Patent Application
20240391895
The present disclosure relates to the field of pharmaceutics and particularly to pyridazine-containing compounds and use thereof in pharmaceutics.
The NOD-like receptor protein 3 (NLRP3) is a protein-coding gene: the protein belongs to the family of nucleotide-binding and oligomerization domain-like receptors (NLRs) and is also known as “pyrin domain-containing protein 3” (Inoue et al., Immunology, 2013, 139, 11-18). The gene encodes a protein containing a pyridine domain, a nucleotide-binding site domain (NBD) and a leucine-rich repeat (LRR) motif. In response to sterile inflammatory danger signals, NLRP3 interacts with an adaptor protein, apoptosis-associated speck-like protein (ASC) and zymogen-1 to form the NLRP3 inflammasome. NLRP3 inflammasome activation then leads to the release of the inflammatory cytokines IL-1b and IL-18, and when dysregulated, can cause many diseases.
Studies have shown that NLRP3 inflammasome activation is associated with a variety of diseases, including: inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and autoinflammatory diseases. Therefore, there is a need to provide new NLRP3 inflammasome pathway inhibitors to provide new options for treating the disease described above.
In a first aspect, the present disclosure provides a compound of formula I or a pharmaceutically acceptable
wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(C═O)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN; R2, R3, R4, R5, R6 and R7:
In some embodiments, R1 is selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(C═O)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN;
In some embodiments, R1 is selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(C═O)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN;
In some embodiments, R1 is selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(CO)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN;
In some embodiments, R1 is selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(C═O)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN;
In some embodiments, R1 is selected from the group consisting of halogen, —OH, —NH2, —CN, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, —NHC(═O)—C1-6 alkyl and —(C═O)NH—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN.
In some embodiments, R1 is selected from the group consisting of —OH, —NH2, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—C1-6 alkyl, and —NHC(═O)—C1-6 alkyl, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN.
In some embodiments, R1 is selected from the group consisting of —OH, —NH2, and the following groups that are optionally substituted with one or more —OH: C1-6 alkyl, —O—C1-6 alkyl and —NHC(═O)—C1-6 alkyl.
In one embodiment, R1 is —OH.
In some embodiments, R1 is —O—C1-6 alkyl, preferably —OCH3 or —OCH2CH3, and more preferably —OCH3.
In some embodiments, R1 is C1-6 alkyl that is optionally substituted with one or more —OH; preferably, R1 is —CH2OH or —CH2CH2OH; more preferably, R1 is —CH2OH.
In one embodiment, R1 is —NH2.
In some embodiments, R1 is —NHC(═O)—C1-6 alkyl that is optionally substituted with one or more —OH; preferably, R1 is —NH2C(═O)CH3.
In some embodiments, R2 and R3, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, —OH, —NH2, —CN, oxo, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas II′-a, II′-b, II′-c, II′-d, II′-f, II′-g, II′-k, II′-l and II′-m, preferably compounds of formulas II′-a, II′-c, II′-d, II′-k, II′-l and II′-m, and more preferably compounds of formulas II′-a, II′-d, II′-k and II′-m, and is most preferably a compound of formula II′-a or II′-k.
In some other embodiments, R2 and R3, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, —OH, —NH2, —CN, oxo, C1-4 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, R2 and R3, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon; preferably, the 5-6 membered cyclic hydrocarbon is cyclopentyl or cyclohexyl; the cyclopentyl or cyclohexyl is optionally substituted with a substituent selected from the group consisting of hydrogen, deuterium, halogen, —OH, C1-6 alkyl and C1-6 haloalkyl;
In some embodiments, the 5-6 membered heterocyclic ring is a 5-6 membered S-containing heterocyclic ring.
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas III′-a, III′-b, III′-c, III′-d, III′-f, III′-g, III′-h and III′-i, preferably compounds of formulas III′-a, III′-b, III′-c, III′-f, III′-g and III′-h, and more preferably compounds of formulas III′-a, III′-c, III′-f and III′-h, and is most preferably a compound of formula III′-a or III′-f.
In some other embodiments, R2 and R3, together with the atoms to which they are attached, form a 5-6 membered heteroaromatic ring that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, —OH, —NH2, —CN, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the 5-6 membered heteroaromatic ring is a 5-membered S-containing heteroaromatic ring.
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas IV′-a, IV′-b, IV′-c, IV′-d, IV′-e, IV′-f, IV′-g, IV′-h, IV′-i, IV′-j, IV′-k and IV′-l, preferably compounds of formulas IV′-a, IV′-b, IV′-c, IV′-d, IV′-g, IV′-h, IV′-i and IV′-j, and more preferably compounds of formulas IV′-a, IV′-d, IV′-g and IV′-j, and is most preferably a compound of formula IV′-a or IV′-g.
In some embodiments, in formula II-a, formula II-b, formulas II′-a to II′-q, formulas III-a to III-p, formulas III′-a to III′-r, formulas IV-a to IV-n and formulas IV′-a to IV′-p, R4, R5, R6 and R1 are independently selected from the group consisting of hydrogen, deuterium, halogen, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylmethylene, and the substituents are deuterium atoms or halogens.
In some embodiments, R4 and R7 are independently selected from the group consisting of hydrogen, deuterium and halogen, and R5 and R6 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6 alkyl that is optionally substituted with one or more deuterium atoms or halogens.
In some embodiments, R4, R5 and R7 are each hydrogen, and R6 is methyl; or, R4, R6 and R7 are each hydrogen, and R5 is methyl.
In some other embodiments, R3 and R4, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas V-a, V-b, V-c, V-d, V-f, V-g, V-k, V-l and V-m, preferably compounds of formulas V-a, V-c, V-d, V-k, V-l and V-m, and more preferably compounds of formulas V-a, V-d, V-k and V-m, and is most preferably a compound of formula V-a or V-k.
In some embodiments, in the compounds of formulas V-a to V-q, R2, R5, R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylmethylene, and the substituents are deuterium atoms or halogens.
In some embodiments, R2 and R7 are independently selected from the group consisting of hydrogen, deuterium and halogen, and R5 and R6 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6 alkyl that is optionally substituted with one or more deuterium atoms or halogens.
In some embodiments, R2, R5 and R7 are each hydrogen, and R6 is methyl; or, R2, R6 and R7 are each hydrogen, and R5 is methyl.
In some other embodiments, R4 and R5, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-h, VI-i, VI-j, VI-k and VI-l, preferably compounds of formulas VI-a, VI-b, VI-c, VI-h, VI-i and VI-j, and is most preferably a compound of formula VI-a or VI-h.
In some embodiments, in the compounds of formulas VI-a to VI-l, R2, R3, R6 and R7 are independently selected from the group consisting of hydrogen, deuterium, halogen, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylmethylene, and the substituents are deuterium atoms or halogens.
In some embodiments, R2 and R7 are independently selected from the group consisting of hydrogen, deuterium and halogen, and R3 and R6 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6 alkyl that is optionally substituted with one or more deuterium atoms or halogens.
In some embodiments, R2 and R7 are each hydrogen, R3 is trifluoromethyl, and R6 is methyl; or, R2 and R7 are each hydrogen, R3 is chlorine, and R6 is methyl.
In some embodiments, R4 and R5, together with the atoms to which they are attached, form phenyl that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of
In some embodiments, R3 and R4, together with the atoms to which they are attached, form phenyl that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some other embodiments, R6 and R7, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-4 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens; R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, halogen, —OH, —NH2, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, —O—Cis alkyl, —S—C1-6 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylmethylene, and the substituents are selected from the group consisting of: deuterium, halogen, —OH, —NH2 and —CN;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas VII-a, VII-b, VII-c, VII-g, VII-h and VII-i, preferably compounds of formulas VII-a, VII-b, VII-g and VII-h, and is more preferably a compound of formula VII-a or VII-g, and most preferably a compound of formula VII-g.
In some other embodiments, R6 and R7, together with the atoms to which they are attached, form a 5-6 membered heterocyclic ring that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, the compound of formula I is selected from the group consisting of compounds of formulas VIII′-a, VIII′-c, VIII′-d, VIII′-f, VIII′-g, VIII′-j, VIII′-k, VIII′-l and VIII′-m, preferably compounds of formulas VIII′-a, VIII′-c, VIII′-d, VIII′-f, VIII′-g, VIII′-j and VIII′-l, and more preferably compounds of formulas VIII′-a, VIII′-c, VIII′-d and VIII′-j, and is most preferably a compound of formula VIII′-a or VIII′-d.
In some embodiments, R6 and R7, together with the atoms to which they are attached, form phenyl that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
In some embodiments, the compound of formula I is selected from the group consisting of:
In some embodiments, R2 and R4 are independently selected from the group consisting of hydrogen, deuterium and halogen, and R3 and R5 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6 alkyl that is optionally substituted with one or more deuterium atoms or halogens.
In some embodiments, R2 and R4 are each hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen, halogen or methyl; preferably, R2, R4 and R5 are each hydrogen, and R3 is trifluoromethyl.
