CN109963853B - Compound with activity of degrading tyrosine protein kinase JAK3 - Google Patents

Abstract

A compound with the activity of degrading tyrosine protein kinase JAK3 has a structural formula shown in a formula I, and can be used for preparing medicines for treating JAK3 related diseases.

Description

A class of compounds with the activity of degrading tyrosine protein kinase JAK3

technical field

The invention belongs to the field of medicine, and in particular relates to a class of compounds having the activity of degrading tyrosine protein kinase JAK3 and its preparation and application.

Background technique

Janus kinases (JAKs) are intracellular non-receptor tyrosine protein kinases that are important for T cell growth, activation and homeostasis regulation, and play a key role in regulating the functions of lymphohematopoietic cells. In mammals, this family contains four major family members, namely JAK1, JAK2, JAK3 and Tyk2. Among them, JAK1, JAK2 and Tyk2 are widely expressed in various tissue cells, and JAK3 is mainly highly expressed in hematopoietic tissues, such as activated B lymphocytes, T lymphocytes, bone marrow cells and thymocytes.

Organ transplant rejection, xenotransplantation, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, atopic dermatitis, type I diabetes due to extensive regulation of the JAK3-STAT signaling pathway JAK3 is also involved in the occurrence of diabetes complications, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, lymphoma, multiple myeloma, alopecia areata, vitiligo and many other diseases , JAK3, as a signaling member, plays a key role in the occurrence of diseases, and has become a drug target for the development and treatment of such diseases in pharmaceutical research and development.

Therefore, those skilled in the art are devoted to developing compounds capable of inhibiting the activity of JAK3.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a compound capable of inhibiting and degrading JAK3, and its preparation and application.

In a first aspect of the present invention, there is provided a compound represented by the following formula I, or a pharmaceutically acceptable salt thereof:

in:

表示单键；

represents a single key;

表示单键或双键；

Indicates a single bond or a double bond;

A is absent or selected from C(=O), C(=O)X1, SOX1, _{SO2X1, C1-8 hydrocarbyl} with or without substituents, _C1 with or without substituents _-8 cyclic hydrocarbon groups, and C _1-8 heterocyclic hydrocarbon groups with or without substituents; wherein X1 is absent or selected from (CR ₁₂ R ₁₃ ) _e O, (CR ₁₂ R ₁₃ ) _e S and NR ₁₄ ; wherein R ₁₂ , R ₁₃ , and R ₁₄ are each independently selected from H, a C _1-8 hydrocarbon group with or without a substituent, a C _1-8 cyclic hydrocarbon group with or without a substituent, and C _1-8 heterocyclic hydrocarbon groups with or without substituents, e is an integer between 0 and 3 (such as 1, 2, or 3);

W is absent or selected from O, NR ₁₇ , -X2C(=O)X3, -X2S(=O) _g X3; wherein R ₁₇ is H, C _1-8 hydrocarbyl with or without substituents, with C _1-8 cyclic hydrocarbon groups with or without substituents, C _1-8 heterocyclic hydrocarbon groups with or without substituents; wherein X2, X3 are each independently absent or selected from O, S, NR ₁₈ , (CH ₂ ) _g O; wherein each g is an integer from 0 to 2; wherein R ₁₈ is H, a C _1-8 hydrocarbon group with or without a substituent, a hydrocarbon group with or without a substituent C _1-8 cyclic hydrocarbon group, C _1-8 heterocyclic hydrocarbon group with or without substituents;

Y is ( _CR22R23 ) _h , _CHX4 ( _CR22R23 ) _h , CX4=CH( _{CR22R23 ) h} or ( _{CR22R23 ) h} ; wherein h is an integer between 0 and ₃₀ ; wherein R ₂₂ and R ₂₃ are each independently selected from H, cyano group, hydroxyl group, amino group, C _1-8 hydrocarbon group with or without substituent group, and C _1-8 ring group with or without substituent group Hydrocarbyl, C _1-8 heterocyclic hydrocarbyl with or without substituents, C _1-8 hydrocarbyloxy with or without substituents; wherein X4 is H, halogen, cyano, nitro , hydroxyl, with or without substituent C _1-8 hydrocarbyloxy, with or without substituent C _1-8 hydrocarbyloxycarbonyl, with or without substituent C _1-8 amino, With or without substituent C _1-8 ester group, with or without substituent C _1-8 aminocarbonyl, with or without substituent C _1-8 hydrocarbyl, with or without substituent A substituted C _1-8 cyclic hydrocarbon group, with or without a substituent C _1-8 heterocyclic hydrocarbon group;

