CN117362323A - PRMT5 inhibitor and application thereof - Google Patents

PRMT5 inhibitor and application thereof Download PDF

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Publication number
CN117362323A
CN117362323A CN202210775564.7A CN202210775564A CN117362323A CN 117362323 A CN117362323 A CN 117362323A CN 202210775564 A CN202210775564 A CN 202210775564A CN 117362323 A CN117362323 A CN 117362323A
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王龙
吴海平
米沅
刘依林
富兴年
王猛
石慧
郭剑南
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Shanghai Sailan Biotechnology Co ltd
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Shanghai Sailan Biotechnology Co ltd
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Priority to CN202210775564.7A priority Critical patent/CN117362323A/en
Priority to PCT/CN2023/105593 priority patent/WO2024002376A1/en
Priority to PCT/CN2023/105594 priority patent/WO2024002377A1/en
Priority to CN202311838498.4A priority patent/CN117800991A/en
Publication of CN117362323A publication Critical patent/CN117362323A/en
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Abstract

The invention provides a compound with methyltransferase inhibiting activity, in particular to a compound with PRMT5 inhibiting activity. The compounds can be used for preparing pharmaceutical compositions for treating diseases related to PRMT5 activity.

Description

PRMT5 inhibitor and application thereof
Technical Field
The invention relates to the field of pharmaceutical compounds, in particular to a compound for inhibiting PRMT5 and application thereof in pharmaceutical compositions.
Background
Epigenetic regulation of gene expression is an important biological determinant of protein production and cell differentiation, playing an important pathogenic role in many human diseases.
Epigenetic regulation involves the genetic modification of genetic material without altering its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones) that control conformational transitions between chromatin transcriptional activity and an inactive state. These covalent modifications may be controlled by enzymes such as methyltransferases (e.g., PRMT 5), many of which are associated with specific genetic alterations that may lead to human disease. PRMT5 plays a role in proliferative diseases, metabolic diseases, blood diseases, and the like.
PRMT5 is a known cell-essential gene, and conditional PRMT5 knockout and siRNA knockout studies indicate that PRMT5 inhibition in normal tissues is associated with a range of diseases (e.g., whole blood cytopenia, infertility, skeletal muscle loss, cardiac hypertrophy). Thus, new strategies are needed to exploit this metabolic vulnerability and preferentially null PRMT5 in tumors against MTAP, while retaining PRMT5 (MTAPWT) in normal tissues. Targeting PRMT5 with MTA synergistic small molecule inhibitors can preferentially target the MTA binding state of PRMT5, is enriched for MTAP null tumor cells, while providing a therapeutic index that is superior to normal cells where MTAP is intact and MTA levels are low.
Accordingly, there is a need in the art to provide novel small molecule compounds that target PRMT5 in MTAP null tumors.
Disclosure of Invention
The invention aims to provide a novel small molecule compound targeting PRMT5 in MTAP null tumors.
In a first aspect of the invention, there is provided a compound of formula I, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein,
ra is selected from the group consisting of:
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N; x is X 3 Is N;
the L is 1 Selected from the group consisting of: chemical bond, -O-, -CHR-, -C (R) R-, carbonyl, -C (S) -;
Ring a is selected from the group consisting of: a substituted or unsubstituted 7-12 membered bridged ring (including carbocycle or heterocycle), a substituted or unsubstituted 7-12 membered spiro ring (including carbocycle or heterocycle), a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl group (including carbocycle or heterocycle, preferably five and six rings), a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably five and six rings), or said A ring is a substituted or unsubstituted 3-7 membered carbocycle or heterocycle, a 5-6 membered aromatic or heteroaromatic ring;
R 8 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, unsubstituted or halogenated C 1 -C 6 Alkyl, or R 8 Is thatAnd when the A ring is a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, a 5-6 membered aromatic or heteroaromatic ring, R 8 Is->
The L is 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, -C (R) R-, carbonyl, S, -NH-;
ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-7 membered heterocycles (including saturated or partially unsaturated cases);
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, -C (R) R-, carbonyl, -C (S) -;wherein R is 7 Selected from the group consisting of: hydrogen or unsubstituted, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-12 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
r is H, halogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 3 -C 6 Cycloalkyl;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
In another preferred embodiment, said L 1 is-CHR-, -C (R) R-; ring a is selected from the group consisting of: a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl, a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl; or A ring is a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, a 5-6 membered aromatic or heteroaromatic ring, R 8 Is thatAnd ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycle, substituted or unsubstituted 3-6 membered heterocycle; l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-.
In another preferred embodiment, R is 2 Selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 Substituted or unsubstituted 5-12 membered heteroaromatic ring.
In another preferred embodiment, R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 An alkyl group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring.
In another preferred embodiment, said L 1 is-CH 2 -、-CH(CH 3 ) -; ring a is selected from the group consisting of:
wherein the C ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases);
or ring a is selected from the group consisting of:
R 8 is thatAnd ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycle, substituted or unsubstituted 3-6 membered heterocycle; l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-.
In another preferred embodiment, said L 3 Is a chemical bond.
In another preferred embodiment, the B ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-6 membered heteroaryl ring.
In another preferred embodiment, R 2 Selected from the group consisting of: r is R 7 、-(CHR)R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from the group consisting of: hydrogen or unsubstituted, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 8 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-8 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings).