In some embodiments, R6 and R7, together with the atoms to which they are attached, form 5-6 membered heteroaryl that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, oxo, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens; preferably, the 5-6 membered heteroaryl is pyridine;
In some embodiments, R6 and R7, together with the atoms to which they are attached, form 5-6 membered heteroaryl that contains 1-2 heteroatoms and is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens; the heteroatoms are selected from the group consisting of oxygen, nitrogen and sulfur atoms, preferably from nitrogen atoms.
In some embodiments, the compound of formula I is selected from the group consisting of:
X is selected from the group consisting of an oxygen atom and a sulfur atom; the R18c is selected from the group consisting of deuterium, halogen, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more halogens; preferably, R18c, is independently selected from the group consisting of deuterium, halogen, C1-6 alkyl and —O—C1-6 alkyl;
In some embodiments, in the compounds of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i or the pharmaceutically acceptable salts thereof, R18c, is independently selected from the group consisting of deuterium, halogen, C1-6 alkyl and —O—C1-6 alkyl.
In some embodiments, in the compounds of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i or the pharmaceutically acceptable salts thereof, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, deuterium, halogen, and the following groups that are optionally substituted with one or more substituents: C1-6 alkyl, C3-6 cycloalkyl and C3-6 cycloalkylmethylene, and the substituents are deuterium atoms or halogens.
In some embodiments, in the compounds of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i or the pharmaceutically acceptable salts thereof, R2 and R4 are independently selected from the group consisting of hydrogen, deuterium and halogen, and R3 and R5 are independently selected from the group consisting of hydrogen, deuterium, halogen, and C1-6 alkyl that is optionally substituted with one or more deuterium atoms or halogens. In some embodiments, in the compounds of formulas X-a, X-b, X-c, X-d, X-e, X-f, X-g, X-h and X-i or the pharmaceutically acceptable salts thereof, R2 and R4 are each hydrogen, R3 is trifluoromethyl or chlorine, and R5 is hydrogen or methyl; preferably, R2, R4 and R5 are each hydrogen, and R3 is trifluoromethyl.
The present disclosure further provides a compound of formula I′ or a pharmaceutically acceptable salt thereof,
In some embodiments, R13 is selected from the group consisting of ethyl, n-propyl, isopropyl and n-butyl, and is preferably ethyl;
In one embodiment, R13 is —S—CF3.
In some embodiments, R13 is selected from the group consisting of:
and more preferably
and is most preferably
In one embodiment, R11 is —OH.
In one embodiment, R11 is —NH2.
In some embodiments, R11 is —O—C1-6 alkyl that is optionally substituted with a deuterium atom or a halogen; preferably, R11 is methoxy or ethoxy; more preferably, R11 is methoxy.
In one embodiment, R11 is —CH2OH.
In some embodiments, R11 is —NHC(═O)—C1-6 alkyl that is optionally substituted with a deuterium atom or a halogen; preferably, R11 is —NHC(═O)—CH3.
In some embodiments, R15, R16 and R17 are independently selected from the group consisting of hydrogen, deuterium, fluorine and methyl.
The present disclosure further provides a compound of formula I″ or a pharmaceutically acceptable salt thereof,
In one embodiment, R21 is —NH2.
In some embodiments, R21 is —O—C1-6 alkyl that is optionally substituted with a deuterium atom or a halogen; preferably, R21 is methoxy or ethoxy; more preferably, R21 is methoxy.
In one embodiment, R21 is —CH2OH.
In some embodiments, R21 is —NHC(═O)—C1-6 alkyl that is optionally substituted with a deuterium atom or a halogen; preferably, R21 is —NHC(═O)—CH3.
In some embodiments, R23 is C1-6 alkyl that is optionally substituted with one or more fluorine atoms; preferably, R23 is trifluoromethyl.
In one embodiment, R23 is chlorine.
In some embodiments, R25, R26 and R27 are independently selected from the group consisting of hydrogen, deuterium, fluorine and methyl.
In some embodiments, in the aforementioned compounds of the present disclosure, Z is O.
In some embodiments, in the aforementioned compounds of the present disclosure, Z is —NH—(CH2)n-, and n is an integer selected from 0-2; n is preferably 0 or 1; n is more preferably 0.
In some embodiments, in the aforementioned compounds of the present disclosure, R8 is selected from 5-10 membered heterocyclyl that is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, oxo, —OR8a, —SR8a, —C(O)R8a, —OC(═O)R8a, —C(═O)OR8a, —C(O)NR8aR8b, —NR8aR8b, —NR8aC(═O)R8b, —NR8aS(═O)2R8b, —S(═O)2R8b, —S(═O)2NR8aR8b, —CN, —NO2, C1-4 alkyl and C3-6 cycloalkyl, and the C1-4 alkyl or C3-6 cycloalkyl is optionally further substituted with one or more deuterium atoms, halogens or —OH;
In some R8 is selected from the group consisting of:
In some embodiments, R8 is selected from the group consisting of:
and is more preferably
and most preferably
In some embodiments, R8 is
In some other embodiments, in the aforementioned compounds of the present disclosure, R8 is selected from the group consisting of aryl and heteroaryl that are optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, oxo, —OR8a, —SR8a, —C(═O)R8a, —OC(═O)R8a, —C(═O)OR8a, —C(O)NR8aR8b, —NR8aR8b, —NR8aC(═O)R8b, —NR8aS(═O)2R8b, —S(═O)2R8a, —S(═O)2NR8a,R8b, —CN, —NO2, C1-4 alkyl and C3-6 cycloalkyl, and the C1-4 alkyl or C3-6 cycloalkyl is optionally further substituted with one or more deuterium atoms, halogens or —OH;
In some embodiments, R8 is selected from the group consisting of:
In some embodiments, R8 is selected from the group consisting of:
and is more preferably
In some other embodiments, in the aforementioned compounds of the present disclosure, R8 is selected from C3-8 cycloalkyl that is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, —OH, —NH2, —CN and C1-4 alkyl, and the C1-4 alkyl is optionally further substituted with one or more deuterium atoms, halogens or —OH.
In some embodiments, R8 is selected from the group consisting of:
In some embodiments, R8 is selected from the group consisting if
In some embodiments, R8 is selected from the group consisting of:
and is more preferably
In some other embodiments, in the aforementioned compounds of the present disclosure, R8 is selected from C2-6 alkyl that is optionally substituted with one or more substituents selected from the group consisting of deuterium, halogen, —OR8a, —SR8a, —C(═O)R8a, —OC(═O)R8a, —C(═O)OR8a, —C(O)NR8aR8b, —NR8aR8b, —NR8aC(O)R8b, —NR8aS(═O)2R8b, —S(═O)2R8a, —S(═O) NR8aR8b, —CN, —NO2, C1-4 alkyl and C3-6 cycloalkyl, and the C1-4 alkyl or C3-6 cycloalkyl is optionally further substituted with one or more deuterium atoms, halogens or —OH;
In some embodiments, R8 is selected from the group consisting of:
In a second aspect, the present disclosure provides a compound or a pharmaceutically salt thereof selected from the group consisting of
In a third aspect, the present disclosure provides a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
In a fourth aspect, the present disclosure further provides an isotopically substituted form of the aforementioned compound; preferably, the isotopic substitution is a substitution with a deuterium atom.
In a fifth aspect, the present disclosure further provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to the first to third aspects or the isotopically substituted form according to the forth aspect, and at least one pharmaceutically acceptable carrier, diluent or excipient.
In some embodiments, a unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
In certain embodiments, the pharmaceutical composition comprises 0.01-99.99% of the aforementioned compound or pharmaceutically acceptable salt thereof on the basis of the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1-99.9% of the aforementioned compound or pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 0.5% 99.5% of the compound or the pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 1%-99% of the compound or the pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises 2%-98% of the compound or the pharmaceutically acceptable salt thereof.
The present disclosure further provides use of the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect as a medicament. In a sixth aspect, the present disclosure further provides use of the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect in the preparation of a medicament for treating a disease associated with NLRP3 activity.
The present disclosure further provides a method for preventing and/or treating a disease associated with NLRP3 activity in a patient, which comprises administering to the patient a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect.
The present disclosure further provides the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect for use in the prevention or treatment of a disease associated with NLRP3 activity. The present disclosure further provides a method for preventing and/or treating a disease associated with NLRP3 activity in a patient, which comprises administering to the patient a therapeutically effective amount of the aforementioned compound or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition.
The disease associated with NLRP3 activity includes inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
The present disclosure further provides use of the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect in the preparation of a medicament for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
The present disclosure further provides use of the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect in the preparation of a medicament for treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
The present disclosure further provides the compound or the pharmaceutically acceptable salt thereof according to the first, second or third aspect, the isotopically substituted form according to the fourth aspect or the pharmaceutical composition according to the fifth aspect for use in the treatment of inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases and/or autoinflammatory diseases.
