, MS m/z:615 (M+1) can be obtained with chloroacetic chloride condensation afterwards+.
The preparation of 104 compound 104 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 104, MS m/z:671 (M+1) can be obtained with the condensation of 3- tetrahydrofuran formic acid afterwards+.
The preparation of 105 compound 105 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 105, MS m/z:641 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 106 compound 106 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-b of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 106, MS m/z:641 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 107 compound 107 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-a of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 107, MS m/z:641 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 108 compound 108 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of 18 intermediate of embodiment, 18 single chiral isomers 18-c 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, with 1- The condensation of Boc- pyrrolidines -3- formic acid, last trifluoroacetic acid, which takes off Boc, can be obtained compound 108, MS m/z:670 (M+1)+.1H NMR(400MHz,DMSO-d6) δ 0.79 (d, J=8.4Hz, 3H) 0.84 (d, J=6.8Hz, 3H) 1.32 (d, J=4.0Hz, 6H) 1.66~1.76 (m, 1H) 1.83~1.91 (m, 1H) 1.97~2.06 (m, 1H) 3.02~3.07 (m, 3H) 3.17~3.21 (m, 2H) 3.78 (s, 3H) 3.87 (s, 3H) 4.11~4.22 (m, 2H) 6.07 (t, J=9.2Hz, 1H) 6.60 (s, 1H) 7.32~ 7.38 (m, 5H) 7.55~7.61 (m, 3H) 7.83 (s, 1H) 7.96 (t, J=6.4Hz, 1H) 8.09 (s, 1H) 8.73~8.96 (brs,3H)。
The preparation of 109 compound 109 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 109, MS m/z:655 (M+1) can be obtained with the condensation of ring fourth formic acid afterwards+.
The preparation of 110 compound 110 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 110, MS m/z:669 (M+1) can be obtained with cyclopentanecarboxylic acid condensation afterwards+.
The preparation of 111 compound 111 of embodiment
The preparation of step 1 intermediate 111-1
Referring to the method that embodiment 1 prepares intermediate 1, using acetaldehyde as starting material, be condensed with ethyl nitroacetate, with Chloro-O-Phenyl magnesium bromide carries out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis, most afterwards through SFC chiral resolution Post separation prepares four single chiral the isomers 111-1a, 111-1b, 111-1c, 111- that can respectively obtain intermediate 111-1 1d。MS m/z:314[M+1]+。
The preparation of step 2 compound 111
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 111-1c of intermediate 111-1 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, finally Compound 111, MS m/z:533 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride+.
The preparation of 112 compound 112 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 112, MS m/z:643 (M+1) can be obtained with n-butyric acie condensation afterwards+.
The preparation of 113 compound 113 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, with The condensation of 1-Boc- pyrrolidines -3- acetic acid, last trifluoroacetic acid, which takes off Boc, can be obtained compound 113, MS m/z:684 (M+1)+.
The preparation of 114 compound 114 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 114, MS m/z:655 (M+1) can be obtained with Cyclopropylacetic acid condensation afterwards+.
The preparation of 115 compound 115 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 19-c of 19 intermediate 19 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 115, MS m/z:669 (M+1) can be obtained with Cyclopropylacetic acid condensation afterwards+.1H NMR (400MHz, DMSO): δ=12.64 (s,1H),8.36(s,1H),8.16(s,1H),7.83(s,1H),7.78(s,1H),7.58(s,1H),7.46(s,1H),7.40 (d, J=2.4Hz, 2H), 7.29 (d, J=2.0Hz, 2H), 6.55 (d, J=2.0Hz, 1H), 6.02 (t, J=10.0Hz, 1H), 4.55-4.51 (m, 1H), 4.28 (d, J=11.2Hz, 1H), 3.77 (s, 3H), 2.68 (t, J=1.6Hz, 1H), 2.34 (t, J =2.0Hz, 1H), 1.85 (s, 1H), 1.63 (m, 1H), 1.47 (d, J=6.4Hz, 6H), 1.31 (s, 6H), 1.25 (s, 1H), 0.81 (t, J=8.0Hz 6H), 0.63-0.57 (m, 4H)
The preparation of 116 compound 116 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 116, MS m/z:671 (M+1) can be obtained with the condensation of 4- methylvaleric acid afterwards+.
The preparation of 117 compound 117 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 117, MS m/z:643 (M+1) can be obtained with isobutyric acid condensation afterwards+.1H NMR(400MHz,DMSO-d6)δ12.57(s, 1H), 8.88 (s, 1H), 8.08 (s, 1H), 7.81 (d, J=0.8Hz, 1H), 7.56 (s, 2H), 7.52-7.43 (m, 2H), 7.43-7.34 (m, 2H), 7.29 (d, J=0.8Hz, 1H), 7.26-7.23 (m, 1H), 6.53 (d, J=2.0Hz, 1H), 6.00 (t, J=10.0Hz, 1H), 4.26 (dd, J1=4.0Hz, J2=10.8Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.45- 2.31 (m, 1H), 2.05-1.95 (m, 1H), 1.90-1.75 (m, 1H), 1.30 (s, 6H), 0.93 (d, J=6.8Hz, 6H), 0.81 (d, J=6.8Hz, 6H)
The preparation of 118 compound 118 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 118, MS m/z:657 (M+1) can be obtained with 3 Methylbutanoic acid condensation afterwards+.
The preparation of 119 compound 119 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-c of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid-acetic acid takes off Cbz is condensed with cyclopropyl formyl chloride, refers again to 18 step 2 method of embodiment, is coupled with 20 intermediate 20 of embodiment, last trifluoro Acetic acid, which takes off Boc protecting group, can be obtained compound 119, MS m/z:710 (M+1)+.1H NMR(400MHz,DMSO-d6)δ8.92 (d, J=6.4Hz, 1H), 8.18 (s, 1H), 7.89 (s, 1H), 7.79 (t, J=5.2Hz, 1H), 7.59 (s, 1H), 7.46~ 7.56 (m, 2H), 7.41 (m, 2H), 7.25~7.29 (m, 2H), 6.54 (s, 1H), 6.02 (t, J=10.4Hz, 1H), 4.43 (s, 1H), 4.26 (dd, J1=3.2Hz, J2=11.6Hz, 1H), 3.76 (s, 3H), 2.94 (s, 2H), 2.11~2.23 (m, 3H), 1.94~2.11 (m, 3H), 1.76~1.91 (m, 2H), 1.58~1.67 (m, 2H), 1.31 (s, 6H), 1.24 (s, 1H), 0.81 (d, J=5.2Hz, 6H), 0.57~0.63 (m, 4H)
The preparation of 120 compound 120 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 120, MS m/z:666 (M+1) can be obtained with the condensation of N- methylamino sulfonic acid chloride afterwards+.
The preparation of 121 compound 121 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 121, MS m/z:678 (M+1) can be obtained with niacin condensation afterwards+.
The preparation of 122 compound 122 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 122, MS m/z:681 (M+1) can be obtained with the condensation of 1- methylpyrazole -4- formic acid afterwards+.
The preparation of 123 compound 123 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 123, MS m/z:657 (M+1) can be obtained with the condensation of cyclopropyl chloro-formate afterwards+.
The preparation of 124 compound 124 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 124, MS m/z:668 (M+1) can be obtained with the condensation of oxazole -2- carboxylic acid afterwards+.
The preparation of 125 compound 125 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 125, MS m/z:677 (M+1) can be obtained with the condensation of cyclopropyl sulfonic acid chloride afterwards+.
The preparation of 126 compound 126 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Afterwards with N, N- dimethyl methyl acyl chlorides, which is condensed, can be obtained compound 126, MS m/z:644 (M+1)+.
The preparation of 127 compound 127 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 127, MS m/z:651 (M+1) can be obtained with mesyl chloride condensation afterwards+.
The preparation of 128 compound 128 of embodiment
The preparation of step 1 intermediate 128-1
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, obtains Amino intermediate takes the intermediate (100mg, 174.48umol), is dissolved in 3ml methanol, addition glyoxylic acid ethyl ester (17.81mg, 174.48umol), it stirs at 60 DEG C 1 hour, NaBH3CN (32.89mg, 523.44umol) is then added and continues 60 DEG C of stirrings Overnight, water quenching is added to go out, ethyl acetate extraction is concentrated under reduced pressure, and intermediate can be obtained through silica gel column chromatography separating purification in crude product 128-1, MS m/z:659 (M+1)+.
The preparation of step 2 compound 128
Intermediate 128-1 (13mg, 19.72umol) is dissolved in 1ml acetic acid, be added potassium cyanate (1.92mg, 23.66umol), reaction is stirred at room temperature overnight, compound 128 can be obtained by MPLC C18 column separating purification after concentration (5.01mg, 7.40umol, 37.52%yield, 96.9%purity), MS m/z:656 (M+1)+.1H NMR(400MHz, DMSO-d6) δ=12.71 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.81 (s, 1H), 7.55 (s, 2H), 7.41-7.33 (m, 2H), 7.31-7.18 (m, 2H), 6.53 (d, J=1.6Hz, 1H), 6.01 (t, J=10.4Hz, 1H), 4.28-4.21(m,1H),3.88(s,3H),3.78(s,3H),3.46(s,2H),1.85(s,1H),1.36(s,4H),1.29 (s,2H),0.83-0.77(m,6H).
The preparation of 129 compound 129 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, with 128 step 1 method of reference implementation example afterwards, carrying out reduction amination with 4- methyl -2- oxopentanoic acid can be obtained compound 129, MS m/z:687(M+1)+.1H NMR(400MHz,MeOD):δ7.98(s,1H),7.86(s,1H),7.71(s,1H),7.63-7.65 (m, 1H), 7.28-7.46 (m, 5H), 6.472-6.476 (d, 1H, J=1.6Hz), 6.094-6.12 (d, 1H, J=10Hz), 4.21-4.27(m,1H),3.96(s,3H),3.86(s,3H),3.71-3.79(m,1H),3.40-3.50(m,1H),1.64- 1.80 (m, 3H), 1.57-1.59 (d, 5H, J=5.2Hz), 1.38-1.41 (m, 3H), 0.99-1.01 (d, 2H, J=7.2Hz), 0.89-0.93(m,9H).
The preparation of 130 compound 130 of embodiment
The preparation of step 1 intermediate 130-1
Compound 129 (20mg, 29.10umol) is dissolved in 10ml methanol, the addition catalytic amount concentrated sulfuric acid (285.42ug, 2.91umol,1.55e-1UL), stirred 12 hours in 60 DEG C, LC-MS tracks raw material and disappears, and water, acetic acid is added after reaction solution concentration Ethyl ester extraction, by silica gel column chromatography separating purification (MeOH:DCM=1:10) after concentration, crude product is prepared through efficient liquid phase again (water:ACN=1:1) it can be obtained intermediate 130-1 (20mg, 25.67umol, 88.20%yield), MS m/z:701 (M +1)+.
The preparation of step 2 compound 130
Referring to 128 step 2 method of embodiment, compound can be obtained with cyanic acid nak response cyclization in acetic acid by 130-1 130, MS m/z:712 (M+1)+.1H NMR(400MHz,MeOD):δ8.52(s,1H),7.98(s,1H),7.86(s,1H), 7.63(s,2H),7.34-7.48(m,3H),6.49(s,1H),6.09-6.12(m,1H),4.63(s,2H),4.19-4.21(m, 1H),3.88-3.96(m,6H),3.34-3.40(m,2H),1.96-2.00(m,1H),1.60-1.66(m,1H),1.46-1.50 (d, 4H, J=16Hz), 1.24-1.27 (m, 2H), 1.02-1.03 (d, 3H, J=6Hz), 0.89-0.91 (d, 3H, J= 6.8Hz), 0.73-0.75 (t, 3H, J=6Hz), 0.35-0.37 (d, 3H, J=6.4Hz)
The preparation of 131 compound 131 of embodiment
The preparation of step 1 intermediate 131-1
Referring to the method that embodiment 1 prepares intermediate 1, using acetaldehyde as starting material, be condensed with ethyl nitroacetate, with Chloro-O-Phenyl magnesium bromide carries out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis, most afterwards through SFC chiral resolution Post separation prepares four single chiral the isomers 131-1a, 131-1b, 131-1c, 131- that can respectively obtain intermediate 131-1 1d。MS m/z:214[M-99]+, 258 [M-55]+。
The preparation of step 2 compound 131
Referring to 74 method of embodiment, passed through by raw material of the single chiral isomers 131-c of 131 intermediate 131-1 of embodiment It crosses and is condensed with 74 intermediate o-phenylenediamine 74-8 of embodiment, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrogenation takes off Finally compound 131, MS m/z:533 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride in Cbz+.1H NMR(400MHz,DMSO- d6): δ=7.83 (s, 1H), 7.64 (s, 1H), 7.46-7.36 (m, 6H), 7.21 (t, J=8.0Hz, 2H), 6.54 (s, 1H), 6.47 (s, 1H), 5.90 (s, 1H), 5.63 (s, 1H), 4.89 (d, J=4.4Hz, 1H), 4.84 (d, J=4.0Hz, 1H), 4.43 (s, 2H), 3.83 (s, 2H), 3.33 (d, J=6.0Hz, 2H), 1.74 (s, 1H), 1.60 (s, 1H), 1.43 (s, 1H), 1.27 (s,6H),1.25(s,1H),0.63-0.58(m,4H).
The preparation of 132 compound 132 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 11-c of 11 intermediate 11 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 132, MS m/z:547 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1H NMR(400MHz,DMSO-d6)δ 8.87 (d, J=8.8Hz, 1H), 7.78 (t, J=5.6Hz, 1H), 7.49~7.62 (m, 2H), 7.47 (d, J=7.6Hz, 1H), 7.42 (d, J=8Hz, 1H), 7.31~7.37 (m, 2H), 7.20~7.26 (m, 2H), 6.3 (d, J=1.6Hz, 1H), 5.70 (s, 1H), 4.00~4.15 (m, 1H), 3.83 (s, 3H), 3.35 (s, 2H), 1.46~1.66 (m, 3H), 1.31 (s, 6H), 1.24 (s, 1H), 0.56~0.65 (m, 7H)
The preparation of 133 compound 133 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 11-a of 11 intermediate 11 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 133, MS m/z:547 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1H NMR(400MHz,DMSO-d6)δ 9.42 (d, J=7.6Hz, 1H), 7.82 (t, J=6Hz, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.53 (d, J=2Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.8Hz, 1H), 7.33 (t, J=7.2Hz, 1H), 7.27~7.29 (m, 1H), 7.15 ~7.21 (m, 1H), 7.12 (d, J=2Hz, 1H), 5.71 (s, 1H), 4.09~4.18 (m, 1H), 3.97 (s, 3H), 3.32 (d, J=6Hz, 2H), 1.96~2.11 (m, 2H), 1.82~1.94 (m, 1H), 1.52~1.58 (m, 1H), 1.27 (d, J=2Hz, 6H), 0.71 (t, J=7.6Hz, 3H), 0.53~0.57 (m, 4H)
The preparation of 134 compound 134 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 11-d of 11 intermediate 11 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 134, MS m/z:547 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 135 compound 135 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 11-b of 11 intermediate 11 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 135, MS m/z:547 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 136 compound 136 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 136, MS m/z:560 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1HNMR(400MHz,DMSO-d6)δ 12.21 (s, 1H), 8.99 (d, J=8.4Hz, 1H), 7.76 (t, J=5.6Hz, 1H), 7.56 (d, J=6.4Hz, 1H), 7.49 (d, J=1.6Hz, 1H), 7.44-7.22 (m, 4H), 7.17-7.12 (m, 2H), 7.10 (s, 1H), 5.95 (t, J=8.8Hz, 1H),4.00(s,3H),3.53-3.50(m,2H),3.32-3.30(m,2H),1.64-1.59(m,1H),1.42-1.31(m, 1H),1.26(s,6H),0.62-0.56(m,4H),0.44-0.39(m,2H),0.31-0.23(m,1H),-0.02--0.05(m, 1H).
The preparation of 137 compound 137 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-a of 12 intermediate 12 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 137, MS m/z:560 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1H NMR(400MHz,DMSO-d6)δ 9.42 (d, J=7.6Hz, 1H), 7.82 (t, J=6Hz, 1H), 7.57 (s, 1H), 7.55 (s, 1H), 7.53 (d, J=2Hz, 1H), 7.51 (s, 1H), 7.43 (d, J=8.8Hz, 1H), 7.33 (t, J=7.2Hz, 1H), 7.27~7.29 (m, 1H), 7.15 ~7.21 (m, 1H), 7.12 (d, J=2Hz, 1H), 5.71 (s, 1H), 4.09~4.18 (m, 1H), 3.97 (s, 3H), 3.32 (d, J=6Hz, 2H), 1.96~2.11 (m, 2H), 1.82~1.94 (m, 1H), 1.52~1.58 (m, 1H), 1.27 (d, J=2Hz, 6H), 0.71 (t, J=7.6Hz, 3H), 0.53~0.57 (m, 4H)
The preparation of 138 compound 138 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-d of 12 intermediate 12 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 138, MS m/z:560 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 139 compound 139 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-b of 12 intermediate 12 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 139, MS m/z:560 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.1HNMR(400MHz,DMSO-d6)δ 12.62 (s, 1H), 8.87 (s, 1H), 7.80 (t, J=6.0Hz, 1H), 7.59-7.47 (m, 4H), 7.40 (dd, J1=1.2Hz, J2=8.0Hz, 1H), 7.35-7.19 (m, 4H), 6.65 (d, J=2.0Hz, 1H), 5.86 (s, 1H), 3.84 (s, 3H), 1.66- 1.59(m,1H),1.31(s,6H),0.65-0.56(m,4H),0.24-0.17(m,1H),0.14-0.07(m,1H),0.02-- 0.02(m,1H).
The preparation of 140 compound 140 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 1-c of 1 intermediate 1 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, and hydrobromic acid takes off Cbz, most Compound 140, MS m/z:639 (M+1) can be obtained with the condensation of cyclopropyl formyl chloride afterwards+.
The preparation of 141 compound 141 of embodiment
Referring to 18 step 2 method of embodiment, it is coupled with 140 compound 140 of embodiment with 2- fluorine pyridine -5- borate Obtain compound 141, MS m/z:656 (M+1)+.
The preparation of 142 compound 142 of embodiment
With 141 compound 141 of embodiment with N in the presence of triethylamine, N- dimethyl-ethylenediamine reacts in tetrahydrofuran Compound 142, MS m/z:724 (M+1) can be obtained+.
The preparation of 143 compound 143 of embodiment
Referring to 18 step 2 method of embodiment, with 140 compound 140 and 1 of embodiment, 5- dimethyl -1H- pyrazoles -4- boric acid Compound 143, MS m/z:655 (M+1) can be obtained in pinacol ester coupling+.
The preparation of 144 compound 144 of embodiment
Referring to 18 step 2 method of embodiment, with 140 compound 140 and 1 of embodiment, 3- dimethyl -1H- pyrazoles -4- boric acid Compound 144, MS m/z:655 (M+1) can be obtained in the coupling of pinacol ester+.
The preparation of 145 compound 145 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-b of 18 intermediate 18 of embodiment 74 intermediate o-phenylenediamine 74-8 of example condensation is applied, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group hydrogenates de- Cbz, most Compound 145, MS m/z:666 (M+1) can be obtained with the condensation of methylamine sulfonic acid chloride afterwards+.1H NMR(400MHz,DMSO-d6)δ 12.47 (d, J=10.0Hz, 1H), 8.84 (dd, J=24.4,9.6Hz, 1H), 8.08 (s, 1H), 7.82 (s, 1H), 7.64- 7.57 (m, 2H), 7.48 (d, J=8.4Hz, 1H), 7.39 (s, 2H), 7.30-7.24 (m, 2H), 6.63 (d, J=5.2Hz, 2H), 6.52 (s, 1H), 6.02 (t, J=10.4Hz, 1H), 4.27 (s, 1H), 3.89 (s, 3H), 3.77 (s, 3H), 3.00 (d, J =6.8Hz, 2H), 2.34 (d, J=4.8Hz, 3H), 1.84 (s, 1H), 1.36 (s, 6H), 0.81 (d, J=6.4Hz, 6H)
The preparation of 146 compound 146 of embodiment
The preparation of step 1 intermediate 146-1
Referring to the method for embodiment 23, paranitrophenylacetic acid ethyl ester is hydrogenated, nitrification meta position introducing nitro, deacetylation, Intermediate 146-1, MS m/z:195 (M+1) can be obtained in hydro-reduction step+.