In another preferred embodiment, said L 1 Is a chemical bond、-CH 2 -、-CH(CH 3 ) -; ring a is selected from the group consisting of:
in another preferred embodiment, R is 3 Selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group.
In a second aspect of the invention, there is provided a compound of formula II, or a pharmaceutically acceptable salt or deuterated product thereof:
II, wherein, the second part is a part of the first part,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
X 3 is N;
R 1 selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), orWherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of: substituted or unsubstitutedBenzene ring, substituted or unsubstituted 5-6 membered heteroaromatic ring, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases); l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-;
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substituents refer to the hydrogen atom on the corresponding group being replaced by one or more substituents selected from the group consisting of Substitution: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
In another preferred embodiment, R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered heteroaromatic ring, or a 5-7 membered saturated ring, and the rings may be substituted or unsubstituted.
In another preferred embodiment, W is S.
In another preferred embodiment, R 1 Selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: a substituted or unsubstituted 7-12 membered bridged ring (including carbocycle or heterocycle), a substituted or unsubstituted 7-12 membered spiro ring (including carbocycle or heterocycle), a substituted or unsubstituted 8-12 membered fused bicyclic ring (including carbocycle or heterocycle, preferably five and six rings), a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably five and six rings), or Wherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of:a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases).
In a third aspect of the invention, there is provided a compound of formula III, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from the group consisting of: o, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the And at least one is O;
R 1 selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), or Wherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (involving saturation or partialCase of partial unsaturation), substituted or unsubstituted 3-6 membered heterocycle (including saturated or partially unsaturated cases); l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-;
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
In a fourth aspect of the invention, there is provided a compound of formula IV, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
R 1 and R is 2 Together form a substituted or unsubstituted 3 to 10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, fused, spiro, or bridged ring);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substituents mentioned refer to the hydrogen atom on the corresponding group being substituted by one or more substituents selected from the group consisting ofThe substitution is as follows: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
In a fifth aspect of the invention there is provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound according to any one of the preceding aspects, a pharmaceutically acceptable salt, racemate, optical isomer, stereoisomer or tautomer thereof, together with one or more pharmaceutically acceptable carriers, excipients, adjuvants and/or diluents.
In a sixth aspect, the invention provides the use of a compound according to any one of the preceding aspects, racemates, optical isomers or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment or prophylaxis of a disease associated with abnormal gene levels or expression of PRMT5, such as corresponding nucleic acid mutations, deletions, or ectopic or fused or over-expressed production of said methyltransferase.
In another preferred embodiment, the disease is selected from the group consisting of: the disease or condition is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have found, for the first time, unexpectedly, a class of compounds having PRMT5 modulating effect through extensive and intensive studies. The present invention has been completed on the basis of this finding.
Terminology
In the present invention, the halogen is F, cl, br or I.
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art. In the present invention, all chemical formulas are intended to cover any optical or geometric isomer (e.g., R, S, or racemate, or cis-trans isomer of an olefin, etc.) possible, unless specifically indicated.
In the present invention, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
In the present invention, the term "C2-C6 alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and the like.
In the present invention, the term "C2-C6 alkynyl" refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
In the present invention, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.
In the present invention, the term "C3-C10 cycloalkenyl" refers to a cyclic alkenyl group having 3 to 10 carbon atoms in the ring, including, without limitation, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecen, and the like. The term "C3-C7 cycloalkenyl" has similar meaning.
In the present invention, the term "C1-C12 alkoxycarbonyl" refers to an alkoxycarbonyl group having 1 to 12 carbon atoms in the alkyl chain, and includes, without limitation, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like.
In the present invention, the term "C1-C12 alkylamino carbonyl" refers to an alkylamino carbonyl group having 1 to 12 carbon atoms in the alkyl chain and includes, without limitation, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, t-butylaminocarbonyl, benzylaminocarbonyl, dimethylaminocarbonyl and the like.
In the present invention, the term "C5-C9 furanosyl" refers to furanosyl having 5 to 9 carbon atoms, wherein the 1-position of the glycosyl is attached to the backbone, including, without limitation, ribofuranosyl, deoxyribofuranosyl, galactofuranosyl, and the like.
In the present invention, the term "C5-C9 pyranosyl" refers to a pyranosyl group having 5 to 9 carbon atoms, wherein the 1-position of the glycosyl group is attached to the main chain, including, without limitation, glucopyranosyl, glucuronopyranosyl, rhamnopyranosyl, galactopyranosyl, mannopyranosyl, xylopyranosyl, and the like.
In the present invention, the term "aromatic ring" or "aryl" has the same meaning, preferably "aryl" is "C6-C12 aryl" or "C6-C10 aryl". The term "C6-C12 aryl" refers to an aromatic cyclic group having 6 to 12 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring. The term "C6-C10 aryl" has similar meaning.
In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to more heteroatoms. Heteroatoms as referred to herein include oxygen, sulfur and nitrogen. Such as furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted.
In the present invention, the term "3-12 membered heterocyclic group" means a saturated or unsaturated 3-12 membered cyclic group containing 1 to 3 hetero atoms selected from oxygen, sulfur and nitrogen in the ring, such as a dioxolyl group and the like. The term "3-7 membered heterocyclyl" has similar meaning.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl group, may be attached to another ring, such as a cycloalkyl group, to form a spirobicyclic ring system, e.g., two rings having one common carbon atom. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): c1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, halogen, hydroxy, carboxyl (-COOH), C1-8 aldehyde, C2-10 acyl, C2-10 ester, C1-C12 alkoxycarbonyl, amino, alkoxy, C1-10 sulfonyl, and the like.