The present disclosure further provides a method for treating and/or preventing an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease and/or an autoinflammatory disease in a patient, which comprises administering to the patient a therapeutically effective amount of the aforementioned compound or pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition. The inflammasome-related disease, the immune disease, the inflammatory disease, the autoimmune disease and/or the autoinflammatory disease may be specifically selected from the group consisting of: autoinflammatory fever syndromes (such as cryo-pyrin-associated periodic syndromes), sickle-cell anemia, systemic lupus erythematosus, liver-related diseases (such as chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis, alcoholic steatohepatitis and alcoholic liver disease), inflammatory arthritis-related diseases (such as gout, chondrocalcinosis, osteoarthritis, rheumatoid arthritis and acute or chronic arthritis), kidney-related diseases (such as hyperoxaluria, lupus nephritis, hypertensive nephropathy, hemodialysis-associated inflammation, type I or type II diabetes and complications thereof (such as nephropathy and retinopathy)), neuroinflammation-related diseases (such as brain infection, acute injury, multiple sclerosis, Alzheimer's disease and neurodegenerative diseases), cardiovascular and metabolic disorders or diseases (such as cardiovascular risk reduction (CvRR), atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure and hypertension), wound healing, scar formation, inflammatory skin diseases (e.g., acne and hidradenitis suppurativa), asthma, sarcoidosis, age-related macular degeneration, and cancer-related diseases/conditions (e.g., myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis, lung cancer and colon cancer).
In some embodiments, the AUC or Cmax in the blood after oral administration of the compounds of the present disclosure compared to compound R1 or compound R2 or compound R3 is expected to be increased by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100% or even higher.
The present disclosure further provides a compound as shown below,
In certain embodiments, the compound is an intermediate.
In some embodiments, R6 and R7, together with the atoms to which they are attached, form a 5-6 membered cyclic hydrocarbon, a 5-6 membered heterocyclic ring, phenyl or 5-6 membered heteroaryl that is optionally substituted with one or more substituents selected from the group consisting of: deuterium, halogen, —OH, —NH2, —CN, oxo, C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl, and the C1-6 alkyl, —O—C1-6 alkyl and C3-6 cycloalkyl are optionally further substituted with one or more deuterium atoms or halogens;
The pharmaceutically acceptable salts of the compounds described herein are selected from the group consisting of inorganic salts and organic salts. The compounds described herein can react with acidic or basic substances to form corresponding salts.
In another aspect, the compounds of the present disclosure may exist in specific step isomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (−)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomer, (L)-isomer, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as an alkyl group. All such isomers and mixtures thereof are included within the scope of the present disclosure.
The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term “tautomer” or “tautomeric form” refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of a lactam-lactim equilibrium is present between A and B as shown below.
All the compounds in the present invention can be drawn as form A or form B. All tautomeric forms fall within the scope of the present invention. The nomenclature of the compounds does not exclude any tautomers.
The compounds of the present disclosure may be asymmetric; for example, the compounds have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically active pure form or in racemic form. The optically active pure form can be isolated from a racemic mixture or synthesized using chiral starting materials or chiral reagents.
Optically active (R)- and (S)-enantiomers, and D- and L-isomers can be prepared by chiral synthesis, chiral reagents or other conventional techniques. If one enantiomer of a certain compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), salts of diastereomers are formed with an appropriate optically active acid or base, followed by resolution of diastereomers by conventional methods known in the art, and the pure enantiomers are obtained by recovery. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The present disclosure also comprises isotopically-labeled compounds which are identical to those recited herein but have one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compound of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11C, 13C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 123I, 125I and 36Cl.
Unless otherwise specified, when a position is specifically assigned deuterium (D), the position should be construed as deuterium with an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). The compounds of examples comprise deuterium having an abundance that is greater than at least 1000 times the natural abundance, at least 2000 times the natural abundance, at least 3000 times the natural abundance, at least 4000 times the natural abundance, at least 5000 times the natural abundance, at least 6000 times the natural abundance, or higher times the natural abundance. The present disclosure also comprises various deuterated forms of the compound of formula (I). Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to synthesize the deuterated forms of the compound of general formula (I) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, tri-deuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
“Optionally” or “optional” means that the event or circumstance subsequently described may, but does not necessarily, occur and that the description includes instances where the event or circumstance occurs or does not occur. For example, “C1-6 alkyl that is optionally substituted with a halogen or cyano” means that the halogen or cyano may, but does not necessarily, exist, and the description includes the instance where alkyl is substituted with a halogen or cyano and the instance where alkyl is not substituted with a halogen and cyano.
In the chemical structure of the compound of the present invention, a bond represents an unspecified configuration—that is, if chiral isomers exist in the chemical structure, the bond “
” may be “
” or “
”, or includes both the configurations of “
” and “
”. Although all of the above structural formulae are drawn as certain isomeric forms for the sake of simplicity, the present disclosure may include all isomers, such as tautomers, rotamers, geometric isomers, diastereomers, racemates and enantiomers.
“Pharmaceutical composition” refers to a mixture containing one or more of the compounds or the physiologically/pharmaceutically acceptable salts or pro-drugs thereof described herein, and other chemical components, for example, physiologically/pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is intended to promote the administration to an organism, so as to facilitate the absorption of the active ingredient, thereby exerting biological activities.
“Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. food and drug administration as acceptable for use in humans or livestock animals.
“Alkyl” refers to a saturated aliphatic hydrocarbon group, including linear and branched groups of 1 to 20 carbon atoms, and alkyl containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, various branched isomers thereof, and the like. Unless otherwise specified, alkyl may be substituted or unsubstituted, and when it is substituted, the substituent may be substituted at any accessible connection site, preferably with one or more groups independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl, and the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano.
“Cycloalkyl” or “cyclic hydrocarbon” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. Polycyclic cycloalkyl includes spiro cycloalkyl, fused cycloalkyl and bridged cycloalkyl.
The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl; non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Unless otherwise specified, cycloalkyl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl and a carboxylate group.
“Heterocyclyl” or “heterocyclic ring” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O)m (where m is an integer of 0 to 2), excluding a ring moiety of —O—O—, —O—S— or —S—S—, and the other ring atoms are carbon atoms. It preferably contains 3 to 12 ring atoms, 1 to 4 of which are heteroatoms; more preferably, it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. The polycyclic heterocycloalkyl includes spiro heterocyclyl, fused heterocyclyl and bridged heterocycloalkyl. Non-limiting examples of “heterocycloalkyl” include:
and the like.
Heterocycloalkyl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of, for example, halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl, and the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano.
The heterocyclyl ring may be fused to an aromatic ring, a heteroaromatic ring or a cyclic hydrocarbon, wherein the ring attached to the parent structure is heterocyclyl; non-limiting examples thereof include:
etc.
“Aryl” or “aromatic ring” refers to a 6- to 14-membered, preferably 6- to 12-membered, all-carbon monocyclic or fused polycyclic (i.e., rings sharing a pair of adjacent carbon atoms) group having a conjugated π-electron system, such as phenyl and naphthyl.
Aryl may be substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl, and the C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5 to 6-membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano.
The aryl ring may be fused to a heteroaromatic ring, a heterocyclic ring or a cyclic hydrocarbon, wherein the ring attached to the parent structure is the aryl ring; non-limiting examples thereof include:
“Heteroaryl” or “heteroaromatic ring” refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. Heteroaryl is preferably 6- to 12-membered, more preferably 5- or 6-membered. For example, its non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazine,
and the like.
Examples of nitrogen atom-containing heteroaryl include, but are not limited to, pyrrolyl, piperazinyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazinyl, tetrazolyl, triazolyl, pyridinyl, pyrazolyl, oxazolyl, thiazolyl, or the like.
Heteroaryl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro, cyano, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-4 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl, and the C1-4 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C5-8 cycloalkenyl, C3-6 cycloalkoxy, 3- to 6-membered heterocycloalkoxy, C5-8 cycloalkenyloxy, C6-10 aryl or 5- to 6-membered heteroaryl is optionally substituted with one or more groups selected from the group consisting of halogen, deuterium, hydroxy, oxo, nitro and cyano.
The heteroaryl ring may be fused to an aromatic ring, a heterocyclic ring or a cyclic hydrocarbon, wherein the ring attached to the parent structure is the heteroaryl ring; non-limiting examples thereof include:
“Halogen” refers to fluorine, chlorine, bromine or iodine.
“Substituted with one or more A, B . . . ” means that it may be substituted with a single substituent or multiple substituents. In the case of substitution with multiple substituents, there may be a plurality of identical substituents, or one combination of or a plurality of combinations of different substituents.
The present disclosure is further described below with reference to examples. However, these examples are not intended to limit the scope of the present disclosure.
Experimental procedures without conditions specified in the examples of the present disclosure are generally conducted according to conventional conditions, or according to conditions recommended by the manufacturer of the starting materials or commercial products. Reagents without specific origins indicated are commercially available conventional reagents.
The structures of the compounds were determined by nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry (MS). NMR shifts (δ) were given in 10−6 (ppm). NMR analysis was performed on a Bruker AVANCE-400 nuclear magnetic resonance instrument, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD) as solvents and tetramethylsilane (TMS) as an internal standard. The spatial configurations of the optical isomers (isomers) of the compounds can be further confirmed by determining single crystal parameters.