The preparation of step 2 compound 146
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-b of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 146, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.1HNMR (400MHz, MeOD): δ 7.51 (d, J=2.0,1H), 7.37-7.35 (m, 2H), 7.24-7.21 (m, 2H), 7.17-7.13 (m, 1H), 7.09-7.05 (m, 2H), 6.90 (d, J=2.0,1H), 5.92 (d, J=10.0,1H), 4.58-4.51 (m, 2H), 4.24-4.20 (m, 1H), 3.54 (s, 2H), 2.69 (s, 3H), 2.45-2.40 (m, 1H), 1.37 (t, J=7.2,3H), 1.05 (d, J=6.8,3H), 0.94 (d, J=8.4,3H)
The preparation of 147 compound 147 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-a of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 147, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 148 compound 148 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 148, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.1HNMR (400MHz, MeOD): δ 8.51 (s, 1H), 7.51 (d, J=6.8,3H), 7.38-7.31 (m, 3H), 7.24-7.19 (m, 2H), 6.47 (s, 1H), 5.99 (d, J=9.6,1H), 4.40-4.29 (m, 2H), 4.20-4.17 (m, 1H), 3.61 (s, 2H), 2.72 (s, 3H), 1.91-1.86 (m, 1H), 1.23 (t, J=7.2,3H), 0.96 (d, J=6.8,3H), 0.85 (d, J=6.8,3H)
The preparation of 149 compound 149 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-d of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 149, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 150 compound 150 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 3-b of 3 intermediate 3 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 150, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 151 compound 151 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 3-a of 3 intermediate 3 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 151, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 152 compound 152 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 3-c of 3 intermediate 3 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 152, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 153 compound 153 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 3-d of 3 intermediate 3 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 153, MS m/z:507 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 154 compound 154 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-b of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Finally compound 154, MS m/z:535 (M+1) can be obtained with methylamine hydrochloride condensation in rapid 6-7, basic hydrolysis+.1HNMR (400MHz,MeOD):δ7.57-7.48(m,3H),7.37-7.30(m,3H),7.24-7.19(m,3H),6.45(s,1H), 5.97 (d, J=10.0,1H), 4.36-4.29 (m, 2H), 4.22-4.18 (m, 1H), 2.67 (d, J=4.0,3H), 1.89- 1.85 (m, 1H), 1.59 (s, 6H), 1.22 (t, J=7.2,3H), 0.94 (d, J=5.6,3H), 0.85 (d, J=6.4,3H)
The preparation of 155 compound 155 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-a of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Finally compound 155, MS m/z:535 (M+1) can be obtained with methylamine hydrochloride condensation in rapid 6-7, basic hydrolysis+.
The preparation of 156 compound 156 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Finally compound 156, MS m/z:535 (M+1) can be obtained with methylamine hydrochloride condensation in rapid 6-7, basic hydrolysis+.1HNMR (400MHz, MeOD): δ 7.50 (d, J=2.0,1H), 7.42-7.35 (m, 2H), 7.27-7.21 (m, 2H), 7.18-7.04 (m, 3H), 6.69 (d, J=2.0,1H), 5.91 (d, J=10.4,1H), 4.56-4.49 (m, 2H), 4.26-4.22 (m, 1H), 2.62 (s, 3H), 2.45-2.40 (m, 1H), 1.52 (s, 6H), 1.35 (t, J=7.2,3H), 1.03 (d, J=6.4,3H), 0.94 (d, J=6.8,3H)
The preparation of 157 compound 157 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-d of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Finally compound 157, MS m/z:535 (M+1) can be obtained with methylamine hydrochloride condensation in rapid 6-7, basic hydrolysis+.
The preparation of 158 compound 158 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment 41 Finally compound 158, MS m/z:615 (M+1) can be obtained with methylamine hydrochloride condensation in step 6-7, basic hydrolysis+.
The preparation of 159 compound 159 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 21-c of 21 intermediate 21 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- ethyl -1H- pyrazoles -5- acyl group, referring again to embodiment 41 Finally compound 159, MS m/z:642 (M+1) can be obtained with methylamine hydrochloride condensation in step 6-7, basic hydrolysis+.
The preparation of 160 compound 160 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Step 6-7 is condensed with D-Leu methyl ester hydrochloride through basic hydrolysis, compound 160 most can be obtained through basic hydrolysis methyl esters afterwards, MS m/z:701(M+1)+.
The preparation of 161 compound 161 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-d of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Step 6-7 is condensed with D-Leu methyl ester hydrochloride through basic hydrolysis, compound 161 most can be obtained through basic hydrolysis methyl esters afterwards, MS m/z:701(M+1)+.
The preparation of 162 compound 162 of embodiment
The preparation of step 1 intermediate 162-1
Boc-D- leucine (2.49g, 10mmol) is dissolved in DMF (25mL), under ice bath be added HBTU (4.17g, 11mmol), DBU (2.58g, 20mmol) and methylsulfonamides (1.9g, 20mmol), finish to be warmed to room temperature and are stirred to react 5 hours. Then it being extracted with water and ethyl acetate, then water phase is extracted with ethyl acetate twice, merge organic phase, anhydrous sodium sulfate is dry, Intermediate 162-1 crude product (1.5g, 6.5mmol, yield 50%) is obtained after evaporating solvent under reduced pressure.MS m/z:309(M+1)+.
The preparation of step 2 intermediate 162-2
Intermediate 162-1 (1.5g, 6.5mmol) is added in methylene chloride (20mL), trifluoroacetic acid is added under ice bath (10mL), ice bath stirring 1 hour, evaporating solvent under reduced pressure was to get 9 crude product of intermediate (0.68g, 11.9mmol, yield 80%), MS m/z:209(M+1)+.
The preparation of step 3 compound 162
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Through basic hydrolysis compound 162 finally can be obtained with 162 step 2 intermediate 162-2 of embodiment condensation, MS m/z in step 6-7: 778(M+1)+.
The preparation of 163 compound 163 of embodiment
The preparation of step 1 intermediate 163-1
It is starting material by Boc-D- leucine, with ethyl chloride sulfonylation referring to 162 step 1-2 method of embodiment Intermediate 163-1, MS m/z:223 (M+1) are obtained with de- Boc protecting group+.
The preparation of step 2 compound 163
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Through basic hydrolysis compound 163 finally can be obtained with 163 step 1 intermediate 163-1 of embodiment condensation, MS m/z in step 6-7: 792(M+1)+.1HNMR(400MHz,DMSO-d6) δ=12.63 (s, 1H), 8.94 (d, J=8.8Hz, 1H), 8.27 (s, 4H), 8.08 (s, 1H), 7.82 (s, 1H), 7.56 (s, 2H), 7.44-7.34 (m, 1H), 7.28 (d, J=2.0Hz, 1H), 7.17 (d, J =8.8Hz, 1H), 6.53 (s, 1H), 6.02 (t, J=10.4Hz, 1H), 4.31-4.25 (m, 1H), 4.05-3.99 (m, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 2.88-2.76 (m, 2H), 1.85 (s, 1H), 1.52 (d, J=6.8Hz, 6H), 1.47- 1.39 (m, 2H), 1.36-1.28 (m, 1H), 0.97 (t, J=7.2Hz, 3H), 0.83-0.78 (m, 12H)
The preparation of 164 compound 164 of embodiment
The preparation of step 1 intermediate 164-1
It is starting material by Boc-D- leucine, with cyclopropyl sulfonyl chloride sulphonyl referring to 162 step 1-2 method of embodiment Change and de- Boc protecting group obtains intermediate 164-1, MS m/z:235 (M+1)+.
The preparation of step 2 compound 164
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Through basic hydrolysis compound 164 finally can be obtained with 163 step 1 intermediate 164-1 of embodiment condensation, MS m/z in step 6-7: 804(M+1)+.
The preparation of 165 compound 165 of embodiment
The preparation of step 1 intermediate 165-1
Boc-D- leucine (2.49g, 10mmol) is dissolved in DMF (25mL), under ice bath be added HBTU (4.17g, 11mmol), DBU (2.58g, 20mmol) and ammonium chloride (1.07g, 20mmol), finish to be warmed to room temperature and are stirred to react 5 hours.So It is extracted afterwards with water and ethyl acetate, then water phase is extracted with ethyl acetate twice, merge organic phase, anhydrous sodium sulfate is dry, subtracts Pressure obtains intermediate 165-1 crude product (1.5g, 6.5mmol, yield 50%) after solvent is evaporated off.MS m/z:231(M+1)+.
The preparation of step 2 intermediate 165-2
Intermediate 165-1 (1.5g, 6.5mmol) is added in DMF (20mL), under ice bath be added Cyanuric Chloride (0.7g, 3.9mmol), it is stirred at room temperature 10 hours, evaporating solvent under reduced pressure is to get intermediate 165-2 crude product (0.64g, 3mmol, yield 46%), MS m/z:213 (M+1)+.
The preparation of step 3 intermediate 165-3
Intermediate 165-2 (0.64g, 3mmol) is added in DMF (20mL), addition Sodium azide (0.29g, 4.5mmol), it stirs 10 hours for 100 DEG C of ammonium chloride (0.24g, 4.5mmol), evaporating solvent under reduced pressure is thick to get intermediate 165-3 Product (0.51g, 2mmol, yield 66%), MS m/z:256 (M+1)+.
The preparation of step 4 intermediate 165-4
Intermediate 165-3 (0.51g, 2mmol) is added in methylene chloride (20mL), trifluoroacetic acid is added under ice bath (10mL), ice bath stirring 1 hour, evaporating solvent under reduced pressure was to get 11 crude product of intermediate (0.28g, 1.8mmol, yield 90%), MS m/z:156(M+1)+.
The preparation of step 5 compound 165
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 165, MS m/z:725 (M+1) finally can be obtained with intermediate 165-4 condensation through basic hydrolysis in step 6-7+.1HNMR (400MHz,DMSO-d6) δ=8.86 (d, J=9.2Hz, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.49 (t, J=6.4Hz, 3H), 7.38 (s, 2H), 7.28 (d, J=2Hz, 1H), 7.11 (d, J=8.8Hz, 1H), 6.51 (d, J= 1.6Hz, 1H), 6.00 (t, J=10.4Hz, 1H), 5.24 (dd, J1=7.6Hz, J2=14.4Hz, 1H), 4.25 (d, J= 10.8Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 1.77~1.86 (m, 1H), 1.70~1.75 (m, 1H), 1.58 (t, J= 7Hz, 1H), 1.52 (d, J=6.4Hz, 6H), 1.29~1.39 (m, 1H), 0.81 (s, 4H), 0.78 (s, 6H), 0.77 (s, 2H)
The preparation of 166 compound 166 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 4-c of 4 intermediate 4 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 166 can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group, MS m/z:482(M+1)+.1H NMR(400MHz,DMSO-d6):δ12.55(s,1H),8.89-8.94(t,1H),7.08-7.56 (m, 6H), 6.563-6.568 (d, J=1.5Hz, 1H), 5.84-5.89 (t, 1H), 4.23-4.26 (m, 1H), 3.87 (s, 3H), 2.98-3.03 (m, 1H), 1.82-1.83 (m, 1H), 1.25-1.27 (d, J=6.8Hz, 5H), 0.78-0.79 (d, J= 7.2Hz,5H).
The preparation of 167 compound 167 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 4-b of 4 intermediate 4 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 167 can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group, MS m/z:482(M+1)+.1H NMR(400MHz,DMSO-d6): δ 12.15 (s, 1H), 9.10-9.12 (d, J=8.8Hz, 1H), 8.21 (s, 1H), 6.97-7.47 (m, 8H), 5.81-5.86 (t, J=1.5Hz, 1H), 4.26-4.30 (m, 1H), 4.06 (s, 3H), 3.87 (s, 1H), 2.91-2.94 (m, 1H), 2.40-2.46 (m, 1H), 1.19-1.27 (d, J=6.8Hz, 6H), 0.84- 0.91 (d, J=7.2Hz, 6H)
The preparation of 168 compound 168 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 94-1c of 94 step 1 intermediate 94-1 of embodiment as raw material By being condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment is condensed through basic hydrolysis, then with D-Leu t-butyl ester hydrochloride, and the last tert-butyl ester is through trifluoroacetic acid water Compound 168, MS m/z:587 (M+1) can be obtained in solution+.
The preparation of 169 compound 169 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 94-1c of 94 step 1 intermediate 94-1 of embodiment as raw material By being condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to Compound 169, MS m/ can be obtained through basic hydrolysis, then with 162 intermediate 162-2 of embodiment condensation in 41 step 6-7 of embodiment z:664(M+1)+.
The preparation of 170 compound 170 of embodiment
Referring to 74 method of embodiment, with Boc-L-3,3- diphenylalamine is that raw material passes through and embodiment 26 intermediate neighbour Phenylenediamine 26 is condensed, cyclization, takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through buck Solution, then be condensed with D-Leu methyl ester hydrochloride, compound 170, MS m/z:621 (M+ most can be obtained through basic hydrolysis methyl esters afterwards 1)+.
The preparation of 171 compound 171 of embodiment
The preparation of step 1 intermediate 171-1
Referring to the method that embodiment 1 prepares intermediate 1, using 1- methyl-1 H- indazole -6- formaldehyde as starting material, warp and nitre Ethyl condensation carries out grignard reaction, nitro zinc powder reduction, Boc protection amino, basic hydrolysis with isopropylmagnesium chloride, most Four single chiral the isomers 171-1a, 171- of intermediate 171-1 can be respectively obtained by the preparation of SFC chiral resolution post separation 1b,171-1c,171-1d。MS m/z:362[M+1]+。
The preparation of step 2 compound 171
Referring to 74 method of embodiment, the single chiral isomers 171-1c with 171 step 1 intermediate 171-1 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 171, MS m/z:641 (M+1)+.
The preparation of 172 compound 172 of embodiment
Referring to 74 method of embodiment, the single chiral isomers 171-1b with 171 step 1 intermediate 171-1 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 172, MS m/z:641 (M+1)+.
The preparation of 173 compound 173 of embodiment
The preparation of step 1 intermediate 173-1
Ethyl nitroacetate (9.50g, 71.34mmol) and cyclobutanone (5g, 71.34mmol) are dissolved in anhydrous tetrahydro furan (200mL) titanium tetrachloride (27.06g, 142.67mmol) is slowly added dropwise at 0 DEG C under nitrogen protection, continues after being added dropwise 0 It DEG C is stirred to react 1 hour.N-methylmorpholine (28.82g, 285.35mmol) is slowly added dropwise into reaction solution, is added dropwise slowly It is warmed to room temperature, continues to be stirred to react 2 hours.Distilled water quenching reaction is added, is extracted with ethyl acetate, merges organic phase, it is anhydrous Sodium sulphate dries, filters, evaporating solvent under reduced pressure, after column chromatographic purifying (eluant, eluent: petroleum ether: ethyl acetate=50:1) in Mesosome 173-1 (10g, 54.00mmol, 75.70%yield).
The preparation of step 2 intermediate 173-2
Referring to the method that embodiment 1 prepares intermediate 1, via intermediate 173-1 and phenyl-magnesium-bromide carry out grignard reaction, Amino, ethyl ester basic hydrolysis are protected in nitro reduction, Boc, most can respectively obtain intermediate through the preparation of SFC chiral resolution post separation afterwards The two single chiral isomers 173-2a and 173-2b, MS m/z:306 [M+1] of 173-2+。
The preparation of step 3 compound 173
Referring to 74 method of embodiment, the single chiral isomers 173-2a with 173 step 2 intermediate 173-2 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 173, MS m/z:585 (M+1)+.
The preparation of 174 compound 174 of embodiment
Referring to 74 method of embodiment, the single chiral isomers 173-2b with 173 step 2 intermediate 173-2 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 174, MS m/z:585 (M+1)+.
The preparation of 175 compound 175 of embodiment
The preparation of step 1 intermediate 175-1
Referring to the method that embodiment 1 prepares intermediate 1, grignard is carried out via intermediate 173-1 and Chloro-O-Phenyl magnesium bromide Reaction, nitro reduction, Boc protect amino, ethyl ester basic hydrolysis, most prepare afterwards through SFC chiral resolution post separation in can respectively obtaining The two single chiral isomers 175-1a and 175-1b, MS m/z:340 [M+1] of mesosome 175-1+。
The preparation of step 2 compound 175
Referring to 74 method of embodiment, the single chiral isomers 175-1a with 173 step 2 intermediate 175-1 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 175, MS m/z:619 (M+1)+.
The preparation of 176 compound 176 of embodiment
Referring to 74 method of embodiment, the single chiral isomers 175-1b with 173 step 2 intermediate 175-1 of embodiment is Raw material passes through to be condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then 41 step 6-7 of reference implementation example is condensed, most afterwards through basic hydrolysis methyl esters through basic hydrolysis, then with D-Leu methyl ester hydrochloride Obtain compound 176, MS m/z:619 (M+1)+.
The preparation of 177 compound 177 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Compound 177, MS m/z:805 (M can be obtained through basic hydrolysis, then with 162 intermediate 162-2 of embodiment condensation in 41 step 6-7 +1)+.1H NMR(400MHz,DMSO-d6) δ=11.77 (s, 1H), 8.80 (d, J=8.8Hz, 1H), 8.17 (s, 1H), 7.83 (s, 1H), 7.59-7.54 (m, 3H), 7.42-7.30 (m, 4H), 7.15 (d, J=8.4Hz, 1H), 6.55 (s, 1H), 6.02 (t, J=10.0Hz, 1H), 4.55-4.49 (m, 1H), 4.37-4.31 (m, 1H), 4.22-4.21 (m, 1H), 3.77 (s, 3H), 3.21 (d, J=1.6Hz, 3H), 1.87 (s, 1H), 1.55-1.45 (m, 12H), 1.25 (s, 1H), 0.85-0.76 (m, 12H)
The preparation of 178 compound 178 of embodiment
Referring to 74 method of embodiment, with the intermediate 19 (mixture of enantiomer 19-c and 19-d) of embodiment 19 for raw material By being condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment is condensed through basic hydrolysis, then with D-Leu methyl ester hydrochloride, most can be obtained afterwards through basic hydrolysis methyl esters Compound 178, MS m/z:729 (M+1)+.1H NMR(400MHz,DMSO-d6) δ 12.50 (s, 2H), 8.81-8.79 (d, J= 9.2Hz, 1H), 8.13-8.11 (d, J=8.4Hz, 1H), 7.80 (s, 1H), 7.63-7.45 (t, J=29.6Hz, 3H), 7.37- 7.36 (t, J=2.8Hz, 2H), 7.26-7.25 (m, 2H), 7.13-7.11 (d, J=8.4Hz, 1H), 6.50 (s, 1H), 6.01- 5.96 (t, J=10Hz, 1H), 4.53-4.46 (m, 1H), 4.23-4.21 (d, J=10Hz, 2H), 4.23 (s, 3H), 1.81 (s, 1H),1.59-1.25(m,15H),0.80–0.75(m,11H).
The preparation of 179 compound 179 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D-Leu methyl ester hydrochloride, compound most can be obtained through basic hydrolysis methyl esters afterwards 179, MS m/z:729 (M+1)+.1HNMR(400MHz,MeOD):δppm 12.20-13.13(m,1.5H),8.86-8.88(d,J =9.2Hz, 1H), 8.15-8.17 (m, 1H), 7.82 (s, 1H), 7.34-7.57 (m, 5H), 7.22-7.27 (m, 2H), 7.12- 7.14(m,1H),6.52-6.53(m,1H),5.93-6.03(m,1H),4.46-4.56(m,1H),4.22-4.26(m,2H), 4.22-4.26 (m, 2H), 3.76 (s, 3H), 1.80-1.84 (m, 1H), 1.49-1.52 (d, J=9.6Hz, 6H), 1.44-1.46 (d, J=6.4Hz, 1H), 0.77-0.85 (m, 11H).
The preparation of 180 compound 180 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D-Leu methyl ester hydrochloride, and simultaneously compound 180 can be obtained in ammonolysis to ester hydrolysis, MS m/z:728(M+1)+.
The preparation of 181 compound 181 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed, last can be obtained of ester hydrolysis through basic hydrolysis, then with D-N- methyl-gamma-hydroxyleucine methyl esters Close object 181, MS m/z:745 (M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.76 (d, J=8.4Hz, 1H), 8.27 (s, 1H), 7.93 (t, J=8.0Hz, 2H), 7.70 (t, J=4.0Hz, 3H), 7.66 (s, 1H), 7.47 (dd, J 1=1.6Hz, J 2 =8.4Hz, 1H), 7.41-7.39 (m, 2H), 7.34 (d, J=8.4Hz, 1H), 6.69 (d, J=2.0Hz, 1H), 6.14 (t, J =8.8Hz, 1H), 4.02 (t, J=8.0Hz, 1H), 3.84 (s, 3H), 2.23 (dd, J=11.9,9.6Hz, 1H), 2.11- 2.02 (m, 2H), 1.53-1.34 (m, 18H), 0.98 (d, J=6.4Hz, 3H), 0.79 (d, J=6.8Hz, 3H)
The preparation of 182 compound 182 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D- cyclopropyl alanine methyl esters, and compound 182, MS can be obtained in last ester hydrolysis m/z:727(M+1)+.1H NMR(400MHz,MeOD)δ8.06(s,1H),7.87(s,1H),7.68(dd,2H),7.59(dd, 1H), 7.44-7.42 (d, J=2.1Hz, 1H), 7.37-7.33 (m, 3H), 6.50 (s, 1H), 6.11 (d, J=9.5Hz, 1H), 4.59 (dt, J=13.6,6.7Hz, 2H), 4.43 (dd, J=7.4,4.9Hz, 1H), 4.19 (dd, J=8.3,6.4Hz, 1H), 3.883 (s, 3H), 3.53-3.48 (m, 1H), 1.98 (dd, J=12.0,7.5Hz, 1H), 1.66 (d, J=12.0Hz, 6H), 1.56 (d, J=12.0Hz, 6H), 1.39-1.23 (m, 3H), 1.03 (d, J=6.9Hz, 3H), 0.89 (d, J=6.9Hz, 3H), 0.61-0.48 (m, 1H), 0.30 (ddd, J=11.5,7.7,3.9Hz, 2H)
The preparation of 183 compound 183 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D- cyclopropylglycine methyl ester, and compound 183, MS can be obtained in last ester hydrolysis m/z:713(M+1)+.1H NMR (400MHz, MeOD) δ 8.06 (s, 1H), 7.87 (s, 1H), 7.65 (d, J=2.9Hz, 2H), 7.57 (d, J=8.4Hz, 1H), 7.43 (dd, J=8.3,2.0Hz, 1H), 7.38-7.31 (m, 3H), 6.51 (d, J=2.2Hz, 1H), 6.12 (d, J=9.2Hz, 1H), 4.59 (m, J=11.8,5.9Hz, 2H), 4.23-4.14 (m, 2H), 3.89 (s, 3H), 3.82 (d, J=9.4Hz, 1H), 1.99 (d, J=4.6Hz, 2H), 1.65 (d, J=7.3Hz, 6H), 1.56 (d, J=6.7Hz, 6H), 1.04 (d, J=5.9Hz, 3H), 0.89 (d, J=6.8Hz, 3H), 0.54 (m, J=12.2,5.0Hz, 1H), 0.46- 0.40(m,2H),0.28–0.22(m,1H).