PRMT5 modulator compounds
The invention provides a compound with PRMT5 modulating activity:
Wherein,
ra is selected from the group consisting of:
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N; x is X 3 Is N;
the L is 1 Selected from the group consisting of: chemical bond, -O-, -CHR-, -C (R) R-, carbonyl, -C (S) -, S, -S (O) 2 -、-S(O)-、-S(ON)-、-COO-、-CONH-；
Ring a is selected from the group consisting of: a substituted or unsubstituted 7-12 membered bridged ring (including carbocycle or heterocycle), a substituted or unsubstituted 7-12 membered spiro ring (including carbocycle or heterocycle), a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl group (including carbocycle or heterocycle, preferably five and six rings), a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably five and six rings), or said A ring is a substituted or unsubstituted 3-7 membered carbocycle or heterocycle, a 5-6 membered aromatic or heteroaromatic ring;
R 8 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, unsubstituted or halogenated C 1 -C 6 Alkyl, or R 8 Is thatAnd when the A ring is a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, a 5-6 membered aromatic or heteroaromatic ring, R 8 Is->
The L is 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, -C (R) R-, carbonyl, S, -NH-;
ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-7 membered heterocycles (including saturated or partially unsaturated cases);
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, -C (S) -, S, -S (O) 2 -, -S (O) -, -COO-; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-12 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
R is H, halogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 3 -C 6 Cycloalkyl;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group,C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent methyltransferase inhibitory activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for treating, preventing and alleviating related diseases caused by abnormal methyltransferase (e.g., PRMT 5) activity or expression amount.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 5-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatibility" herein refers to the presence of a compound in the compositionThe components can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g. ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds. In some preferred embodiments, the compounds of the invention may form PROTAC together with other small molecule compounds or ADC administration together with other large molecule compounds such as mab.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 5 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
The definitions of the individual abbreviations are as follows:
the starting materials may be obtained commercially or prepared by methods known or disclosed in the art.
Purification of intermediates and compounds is carried out by conventional chemical experimental procedures such as normal phase or reverse phase chromatography or recrystallization. Normal phase chromatography is a pre-packed silica gel column or a preparative thin layer chromatography. The silica gel chromatographic column is mainly a glass column or a rapid preparation chromatograph. The mobile phase of normal phase chromatography is selected and proportioned from petroleum ether/ethyl acetate, methylene chloride/methanol or other suitable solvents. Reverse phase preparative liquid chromatography using a C18 column was performed using either preparative liquid chromatography or flash preparative chromatography, 214nM and 254nM or preparative liquid chromatography-mass spectrometry using water/acetonitrile with 0.1% hydrochloric acid, water/acetonitrile with 0.1% ammonium bicarbonate, water/acetonitrile with 0.1% formic acid, water/acetonitrile with 0.1% ammonia water/acetonitrile, water/acetonitrile with 0.1% trifluoroacetic acid, or other suitable solvent system as mobile phase for gradient elution.
Intermediate and compound structural characterization using Nuclear Magnetic Resonance (NMR) and mass spectrometry (LCMS) methods. The nuclear magnetic resonance spectrometer used for nuclear magnetic resonance is Bruker Assetnd 400 or Varian 400 or ZKNJ BIXI-1300MHz or Bruker Avance III MHz or Bruker AVANCE Neo MHz. The solvent is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol or other labeled deuterated solvents. Spectral data is reported in a pattern: chemical shift δ (number of peak splits, coupling constant J (Hz), number of hydrogens). Tetramethylsilane served as an internal 15 standard for chemical shift and its chemical shift was set to zero (δ,0 ppm). Some abbreviations have the meaning s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).
Representative methods for liquid chromatography-mass spectrometry (LCMS) in the characterization of intermediates and compounds structures are as follows:
the method comprises the following steps: performed on an Agilent LC1260 system coupled to a 6120 single quadrupole mass spectrometer
Column: waters CORTECS C-18,2.7 μm, 4.6X30 mm. Solvent A is 0.05% formic acid aqueous solution, solvent 20B is 0.05% formic acid acetonitrile solution, and the solvent A is kept for 2.5 minutes from 5% acetonitrile to 95% acetonitrile for one minute; the flow rate is 1.8mL/min; column temperature 40 ℃.
Column: XSelect CSH C18,3.5 μm,4.6 x 50mm. Solvent A is 0.05% ammonia water solution, solvent B is 0.05% acetonitrile solution of ammonia, and the solvent A is kept for 2.5 minutes from 5% acetonitrile to 95% acetonitrile in one minute; the flow rate is 1.8mL/min; column temperature 40 ℃.
The second method is as follows: performed on an Agilent LC/MSD 1200 system coupled with a quadrupole mass spectrometer.
Column ODS2000 (50X 4.6mm,5 μm) (ES (+) or (-) ionization mode), temperature 30 ℃; the flow rate was 1.5mL/min.