HPLC analysis was performed on Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high performance liquid chromatograph (ACQUITY UPLC BEH C18 1.7 μm 2.1×50 mm column, Ultimate XB-C18 3.0×150 mm column, or Xtimate C18 2.1×30 mm column). MS analysis was performed on a Waters SQD2 mass spectrometer in the positive/negative ion scan mode with a mass scan range of 100-1200.
Chiral HPLC analysis was performed using a Chiralpak IC-3 100×4.6 mm I.D., 3 μm; Chiralpak AD-3 150×4.6 mm I.D., 3 μm; Chiralpak AD-3 50×4.6 mm I.D., 3 μm; Chiralpak AS-3 150×4.6 mm I.D., 3 μm; Chiralpak AS-3 100×4.6 mm I.D., 3 μm; ChiralCel OD-3 150×4.6 mm I.D., 3 μm; Chiralcel OD-3 100×4.6 mm I.D., 3 μm; ChiralCel OJ-H 150×4.6 mm I.D., 5 μm; or Chiralcel OJ-3 150×4.6 mm I.D., 3 μm column.
Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, 0.15-0.2 mm layer thickness, were adopted for thin-layer chromatography (TLC) analysis and 0.4-0.5 mm layer thickness for TLC separation and purification.
Flash column purification was performed on a Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) system.
Forward column chromatography generally used 100-200 mesh, 200-300 mesh or 300-400 mesh Yantai Huanghai silica gel as a carrier, or used a Changzhou Santai pre-fill ultrapure forward phase silica gel column (40-63 μm, 60 g, 12 g, 25 g, 40 g, 80 g or other specifications).
Reverse phase column chromatography generally used a Changzhou Santai pre-fill ultrapure C18 silica gel column (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g or other specifications).
High pressure column purification was performed on a Waters AutoP system in combination with a Waters XBridge BEH C18 OBD Prep Column, 130 Å, 5 μm, 19 mm×150 mm or Atlantis T3 OBD Prep Column, 100 Å, 5 μm, 19 mm×150 mm.
Preparative chiral chromatography used a DAICEL CHIRALPAK IC (250 mm×30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm×30 mm, 5 μm) column.
Known starting materials in the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from Shanghai Titan Scientific, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals, and other companies.
In the examples, the reactions can all be performed in an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of argon or nitrogen.
The hydrogen atmosphere means that the reaction flask is connected to a balloon containing about 1 L of hydrogen.
Pressurized hydrogenation reactions were performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogenator or an HC2-SS hydrogenator.
Hydrogenation reactions generally involved 3 cycles of vacuumization and hydrogen purging.
Microwave reactions were performed on a CEM Discover-S 908860 microwave reactor.
In the examples, a solution refers to an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is room temperature, i.e., 20°c to 30°c, unless otherwise specified.
Compound 1a (100 mg, 0.492 mmol), compound 1b (56.23 mg, 0.492 mmol) and diisopropylethylamine (0.24 mL, 1.48 mmol) were mixed in NMP, and the mixture was microwaved at 180° C. until the reaction was complete. The reaction was cooled to room temperature and quenched by addition of 1 M sodium hydroxide. The mixture was extracted with dichloromethane. The organic phases were separated, combined, washed with brine, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 0-10% methanol in dichloromethane) to give compound 1c (30 mg, yield: 19.5%).
LCMS: tR=0.575 min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 281.1 [M+H]+.
Compound 1c (15 mg, 0.053 mmol), compound 1d (17.60 mg, 0.085 mmol) and a 1 M sodium bicarbonate solution (0.13 mL) were mixed in dioxane (1 mL), and tetrakis(triphenylphosphine)palladium(0) (12.35 mg, 0.011 mmol) was added in a nitrogen atmosphere. The mixture was microwaved at 160° C. in a nitrogen atmosphere until the reaction was complete. The mixture was cooled to room temperature and then concentrated in vacuo to give a crude product. The crude product was purified by reversed-phase preparative HPLC [column: Boston Prime C18 150×30 mm×5 μm, 20-60% (A: water 0.05% ammonia water v/v. B: acetonitrile), flow rate: 30 mL/min] and lyophilized to give compound 1 (5.1 mg, yield: 23.7%).
LCMS: tR=3.140 min in 0-95CD_7MIN.M (Waters Xbridge C18 30×2.0 mm, 3.5 μm) ES-MS m/z 407.2 [M+H]+.
1H NMR: (400 MHz, DMSO-d6) δ=7.41-7.15 (m, 3H), 3.89 (br d, J=15.3 Hz, 1H), 3.97-3.80 (m, 1H), 3.51-3.37 (m, 7H), 2.56-2.51 (m, 3H), 2.47-2.25 (m, 3H), 2.15-1.51 (m, 3H), 1.30-1.11 (m, 2H)
Compound 2 was prepared by using the method described in Example 1 and using 2a as the starting material.
LCMS: tR=3.75 min in 0-95CD_7MIN.M (Waters Xbridge C18 30×2.0 mm, 3.5 μm) ES-MS m/z 393.2 [M+H]+.
1H NMR: (400 MHz, DMSO-d6) δ ppm 13.52 (br s, 1H), 7.75 (br d, J=8.4 Hz, 1H), 7.22 (br s, 2H), 6.35 (br d, J=7.6 Hz, 1H), 4.29-4.19 (m, 1H), 3.11 (br t, J=7.2 Hz, 2H), 2.94 (br d, J=8.8 Hz, 1H), 2.78 (br t, J=7.2 Hz, 2H), 2.69-2.60 (m, 1H), 2.18 (s, 3H), 2.12-2.01 (m, 2H), 1.96-1.81 (m, 3H), 1.75-1.66 (m, 1H), 1.62-1.49 (m, 1H), 1.44-1.30 (m, 1H).
Compound 3 was prepared by using the method described in Example 1 and using 3a as the starting material.
LCMS: tR=1.027 min in 10-80AB 4 min 220&254_Shimadzu.1cm (Chromolith Flash RP-C18 25-3 mm), MS (ESI) m/z=403.2 [M+H]+.
1H NMR: (400 MHz, CDCl3) δ ppm 8.88 (br s, 1H), 8.15 (d, J=8.4 Hz, 1H), 7.96 (t, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.24 (d, J=8.4 Hz, 1H), 5.12 (br, 1H), 3.87-3.67 (m, 1H), 3.66-3.53 (m, 1H), 3.14-3.03 (m, 1H), 2.94-2.80 (m, 4H), 2.77 (br, 1H), 2.57-2.43 (m, 1H), 2.36 (br, 1H), 1.89 (br, 1H), 1.81-1.70 (m, 1H).
(R)-5-(4-Methyl-6-((1-methyl piperidin-3-yl)amino)pyridazin-3-yl)-2,3-dihydro-1H-inden-4-ol
Compound 4a (250 mg, 1.173 mmol), compound 4b (1.520 mL, 5.867 mmol) and potassium acetate (345.45 mg, 3.520 mmol) were mixed in dioxane (6 mL), and Pd(dppf)Cl2·CH2Cl2 (96.76 mg, 0.117 mmol) was added in a nitrogen atmosphere. The mixture was stirred at 90° C. in a nitrogen atmosphere until the reaction was complete. The mixture was cooled to room temperature and then diluted by addition of water (15 mL). The mixture was extracted with ethyl acetate (20 mL×2). The organic phases were separated, combined, washed with brine (30 mL×3), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 0-20% ethyl acetate in n-hexane) to give compound 4c (170 mg, yield: 55.7%).
1H NMR (400 MHz, CDCl3) δ ppm 7.92 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 6.82 (d, J=7.2 Hz, 1H), 2.93-2.88 (m, 4H), 2.11-2.06 (m, 2H), 1.36 (s, 12H).
Compound 4d (200 mg, 1.227 mmol), compound 4e (168.12 mg, 1.472 mmol) and diisopropylethylamine were mixed in NMP (2 mL), and the mixture was microwaved at 120° C. until the reaction was complete. The mixture was cooled to room temperature and then diluted by addition of water (10 mL). The mixture was extracted with dichloromethane (10 mL×3). The organic phases were separated, combined, washed with brine (5 mL×3), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 0-10% methanol in dichloromethane) to give compound 4f (80 mg, yield: 27.1%).
Compound 4 was prepared by using the method described in step 2 of Example 1 and using compound 4c and compound 4f as the starting materials.
LCMS: tR=2.8 min in 10-80CD 7 min 220&254 Shimadzu.1cm ES-MS m/z 339.2 (M+H)+.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 6.61 (d, J=8.0 Hz, 1H), 4.04 (s, 1H), 2.90-2.84 (m, 4H), 2.18 (s, 3H), 2.08 (s, 3H), 2.04-2.02 (m, 3H), 1.89-1.77 (m, 2H), 1.45-1.64 (m, 2H), 1.23-1.33 (m, 2H).
Compound 5 was prepared by using the method described in Example 4 and using compound 5a as the starting material.