The preparation of 184 compound 184 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D-PROLINE methyl esters, and compound 184 can be obtained in last ester hydrolysis, MS m/z: 713(M+1)+.1H NMR(400MHz,DMSO-d6): δ=8.38-8.33 (m, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.57-7.50(m,2H),7.37-7.33(m,1H),7.27-7.24(m,1H),6.64-6.61(m,1H),6.07-5.98(m, 1H),4.54-4.52(m,1H),4.27-4.19(m,2H),3.79(s,3H),2.70-2.68(m,3H),2.03-2.01 (m1H),1.87-1.85(m,1H),1.66-1.59(m,3H),1.53-1.44(m,13H),1.27-1.24(m,1H),0.80 (s,6H)。
The preparation of 185 compound 185 of embodiment
The preparation of step 1 intermediate 185-1
Referring to the method for 18 step 2 of embodiment, after intermediate 1-4 and 1- cyclopropylpyrazol -4- boric acid Knit-the-brows any alcohol ester coupling Again through hydrolyzing, four single chiral isomers of intermediate 185-1 can be most respectively obtained through the preparation of SFC chiral resolution post separation afterwards 185-1a,185-1b,185-1c,185-1d。MS m/z:448[M+1]+。
The preparation of step 2 compound 185
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 185-1c of intermediate 185-1 The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with D-Leu methyl ester hydrochloride, and compound 185 can be obtained in last ester hydrolysis, MS m/z: 727(M+1)+.
The preparation of 186 compound 186 of embodiment
The preparation of step 1 intermediate 186-1
Referring to the method that embodiment 1 prepares intermediate 1, using the chloro- 5- bromobenzaldehyde of 2- as starting material, warp and nitro-acetic acid Ethyl ester condensation carries out grignard reaction, nitro zinc powder reduction, Boc protection amino with cyclopropyl magnesium chloride, and intermediate can be obtained 186-1, MS m/z:446 [M+1]+。
The preparation of step 2 intermediate 186-2
Referring to the method for 18 step 2 of embodiment, where alcohol ester is coupled by intermediate 186-1 and 1- isopropylpyrazol -4- boric acid Knit-the-brows Afterwards again through hydrolyzing, four single chiral isomeries of intermediate 186-1 can be most respectively obtained through the preparation of SFC chiral resolution post separation afterwards Body 186-2a, 186-2b, 186-2c, 186-2d.MS m/z:448[M+1]+。
The preparation of step 3 compound 186
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 186-2c of intermediate 186-2 The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with D-Leu methyl ester hydrochloride, and compound 186 can be obtained in last ester hydrolysis, MS m/z: 727(M+1)+.1H NMR(400MHz,Methanol-d4)δ8.04(s,1H),7.80(m,1H),7.73-7.67(s,2H), 7.59 (d, J=8.5Hz, 1H), 7.43-7.33 (m, 4H), 6.63 (s, 1H), 5.95-5.93 (m, 1H), 4.61-4.54 (m, 1H),4.48-4.45(m,1H),3.87(s,3H),1.68-1.66(m,3H),1.64-1.62(m,3H),1.60-1.58(m, 2H), 1.55 (d, J=6.7Hz, 6H), 1.51-1.46 (m, 1H), 1.31-1.29 (m, 1H), 0.90-0.83 (m, 6H), 0.38- 0.32(m,1H),0.29-0.22(m,1H),0.15–0.07(m,1H),-0.17--0.23(m,1H).
The preparation of 187 compound 187 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 186-2c of intermediate 186-2 The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with D- cyclopropylglycine methyl ester, and compound 187 can be obtained in last ester hydrolysis, MS m/z: 711(M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.19 (s, 1H), 7.85 (s, 1H), 7.76 (s, 1H), 7.66 (d, J= 7.9Hz,2H),7.48–7.42(m,1H),7.41–7.31(m,3H),6.63(s,1H),5.96(s,1H),4.58–4.46(m, 1H),3.80(s,3H),3.48–3.40(m,1H),1.59–1.54(m,3H),1.54(s,3H),1.47–1.45(m,3H), 1.44(s,3H),1.33–1.21(m,1H),1.16–1.04(m,1H),0.56–0.44(m,1H),0.41–0.24(m,3H), 0.23–-0.10(m,5H),-0.18–-0.34(m,1H).
The preparation of 188 compound 188 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 186-2c of intermediate 186-2 The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with D- cyclopropyl alanine methyl esters, and compound 188 can be obtained in last ester hydrolysis, MS m/z: 725(M+1)+.1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.87(s,1H),7.80(s,1H),7.74–7.64(m, 2H), 7.52-7.33 (m, 4H), 6.66 (s, 1H), 6.03 (s, 1H), 4.52 (dt, J=13.3,6.6Hz, 1H), 4.29 (dd, J =9.3,4.7Hz, 1H), 3.82 (s, 3H), 1.69-1.61 (m, 1H), 1.58 (s, 3H), 1.56 (s, 3H), 1.47 (s, 3H), 1.46(s,3H),1.33–1.22(m,1H),0.62–0.48(m,1H),0.36–0.21(m,3H),0.19–0.10(m,1H), 0.09–-0.03(m,3H),-0.04–-0.13(m,1H),-0.16–-0.32(m,1H).
The preparation of 189 compound 189 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed, last can be obtained of ester hydrolysis through basic hydrolysis, then with (S) -3- amido tetrahydrofuran -3- methyl formate Close object 189, MS m/z:729 (M+1)+.1H NMR(401MHz,MeOD)δ8.04–8.02(m,1H),7.85–7.83(m,1H), 7.64–7.60(m,2H),7.55–7.51(m,1H),7.39(s,1H),7.31(s,4H),6.49–6.46(s,1H),6.11– 6.06(m,1H),4.60–4.53(m,1H),4.21–4.15(m,2H),3.86(s,3H),2.42–2.19(m,2H),2.03– 1.93 (m, 1H), 1.61 (s, 6H), 1.54 (d, J=6.8Hz, 6H), 1.00 (s, 3H), 0.87 (d, J=6.6Hz, 3H)
The preparation of 190 compound 190 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with 3- amino oxetanes -3- Ethyl formate, and chemical combination can be obtained in last ester hydrolysis Object 190, MS m/z:715 (M+1)+.1H NMR (400MHz, MeOD) δ 8.07 (s, 1H), 7.88 (s, 1H), 7.74 (d, J= 5.8Hz, 1H), 7.64 (d, J=9.0Hz, 1H), 7.45-7.33 (m, 3H), 6.50-6.48 (m, 1H), 6.10 (s, 1H), 4.30 (d, J=6.6Hz, 1H), 4.12 (m, 2H), 3.86 (m, 2H), 1.67 (s, 2H), 1.56 (d, J=6.8Hz, 2H), 1.26 (t, J =7.1Hz, 2H), 1.22 (s, 1H), 1.00 (t, J=7.4Hz, 3H), 0.94-0.86 (m, 3H)
The preparation of 191 compound 191 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with 1- 1-aminocyclopropane-1-carboxylic acid methyl esters, and compound 191 can be obtained in last ester hydrolysis, MS m/z:699(M+1)+.1H NMR(400MHz,MeOD)δ8.04(s,1H),7.85(s,1H),7.62(s,2H),7.52(d,J =8.4Hz, 1H), 7.41 (dd, J=8.3,2.0Hz, 1H), 7.31 (ddd, J=10.4,9.7,5.0Hz, 3H), 6.47 (s, 1H), 6.08 (d, J=9.5Hz, 1H), 4.56 (m, 1H), 4.20-4.14 (m, 1H), 3.86 (s, 3H), 2.00-1.91 (m, 1H), 1.59 (s, 6H), 1.53 (d, J=6.7Hz, 6H), 1.45 (dd, J=7.8,4.6Hz, 2H), 1.01 (d, J=3.8Hz, 2H), 1.00-0.96 (m, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 192 compound 192 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with L-Leu methyl ester hydrochloride, compound most can be obtained through basic hydrolysis methyl esters afterwards 192, MS m/z:729 (M+1)+.1H NMR (400MHz, MeOD) δ 8.09 (s, 1H), 7.89 (s, 1H), 7.69 (d, J= 1.3Hz, 1H), 7.67 (d, J=1.3Hz, 3H), 7.66 (d, J=1.2Hz, 1H), 7.64 (d, J=1.6Hz, 2H), 7.40 (d, J=8.2Hz, 2H), 7.37 (d, J=1.7Hz, 1H), 6.54 (s, 1H), 6.15 (d, J=8.9Hz, 1H), 4.58 (dd, J= 13.4,6.7Hz, 1H), 4.48 (d, J=4.8Hz, 1H), 4.18 (s, 1H), 3.91 (s, 3H), 2.04 (s, 1H), 1.66 (d, J =15.1Hz, 6H), 1.56 (d, J=6.7Hz, 6H), 1.32-1.29 (m, 3H), 1.07 (d, J=6.1Hz, 3H), 0.90 (d, J =6.5Hz, 3H), 0.88-0.83 (m, 6H)
The preparation of 193 compound 193 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with D-PROLINE methyl esters, and simultaneously compound 193, MS can be obtained in ammonolysis to last ester hydrolysis m/z:712(M+1)+.1H NMR (400MHz, MeOD) δ 7.82 (d, J=5.1Hz, 1H), 7.53-7.44 (m, 4H), 7.29 (s, 2H), 7.17 (d, J=7.9Hz, 1H), 7.10 (d, J=14.2Hz, 1H), 6.93 (s, 1H), 6.01 (d, J=7.5Hz, 1H), 4.63(s,1H),4.49(s,1H),4.42–4.36(m,1H),4.13(s,3H),2.83(s,2H),2.58–2.41(m,2H), 2.10-1.99 (m, 1H), 1.76-1.56 (m, 5H), 1.51 (d, J=5.4Hz, 6H), 1.34-1.30 (m, 2H), 1.24-1.19 (m,3H),0.92(s,3H).
The preparation of 194 compound 194 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with the cis- 3- L-Hydroxyproline methyl ester of D-, and compound 194 can be obtained in last ester hydrolysis, MS m/z:729(M+1)+.1H NMR(400MHz,Methanol-d4)δ8.04(s,1H),7.85(s,1H),7.62(s,1H), 7.57-7.56 (m, 1H), 7.42-7.40 (m, 1H), 7.36-7.27 (m, 3H), 7.24 (d, J=8.6Hz, 1H), 6.47 (s, 1H), 6.10 (d, J=8.5Hz, 1H), 4.60-4.51 (m, 1H), 4.45-4.42 (m, 1H), 4.20-4016 (m, 1H), 4.10 (s,1H),3.94-3.91(m,1H),3.86(s,3H),3.50–3.41(m,1H),3.14–3.05(m,1H),2.83–2.74 (m,1H),2.29-2.25(m,1H),1.98-1.95(m,1H),1.72-1.68(m,1H),1.61(s,2H),1.58(s,2H), 1.53 (d, J=6.7Hz, 6H), 1.50-1.47 (m, 1H), 1.02 (d, J=6.7Hz, 2H), 0.88 (d, J=6.7Hz, 4H)
The preparation of 195 compound 195 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with azepan -2- methyl formate, and compound 195 can be obtained in last ester hydrolysis, MS m/z:729(M+1)+.1H NMR (400MHz, MeOD) δ 8.06 (s, 1H), 7.87 (s, 1H), 7.61 (d, J=29.3Hz, 3H), 7.51 (s, 1H), 7.43 (dd, J=8.3,1.9Hz, 1H), 7.34 (d, J=8.4Hz, 2H), 7.27 (d, J=7.9Hz, 1H), 7.19 (d, J=8.4Hz, 1H), 6.53 (s, 1H), 6.13 (d, J=8.6Hz, 1H), 4.59 (dt, J=13.4,6.8Hz, 1H), 4.49 (s, 1H), 4.28 (s, 1H), 4.13 (s, 2H), 3.91 (d, J=5.4Hz, 3H), 2.19 (d, J=16.9Hz, 1H), 2.02 (s, 2H), 1.87 (s, 2H), 1.62 (d, J=15.2Hz, 6H), 1.56 (d, J=6.7Hz, 6H), 1.44 (s, 2H), 1.22 (d, J=18.8Hz, 2H), 1.08 (s, 3H), 0.88 (d, J=6.7Hz, 3H)
The preparation of 196 compound 196 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with the trans- 3- L-Hydroxyproline methyl ester of D-, and compound 196 can be obtained in last ester hydrolysis, MS m/z:729(M+1)+.1H NMR(400MHz,Methanol-d4)δ8.14(s,1H),7.93(s,1H),7.79-7.73(d, J=4.1Hz, 3H), 7.58-7.50 (m, 3H), 7.44-7.38 (m, 3H), 7.36-7.29 (m, 3H), 7.27-7.25 (m, 2H), 6.69 (t, J=4.1Hz, 1H), 6.28 (d, J=7.4Hz, 1H), 4.63-4.56 (m, 2H), 4.45-4.33 (m, 2H), 4.14- 4.05 (m, 2H), 3.99 (d, J=1.9Hz, 4H), 3.76-3.61 (m, 3H), 2.29 (dd, J=13.6,6.9Hz, 2H), 1.67 (d, J=3.2Hz, 2H), 1.62 (d, J=3.9Hz, 2H), 1.56 (dd, J=6.5,4.5Hz, 8H), 1.44 (d, J= 18.4Hz, 10H), 1.32-1.18 (m, 6H), 1.13-1.00 (m, 7H), 0.91 (d, J=6.5Hz, 3H), 0.79 (dd, J= 16.2,6.7Hz,4H).
The preparation of 197 compound 197 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with (R)-morpholine -3- methyl formate hydrochloride, and compound can be obtained in last ester hydrolysis 197, MS m/z:729 (M+1)+.1H NMR(400MHz,Methanol-d4)δ8.14(s,1H),7.92(s,1H),7.80(d,J =11.0Hz, 2H), 7.72 (d, J=6.5Hz, 1H), 7.67-7.57 (m, 2H), 7.57-7.45 (m, 2H), 7.44-7.28 (m, 2H), 6.71 (s, 1H), 6.33 (dd, J=8.4,3.5Hz, 1H), 4.59 (d, J=10.4Hz, 2H), 4.16 (d, J= 12.9Hz, 2H), 3.97 (d, J=9.0Hz, 3H), 3.03-2.91 (m, 1H), 2.76 (dd, J=11.4,3.8Hz, 1H), 2.31-2.08 (m, 2H), 1.90 (d, J=4.4Hz, 1H), 1.80-1.45 (m, 14H), 1.18 (d, J=6.5Hz, 3H), 1.06 (d, J=2.7Hz, 1H), 0.91 (d, J=6.6Hz, 3H)
The preparation of 198 compound 198 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7, through basic hydrolysis, then with (R) -- cyclobutylamine-2-carboxylic acid methyl esters is condensed, and compound can be obtained in last ester hydrolysis 198, MS m/z:699 (M+1)+.1H NMR(400MHz,Methanol-d4)δ8.06(s,1H),7.87(s,1H),7.68– 7.54 (m, 3H), 7.54-7.40 (m, 2H), 7.40-7.27 (m, 4H), 6.52 (d, J=2.2Hz, 1H), 6.13 (d, J= 9.2Hz,1H),4.62–4.53(m,2H),4.13(s,2H),3.90(s,3H),2.10–1.76(m,3H),1.71–1.44(m, 16H), 1.31 (s, 1H), 1.25-1.21 (m, 1H), 1.06 (d, J=6.8Hz, 3H), 0.90 (d, J=6.8Hz, 4H)
The preparation of 199 compound 199 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 step 6-7 are condensed through basic hydrolysis, then with the fluoro- L-PROLINE methyl esters of trans- -4-, and compound can be obtained in last ester hydrolysis 199, MS m/z:731 (M+1)+.1H NMR (400MHz, MeOD) δ 8.06 (s, 1H), 7.87 (s, 1H), 7.66 (d, J= 12.4Hz, 1H), 7.59 (d, J=8.1Hz, 2H), 7.43 (dd, J=8.3,1.9Hz, 1H), 7.38-7.33 (m, 2H), 7.28 (d, J=9.4Hz, 1H), 6.50 (s, 1H), 6.12 (d, J=9.4Hz, 1H), 4.59 (dt, J=13.5,6.9Hz, 2H), 4.18 (s, 1H), 3.89 (s, 3H), 2.55-2.36 (m, 2H), 2.00 (d, J=5.1Hz, 2H), 1.88 (s, 1H), 1.62 (d, J= 8.6Hz, 6H), 1.56 (d, J=6.7Hz, 6H), 1.05 (d, J=6.0Hz, 3H), 0.90 (d, J=6.7Hz, 3H)
The preparation of 200 compound 200 of embodiment
Referring to 74 method of embodiment, passed through by raw material of the single chiral isomers 186-2c of 186 intermediate 186-2 of embodiment It crosses and is condensed with 26 intermediate o-phenylenediamine 26 of embodiment, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to reality 41 step 6-7 of example is applied, compound 187, MS m/z:725 can be obtained through basic hydrolysis, then with the condensation of D- cyclopropylglycine methyl ester (M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.19 (d, J=2.0Hz, 1H), 7.84 (d, J=0.8Hz, 1H), 7.73- 7.68 (m, 1H), 7.58 (d, J=7.2Hz, 1H), 7.44-7.41 (m, 1H), 7.38-7.35 (m, 2H), 7.21 (d, J= 8.4Hz, 1H), 6.63 (d, J=4.0Hz, 1H), 5.95 (s, 1H), 4.55-4.49 (m, 1H), 3.80 (s, H), 3.62 (s, 3H),3.61–3.60(m,2H),1.54–1.45(m,12H),1.16–1.08(m,2H),0.52–0.48(m,1H),0.41–- 0.02(m,7H),-0.29(s,1H).
Apply the preparation of 201 compound 201 of example
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 186-2c of intermediate 186-2 The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 201, MS m/z:739 (M+1) can be obtained through basic hydrolysis, then with the condensation of D- cyclopropyl alanine methyl esters in rapid 6-7+.1H NMR(400MHz,DMSO-d6) δ 8.21 (s, 1H), 7.87 (s, 1H), 7.79 (s, 1H), 7.74 (d, J=8.6Hz, 1H), 7.69 (d, J=1.2Hz, 1H), 7.47 (dd, J=8.3,2.1Hz, 1H), 7.44-7.36 (m, 3H), 6.65 (s, 1H), 6.02 (s, 1H),4.57–4.47(m,1H),4.35–4.28(m,1H),3.81(s,3H),1.69–1.61(m,1H),1.56(s,3H), 1.55(s,3H),1.48–1.46(m,3H),1.46–1.43(m,3H),1.32–1.21(m,1H),0.63–0.52(m,1H), 0.36–0.25(m,3H),0.20–0.10(m,1H),0.09–-0.03(m,3H),-0.04–-0.11(m,1H),-0.16–- 0.30(m,1H).
The preparation of 202 compound 202 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-c of the intermediate 19 of embodiment 19 be raw material by with The condensation of 23 intermediate o-phenylenediamine 23 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Compound 202, MS m/z:615 (M+1) finally can be obtained with methylamine condensation through basic hydrolysis in 41 step 6-7+.1H NMR (400MHz,MeOD)δ8.50(s,1H),8.03(s,1H),7.84(s,1H),7.61(s,1H),7.56(s,1H),7.54– 7.47(m,1H),7.43–7.38(m,1H),7.38–7.29(m,2H),7.29–7.22(m,1H),6.47(s,1H),6.08(d, J=9.7Hz, 1H), 4.21-4.13 (m, 1H), 3.84 (s, 3H), 3.78-3.71 (m, 1H), 2.69 (s, 3H), 1.93 (d, J= 7.1Hz, 1H), 1.57-1.46 (m, 9H), 0.99 (d, J=6.2Hz, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 203 compound 203 of embodiment
Referring to 74 method of embodiment, using the single chiral isomers 19-d of the intermediate 19 of embodiment 19 be raw material by with The condensation of 23 intermediate o-phenylenediamine 23 of embodiment, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Compound 203, MS m/z:615 (M+1) finally can be obtained with methylamine condensation through basic hydrolysis in 41 step 6-7+.1H NMR (400MHz,CD3OD) δ=7.69 (s, 1H), 7.52-7.44 (m, 4H), 7.29-7.25 (m, 3H), 7.13-7.08 (d, J= 22.0,1H), 6.95 (s, 1H), 6.02-5.99 (d, J=8.8,1H), 4.50-4.32 (m, 1H), 4.21-4.14 (m, 1H), 4.11 (s, 3H), 3.74-3.68 (m, 1H), 2.7-2.68 (d, J=2.8,3H), 2.53-2.45 (m, 1H), 1.50-1.44 (m, 9H), 1.21-1.18 (t, J=6.8,3H), 0.95-0.92 (m, 3H)
The preparation of 204 compound 204 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 6-c of the intermediate 6 of embodiment 6 41 intermediate o-phenylenediamine 41-1 of example condensation is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Compound 204, MS m/z:518 (M+1) finally can be obtained with methylamine condensation through basic hydrolysis in 41 step 6-7+.