Z is (CR ₂₄ R ₂₅ ) _i , CHX5(CR ₂₄ R ₂₅ ) _i , CX5=CH(CR ₂₄ R ₂₅ ) _i or C≡C(CR ₂₄ R ₂₅ ) _i ; where i is between 0 and 30 Integer; wherein R ₂₄ , R ₂₅ are each independently selected from H, cyano, hydroxyl, amino, C _1-8 hydrocarbyl with or without substituent, with or without substituent C _1-8 Cyclic hydrocarbon group, with or without substituent C _1-8 heterocyclic hydrocarbon group, with or without substituent C _1-8 hydrocarbonoxy group; wherein X5 is H, halogen, cyano, nitro, hydroxyl, With or without substituent C _1-8 hydrocarbyloxy, with or without substituent C _1-8 hydrocarbyloxycarbonyl, with or without substituent C _1-8 amino, with or without substituent C _1-8 ester group, with or without substituent C _1-8 aminocarbonyl, with or without substituent C _1-8 hydrocarbyl, with or without substituent base C _1-8 cyclic hydrocarbon group, with or without substituent C _1-8 heterocyclic hydrocarbon group;

B is absent or selected from O, C=O, S, NR ₁₅ , -NR ₁₅ C(=O)-, -C(=O)NR ₁₅ -, -C(=O)O-, OC(=O) O-, -NR ₁₅ C(=O)O-, -OC(=O)NR ₁₅ -, -NR ₁₅ C(=O)NR ₁₆ -, C _1-12 with or without substituents Hydrocarbon group, C _1-12 cyclic hydrocarbon group with or without substituent, and C _1-12 heterocyclic hydrocarbon group with or without substituent; wherein R ₁₅ and R ₁₆ are each independently selected from H , C _1-8 hydrocarbon groups with or without substituents, C _1-8 cyclic hydrocarbon groups with or without substituents, and C _1-8 heterocyclic groups with or without substituents Cyclohydrocarbyl;

X is selected from CR ₁₉ R ₂₀ , C(=O), S(=O), SO ₂ , NR ₂₁ ; wherein R ₁₉ and R ₂₀ are each independently selected from H, cyano, hydroxyl, amino, with or without C _1-8 hydrocarbyl with substituents, C _1-8 cyclohydrocarbyl with or without substituents, C _1-8 heterocyclic hydrocarbyl with or without substituents, with or without substituents Unsubstituted C _1-8 hydrocarbyloxy; wherein R ₂₁ is selected from H, C _1-8 hydrocarbyl with or without substituent, C _1- with or without substituent ₈ cyclic hydrocarbon group, C _1-8 heterocyclic hydrocarbon group with or without substituent;

R ₁ , R ₆ , R ₁₀ are each independently selected from H, C _1-8 hydrocarbon group with or without substituent, cyclic hydrocarbon group with or without substituent, with or without substituent Heterocyclic hydrocarbon group, C _1-6 acyl group with or without substituent;

R ₂ and R ₅ are each independently selected from: hydrogen, OR ₃₃ , NR ₃₄ R ₃₅ , cyano, halogen, C _1-8 hydrocarbon groups with or without substituents, with or without substituents Cyclic hydrocarbon group, heterocyclic hydrocarbon group with or without substituent, C _1-6 acyl group with or without substituent, amide group with or without substituent; wherein R ₃₃ , R ₃₄ , R ₃₅ is each independently selected from H, C _1-8 hydrocarbon group with or without substituent, cyclic hydrocarbon group with or without substituent, and heterocyclic hydrocarbon group with or without substituent;