Example synthesis general procedure:
wherein intermediate a can be any of the intermediates in table 2:
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intermediate B may be any of the intermediates in table 3:
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the general method comprises the following steps: synthesis of intermediate A1
The synthetic route is as follows:
step 1: n- (4-bromophenyl) -2-oxocyclopentane-1-carboxamide (2)
A mixture of methyl 2-oxocyclopentane-1-carboxylate (50 g,0.35 mol) and 4-bromoaniline (121 g,0.70 mol) in toluene (300 mL) was stirred at 110℃for 12 hours. The mixture was then added to 2M aqueous HCl (100 mL) and diluted with water (300 mL). The reaction was extracted with ethyl acetate (300 mL. Times.3). The organic layer was washed with brine (200 mL. Times.3) and dried over anhydrous sodium sulfate. The organic phase is then filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting from 0% to 30% with EA/PE solution over 20 min to give N- (4-bromophenyl) -2-oxocyclopentane-1-carboxamide (25 g, 21% yield) as a pale yellow, hard solid. LC-MS: rt=1.257 min, (ESI) M/z [ M+H ] ] + 283.0,[M+2+H] + 285.0；C 12 H 12 BrNO 2
Step 2: 8-bromo-2, 3-dihydro-1H-cyclopenta [ c ] quinolin-4-ol (3)
A mixture of N- (4-bromophenyl) -2-oxocyclopentane-1-carboxamide (25.0 g,0.088 mol) in concentrated sulfuric acid (100 mL) was stirred at 100deg.C for 12 hours. The mixture was poured into ice water (500 mL). NaHCO 3 is added until the pH is 7-8. The precipitate formed was filtered and washed with some cold methanol (50 mL). The filtrate was filtered. The combined solids were dried and recrystallized from ethanol (20 mL) to give 8-bromo-2, 3-dihydro-1H-cyclopentadiene [ c ] as a light brown solid]Quinolin-4-ol (6 g,26% yield). LC-MS: rt=1.299 min, (ESI) M/z [ M+H ]] + 264.0；[M+2+H] + 266.0,C 12 H 10 BrNO
Step 3: 4-hydroxy-2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxylic acid methyl ester (4)
8-bromo-2, 3-dihydro-1H-cyclopentadiene [ c ]]Quinolin-4-ol (6.0 g,23 mmol), et3N (6.9 g,68 mmol) and Pd (dppf) Cl2 (3.3 g, 4.40mmol in MeOH (100 mL) were stirred at 100deg.C under CO for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 10% over 20 min to give 4-hydroxy-2, 3-dihydro-1H-cyclopentadiene [ c ]]Quinoline-8-carboxylic acid methyl ester (3 g,54% yield) was a brown solid. LC-MS: rt=1.183 min, (ESI) M/z [ M+H ]] + 244.09,C 14 H 13 NO 3
Step 4:4- (((trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxylic acid methyl ester (5)
To 4-hydroxy-2, 3-dihydro-1H-cyclopenta [ c ]]To a solution of methyl quinoline-8-carboxylate (9.3 g,0.038 mol) and pyridine (9.1 g,0.11 mmol) in DCM (200 mL) was added trifluoromethanesulfonic anhydride (21.6 g,0.076 mol) at 0deg.C. The mixture was then stirred at 20℃for 12 hours. The reaction was quenched with NaHCO3 (aq.) (200 mL) and then extracted with DCM (200 mL. Times.3). The organic solution was washed with brine (200 mL). The organic phase was dried over Na 2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a PE solution of EA from 0% to 30% over 20 min to give methyl 4- (((trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-cyclopenta [ c)]Quinoline-8-carboxylic acid salt (11.0 g,77% yield) as yellow solid. 1 H NMR(400MHz,CDCl 3 )δ8.57(d,J＝2.0Hz,1H),8.30(dd,J＝8.8,2.0Hz,1H),8.08(d,J＝8.8Hz,1H),4.01(s,3H),3.43(t,J＝8.0Hz,2H),3.21(t,J＝8.0Hz,2H),2.55–2.32(m,2H).LC-MS:Rt＝1.544min,(ESI)m/z.376.1[M+H] + .C 15 H 12 F 3 NO 5 S 375.04.
Step 5:4- ((4-methoxybenzyl) amino) -2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxylic acid methyl ester (6)
To stirred 4- (((trifluoromethyl) sulfonyl) oxy) -2, 3-dihydro-1H-cyclopenta [ c ]]To a solution of methyl quinoline-8-carboxylate (11.0 g,29 mmol) in dioxane (100 mL) was added Cs at 20deg.C 2 CO 3 (28.6g,88mmol)、Pd 2 (dba) 3 (2.7 g,2.93 mmol), xantphos (3.4 g,5.86 mmol) and PMBNH 2 (6.0 g,0.044 mmol). The reaction mixture was taken up in N 2 Stirring is carried out for 12 hours at 110℃under an atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 5% over 20 min to give methyl 4- ((4-methoxybenzyl) amino) -2, 3-dihydro-1H-cyclopenta-di [ c ] ]Quinoline-8-carboxylic acid salt (8.1 g,76% yield) as yellow solid. 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝2.0Hz,1H),8.11(dd,J＝8.8,2.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.36(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.79(s,2H),3.95(s,3H),3.80(s,3H),3.24(t,J＝8.0Hz,2H),2.80(t,J＝8.0Hz,2H),2.36–2.19(m,2H).LC-MS:Rt＝1.036min,(ESI)m/z.363.1[M+H] + .C 22 H 22 N 2 O 3 362.16.