The preparation of 205 compound 205 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 205, MS m/z:493 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 206 compound 206 of embodiment
Referring to 74 method of embodiment, using 2 intermediate 2 of embodiment (single chiral isomers 2-c be raw material by and implementation 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 206, MS m/z:564 (M can be obtained with R-N- methyl-2-amino-propionamide condensation in 41 step 6-7, basic hydrolysis +1)+.
The preparation of 207 compound 207 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 207, MS m/z:550 (M+1) can be obtained with R-2- amino-propionamide condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 208 compound 208 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 5-c of 5 intermediate 5 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 208, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:494(M+1)+.
The preparation of 209 compound 209 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 4-c of 4 intermediate 4 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 209, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:482(M+1)+.
The preparation of 210 compound 210 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 4-d of 4 intermediate 4 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 210, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:482(M+1)+.
The preparation of 211 compound 211 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-d of 2 intermediate 2 of embodiment The condensation of 37 intermediate o-phenylenediamine 37 of example, cyclization take off Boc, and compound 211, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:574(M+1)+.
The preparation of 212 compound 212 of embodiment
Referring to 74 method of embodiment, using 2 intermediate of embodiment, 2 single chiral isomers 2-c as raw material process and embodiment The condensation of 37 intermediate o-phenylenediamines 37, cyclization take off Boc, and compound 212, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:574(M+1)+.
The preparation of 213 compound 213 of embodiment
Referring to 74 method of embodiment, with 2 intermediate 2 (the four chiral isomer mixtures not split) of embodiment for raw material By being condensed with 35 intermediate o-phenylenediamine 35 of embodiment, cyclization takes off Boc, and upper 1- methyl-1 H- pyrazoles -5- acyl group can be changed Close object 213, MS m/z:516 (M+1)+.
The preparation of 214 compound 214 of embodiment
The preparation of step 1 intermediate 214-1
Referring to 38 method of embodiment, by intermediate 38-1 and 2- (bromo- 1, the 3- dimethyl -1H- pyrazoles -5- base of 4-) acetic acid first Intermediate 214-1, MS m/z:261 (M+1) can be obtained in ester coupling+.
The preparation of step 2 compound 214
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment Body o-phenylenediamine 214-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, Finally compound 214, MS m/z:601 (M+1) can be obtained with the condensation of 2- propylamine in basic hydrolysis+.
The preparation of 215 compound 215 of embodiment
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-b of 2 intermediate 2 of embodiment Body o-phenylenediamine 214-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, Finally compound 215, MS m/z:627 (M+1) can be obtained with cyclopentamine condensation in basic hydrolysis+.
The preparation of 216 compound 216 of embodiment
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment Body o-phenylenediamine 214-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, Finally compound 216, MS m/z:627 (M+1) can be obtained with cyclopentamine condensation in basic hydrolysis+.
The preparation of 217 compound 217 of embodiment
The preparation of step 1 intermediate 217-1
Referring to 38 method of embodiment, by intermediate 38-1 and bromo pyrazoles object " the bromo- 2- methyl-of 6- benzyl -4- methyl -3- Intermediate 217-1, MS m/ can be obtained in 4,5,7,8- tetrahydro -6H- pyrazoles [1,5-d] diazepine -4,6- dicarboxylic esters " coupling z:450(M+1)+.
The preparation of step 2 compound 217
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment Body o-phenylenediamine 217-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, Basic hydrolysis is condensed with cyclopentamine, and last palladium carbon, which hydrogenates de- benzyloxycarbonyl protecting group, can be obtained compound 217, MS m/z:682 (M+ 1)+.
The preparation of 218 compound 218 of embodiment
The preparation of step 1 intermediate 218-1
Referring to 38 method of embodiment, by intermediate 38-1 and bromo pyrazoles object " the bromo- 2- methyl -4,5 of methyl -3-, 7,8- tetra- Intermediate 218-1, MS m/z:317 (M+1) can be obtained in hydrogen pyrazoles [1,5-d] [Isosorbide-5-Nitrae] oxaza heptane -4- carboxylate " coupling+.
The preparation of step 2 compound 218
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment Body o-phenylenediamine 218-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, Compound 218, MS m/z:683 (M+1) can be obtained with cyclopentamine condensation in basic hydrolysis+.
The preparation of 219 compound 219 of embodiment
Referring to 74 method of embodiment, pass through and centre by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment Body o-phenylenediamine 217-1 condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, then hydrogenate de- benzyloxycarbonyl group through palladium carbon Compound 219, MS m/z:629 (M+1) can be obtained in protecting group+.
The preparation of 220 compound 220 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 40 intermediate o-phenylenediamine 40 of example, cyclization take off Boc, and compound 220 can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group, MS m/z:601(M+1)+.1H NMR (400MHz, MeOD): δ=7.67-7.61 (m, 1H), 7.53-7.51 (m, 1H), 7.47- 7.34 (m, 3H), 7.27-7.21 (m, 2H), 6.49 (s, 1H), 6.02 (d, J=9.6Hz, 1H), 5.03-4.98 (m, 1H), 4.73 (s, 1H), 4.24-4.16 (m, 1H), 3.93 (s, 3H), 2.79 (s, 3H), 2.26 (d, J=6.4Hz, 4H), 2.16 (d, J =3.6Hz, 2H), 1.99-1.93 (m, 1H), 1.76 (d, J=7.2Hz, 3H), 0.99 (d, J=6.8Hz, 2H), 0.89 (d, J =6.8Hz, 3H).
The preparation of 221 compound 221 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Step 6-7 is condensed, last ester hydrolysis and can be obtained of ammonolysis through basic hydrolysis, then with 4- amino tetrahydro pyran -4- carboxylate methyl ester Close object 221, MS m/z:632 (M+1)+.
The preparation of 222 compound 222 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 222, MS m/z:602 (M+1) can be obtained through basic hydrolysis, then with 3- (R)-amino piperidine -2- ketone condensation in step 6-7+ .1H NMR(400MHz,Methanol-d4)δ7.91(s,1H),7.81-7.76(m,2H),7.69-7.67(m,2H),7.62- 7.52(m,2H),7.49–7.37(m,4H),7.34-7.30(m,2H),6.67(s,1H),5.96-5.91(m,1H),4.28- 4.21 (m, 1H), 3.95 (s, 3H), 3.31-3.28 (m, 2H), 1.94-1.83 (m, 4H), 1.67 (d, J=5.2Hz, 6H), 0.68-.055(m,1H),0.25-0.19(m,2H),-0.02-0.08(m,1H).
The preparation of 223 compound 223 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 223, MS m/ can be obtained through basic hydrolysis, then with the fluoro- D- prolineamide condensation of (2R, 4S)-trans- -4- in step 6-7 z:620(M+1)+.1H NMR (400MHz, MeOD) δ 7.57 (d, J=8.1Hz, 1H), 7.41 (d, J=2.1Hz, 2H), 7.39 (s, 1H), 7.36-7.30 (m, 2H), 7.28 (s, 1H), 7.26 (s, 1H), 7.23 (d, J=6.9Hz, 1H), 6.63 (s, 1H), 5.84 (s, 1H), 5.02 (s, 1H), 4.64-4.58 (m, 2H), 3.91 (d, J=1.1Hz, 3H), 3.14-3.51 (m, 1H), 1.66 (s, 3H), 1.60 (s, 3H), 0.91 (m, J=13.5,7.5Hz, 3H), 0.33 (m, J=13.1,8.7,4.0Hz, 2H), 0.24(s,2H),0.07–0.00(m,2H),-0.25(s,2H).
The preparation of 224 compound 224 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 224, MS m/z:588 (M+1) can be obtained through basic hydrolysis, then with the condensation of 1- amino-cyclopropane formamide in step 6-7+.1H NMR (400MHz, MeOD) δ 7.90 (d, J=1.1Hz, 1H), 7.79 (d, J=8.7Hz, 1H), 7.69 (dd, J=8.8, 1.7Hz, 1H), 7.60-7.54 (m, 1H), 7.48 (dd, J=7.9,1.3Hz, 1H), 7.44 (d, J=2.2Hz, 1H), 7.40 (td, J=7.6,1.3Hz, 1H), 7.32 (ddd, J=7.5,4.8,1.7Hz, 1H), 6.67 (t, J=2.5Hz, 1H), 5.95 (s, 1H), 3.96 (s, 3H), 3.45 (s, 1H), 2.88 (s, 1H), 1.65 (s, 6H), 1.51 (q, J=7.9,4.6Hz, 2H), 1.06 (q, J=7.9,4.6Hz, 2H), 0.97-0.85 (m, 1H), 0.51-0.41 (m, 1H), 0.40-0.30 (m, 1H), 0.25- 0.14(m,1H),-0.04(s,1H).
The preparation of 225 compound 225 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 225, MS m/z:616 (M+1) can be obtained through basic hydrolysis, then with the condensation of D- cyclopropyl alanimamides in step 6-7+.1H NMR (400MHz, MeOD) δ 7.85 (d, J=1.3Hz, 1H), 7.81 (s, 1H), 7.78 (s, 1H), 7.66 (dd, J=8.8, 1.7Hz, 1H), 7.56 (dd, J=6.4,4.9Hz, 1H), 7.48 (dd, J=8.0,1.3Hz, 1H), 7.45 (d, J=2.2Hz, 1H), 7.40 (t, J=7.4Hz, 1H), 7.36-7.30 (m, 1H), 7.17 (dd, J=7.7,4.1Hz, 1H), 5.94-5.85 (m, 1H), 4.58-4.37 (m, 1H), 3.59-3.45 (m, 2H), 3.27-2.95 (m, 1H), 1.70 (d, J=3.2Hz, 6H), 1.59- 1.50 (m, 2H), 0.68-0.60 (m, 2H), 0.51-0.43 (m, 1H), 0.43-0.35 (m, 3H), 0.18 (dd, J=9.9, 5.4Hz,2H),0.08–0.02(m,2H).
The preparation of 226 compound 226 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Step 6-7, through basic hydrolysis, ammonolysis finally, which occurs, with ammonium hydroxide can be obtained compound 226, MS m/z:505 (M+1)+.1H NMR (400MHz, Methanol-d4) δ 7.84 (d, J=1.2Hz, 1H), 7.80 (dd, J=8.4,0.8Hz, 1H), 7.68-7.65 (m, 1H), 7.60-7.55 (m, 1H), 7.48 (dd, J=8.0 1.2Hz, 1H), 7.44 (d, J=2.0Hz, 1H), 7.42-7.38 (m, 1H), 7.32-7.28 (m, 1H), 6.66 (d, J=2.0Hz, 1H), 5.94 (s, 1H), 3.96 (s, 3H), 3.52-3.45 (m, 1H),1.68(s,6H),1.63(s,1H),1.31(s,1H),0.48–0.42(m,1H),0.40-0.33(m,1H),0.21- 0.16(m,1H),-0.04(s,1H).
The preparation of 227 compound 227 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 227, MS m/z:588 (M+ can be obtained through basic hydrolysis, then with 3- (R)-amino -2-Pyrrolidone condensation in step 6-7 1)+.1H NMR (400MHz, Methanol-d4) δ 7.93 (s, 1H), 7.81 (d, J=8.8Hz, 1H), 7.71 (dd, J=8.4, 1.6Hz, 1H), 7.58 (d, J=7.6Hz, 1H), 7.47 (dd, J=8.0,1.6Hz, 1H), 7.43-7.42 (m, 1H), 7.39 (dd, J=7.6,1.6Hz, 1H), 7.34-7.30 (m, 1H), 6.67 (d, J=2.0Hz, 1H), 6.00 (s, 1H), 4.46 (t, J =8.8Hz, 1H), 3.96 (s, 3H), 3.38 (dd, J=9.6,2.8Hz, 2H), 2.47-2.39 (m, 1H), 2.14-2.02 (m, 1H), 1.68 (d, J=2.4Hz, 6H), 1.31 (s, 1H), 0.48-0.35 (m, 2H), 0.22-0.16 (m, 1H) ,-0.06 (s, 1H).
The preparation of 228 compound 228 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 228, MS m/z:616 (M+1) can be obtained through basic hydrolysis, then with the condensation of penta formamide of 1- amino -1- ring in step 6-7+ .1H NMR (400MHz, Methanol-d4) δ 7.87 (d, J=1.6Hz, 1H), 7.81 (d, J=8.8Hz, 1H), 7.66-7.63 (m,1H),7.59–7.54(m,1H),7.48-7.46(m,1H),7.44-7.42(m,1H),7.40-7.37(m,1H),7.34- 7.30 (m, 1H), 6.67 (d, J=2.0Hz, 1H), 6.00 (s, 1H), 3.96 (s, 3H), 3.45 (s, 1H), 2.18-2.13 (m 2H),2.00–1.94(m,2H),1.76–1.50(m,12H),1.30(s,1H),0.49-0.42(m,1H),0.38-0.31(m, 1H),0.22–0.16(m,1H).
The preparation of 229 compound 229 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 229, MS m/z:602 (M+ can be obtained through basic hydrolysis, then with the condensation of R-2- amino -2- cyclopropyl acetamide in step 6-7 1)+.1H NMR(400MHz,DMSO-d6)δ7.57–7.46(m,3H),7.43–7.34(m,2H),7.38–7.20(m,2H), 7.24–7.11(m,1H),6.65-6.64(m,1H),5.90-5.81(m,1H),3.82(s,3H),3.81–3.70(m,2H), 1.56-1.44 (m, 8H), 1.53 (d, J=4.8Hz, 3H), 1.21 (d, J=6.6Hz, 4H), 1.02-0.95 (m, 1H), 0.38- 0.28(m,3H),0.23-0.18(m,1H),0.14-0.08(m,2H),0.01--0.09(m,1H)-0.33--0.41(m,1H).
The preparation of 230 compound 230 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 230, MS m/z:618 can be obtained through basic hydrolysis, then with the condensation of 3- amido tetrahydrofuran -3- formamide in step 6-7 (M+1)+.1H NMR(400MHz,Methanol-d4)δ7.58(s,2H),7.41–7.39(m,2H),7.33–7.30(m,2H), 7.25 (dd, J=7.8,1.6Hz, 1H), 6.63 (s, 1H), 5.84 (s, 1H), 4.21 (d, J=9.4Hz, 1H), 3.90 (s, 3H), 3.86 (dd, J=9.5,2.4Hz, 1H), 3.79-3.69 (m, 1H), 2.44-2.37 (m, 1H), 2.26-2.17 (m, 1H), 1.68-1.61 (m, 7H), 1.31 (s, 3H), 0.91 (d, J=9.2Hz, 1H), 0.34-0.23 (m, 3H), 0.04 (dd, J= 9.6,4.8Hz,1H).
The preparation of 231 compound 231 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 231, MS m/z:602 (M+1) can be obtained through basic hydrolysis, then with the condensation of 1- amino cyclobutane formamide in step 6-7+.1H NMR(400MHz,Methanol-d4)δ7.64–7.52(m,3H),7.41-7.39(m,2H),7.35-7.31(m,2H),7.28– 7.21(m,1H),6.63(s,1H),5.84(s,1H),3.90(s,3H),2.63–2.56(m,2H),2.20-2.12(m,2H), 1.93–1.86(m,3H),1.66(s,7H),1.31-1.24(m,1H),0.435–0.21(m,2H),0.07-0.03(m,1H).
The preparation of 232 compound 232 of embodiment
Referring to 74 method of embodiment, passed through and implementation with the single chiral isomers 12-c raw material of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with 1- amino cyclobutane formate methyl esters, and compound 232, MS m/ can be obtained in last ester hydrolysis z:603(M+1)+.1H NMR (400MHz, Methanol-d4) δ 7.69 (s, 1H), 7.59 (d, J=8.4Hz, 2H), 7.43- 7.20(m,8H),6.65(s,1H),5.87(s,1H),3.90(s,3H),3.62(s,1H),3.19–3.12(m,1H),3.00 (s, 1H), 2.84 (s, 1H), 2.57-2.35 (m, 5H), 1.94 (s, 18H), 1.78 (d, J=3.6Hz, 1H), 1.65 (s, 6H), 1.37–1.20(m,4H),0.36–0.18(m,2H).
The preparation of 233 compound 233 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 12-c of 12 intermediate 12 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 233, MS m/z:618 (M+1) can be obtained through basic hydrolysis, then with the condensation of D- leucyl amine in step 6-7+.1H NMR (400MHz, Methanol-d4) δ 7.85 (s, 1H), 7.79 (d, J=8.8Hz, 1H), 7.65-7.62 (m, 3H), 7.49-7.40 (m, 3H), 7.32-7.23 (m, 2H), 6.65 (d, J=2.0Hz, 1H), 5.93 (s, 1H), 4.49 (dd, J=10.4,4.4Hz, 1H),3.96(s,3H),3.54–3.45(m,1H),1.69(s,6H),0.92-0.87(m,6H),0.49-0.42(m,1H), 0.37(s,1H),0.21-0.15(m,1H).
The preparation of 234 compound 234 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine 26 of embodiment with 9 intermediate 9 of embodiment referring to 74 method of embodiment Condensation, cyclization, take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with R- Compound 234, MS m/z:648 (M+1) can be obtained in the condensation of 2- amino -2- cyclobutyl-N- methylacetamide+.
The preparation of 235 compound 235 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine of embodiment with 10 intermediate 10 of embodiment referring to 74 method of embodiment 26 condensations, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with Compound 235, MS m/z:648 (M+1) can be obtained in the condensation of R-2- amino -2- cyclobutyl-N- methylacetamide+.1H NMR (400M,MeOD)δ7.70-7.79(m,2H),7.65-7.69(m,1H),7.50-7.60(m,3H),7.43-7.49(m,1H), 7.35-7.42(m,2H),7.18-7.28(m,1H),6.89-7.01(m,2H),6.06-6.10(m,1H),5.71-5.73(m, 1H),5.67-5.70(m,1H),4.28-4.35(m,1H),4.00(s,1H),3.90(s,2H),2.71-2.72(m,3H), 2.49-2.60(m,1H),1.82-1.98(m,4H),1.74-1.81(m,1H),1.63-1.69(m,6H),0.60-0.67(m, 1H),0.45-0.54(m,2H),0.31-0.43(m,2H).
The preparation of 236 compound 236 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine 26 of embodiment with 8 intermediate 8 of embodiment referring to 74 method of embodiment Condensation, cyclization, take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with R- Compound 236, MS m/z:594 (M+1) can be obtained in the condensation of 2- amino-2-methyl-N- methylacetamide+.
The preparation of 237 compound 237 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine 26 of embodiment with 8 intermediate 8 of embodiment referring to 74 method of embodiment Condensation, cyclization, take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with R- Compound 237, MS m/z:622 (M+1) can be obtained in the condensation of 2- amino -2- isopropyl-N- methylacetamide+.
The preparation of 238 compound 238 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine 26 of embodiment with 7 intermediate 7 of embodiment referring to 74 method of embodiment Condensation, cyclization, take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with R- Compound 238, MS m/z:566 (M+1) can be obtained in 2- amino-2-methyl-acetamide condensation+.1H NMR(400M,CDCl3)δ 8.18(s,1H),7.88-8.06(m,1H),7.58-7.67(m,1H),7.50-7.57(m,1H),7.38-7.48(m,2H), 7.30-7.38(m,2H),7.14-7.28(m,4H),6.78-6.90(m,1H),6.34-6.43(m,1H),5.84-6.09(m, 3H),5.71-5.78(m,1H),5.54-5.60(m,1H),5.31-5.39(m,1H),4.49-4.57(m,1H),4.00-4.07 (m,2H),3.94-3.98(m,1H),3.35-3.42(m,2H),3.24(s,1H),1.58-1.72(m,6H),1.23-1.32 (m,3H).
The preparation of 239 compound 239 of embodiment
It is that raw material passes through and 26 intermediate o-phenylenediamine 26 of embodiment with 7 intermediate 7 of embodiment referring to 74 method of embodiment Condensation, cyclization, take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step 6-7 of embodiment, through basic hydrolysis, then with R- Compound 239, MS m/z:580 (M+1) can be obtained in the condensation of 2- amino-2-methyl-N- methylacetamide+.1H NMR(400M, CDCl3)δ8.14(s,1H),7.61-7.72(m,2H),7.50-7.59(m,2H),7.46-7.49(m,1H),7.41-7.45 (m,1H),7.30-7.37(m,3H),7.14-7.26(m,4H),6.81-6.89(m,1H),6.28-6.41(m,2H),6.01- 6.10(m,1H),5.82-5.95(m,2H),5.55-5.61(m,1H),5.31-5.41(m,1H),4.39-4.55(m,2H), 4.03-4.13(m,3H),3.95-4.02(m,2H),3.36-3.48(m,3H),3.24(s,2H),2.70-2.83(m,5H), 1.66(s,9H),1.17-1.36(m,6H).
