CN116726010A

CN116726010A - Application of macrolide derivative in preparation of medicines for inhibiting pro-inflammatory cytokine acting agents

Info

Publication number: CN116726010A
Application number: CN202210190915.8A
Authority: CN
Inventors: 邵长伦; 姚波; 姜瑶瑶; 刘建玉; 武艳伟; 高阳; 魏美燕
Original assignee: Ocean University of China
Current assignee: Ocean University of China
Priority date: 2022-03-01
Filing date: 2022-03-01
Publication date: 2023-09-12

Abstract

The invention relates to the field of biological medicine, in particular to application of a macrolide derivative shown in a formula (I) in preparing a medicament for inhibiting a pro-inflammatory cytokine acting agent, which has the potential of being developed into a novel medicament for inhibiting inflammatory factor activity.

Description

Application of macrolide derivative in preparation of medicines for inhibiting pro-inflammatory cytokine acting agents

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to application of a macrolide derivative in preparing a medicament for inhibiting a pro-inflammatory cytokine acting agent.

Background

Sepsis is a systemic immune dysregulation reaction caused by infection, has the characteristics of urgent onset and serious illness, can cause multiple organ function injury, has a death rate of up to 40 percent, and is one of the most main death reasons of clinical critical patients. At present, the mortality rate of sepsis is reduced to a certain extent by controlling the infection source, timely using antibiotics, shock resuscitation, supporting organ dysfunction and the like, but sepsis is still the primary cause of death in Intensive Care Unit (ICU) patients. Therefore, development of a drug for treating sepsis is still urgent. Serious immune system dysfunction is a common pathophysiological change in sepsis. Recent reports indicate that inflammatory responses during sepsis are complex overlaps of pro-inflammatory/anti-inflammatory factors. In the acute stage of sepsis, inflammatory factor release caused by infection can generate organism cascade reaction, cause inflammatory reaction waterfall effect, represent systemic inflammatory reaction syndrome, and can cause organ function acute failure. Thus, the elimination or inhibition of inflammatory factors is an important direction in sepsis treatment.

Brefeldin A (English name: brefeldin A, abbreviated BFA) is a class of macrolide fungal metabolites, and was isolated from Penicillium decumbens in 1958 by Singleton et al (Singleton, V.L. et al. Nature1958, 181, 1072-1073) determined its absolute configuration by single crystal, CD, asymmetric synthesis by Weber et al in 1971 (Web)er, H. P. et, al. Helv. Chim. Acta , 1971, 54, 2763−2766）。

Previous studies have demonstrated that BFA is capable of inhibiting inflammatory responses in endotoxin lung lesions (Wang Xuefeng, et al, chinese general medicine, 2018, 16, 688-720). However, BFA is not ideal due to its own pharmacokinetic properties (low bioavailability, poor water solubility, low plasma exposure, short plasma half-life, high toxicity) and cannot be used clinically as a drug (Sausville, e.a. et al.Cancer. J. Sci. Am. 1996, 2, 52-58). In order to overcome the defects, the structural modification of BFA is emphasized, and a compound which can keep high activity and inhibit the effect of proinflammatory cytokines and has good pharmacokinetic properties is expected to be found to be clinically used as a medicament.

Disclosure of Invention

The following is merely a general description of some aspects of the invention and is not limited in this regard. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification is different from that of the cited document, the disclosure of the present specification controls.

The invention provides a new class of macrolide derivatives for use in preparing an inhibitor of inflammatory factor activity, and provides a medicament for treating sepsis, septic shock, sepsis-related encephalopathy, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-related coagulation dysfunction, alzheimer's disease, parkinson's disease, cerebral apoplexy, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, liver cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerulosclerosis, hepatic fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesion, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, sarcomas, neurofibromas, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, fibrositis, hemorrhagic inflammation, necrotizing inflammation, hemorrhagic inflammation, and neurodegenerative diseases. The compound has stable property and good safety, can greatly improve BFA content (improve blood plasma Cmax and blood plasma exposure) in a mammal body, and can greatly improve the problem of unsatisfactory in-vivo efficacy caused by unsatisfactory BFA pharmacokinetic properties, thereby having better clinical application prospect.

Specifically: in one aspect, the invention relates to the use of a macrolide derivative in the manufacture of a medicament for inhibiting a pro-inflammatory cytokine agent. The compound is shown in a formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof:

（I）；

wherein R is ₁ , R ₂ Each independently is H or, R ₁ , R ₂ H cannot be the same time;

x is selected from C, O;

l is selected from single bond, double bond or-C _1-6 Alkylene-or absent;

z is selected from C _1-20 Aminoalkyl, C _3-12 Cycloalkyl, aminophenyl, substituted or unsubstituted benzene, pyridine, quinoline or isoquinoline rings, Z is each independently optionally substituted with 1, 2, 3 or 4 groups selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, C _1-3 Alkyl, C _1-3 Haloalkyl, C _1-3 Alkoxy, C _1-3 Haloalkoxy, C _1-3 Alkylthio, C _1-3 Haloalkylthio, C _3-6 A cycloalkyl, 3-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl substituent;

R ₃ hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxy, alkyl,haloalkyl, alkoxy, alkylamino, alkanoyl, hydroxyalkoxy, hydroxyalkanamino, hydroxyalkanoyl, haloalkoxy, haloalkamino, haloalkoyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylacyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkanoyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkanoyl, aryl, aryloxy, aroyl, arylamino, arylalkyloxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkyloxy, heterocycloalkyl, heterocyclyloxy, heterocyclylamino, heterocyclylacyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkylacyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused bicyclic group aliphatic, fused heterobicyclic group aliphatic, fused bicyclic group oxy, fused heterobicyclic group oxy, fused bicyclic group amino, fused heterobicyclic group amino, fused bicyclic group alkoxy, fused heterobicyclic group alkoxy, fused bicyclic group alkylamino, fused heterobicyclic group alkylamino, fused bicyclic group alkoxy, fused heterobicyclic group oxyalkoxy, fused bicyclic group amino alkoxy, fused heterobicyclic group amino alkoxy, fused bicyclic group-C (=o) -, fused bicyclic group-C (=o) O-, fused heterobicyclic group-C (=o) -, fused heterobicycloyl-C (=o) O-, fused bicycloamino-C (=o) -, fused heterobicycloamino-C (=o) -, fused bicycloyl-C (=o) N (R) ₄ ) -, fused heterobicycloyl-C (=o) N (R ₄ ) -, spirobicycloyl, spirobicycloaliphatic, spirobicyclooxy, spirobicycloamino, spirobicycloalkoxy, spirobicycloalkyloxy, spirobicycloalkylamino, spirobicyclooxyalkoxy, spirodicyclooxyalkoxy, spirodicycloaminoalkoxy, spirodicyclo-C (=o) -, spirodicyclo-C (=o) O-, spirodicycloamino-C (=o) -, spirodicyclo-C (=o) N (R) ₄ ) -, spirobicyclic-C (=o) N (R ₄ )-, R ₅ R ₄ N-, -C(=O)NR ₄ R ₅ , -OC(=O)NR ₄ R ₅ , -OC(=O)OR ₄ , -N(R4)C(=O)NR ₄ R ₅ , -N(R ₄ )C(=O)OR ₅ , -N(R ₄ )C(=O)-R ₅ , R ₄ R ₅ N-S(=O)t-, R ₄ S(=O)t-, R ₄ S(=O)tN(R ₅ )-, R ₅ R ₄ N-alkyl, R ₄ S (=O) t-alkyl, R ₄ R ₅ N-C (=o) -alkyl, R ₅ R ₄ N-alkoxy, R ₄ S (=O) t-alkoxy, R ₄ R ₅ N-C (=o) -alkoxy, aryl- (CH) ₂ )p-G-(CH ₂ ) m-, heteroaryl- (CH) ₂ )p-G-(CH ₂ ) m-, heterocyclyl- (CH) ₂ )p-G-(CH ₂ ) m-, or cycloalkyl- (CH) ₂ )p-G-(CH ₂ ) m-, wherein G is O, S, NR ₆ , S(=O), S(=O) ₂ , C(=O), -C(=O)N(R ₄ )-, -OC(=O)N(R ₄ )-, -OC(=O)-, -N(R ₄ )C(=O)N(R ₄ )-, -(R ₄ ) N-S (=O) t-, -OS (=O) t-, or-OS (=O) tN (R) ₄ ) T is l or 2, p and m are each independently 0, l, 2, 3 or 4, or wherein aryl- (CH) ₂ )p-G-(CH ₂ ) m-, heteroaryl- (CH) ₂ )p-G-(CH ₂ ) m-, heterocyclyl- (CH) ₂ )p-G-(CH ₂ ) m-, or cycloalkyl- (CH) ₂ )p-G-(CH ₂ ) m-may be substituted with one or more substituents selected from F, cl, br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano, where Z is a benzene ring, R ₃ Cannot be hydrogen;

R ₆ can be hydrogen, R ₅ R ₄ NC(=O)-, R ₅ OC(=O)-, R ₅ C(=O)-, R ₅ R ₄ NS(=O)-, R ₅ OS(=O)-, R ₅ S(=O)-, R ₅ R ₄ NS(=O) ₂ -, R ₅ OS(=O) ₂ -, R ₅ S(=O) ₂ -, aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyloxy aliphatic, arylamino aliphatic, heterocyclylamino aliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl or carbonA cyclic group;

each R is ₅ And R is ₄ Independently hydrogen, aliphatic, halo-aliphatic, hydroxy-aliphatic, amino-aliphatic, alkoxy-aliphatic, alkylamino-aliphatic, alkylthio-aliphatic, aryl-aliphatic, heteroaryl-aliphatic, heterocyclyl-aliphatic, cycloalkyl-aliphatic, aryloxy-aliphatic, heterocyclyloxy-aliphatic, cycloalkyloxy-aliphatic, arylamino-aliphatic, heterocyclylamino-aliphatic, cycloalkylamino-aliphatic, aryl, heteroaryl, heterocyclyl or cycloalkyl; when R is ₅ And R is ₄ R being bound to the same nitrogen atom _5, R ₄ And the nitrogen atom may optionally form a substituted or unsubstituted 3-8 membered ring, a fused bicyclic ring or a spirobicyclic ring, wherein the hetero atom in the heterocyclic group, heteroaryl group, fused heterobicyclic group or spiroheterobicyclic group referred to in the above groups is 1 to 5 hetero atoms independently selected from N, O, S, se;

R is as described above ₃ , R ₄ , R ₅ , R ₆ The radicals may be selected from the group consisting of hydroxy, hydroxymethyl, carboxy, acetamido, alkyl (e.g., methyl, ethyl, propyl), alkoxy (e.g., methoxy, ethoxy, t-butoxy), alkylamino, cycloalkyl, alkenyl, alkynyl, trifluoromethyl, trifluoroacetyl, mercapto, halogen, nitro, amino, azido (-N) ₃ ) One or more of guanidino, cyano, t-butoxycarbonyl (-Boc), carbonyl (-c=o), oxo (=o), thio (=s), sulfonyl, aryl, heteroaryl, heterocyclyl.