Step 6: 4-amino-2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxylic acid methyl ester (7)
4- ((4-methoxybenzyl) amino) -2, 3-dihydro-1H-cyclopenta-di [ c ]]Quinoline-8-carboxylic acid methyl ester (8.1 g,20 mmol) in CF 3 The solution in COOH (50 mL) was stirred at 70℃for 12 hours. The solvent was then removed and the residue was dissolved in DCM (200 mL). NaHCO for organic phase 3 (aq.) (300 mL) washed and with Na 2 SO 4 And (5) drying. The mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 5% over 20 min to give 4-amino-2, 3-dihydro-1H-cyclopentadiene [ c ]]Quinoline-8-carboxylic acid methyl ester (4.6 g,85% yield) was a yellow solid. LC-MS: rt=0.921 min, (ESI) M/z.243.1[ M+H ]] + .C 14 H 14 N 2 O 242.11.
Step 7: 4-amino-2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxylic acid (intermediate A1)
4-amino-2, 3-dihydro-1H-cyclopenta [ c ]]Quinoline-8-carboxylic acid methyl ester (0.60 g,2.31 mmol) in HCl (4 mol/L in H 2 O) (20 mL) was stirred at 95℃for 12 hours. The solvent is then removed and the residue is 4-amino-2, 3-dihydro-1H-cyclopenta [ c ]]Quinoline-8-carboxylic acid (500 mg,88% yield) was a white solid which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ8.65(s,2H),8.31(s,1H),8.22(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,2H),3.32(t,J＝8.0Hz,2H),2.95(t,J＝8.0Hz,2H),2.34–2.20(m,2H).LC-MS:Rt＝0.763min,(ESI)m/z.229.1[M+H] + .C 13 H 12 N 2 O 2 228.09.
The general method comprises the following steps: synthesis of intermediate B1
Step 1: N-methoxy-N-methylpyrazolo [1,5-a ] pyridine-2-carboxamide (1)
To pyrazolo [1,5-a ]]To a solution of pyridine-2-carboxylic acid (2.0 g,12.3 mmol) and HATU (7.0 g,18.5 mmol) in DMF (100 mL) was added Et3N (6.2 g,61.7 mmol) and methoxy (meth) amine (1.9 g,30.83 mmol), 25 ℃. The mixture was then stirred at 25 ℃ for 12 hours. The reaction was quenched with water (100 mL) and then extracted with EA (100 mL. Times.3). The organic solution was washed with brine (100 mL). The organic phase was dried over Na 2so 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 10% over 20 min to give N-methoxy-N-methylpyrazolo [1,5-a ]]Pyridine-2-carboxamide (2.01 g,79% yield) was a yellow solid. LC-MS: rt=1.049 min, (ESI) M/z [ M+H ]] + 206.1；C10H11N3O2.
Step 2: pyrazolo [1,5-a ] pyridine-2-carbaldehyde (3)
At-60 ℃ to N-methoxy-N-methylpyrazolo [1,5-a ]]To a solution of pyridine-2-carboxamide (1.5 g,7.31 mmol) in THF (20 mL) was added LiAlH 4 (439 mg,10.96 mmol). The mixture was then stirred at-60℃for 2 hours. The reaction was quenched with water (40 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting from 0% to 10% with MeOH in DCM over 20 min to give pyrazolo [1,5-a ] as a yellow oil ]Pyridine-2-carbaldehyde (450 mg,42% yield). LC-MS: rt=1.071 min, (ESI) M/z [ M+H ]]+147.1；C8H6N2O
Step 3: n- (pyrazolo [1,5-a ] pyridin-2-ylmethyl) -1- (pyrimidin-2-yl) ethane-1-amine (intermediate B1)
To a solution of pyrazolo [1,5-a ] pyridine-2-carbaldehyde (100 mg,0.68 mmol) in MeOH (5 mL) was added 1- (pyrimidin-2-yl) ethylamine (126 mg,1.03 mmol) and NaBH3CN (86 mg, 1.37 mmol) and reacted at 25 ℃. The mixture was then stirred at 25 ℃ for 2 hours. The reaction was quenched with water (1 mL) and the solvent concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting from 0% to 5% with MeOH in DCM over 20 min to give N- (pyrazolo [1,5-a ] pyridin-2-ylmethyl) -1- (pyrimidin-2-yl) ethylamine (40 mg, 23% yield) as a yellow oil. LC-MS: rt=0.521 min, (ESI) M/z, [ m+h ] +254.2; C14H15N5
The general method comprises the following steps: synthesis of Compound 46
Step 1: 4-amino-N- (pyrazolo [1,5-a ] pyridin-2-ylmethyl) -N- (1- (pyrimidin-2-yl) ethyl) -2, 3-dihydro-1H-cyclopenta [ c ] quinoline-8-carboxamide (compound 46)