The preparation of 240 compound 240 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, then with N, N- dimethyl-ethylenediamine condensation compound 240, MS m/z:578 (M+1) can be obtained+.
The preparation of 241 compound 241 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 241, MS m/z:620 (M+1) can be obtained through basic hydrolysis, then with the condensation of N- (2- amino-ethyl) morpholine in rapid 6-7+.
The preparation of 242 compound 242 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with D-Leu methyl esters, and compound 242, MS m/z:621 (M+ can be obtained in last ester hydrolysis 1)+.1HNMR (400MHz, MeOD): δ=8.52 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.63 (s, 2H), 7.34- 7.48(m,3H),6.49(s,1H),6.09-6.12(m,1H),4.63(s,2H),4.19-4.21(m,1H),3.88-3.96(m, 6H), 3.34-3.40 (m, 2H), 1.96-2.00 (m, 1H), 1.60-1.66 (m, 1H), 1.46-1.50 (d, 4H, J=16Hz), 1.24-1.27 (m, 2H), 1.02-1.03 (d, 3H, J=6Hz), 0.89-0.91 (d, 3H, J=6.8Hz), 0.73-0.75 (t, 3H, J=6Hz), 0.35-0.37 (d, 3H, J=6.4Hz)
The preparation of 243 compound 243 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 243, MS m/z:698 (M+1) can be obtained through basic hydrolysis, then with 162 intermediate 162-2 of embodiment condensation in rapid 6-7+。
The preparation of 244 compound 244 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 244, MS m/z:645 (M+1) can be obtained through basic hydrolysis, then with 165 intermediate 165-4 of embodiment condensation in rapid 6-7+。
The preparation of 245 compound 245 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 245, MS m/z:724 (M+1) can be obtained through basic hydrolysis, then with 164 intermediate 164-1 of embodiment condensation in rapid 6-7+。
The preparation of 246 compound 246 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 246, MS m/z:712 (M+1) can be obtained through basic hydrolysis, then with 163 intermediate 163-1 of embodiment condensation in rapid 6-7+。
The preparation of 247 compound 247 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 247, MS m/z:620 (M+1) can be obtained through basic hydrolysis, then with the condensation of D- leucyl amine in rapid 6-7+。
The preparation of 248 compound 248 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with R-2- cyclopropyl-glycine methyl ester, compound 248, MS most can be obtained through ester hydrolysis afterwards m/z:605(M+1)+。
The preparation of 249 compound 249 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed with R-2- amino -2- cyclopropyl methyl-ethyl acetate through basic hydrolysis, compound most can be obtained through ester hydrolysis afterwards 249, MS m/z:619 (M+1)+.
The preparation of 250 compound 250 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed with D-PROLINE methyl esters through basic hydrolysis, compound 250, MS m/z:605 (M+ most can be obtained through ester hydrolysis afterwards 1)+.1H NMR (400MHz, MeOD) δ 7.58-7.55 (m, 2H), 7.53-7.50 (m, 1H), 7.37 (dd, J=14.5,5.8Hz, 3H), 7.28-7.22 (m, 2H), 6.52 (s, 1H), 6.02 (d, J=9.0Hz, 1H), 4.45 (m, 1H), 4.18 (s, 1H), 3.95 (s, 3H), 2.94-2.88 (m, 2H), 2.13 (m, 2H), 1.96 (m, 1H), 1.82-1.68 (m, 2H), 1.61 (d, J=6.8Hz, 6H), 1.02 (d, J=5.7Hz, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 251 compound 251 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis with D-PROLINE methyl esters, then compound 251 can be obtained through ester hydrolysis and ammonolysis, MS m/z: 604(M+1)+.1H NMR(400MHz,MeOD)δ7.60–7.48(m,3H),7.39(dm,3H),7.24(m,2H),6.51(s, 1H), 6.02 (d, J=9.0Hz, 1H), 4.44 (m, 1H), 4.18 (s, 1H), 3.94 (s, 3H), 2.92 (m, 2H), 1.96 (m, 1H), 1.80-1.68 (m, 2H), 1.65 (s, 3H), 1.57 (s, 3H), 1.54-1.42 (m, 2H), 0.99 (d, J=17.1Hz, 3H), 0.87 (d, J=6.4Hz, 3H)
The preparation of 252 compound 252 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis with 1- amino-cyclopropane methyl formate, then compound 252 can be obtained through ester hydrolysis, MS m/z: 591(M+1)+.1H NMR(400MHz,Methanol-d4)δ7.61(s,1H),7.54–7.46(m,2H),7.39–7.34(m, 1H), 7.34-7.26 (m, 2H), 7.25-7.13 (m, 2H), 6.46 (s, 1H), 5.96 (d, J=9.5Hz, 1H), 4.27-4.12 (m,1H),4.09(s,1H),3.90(s,3H),1.95-1.81(m 1H),1.59(s,6H),1.52(s,2H),1.47-1.39 (m, 2H), 1.00-0.91 (m, 6H), 0.84 (d, J=6.8Hz, 3H)
The preparation of 253 compound 253 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 253, MS m/z:590 (M+1) can be obtained with 3- (R)-amino -2-Pyrrolidone condensation through basic hydrolysis in rapid 6-7+.1H NMR(400MHz,MeOD)δ7.65(s,1H),7.57–7.49(m,3H),7.42–7.31(m,4H),7.27–7.21(m,2H), 6.48 (s, 1H), 5.99 (d, J=9.5Hz, 1H), 4.45-4.36 (m, 1H), 4.30-4.17 (m, 1H), 3.92 (s, 3H), 2.48-2.35 (m, 2H), 2.08-1.85 (m, 3H), 1.64 (d, J=6.5Hz, 6H), 0.96 (t, J=6.5Hz, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 254 compound 254 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 254, MS m/z:618 (M+ can be obtained with the condensation of R-2- amino -2- cyclopropyl methyl acetamide through basic hydrolysis in rapid 6-7 1)+.1H NMR(400MHz,DMSO-d6)δ7.55-7047(m,2H),7.43-7.38(m,2H),7.34–7.29(m,2H), 7.26-7.14 (m, 2H), 6.86 (d, J=8.4Hz, 1H), 6.48-6.47 (m, 1H), 5.88 (d, J=11.0Hz, 1H), 4.31-4.19 (m, 2H), 3.82 (s, 3H), 1.80-1.68 (m, 1H), 1.54 (d, J=7.3Hz, 6H), 1.40-1.33 (m, 1H),0.80-0.75(m,6H),0.52-0.44(m,1H),0.26-0.22(m,2H),-0.03--0.13(m,3H).
The preparation of 255 compound 255 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 255, MS m/z:618 (M+1) can be obtained with the condensation of R-2- amino -2- cyclopentane formamide through basic hydrolysis in rapid 6-7+.1H NMR(400MHz,DMSO-d6)δ7.64–7.46(m,3H),7.44-7.39(m,2H),7.37–7.29(m,2H),7.25-7.21 (m, 1H), 7.13 (d, J=8.6Hz, 1H), 6.90 (s, 1H), 6.49-6.44 (m, 1H), 5.88 (d, J=9.6Hz, 1H), 3.82(s,3H),1.98-1.92(m,3H),1.84-1.75(m,4H),1.52(s,6H),1.45-1.41(m,2H),0.78(d, J=6.9Hz, 6H)
The preparation of 256 compound 256 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, compound 256, MS m/z:507 (M+1) is can be obtained in last ammonolysis+.1H NMR(400MHz,DMSO-d6) δ 12.53 (d, J=14.8Hz, 1H), 8.76 (dd, J=31.2,9.4Hz, 1H), 7.61-7.56 (m, 1H), 7.47-7.40 (m, 3H), 7.34-7.20 (m, 2H), 7.25-7.16 (m, 2H), 6.87-6.80 (m, 2H), 6.50 (d, J=2.4Hz, 1H), 5.90 (t, J=10.0Hz, 1H), 4.32-4.24 (m, 1H), 4.12 (d, J=7.6Hz, 1H), 3.83 (s, 3H), 3.18 (d, J= 4.4Hz, 1H), 1.78 (d, J=9.2Hz, 1H), 1.50 (s, 6H), 0.78 (t, J=7.2Hz, 6H)
The preparation of 257 compound 257 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 257, MS m/z:521 (M+1) can be obtained with methylamine hydrochloride condensation through basic hydrolysis in rapid 6-7+.
The preparation of 258 compound 258 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 258, MS m/z:604 (M+1) can be obtained with R-2- amino -2- cyclopropyl-acetamide condensation through basic hydrolysis in rapid 6-7+.1H NMR(400MHz,DMSO-d6) δ 7.56 (d, J=13.5Hz, 2H), 7.43 (dd, J=8.0,2.4Hz, 2H), 7.38-7.28 (m, 2H), 7.26-7.21 (m, 1H), 7.18 (d, J=8.6Hz, 1H), 6.51 (s, 1H), 5.92 (d, J=11.2Hz, 1H), 4.25 (d, J=10.9Hz, 1H), 3.84 (s, 3H), 3.80-3.73 (m, 1H), 2.68 (dd, J=3.7,1.8Hz, 1H), 2.34 (dt, J=3.6,1.8Hz, 1H), 1.81 (s, 1H), 1.53 (s, 6H), 1.46 (d, J=8.5Hz, 1H), 1.00 (dt, J= 11.0,4.1Hz, 1H), 0.81 (t, J=11.9Hz, 6H), 0.44-0.28 (m, 3H), 0.16 (d, J=3.7Hz, 1H) ,-0.05 (s,1H).
The preparation of 259 compound 259 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 259, MS m/z:590 (M+1) can be obtained with the condensation of 1- amino-cyclopropane formamide through basic hydrolysis in rapid 6-7+.
The preparation of 260 compound 260 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 260, MS m/z:620 (M+1) can be obtained with the condensation of 3- amido tetrahydrofuran -3- formamide through basic hydrolysis in rapid 6-7+ .1H NMR(400MHz,Methanol-d4)δ7.78(s,1H),7.75–7.66(m,3H),7.65–7.57(m,3H),7.54– 7.43 (m, 5H), 7.38 (d, J=8.0Hz, 1H), 7.34-7.28 (m, 2H), 7.24 (dd, J=8.0,1.2Hz, 1H), 7.16- 7.12 (m, 1H), 7.08 (d, J=2.0Hz, 1H), 6.71 (s, 1H), 6.14 (d, J=8.0Hz, 1H), 5.92 (d, J= 11.4Hz, 1H), 4.45 (dd, J=11.4,5.2Hz, 1H), 4.27-4.21 (m, 2H), 4.08 (s, 3H), 3.99 (s, 3H), 3.92 (qd, J=8.4,4.8Hz, 2H), 3.85-3.69 (m, 4H), 2.61 (dt, J=12.8,6.4Hz, 1H), 2.40 (dq, J =13.2,8.4Hz, 2H), 2.29-2.24 (m, 3H), 1.63 (dd, J=27.46 2.4Hz, 11H), 1.35-1.31 (m, 1H), 1.13 (d, J=6.8Hz, 3H), 1.02 (dd, J=15.6,6.8Hz, 5H), 0.87 (d, J=6.8Hz, 4H)
The preparation of 261 compound 261 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed through basic hydrolysis, then with 4- amino tetrahydro pyran -4- carboxylate methyl ester, and simultaneously chemical combination can be obtained in ammonolysis to last ester hydrolysis Object 261, MS m/z:634 (M+1)+.
The preparation of 262 compound 262 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 262, MS m/z:604 (M+1) can be obtained through basic hydrolysis, then with 3- (R)-amino piperidine -2- ketone condensation in rapid 6-7+ .1H NMR(400MHz,Methanol-d4)δ7.83(s,1H),7.73-7.69(m,2H),7.65-7.62(m,2H),7.57– 7.53(m,2H),7.45(s,2H),7.40-7.37(m,1H),7.34–7.24(m,3H),6.68(s,1H),6.13-6.09(m, 1H),5.82-5.87(m,1H),4.43-4.37(m,1H),4.24-4.18(m,3H),4.08(s,2H),3.99(s,3H), 3.30-3.27(m,3H),2.20-2.11(m,2H),1.98-1.95(m,3H),1.93–1.80(m,6H),1.67-1.63(m, 6H), 1.60-1.57 (m, 5H), 1.33 (t, J=7.3Hz, 3H), 1.12 (d, J=6.5Hz, 3H), 1.05-1.01 (m, 3H), 0.88 (d, J=6.7Hz, 3H)
The preparation of 263 compound 263 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 263, MS m/z:604 (M+1) can be obtained through basic hydrolysis, then with the condensation of 1- amino cyclobutane formamide in rapid 6-7+.
The preparation of 264 compound 264 of embodiment
The preparation of step 1 intermediate 264-1
The bromo- 2- Nitro-phenol (4.36g, 20.00mmol) of 4- and 4- methoxybenzyl bromine (8.04g, 40.00mmol) is molten 80 DEG C are warming up in DMF (40.00mL) reaction solution and is stirred 2 hours, and end of reaction is cooled to room temperature, and is diluted with water, DCM extraction It takes (2 × 60ml), merges organic phase, wash (3 × 60ml), saturated sodium-chloride water solution washing, anhydrous sodium sulfate is dry, mistake Intermediate can be obtained through silica gel column chromatography separating purification (petrol ether/ethyl acetate 30:1) in filter, filtrate decompression concentration, crude product 264-1 (3.70g, 10.94mmol, 54.70%yield), LC-MS is not responding to.
The preparation of step 2 intermediate 264-2
Intermediate 264-1 (6.00g, 17.74mmol), ethyl acrylate (5.33g, 53.22mmol) are dissolved in acetonitrile (50mL) is warming up to 90 DEG C under mixture nitrogen protection and stirs 12 hours, be cooled to room temperature, be diluted with water after reduced pressure, DCM extracts (2 × 60ml), merges organic phase, washes (3 × 60ml), saturated sodium-chloride water solution washing, and anhydrous sodium sulfate is dry It is dry, filtering, filtrate decompression concentration, during crude product can be obtained through silica gel column chromatography separating purification (petrol ether/ethyl acetate 20:1) Mesosome 264-2 (3.50g, 9.79mmol, 55.21%yield), MS m/z:358 (M+1)+.
The preparation of step 3 intermediate 264-3
Intermediate 264-2 (1.50g, 4.20mmol) is dissolved in 30ml to be dissolved in methanol, PtO2 is added under nitrogen atmosphere (50mg), normal pressure hydrogenation reaction overnight, after raw material disappears, add 10%Pd/C (50mg), and normal pressure hydrogenation reaction is stayed overnight, through silicon Diatomaceous earth filters, and filtrate decompression is concentrated to dryness, crude product through MPLC C18 reverse phase column purification obtain intermediate 264-3 (800.00mg, 3.82mmol, 91.03%yield), MS m/z:210 (M+1)+.
The preparation of step 3 intermediate 264-4
Intermediate 264-3 (300.00mg, 1.43mmol) is dissolved in DCM (10mL), sequentially adds 41 intermediate of embodiment 41-3 (419.50mg, 1.43mmol), EDCI (273.13mg, 1.43mmol), HOAT (194.48mg, 1.43mmol) and Reaction 2 hours, saturated common salt water washing, anhydrous sodium sulfate is stirred at room temperature in DIPEA (553.41mg, 4.29mmol), reaction solution It dries, filters, is concentrated under reduced pressure, intermediate can be obtained through silica gel column chromatography separating purification (methylene chloride/methanol 20:1) in crude product 264-4 (544mg, 1.14mmol, 80%yield), MS m/z:485 (M+1)+.
The preparation of step 5 intermediate 264-5
Intermediate 264-4 (500.00mg, 1.03mmol) is dissolved in 15mL toluene, addition TsOH (268.26mg, 5.15mmol), 100 DEG C are warming up to and is stirred 15 hours, end of reaction, is concentrated under reduced pressure, silica gel column chromatography separating purification (dichloromethane Alkane/methanol 30:1) intermediate 264-5 (130.00mg, 278.63umol, 27.05%yield), MS m/z:467 can be obtained (M+1)+.
The preparation of step 6 intermediate 264-6
Intermediate 264-6 (100.00mg, 214.33umol) is dissolved in 5ml ethyl alcohol, addition NaOH (17.15mg, 428.66umol), it is stirred overnight at room temperature, end of reaction, with 1N HCl tune pH value~6, ethyl acetate extraction is concentrated under reduced pressure into It is dry, obtain the crude product (93.00mg, 212.08umol, 98.95%yield) of intermediate 264-6, it is not purified be directly used in it is next Step.MS m/z:439(M+1)+.
The preparation of step 7 intermediate 264-7
Intermediate 264-6 (50.00mg, 114.02umol) is dissolved in DCM (5mL), sequentially adds the D-Leu tert-butyl ester (23.49mg, 125.42umol), EDCI (26.13mg, 136.82umol), HOAT (18.61mg, 136.82umol) and DIPEA Reaction 2 hours is stirred at room temperature in (73.54mg, 570.10umol), reaction solution, and saturated common salt water washing, anhydrous sodium sulfate is dry, Filtering, is concentrated under reduced pressure, and intermediate 264-7 can be obtained through silica gel column chromatography separating purification (methylene chloride/methanol 30:1) in crude product (40.00mg, 65.81umol, 57.72%yield), MS m/z:608 (M+1)+.
The preparation of step 8 compound 264
Intermediate 264-7 (40.00mg, 65.81umol) is dissolved in 2ml methylene chloride, and 2mL trifluoroacetic acid is added under ice bath, Drop finishes, and stirs 3 hours under ice bath, end of reaction, is concentrated under reduced pressure, and crude product can obtain compound 264 through MPLC reverse phase C18 column purification (5.10mg, 8.80umol, 13.37%yield), MS m/z:552 (M+1)+.
The preparation of 265 compound 265 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 265, MS m/ can be obtained through basic hydrolysis, then with the condensation of (R) -7- amino -5- azaspiro [2.4] hept- 4- ketone in rapid 6-7 z:604(M+1)+.1H NMR(400MHz,DMSO-d6)δ7.60-7.55(m,1H),7.53-7.47(m,1H),7.47–7.38 (m,3H),7.35–7.29(m,2H),7.25-7.19(m,1H),7.13-7.08(m,1H),6.49-6.47(m,1H),5.88 (d, J=11.1Hz, 1H), 4.51-4.43 (m, 1H), 4.28-4.17 (m, 1H), 3.82 (s, 3H), 3.11-3.05 (m, 1H), 1.78-1.71(m,1H),1.57–1.42(m,6H),0.87–0.68(m,8H),0.52-0.42(m,2H).
The preparation of 266 compound 266 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 27 intermediate o-phenylenediamine 27 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 266, MS m/z:622 (M+1) can be obtained with R-2- amino -2- cyclopropyl-acetamide condensation through basic hydrolysis in rapid 6-7+.1H NMR(400MHz,DMSO-d6) δ 7.54-7.30 (m, 8H), 7.24 (d, J=7.6Hz, 2H), 6.65 (s, 1H), 6.48 (s, 1H), 5.90 (d, J=11.2Hz, 2H), 4.27 (t, J=6.8Hz, 1H), 3.82 (s, 3H), 1.80 (s, 2H), 1.57-1.41 (m, 8H), 1.24 (s, 3H), 0.98 (d, J=6.4Hz, 2H), 0.90-0.72 (m, 9H), 0.39-0.30 (m, 4H), 0.16 (s, 2H).
The preparation of 267 compound 267 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 267, MS m/z:578 (M+1) can be obtained through basic hydrolysis, then with (R) -2- amino-propionamide condensation in rapid 6-7+.1H NMR(400MHz,DMSO-d6) δ 7.69 (d, J=8.9Hz, 2H), 7.55-7.46 (m, 1H), 7.46-7.34 (m, 4H), 7.28 (td, J=7.7,1.6Hz, 1H), 6.61 (d, J=1.8Hz, 1H), 6.02 (d, J=9.6Hz, 1H), 4.26-4.20 (m, 1H), 4.15 (dd, J=9.4,5.9Hz, 1H), 3.86 (s, 3H), 1.92 (dd, J=13.1,6.3Hz, 1H), 1.53 (s, 6H), 1.17 (d, J=7.1Hz, 3H), 0.90 (d, J=6.6Hz, 3H), 0.77 (d, J=6.7Hz, 3H)
The preparation of 268 compound 268 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 268 can be obtained through basic hydrolysis, then with the condensation of (R) -3- amino -3- N-methyl-2-2-pyrrolidone N, MS m/z in rapid 6-7: 604(M+1)+.