In some embodiments, L is selected from a single bond, a double bond, a methylene, ethylene, propylene, butylene, or absent, Z is selected from aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminoisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aminophenyl, a substituted or unsubstituted pyridine ring, quinoline ring, or isoquinoline ring, Z is each independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl, or pyrimidinyl;

R ₃ Selected from H, deuterium, F, cl, br, I, hydroxy, amino, nitro, cyano, C1-C20 alkyl, C1-C20 haloalkyl, C1-C20 alkoxy, C1-C20 alkylamino, C1-C20 alkanoyl, hydroxy C1-C20 alkoxy, hydroxy C1-C20 alkylamino, hydroxy C1-C20 alkanoyl, C1-C20 haloalkoxy, C1-C20 haloalkylamino, C1-C20 haloalkoyl, C1-C20 aminoalkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkyloxy, C3-C10 cycloalkylamino, C3-C10 cycloalkylacyl, C2-C8 alkenyl, C2-C8 alkynyl, C6-C10 aryl, C6-C10 aryloxy, C6-C10 aroyl, C6-C10 arylamino, C6-C10 arylC 1-C6 alkoxy, C6-C10 arylalkylamino, C5-C12 heteroaryl, C5-C12 heteroaryloxy, C5-C12 heteroarylacyl, C5-C12 heteroarylamino, C5-C12 heteroarylC 1-C6 alkoxy, C5-C12 heteroarylC 1-C6 alkylamino, C4-C12 heterocyclylC 1-C6 alkanoyl, C4-C12 heterocycloalkyl, C4-C12 heterocyclyloxy, C4-C12 heterocyclylamino, C4-C12 heterocyclylacyl, C4-C12 heterocyclylC 1-C6 alkoxy, C4-C12 heterocyclylC 1-C6 alkylamino, C4-C12 heterocyclylC 1-C6 alkanoyl, R ₅ R ₄ N-, -C(=O)NR ₄ R ₅ , -OC(=O)NR ₄ R ₅ , -OC(=O)OR ₄ , -N(R ₄ )C(=O)NR ₄ R ₅ , -N(R ₄ )C(=O)OR ₅ , -N(R ₄ )C(=O)-R ₅ , R ₄ R ₅ N-S(=O) _t -, R ₄ S(=O) _t -, R ₄ S(=O) _t -NR ₅ -, R ₅ R ₄ N-C1-C6 alkyl, R ₄ S(=O) _t -C1-C6 alkyl, R ₄ R ₅ N-C (=O) -C1-C6 alkyl, R ₅ R ₄ N-C1-C6 alkoxy, R ₄ S(=O) _t -C1-C6 alkoxy, R ₄ R ₅ N-C (=O) -C1-C6 alkoxy, C6-C10 aryl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, C5-C12 heteroaryl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, C4-C12 heterocyclyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, or C3-C10 cycloalkyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, where G is O, S, NR ₆ , S(=O), S(=O) ₂ , C(=O), -C(=O)N(R ₄ )-, -OC(=O)N(R ₄ )-, -OC(=O)-, -N(R ₄ )C(=O)N(R ₄ )-, -(R ₄ )N-S(=O) _t -, -OS(=O) _t -, or-OS (=o) _t N(R ₄ ) -; t is l or 2; p and m are each independently 0, l, 2, 3 or 4; or wherein C6-C10 aryl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, C5-C12 heteroaryl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, C4-C12 heterocyclyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, or C3-C1 cycloalkyl- (CH) ₂ ) _p -G-(CH ₂ ) _m May be substituted with one or more substituents selected from F, cl, br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano, where Z is a benzene ring, R ₃ Cannot be H;

R ₆ selected from H, deuterium, R ₅ R ₄ NC(=O)-, R ₅ OC(=O)-, R ₅ C(=O)-, R ₅ R ₄ NS(=O)-, R ₅ OS(=O)-, R ₅ S(=O)-, R ₅ R ₄ NS(=O) ₂ -, R ₅ OS(=O) ₂ -, R ₅ S(=O) ₂ -, C1-C3 aliphatic, C1-C3 halogenated aliphatic, C1-C3 hydroxyaliphatic, C1-C3 aminoaliphatic, C1-C3 alkoxyC 1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio C1-C3 aliphatic, C6-C10 arylamino C1-C3 aliphatic, C5-C9 heteroarylC 1-C3 aliphatic, C4-C10 heterocycloalkenyl C1-C3 aliphatic, C3-C10 cycloalkylC 1-C3 aliphatic, C6-C10 aryloxy C1-C3 aliphatic, C4-C10 heterocyclyloxy C1-C3 aliphatic, C3-C10 cycloalkyloxy C1-C3 aliphatic, C6-C10 arylamino C1-C3 aliphatic, C4-C10 heterocyclylaminoc C1-C3 aliphatic, C3-C10 cycloalkylamino C1-C3 aliphatic, C6-C10 heteroaryloxy C1-C3 aliphatic, C4-C10 heterocyclylaminocycloalkyl or C10 heterocycloaliphatic;

wherein each R is ₅ And R is ₄ Independently H, deuterium, C1-C3 aliphatic, C1-C3 halogenated aliphatic, C1-C3 hydroxy aliphatic, C1-C3 amino aliphatic, C1-C3 alkoxy C1-C3 aliphatic, C1-C3 alkylamino C1-C3 aliphatic, C1-C3 alkylthio C1-C3 aliphatic, C6-C10 aryl C1-C3 aliphatic, C5-C9 heteroaryl C1-C3 aliphatic, C4-C10 heterocyclyl C1-C3 aliphatic A group, C3-C10 cycloalkyl C1-C3 aliphatic, C6-C10 aryloxy C1-C3 aliphatic, C4-C10 heterocyclyloxy C1-C3 aliphatic, C3-C10 cycloalkyloxy C1-C3 aliphatic, C6-C10 arylamino C1-C3 aliphatic, C4-C10 heterocyclylamino C1-C3 aliphatic, C3-C10 cycloalkylamino C1-C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryl, C4-C10 heterocyclyl or C3-C10 cycloalkyl; when R is ₅ And R is ₄ R being bound to the same nitrogen atom ₅ , R ₄ And nitrogen optionally form a substituted or unsubstituted 3-8 membered ring, a fused bicyclic ring or a spirobicyclic ring, wherein the hetero atom in the heterocyclic group, heteroaryl group, fused heterobicyclic group or spiroheterobicyclic group referred to in the above groups is 1 to 5 hetero atoms independently selected from N, O, S;

In some embodiments, R ₃ Selected from H, deuterium, F, cl, br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, C ₅ H ₁₁ , C ₆ H ₁₃ , C ₈ H ₁₇ Trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, t-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropylacyl, 2-hydroxypropionyl, 2-aminopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoyl, heptanoyl, methacryloyl, phenyl, benzoyl, p-nitrophenyl, p-methylbenzoyl, m-fluorobenzoyl, p-aminobenzoyl, p-methoxybenzoyl, 2, 4-dimethylbenzoyl, m-azidobenzoyl, benzyl, p-chlorobenzyl, vinyl, propenyl, allyl, n-butylbenzoylAlkenyl, isobutenyl, N-pentenyl, isopentenyl, cyclopropyl, cyclopropanoyl, cyclopentanoyl, cyclohexanoyl, 3-pyridineformyl, naphthyl, phenethylimidazolyl, pyridinyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, piperidinyl, piperazinyl, indolyl, carbazolyl, benzofuranyl tetrahydrofuranyl, tetrahydropyranyl, pyrimidinyl, purinyl, -N (CH) ₃ ) ₂ -C (c=o) NH-C1-C4 alkyl, -OC (c=o) -NH-C1-C4 alkyl, -OC (o=o) O-C1-C4 alkyl, -NHC (=o) NH-C1-C4 alkyl, -NHC (=o) O-C1-C4 alkyl, -NHC (=o) -C1-C4 alkyl, C1-C4 alkyl-NH-S (=o) ₂ -, C1-C4 alkyl S (=o) ₂ -, C1-C4 alkyl S (=o) ₂ NH-, phenyl- (CH) ₂ ) _P -G-(CH ₂ ) _m -, fluorophenyl- (CH) ₂ ) _P -G-(CH ₂ ) _m -, thiazolyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, pyridinyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, phenylethyl, cyclohexyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -wherein G is O, S (=o) ₂ C (=O), p and m are each independently 0, 1, 2 or 3, or wherein C6-C10 aryl- (CH) ₂ ) _P -G-(CH ₂ ) _m Can be substituted by one or more substituents selected from F, cl, br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano, or R ₃ Optionally substituted with F, cl, br, I, hydroxy, hydroxymethyl, carboxy, acetamido, C1-C6 alkyl (e.g., methyl, ethyl, propyl), C1-C6 alkoxy, C1-C6 alkylamino, trifluoromethyl, trifluoroacetyl, mercapto, nitro, amino, azido (-N) ₃ ) One or more of guanidino, cyano, t-butoxycarbonyl (-Boc), carbonyl (-c=o), oxo (=o), thio (=s), sulfonyl, phenyl; wherein, when Z is benzene ring, R ₃ And cannot be H.

In some embodiments, the compounds of the present invention include, but are not limited to, structures of one of the following or stereoisomers, nitroxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof:

。

In another aspect, the invention relates to the use of a compound disclosed herein in the manufacture of a medicament for inhibiting pro-inflammatory cytokine action, for the treatment of sepsis, septic shock, sepsis-associated encephalopathy, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-associated coagulation dysfunction, alzheimer's disease, parkinson's disease, cerebral apoplexy, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, liver cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerulosclerosis, hepatic fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, sarcomas, neurofibromas, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, fibrositis, ulcerative colitis, necrotizing inflammation, neurodegenerative diseases.

Any of the embodiments of any of the aspects of the application may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present application, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.

The foregoing merely outlines certain aspects of the application and is not limited in this regard. These and other aspects are described more fully below.

Detailed description of the application

Definitions and general terms

Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be found in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato:1999, and "March's Advanced Organic Chemistry" by Michael b. Smith and Jerry March, john Wiley & Sons, new york:2007, the entire contents of which are incorporated herein by reference.

The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention. It is to be understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "optionally" whether or not preceding the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may have a substituent substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents for a particular group, then the substituents may be the same or different for each position. Wherein the substituents may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=o), carboxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e.and Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994.

Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or are usedRAndSto represent the absolute configuration of the molecule with respect to one or more chiral centers thereof. Prefix (prefix)dAndlor (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or lIndicating that the compound is levorotatory. Prefix (+) ordIs dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. 50:50 of enantiomersMixtures are referred to as racemic mixtures or racemates, which can occur when there is no stereoselectivity or stereospecificity during a chemical reaction.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, e.g. (. Times.)R)-、(S) -or%R, S) -in the form of a configuration. In some embodiments, each asymmetric atom isR) -or%S) Configuration aspects having at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optical activity [ ] R) -or%S) Isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (Wiley Interscience, new York, 1981); principles of AsymmetricSynthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012)； Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962)； Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972)；Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007)。

The compounds of the invention may be optionally substituted with one or more substituents, as described in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, and classes of compounds encompassed by the invention.

In addition, unless explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

The term "aliphatic" or "aliphatic group" as used herein refers to a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more degrees of unsaturation. Unless otherwise specified, an aliphatic group contains from 1 to 20 carbon atoms, some embodiments are aliphatic groups containing from 1 to 10 carbon atoms, other embodiments are aliphatic groups containing from 1 to 8 carbon atoms, other embodiments are aliphatic groups containing from 1 to 6 carbon atoms, other embodiments are aliphatic groups containing from 1 to 4 carbon atoms, and other embodiments are aliphatic groups containing from 1 to 3 carbon atoms. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl or alkynyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, hexyl, isobutyl, sec-butyl, vinyl and the like.

The term "halogenated aliphatic" as used herein means that an aliphatic group is substituted with one or more halogen atoms, the same or different, as defined herein, and such examples include, but are not limited to, trifluoromethyl, trifluoroethyl, chloromethyl, 2-chlorovinyl, and the like.

The term "hydroxy aliphatic" as used herein means that an aliphatic group is substituted with one or more hydroxy groups, wherein the aliphatic group has the meaning as described herein, and such examples include, but are not limited to, hydroxyethyl, 2-hydroxypropyl, hydroxymethyl, and the like.

The term "aminoaliphatic" as used herein means that an aliphatic radical is substituted with one or more amino groups wherein the aliphatic radical has the meaning as described herein, examples of which include, but are not limited to, aminomethyl, 2-aminoethyl, 2-aminoisopropyl, and the like.