4-amino-2, 3-dihydro-1H-cyclopentadiene [ c ]]Quinoline-8-carboxylic acid (80 mg,0.35 mmol) in SOCl 2 The solution in (2 mL) was stirred at 70℃for 12 hours. The solvent was concentrated to dryness and used directly in the next reaction. In N- (pyrazolo [1, 5-a) ]Pyridin-2-ylmethyl) -1- (pyrimidin-2-yl) ethan-1-amine (35 mg,0.14 mmol) and Et 3 To a solution of N (140 mg, 1.38) at 0deg.C, 4-amino-2, 3-dihydro-1H-cyclopenta-di [ c ] was added to THF (15 mL)]Quinoline-8-carbonyl chloride (80 mg,0.32 mmol). The mixture was then stirred at 25 ℃ for 12 hours. With NaHCO 3 (aq.) (20 mL) the reaction was quenched and then extracted with EA (20 mL. Times.3). The organic solution was washed with brine (20 mL). Na for organic phase 2 SO 4 Drying and filtering. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH in DCM from 0% to 5% over 20 min to give 4-amino-N- (pyrazolo [1, 5-a)]Pyridin-2-ylmethyl) -N- (1- (pyrimidin-2-yl) ethyl) -2, 3-dihydro-1H-cyclopentadiene [ c]Quinoline-8-carboxamide (2.3 mg,4% yield) was a yellow solid (compound 46). 1H NMR (400 MHz, meOD) delta 8.75 (s, 2H), 8.40 (s, 2H), 7.87-7.61 (M, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 6.83 (s, 1H), 6.51 (s, 1H), 5.68 (s, 1H), 5.40 (s, 1H), 4.73-4.53 (M, 2H), 3.24 (s, 2H), 2.94 (s, 2H), 2.41-2.13 (M, 2H), 1.84-1.65 (M, 3H) LC-MS: rt=0.981 min, (ESI) M/z.464.2[ M+H ]] + .C27H25N7O
The following compounds were synthesized based on the general procedure and the products are shown in Table 4
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Biological test example 1PRMT5 in vitro inhibitory Activity assay
Experimental materials
PRMT5 (Active Motif, catalog number 31921), [ 3 H]SAM (Perkin Elmer, catalog number NET155V001 MC), SAM (Sigma, catalog number A7007), MTA (Sigma, catalog number D5011), SAH (Sigma, catalog number A9384), 384 well plates (Perkin Elmer, catalog number 6007299), echo 550 (manufacturer: labcyte, model: echo 550), 384-well flash plate (manufacturer: perkin Elmer, model: SMP410A001 PK)
Experimental method
1. Enzymatic reaction process
(1) 1x assay buffer (modified Tris Buffer) is configured.
(2) Dilution of the compound: the compounds were dissolved in 100% dmso and the compound solution was added to 384 well plates using Echo 550.
(3) Preparing an enzyme solution: PRMT5 is added into 1x assay buffer to prepare enzyme solution 1; PRMT5 and MTA were added to 1x assay buffer configuration enzyme solution 2.
(4) Preparing a substrate solution: the peptide fragment and [3H ] -SAM were added to a 1x assay buffer.
(5) mu.L of enzyme solution was added to 384-well plates, and negative control wells were added to 15. Mu.L of 1 Xassay buffer and incubated for 30 minutes at room temperature.
(6) mu.L of substrate solution was added to each well and incubated at room temperature for 90 minutes.
(7) Preparing a termination reaction solution: the precooled SAM was added to a 1x assay buffer.
(8) The reaction was terminated by adding 10. Mu.L of the termination reaction solution to each well.
(9) 25. Mu.L/well of the mixed solution was transferred to Flashplate and incubated for 1 hour at room temperature.
(10) The Flashplate was washed three times with dH2O+0.1% Tween-20 solution.
(11) The emission values were read with Microbeta. .
2. Data analysis
(1) The raw data is converted into% inhibition according to equation 1:
equation 1: % inhibition= (Max-Signal)/(Max-Min) 100
(2) The% inhibition data is taken into XL-Fit equation 2 to obtain IC50 values:
equation 2: y=bottom+ (Top-Bottom)/(1+ (IC 50/X) ×hillslope)
Wherein Y is% inhibition and X is the compound concentration.
Biological test example 2 in vitro proliferation inhibition experiments on HCT116, HCT116-MTAP-KO cells
Experimental materials
The HCT116 cell line is purchased from a cell bank of China academy of sciences, and the CRISPR/Cas9 technology is utilized to knock out the MTAP gene, so that the HCT116-MTAP-KO cell line is obtained.
McCoy'5A medium (Gibco, catalog number 16600082), fetal bovine serum (Gibco, catalog number 10099141C), penicillin-streptomycin double antibody (Gibco, catalog number 15140122), pancreatin (Gibco, catalog number 25200056), cellTiter-Glo detection kit (Promega, catalog number G7572), 384-well transparent flat-bottom melanocyte plates (Corning, catalog number 3764), ultra microscale sample applicator (Tecan, catalog number D300 e), multifunctional enzyme-labeled instrument (Biotek, catalog number SyneryHTX)
Experimental method
1. Cell culture: HCT116 and HCT116-MTAP-KO cell culture conditions were McCoy'5A medium+10% fetal bovine serum+1% penicillin-streptomycin diabodies; ensuring that the cell is always in the logarithmic growth phase, and the cell activity rate is more than 95%.
2. Compound concentration gradient preparation: the test compound was added to 384-well plates by an ultra-microscale sample applicator, and three wells were set starting from 30. Mu.M (HCT 116 cells) or 3. Mu.M (HCT 116-MTAP-KO cells), 3-fold dilution with DMSO, and 9 total concentrations.