The preparation of 269 compound 269 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 269, MS m/z:592 (M+ can be obtained through basic hydrolysis, then with the condensation of (R) -2- Amino-N-methyl propionamide in rapid 6-7 1)+.1H NMR(400MHz,DMSO-d6) δ 7.64 (d, J=8.9Hz, 2H), 7.47 (d, J=7.5Hz, 1H), 7.44-7.30 (m, 4H), 7.26 (dd, J=12.1,4.6Hz, 1H), 6.56 (s, 1H), 5.97 (d, J=9.7Hz, 1H), 4.25-4.20 (m, 1H), 4.16 (s, 1H), 3.84 (s, 3H), 1.87 (s, 1H), 1.51 (d, J=9.5Hz, 6H), 1.14 (d, J=7.1Hz, 3H), 0.86 (d, J=6.5Hz, 3H), 0.77 (d, J=6.7Hz, 3H)
The preparation of 270 compound 270 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 is condensed, ester hydrolysis through basic hydrolysis with (R) -2- amino-propanoate, is finally condensed with 3- amido tetrahydrofuran Obtain compound 270, MS m/z:648 (M+1)+.1H NMR(400MHz,DMSO-d6)δ7.68–7.60(m,2H),7.47(d,J =7.4Hz, 1H), 7.43-7.30 (m, 4H), 7.29-7.22 (m, 1H), 6.56 (s, 1H), 5.98 (d, J=9.5Hz, 1H), 4.26–4.21(m,1H),4.21–4.10(m,3H),3.84(s,3H),2.06–1.98(m,1H),1.90–1.83(m,1H), 1.53 (d, J=9.0Hz, 6H), 1.14 (dd, J=7.1,1.4Hz, 3H), 0.86 (d, J=6.6Hz, 3H), 0.78 (d, J= 6.8Hz,3H).
The preparation of 271 compound 271 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R) -2- amino-N, compound 271, MS m/z:606 is can be obtained in the condensation of N '-dimethyl propionamide (M+1)+.1H NMR(400MHz,DMSO-d6) δ 7.66 (d, J=8.4Hz, 2H), 7.49 (d, J=7.7Hz, 1H), 7.45- 7.32 (m, 4H), 7.28 (t, J=6.9Hz, 1H), 6.58 (s, 1H), 5.98 (d, J=9.7Hz, 1H), 4.73-4.61 (m, 1H), 4.16 (dd, J=9.9,6.0Hz, 1H), 3.85 (s, 3H), 3.00-2.89 (m, 3H), 2.78 (dd, J=13.6, 6.7Hz, 3H), 1.94-1.83 (m, 1H), 1.57-1.44 (m, 6H), 1.12 (t, J=9.7Hz, 3H), 0.88 (d, J= 6.4Hz, 3H), 0.78 (d, J=6.7Hz, 3H)
The preparation of 272 compound 272 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 272, MS m/z:606 (M+1) can be obtained with the condensation of (R) -2- amino-N- ethyl propionamide through basic hydrolysis in 6-7+ .1H NMR(400MHz,DMSO-d6) δ 7.68 (d, J=7.9Hz, 2H), 7.55-7.46 (m, 1H), 7.46-7.33 (m, 4H), 7.32-7.24 (m, 1H), 6.59 (s, 1H), 6.00 (d, J=9.9Hz, 1H), 4.27-4.12 (m, 2H), 3.85 (s, 3H), 3.08-2.95 (m, 2H), 1.93-1.83 (m, 1H), 1.51 (dd, J=28.2,6.2Hz, 6H), 1.15 (d, J=9.7Hz, 3H), 0.99-0.91 (m, 3H), 0.89 (d, J=10.6,4.5Hz, 3H), 0.78 (d, J=6.7Hz, 3H)
The preparation of 273 compound 273 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 273, MS m/z:620 (M+ can be obtained with the condensation of (R) -2- amino-N- isopropyl propionamide through basic hydrolysis in rapid 6-7 1)+.1H NMR(400MHz,DMSO-d6) δ 7.77-7.64 (m, 2H), 7.51 (d, J=7.2Hz, 1H), 7.41 (dt, J= 13.7,6.9Hz, 4H), 7.30 (dd, J=10.7,4.5Hz, 1H), 6.59 (s, 1H), 6.00 (d, J=9.7Hz, 1H), 4.23- 4.11 (m, 2H), 3.85 (s, 3H), 1.91 (d, J=6.2Hz, 1H), 1.62-1.46 (m, 6H), 1.15 (d, J=7.1Hz, 3H), 1.04-0.92 (m, 6H), 0.90 (d, J=6.6Hz, 3H), 0.78 (d, J=6.7Hz, 3H)
The preparation of 274 compound 274 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 274, MS m/z:618 (M+ can be obtained with the condensation of (R) -2- amino-N-cyclopropyl propionamide through basic hydrolysis in rapid 6-7 1)+.1H NMR(400MHz,DMSO-d6) δ 7.67 (s, 2H), 7.48 (d, J=7.6Hz, 1H), 7.37 (d, J=14.2Hz, 4H), 7.30-7.23 (m, 1H), 6.57 (s, 1H), 5.98 (d, J=9.6Hz, 1H), 4.20-4.08 (m, 2H), 1.94-1.80 (m, 1H), 1.47 (dd, J=28.3,9.5Hz, 6H), 1.11 (d, J=7.1Hz, 3H), 0.86 (d, J=6.2Hz, 3H), 0.76 (d, J=6.5Hz, 3H), 0.56 (d, J=5.4Hz, 2H), 0.27 (s, 2H)
The preparation of 275 compound 275 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 275, MS m/z:632 can be obtained with the condensation of (R) -2- amino-N- cyclopropyl methyl propanamide through basic hydrolysis in rapid 6-7 (M+1)+.1H NMR(400MHz,DMSO-d6)δ7.76–7.60(m,2H),7.56–7.46(m,1H),7.46–7.32(m,4H), 7.30-7.21 (m, 1H), 6.58 (d, J=1.6Hz, 1H), 6.00 (d, J=10.0Hz, 1H), 4.29-4.22 (m, 1H), 4.21-4.13 (m, 1H), 3.85 (s, 3H), 2.97-2.85 (m, 2H), 1.92-1.81 (m, 1H), 1.51 (d, J=28.5, 7.6Hz, 6H), 1.17 (d, J=7.1Hz, 3H), 0.87 (d, J=6.6Hz, 3H), 0.78 (d, J=6.7Hz, 3H), 0.39- 0.27(m,2H),0.12–0.02(m,2H).
The preparation of 276 compound 276 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 276, MS can be obtained with the condensation of (R) -2- amino-N- (4- amino tetrahydro pyran) propionamide through basic hydrolysis in rapid 6-7 m/z:662(M+1)+.1H NMR(400MHz,DMSO-d6) δ 7.62 (d, J=8.6Hz, 2H), 7.47 (d, J=7.9Hz, 1H), 7.42-7.23 (m, 5H), 6.54 (s, 1H), 5.94 (d, J=9.7Hz, 1H), 4.24-4.20 (m, 1H), 4.18 (s, 2H), 3.83 (s, 3H), 3.33-3.24 (m, 2H), 1.85 (s, 2H), 1.59 (s, 2H), 1.54 (t, J=15.7Hz, 6H), 1.25 (d, J=22.6Hz, 3H), 1.14 (d, J=7.2Hz, 3H), 0.85 (d, J=6.3Hz, 3H), 0.77 (d, J=6.8Hz, 3H)
The preparation of 277 compound 277 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 277, MS m/z:604 (M+1) can be obtained with the condensation of (R) -3- methyl -2- carbonyl piperazine through basic hydrolysis in rapid 6-7+ .1H NMR(400MHz,DMSO-d6) δ 8.67 (d, J=9.2Hz, 1H), 7.82 (s, 1H), 7.66 (d, J=8.4Hz, 1H), 7.57-7.32 (m, 5H), 7.24 (dd, J=9.2,4.4Hz, 1H), 7.10 (d, J=6.4Hz, 1H), 6.59 (s, 1H), 5.98 (t, J=9.6Hz, 1H), 4.71 (s, 1H), 4.19 (s, 1H), 3.87 (s, 3H), 2.74 (d, J=46.4Hz, 4H), 1.92 (s, 1H), 1.51 (d, J=26.0Hz, 6H), 1.31-1.16 (m, 3H), 0.82 (dd, J=34.4,6.4Hz, 6H)
The preparation of 278 compound 278 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 278, MS m/z:620 can be obtained with the condensation of R-2- Amino-N-methyl -3- methylbutyryl amine through basic hydrolysis in rapid 6-7 (M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.65 (d, J=9.2Hz, 1H), 7.84 (s, 1H), 7.64 (d, J=9.2Hz, 2H),7.47-7.38(m,4H),7.33–7.20(m,2H),6.70(s,2H),6.58(s,1H),5.98(s,1H),4.18(s, 2H), 4.11-4.04 (m, 1H), 3.85 (s, 3H), 1.86 (dd, J=13.6,6.8Hz, 3H), 1.55 (d, J=7.6Hz, 5H), 0.91–0.61(m,10H),0.01(s,1H).
The preparation of 279 compound 279 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 279, MS m/z:606 (M+1) can be obtained with the condensation of R-2- amino -3- methylbutyryl amine through basic hydrolysis in rapid 6-7+ .1H NMR(400MHz,DMSO-d6) δ 8.64 (d, J=7.6Hz, 1H), 7.66 (d, J=10.0Hz, 2H), 7.49 (d, J= 7.2Hz,1H),7.42-7.25(m,5H),7.02(s,1H),6.70–6.55(m,2H),6.00(s,1H),4.20–4.07(m, 2H), 3.87 (s, 3H), 1.90 (dt, J=13.2,6.8Hz, 2H), 1.55 (d, J=4.0Hz, 5H), 0.89 (d, J=6.0Hz, 2H), 0.79 (dd, J=10.4,6.8Hz, 5H), 0.68 (d, J=6.8Hz, 3H)
The preparation of 280 compound 280 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Through basic hydrolysis compound 280 can be obtained with the condensation of 2- amino -2- cyclobutyl-N- methyl acetamide, MS m/z in rapid 6-7: 632(M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.72 (d, J=10.0Hz, 1H), 7.71 (s, 1H), 7.57 (s, 4H), 7.42 (d, J=8.0Hz, 2H), 7.33 (d, J=2.0Hz, 2H), 7.22 (dd, J=14.4,7.2Hz, 3H), 6.70 (s, 2H), 6.53 (s, 1H), 5.93 (s, 1H), 4.25 (t, J=8.4Hz, 3H), 3.84 (s, 3H), 2.42-2.33 (m, 3H), 1.87- 1.44 (m, 14H), 1.26 (dd, J=12.4,5.54Hz, 3H), 0.78 (d, J=6.8Hz, 5H)
The preparation of 281 compound 281 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 281, MS m/z:618 (M+1) can be obtained with the sweet amine amide condensation of cyclobutyl through basic hydrolysis in rapid 6-7+.1H NMR (400MHz,DMSO-d6) δ 8.73 (d, J=9.2Hz, 2H), 7.71-7.40 (m, 7H), 7.31 (d, J=2.0Hz, 2H), 7.24-7.03 (m, 4H), 6.96 (s, 1H), 6.51 (d, J=14.8Hz, 4H), 5.90 (s, 2H), 4.31-4.19 (m, 3H), 3.83 (s, 3H), 3.06 (s, 1H), 2.34 (s, 1H), 1.74 (d, J=38.4Hz, 6H), 1.53 (s, 7H), 1.31-1.21 (m, 3H),0.77(s,6H).
The preparation of 282 compound 282 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 27 intermediate o-phenylenediamine 27 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 282, MS m/z:622 (M+1) can be obtained with the condensation of 1- amino cyclobutane formamide through basic hydrolysis in rapid 6-7+ .1HNMR (400MHz, MeOD): δ=7.72-7.64 (m, 1H), 7.52-7.51 (m, 1H), 7.42-7.34 (m, 3H), 7.27- 7.23 (m, 1H), 6.48 (s, 1H), 5.98 (d, J=9.6Hz, 1H), 4.60 (s, 1H), 4.25-4.24 (m, 1H), 3.96 (s, 3H),2.62-2.55(m,2H),2.21-2.14(m,2H),1.95-1.89(m,2H),1.63(s,6H),0.99-0.97(m, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 283 compound 283 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 27 intermediate o-phenylenediamine 27 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 283, MS m/z:636 (M+ can be obtained with 1- amino cyclobutane-N-METHYLFORMAMIDE condensation through basic hydrolysis in rapid 6-7 1)+.1HNMR (400MHz, MeOD): δ=7.74-7.62 (m, 1H), 7.52-7.51 (m, 1H), 7.42-7.31 (m, 3H), 7.27-7.23 (m, 1H), 6.48 (s, 1H), 5.98 (d, J=9.2Hz, 1H), 4.60 (s, 1H), 4.25-4.23 (m, 1H), 3.93(s,3H),2.78(s,3H),2.60-2.53(m,2H),2.21-2.13(m,2H),1.93-1.89(m,2H),1.63(s, 6H), 0.99-0.98 (m, 1H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 284 compound 284 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 284, MS m/z:601 (M+1) can be obtained with the condensation of 1- (1H- pyrazole-3-yl) ethamine through basic hydrolysis in rapid 6-7+.
The preparation of 285 compound 285 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 285, MS m/z:601 (M+1) can be obtained with the condensation of 1- (1H- imidazoles) -4- ethamine through basic hydrolysis in rapid 6-7+.
The preparation of 286 compound 286 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound can be obtained with (1R, 2R) -2- amino cyclobutane-(N- methyl) -1- formamide condensation condensation through basic hydrolysis in rapid 6-7 286, MS m/z:618 (M+1)+.1H NMR (400MHz, MeOD) δ 7.56-7.53 (m, 2H), 7.49 (d, J=8.0Hz, 1H), 7.36 (dd, J=8.8,1.6Hz, 1H), 7.34-7.25 (m, 3H), 7.21-7.15 (m, 1H), 6.53 (s, 1H), 5.96 (d, J =8.4Hz, 1H), 4.06 (t, J=7.6Hz, 1H), 3.86 (s, 3H), 2.59 (s, 3H), 1.98 (s, 1H), 1.51 (s, 6H), 1.19 (s, 1H), 0.97 (d, J=6.4Hz, 2H), 0.91-0.88 (m, 1H), 0.77 (t, J=6.8Hz, 3H)
The preparation of 287 compound 287 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound can be obtained with (1S, 2R) -2- amino cyclobutane-(N- methyl) -1- formamide condensation condensation through basic hydrolysis in rapid 6-7 287, MS m/z:618 (M+1)+.1H NMR(400MHz,MeOD)δ7.64-7.55(m,6H),7.40-7.24(m,6H),6.54 (s,1),6.04–6.00(m,1H),4.27–4.18(m,3H),3.95(s,3H),2.68(s,2H),2.51(s,2H),2.00- 1.93 (m, 3H), 1.61 (d, J=2.4Hz, 6H), 1.42-1.25 (m, 12H), 1.04 (d, J=7.2Hz, 3H), 0.94- 0.87(m,7H).
The preparation of 288 compound 288 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound can be obtained with the condensation condensation of (1S, 2R) -2- Aminocyclopentane-(N- methyl) -1- formamide through basic hydrolysis in rapid 6-7 288, MS m/z:632 (M+1)+.1H NMR (400MHz, MeOD) δ 7.71-7.67 (m, 2H), 7.59 (d, J=7.6Hz, 1H), 7.48-7.38 (m, 4H), 7.30-7.27 (m, 1H), 6.66 (s, 1H), 6.11 (d, J=8.4Hz, 1H), 4.29 (dd, J= 14.0,6.8Hz, 1H), 4.20 (s, 1H), 3.98 (s, 3H), 3.80-3.70 (m, 4H), 3.25 (q, J=7.6Hz, 4H), 2.81 (d, J=8.0Hz, 1H), 2.68 (s, 1H), 2.54 (s, 2H), 2.07 (s, 1H), 1.93-1.78 (m, 3H), 1.68-1.51 (m, 9H), 1.09 (d, J=5.6Hz, 3H), 0.87 (d, J=6.8Hz, 3H), 0.12 (s, 1H)
The preparation of 289 compound 289 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Through basic hydrolysis compound 289 can be obtained with the condensation of (R) -2- amino-N- (4- methyl piperazine) propionamide, MS m/z in rapid 6-7: 661(M+1)+.1H NMR(400MHz,DMSO-d6) δ 7.67 (d, J=8.8Hz, 2H), 7.52 (d, J=2.1Hz, 2H), 7.41 (ddd, J=13.3,9.9,8.3Hz, 4H), 7.30-7.24 (m, 2H), 6.60 (d, J=1.6Hz, 1H), 6.02 (d, J= 10.0Hz, 1H), 3.86 (s, 3H), 2.78 (s, 7H), 1.53 (d, J=4.8Hz, 6H), 1.13 (d, J=6.8Hz, 3H), 0.89-0.85 (m, 3H), 0.77 (d, J=6.7Hz, 3H)
The preparation of 290 compound 290 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Through basic hydrolysis compound 290 can be obtained with the condensation of (R) -2- amino-N- tetrahydro pyrrolidine propionamide, MS m/z in rapid 6-7: 632(M+1)+.1H NMR(400MHz,DMSO-d6) δ 7.69 (d, J=9.0Hz, 2H), 7.51 (dd, J=12.5,4.8Hz, 2H), 7.43-7.37 (m, 4H), 7.31-7.25 (m, 2H), 6.03 (d, J=9.5Hz, 1H), 3.86 (s, 3H), 1.53 (d, J= 6.6Hz, 6H), 1.30-1.21 (m, 4H), 1.16-1.06 (m, 4H), 0.92-0.87 (m, 4H), 0.77 (d, J=6.7Hz, 3H).
The preparation of 291 compound 291 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 291, MS m/z:648 (M+1) can be obtained with the condensation of (R) -2- amino-N- morpholine propionamide through basic hydrolysis in rapid 6-7+.
The preparation of 292 compound 292 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 292, MS m/ can be obtained with the condensation of 3- amido tetrahydrofuran -4- (N- cyclopropyl) formamide through basic hydrolysis in rapid 6-7 z:660(M+1)+.1H NMR (400MHz, MeOD) δ 7.70 (dd, J=20.0,8.4Hz, 2H), 7.61 (d, J=13.2Hz, 1H), 7.54 (dd, J=12.4,8.4Hz, 1H), 7.50-7.36 (m, 3H), 7.34-7.27 (m, 1H), 6.67 (s, 1H), 6.08 (d, J=7.6Hz, 1H), 4.56 (d, J=4.4Hz, 1H), 4.17 (s, 1H), 4.08 (s, 1H), 3.98 (s, 2H), 1.69- 1.61 (m, 4H), 1.56 (s, 1H), 1.15-0.98 (m, 4H), 0.87 (d, J=6.8Hz, 2H), 0.76-0.68 (m, 1H), 0.51–0.42(m,1H).
The preparation of 293 compound 293 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 293 can be obtained with the condensation of (3S, 4R) -3- amino furan -4- (N- cyclopropyl) formamide through basic hydrolysis in rapid 6-7, MS m/z:658(M+1)+.1H NMR (400MHz, MeOD) δ 7.79-7.67 (m, 1H), 7.58 (d, J=21.2Hz, 1H), 7.54-7.38 (m, 2H), 7.34-7.23 (m, 1H), 6.64 (s, 1H), 6.09 (d, J=8.0Hz, 1H), 4.28 (d, J= 7.2Hz,1H),4.19(s,1H),4.09(s,1H),3.98(s,2H),2.51–2.35(m,1H),1.99–1.49(m,10H), 1.40-1.26 (m, 4H), 1.18-0.99 (m, 3H), 0.88 (d, J=6.8Hz, 3H), 0.61 (d, J=6.8Hz, 2H), 0.37 (dd, J=13.2,9.2Hz, 2H)
The preparation of 294 compound 294 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 294, MS m/z:602 can be obtained with the condensation of 1- (2H-1,2,4- triazole -3- bases) ethamine through basic hydrolysis in rapid 6-7 (M+1)+.
The preparation of 295 compound 295 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 295, MS m/z:591 (M+1) can be obtained with the condensation of 4- amino tetrahydro pyran through basic hydrolysis in rapid 6-7+.1H NMR (400MHz,DMSO-d6) δ 7.64 (d, J=8.4Hz, 1H), 7.58 (s, 1H), 7.50 (dd, J=12.2,5.3Hz, 2H), 7.39 (dd, J=4.9,2.8Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 6.58 (s, 1H), 5.97 (d, J=9.9Hz, 1H), 3.85 (s, 3H), 3.36-3.22 (m, 4H), 2.07 (s, 6H), 1.89 (s, 1H), 1.56 (d, J=13.0Hz, 2H), 1.51 (s, 6H), 1.43 (s, 2H), 1.06 (t, J=7.0Hz, 6H)
The preparation of 296 compound 296 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Through basic hydrolysis compound 296 can be obtained with the condensation of R-2- amino -2- isopropyl-N- cyclopropyl acetamide, MS m/z in rapid 6-7: 646(M+1)+.1H NMR(400MHz,DMSO-d6) δ 7.92 (s, 1H), 7.65-7.54 (m, 2H), 7.47 (d, J=8.5Hz, 1H), 7.45-7.36 (m, 2H), 7.31 (dd, J=7.1,4.9Hz, 2H), 7.22 (t, J=7.7Hz, 1H), 7.13 (t, J= 9.3Hz, 1H), 6.65-6.56 (m, 1H), 5.90 (d, J=10.9Hz, 1H), 3.82 (s, 3H), 1.86-1.73 (m, 3H), 1.52 (d, J=12.4Hz, 7H), 1.41-1.33 (m, 2H), 1.25 (dd, J=20.6,6.9Hz, 5H), 0.94-0.84 (m, 3H), 0.78 (d, J=6.0Hz, 5H), 0.74 (d, J=6.8Hz, 4H), 0.68-0.61 (m, 3H), 0.57 (d, J=7.0Hz, 2H), 0.30 (dd, J=11.5,5.0Hz, 2H)
The preparation of 297 compound 297 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with 3- (ALPHA- aminoethyl) -5- methyl -4-H-1, compound 297 is can be obtained in the condensation of 2,4- triazoles, MS m/z:616(M+1)+.