1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.72 (d, J=8 Hz, 2H), 7.42 (t, J=7.4 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.24 (s, 1H), 6.71 (s, 1H), 6.65 (d, J=8.0 Hz, 1H), 4.06 (s, 1H), 2.94 (br, 1H), 2.60-2.55 (m, 1H), 2.47-2.41 (m, 1H), 2.33 (s, 1H), 2.09 (s, 1H), 1.87-1.84 (m, 1H), 1.72-1.75 (m, 1H), 1.60-1.56 (m, 1H), 1.37-1.42 (m, 1H).
Compound 6 was prepared by using the method described in Example 4 and using compound 6a as the starting material.
LCMS: tR=2.9 min in 10-80CD 7 min 220&254 Shimadzu.1cm ES-MS m/z 339.2 (M+H)+.
1H NMR (400 MHz, DMSO-d6) δ ppm 9.47 (s, 1H), 6.97 (s, 1H), 6.76 (s, 1H), 6.65 (s, 1H), 6.50 (d, J=8.0 Hz, 1H), 4.08-3.95 (m, 1H), 2.80 (br, 5H), 2.17 (s, 3H), 2.07-1.97 (m, 6H), 1.85 (br, 3H), 1.70 (br, 1H), 1.53 (br, 1H), 1.27 (br, 1H)
Compound 7a (100 mg, 0.415 mmol) and zinc powder (271 mg, 4.15 mmol) were mixed in acetic acid (2 mL), and the mixture was stirred at 100° C. until the reaction was complete. The mixture was cooled to room temperature and then diluted by addition of water (20 mL). The mixture was extracted with ethyl acetate (20 mL×3). The organic phases were separated, combined, washed with brine (20 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 10-20% ethyl acetate in petroleum ether) to give compound 7b (40 mg, yield: 34.0%).
1H NMR: (400 MHz, CDCl3) δ ppm 7.09 (d, J=8.0 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 2.96 (q, J=7.2 Hz, 4H), 2.15-2.06 (m, 2H). Step 2: Synthesis of (compound 7d)
Compound 7d was prepared by using the method described in Example 4 and using compound 7b as the starting material.
LCMS: tR=2.973 min in 0-30AB 7 min 220&254 Shimadzu.1cm ES-MS m/z=353.2 [M+H]+.
1H NMR: 1H NMR (400 MHz, CDCl3) δ ppm 7.23-7.18 (m, 1H), 6.87-6.74 (m, 2H), 3.75 (s, 1H), 3.71-3.71 (m, 1H), 3.71 (s, 2H), 2.93-2.86 (m, 4H), 2.60-2.46 (m, 4H), 2.42-2.32 (m, 3H), 2.07-2.01 (m, 3H), 1.99 (s, 3H), 1.90-1.72 (m, 2H), 1.26 (br t, J=7.2 Hz, 1H).
A solution of compound 7d (30 mg, 0.085 mmol) in dichloromethane (2 mL) was cooled to −78° C., and boron tribromide (213 mg, 0.85 mmol) was added dropwise. The mixture was warmed to room temperature and stirred until the reaction was complete. The reaction was quenched by addition of methanol (2 mL), and the solvent was removed in vacuo to give a crude product. The crude product was purified by reversed-phase preparative HPLC (Column Boston Prime C18 150×30 mm×5 μm; Condition water (0.05% ammonia hydroxide v/v)-ACN; Begin B 40; End B 70; Flow Rate (mL/min)) to give compound 7 (5.8 mg, yield: 20.1%).
LCMS: tR=4.403 min in 0-60CD_7 min_220&254_Shimadzu.1cm, MS (ESI) m/z=339.3 [M+H]+.
1H NMR: (400 MHz, CD3OD) δ ppm 7.08 (d, J=8.0 Hz, 1H), 6.76 (s, 1H), 6.68 (d, J=8.0 Hz, 1H), 4.12 (dt, J=4.6, 9.2 Hz, 1H), 3.17-3.02 (m, 1H), 2.92-2.83 (m, 2H), 2.79 (br dd, J=8.0, 16.4 Hz, 2H), 2.33 (d, J=2.1 Hz, 4H), 2.20 (br d, J=6.4 Hz, 2H), 2.04 (d, J=0.8 Hz, 6H), 1.90-1.78 (m, 1H), 1.78-1.64 (m, 1H), 1.45-1.41 (m, 1H).
Compound 8a (3.0 g, 11.86 mmol) was dissolved in dichloromethane (30 mL), and DAST (3.82 g, 23.7 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction was quenched by addition of water (50 mL) and diluted by addition of dichloromethane (50 mL). The organic phase was separated, washed with saturated sodium bicarbonate solution (30 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give compound 8b (3.10 g, yield: 95.1%).
1H NMR (400 MHz, CDCl3) Shift=7.92 (s, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 6.92 (t, J=54.4 Hz, 1H)
Compound 8 was prepared by using the method described in Example 4 and using compound 8b as the starting material.
LCMS: tR=2.25 min in 5-95AB_7 min 220&254_Agilent.M ES-MS m/z 362.2 [M+H]+.
1H NMR (400 MHz, CDCl3) Shift=8.61 (s, 1H), 8.05 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.68 (t, J=55.4 Hz, 1H), 6.72 (s, 1H), 4.46 (br s, 2H), 3.03-2.73 (m, 2H), 2.48 (s, 4H), 2.24-1.87 (m, 5H), 1.82-1.66 (m, 2H)
Compound 9 was prepared by using the method described in Example 4 and using compound 9a as the starting material.
LCMS: tR=2.76 min in 10-80CD 7 min 220&254 Shimadzu.1cm ES-MS m/z 349.2 [M+H]+.
Compound 10b was prepared by using the method described in step 2 of Example 4 and using compound 10a as the starting material.
1H NMR: (400 MHz, CDCl3) δ ppm 7.35 (d, J=9.2 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 4.00-3.94 (m, 1H), 2.79-2.75 (m, 1H), 2.49-2.47 (m, 1H), 2.16 (s, 3H), 2.06-2.03 (m, 1H), 1.93-1.90 (m, 1H), 1.77-1.75 (m, 1H), 1.69-1.67 (m, 1H), 1.54-1.49 (m, 1H), 1.28-1.21 (m, 1H).
Compound 10 was prepared by using the method described in Example 7 and using compound 10c as the starting material.
LCMS: ES-LCMS m/z 335.2 [M+H]+.
1H NMR: (400 MHz, CDCl3) δ ppm 7.90 (d, J=8.4 Hz, 1H), 7.85-7.74 (m, 3H), 7.43 (t, J=7.2 Hz, 1H), 7.37-7.33 (m, 1H), 7.30 (d, J=9.2 Hz, 1H), 6.89 (br d, J=9.2 Hz, 1H), 4.34 (br s, 1H), 2.83-2.51 (m, 3H), 2.36 (br s, 3H), 1.89 (br s, 5H), 1.26 (br s, 1H).
Compound 11a (2 g, 10.0 mmol) was mixed with 50% sulfuric acid (40 mL), the mixture was cooled to −5° C., a solution of sodium nitrite (759 mg, 11 mmol) (20 mL) was added dropwise, the temperature was maintained, and then cuprous thiocyanate (20 mmol) and potassium thiocyanate (20 mmol) were added. The final mixture was stirred at 0° C. until the reaction was complete. The mixture was filtered, and the filter cake was collected and dissolved in ethyl acetate (50 mL). The solution was washed with brine (30 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 2-10% ethyl acetate in petroleum ether) to give compound 11b (0.5 g, yield: 20.7%).
1H NMR: (400 MHz, CDCl3) δ ppm 7.59 (d, J=8.0 Hz, 1H), 7.04-6.98 (m, 2H), 3.95 (s, 3H).
Potassium trifluoroacetate (374 mg, 2.46 mmol), ferrous chloride (78 mg, 0.61 mmol) and compound 11b (500 mg, 2.05 mmol) were mixed in DMF (5 mL), and the mixture was stirred at 140° C. in a nitrogen atmosphere until the reaction was complete. The mixture was diluted by addition of water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic phases were separated, combined, washed with brine (20 mL×3), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 0-3% ethyl acetate in petroleum ether) to give compound 11c (40 mg, yield: 34.0%).
1H NMR: (400 MHz, DMSO-d6) δ ppm 7.76 (d, J=8.4 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.24 (dd, J=1.6, 8.0 Hz, 1H), 3.91 (s, 3H).
Compound 11 was prepared by using the method described in Example 7 and using compound 11c as the starting material.
LCMS: tR=1.161 min in 10-80AB_7 min_220&254_Shimadzu.1cm; MS (ESI) m/z=399.2 [M+H]+.
1H NMR: (400 MHz, CDCl3) δ ppm 8.58 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.42-7.37 (m, J=1.5 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.85 (s, 1H), 4.56 (br s, 1H), 3.09 (br s, 2H), 2.79 (br s, 2H), 2.55 (br s, 3H), 2.46 (s, 4H), 1.82-1.63 (m, J=14.9 Hz, 2H), 1.26 (s, 1H).
Compound 12 was prepared by using the method described in Example 7 and using compound 12a as the starting material.
LCMS: ES-LCMS m/z 343.1 [M+H]+.