3. Compound-treated cells: pancreatin digested HCT116 or HCT116-MTAP-KO cell suspensions were added to 384 well plates spotted with test compounds at 40 μl per well, i.e. 100 cells per well, with a final DMSO concentration of 0.4%. The cell culture plates were placed in a 5% carbon dioxide incubator at 37 degrees celsius for 6 days.
4. And (3) detection: to the cell culture plate, 20. Mu.L CellTiter-Glo reagent per well was added and incubated for 30 minutes with shaking at room temperature. The luminescence signal at 578nm was detected using a multifunctional microplate reader.
5. Data analysis:
GraphPad Prism 8.0 software uses four parametersThe inhibitor-response model fits the data to obtain the IC for the test compound 50 Values (half inhibition concentration).
The biological activity of some compounds was determined experimentally and is shown in Table 5:
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all documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (14)

1. A compound of formula I, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein,
ra is selected from the group consisting of:
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N; x is X 3 Is N;
the L is 1 Selected from the group consisting of: chemical bond, -O--CHR-, -C (R) R-, carbonyl, -C (S) -;
ring a is selected from the group consisting of: a substituted or unsubstituted 7-12 membered bridged ring (including carbocycle or heterocycle), a substituted or unsubstituted 7-12 membered spiro ring (including carbocycle or heterocycle), a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl group (including carbocycle or heterocycle, preferably five and six rings), a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably five and six rings), or said A ring is a substituted or unsubstituted 3-7 membered carbocycle or heterocycle, a 5-6 membered aromatic or heteroaromatic ring;
R 8 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, unsubstituted or halogenated C 1 -C 6 Alkyl, or R 8 Is thatAnd when the A ring is a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, a 5-6 membered aromatic or heteroaromatic ring, R 8 Is->
The L is 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, -C (R) R-, carbonyl, S, -NH-;
ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-7 membered heterocycles (including saturated or partially unsaturated cases);
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, -C (R) R-, carbonyl, -C (S) -; wherein R is 7 Selected from the group consisting of: hydrogen or unsubstituted, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, includingA monocyclic, fused, spiro, or bridged ring), a substituted or unsubstituted 3-10 membered heterocyclic ring (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-12 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
R is H, halogen, substituted or unsubstituted C 1 -C 4 Alkyl, substituted or unsubstituted C 1 -C 4 Alkoxy, substituted or unsubstituted C 3 -C 6 Cycloalkyl;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
2. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, wherein L 1 is-CHR-, -C (R) R-; ring a is selected from the group consisting of: a substituted or unsubstituted 8-12 membered fused bicyclic heterocyclyl, a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl; or A ring is a substituted or unsubstituted 3-7 membered carbocyclic or heterocyclic ring, a 5-6 membered aromatic or heteroaromatic ring, R 8 Is thatAnd ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycle, substituted or unsubstituted 3-6 membered heterocycle; l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-.
In another preferred embodiment, R is 2 Selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 Substituted or unsubstituted 5-12 membered heteroaromatic ring.
In another preferred embodiment, R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 An alkyl group, a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-7 membered heteroaromatic ring.
3. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, wherein L 1 is-CH 2 -、-CH(CH 3 ) -; ring a is selected from the group consisting of:
wherein the C ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases);
Or ring a is selected from the group consisting of:
R 8 is thatAnd ring B is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycle, substituted or unsubstituted 3-6 membered heterocycle; l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-.
In another preferred embodiment, said L 3 Is a chemical bond.
In another preferred embodiment, the B ring is a substituted or unsubstituted benzene ring, or a substituted or unsubstituted 5-6 membered heteroaryl ring.
4. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, wherein R 2 Selected from the group consisting of: r is R 7 、-(CHR)R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 7 Selected from the group consisting of: hydrogen or unsubstituted, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 8 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-8 membered heterocycles (including saturated or partially unsaturated cases, inclusiveIncluding monocyclic, fused, spiro, or bridged rings).
5. The compound of claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, wherein L 1 Is a chemical bond, -CH 2 -、-CH(CH 3 ) -; ring a is selected from the group consisting of:
6. the compound of claim 1, or a pharmaceutically acceptable salt or deuterated product thereof, wherein R 3 Selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group.
7. A compound of formula II, or a pharmaceutically acceptable salt or deuterated product thereof:
II, wherein, the second part is a part of the first part,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
X 3 is N;
R 1 selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), orWherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases); l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-;
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered A heterocycle; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
8. The compound of claim 7, or a pharmaceutically acceptable salt or deuterated product thereof, wherein R 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered heteroaromatic ring, or a 5-7 membered saturated ring, and the rings may be substituted or unsubstituted.
In another preferred embodiment, W is S.
In another preferred embodiment, R 1 Selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: a substituted or unsubstituted 7-12 membered bridged ring (including carbocycle or heterocycle), a substituted or unsubstituted 7-12 membered spiro ring (including carbocycle or heterocycle), a substituted or unsubstituted 8-12 membered fused bicyclic ring (including carbocycle or heterocycle, preferably five and six rings), a substituted or unsubstituted 7-10 membered fused bicyclic heteroaryl group (preferably five and six rings), orWherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases).