The preparation of 298 compound 298 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 298, MS m/z:632 (M+1) can be obtained with the sweet amine amide condensation of D- cyclobutyl-N- methyl through basic hydrolysis in rapid 6-7+ .1H NMR(400MHz,DMSO-d6)δ7.74–7.66(m,1H),7.64–7.60(m,1H),7.59–7.55(m,1H),7.50– 7.45(m,1H),7.45–7.37(m,2H),7.35–7.28(m,2H),7.25–7.19(m,1H),7.19–7.12(m,1H), 6.71–6.58(m,2H),6.51–6.45(m,1H),5.94–5.85(m,1H),4.32–4.17(m,3H),4.07–4.04(m, 1H),3.87–3.80(m,3H),1.86–1.58(m,8H),1.53(s,7H),1.49–1.42(m,1H),0.81–0.71(m, 6H).
The preparation of 299 compound 299 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 299, MS m/z:646 (M+1) can be obtained with the condensation of D- cyclobutyl-N- ethyl glycinamide amine amide through basic hydrolysis in rapid 6-7+.
The preparation of 300 compound 300 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment 300, MS m/z:634 (M+1) can be obtained with the condensation of R-2- amino -3- methyl-N ethyl butyramide through basic hydrolysis in rapid 6-7+.1H NMR(400MHz,DMSO-d6) δ 7.82 (s, 1H), 7.63 (s, 1H), 7.57 (d, J=7.9Hz, 1H), 7.47 (d, J= 8.5Hz, 1H), 7.41 (t, J=7.8Hz, 2H), 7.31 (d, J=8.3Hz, 2H), 7.25-7.19 (m, 1H), 7.14 (t, J= 9.0Hz, 1H), 6.64-6.50 (m, 2H), 6.48 (s, 1H), 5.89 (d, J=11.2Hz, 1H), 4.28-4.21 (m, 1H), 4.10-4.04 (m, 2H), 3.83 (s, 3H), 1.53 (d, J=9.8Hz, 5H), 0.95 (dd, J=13.7,7.0Hz, 3H), 0.78 (d, J=5.4Hz, 8H), 0.69-0.63 (m, 3H)
The preparation of 301 compound 301 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 27 intermediate o-phenylenediamine 27 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment 301, MS m/z:638 (M+1) can be obtained with the condensation of R-2- amino -3- methyl-N-methyl butyramide through basic hydrolysis in rapid 6-7+ .1HNMR (400MHz, MeOD): δ=7.74-7.65 (m, 1H), 7.51 (d, J=7.2Hz, 1H), 7.41-7.23 (m, 4H), 6.48 (s, 1H), 5.98 (d, J=9.6Hz, 1H), 4.27-4.20 (m, 1H), 4.16 (d, J=7.6Hz, 1H), 3.93 (s, 3H), 2.71 (s, 3H), 1.96-1.85 (m, 2H), 1.63 (s, 5H), 0.98 (d, J=6.8Hz, 3H), 0.90-0.87 (m, 6H), 0.82 (d, J=6.4Hz, 3H)
The preparation of 302 compound 302 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 302, MS m/z:573 (M+1) can be obtained with the condensation of 4- amino-pyrazol through basic hydrolysis in rapid 6-7+.1HNMR (400MHz, MeOD): δ=7.68 (s, 1H), 7.60-7.58 (m, 1H), 7.54-7.49 (m, 2H), 7.39-7.34 (m, 3H), 7.26-7.23 (m, 1H), 6.50 (s, 1H), 6.01 (d, J=9.6Hz, 1H), 5.36 (t, d=4.8Hz, 1H), 4.21-4.19 (m, 1H), 3.93 (s, 3H), 2.21 (t, J=7.6Hz, 1H), 2.06-2.03 (m, 4H), 1.72 (s, 3H), 1.65-1.61 (m, 1H), 1.00-0.99 (m, 2H), 0.94-0.90 (m, 2H), 0.86 (d, J=6.8Hz, 2H)
The preparation of 303 compound 303 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 27 intermediate o-phenylenediamine 27 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and R- cyclobutyl-N- methyl is sweet amide condensed 303, MS m/z:650 (M+1) can be obtained+.1HNMR (400MHz, MeOD): δ=7.73-7.64 (m, 1H), 7.51 (d, J=7.6Hz, 1H), 7.41-7.23 (m, 4H), 6.48 (s, 1H), 5.98 (d, J=9.6Hz, 1H), 4.34 (d, d=8.8Hz, 1H), 4.27-4.22 (m, 1H), 3.93 (s, 3H), 2.70 (s, 3H), 2.52-2.49 (m, 1H), 2.26-2.19 (m, 1H), 1.93-1.71 (m, 5H), 1.63 (d, J=8.0Hz, 6H), 0.98 (d, J=6.4Hz, 3H), 0.87 (d, J=6.8Hz, 3H)
The preparation of 304 compound 304 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- morpholine is sweet amide condensed compound 304, MS m/z:688 (M+1) can be obtained+ .1H NMR(400MHz,DMSO-d6) δ 8.82 (s, 2H), 8.34 (s, 1H), 7.63 (s, 1H), 7.56 (d, J=7.4Hz, 1H), 7.47 (s, 1H), 7.44-7.37 (m, 2H), 7.31 (d, J=8.5Hz, 2H), 7.23-7.10 (m, 4H), 6.49 (s, 1H), 5.93-5.86 (m, 2H), 4.68 (t, J=8.4Hz, 2H), 4.24 (s, 2H), 3.82 (s, 3H), 3.54-3.37 (m, 8H), 1.84–1.57(m,9H),1.57–1.47(m,6H),0.80–0.69(m,6H).
The preparation of 305 compound 305 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R)-cyclobutyl-N- (4- methyl piperazine) it is sweet it is amide condensed compound 305 can be obtained, MS m/z: 701(M+1)+.1H NMR(400MHz,DMSO-d6) δ 8.82 (s, 2H), 8.34 (s, 1H), 7.63 (s, 1H), 7.56 (d, J= 7.4Hz, 1H), 7.47 (s, 1H), 7.44-7.37 (m, 2H), 7.31 (d, J=8.5Hz, 2H), 7.23-7.10 (m, 4H), 6.49 (s, 1H), 5.93-5.86 (m, 2H), 4.68 (t, J=8.4Hz, 2H), 4.24 (s, 2H), 3.82 (s, 3H), 3.54-3.37 (m, 8H),1.84–1.57(m,9H),1.57–1.47(m,6H),0.80–0.69(m,6H).
The preparation of 306 compound 306 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- (1- methyl piperidine -4- base) is sweet amide condensed compound 306, MS can be obtained m/z:715(M+1)+.1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),7.62(s,2H),7.51–7.38(m,4H), 7.31 (s, 2H), 7.23 (d, J=7.8Hz, 1H), 7.15 (s, 2H), 6.49 (s, 1H), 5.96-5.86 (m, 2H), 4.32- 4.21(m,3H),3.83(s,3H),2.13(s,3H),1.97–1.87(m,3H),1.85–1.56(m,10H),1.56–1.44 (m, 6H), 0.78 (d, J=4.6Hz, 5H)
The preparation of 307 compound 307 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- (1- methyl nafoxidine -3R- base) is sweet amide condensed compound can be obtained 307, MS m/z:701 (M+1)+.1H NMR (400MHz, MeOD) δ 7.74 (s, 1H), 7.69 (d, J=8.8Hz, 1H), 7.59 (d, J=7.2Hz, 1H), 7.53-7.50 (m, 1H), 7.41 (d, J=9.2Hz, 2H), 7.34 (d, J=8.0Hz, 1H), 7.27 (t, J=7.6Hz, 1H), 7.07 (t, J=16.0Hz, 1H), 6.71 (s, 1H), 6.12 (d, J=8.0Hz, 1H), 4.37 (s, 1H), 4.24-4.18 (m, 1H), 4.14-4.10 (m, 1H), 3.97 (s, 3H), 2.94 (s, 3H), 2.54 (d, J=7.6Hz, 2H), 2.14-1.78 (m, 8H), 1.63 (d, J=7.2Hz, 7H), 1.28 (s, 1H), 1.10 (d, J=5.2Hz, 3H), 0.84 (d, J=6.8Hz, 3H)
The preparation of 308 compound 308 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R)-cyclobutyl-N- (1- methyl piperidine -3S- base) it is sweet it is amide condensed compound 308 can be obtained, MS m/z:715(M+1)+.1HNMR (400MHz, MeOD): δ=8.43 (s, 1H), 7.64 (s, 1H), 7.57-7.51 (m, 2H), 7.39-7.34 (m, 2H), 7.31-7.23 (m, 2H), 6.51 (s, 1H), 6.01 (d, J=9.2Hz, 1H), 4.32-4.19 (m, 2H), 3.93 (m, J=2.0Hz, 3H), 3.22-3.08 (m, 2H), 2.67 (d, J=3.6Hz, 3H), 2.58-2.41 (m, 2H), 2.02-1.95 (m, 1H), 1.94-1.81 (m, 5H), 1.64 (d, J=5.6Hz, 6H), 1.48-1.41 (m, 2H), 1.01-0.98 (m, 3H), 0.86 (d, J=6.8Hz, 3H)
The preparation of 309 compound 309 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R)-cyclobutyl-N- (1- methyl piperidine -3R- base) it is sweet it is amide condensed compound 309 can be obtained, MS m/z:715(M+1)+.
The preparation of 310 compound 310 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound can be obtained with the condensation of (R) -2- amino-N- (1- methyl nafoxidine -3S- base) propionamide through basic hydrolysis in rapid 6-7 310, MS m/z:661 (M+1)+.1H NMR(400M,MeOD)δ7.77-7.82(m,1H),8.31-8.45(m,1H),7.22- 7.67(m,6H),6.51(s,1H),5.92-6.06(m,1H),5.51(s,1H),4.12-4.40(m,3H),3.89-3.98(m, 2H),3.38-3.57(m,2H),3.11-3.28(m,2H),2.81-2.93(m,2H),2.67-2.80(m,1H),2.32-2.51 (m,2H),1.86-2.07(m,2H),1.54-1.72(m,4H),1.23-1.33(m,2H),0.94-1.04(m,2H),0.81- 0.92(m,2H).
The preparation of 311 compound 311 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 can be obtained through basic hydrolysis with the condensation of (R) -2- amino -3- methyl-N- (1- methyl nafoxidine -3S- base) butyramide Compound 311, MS m/z:689 (M+1)+.
The preparation of 312 compound 312 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- (1- methyl nafoxidine -3R- base) is sweet amide condensed compound can be obtained 312, MS m/z:701 (M+1)+.1H NMR (400MHz, MeOD) δ 8.43 (s, 1H), 7.64 (s, 1H), 7.54 (dd, J= 17.6,8.0Hz, 2H), 7.39-7.34 (m, 3H), 7.31-7.23 (m, 2H), 6.52 (s, 1H), 6.00 (d, J=8.8Hz, 1H),4.34(s,1H),4.28–4.25(m,1H),4.22-4.17(m,1H),3.94(s,3H),3.51-3.40(s,2H), 3.23-3.12 (m, 3H), 2.86 (d, J=12.4Hz, 3H), 2.60-2.52 (m, 3H), 2.00-1.75 (m, 8H), 1.64 (d, J =7.6Hz, 8H), 1.41 (d, J=11.2Hz, 2H), 1.30 (d, J=9.3Hz, 7H), 0.99 (s, 4H), 0.86 (d, J= 6.8Hz,3H).
The preparation of 313 compound 313 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7 can be obtained through basic hydrolysis with the condensation of (R) -2- amino -3- methyl-N- (1- methyl nafoxidine -3R- base) butyramide Compound 313, MS m/z:689 (M+1)+.1H NMR(400MHz,MeOD)δ8.48(s,1H),7.64(s,1H),7.56(d,J =8.0Hz, 1H), 7.52 (d, J=4.0Hz, 1H), 7.42-7.32 (m, 3H), 7.30-7.22 (m, 2H), 6.52 (s, 1H), 6.01 (d, J=8.0Hz, 1H), 4.35 (s, 1H), 4.19 (s, 1H), 4.14-4.07 (m, 1H), 3.94 (d, J=1.2Hz, 3H), 3.37 (s, 1H), 3.15-3.02 (m, 2H), 2.78 (d, J=17.6Hz, 3H), 2.47-2.34 (m, 1H), 2.02-1.86 (m, 3H), 1.65 (s, 6H), 1.00 (d, J=5.2Hz, 3H), 0.94-0.82 (m, 6H), 0.82-0.72 (m, 3H)
The preparation of 314 compound 314 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R) -2- amino -- compound can be obtained in the condensation of N- (1- methyl nafoxidine -3R- base) propionamide 314, MS m/z:661 (M+1)+.1H NMR(400M,MeOD)δ7.77-7.82(m,1H),7.69-7.75(m,1H),7.56- 7.65(m,2H),7.43-7.49(m,2H),7.36-7.40(m,1H),7.26-7.34(m,1H),6.70-6.77(m,1H), 6.11-6.16(m,1H),4.39-4.44(m,1H),4.23-4.32(m,1H),4.14-4.21(m,1H),4.00(s,3H), 3.78-3.88(m,1H),3.58-3.67(m,1H),3.12-3.19(m,1H),2.93-3.02(m,3H),2.51-2.62(m, 1H),2.31-2.43(m,1H),2.02-2.22(m,3H),1.58-1.71(m,6H),1.28-1.34(m,3H),1.09-1.18 (m,3H),0.84-0.91(m,3H).
The preparation of 315 compound 315 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 29 intermediate o-phenylenediamine 29 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 315 can be obtained through basic hydrolysis, then with the condensation of R-2- amino -3- methyl-N-methyl butyramide, MS m/z in rapid 6-7: 638(M+1)+.1H NMR (400MHz, MeOD) δ 7.54 (d, J=8.0Hz, 1H), 7.46 (d, J=1.2Hz, 1H), 7.43- 7.37 (m, 4H), 7.28-7.24 (m, 2H), 7.13-7.10 (m, 1H), 6.62 (s, 1H), 6.07 (d, J=8.4Hz, 1H), 4.14-4.10 (m, 3H), 3.97 (s, 3H), 2.71 (d, J=3.2Hz, 4H), 2.03-1.89 (m, 3H), 1.64 (d, J= 0.8Hz, 6H), 1.58 (d, J=1.6Hz, 1H), 1.07 (d, J=6.4Hz, 3H), 1.01 (t, J=6.4Hz, 2H), 0.89- 0.84 (m, 6H), 0.80 (d, J=6.8Hz, 3H), 0.75 (d, J=6.8Hz, 1H)
The preparation of 316 compound 316 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 29 intermediate o-phenylenediamine 29 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, then with (R)-cyclobutyl-N- methyl is sweet amide condensed compound 316, MS m/z:650 (M+ can be obtained 1)+.1H NMR (400MHz, MeOD) δ 7.53 (d, J=8.0Hz, 1H), 7.43 (d, J=1.2Hz, 1H), 7.42 (d, J= 2.0Hz, 1H), 7.39 (s, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.09 (dd, J=12.4,1.2Hz, 1H), 6.60 (s, 1H), 6.05 (d, J=8.0Hz, 1H), 4.32-4.29 (m, 1H), 4.16-4.11 (m, 1H), 3.97 (s, 3H), 2.70 (s, 3H), 2.57-2.51 (m, 1H), 2.04-1.73 (m, 8H), 1.64 (t, J=5.2Hz, 7H), 1.31 (s, 4H), 1.07 (d, J= 6.4Hz, 3H), 0.86 (d, J=6.8Hz, 3H)
The preparation of 317 compound 317 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 28 intermediate o-phenylenediamine 28 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, then with (R)-cyclobutyl-N- methyl is sweet amide condensed compound 317, MS m/z:650 (M+ can be obtained 1)+.1H NMR (400MHz, MeOD) δ 7.53 (d, J=8.4Hz, 1H), 7.47-7.43 (m, 2H), 7.41 (d, J=2.0Hz, 1H), 7.38-7.32 (m, 2H), 7.26-7.22 (m, 1H), 6.62 (s, 1H), 6.05 (d, J=8.0Hz, 1H), 4.33-4.29 (m, 1H), 4.07 (t, J=7.2Hz, 1H), 3.95 (s, 3H), 2.68 (s, 3H), 2.48 (dd, J=15.2,6.8Hz, 1H), 2.01-1.68 (m, 8H), 1.60 (d, J=14.0Hz, 6H), 1.07 (d, J=6.4Hz, 3H), 0.82 (d, J=6.8Hz, 3H)
The preparation of 318 compound 318 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 318 can be obtained through basic hydrolysis, then with the condensation of 1- (5- methyl-1 H- pyrazole-3-yl) isobutyl amine, MS m/z in rapid 6-7: 643(M+1)+.1H NMR(400MHz,DMSO-d6)δ7.65–7.61(m,1H),7.48–7.35(m,4H),7.35–7.27(m, 3H),7.24–7.16(m,2H),7.15–7.08(m,2H),6.56–6.44(m,3H),5.97–5.82(m,3H),5.81–5.64 (m,3H),4.78–4.50(m,5H),4.38–4.19(m,4H),3.83(s,3H),2.92–2.88(m,1H),2.15–2.04 (m,4H),2.02–1.86(m,3H),1.86–1.74(m,3H),1.60–1.44(m,7H),0.83–0.75(m,5H),0.71– 0.59(m,6H).
The preparation of 319 compound 319 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 319, MS m/ can be obtained through basic hydrolysis, then with the condensation of 1- (5- methyl-1 H- pyrazole-3-yl) ring fourth methylamine in rapid 6-7 z:655(M+1)+.1H NMR(400MHz,DMSO-d6)δ8.96–8.70(m,2H),8.37–8.04(m,3H),7.67–7.50 (m,2H),7.50–7.36(m,3H),7.36–7.28(m,2H),7.28–7.19(m,1H),7.19–7.08(m,1H),7.08– 6.85(m,2H),6.56–6.47(m,1H),5.95–5.82(m,2H),5.72–5.65(m,1H),5.03–4.74(m,3H), 4.38–4.17(m,2H),3.83(s,3H),2.13–2.03(m,3H),1.81–1.59(m,6H),1.56–1.40(m,6H), 1.03 (d, J=6.5Hz, 11H), 0.78-0.69 (m, 4H)
The preparation of 320 compound 320 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 320, MS m/ can be obtained through basic hydrolysis, then with the condensation of N- methyl-(1- tetrahydrofuran -3R- base) acetamide in rapid 6-7 z:648(M+1)+.1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.68(s,1H),7.63–7.54(m,1H),7.47 (d, J=8.5Hz, 1H), 7.41 (t, J=7.3Hz, 2H), 7.31 (dd, J=7.1,5.4Hz, 2H), 7.22 (t, J=6.9Hz, 1H), 7.17-6.93 (m, 3H), 6.47 (s, 1H), 5.88 (d, J=11.1Hz, 1H), 4.28-4.16 (m, 2H), 3.81 (s, 3H), 3.58 (dd, J=10.7,5.2Hz, 2H), 3.35 (d, J=7.3Hz, 1H), 1.75 (s, 3H), 1.52 (d, J=8.1Hz, 6H), 0.77 (d, J=6.3Hz, 6H)
The preparation of 321 compound 321 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- (1- methyl-1-cyclopropyl alcohol) is sweet amide condensed compound 321, MS can be obtained m/z:688(M+1)+.
The preparation of 322 compound 322 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- (1- methyl-1-methoxy cyclopropane) is sweet amide condensed compound can be obtained 322, MS m/z:702 (M+1)+.
The preparation of 323 compound 323 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Compound 323 can be obtained through basic hydrolysis, then with the condensation of (R)-N- methyl-(1- tetrahydrofuran -3S- base) acetamide in rapid 6-7, MS m/z:648(M+1)+.1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.68(s,1H),7.63–7.54(m,1H), 7.47 (d, J=8.5Hz, 1H), 7.41 (t, J=7.3Hz, 2H), 7.31 (dd, J=7.1,5.4Hz, 2H), 7.22 (t, J= 6.9Hz, 1H), 7.17-6.93 (m, 3H), 6.47 (s, 1H), 5.88 (d, J=11.1Hz, 1H), 4.28-4.16 (m, 2H), 3.81 (s, 3H), 3.58 (dd, J=10.7,5.2Hz, 2H), 3.35 (d, J=7.3Hz, 1H), 1.75 (s, 3H), 1.52 (d, J =8.1Hz, 6H), 0.77 (d, J=6.3Hz, 6H)
The preparation of 324 compound 324 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R)-cyclobutyl-N- (1- methyl-1-F cyclopropane) it is sweet it is amide condensed compound 324 can be obtained, MS m/z:690(M+1)+.1H NMR(400MHz,DMSO-d6)δ8.89–8.67(m,3H),8.23(s,1H),8.12(s,2H), 7.63 (s, 1H), 7.57 (d, J=8.5Hz, 1H), 7.54-7.37 (m, 4H), 7.31 (t, J=7.2Hz, 3H), 7.27-7.18 (m, 2H), 7.18-7.07 (m, 2H), 6.70 (dd, J=22.6,8.2Hz, 2H), 6.49 (s, 2H), 5.96-5.85 (m, 2H), 4.33 (t, J=8.6Hz, 1H), 4.26 (d, J=7.6Hz, 2H), 3.83 (s, 3H), 1.85-1.59 (m, 8H), 1.52 (s, 7H), 1.24 (s, 1H), 0.89 (d, J=19.0Hz, 3H), 0.78 (d, J=6.5Hz, 6H), 0.62 (d, J=8.7Hz, 3H)
The preparation of 325 compound 325 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R)-cyclobutyl-N- (2- fluoro ethyl) it is sweet it is amide condensed compound 325 can be obtained, MS m/z: 664(M+1)+.1H NMR(400MHz,MeOD)δ8.25(s,1H),7.64(s,1H),7.58(s,1H),7.56–7.49(m, 1H), 7.45-7.29 (m, 4H), 7.25 (dd, J=10.7,4.5Hz, 1H), 6.74 (d, J=8.0Hz, 1H), 6.52 (s, 2H), 6.01 (d, J=9.2Hz, 1H), 4.50-4.42 (m, 1H), 4.41-4.30 (m, 2H), 4.19 (s, 1H), 3.94 (s, 3H), 3.58(s,1H),3.50(s,1H),3.47–3.41(m,1H),2.64–2.41(m,3H),2.04–1.76(m,7H),1.76– 1.59 (m, 7H), 1.53-1.37 (m, 3H), 1.31 (s, 1H), 1.00 (d, J=6.3Hz, 4H), 0.88 (t, J=13.7Hz, 4H).