The term "alkyl" as used herein includes monovalent hydrocarbon radicals of 1 to 20 carbon atoms, or 1 to 10 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms saturated straight or branched chain, wherein the alkyl radicals may be independently optionally substituted with one or more substituents described herein. Examples of alkyl groups more advanced than one year include, but are not limited to, methyl (Me, -CH) ₃ ) Ethyl (Et, -CH) ₂ CH ₃ ) N-propyl (n-Pr, -CH) ₂ CH ₂ CH ₃ ) Isopropyl (i-Pr, -CH (CH) ₃ ) ₂ ) N-butyl (n-Bu, -CH) ₂ CH ₂ CH ₂ CH ₃ ) Isobutyl (i-Bu, -CH) ₂ CH(CH ₃ ) ₂ ) Sec-butyl (s-Bu, -CH (CH) ₃ )CH ₂ CH ₃ ) Tert-butyl (t-Bu, -C (CH) ₃ ) ₃ ) N-pentyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-pentyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₃ ) 3-pentyl (-CH (CH) ₂ CH ₃ ) ₂ ) 2-methyl-2-butyl (-C (CH) ₃ ) ₂ CH ₂ CH ₃ ) 3-methyl-2-butyl (-CH (CH) ₃ )CH(CH ₃ ) ₂ ) 3-methyl-1-butyl (-CH) ₂ CH ₂ CH(CH ₃ ) ₂ ) 2-methyl-1-butyl (-CH) ₂ CH(CH ₃ )CH ₂ CH ₃ ) N-hexyl (-CH) ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) 2-hexyl (-CH (CH) ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ) 3-hexyl (-CH (CH) ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ ) 2-methyl-2-pentyl (-C (CH) ₃ ) ₂ CH ₂ CH ₂ CH ₃ ) 3-methyl-2-pentyl (-CH (CH) ₃ )CH(CH ₃ )CH ₂ CH ₃ ) 4-methyl-2-pentyl (-CH (CH) ₃ )CH ₂ CH(CH ₃ ) ₂ ) 3-methyl-3-pentyl (-C (CH) ₃ )(CH ₂ CH ₃ ) ₂ ) 2-methyl-3-pentyl (-CH (CH) ₂ CH ₃ )CH(CH ₃ ) ₂ ) 2, 3-dimethyl-2-butyl (-C (CH) ₃ ) ₂ CH(CH ₃ ) ₂ ) 3, 3-dimethyl-2-butyl (-CH (CH) ₃ )C(CH ₃ ) ₃ ) N-heptyl, n-octyl, and the like. The term "alkyl" and its prefix "alkane" are used herein to encompass both straight and branched saturated carbon chains.

The term "alkenyl" means a straight or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is sp ² Double bonds, wherein the alkenyl groups may be independently optionally substituted with one or more substituents described herein, include the positioning of groups having "anti" "positive" or "E Z", specific examples of which include, but are not limited to, vinyl (-ch=ch) ₂ ) Allyl (-CH) ₂ CH=CH ₂ ) And so on.

The term "alkynyl" means a straight or branched chain monovalent hydrocarbon radical of 2 to 12 carbon atoms, or 2 to 8 carbon atoms, or 2 to 6 carbon atoms, or 2 to 4 carbon atoms, wherein at least one position is unsaturated, i.e., one C-C is an sp triple bond, wherein the alkynyl group may be independently optionally substituted with one or more substituents described herein, specific examples include, but are not limited toEthynyl (-C tricH), propargyl (-CH) ₂ C trich), and so on.

The term "hydroxy-substituted alkyl" means that the alkyl group is substituted with one or more hydroxy groups, wherein the alkyl group has the meaning described herein. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, l, 2-dihydroxyethyl, and the like.

The terms "carbocycle", "carbocyclyl", "cycloalkyl" refer to a monovalent or polyvalent, non-aromatic, saturated or partially unsaturated ring, and do not contain heteroatoms, including single rings of 3-12 carbon atoms or bi-or tri-rings of 7-12 carbon atoms. The bi-carbocyclic ring having 7 to 12 atoms may be bicyclo [4.5 ]], [5.5], [5.6]Or [6.6]The system, while the bicyclic ring having 9 or 10 atoms, may be bicyclo [5.6 ]]Or [6.6]A system. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of cycloaliphatic radicals further include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexanedienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl and the like. And the "carbocycle", "carbocyclyl", "cycloalkyl" may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "cycloalkyloxy" or "carbocyclyloxy" includes optionally substituted cycloalkyl or carbocyclyl, as defined herein, attached to and linked by an oxygen atom to the remaining molecule, examples of which include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, hydroxy-substituted cyclopropyloxy, and the like.

The term "cycloalkylamino" means that the amino group is substituted with one or two cycloalkyl groups, where cycloalkyl has the meaning as described herein, such examples include, but are not limited to, cyclopropylamino, cyclopentylamino, cyclohexylamino, hydroxy-substituted cyclopropylamino, dicyclohexylamino, and the like.

The term "cycloalkyloxy aliphatic" means that an aliphatic group is substituted with one or more cycloalkyloxy groups, where aliphatic and cycloalkyloxy groups have the meaning as described herein, such examples include, but are not limited to, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopentyloxymethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, halocyclopropyloxyethyl, and the like.

The term "cycloalkylamino aliphatic" means that an aliphatic group is substituted with one or more cycloalkylamino groups, where the aliphatic group and cycloalkylamino group have the meaning as described herein, such examples include, but are not limited to, cyclopropylaminomethyl, cyclopropylaminohexyl, cyclopentylaminomethyl, cyclopentylaminoethyl, cyclohexylaminoethyl, halocyclopropylaminoethyl, and the like.

The term "cycloalkyl aliphatic" or "carbocyclylaliphatic" means that an aliphatic group may be substituted with one or more cycloalkyl groups or carbocyclyl groups, wherein cycloalkyl, or carbocyclyl and aliphatic groups have the meanings as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopentylmethyl, cyclohexylethyl, and the like.

The terms "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" are used interchangeably herein to refer to a monocyclic, bicyclic, or tricyclic ring system in which one or more atoms in the ring are independently optionally replaced by a heteroatom, and the ring may be fully saturated or contain one or more unsaturations, but is in no way aromatic, only one point of attachment to other molecules. The hydrogen atoms on one or more rings are independently optionally substituted with one or more substituents described herein. Some of which are The "heterocycle", "heterocyclyl", "heteroalicyclic" or "heterocyclic" groups being a single ring of 3-7 membered rings (1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P are optionally substituted by one or more oxygen atoms to give a compound such as SO, SO ₂ , PO, PO ₂ When said ring is a three-membered ring, wherein there is only one heteroatom), or a 7-to 10-membered bicyclic ring (4-9 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ , PO, PO ₂ Is a group of (2).

The heterocyclic group may be a carbon group or a heteroatom group. "heterocyclyl" also includes groups formed by the merging of a heterocyclic group with a saturated or partially unsaturated ring or heterocycle. Examples of heterocycles include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazalkyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, homopiperidinyl, epoxypropyl, azepanyl, oxepinyl, thiepanyl, 4-methoxy-piperidin-1-yl, l, 2, 3, 6-tetrahydropyridin-1-yl, oxaazepinyl, diazazinyl, thiazepinyl, pyrrolin-1-yl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, dihydropyranyl, tetrahydropyranyl, dioxacyclohexyl, l, 3-dioxanyl, pyrazolinyl, dithianyl, dithiadienyl, dihydrothienyl, pyrazolidinimidazolinyl, imidazolidinyl, l, 2, 3, 4-tetrahydroisoquinolinyl, l, 2, 6-thiadiazinoyl, 1-dioxo-2-yl, 4-hydroxy-l, 4-azaphosphan 4-oxide-1-yl, 2-hydroxy-1- (piperazin-1-yl) ethanon-4-yl, 2-hydroxy-1- (5, 6-dihydro-l, 2, 4-triazine-l (4) H) -yl) ethanon-4-yl, 5, 6-dihydro-4H-1, 2, 4-oxadiazin-4-yl, 2-hydroxy-1- (5, 6-dihydropyridin-l (2)H) -yl) ethanon-4-yl, 3-azabicyclo [3.1.0]Hexyl, 3-azabicyclo [4.1.0]Heptyl, azabicyclo [2.2.2]Hexyl, 2-methyl-5, 6, 7, 8-tetrahydro- [1.2.4]Triazole [1, 5-c ]]Pyrimidin-6-yl, 4, 5, 6, 7-tetrahydroisoxazole [4, 3-c]Pyridin-5-yl, 3H-indolyl 2-oxo-5-azabicyclo [2.2.1]Heptan-5-yl, 2-oxo-5-azabicyclo [2.2.2]Octane-5-yl, quinolizinyl and N-pyridyl urea. Examples of heterocyclic groups also include l, 1-dioxothiomorpholinyl, and wherein two carbon atoms in the ring are replaced by oxygen atoms such as pyrimidinedione groups. And the heterocyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, oxo (=o), hydroxy, amino, halogen, cyano, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "heterocyclylaliphatic" refers to heterocyclyl-substituted aliphatic radicals wherein heterocyclyl and aliphatic radicals have the meaning as described herein, examples of which include, but are not limited to, pyrrole-2-methyl, piperidine-2-ethyl, piperazine-2-ethyl, piperidine-2-methyl, and the like.

The term "heterocyclyloxy" includes optionally substituted heterocyclyls, as defined herein, attached to an oxygen atom, wherein the oxygen atom is attached to the remainder of the molecule, examples of which include, but are not limited to, pyrrole-2-oxy, pyrrole-3-oxy, piperidine-2-oxy, piperidine-3-oxy, piperazine-2-oxy, piperidine-4-oxy, and the like.

The term "heterocyclylamino" means that the amino group is substituted with one or two heterocyclyl groups, wherein the nitrogen atom is attached to the remainder of the molecule and the heterocyclyl has the meaning as described herein, examples of which include, but are not limited to, pyrrole-2-amino, pyrrole-3-amino, piperidine-2-amino, piperidine-3-amino, piperidine-4-amino, piperazine-2-amino, dipyrrole-2-amino, and the like.

The term "heterocyclyloxyaliphatic" means that an aliphatic group is substituted with one or more heterocyclyloxy groups, wherein the aliphatic group and the heterocyclyloxy group have the meanings as described herein, such examples include, but are not limited to, pyrrole-2-oxymethyl, piperazine-3-oxyethyl, piperazine-2-oxyethyl, morpholine-2-oxymethyl, piperidine-2-oxyethyl, and the like. The term "heterocyclylaminoaliphatic" means that an aliphatic group is substituted with one or more heterocyclylamino groups, where aliphatic and heterocyclylamino groups have the meaning as described herein, and such examples include, but are not limited to, pyrrole-2-aminomethyl, piperazine-3-aminoethyl, piperazine-2-aminoethyl, piperidine-2-aminoethyl, morpholine-2-aminomethyl, and the like.

The term "heteroatom" means one or more of O, S, N, P and Se, including any oxidation state forms of N, S and P, primary, secondary, tertiary and quaternary ammonium salt forms, or forms in which hydrogen on the nitrogen atom in the heterocycle is replaced, e.g., N (like 3, 4-dihydro-2H-N in pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" refers to F, cl, br or I.

The term "unsaturated" as used in the present invention means that the moiety contains one or more unsaturations.

The term "alkoxy" as used herein, refers to an alkyl group, as defined herein, attached to the main carbon chain through an oxygen atom ("alkoxy"), examples of which include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, and the like. And the alkoxy group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, hydroxy, amino, halogen, cyano, alkoxy, alkyl, alkenyl, alkynyl, mercapto, nitro, and the like.

The term "hydroxy-substituted alkoxy" or "hydroxyalkoxy" means that the alkoxy group is substituted with one or more hydroxy groups, wherein alkoxy has the meaning as described herein, such examples include, but are not limited to, methyloxy, 2-hydroxyethoxy, 2-hydroxypropoxy, 2-hydroxyisopropoxy, and the like.

The term "aminoalkyloxy" means that the alkoxy group is substituted with one or more amino groups, wherein alkoxy has the meaning as described herein, such examples include, but are not limited to, aminomethoxy, 2-aminoethoxy, 2-aminopropoxy, 2-aminoisopropoxy, and the like.

The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" refer to alkyl, alkenyl or alkoxy groups which may be substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, 2-chloro-vinyl, trifluoromethoxy and the like.

The term "aryl" means a monocyclic, bicyclic, and tricyclic carbocyclic ring system containing a total of 6-14 membered rings, wherein at least one ring system is aromatic, wherein each ring system contains a 3-7 membered ring, and only one attachment point is attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring", e.g., aromatic rings may include phenyl, naphthyl, and anthracene. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "fluorophenyl" means a phenyl group substituted with one or more fluorine atoms.

The term "arylaliphatic" means that an aliphatic group is substituted with one or more aryl groups, wherein the aliphatic and aryl groups have the meaning as described herein, such examples include, but are not limited to, phenethyl, benzyl, p-toluylethyl, styryl, and the like.