9. A compound of formula III, or a pharmaceutically acceptable salt or deuterated product thereof:
wherein,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from the group consisting of: o, S, NR or C (R) 2 The method comprises the steps of carrying out a first treatment on the surface of the And at least one is O;
R 1 selected from the group consisting of: r is R 6 、-L 1 R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 1 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 6 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 Substituted or unsubstituted 5-12 membered heteroaromatic ring, takenSubstituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), orWherein the A ring is a 5-6 membered aromatic or heteroaromatic ring and the B ring is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5-to 6-membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles (including saturated or partially unsaturated cases); l (L) 3 Selected from the group consisting of: chemical bond, -O-, -CHR-, carbonyl, S, or-NH-;
R 2 selected from the group consisting of: r is R 7 、-L 2 R 7 The method comprises the steps of carrying out a first treatment on the surface of the Wherein, the L 2 Selected from the group consisting of: -O-, -CHR-, carbonyl, S, -NH-, -NHC (O) -, -NHS (O) 2 -、-NHC(O)NH-、-NHC(S)NH-、-COO-、-O-S(O) 2 -; wherein R is 7 Selected from the group consisting of: substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 6-10 An aromatic ring, a substituted or unsubstituted 5-12 membered heteroaromatic ring, a substituted or unsubstituted C 3 -C 10 Carbocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings), substituted or unsubstituted 3-10 membered heterocycles (including saturated or partially unsaturated cases, including monocyclic, fused, spiro, or bridged rings);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogenHydroxyl, carboxyl, mercapto, benzyl, C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
10. A compound of formula IV, or a pharmaceutically acceptable salt or deuterated product thereof:
IV, wherein, the step of carrying out the process,
w is O or S;
X 1 、X 2 each independently selected from the group consisting of: CR, N;
R 1 and R is 2 Together form a substituted or unsubstituted 3 to 10 membered heterocyclic ring (including saturated or partially unsaturated, including monocyclic, fused, spiro, or bridged ring);
R 3 selected from the group consisting of: H. halogen, cyano, amino, nitro, hydroxy, mercapto, aldehyde, carboxyl, sulfonyl, substituted or unsubstituted C 1 -C 6 An alkyl group;
R 4 and R is 5 Each independently selected from the group consisting of: H. halogen, cyano, substituted or unsubstituted C 1 -C 6 Alkyl, substituted or unsubstituted C 1 -C 6 Alkoxy, substituted or unsubstituted C 3 -C 6 Carbocycles (including saturated or partially unsaturated cases), substituted or unsubstituted 3-6 membered heterocycles; or R is 4 And R is 5 Together with the ring atoms to which they are attached, form a 5-7 membered saturated or unsaturated ring, and said ring may be substituted or unsubstituted;
r is H, halogen or C 1 -C 4 Alkyl, or C 3 -C 6 An alkyl group;
in the formulae described above, the substitution means that the hydrogen atom on the corresponding group is substituted by one or more substituents selected from the group consisting of: deuterium, tritium, halogen, hydroxy, carboxyl, mercapto, benzyl and C 1 -C 12 Alkoxycarbonyl group, C 1 -C 6 Aldehyde group, amino group, C 1 -C 6 Amide, nitro, cyano, unsubstituted or halogenated C 1 -C 6 Alkyl, unsubstituted or halogenated C 3 -C 8 Cycloalkyl, C 2 -C 10 Alkenyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl-amino, C 6 -C 10 Aryl, five-membered or six-membered heteroaryl, five-membered or six-membered non-aromatic heterocyclic group, -O- (C) 6 -C 10 Aryl), -O- (five-membered or six-membered heteroaryl), C 1 -C 12 Alkylaminocarbonyl, unsubstituted or halogenated C 2 -C 10 Acyl, sulfonyl (-SO) 2 -OH), phosphoryl (-PO) 3 -OH), unsubstituted or halogenated C 1 -C 4 alkyl-S (O) 2 -, unsubstituted or halogenated C 1 -C 4 alkyl-SO-.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt or deuterated product thereof, wherein the compound has a structure selected from the group consisting of:
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12. a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound, pharmaceutically acceptable salt, racemate, optical isomer, stereoisomer, or tautomer thereof according to any one of claims 1-11, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, and/or diluents.
13. Use of a compound, racemate, optical isomer, or pharmaceutically acceptable salt thereof according to any of claims 1-11 in the manufacture of a medicament for the treatment or prevention of a disease associated with abnormal levels or expression of PRMT5 gene (e.g., corresponding nucleic acid mutation, deletion, or ectopic or fusion or overexpression of said methyltransferase).
14. The use according to claim 13, wherein the disease is selected from the group consisting of: the disease or condition is ovarian cancer, lung cancer, lymphoma, glioblastoma, colon cancer, melanoma, gastric cancer, pancreatic cancer, or bladder cancer.
CN202210775564.7A 2022-07-01 2022-07-01 PRMT5 inhibitor and application thereof Pending CN117362323A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CN202210775564.7A CN117362323A (en) 2022-07-01 2022-07-01 PRMT5 inhibitor and application thereof
PCT/CN2023/105593 WO2024002376A1 (en) 2022-07-01 2023-07-03 Prmt5 inhibitors and use thereof
PCT/CN2023/105594 WO2024002377A1 (en) 2022-07-01 2023-07-03 Class of prmt5 inhibitors and use thereof
CN202311838498.4A CN117800991A (en) 2022-07-01 2023-12-28 PRMT5 inhibitor and application thereof

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