The preparation of 326 compound 326 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 23 intermediate o-phenylenediamine 23 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, with (R) -2- amino-N, compound 326, MS m/z:592 is can be obtained in the condensation of N '-dimethyl propionamide (M+1)+.
The preparation of 327 compound 327 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 23 intermediate o-phenylenediamine 23 of example, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to 41 step of embodiment Rapid 6-7, through basic hydrolysis, and (R)-cyclobutyl-N- methyl is sweet amide condensed compound 327, MS m/z:618 (M+1) can be obtained+ .1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.42(s,1H),8.06–7.76(m,2H),7.65–7.36(m,4H), 7.36-7.26 (m, 2H), 7.24-7.19 (m, 2H), 6.54 (s, 1H), 5.90 (t, J=7.2Hz, 1H), 4.35-4.14 (m, 2H), 3.83 (d, J=3.2Hz, 3H), 2.57 (d, J=4.4Hz, 1H), 2.48 (d, J=4.4Hz, 2H), 1.97-1.43 (m, 8H), 1.38-1.35 (m, 3H), 0.77-0.74 (d, J=6.1Hz, 6H)
The preparation of 328 compound 328 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example, cyclization take off Boc protecting group, with 1,6- dihydro -1- methyl -6- oxo -2-Pyridinecarboxylic Acid Referring again to 41 step 6-7 of embodiment, through basic hydrolysis, compound can be obtained with the condensation of 1- amino -1- ring fourth formamide in condensation 328, MS m/z:631 (M+1)+.1H NMR(400MHz,DMSO-d6) δ 9.42 (d, J=8.8Hz, 1H), 7.64 (d, J= 29.6Hz, 3H), 7.48 (d, J=8.0Hz, 2H), 7.40 (t, J=7.2Hz, 1H), 7.28 (dd, J=9.2,7.2Hz, 3H), 6.83 (s, 1H), 6.55 (s, 1H), 6.38 (dd, J=9.2,1.0Hz, 1H), 5.95-5.85 (m, 1H), 5.73 (d, J= 6.4Hz, 1H), 4.22 (dd, J=11.2,4.4Hz, 1H), 2.85 (s, 3H), 2.06 (d, J=14.4Hz, 3H), 1.76 (d, J =8.0Hz, 3H), 1.54 (s, 6H), 0.79 (t, J=6.4Hz, 5H)
The preparation of 329 compound 329 of embodiment
Referring to 74 method of embodiment, pass through and reality by raw material of the single chiral isomers 18-c of 18 intermediate 18 of embodiment The condensation of 26 intermediate o-phenylenediamine 26 of example is applied, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment 41 Compound 329, MS m/z:700 finally can be obtained with the condensation of D-2- amino -4- methylpentanamide through basic hydrolysis in step 6-7 (M+1)+.
The preparation of 330 compound 330 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 2-c of 2 intermediate 2 of embodiment 146 intermediate o-phenylenediamine 146-1 of example condensation, cyclization take off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Finally compound 330, MS m/z:493 (M+1) can be obtained with methylamine hydrochloride condensation in 41 step 6-7, basic hydrolysis+.
The preparation of 331 compound 331 of embodiment
Referring to 74 method of embodiment, pass through and implementation by raw material of the single chiral isomers 5-a of 5 intermediate 5 of embodiment The condensation of 30 intermediate o-phenylenediamine 30 of example, cyclization take off Boc, and compound 331, MS can be obtained in upper 1- methyl-1 H- pyrazoles -5- acyl group m/z:494(M+1)+.
The preparation of 332 compound 332 of embodiment
Referring to 57 step 1-6 method of embodiment, intermediate 15 and 26 intermediate 26 of embodiment are condensed, and close imidazole ring, are taken off Boc, introduces 1- ethyl -1H- pyrazoles -5- acyl group, and finally compound 332, MS m/ can be obtained with methylamine condensation in ethyl ester hydrolysis z:465[M+1]+。
The preparation of 333 compound 333 of embodiment
Referring to 74 method of embodiment, with 171 step 1 intermediate 171-1 of embodiment (the four isomers mixing not split Object) it is that raw material passes through and the condensation of 26 intermediate o-phenylenediamine 26 of embodiment, cyclization, de- Boc, upper 1- methyl-1 H- pyrazoles -5- acyl Referring again to 41 step 6-7 of embodiment, through basic hydrolysis, compound 333 finally can be obtained with R-2- amino-propionamide condensation in base, MS m/z:598(M+1)+.
The preparation of 334 compound 334 of embodiment
It referring to 41 step 4-7 of embodiment, is successively condensed by intermediate 41-3 and the intermediate 34-2 of embodiment 34, closes miaow Azoles ring, ethyl ester hydrolysis, is condensed with D-Leu t-butyl ester hydrochloride, and chemical combination can be obtained through trifluoroacetic acid hydrolysis in the last tert-butyl ester Object 334, MS m/z:549 [M+1]+.
The preparation of 335 compound 335 of embodiment
It referring to 41 step 4-7 of embodiment, is successively condensed by intermediate 41-3 and the intermediate 36 of embodiment 36, closes imidazoles Compound 335, MS m/z:461 [M+1] can be obtained in ring+.
The preparation of 336 intermediate 336 of embodiment
The preparation of step 1 intermediate 336-1
Referring to 38 step 3 method of embodiment, by intermediate 38-1 and 2- (bromo- 1, the 3- dimethyl -1H- pyrazoles -5- base of 4-) Intermediate 336-1, MS m/z:275 [M+1] can be obtained in methyl acetate coupling+
The preparation of step 2 compound 336
Referring to 74 method of embodiment, with (mixture of enantiomter 2-c and 2-d) of 2 intermediate 2 of embodiment for raw material By being condensed with intermediate o-phenylenediamine 336-1, cyclization takes off Boc, upper 1- methyl-1 H- pyrazoles -5- acyl group, referring again to embodiment Compound 336, MS m/z:641 (M+1) finally can be obtained with cyclopentamine condensation through basic hydrolysis in 41 step 6-7+。
In order to illustrate beneficial effects of the present invention, the present invention provides following tests example.
Test example 1IL-17 enzyme linked immunosorbent assay (ELISA) (ELISA) experiment
Quantitative detection has been carried out to the inhibition situation that receptor-ligand combines to IL-17a inhibitor by competitive ELISA. By 0.2 μ g/ml IL-17a (Sino Biological lnc.Cat#12047-H07B) with the 100 every holes μ l 37 in 96 orifice plates Degree is incubated for 30 minutes.With PBST (PBS, 0.05%Tween-20) board-washing 4 times, the 200 every hole μ l, it is de- to be added 200 μ l 5% every time Rouge milk on 25 degree of shaking tables in being incubated for 30 minutes.Prepare 100X concentration untested compound, concentration is from 0.003 μM to 30 μM.With It is added 89 μ l PBST after PBST (PBS, 0.05%Tween-20) board-washing 4 times and after 1 μ l 100X concentration untested compound mixes In 25 degree preincubate 10 minutes.10 μ l 16nM IL-17R are added in being incubated for 30 minutes on 25 degree of shaking tables.After board-washing 4 times, it is added The anti-Fc label H RP coupled antibody of 100 μ l on 25 degree of shaking tables in being incubated for 30 minutes.After board-washing 4 times, it is molten that 100 μ l tmb substrates are added 25 degree of liquid are protected from light incubation.After 20%HCl is added, using microplate reader in 450nm wavelength detecting absorbance value.
The detection of IL-17A inhibitory activity is carried out to the compound of embodiment preparation according to the method described above, test result is shown in Table 1, wherein measuring the IC of each compound50According to illustrating to classify, in table 1:
"+" indicates IC50Measured value is greater than 1uM and less than 100 μM；
" ++ " indicates IC50Measured value is less than 1uM and is greater than 250nM；
" +++ " indicates IC50Measured value is less than 250nM.
Table 1, compound are to the inhibitory activity of IL-17A
Experiments have shown that the compound of the embodiment of the present invention have good IL-17A inhibitory activity, can effective for The treatment of IL-17A activity abnormal diseases.
In conclusion noval chemical compound shown in Formulas I disclosed by the invention, shows good IL-17A inhibitory activity, A kind of new medicinal possibility is provided to the abnormal relevant disease of IL-17A activity for clinical treatment.

Claims (23)

1. Formulas I compound represented or its stereoisomer or its pharmaceutically acceptable salt:
Wherein,
X is selected from O, S, NR1’；
R1、R2It is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 circle heterocyclic ring alkane Base, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics ,-S (O)2R6、-S(O)R6、-S(O)2NR6R7、-S(O)NR6R7、-C(O)R6、-C (O)OR6、-C(O)NR6R7、-P(O)(OR7)R6、-P(O)R6 R7、-P(O)R6(NR6 R7)、-P(O)(NR6R7)(NR6 R7)、-P (O)(OR7)(NR6 R7)、P(O)(OR7)(OR7)；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic By m RcReplace；
R6、R7It is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 circle heterocyclic ring alkane Base, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic quilt M RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd、-SRd、-NRdRd, halogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 First naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings；Wherein Rd, alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl, virtue Ring is by m RcReplace；Alternatively, R3And R3’Connect into 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；
RdSelected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan Aromatic ring, 5~10 yuan of hetero-aromatic rings；
B ring is selected from 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Wherein cycloalkanes Base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R1’Selected from hydrogen, C1~10Alkyl；
L1It is selected from
R is 0,1,2,3；
R8And R9It is independently chosen from hydrogen, halogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 The Heterocyclylalkyl of member；Wherein alkyl, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl are by m RcReplace；
Alternatively, R8And R9It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaryls Ring；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace；
L2Selected from-C (O) NR10-、-NR10C(O)-、-C(O)-、-C(O)O-、-S(O)2NR10-、-S(O)NR10-、-NR10S (O)2-、-NR10S(O)-、-P(O)NR10-、-NR10P (O)-or nothing；
R10Selected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, wherein alkane Base, alkenyl, alkynyl, naphthenic base, Heterocyclylalkyl are by m RcReplace；
R4And R5It is independently chosen from hydrogen, halogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 yuan Heterocyclylalkyl, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics ,-CN ,-NO2、-ORa、-OC(O)Ra、-OC(O)NRaRb、-OS(O)2Ra、-SRa、-S(O)2Ra、-S(O)2NRaRb、-OS(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、-NRaC (O)Rb、-NRaC(O)ORb、-NRaC(O)NRaRb、-NRaS(O)2Rb、-NRaS(O)2NRaRb；Wherein Ra、Rb, alkyl, alkenyl, alkynes Base, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；Wherein naphthenic base, Heterocyclylalkyl are by m RcReplace；
X1Selected from CR11Or N；
X2Selected from NR12, O, S or-(CR13=CR14)-；
X4Selected from N or CH；
R11Selected from hydrogen, halogen ,-CN ,-NO2、C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, C1~10Halogenalkyl, 3~10 yuan Naphthenic base, 3~10 yuan of Heterocyclylalkyl ,-ORa、-NRaRb；
R12Selected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl ,-S (O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb；
R13、R14It is independently chosen from hydrogen, halogen ,-CN ,-NO respectively2、C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, C1~10Halogen alkane Base, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl ,-ORa、-NRaRb；Wherein alkyl, alkenyl, alkynyl, naphthenic base, miscellaneous Naphthenic base is by m RcReplace；
M is 0,1,2,3,4；
Ra、RbIt is independently chosen from hydrogen, C respectively1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl ,-S (O)2Rd、-S(O)Rd、-P(O)2Rd、-P (O)Rd, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Wherein, alkyl, alkenyl, Alkynyl, naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace；
RcIt is independently chosen from C respectively1~10Alkyl ,=S ,=O, halogen ,-CN ,-NO2、-ORa、-OC(O)Ra、-OS(O)2Ra、-SRa、-S (O)2Ra、-S(O)2NRaRb、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、-NRaC(O)Rb、-NRaS(O)2Rb, 3~10 First naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics, wherein alkyl, 3~10 yuan of naphthenic base, 3 ~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics are by 0~3 C1~10Alkyl, halogen ,-NRaRb、-ORd、-C (O)NRaRb, 3~10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics replace.
2. compound according to claim 1 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In:
R1、R2It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~ 10 yuan of heteroaromatics ,-S (O)2R6、-S(O)R6、-S(O)2NR6R7、-C(O)R6、-C(O)OR6、-C(O)NR6R7；Wherein alkyl, ring Alkyl, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R6、R7It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~ 10 yuan of heteroaromatics；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd, halogen, C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 First aromatic ring；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring are by m RcReplace；Alternatively, R3And R3’Connect into 3~10 yuan of cycloalkanes Base；
RdSelected from hydrogen, C1~10Alkyl, C2~10Alkenyl, C2~10Alkynyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan Aromatic ring, 5~10 yuan of hetero-aromatic rings；
R8And R9It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl；Wherein alkane Base, naphthenic base, Heterocyclylalkyl are by m RcReplace；
Alternatively, R8And R9It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan of heteroaryls Ring；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring can be further by m RcReplace；
R10Selected from hydrogen, C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, wherein alkyl, naphthenic base, Heterocyclylalkyl quilt M RcReplace；；
R4And R5It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl, 6~10 First aromatic ring, 5~10 yuan of heteroaromatics ,-CN ,-NO2、-ORa、-OC(O)Ra、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、- NRaC(O)Rb、-NRaC(O)NRaRb、-NRaS(O)2Rb、-NRaS(O)2NRaRb、-S(O)2Ra、-S(O)2NRaRb；Wherein alkyl, ring Alkyl, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl；Wherein naphthenic base, Heterocyclylalkyl quilt M RcReplace；
R11Selected from hydrogen, halogen, C1~6Alkyl；
R12Selected from hydrogen, C1~6Alkyl；
R13、R14It is independently chosen from hydrogen, halogen, C respectively1~6Alkyl, C2~6Alkenyl；Wherein alkyl, alkenyl are by m RcReplace；
M is 0,1,2,3；
Ra、RbIt is independently chosen from hydrogen, C respectively1~6Alkyl, C2~6Alkenyl, C2~6Alkynyl ,-S (O)2Rd、-S(O)Rd、-P(O)2Rd、-P(O) Rd3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan of hetero-aromatic rings；Wherein, alkyl, alkenyl, alkynes Base, naphthenic base, Heterocyclylalkyl, aromatic ring, hetero-aromatic ring are by m RcReplace.
3. compound according to claim 2 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In:
R1、R2It is independently chosen from hydrogen ,-S (O) respectively2R6、-S(O)R6、-S(O)2NR6R7、-C(O)R6、-C(O)OR6、-C(O)NR6R7；
R6、R7It is miscellaneous that it is independently chosen from hydrogen, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan of virtues respectively Ring；Wherein naphthenic base, Heterocyclylalkyl, aromatic ring, heteroaromatic are by m RcReplace；
R3、R3’It is independently chosen from hydrogen ,-OR respectivelyd、C1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 5~10 yuan of virtues Ring；Wherein alkyl, naphthenic base, Heterocyclylalkyl, aromatic ring are by m RcReplace；Alternatively, R3And R3’Connect into 3~8 yuan of naphthenic base；
R8And R9It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 yuan of Heterocyclylalkyl；
Alternatively, R8And R9It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~10 yuan of heteroaryls Ring；
R4And R5It is independently chosen from hydrogen, C respectively1~6Alkyl, 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls, 6~10 yuan of aromatic rings, 5~ 10 yuan of heteroaromatics ,-ORa、-C(O)Ra、-C(O)ORa、-C(O)NRaRb、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaS (O)2Rb、-NRaS(O)2NRaRb、-S(O)2Ra、-S(O)2NRaRb,；Wherein alkyl-cycloalkyl, Heterocyclylalkyl, aromatic ring, heteroaromatic can Further by m RcReplace；
Alternatively, R4And R5It is connected to form 3~10 yuan of naphthenic base, 3~10 membered heterocycloalkyls；Wherein naphthenic base, Heterocyclylalkyl can be into one Step is by m RcReplace；
R11Selected from hydrogen, C1~6Alkyl；
R12Selected from hydrogen, C1~6Alkyl；
R13、R14It is independently chosen from hydrogen, C respectively1~6Alkyl, C2~6Alkenyl；Wherein alkyl, alkenyl are by m RcReplace；
M is 0,1,2.
4. compound according to claim 1 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: compound shown in Formulas I is as shown in Formula II a:
Wherein,
Ra’Selected from C1~6Alkyl.
5. compound according to claim 4 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: compound shown in Formula II a is as shown in Formula II a-1 or IIa-2:
Wherein,
Ra’Selected from C1~6Alkyl.
6. compound according to claim 5 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: compound shown in Formula II a-1 is as shown in formula III a-1 or IIIa-2:
7. compound according to claim 6 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: R5’For halogen, CN；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
8. compound according to claim 6 or 7 or its stereoisomer or its pharmaceutically acceptable salt, feature It is: compound shown in formula III a-1 or formula III a-2 specifically:
9. compound according to claim 6 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: R5’For halogen and 5~10 yuan of hetero-aromatic rings, wherein 5~10 yuan of heteroaromatics can be further by 0~3 C1~10Alkyl replace, 3~ 10 membered heterocycloalkyls, 5~10 yuan of aromatic rings, 5~10 yuan of heteroaromatics replace；
N is selected from 0,1,2,3；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
10. compound according to claim 6 or 9 or its stereoisomer or its pharmaceutically acceptable salt, special Sign is: compound shown in formula III a-1 or formula III a-2 specifically:
11. compound according to claim 6 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: R5’For halogen and-ORa；N is selected from 0,1,2,3；L2For nothing.
12. the compound according to claim 6 or 11 or its stereoisomer or its pharmaceutically acceptable salt, special Sign is: compound shown in formula III a-1 or formula III a-2 specifically:
13. compound according to claim 5 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: compound shown in Formula II a-1 is as shown in formula III b-1 or IIIb-2:
Wherein,
Ra’Selected from substituted or unsubstituted C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
14. compound according to claim 13 or its stereoisomer or its pharmaceutically acceptable salt, feature It is: compound shown in formula III b-1 or IIIb-2 specifically:
15. compound according to claim 5 or its stereoisomer or its pharmaceutically acceptable salt: Formula II a-1 Shown compound is as shown in formula III c:
Ra’、RcIt is respectively selected from C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C(O)-、-C (O)-,-C (O) O- or nothing.
16. compound according to claim 15 or its stereoisomer or its pharmaceutically acceptable salt, feature It is: compound shown in formula III c specifically:
17. compound according to claim 5 or its stereoisomer or its pharmaceutically acceptable salt: Formula II a-2 Shown compound is as shown in formula III d:
Wherein,
Ra’Selected from substituted or unsubstituted C1~6Alkyl；R5’For hydrogen, halogen；N is selected from 0,1,2；L2For-C (O) NR10-、-NR10C (O)-,-C (O)-,-C (O) O- or nothing.
18. compound according to claim 17 or its stereoisomer or its pharmaceutically acceptable salt: formula III d Shown compound specifically:
19. compound according to claim 1 or its stereoisomer or its pharmaceutically acceptable salt, feature exist In: compound shown in Formulas I is as shown in Formula II b:
Wherein,
Ra’Selected from C1~6Alkyl.
20. compound according to claim 19 or its stereoisomer or its pharmaceutically acceptable salt, feature It is: compound shown in Formula II b specifically:
21. the described in any item compounds of claim 1-20 or its stereoisomer or its pharmaceutically acceptable salt are being made Purposes in the drug for the disease that standby treatment IL-17A is mediated.
22. purposes according to claim 21, it is characterised in that: the disease that the IL-17A is mediated be with inflammation, itself One or more of immunity disease, infectious diseases, cancer, the relevant disease of precancer syndrome.
23. a kind of drug, it is characterised in that: it is with the described in any item compounds of claim 1~20 or its alloisomerism Body or its pharmaceutically acceptable salt, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
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