The term "aryloxy" or "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to and linked by an oxygen atom to the remainder of the molecule, wherein the aryl groups have the meaning as described herein, and such examples include, but are not limited to, phenoxy, tolyloxy, ethylphenoxy, and the like.

The term "arylamino" refers to the substitution of an amino group with one or two aryl groups, where aryl has the meaning as described herein, such examples include, but are not limited to, phenylamino, p-fluorophenylamino, diphenylamino, xylylamino, di-p-tolylamino, and the like.

The term "aryloxyaliphatic" means that an aliphatic radical is substituted with one or more aryloxy groups, wherein aryloxy and aliphatic radicals have the meaning as described herein, such examples include, but are not limited to, phenoxymethyl, phenoxyethyl, tolyloxyethyl, phenoxypropyl, and the like.

The term "heteroaryloxy aliphatic" means that an aliphatic group is substituted with one or more heteroaryloxy groups, wherein heteroaryloxy and aliphatic groups have the meaning as described herein, and such examples include, but are not limited to, furanoxymethyl, pyrimidinoxyethyl, and the like.

The term "arylamino aliphatic" means that an aliphatic radical is substituted with one or more arylamino groups, wherein the arylamino and aliphatic radicals have the meanings as described herein, and such examples include, but are not limited to, phenylaminomethyl, phenylaminoethyl, toluylaminoethyl, phenylaminopropyl, phenylaminoallyl, and the like.

The term "arylalkoxy" means an alkoxy group substituted with one or more aryl groups, wherein aryl and alkoxy have the meaning described herein, such examples include, but are not limited to, phenylmethoxy, phenylethoxy, p-tolylmethoxy, phenylpropyloxy, and the like. And the aryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "arylalkylamino" means that the alkylamino group is substituted with one or more aryl groups, wherein aryl and alkoxy have the meaning described herein, examples of which include, but are not limited to, phenylmethylamino, phenylethanamino, phenylpropanamino, p-tolylmethylamino and the like.

The term "heteroaryl"May be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" to denote monocyclic, bicyclic, and tricyclic ring systems containing a total of 5-14 membered rings, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system includes a 3-7 membered ring and only one attachment point is attached to the remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "aromatic heterocycle" or "heteroaromatic". And the heteroaryl group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

Other embodiments are where the aromatic heterocycle includes, but is not limited to, the following monocyclic rings: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, l, 2, 3-oxadiazolyl, l, 2, 5-oxadiazolyl, l, 2, 4-oxadiazolyl, 2-triazolyl, 3-thiotriazinyl, 2-thienyl, 3-triazolyl, 2-thiotriazinyl, 3-thiotriazinyl, benzo [ d ] thiazol-2-yl, imidazo [1, 5-a ] pyridin-6-yl, also includes the following bicyclic rings, but is in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, benzothiazolyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).

The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to and linked by an oxygen atom to the remainder of the molecule, wherein heteroaryl groups have the meaning as described herein, examples of which include, but are not limited to, pyridin-2-oxy, thiazole-2-oxy, imidazole-2-oxy, pyrimidine-2-oxy, and the like.

The term "carboxyalkoxy" means that the alkoxy group is substituted with one or more carboxyl groups, wherein alkoxy and carboxyl groups have the meaning as described herein, examples of which include, but are not limited to, carboxymethoxy, carboxyethoxy, and the like.

The term "alkylthio" includes Cl-C10 straight or branched chain alkyl groups attached to a divalent sulfur atom. Some of these examples are those wherein the alkylthio group is a lower C1-C3 alkylthio group, examples of which include, but are not limited to, methylthio (CH ₃ S-). The term "haloalkylthio" includes the attachment of the haloalkyl of Cl-C10 to a divalent sulfur atom. Some of these embodiments are those wherein haloalkylthio is a lower C1-C3 haloalkylthio, examples of which include, but are not limited to, trifluoromethylthio.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted by one or two alkyl groups. Some of these are lower alkylamino groups in which one or two C1-C6 alkyl groups are attached to the nitrogen atom. Still other embodiments are where the alkylamino group is a lower alkylamino group of C1-C3. Suitable alkylamino groups may be mono-or di-alkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino, and the like.

The term "heteroarylamino" means that the amino group is substituted with one or two heteroaryl groups, where heteroaryl has the meaning described herein, examples of which include, but are not limited to, N-thienylamino and the like. Some of these embodiments are those wherein the heteroaryl ring on the heteroaryl amino group may be further substituted.

The term "heteroaryl aliphatic" means that an aliphatic group is substituted with one or more heteroaryl groups, where heteroaryl and aliphatic groups have the meaning described herein, examples of which include, but are not limited to, thiophene-2-propenyl, pyridine-4-ethyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.

The term "heteroarylalkyl" means an alkyl group substituted with one or more heteroaryl groups, where heteroaryl and alkyl groups have the meaning described herein, examples of which include, but are not limited to, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, and the like.

The term "heteroarylalkylamino" includes heteroarylalkyl groups containing a nitrogen atom attached to other groups through a nitrogen atom, wherein the heteroarylalkyl has the meaning as described herein, and such examples include, but are not limited to, pyridin-2-ylmethylamino, thiazol-2-ylethylamino, imidazol-2-ylethylamino, pyrimidin-2-ylpropylamino, pyrimidin-2-ylmethylamino and the like.

The term "heteroarylalkoxy" includes heteroarylalkyl groups containing an oxygen atom through which the heteroarylalkyl group is attached to another group, wherein the heteroarylalkyl has the meaning as described herein, and such examples include, but are not limited to, pyridin-2-ylmethoxy, thiazol-2-ylethoxy, imidazol-2-ylethoxy, pyrimidin-2-ylpropoxy, pyrimidin-2-ylmethylamino.

The terms "fused bicyclic", "fused ring", "fused bicyclic group", "fused ring group" refer to a saturated or unsaturated fused ring system, and refer to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). Each ring in the fused bicyclic ring is either carbocyclic or heteroalicyclic, examples of which include, but are not limited to, hexahydrofuro [3, 2-b]Furan, 2, 3, 3a, 4, 7, 6-hexahydro-1H-indene, 7-azabicyclo [2.3.0]Heptane, fused bicyclo [3.3.0 ]]Octane, condensed bicyclo [3.1.0]Hexane, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthalene, all of which are contained in the fused bicyclic ringIs within the system of (2). And the fused bicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, oxo (=o), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "fused heterobicyclic group" means a saturated or unsaturated fused ring system, and refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturation, but the core structure does not contain aromatic or heteroaromatic rings (but the aromatic may be a substituent thereon). And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ , PO, PO ₂ Such examples include, but are not limited to, hexahydrofuro [3, 2-b]Furan, 7-azabicyclo [2.3.0 ]]Heptane, and the like. And the fused heterobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, oxo (=o), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "fused bicyclic aliphatic" means that an aliphatic group is substituted with one or more fused bicyclic groups, wherein the aliphatic group and the fused bicyclic group have the meanings as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylethyl, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylmethyl, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylpropyl, fused bicyclo [3.3.0] octanylmethyl, fused bicyclo [3.1.0] hexane-ethyl, and the like.

The term "fused heterobicyclic aliphatic" means that the aliphatic group is substituted with one or more fused heterobicyclic groups, wherein the aliphatic group and fused heterobicyclic groups have the meaning as described herein, such examples include, but are not limited to, hexahydrofuro [3, 2-b ] furan-2-ylethyl, hexahydrofuro [3, 2-b ] furan-2-ylmethyl, 7-azabicyclo [2.3.0] heptane-2-ylethyl, 7-azabicyclo [2.3.0] heptane-4-ylmethyl, and the like.

The term "fused bicyclooxy" includes optionally substituted fused bicyclic radicals, as defined herein, attached to and linked to the remainder of the molecule by an oxygen atom, such examples including, but not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthyloxy, fused bicyclo [3.3.0] octane-2-oxy, fused bicyclo [3.1.0] hexane-2-oxy, and the like.

The term "fused heterobicyclooxy" includes optionally substituted fused heterobicyclooxy groups, as defined herein, attached to and linked by an oxygen atom to the remainder of the molecule, examples of which include, but are not limited to hexahydro-furo [3, 2-b ] furan-2-yloxy, 7-azabicyclo [2.3.0] heptane-4-yloxy and the like.

The term "fused bicyclic amino" means that the amino group is substituted with one or two fused bicyclic groups, wherein the fused bicyclic groups have the meaning as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylamino, bis (1, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylamino, fused bicyclo [3.3.0] octanylamino, fused bicyclo [3.1.0] hexanylamino, and the like.

The term "fused heterobicyclic amino" means that the amino group is substituted with one or two fused heterobicyclic groups, wherein the fused heterobicyclic groups have the meaning as described herein, such examples include, but are not limited to, hexahydro-furo [3, 2-b ] furan-2-ylamino, 7-azabicyclo [2.3.0] heptane-4-ylamino, and the like.

The term "fused bicyclic alkylamino" means that the alkylamino group is substituted with one or more fused bicyclic groups, wherein the fused bicyclic groups have the meaning as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthalenyl methylamino, bis (1, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthalenyl) methylamino, fused bicyclo [3.3.0] octanyl methylamino, fused bicyclo [3.1.0] hexanemethylamino, and the like.

The term "fused heterobicyclic alkylamino" means that the alkylamino group is substituted with one or more fused heterobicyclic groups, wherein the fused heterobicyclic groups have the meaning as described herein, such examples include, but are not limited to hexahydro-furo [3, 2-b ] furan-2-ylmethylamino, 7-azabicyclo [2.3.0] heptane-4-ylmethylamino and the like.

The term "fused bicyclic alkoxy" means that the alkoxy group is substituted with one or more fused bicyclic groups, wherein the alkoxy and fused bicyclic groups have the meaning as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylmethoxy, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthylethoxy, fused bicyclo [3.3.0] octanethoxy, fused bicyclo [3.1.0] hexane-propoxy and the like.

The term "fused heterobicycloalkoxy" means that the alkoxy group is substituted with one or more fused heterobicycloyl groups, wherein the alkoxy and fused heterobicycloyl groups have the meaning as described herein, such examples include, but are not limited to, hexahydro-furo [3, 2-b ] furan-2-ylpropoxy, 7-azabicyclo [2.2.1] heptane-2-ylethoxy, 7-azabicyclo [2.3.0] heptane-4-ylpropoxy, hexahydro-furo [3, 2-b ] furan-2-ylethoxy, 7-azabicyclo [2.3.0] heptane-2-ylpropoxy, 7-azabicyclo [2.3.0] heptane-4-ylethoxy, and the like.

The term "fused bicyclooxyalkoxy" means an alkoxy group substituted with one or more fused bicyclooxy groups wherein alkoxy and fused bicyclooxy have the meaning as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthyloxy methoxy, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydronaphthyloxy ethoxy, fused bicyclo [3.3.0] octane-2-oxyethoxy, fused bicyclo [3.1.0] hexane-2-oxypropoxy, and the like.

The term "fused heterobicyclooxyalkoxy" means that the alkoxy group is substituted with one or more fused heterobicyclooxy groups, wherein alkoxy and fused heterobicyclooxy have the meaning as described herein, such examples include, but are not limited to, hexahydro-furo [3, 2-b ] furan-2-yloxypropoxy, 7-azabicyclo [2.2.1] heptane-2-yloxyethoxy, 7-azabicyclo [2.3.0] heptane-4-yloxypropoxy, hexahydro-furo [3, 2-b ] furan-2-yloxyethoxy, 7-azabicyclo [2.3.0] heptane-2-yloxypropoxy, 7-azabicyclo [2.3.0] heptane-4-yloxyethoxy, and the like.

The term "fused bicyclic amino alkoxy" means that the alkoxy group is substituted with one or more fused bicyclic amino groups, wherein the alkoxy and fused bicyclic amino groups have the meaning as described herein, such examples include, but are not limited to, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydro-naphthylamino ethoxy, l, 2, 3, 4, 4a, 5, 8, 8 a-octahydro-naphthylamino propoxy, bis (1, 2, 3, 4, 4a, 5, 8, 8 a-octahydro-naphthyl) amino propoxy, fused bicyclo [3.3.0] octane-2-aminoethoxy, fused bicyclo [3.1.0] hexane-2-aminopropoxy, and the like.