1H NMR: (400 MHz, DMSO-d6) δ ppm 13.97 (br s, 1H), 8.08 (s, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.44-7.36 (m, 2H), 6.21 (br d, J=7.6 Hz, 1H), 4.24 (br d, J=8.4 Hz, 1H), 2.92 (br d, J=7.6 Hz, 2H), 2.61 (br s, 2H), 2.23 (s, 3H), 2.19 (s, 3H), 1.97-1.90 (m, 2H), 1.86 (br s, 1H), 1.73-1.67 (m, 1H), 1.62-1.53 (m, 1H), 1.48-1.39 (m, 1H).
Compound 13 was prepared by using the method described in Example 7 and using compound 13a as the starting material.
1H NMR: (400 MHz, CDCl3) δ=8.48 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.35 (d, J=5.2 Hz, 1H), 6.67 (s, 1H), 5.57 (br s, 1H), 4.20 (br s, 1H), 2.55 (br s, 2H), 2.49 (s, 3H), 2.30 (s, 3H), 2.24-2.18 (m, 1H), 1.91-1.52 (m, 6H).
Compound 14b was prepared by using the method described in step 2 of Example 4 and using compound 14a as the starting material.
LCMS: tR=0.4 min in 5-95AB_1min_220&254_Agilent.M ES-MS m/z 228.1 [M+H]+.
1H NMR: (400 MHz, CDCl3) δ ppm 7.03 (s, 1H), 4.42 (br s, 1H), 4.28 (br s, 1H), 3.87 (br s, 1H), 2.73 (br s, 2H), 2.44 (s, 3H), 2.20-2.16 (m, 2H), 1.46 (s, 3H).
Compound 14 was prepared by using the method described in step 2 of Example 1 and using compound 14b as the starting material.
LCMS: tR=2.761 min in 0-95CD_7MIN.M (Waters Xbridge C18 30×2.0 mm, 3.5 μm) ES-MS m/z 326.2 [M+H]+.
1H NMR: (400 MHz, DMSO-d6) δ ppm 9.70 (br s, 1H), 7.01 (d, J=7.6 Hz, 1H), 6.95 (d, J=6.8 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.64 (s, 1H), 4.99 (s, 1H), 3.97-3.85 (m, 1H), 2.89-2.82 (m, 4H), 2.45-2.37 (m, 2H), 2.09 (s, 3H), 2.07-1.99 (m, 2H), 1.98-1.90 (m, 2H), 1.28 (s, 3H).
Compound 15 was prepared by using the method described in Example 14 and using 3a as the starting material.
LCMS: tR=2.415 min in 0-95CD_7MIN.M (Waters Xbridge C18 30×2.0 mm, 3.5 μm) ES-MS m/z 390.1 [M+H]+.
1H NMR: (400 MHz, DMSO-d6) δ ppm 10.34 (br s, 1H), 8.42 (d, J=8.4 Hz, 1H), 7.89-7.82 (m, 1H), 7.77 (t, J=7.2 Hz, 1H), 7.62 (br d, J=5.6 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.32-7.24 (m, 2H), 5.00 (s, 1H), 4.31-4.14 (m, 1H), 2.46 (br d, J=2.8 Hz, 2H), 2.22-2.13 (m, 2H), 1.33 (s, 3H).
Compound 16a (1 g, 11.6 mmol) and potassium carbonate (0.16 g, 1.16 mmol) were mixed in tetrahydropyrrole (0.95 mL, 11.6 mmol), and the mixture was stirred at 0° C. until the reaction was complete. The mixture was filtered, and the filtrate was concentrated in vacuo to give compound 16b (1.5 g, yield: 92.8%).
LCMS: ES-LCMS m/z 140.1 [M+H]+.
Compound 16b (300 mg, 2.16 mmol) and 3,6-dichlorotetrazine (325 g, 2.16 mmol) were mixed in dichloromethane (5 mL), and the mixture was stirred at 0° C. until the reaction was complete. The mixture was diluted by addition of water (5 mL) and extracted with dichloromethane (5 mL×3). The organic phases were separated, combined, washed with brine (5 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 0-20% ethyl acetate in petroleum ether) to give compound 16c (70 mg, yield: 15.3%).
LCMS: tR=0.568 min in 5-95AB_1min 220&254_Agilent.M ES-MS m/z 191.0 (M+H)+
1H NMR: (400 MHz, CDCl3) δ ppm 5.24 (s, 4H)
Compound 16 was prepared by using the method described in Example 1 and using 16c as the starting material.
1H NMR (400 MHz, DMSO-d6) δ=8.14 (s, 1H), 7.47 (br d, J=8.0 Hz, 1H), 7.26-7.22 (m, 2H), 6.88 (br d, J=7.0 Hz, 1H), 5.26 (br s, 2H), 4.97 (br s, 2H), 4.30 (br s, 1H), 2.33 (br s, 3H), 2.15-1.88 (m, 4H), 1.77 (br s, 1H), 1.61 (br d, J=12.0 Hz, 1H), 1.38 (br d, J=12.3 Hz, 1H), 1.23 (br s, 2H).
Compound 17 was prepared by using the method described in Example 7 and using 7c as the starting material.
LCMS: ES-LCMS m/z 339.2 [M+H]+.
Compound 18a (500 mg, 1.6 mmol), cyclopropylboronic acid (505 mg, 5.87 mmol) and potassium carbonate (883 mg, 6.39 mmol) were mixed in dioxane (10 mL) and water (5 mL), and Pd(dppf)Cl2·CH2Cl2 (65.9 mg, 0.080 mmol) was added in a nitrogen atmosphere. The mixture was stirred at 120° C. in a nitrogen atmosphere until the reaction was complete. The mixture was cooled to room temperature and then diluted by addition of ethyl acetate (20 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give crude compound 18b. The crude product was directly used in the next step.
Compound 18 was prepared by using the method described in Example 7 and using 18b as the starting material.
LCMS: ES-LCMS m/z 339.3 [M+H]+.
1H NMR (400 MHz, CDCl3) δ=7.20 (d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.69 (s, 1H), 6.63 (br s, 1H), 4.32 (br s, 1H), 2.95-2.45 (m, 4H), 2.41 (s, 3H), 2.36-2.19 (m, 1H), 2.05 (s, 3H), 1.98-1.92 (m, 1H), 1.88-1.54 (m, 4H), 1.05-0.95 (m, 2H), 0.81-0.71 (m, 2H).
Compound 19c was prepared by using the method described in Example 1 and using 19a as the starting material.
LCMS: ES-LCMS m/z 493.3 [M+H]+.
Compound 19c (180 mg, 0.365 mmol) was dissolved in a solution of hydrochloric acid in dioxane (2 mL), and the mixture was stirred at room temperature until the reaction was complete. The mixture was concentrated in vacuo to give the hydrochloride of compound 19d (220 mg, yield: 92.0%).
LCMS: ES-LCMS m/z 393.3 [M+H]+.
Compound 19d (20 mg, 0.05 mmol) and diisopropylethylamine (0.017 mL, 0.10 mmol) were dissolved in acetonitrile (2 mL), and bromoethanol (6.37 mg, 0.05 mmol) was added. The mixture was stirred at 70° C. until the reaction was complete. The mixture was concentrated in vacuo to give a crude product. The crude product was purified by reversed-phase preparative HPLC to give compound 19 (2.9 mg, yield: 12.9%).
LCMS: ES-LCMS m/z 437.2 [M+H]+.
1H NMR (400 MHz, CD3OD) δ=7.37 (d, J=7.8 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.18 (s, 1H), 4.71-4.60 (m, 2H), 3.80-3.55 (m, 4H), 3.06 (br d, J=7.3 Hz, 2H), 2.55-2.44 (m, 4H), 2.21-2.07 (m, 2H), 2.03-1.84 (m, 4H), 1.83-1.70 (m, 3H).
Compound 20 was prepared by using the method described in Example 2 and using 2b as the starting material.
LCMS: tR=0.719 min in 5-95AB_1min 220&254_Agilent.M ES-MS m/z 343.1 [M+H]+.
1H NMR (400 MHz, CD3OD) Shift=7.26 (dt, J=6.8, 8.3 Hz, 1H), 6.78-6.66 (m, 2H), 4.48-4.38 (m, 1H), 3.09 (br s, 1H), 2.88 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.7 Hz, 2H), 2.70 (br s, 1H), 2.36 (s, 3H), 2.31 (br d, J=13.1 Hz, 2H), 2.15 (quin, J=7.7 Hz, 2H), 2.00 (br s, 1H), 1.92-1.81 (m, 1H), 1.79-1.68 (m, 1H), 1.57 (br s, 1H)
Compound 21 was prepared by using the method described in Example 14 and using 21a as the starting material.
LCMS: tR=0.774 min in 5-95AB_1min 220&254_Agilent.M ES-MS m/z 340.2 [M+H]+.