The term "fused heterobicyclic amino alkoxy" means that the alkoxy group is substituted with one or more fused heterobicyclic amino groups, wherein the alkoxy and fused heterobicyclic amino groups have the meaning as described herein, such examples include, but are not limited to, 7-azabicyclo [2.2.1] heptane-2-ylamino ethoxy, 7-azabicyclo [2.3.0] heptane-4-ylamino propoxy, hexahydro-furo [3, 2-b ] furan-2-ylamino ethoxy, hexahydro-furo [3, 2-b ] furan-2-ylamino propoxy, hexahydro-furo [3, 2-b ] furan-2-ylamino methoxy and the like.

The terms "spirocyclic group", "spirocyclic ring", "spirobicyclic group", "spirobicyclic ring" denote that one ring originates from a particular cyclic carbon on another ring. For example, as described below, a saturated bridged ring system (rings B and B') is referred to as "fused A bicyclic ring ", whereas ring a and ring B share one carbon atom in two saturated ring systems, is called" spiro ". Each ring within the spiro ring is either carbocyclic or heteroalicyclic. Examples include, but are not limited to, 2, 7-diazaspiro [4.4 ]]Nonan-2-yl, 7-oxo-2-azaspiro [4.5 ]]Decan-2-yl, 4-azaspiro [2.4 ]]Heptan-5-yl, 4-oxaspiro [2.4 ]]Heptan-5-yl, 5-azaspiro [2.4 ]]Heptan-5-yl, spiro [2.4]Heptyl, spiro [4.4 ]]Nonylalkyl, 7-hydroxy-5-azaspiro [2.4 ]]Heptane-5-yl, and the like. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, oxo (=o), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "spirobicyclic group" means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, one saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", whereas rings a and B share one carbon atom in two saturated ring systems and are referred to as "spiro rings". And at least one ring system comprises one or more heteroatoms, wherein each ring system comprises a 3-7 membered ring, i.e. comprising 1-6 carbon atoms and 1-3 heteroatoms of N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give a ring like SO, SO ₂ , PO, PO ₂ Such examples include, but are not limited to, 4-azaspiro [2.4]]Heptan-5-yl, 4-oxaspiro [2.4]]Heptan-5-yl, 5-azaspiro [2.4]]Heptan-5-yl, 7-hydroxy-5-azaspiro [2.4]]Heptane-5-yl, and the like. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituents may be, but are not limited to, haloalkyl, oxo (=o), hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclyl, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C (=o) -, alkyl-S (=o) -, alkylbase-S (=O) ₂ -hydroxy-substituted alkyl-S (=o) -, hydroxy-substituted alkyl-S (=o) ₂ -, carboxyalkoxy, and the like.

The term "spirobicyclo aliphatic" means that an aliphatic group is substituted with one or more spirobicyclo groups, wherein the aliphatic group and spirobicyclo groups have the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptanylmethyl, spiro [2.4] heptanylethyl, spiro [2.4] heptanylpropyl, spiro [4.4] nonanylmethyl, spiro [4.4] nonanylethyl, 4-azaspiro [2.4] heptan-5-ylmethyl, 4-azaspiro [2.4] heptan-5-ylethyl, 4-oxaspiro [2.4] heptan-5-ylethyl, 5-azaspiro [2.4] heptan-5-ylpropyl, 7-hydroxy-5-azaspiro [2.4] heptan-5-ylpropyl, and the like.

The term "spirobicyclic aliphatic" means that the aliphatic group is substituted with one or more spirobicyclic groups, wherein the aliphatic group and spirobicyclic groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptan-5-ylmethyl, 4-azaspiro [2.4] heptan-5-ylethyl, 4-oxaspiro [2.4] heptan-5-ylethyl, 5-azaspiro [2.4] heptan-5-ylpropyl, 7-hydroxy-5-azaspiro [2.4] heptan-5-ylpropyl, and the like.

The term "spirobicyclooxy" includes optionally substituted spirobicyclooxy groups, as defined herein, attached to and linked by an oxygen atom to the remainder of the molecule, examples of which include, but are not limited to, spiro [2.4] heptane-2-oxy, spiro [2.4] heptane-3-oxy, spiro [2.4] heptane-4-oxy, spiro [4.4] nonane-2-oxy, spiro [4.4] nonane-4-oxy, 4-azaspiro [2.4] heptane-5-oxy, and the like.

The term "spirodicyclooxy" includes optionally substituted spirodicyclooxy groups, as defined herein, attached to and linked by an oxygen atom to the remainder of the molecule, examples of which include, but are not limited to, 4-azaspiro [2.4] heptane-5-yloxy, 4-oxaspiro [2.4] heptane-5-yloxy, 5-azaspiro [2.4] heptane-5-yloxy, and the like.

The term "spirobicycloamino" means that the amino group is substituted with one or two spirobicycloyl groups, wherein spirobicycloyl has the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptane-2-amino, spiro [2.4] heptane-3-amino, spiro [2.4] heptane-4-amino, spiro [4.4] nonane-2-amino, spiro [4.4] nonane-4-amino, 4-azaspiro [2.4] heptane-5-amino, and the like.

The term "spirobicyclic amino" means that the amino group is substituted with one or two spirobicyclic groups, wherein spirobicyclic groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptane-5-ylamino, 4-azaspiro [2.4] heptane-2-ylamino, 4-oxaspiro [2.4] heptane-5-ylamino, 5-azaspiro [2.4] heptane-5-ylamino, and the like.

The term "spirobicycloalkoxy" means that the alkoxy group is substituted with one or more spirobicyclogroups, wherein spirobicyclogroups and alkoxy groups have the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptane-2-methoxy, spiro [2.4] heptane-3-ethoxy, spiro [2.4] heptane-4-ethoxy, spiro [4.4] nonane-2-methoxy, spiro [4.4] nonane-4-propoxy, 4-azaspiro [2.4] heptane-5-methoxy, and the like.

The term "spirobicycloalkoxy" means that the alkoxy group is substituted with one or more spirobicyclogroups, wherein spirobicyclogroups and alkoxy groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptan-5-ylmethoxy, 4-azaspiro [2.4] heptan-2-ylethoxy, 4-oxaspiro [2.4] heptan-5-ylethoxy, 5-azaspiro [2.4] heptan-5-ylpropoxy, and the like.

The term "spirobicycloalkylamino" means that the alkylamino group is substituted with one or more spirobicyclo groups, wherein spirobicyclo groups and alkylamino groups have the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptane-2-methylamino, spiro [2.4] heptane-3-ethylamino, spiro [2.4] heptane-4-ethylamino, spiro [4.4] nonane-2-methylamino, spiro [4.4] nonane-4-propylamino, 4-azaspiro [2.4] heptane-5-methylamino, and the like.

The term "spirodicycloalkylamino" alkylamino groups is substituted with one or more spirodicyclo groups, wherein spirodicyclo groups and alkylamino groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptane-5-ylmethylamino, 4-azaspiro [2.4] heptane-2-ylethylamino, 4-oxaspiro [2.4] heptane-5-ylethylamino, 5-azaspiro [2.4] heptane-5-ylpropylamino, and the like.

The term "spirobicyclooxyalkoxy" means an alkoxy group substituted with one or more spirobicyclooxyalkyl groups, wherein spirobicyclooxy and alkoxy groups have the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptane-2-oxyethoxy, spiro [2.4] heptane-3-oxypropoxy, spiro [2.4] heptane-4-oxypropoxy, spiro [4.4] nonane-2-oxyethoxy, spiro [4.4] nonane-4-oxypropoxy, 4-azaspiro [2.4] heptane-5-oxypropoxy, and the like.

The term "spirobicyclooxyalkyl" means an alkoxy group substituted with one or more spirobicyclooxyalkyl groups, wherein spirobicyclooxyalkyl and alkoxy groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptane-5-yloxyethoxy, 4-oxaspiro [2.4] heptane-5-yloxyethoxy, 5-azaspiro [2.4] heptane-5-yloxyethoxy, 4-azaspiro [2.4] heptane-5-yloxypropoxy, 4-oxaspiro [2.4] heptane-5-yloxypropoxy, 5-azaspiro [2.4] heptane-5-yloxypropoxy, and the like.

The term "spirobicycloamino alkoxy" means that the alkoxy group is substituted with one or more spirobicycloamino groups, wherein alkoxy and spirobicycloamino groups have the meaning as described herein, such examples include, but are not limited to, spiro [2.4] heptane-2-aminoethoxy, spiro [2.4] heptane-3-aminopropoxy, spiro [2.4] heptane-4-aminoethoxy, spiro [4.4] nonane-2-aminoethoxy, spiro [4.4] nonane-4-aminopropoxy, 4-azaspiro [2.4] heptane-5-aminopropoxy, and the like.

The term "spirodicycloaminoalkyloxy" means that the alkoxy group is substituted with one or more spirodicycloalkylamino groups, wherein the alkoxy and spirodicycloamino groups have the meaning as described herein, such examples include, but are not limited to, 4-azaspiro [2.4] heptane-5-ylaminoethoxy, 4-azaspiro [2.4] heptane-2-ylaminodioxy, 4-oxaspiro [2.4] heptane-5-ylaminoethoxy, 5-azaspiro [2.4] heptane-5-ylaminopropoxy, and the like.

The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W. Greene, protective Groups in Organic Synthesis, john Wiley&Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

The term "prodrug" as used herein means a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C ₁ -C ₂₄ ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following Literature: t, higuchi and V. Stilla, pro-drugs as Novel Delivery Systems, vol.14 of the A.C.S. Symposium Series, edward B, roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press, 1987, J. Rautioet al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and S. J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345。

"metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al.Describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoates, bisulfate, borates, butyrates, camphoric acid saltsCamphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumaric acid, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodite, 2-hydroxy-ethane sulfonate, lactobionic aldehyde, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 Sulfonate and aromatic sulfonate.

"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in other embodiments, one of the present compound molecules may be associated with more than one water molecule, such as a dihydrate, and in still other embodiments, one of the present compound molecules may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.

The term "solubility" as used herein refers to the mass of solute dissolved by a solid material when it reaches saturation in 100g of solvent at a certain temperature. For the test of solubility, reference is made to the following documents: (ZHU Shang-bin, et al Preparation, development, and physicochemical properties of arbutin phospholipid complex [ J ]. Chinese Traditional and Herbal drugs 2020:1-10).

The term "acute toxicity" as used herein refers to the toxic effect or even death caused by the body (human or laboratory animal) after one (or more than one 24 hour period) exposure to a foreign compound. However, the degree of toxicity and severity of the compound in the laboratory animal may vary depending on the nature and amount of the compound contacted. Some compounds can develop toxic symptoms and even die within minutes of exposure to the lethal dose of the experimental animal. While some compounds show symptoms of poisoning and death after a few days, i.e. delayed death. In addition, the manner or route of exposure of the test animal to the compound varies, as does the meaning of "one time". By oral contact and various modes of injection contact, "one time" is meant that the test compound is instantaneously introduced into the body of the experimental animal. While inhalation through the respiratory tract and contact with the skin, "one time" refers to the process of the test animal continuously contacting the test compound for a specific period of time, so "one time" contains a time factor.

The term "treating" any disease or disorder as used herein refers to all slowing, interrupting, arresting, controlling or stopping the progression of the disease or disorder, but does not necessarily mean that the symptoms of all diseases or disorders are all absent, and includes prophylactic treatment of such symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation of a disease or disorder.

The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response in an individual (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) At least partially alleviating, inhibiting, preventing and/or improving the release of pro-inflammatory cytokines. In another embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is effective to at least partially reduce or inhibit the release of a proinflammatory cytokine when administered to a cell, or organ, or non-cellular biological material, or medium.

The terms "administration" and "administering" of a compound as used herein should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the art may have an effect on pro-inflammatory cytokine release by treating a patient presently suffering from such a disorder, or prophylactically treating a patient suffering from such a disorder, with an effective amount of a compound of the invention.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any products that result directly or indirectly from mixing, compounding or aggregation of any two or more ingredients, or from decomposition of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.

The compounds of formula (I) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.

The compounds of formula (I) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying the compound of formula (I) and/or for separating enantiomers of the compound of formula (I).