1H NMR (400 MHz, CDCl3) Shift=7.05 (d, J=7.8 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.62 (br s, 1H), 4.41-4.24 (m, 1H), 2.97 (td, J=7.4, 19.0 Hz, 4H), 2.75 (ddd, J=2.8, 7.4, 9.9 Hz, 2H), 2.35 (s, 3H), 2.18-2.06 (m, 8H), 1.47 (s, 3H)
Compounds 22 and 23 were prepared by using the method described in Example 15 and using 22a as the starting material.
1H NMR: (400 MHz,CD3OD) δ ppm 9.08 (m, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.80 (dd, J=8.0, 4.4 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 4.39-4.31 (m, 1H), 2.72-2.67 (m, 2H), 2.27-2.21 (m, 2H), 1.45 (s, 3H).
1H NMR: (400 MHz,CD3OD) δ ppm 9.15 (br s, 1H), 8.80 (dd, J=8.4, 2.4 Hz, 1H), 8.49 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.22 (d, J=6.8 Hz, 1H), 4.34-4.26 (m, 1H), 2.71-2.66 (m, 2H), 2.27-2.22 (m, 2H), 1.46 (s, 3H).
Compounds 24 and 25 were prepared by using the method described in Example 15 and using compound 24a as the starting material.
1H NMR: (400 MHz,CD3OD) δ ppm 9.70 (br s, 1H), 8.84 (d, J=6.0 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.47 (d, J=5.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 4.39-4.31 (m, 1H), 2.72-2.67 (m, 2H), 2.29-2.24 (m, 2H), 1.46 (s, 3H).
1H NMR: (400 MHz,CD3OD) δ ppm 8.91 (m, 2H), 8.21 (d, J=5.6 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.28 (s, 1H), 4.35-4.27 (m, 1H), 2.71-2.66 (m, 2H), 2.28-2.23 (m, 2H), 1.45 (s, 3H).
Compound 26 was prepared by using the method described in Example 16 and using compound 16c as the starting material.
1H NMR (400 MHz, CD3OD) Shift=7.42 (d, J=8.4 Hz, 1H), 7.21-7.20 (m, 2H), 5.39 (t, J=3.2 Hz, 2H), 5.05 (t, J=3.2 Hz, 2H), 4.19 (m, 1H), 2.61 (m, 2H), 2.14 (m, 2H), 1.43 (s, 3H).
Compound 27a (1.0 g, 6.17 mmol) was dissolved in DMF (6 mL), and NBS (0.99 g, 5.55 mmol) was added. The mixture was stirred at room temperature until the reaction was complete. The reaction was diluted by addition of dichloromethane (10 mL) and saturated sodium chloride solution (10 mL). The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by reversed-phase flash column chromatography (eluent: 0-60% acetonitrile in water) to give compound 27b (680 mg, yield: 45.7%).
Compound 27b (300 mg, 1.24 mmol) was dissolved in a mixed solvent of trifluoroacetic acid ( ) and triethylsilane ( ), and the mixture was stirred at 90° C. until the reaction was complete. The mixture was directly concentrated by rotary evaporation to remove the solvent and diluted by addition of dichloromethane (10 mL) and saturated sodium bicarbonate solution (10 mL). The organic phase was separated, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated in vacuo to give a crude product. The crude product was purified by flash column chromatography (eluent: 10% dichloromethane in petroleum ether) to give compound 27c (200 mg, yield: 70.8%).
Compound 27 was prepared by using the method described in Example 4 and using compound 27c as the starting material.
1H NMR (400 MHz, CD3OD) Shift=7.00 (d, J=8.0 Hz, 1H), 6.81 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.18 (m, 1H), 2.96 (m, 1H), 2.77 (t, J=5.6 Hz, 2H), 2.69 (t, J=5.8 Hz, 2H), 2.56 (m, 5H), 2.20 (m, 4H), 2.03 (m, 1H), 1.98 (m, 1H), 1.85-1.79 (m, 5H), 1.61 (m, 2H).
Compound 28 was prepared by using the method described in Example 18 and using compound 18c as the starting material.
LCMS: tR=2.657 min in 5-95AB_7 min 220&254_Agilent.M ES-MS m/z 326.1 [M+H]+.
1H NMR (400 MHz, CD3OD) Shift=7.10 (d, J=7.6 Hz, 1H), 6.74 (s, 1H), 6.69 (d, J=7.6 Hz, 1H), 6.63 (s, 1H), 4.05-3.98 (m, 1H), 2.62-2.57 (m, 2H), 2.16 (s, 3H), 2.08-2.03 (m, 2H), 1.91-1.87 (m, 1H), 1.41 (s, 3H), 1.01-0.98 (m, 2H), 0.72-0.69 (m, 2H).
Compound 29 was prepared by using the method described in Example 18 and using compound 18c as the starting material.
LCMS: tR=0.57 min in 5-95AB_1.5 min 220&254_Agilent.M ES-MS m/z 340.2 [M+H]+.
1H NMR (400 MHz, CD3OD) Shift=7.07 (d, J==7.6 Hz, 1H), 6.68 (d, J==7.6 Hz, 1H), 6.63 (s, 1H), 4.19-4.09 (m, 1H), 2.64-2.59 (m, 2H), 2.18 (s, 3H), 2.15-2.08 (m, 5H), 1.90 (m, 1H), 1.42 (s, 3H), 1.01-0.98 (m, 2H), 0.72-0.70 (m, 2H).
Compound 30 was prepared by using the method described in Example 18 and using compound 18c as the starting material.
LCMS: tR=3.11 min in 5-95AB_7 min 220&254_Agilent.M ES-MS m/z 362.2 [M+H]+.
1H NMR (400 MHz, CD3OD) Shift=8.27 (d, J==8.0 Hz, 1H), 7.86 (t, J==7.6 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.71 (s, 1H), 4.35-4.27 (m, 1H), 2.71-2.66 (m, 2H), 2.26-2.22 (m, 2H), 1.94 (m, 1H), 1.46 (s, 3H), 1.04-1.00 (m, 2H), 0.77-0.74 (m, 2H).
Compound 31 was prepared by using the method described in Example 14 and using compound 15a as the starting material.
LCMS: tR=0.81 min in 5-95AB_1.5 min 220&254_Agilent.M ES-MS m/z 362.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) Shift=9.47 (br, 1H), 8.42 (d, J==7.6 Hz, 1H), 7.86 (t, J==7.2 Hz, 1H), 7.79 (t, J==7.2 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.55 (d, J=6.4 Hz, 1H), 7.10 (d, J==7.6 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 5.00 (s, 1H), 2.94 (t, J==7.4 Hz, 2H), 2.88 (t, J==7.4 Hz, 1H), 2.21-2.18 (m, 2H), 2.10-2.06 (m, 2H), 3.16 (br, 4H).
Compound 32 was prepared by using the method described in Example 19 and using compound 16c as the starting material.
1H NMR (400 MHz, CD3OD) δ=8.50 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.27-7.16 (m, 2H), 5.36 (t, J=3.0 Hz, 2H), 5.05 (br s, 2H), 4.55-4.44 (m, 1H), 3.80 (t, J=5.5 Hz, 2H), 3.50 (br d, J=10.8 Hz, 1H), 3.13 (br s, 1H), 3.01-2.83 (m, 2H), 2.76-2.64 (m, 1H), 2.59 (br s, 1H), 2.09 (br d, J=8.8 Hz, 1H), 2.03-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.74-1.55 (m, 1H).
Compounds 33 and 34 were prepared by using the method described in Example 15 and using compounds 24b and 24c as the starting materials.
1H-NMR: (400 MHz, METHANOL-d4) Shift=9.71 (s, 1H), 8.84 (d, J=5.7 Hz, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.05 (s, 1H), 7.01 (br d, J=8.8 Hz, 1H), 4.36 (quin, J=7.8 Hz, 1H), 2.78-2.61 (m, 2H), 2.34-2.20 (m, 2H), 1.45 (s, 3H).
1H-NMR: (400 MHz, METHANOL-d4) Shift=8.93 (d, J=5.8 Hz, 1H), 8.83 (s, 1H), 8.24 (d, J=6.1 Hz, 1H), 7.12 (br s, 2H), 4.34 (br d, J=8.3 Hz, 1H), 2.75-2.64 (m, 3H), 2.28 (br d, J=8.6 Hz, 3H), 1.45 (s, 3H).
Compound 35 was prepared by using the method described in Example 15 and using compound 16d as the starting material.
1H-NMR: (400 MHz, CD3OD) δ=7.08-6.96 (m, 2H), 5.10-5.04 (m, 2H), 4.65-4.56 (m, 2H), 3.68-3.60 (m, 1H), 3.01-2.86 (m, 1H), 2.56-2.45 (m, 3H), 2.43-2.30 (m, 1H), 2.15-2.01 (m, 1H), 1.97-1.90 (m, 1H), 1.86-1.74 (m, 1H), 1.65-1.53 (m, 1H), 1.40-1.24 (m, 2H).
Compound 36 was prepared by using the method described in compound 19 and using compounds 4d and 19a as the starting materials.