Pharmaceutically acceptable acid addition salts may be formed from the reaction of a compound of the present disclosure with an inorganic or organic acid, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite/iodide, isethionate, lactate, lactobionic aldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.

Pharmaceutically acceptable base addition salts may be formed from the compounds of the present disclosure by reaction with inorganic or organic bases.

Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (choline), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include both solvated and unsolvated forms of the presently disclosed compounds.

Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as ² H、 ³ H、 ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I。

In another aspect, the compounds of the invention include isotopically enriched compounds defined in the invention, e.g., wherein a radioisotope, such as ³ H、 ¹⁴ C and C ¹⁸ F, or in which non-radioactive isotopes are present, e.g ² H and ¹³ those of C. Such isotopically enriched compounds are useful in metabolic studies (using ¹⁴ C) Reaction kinetics studies (using, for example ² H or ³ H) Detection or imaging techniques, e.g. Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, orCan be used in radiotherapy of patients. ¹⁸ F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques familiar to those skilled in the art or by describing the examples and processes of preparation of the present invention using a suitable isotopically labelled reagent in place of the one previously used unlabelled reagent.

In addition, heavier isotopes are in particular deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D ₂ O and acetone-d ₆ 、DMSO-d ₆ Those solvates of (a).

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention. In one embodiment, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient, adjuvant, vehicle, or combination thereof. In another embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray form.

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound of the present disclosure, such as the compounds listed in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

The present invention provides methods of treating, preventing or ameliorating a disease or disorder comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more agents for preventing or treating conditions including sepsis, septic shock, sepsis-associated brain disease, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-associated clotting dysfunction, alzheimer's disease, parkinson's disease, cerebral apoplexy, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, sarcomas, neurofibromas, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, cellulitis, suppurative inflammation, hemorrhagic inflammation, necrotizing inflammation, catarrhal inflammation, neurodegenerative diseases, and the active compounds of the invention are different from those disclosed herein.

The medicament for preventing or treating sepsis, septic shock, sepsis-associated brain disease, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-associated coagulation dysfunction, alzheimer's disease, parkinson's disease, cerebral stroke, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, myosarcoma, neurofibromatosis, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, cellulitis, suppurative inflammation, pancreatitis, necrotizing inflammation, catarrhal inflammation, neurodegenerative diseases includes, but is not limited to: heat toxin, xuebijing, ginseng and aconitum injection, tobramycin, dexamethasone, gentamicin, tobramycin, cephalosporin, glucocorticoid, gentian liver-purging pill, calculus-removing medicinal granules, qingqing anti-stranguria pill norepinephrine, rivaroxaban tablet, PPI, H2-receptor antagonist, antacid and gastric mucosa protectant, cimetidine, heparin, low molecular dextran, aspirin or any combination thereof.

The dosage of the active ingredient in the compositions of the present invention may vary, however, the amount of active ingredient must be such that an appropriate dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment in a dosage that provides optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent medication, and other factors that will be recognized by those skilled in the art. The dosage range is typically about 0.5. 0.5 mg to 1.0. 1.0 g per patient per day, and may be administered in single or multiple doses. In one embodiment, the dosage ranges from about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; in yet another embodiment about 5 mg to 50 mg per patient per day.

It will also be appreciated that certain compounds of the invention may exist in free form and for use in therapy, or if appropriate in the form of pharmaceutically acceptable derivatives thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the invention or metabolites or residues thereof when administered to a patient in need thereof.

The disclosed pharmaceutical or pharmaceutical compositions may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in powder or syrup form. Typically, the patient is administered at a dosage level of between 0.0001 and 10 mg per kg body weight per day to obtain an effective effect. Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the presently disclosed pharmaceutical compositions may generally contain, for example, from 0.5 mg to 1 g, or from 1 mg to 700 mg, or from 5 mg to 100 mg of a presently disclosed compound.

When the pharmaceutical compositions of the present invention contain one or more other active ingredients in addition to the compound of the present invention, the compound weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another agent, the weight ratio of the compound of the present invention to the other agent typically ranges from about 1000:1 to about 1:1000, such as from about 200:1 to about 1:200. Mixtures of the compounds according to the invention with other active ingredients are generally also within the abovementioned ranges, but in each case an effective dose of each active ingredient should be used.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients that facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.

The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), the Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, the Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, lippincott Williams & Wilkins, philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J.Swarbrick and J.C. Boylan, 1988-1999, marcel Dekker, new York, the contents of each of which are incorporated herein by reference. In addition to any conventional carrier medium that is incompatible with the compounds of the present invention (e.g., produces any adverse biological effect or otherwise interacts in a deleterious manner with any of the other components of the pharmaceutically acceptable composition), its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by the desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, such as aerosols, solutions and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In one embodiment, the presently disclosed compounds may be formulated into oral dosage forms. In another embodiment, the presently disclosed compounds may be formulated into an inhalation dosage form. In another embodiment, the presently disclosed compounds may be formulated for nasal administration. In yet another embodiment, the presently disclosed compounds may be formulated into transdermal dosage forms. In yet another embodiment, the presently disclosed compounds may be formulated into topical dosage forms.

The pharmaceutical compositions provided herein may be provided in compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, or enteric tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet and a compression coated or dry coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate form alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be prepared as described in U.S. Pat. nos. 4,328,245, 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is completely dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for accurate and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredient provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550, 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may further include one or more antioxidants such as Butylated Hydroxytoluene (BHT), butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulphite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, as appropriate. It may also be formulated in an extended-release or sustained-release composition, for example, by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical compositions provided by the present invention may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms may be prepared by the method described in U.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided in non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and carbon dioxide sources.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.

The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided herein may be administered parenterally, by injection, infusion or implantation, for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical sciences (see Remington: the Science and Practice of Pharmacy, supra).

Pharmaceutical compositions contemplated for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water miscible vehicles, non-aqueous vehicles, antimicrobial or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, medium chain triglycerides of hydrogenated soybean oil and coconut oil, and palm seed oil. Water-miscible carrier packageIncluding, but not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol,N-methyl-2-pyrrolidone,N,NDimethylacetamide and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercuric agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and glucose. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfites and sodium metabisulfites. Suitable local anesthetics include, but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax refund sorbitol monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (CAPTISOL ^® , CyDex, Lenexa, KS）。

The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powder and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile dry insoluble product reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile ready-to-use emulsion.

The pharmaceutical compositions may be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as an implanted depot. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

Suitable internal matrices include polymethyl methacrylate, polymethyl butyl acrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate for coaches.

Suitable external polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxy ethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for inhaled administration to a patient, such as dry powder, aerosol, suspension or solution compositions. In one embodiment, the present inventionThe disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound as disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. The fine powder can be prepared by, for example, micronization and grinding. In general, the size-reduced (e.g., micronized) compound may be produced by a D of about 1 to 10 microns ₅₀ Values (e.g., measured using laser diffraction methods) are defined.

Aerosols may be formulated by suspending or dissolving the presently disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134 a), 1-difluoroethane (HFA-152 a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227 a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the disclosed compounds are typically administered to patients by means of Metered Dose Inhalers (MDI). Such devices are known to those skilled in the art

The aerosols may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, improve valve characteristics, improve solubility, or improve taste.

Pharmaceutical compositions suitable for transdermal administration may be formulated as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch by ion permeation, as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base may include water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.

Lotions may be formulated with water or oil and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

The topical powders may be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or nonaqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; a occlusive dressing covering the skin is preferably used. The adhesive reservoir system may allow for continuous or prolonged administration.

Use of the compounds and compositions of the invention

The disclosed compounds or pharmaceutical compositions may be used in the preparation of a medicament for the treatment, prevention, amelioration, control or alleviation of a pro-inflammatory cytokine excessive release disease in a mammal, including a human.

Specifically, the compounds of the present invention may be used for the prevention or treatment of sepsis, septic shock, sepsis-associated brain disease, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-associated coagulation dysfunction, alzheimer's disease, parkinson's disease, cerebral stroke, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, sarcomas, neurofibromas, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, cellulitis, suppurative inflammation, hemorrhagic inflammation, necrotisitis, catarrhal inflammation, neurodegenerative diseases.

The compounds or compositions of the present invention may be applied to, but are in no way limited to, the use of an effective amount of a compound or composition of the present invention to prevent, treat or ameliorate an inflammation-related disorder in a mammal, including a human, when administered to a patient.

The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.

Therapeutic method

In one embodiment, the presently disclosed methods of treatment comprise administering to a patient in need thereof a safe and effective amount of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention. Embodiments of the present disclosure include methods of treating the above-mentioned diseases by administering to a patient in need thereof a safe and effective amount of a compound of the present disclosure or a pharmaceutical composition comprising the compound of the present disclosure.

In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered by any suitable route of administration, including systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, and rectal administration. Typical parenteral administration refers to administration by injection or infusion and includes intravenous, intramuscular, and subcutaneous injection or infusion. Topical administration includes application to the skin, intraocular, otic, intravaginal, inhalation, and intranasal administration. In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered orally. In another embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered by inhalation. In yet another embodiment, the presently disclosed compounds or compounds comprising the presently disclosed compounds may be administered intranasally.

In one embodiment, the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds may be administered at one time or, depending on the dosing regimen, at several times at different time intervals over a specified period of time. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be performed until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. Suitable dosing regimens for the presently disclosed compounds, or pharmaceutical compositions comprising the presently disclosed compounds, depend on the pharmacokinetic properties of the compounds, such as dilution, distribution, and half-life, which can be determined by the skilled artisan. Furthermore, suitable dosing regimens for the presently disclosed compounds or pharmaceutical compositions comprising the presently disclosed compounds, including the duration of time for which the regimen is practiced, depend on the disease being treated, the severity of the disease being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and the like, among other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that adjustment of the regimen may be required for the individual patient's response to the regimen, or as the individual patient needs to change over time.

The presently disclosed compounds may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately from other therapeutic agents by the same or different routes of administration, or in pharmaceutical compositions therewith.

For individuals ranging from about 50 to about 70 kg, the presently disclosed pharmaceutical compositions and combinations may be in unit dosage form containing from about 1 to about 1000 mg, or from about 1 to about 500 mg, or from about 1 to about 250 mg, or from about 1 to about 150 mg, or from about 0.5 to about 100 mg, or from about 1 to about 50 mg, active ingredient. The therapeutically effective amount of a compound, pharmaceutical composition or combination thereof is dependent on the species, weight, age and condition of the individual, the disease (disorder) or disease (disorder) being treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of the respective active ingredients required to prevent, treat or inhibit the disease (disorder) or the progression of the disease (disease).

The dose characteristics cited above have been demonstrated in vitro and in vivo tests using advantageous mammals (e.g. mice, rats, dogs, monkeys) or isolated organs, tissues and specimens thereof. The compounds disclosed are used in vitro in the form of solutions, for example aqueous solutions, and also in the form of suspensions or aqueous solutions, for example, in the intestine in vivo, parenterally, in particular intravenously.

In one embodiment, a therapeutically effective dose of a compound of the present disclosure is about 0.1 mg to about 2,000 mg per day. The pharmaceutical composition thereof should provide a dose of the compound of about 0.1 mg to about 2,000 mg. In a particular embodiment, the pharmaceutical dosage unit form prepared can provide from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the principal active ingredient or a combination of principal ingredients per dosage unit form. In a particular embodiment, the pharmaceutical dosage unit form prepared provides about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of the primary active ingredient.

Furthermore, the compounds disclosed herein may be administered in prodrug form. In the present invention, a "prodrug" of a disclosed compound of the present invention is a functional derivative that, upon administration to a patient, ultimately releases the disclosed compound of the present invention in vivo. When a compound of the present disclosure is administered in a prodrug form, one skilled in the art can practice one or more of the following modes: (a) altering the in vivo onset time of the compound; (b) altering the duration of in vivo action of the compound; (c) altering in vivo delivery or distribution of the compound; (d) altering the in vivo solubility of the compound; and (e) overcoming side effects or other difficulties faced by the compounds. Typical functional derivatives useful for the preparation of prodrugs include variants of compounds that cleave chemically or enzymatically in vivo. These variants, including the preparation of phosphates, amides, esters, thioesters, carbonates and carbamates, are well known to those skilled in the art.