1H NMR: (400 MHz, CD3OD) δ=8.50 (s, 1H), 7.88 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H), 6.62 (s, 1H), 4.52-4.40 (m, 1H), 3.83 (t, J=5.4 Hz, 2H), 3.57 (br d, J=10.0 Hz, 1H), 3.28-3.19 (m, 1H), 3.12-2.95 (m, 2H), 2.83 (br t, J=10.4 Hz, 1H), 2.75 (br t, J=10.8 Hz, 1H), 2.28 (s, 3H), 2.09 (br d, J=12.0 Hz, 1H), 2.05-1.97 (m, 1H), 1.95-1.83 (m, 2H), 1.79-1.67 (m, 1H), 1.03-0.94 (m, 2H), 0.74-0.67 (m, 2H).
Compound 37 was prepared by using the method described in Example 4 and using compound 14b as the starting material.
1H NMR: (400 MHz, CD3OD) δ=6.79 (d, J=0.2 Hz, 1H), 6.77 (s, 1H), 4.01 (penta, J=7.8 Hz, 1H), 2.99 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.61-2.58 (m, 2H), 2.21-2.18 (m, 5H), 2.06-2.03 (m, 2H), 1.42 (s, 3H).
Compound 38 was prepared by using the method described in Example 15 and using 22c as the starting material.
1H NMR: (400 MHz, DMSO-d6) δ=9.39 (br, 1H), 9.10 (dd, J=8.4, 1.2 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 5.00 (s, 1H), 4.36-4.26 (m, 1H), 2.93 (t, J=7.2 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H), 2.32-2.22 (m, 2H), 2.18-2.08 (m, 2H), 1.33 (s, 3H).
Compounds 39 and 40 were prepared by using the method described in Example 15 and using 24b and 24c as the starting materials.
1H NMR: (400 MHz,CD3OD) δ ppm 9.05 (br s, 1H), 8.90 (d, J=5.6 Hz, 1H), 8.21 (d, J=5.6 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 4.01 (penta, J=7.8 Hz, 1H), 3.01 (t, J=7.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.70-2.61 (m, 2H), 2.26-2.17 (m, 4H), 1.42 (s, 3H).
1H NMR: (400 MHz,CD3OD) δ ppm 9.69 (s, 1H), 8.85 (d, J=5.6 Hz, 1H), 7.64 (d, J=5.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 4.35 (penta, J=7.8 Hz, 1H), 3.01 (t, J=7.6 Hz, 2H), 2.96 (t, J=7.6 Hz, 2H), 2.71-2.61 (m, 2H), 2.28-2.16 (m, 4H), 1.47 (s, 3H).
Compound 41 was prepared by using the method described in compound 18 and using compound 18c as the starting material.
1H NMR (400 MHz, CD3OD) δ ppm 9.70 (s, 1H), 8.86 (d, J=5.7 Hz, 1H), 7.57 (d, J=5.6 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 6.79 (br d, J=7.8 Hz, 1H), 6.73 (s, 1H), 5.43-5.43 (m, 1H), 4.34 (quin, J=7.8 Hz, 1H), 2.76-2.65 (m, 2H), 2.35-2.23 (m, 2H), 2.02-1.90 (m, 1H), 1.08-0.99 (m, 2H), 0.81-0.70 (m, 2H).
Compounds 42 and 43 were prepared by using the method described in Example 15 and using 42a as the starting material.
1H NMR: (400 MHz,CD3OD) δ ppm 7.40 (d, J=7.6 Hz, 1H), 7.24 (d, J=7.6 Hz, 1H), 4.48 (s, 2H), 4.21 (penta, J=7.6 Hz, 1H), 4.02 (t, J=7.6 Hz, 2H), 2.68-2.56 (m, 4H), 2.16-2.02 (m, 2H), 1.43 (s, 3H).
1H NMR: (400 MHz,CD3OD) δ ppm 7.42 (d, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 4.61 (s, 2H), 4.19 (penta, J=7.6 Hz, 1H), 3.89 (t, J=7.6 Hz, 2H), 2.70-2.58 (m, 4H), 2.14-2.00 (m, 2H), 1.41 (s, 3H).
Compound 44 was prepared by using the method described in Example 15 and using compound 15a as the starting material.
1H-NMR: (400 MHz, DMSO-d6) δ=10.78 (br, 1H), 8.48 (d, J=8.0 Hz, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.81 (t, J=7.7 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.17 (s, 1H), 5.05 (s, 1H), 4.28-4.22 (m, 1H), 2.28-2.20 (m, 2H), 1.34 (s, 3H).
Compound 45 was prepared by using the method described in Example 15 and using compound 24b as the starting material.
1H-NMR: (400 MHz, DMSO-d6) δ=9.81 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.08 (d, J=6.4 Hz, 1H), 7.20 (s, 1H), 7.13-7.03 (m, 2H), 5.05 (br s, 1H), 4.49-4.15 (m, 1H), 2.52-2.52 (m, 2H), 2.26 (br t, J=0.2 Hz, 1H), 2.16 (br t, J=10.0 Hz, 1H), 1.99 (s, 3H), 1.35 (s, 3H).
Compound 46 was prepared by using the method described in Example 15 and using compound 15a as the starting material.
1H-NMR: (400 MHz, CD3OD) δ=8.39 (d, J=8.4 Hz, 1H), 7.97-7.87 (m, 1H), 7.86-7.78 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 4.39-4.22 (m, 1H), 2.76-2.63 (m, 2H), 2.36-2.20 (m, 2H), 2.06 (s, 3H), 1.45 (s, 3H).
Compound 47 was prepared by using the method described in Example 15 and using compound 16d as the starting material.
1H-NMR: (400 MHz, DMSO-d6) δ=8.16 (s, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 6.50 (br d, J=6.9 Hz, 1H), 4.95 (br s, 2H), 4.81 (br s, 1H), 4.69 (br s, 1H), 4.29 (br s, 1H), 3.13-3.01 (m, 1H), 2.78-2.63 (m, 1H), 2.26 (s, 3H), 2.08 (s, 3H), 1.94 (br d, J=12.8 Hz, 2H), 1.75 (br d, J=13.9 Hz, 1H), 1.59 (br d, J=12.1 Hz, 1H), 1.34 (br d, J=11.4 Hz, 1H).
Compound 48 was prepared by using the method described in Example 15 and using compound 2b as the starting material.
LCMS: ES-LCMS m/z 411.3 [M+H]+.
Compound 49 was prepared by using the method described in Example 19 and using compound 32a as the starting material.
LCMS: ES-LCMS m/z 443.3 [M+H]+.
Compounds 50 and 51 were prepared by using the method described in compound 16 and using compound 42c as the starting material.
Compound 50: LCMS: ES-LCMS m/z 409.3 [M+H]+.
Compound 51: LCMS: ES-LCMS m/z 409.3 [M+H]+.
Compounds 52 and 53 were prepared by using the method described in compound 32 and using compound 16c as the starting material.
Compound 52: LCMS: ES-LCMS m/z 439.3 [M+H]+.
Compound 53: LCMS: ES-LCMS m/z 439.3 [M+H]+.
The present disclosure is further described and explained below with reference to test examples. However, these test examples are not intended to limit the scope of the present disclosure.
Compounds R1, R2 and R3 were synthesized as reported in WO2020234715.
Day 1: PBMCs were separated from human blood by density gradient centrifugation and washed twice with PBS containing 2% FBS (centrifuged at 300 g for 8 min). Monocytes were then isolated from the PBMCs using a human pan-monocyte isolation kit and an LS column. The cells were stained with CD14-FITC at 4° C. for 30 min, and FACS was run on BD FACS Verse to analyze the purity of the pan-monocytes. The cells were counted, and the cell density was adjusted to 2.5×105 cells/mL. The cells were seeded into a 96-well plate at 2.5×104 monocytes/100 mL suspension/well. The plate was incubated overnight at 37° C. in 5% CO2.
Day 2: Test compounds were pre-titrated so that all titration points, including the DMSO control well, contained 0.1% DMSO. The medium was removed, and the monocytes were pre-treated (by adding 150 mL of compound (diluted in serum-free 1640 medium) or DMSO to their respective wells and incubating the cells at 37° C. in 5% CO2 for 0.5 h). The cells were then treated (by adding 25 mL of a 1640 (serum-free) solution containing 700 ng/mL LPS (the final concentration was 100 ng/mL) and incubating the cells at 37° C. in 5% CO2 for 3.5 h). At the end of the 3.5 hours' incubation, the cells were stimulated (by adding 25 mL of 40 mM ATP (the final concentration would be 5 mM) to treat the cells for 45 min). 80 mL of supernatant was transferred to a new plate and stored at 80° C.
Day 3: The supernatant solution was 20-fold diluted for human monocyte IL-1b ELISA according to the manufacturer's instructions.
Days 3-4: ELISA experiment
3) A test dilution was added to the plate at ≥200 μL/well. The plate was incubated at room temperature for 1 h.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011562172.X | Dec 2020 | CN | national |
| 202110090687.2 | Jan 2021 | CN | national |
| 202110172665.0 | Feb 2021 | CN | national |
| 202110592769.7 | May 2021 | CN | national |
| 202110791592.3 | Jul 2021 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/141211 | 12/24/2021 | WO |