Drawings

FIG. 1C 57BL/6 mice hippocampal CA3 region brain tissue HE staining.

Detailed Description

The following specific examples serve to further illustrate the invention, but the invention is by no means limited to these examples.

EXAMPLE 1 mixture nanomicelle M-BFA

Dissolving 1 mg compound 1, 10 mg polyethylene glycol 1000 vitamin E succinate (TPGS) and 5 mg Pluronic F127 (F127) in 1 mL dimethyl sulfoxide (DMSO), uniformly stirring, slowly dripping into deionized water, stirring with force, uniformly mixing, removing DMSO by dialysis, and lyophilizing to obtain M-compound 1. Its BFA loading (DLC) and loading efficiency (DLE) reach 5.06% and 92.55%.

Example 2 solubility test

Test purpose: to compare the solubility and stability differences of the compounds of the present invention with BFA

The testing method comprises the following steps: 2 mg BFA and 20 mg of the present invention compounds 1, 2, 3, 4, 6, 9, 10, 13, 14, 19, 20, 70, 74 were added to 5% solvent+95% salt solvent of 2 mL, respectively, sonicated for 10 min, after 5 min of suspension, the compound solubility was observed and sedimentation was observed by standing for 3d, and the solution stability was analyzed by HPLC.

The results showed that compounds 2, 6, 9, 13, 14, 19, 20, 70, 74 of the present invention were completely dissolved in 5% solutol+95% saline solvent, exhibited a clear state and no sedimentation in 3d, and were substantially uniform in the peak area of 3d by HPLC analysis. BFA is insoluble, is in a cloudy state and settles significantly after 3 d. The compounds 1, 3, 4 and 10 are completely dissolved and are in a clear state, sedimentation phenomenon occurs in 3d, the peak area of HPLC analysis is reduced, and the compounds can be dissolved again after oscillation. Thus, the compounds of the present invention have much higher solubility (greater than 10 mg/mL) than BFA (less than 1 mg/mL), exhibiting significant dosing advantages.

Example 3 acute toxicity test

Test purpose: the toxic effect of the compounds following intraperitoneal injection (ip.) into mice was observed.

Test materials:

1) Medicament: the compound of the invention is prepared into a proper concentration for standby.

2) Animals: kunming mice, 18-22g in body weight, male. Animal license number supplied by experimental animals breeding limited, dendranthema morifolium: SCXK (robust 20140007).

The test method comprises the following steps:

kunming mice were randomly grouped by body weight, 6 per group, i.e., normal control group, BFA high and low dose group (100 mg/kg and 50 mg/kg, respectively), and part of the compounds of the invention high and low dose group (BFA effective dose conversion). After administration, the behavior and activity, mental state, ingestion, drinking water and other state reactions and death conditions of animals are observed. Following continuous administration of 14 d, all animals were weighed, sacrificed, dissected and visually inspected for abnormalities.

Results of intraperitoneal injection test:

a) The high dose group of BFA died at administration 12 d and the low dose group died at administration 14 d.

b) Animals with high and low doses of the compounds 1, 6, 10, 13, 14, 70 and 73 provided by the invention have good mental states and no death, and the compound provided by the invention is smoother in fur than animals with BFA in the administration process. 14 d, the anatomical result shows that all animal anatomies observe that each viscera has no obvious abnormality.

c) Animals in the dosing group had slightly lower body weight than the normal control group, but were statistically significantly less different.

The results show that compared with BFA, the compound provided by the invention has obviously reduced toxicity after being administered to mice and has a certain degree of attenuation effect.

EXAMPLE 4 pharmacokinetic evaluation

The test method comprises the following steps:

SD rats were weighed after overnight fast and randomized according to body weight. Accurately weighing a proper amount of tested compound, adding 5% DMSO, 10% Solutol and 85% Saline in the final volume, and mixing thoroughly by vortex or ultrasound to obtain 4 mg/mL of administration solution for intravenous injection administrationiv). Venous blood was then collected at time points 0, 0.083 (intravenous only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours, collected via the jugular vein or other suitable means, each sample was approximately 0.20. 0.20 mL, anticoagulated with heparin sodium (6.25. Mu.L 200 mM DDVP/tube added), placed on ice after collection, and the plasma was centrifuged over 2 hours (centrifugation conditions: centrifugal force 6800g,6 minutes, 2-8 ℃). The collected plasma samples are stored in a refrigerator at-70 ℃ before analysis, and the residual plasma samples after analysis are stored at-20 ℃ or-70 ℃ until LC/MS/MS analysis is performed. The quality control sample accuracy evaluation is performed while the sample is analyzed, and an accuracy of more than 66% of the quality control sample is required to be between 80 and 120%. When plasma drug concentration-time curves were plotted, BLQ was all recorded as 0. When the drug generation parameter calculation is carried out, the concentration before drug administration is calculated according to 0; BLQ (including "No peak") preceding Cmax is calculated as 0; BLQ (including "No peak") occurring after Cmax does not participate in the calculation. Pharmacokinetic parameters such as AUC (0-T), T1/2, cmax, tmax, MRT, etc. were calculated using WinNonlin from blood concentration data of brefeldin A at different time points.

The pharmacokinetic properties of the compounds of the application were tested by the above assays.

Test results

TABLE 1 pharmacokinetic Activity of the Compounds of the application

Conclusion: the Cmax and AUC values of BFA released by the in vivo metabolism of the compound of the application are higher, i.e. the BFA content produced by the in vivo metabolism of the compound of the application is higher, compared with the BFA, thereby greatly improving the BFA content in rats.

Example 5 biological Activity test

Test purpose: testing the Effect of the Compounds of the application on inflammatory factors (IL-6, TNF-alpha, IL-1 beta, etc.) in endotoxin cell models and sepsis animal models

Cell culture and test compound preparation:

murine microglial cells BV2 were placed in MEM medium containing 10% FBS (fetal bovine serum), 100U/ml penicillin and 100. Mu.g/ml streptomycin and incubated in a 5% CO2 cell incubator at 37 ℃. Until the cells grow to 80% -90%, digestion with pancreatin and passage are carried out, and the cells are kept in a good logarithmic growth phase.

All samples to be tested were dissolved in DMSO.

Experimental animals:

C57/BL6J mice, male, body weight 22-25g, grade SPF, purchased from Peking Violet laboratory animal technologies Co., ltd., animal license number: SCXK (Beijing 2021-0006). Experimental environment: constant temperature (22+/-2) deg.C, humidity 40% -70%, and free drinking and eating. All procedures and experimental procedures were in compliance with the regulations for experimental animal management.

Experiment one: determination of cytokines in microglia

Will be 100µBV2 cells in L logarithmic growth phase were seeded in 96-well plates at cell densities of 1X 10 ⁴ Cell number/well, cultured overnight at 37 ℃. Setting up a normal group and a model group (final LPS concentration 1μg/mL stimulation) and the dosing group (stimulation with different concentrations of compound), the compound was administered 24 hours after LPS action. After administration, culture supernatants were collected at 2h, 4h, and 6h, respectively, and stored at-80℃and IL6 and TNF- α values in the supernatants were determined using ELISA kits.

As shown in table 2, endotoxin was able to increase IL-6 levels, and compound 1, 13, 14, 70, 73 of the present application was able to decrease IL-6 levels; endotoxins are capable of increasing TNF- α levels and compounds of the present application are capable of decreasing TNF- α levels.

TABLE 2 Effect of the inventive compounds on IL-6 in endotoxin BV2 cell models

Note that: in the table, "A" indicates that the IL-6 concentration value is less than 1 ng/mL, "B" indicates that the IL-6 concentration value is between 1 and 10 ng/mL, "C" indicates that the IL-6 concentration value is between 10 and 20 ng/mL, and "D" indicates that the IL-6 concentration value is greater than 20 ng/mL.

TABLE 3 Effect of the inventive compounds on TNF- α in endotoxin BV2 cell model

Note that: in the table, "A" means that the TNF-alpha concentration value is less than 200 pg/mL, "B" means that the TNF-alpha concentration value is between 200 and 400 pg/mL, "C" means that the TNF-alpha concentration value is between 400 and 600 pg/mL, and "D" means that the TNF-alpha concentration value is greater than 600 pg/mL.

Experiment II: influence of the inventive Compounds on survival and cognitive function of sepsis mice

45 mice were randomly divided into a sham operation group, a CLP model group and a clp+ compound group, 15 mice per group, the CLP group and the clp+ compound group were subjected to cecal ligation and perforation, the sham operation group was given only open abdomen and flip intestine, the 2H clp+ compound was intraperitoneally injected with the compound after the operation, the sham operation group and the CLP group were intraperitoneally injected with the same dose of the cosolvent, the survival rate was observed for 10 days after the operation, a survival rate curve was drawn, and a water maze experiment was performed in parallel to evaluate the cognitive function of the mice.

As shown in Table 4, sepsis increases IL-6 levels in brain tissue and compound 70 of the present application decreases IL-6 levels in brain tissue.

TABLE 4 effects of Compound 70 of the application on IL-6 levels in brain tissue of sepsis model mice

Note that: in the table, "A" indicates that the IL-6 concentration value is less than 0.1 pg/mL, "B" indicates that the IL-6 concentration value is between 0.1 and 1 pg/mL, "C" indicates that the IL-6 concentration value is between 1 and 10 pg/mL, and "D" indicates that the IL-6 concentration value is greater than 10 pg/mL.

Experiment III: influence of Compounds on the neuroinflammatory response of sepsis mice

45 mice were randomly divided into a sham operation group, a CLP model group and a clp+ compound group, 15 mice per group, the CLP group and the clp+ compound group were subjected to cecal ligation and perforation, the sham operation group was given only open abdomen and flip intestine, the 2H clp+ compound was intraperitoneally injected after the operation, the sham operation group and the CLP group were intraperitoneally injected with the same dose of the cosolvent, the microcirculation of the cerebral cortex of the mice was observed 24 hours after the operation, the brain tissue was sampled, blood specimens were left, brain tissue inflammation factor (IL-6, TNF- α) was detected, and pathology was performed (microglial activation, blood brain barrier destruction).

The cytotoxicity results are shown in table 5, and the BV2 cell inhibition rates of the compounds 1, 13, 14, 70, 73 of the present application are different, but the toxicity is significantly reduced compared with BFA; the results of the rat brain hippocampal CA3 zone HE staining are shown in FIG. 1, and the a, b, c, d groups represent sham surgery group, CLP model group, CLP+ compound 70 group, and CLP+ positive drug (Dexmedetomidine) group. Arrows show inflammatory cell infiltration. Compound 70 can significantly reduce inflammatory cell infiltration, and its effect is equivalent to that of positive drugs.

TABLE 5 Compounds of the application at 20μCytotoxic effects on BV2 at M

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Note that: in the table, "A" indicates that the inhibition rate is less than 10%, B "indicates that the inhibition rate is between 10% and 40%, C" indicates that the inhibition rate is between 40% and 70%, and D "indicates that the inhibition rate is greater than 70%.

In conclusion, the compound realizes the outstanding progress of attenuation and synergism on the basis of BFA, and simultaneously greatly improves the solubility, and the compound can inhibit the release of relevant inflammatory factors, thereby having further research value and wide development prospect in the aspect of treating sepsis.

Finally, it should be noted that there are other ways to implement the application. Accordingly, the embodiments of the present application are to be construed as illustrative, not restrictive of the application, but may be modified and equivalents added to the scope of the application as defined by the appended claims. All publications or patents cited herein are incorporated by reference.

Claims

1. Use of macrolide derivatives in the preparation of a medicament for inhibiting pro-inflammatory cytokine action agents.

2. The use according to claim 1, wherein the compound is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (I):

（I）；

x is selected from C, O;

l is selected from single bond, double bond or-C _1-6 Alkylene-or absent;

R ₃ is hydrogen, deuterium, halogen, hydroxy, amino, nitro, cyano, carboxy, alkyl, haloalkyl, alkoxy, alkylamino, alkanoyl, hydroxyalkoxy, hydroxyalkanamino, hydroxyalkanoyl, haloalkoxy, haloalkylamino, haloalkoyl, aminoalkoxy, cycloalkyl, cycloalkyloxy, cycloalkylamino, cycloalkylacyl, alkenyl, alkenylalkoxy, alkenylalkylamino, alkenylalkanoyl, alkynyl, alkynylalkoxy, alkynylalkylamino, alkynylalkanoyl, aryl, aryloxy, aroyl, arylamino, arylalkoxy, arylalkylamino, heteroaryl, heteroaryloxy, heteroarylacyl, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkanoyl, heterocycloalkyl, heterocyclyloxy, heterocyclylamino, heterocyclylacyl, heterocyclylalkoxy, heterocyclylalkylamino, heterocyclylalkylacyl, azidoalkoxy, fused bicyclic group, fused heterobicyclic group, fused bicyclic group aliphatic, fused heterobicyclic group aliphatic, fused bicyclic group oxy, fused heterobicyclic group oxy, fused bicyclic amino, fused heterobicyclic amino, fused bicyclic alkoxy, fused heterobicyclic amino, fused bicyclic alkylamino, fused bicyclic alkoxy, fused bicyclic alkylamino, fused heterobicyclic alkoxyalkoxy, fused bicyclic amino alkoxy, fused heterobicyclic amino alkoxy, fused bicyclic group-C (=O) -, fused bicyclic group-C (=o) O-, fused heterobicyclic group-C (=o) O-, fused bicyclic amino-C (=o) -, fused heterobicyclic amino-C (=o) -, fused bicyclic group-C (=o) N (R) ₄ ) -, fused heterobicycloyl-C (=o) N (R ₄ ) -, spirobicycloyl, spirobicycloaliphatic, spirobicyclooxy, spirobicycloamino, spirobicycloalkoxy, spirobicycloalkyloxy, spirobicycloalkylamino, spirobicyclooxyalkoxy, spirodicyclooxyalkoxy, spirodicycloaminoalkoxy, spirodicyclo-C (=o) -, spirodicyclo-C (=o) O-, spirodicycloamino-C (=o) -, spirodicyclo-C (=o) N (R) ₄ ) -, spirobicyclic-C (=o) N (R ₄ )-, R ₅ R ₄ N-, -C(=O)NR ₄ R ₅ , -OC(=O)NR ₄ R ₅ , -OC(=O)OR ₄ , -N(R4)C(=O)NR ₄ R ₅ , -N(R ₄ )C(=O)OR ₅ , -N(R ₄ )C(=O)-R ₅ , R ₄ R ₅ N-S(=O)t-, R ₄ S(=O)t-, R ₄ S(=O)tN(R ₅ )-, R ₅ R ₄ N-alkyl, R ₄ S (=O) t-alkyl, R ₄ R ₅ N-C (=o) -alkyl, R ₅ R ₄ N-alkoxy, R ₄ S (=O) t-alkoxy, R ₄ R ₅ N-C (=o) -alkoxy, aryl- (CH) ₂ )p-G-(CH ₂ ) m-, heteroaryl- (CH) ₂ )p-G-(CH ₂ ) m-, heterocyclyl- (CH) ₂ )p-G-(CH ₂ ) m-, or cycloalkyl- (CH) ₂ )p-G-(CH ₂ ) m-, wherein G is O, S, NR ₆ , S(=O), S(=O) ₂ , C(=O), -C(=O)N(R ₄ )-, -OC(=O)N(R ₄ )-, -OC(=O)-, -N(R ₄ )C(=O)N(R ₄ )-, -(R ₄ ) N-S (=O) t-, -OS (=O) t-, or-OS (=O) tN (R) ₄ ) T is l or 2, p and m are each independently 0, l, 2, 3 or 4, or wherein aryl- (CH) ₂ )p-G-(CH ₂ ) m-, heteroaryl- (CH) ₂ )p-G-(CH ₂ ) m-, heterocyclyl- (CH) ₂ )p-G-(CH ₂ ) m-, or cycloalkyl- (CH) ₂ )p-G-(CH ₂ ) m-may be substituted with one or more substituents selected from F, cl, br, I, alkyl, alkenyl, alkynyl, alkoxy or cyano, where Z is a benzene ring, R ₃ Cannot be hydrogen;

R ₆ can be hydrogen, R ₅ R ₄ NC(=O)-, R ₅ OC(=O)-, R ₅ C(=O)-, R ₅ R ₄ NS(=O)-, R ₅ OS(=O)-, R ₅ S(=O)-, R ₅ R ₄ NS(=O) ₂ -, R ₅ OS(=O) ₂ -, R ₅ S(=O) ₂ -, aliphatic, halogenated aliphatic, hydroxy aliphatic, amino aliphatic, alkoxy aliphatic, alkylamino aliphatic, alkylthio aliphatic, aryl aliphatic, heteroaryl aliphatic, heterocyclyl aliphatic, cycloalkyl aliphatic, aryloxy aliphatic, heterocyclyloxy aliphatic, cycloalkyl oxy aliphatic, arylamino aliphatic, heterocyclyl aminoCycloaliphatic, cycloalkylamino aliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;

3. The use according to claim 1, wherein L is selected from single bond, double bond, methylene, ethylene, propylene, butylene or absent, Z is selected from aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminoisopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aminophenyl, substituted or unsubstituted pyridine, quinoline or isoquinoline ring, Z is independently and optionally substituted with 1, 2, 3 or 4 substituents selected from deuterium, F, cl, br, I, hydroxy, amino, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phenyl, thiazolyl, pyrazolyl, oxazolyl, pyridinyl or pyrimidinyl;

wherein each R is ₅ And R is ₄ Independently H, deuterium, C1-C3 aliphatic, C1-C3 halogenated aliphatic, C1-C3 hydroxy aliphatic, C1-C3 amino aliphatic An aliphatic, C1-C3 alkoxy-C1-C3 aliphatic, C1-C3 alkylamino-C1-C3 aliphatic, C1-C3 alkylthio-C1-C3 aliphatic, C6-C10 aryl-C1-C3 aliphatic, C5-C9 heteroaryl-C1-C3 aliphatic, C4-C10 heterocyclyl-C1-C3 aliphatic, C3-C10 cycloalkyl-C1-C3 aliphatic, C6-C10 aryloxy-C1-C3 aliphatic, C4-C10 heterocyclyloxy-C1-C3 aliphatic, C3-C10 cycloalkyloxy-C1-C3 aliphatic, C6-C10 arylamino-C1-C3 aliphatic, C4-C10 heterocyclylamino-C1-C3 aliphatic, C3-C10 cycloalkylamino-C1-C3 aliphatic, C6-C10 aryl, C5-C10 heteroaryl, C4-C10 heterocyclyl or C3-C10 cycloalkyl; when R is ₅ And R is ₄ R being bound to the same nitrogen atom ₅ , R ₄ And nitrogen optionally form a substituted or unsubstituted 3-8 membered ring, a fused bicyclic ring or a spirobicyclic ring, wherein the hetero atom in the heterocyclic group, heteroaryl group, fused heterobicyclic group or spiroheterobicyclic group referred to in the above groups is 1 to 5 hetero atoms independently selected from N, O, S;

4. The use according to claim 1, wherein R ₃ Selected from H, deuterium, F, cl, br, I, hydroxy, amino, nitro, cyano, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, C ₅ H ₁₁ , C ₆ H ₁₃ , C ₈ H ₁₇ Trifluoromethyl, hydroxymethyl, aminomethyl, methoxy, ethoxy, t-butoxy, methylamino, ethylamino, isopropylamino, 3-hydroxy-propyl, acetyl, trifluoroacetyl, cyanoacetyl, methylaminoacetyl, propionyl, isopropylacyl, 2-hydroxypropionyl, 2-aminopropionyl, 2-chloropropionyl, 2-bromopropionyl, pentanoyl, hexanoylHeptanoyl, methacryloyl, phenyl, benzoyl, p-nitrophenyl, p-methylbenzoyl, m-fluorobenzoyl, p-aminobenzoyl, p-methoxybenzoyl, 2, 4-dimethylbenzoyl, m-azidobenzoyl, benzyl, p-chlorobenzyl, ethenyl, propenyl, allyl, N-butenyl, isobutenyl, N-pentenyl, isopentenyl, cyclopropyl, cyclopropoyl, cyclopentanoyl, cyclohexenyl, 3-pyridineformyl, naphthyl, phenethylimidazolyl, pyridinyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, piperidinyl, piperazinyl, indolyl, carbazolyl, benzofuranyl tetrahydrofuranyl, tetrahydropyranyl, pyrimidine bases, purine bases, -N (CH) ₃ ) ₂ -C (c=o) NH-C1-C4 alkyl, -OC (c=o) -NH-C1-C4 alkyl, -OC (o=o) O-C1-C4 alkyl, -NHC (=o) NH-C1-C4 alkyl, -NHC (=o) O-C1-C4 alkyl, -NHC (=o) -C1-C4 alkyl, C1-C4 alkyl-NH-S (=o) ₂ -, C1-C4 alkyl S (=o) ₂ -, C1-C4 alkyl S (=o) ₂ NH-, phenyl- (CH) ₂ ) _P -G-(CH ₂ ) _m -, fluorophenyl- (CH) ₂ ) _P -G-(CH ₂ ) _m -, thiazolyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, pyridinyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -, phenylethyl, cyclohexyl- (CH) ₂ ) _p -G-(CH ₂ ) _m -wherein G is O, S (=o) ₂ C (=O), p and m are each independently 0, 1, 2 or 3, or wherein C6-C10 aryl- (CH) ₂ ) _P -G-(CH ₂ ) _m Can be substituted by one or more substituents selected from F, cl, br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano, or R ₃ Optionally substituted with F, cl, br, I, hydroxy, hydroxymethyl, carboxy, acetamido, C1-C6 alkyl (e.g., methyl, ethyl, propyl), C1-C6 alkoxy, C1-C6 alkylamino, trifluoromethyl, trifluoroacetyl, mercapto, nitro, amino, azido (-N) ₃ ) One or more of guanidino, cyano, t-butoxycarbonyl (-Boc), carbonyl (-c=o), oxo (=o), thio (=s), sulfonyl, phenyl; wherein, when Z is benzene ring, R ₃ And cannot be H.

5. The use according to claim 1, wherein the compound has the structure of one of the following or a tautomer or pharmaceutically acceptable salt thereof:

。

6. The use according to claim 1, wherein the pharmaceutical composition comprises a compound according to any one of claims 2-5.

7. The use of claim 6, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, polymeric micelle, or combination thereof.

8. The use according to claim 7, wherein the hydrophilic block of the polymeric micelle further comprises one or more of polyethylene glycol or derivatives thereof, polyvinylpyrrolidone, polyoxazoline, polyacrylic acid, polyethylenimine, chitosan, dextran, hyaluronic acid, hydroxyethylcellulose and functional derivatives thereof, and/or combinations thereof; the hydrophobic block comprises one or more selected from the group consisting of polylactide, polyglycolide, polymmandelic acid, polycaprolactone, polydioxanone-2-one, polyamino acid, polyorthoester, polysorbates, polycarbonates, and functional derivatives thereof, and/or combinations thereof.

9. The use according to claim 8, wherein the molecular weight of the hydrophilic block and the hydrophobic block of the polymeric micelle is between 300 and 20000.

10. Use according to claim 1, characterized in that the medicament is a novel medicament for the prevention or treatment of sepsis, septic shock, sepsis-related encephalopathy, sepsis cardiomyopathy, sepsis lung injury, sepsis kidney injury, sepsis liver injury, sepsis gastrointestinal tract injury, sepsis-related coagulation dysfunction, alzheimer's disease, parkinson's disease, cerebral apoplexy, acute lung injury or acute respiratory distress syndrome, pulmonary fibrosis, pancreatitis, cirrhosis, gastritis, inflammatory bowel disease, crohn's disease, ulcerative colitis, nephritis, arteriovenous thrombosis, connective tissue disease, renal interstitial fibrosis, glomerulosclerosis, hepatic fibrosis, peritoneal fibrosis, myocardial fibrosis, skin fibrosis, post-operative adhesions, benign prostatic hypertrophy, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, myosarcoma, neurofibromas, interstitial fibrosis, diabetic nephropathy, vascular fibrosis, serositis, fibrositis, suppurative inflammation, hemorrhagic inflammation, necrotizing inflammation, catarrhal inflammation.