R ₃ , R ₇ , R ₈ , R ₉ are each independently selected from: H, OR ₂₇ , NR ₂₈ R ₂₉ , cyano, halogen, nitro, C _1-8 hydrocarbyl with or without substituents, Cyclohydrocarbyl with or without substituents, heterocyclic hydrocarbyl with or without substituents, X6S(=O)kR ₃₀ , X6C(=O)R ₃₁ ; wherein _k is between 0 and 2 an integer of ; wherein R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ are independently selected from H, C _1-8 hydrocarbon groups with or without substituents, cyclic hydrocarbon groups, and heterocyclic hydrocarbon groups; wherein X6 is missing Or selected from O, S, NR ₃₂ ; wherein R ₃₂ is H, C _1-8 hydrocarbyl with or without substituents, cyclic hydrocarbyl with or without substituents, and with or without substituents Substituted heterocyclic hydrocarbon groups;

R ₄ is selected from H, cyano group, carboxyl group, C _1-8 hydrocarbon group with or without substituent group, hydrocarbon oxycarbonyl group with or without substituent group;

a is an integer between 0 and 5 (such as 1, 2, 3, 4, 5);

b is an integer between 0 and 3 (such as 1, 2, 3);

c is an integer between 0 and 30 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);

d is an integer between 0 and 9 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9).

In another preferred example, A is deleted; W is X2C(=O)X3, wherein X2 is NR ₁₈ and X3 is deleted, or X3 is NR ₁₈ and X2 is deleted; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are each independently selected from H, hydroxyl, and C _1-4 hydrocarbon groups with or without substituents, h is an integer between 1 and 6; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are each independently selected from H, hydroxyl, and C _1-4 hydrocarbon groups with or without substituents, i is an integer between 1 and 6; c is 0.

In another preferred example, A is deleted; W is deleted or O; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are each independently selected from H, hydroxyl, with or without substituents Hydrocarbyl group of C _1-4 , h is an integer between 0 and 3; B is O; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are each independently selected from H, hydroxyl, with or without Substituted C _1-4 hydrocarbyl, i is an integer between 0 and 3; c is an integer between 1 and 6.

In another preferred embodiment, A is C(=O)X1, wherein X1 is deleted or selected from (CR ₁₂ R ₁₃ ) _e O, and (CR ₁₂ R ₁₃ ) _e S, wherein e is between 0 and 2 Integer, R ₁₂ , R ₁₃ , R ₁₄ are each independently hydrogen or C _1-4 alkyl; W is O or NR ₁₇ , wherein R ₁₇ is H, or C _1- with or without substituents The hydrocarbon group of ₄ ; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are each independently selected from H, hydroxy, and C _1-4 hydrocarbon groups with or without substituents, and h is 0 to 3 an integer between; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ , R ₂₅ are each independently selected from H, hydroxy, and C _1-4 hydrocarbon groups with or without substituents, and i is 0 to an integer between 3; B is 0; c is an integer between 1 and 4.

In another preferred example, A is SO ₂ X1, wherein X1 is deleted or selected from O, and S; W is O; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are independently selected from H , hydroxyl, C _1-4 hydrocarbon group with or without substituent, h is an integer between 1 and 6; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are independently selected from H, hydroxy, C _1-4 hydrocarbyl with or without substituents, i is an integer between 0 and 3; c is 0.

In another preferred embodiment, A is missing; W is NR ₁₇ , wherein R ₁₇ is H, or a C _1-4 hydrocarbon group with or without substituents; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are independently selected from H, hydroxyl, and C _1-4 hydrocarbon groups with or without substituents, h is an integer between 0 and 3; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are each independently selected from H, hydroxyl, and C _1-4 hydrocarbon groups with or without substituents, i is an integer between 0 and 4; B is O; c is one of 1 to 6 integer between.

In another preferred example, A is deleted; W is deleted; Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are each independently selected from H, hydroxyl, C _1- with or without substituents The hydrocarbon group of ₄ , h is an integer between 0 and 3; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are each independently selected from H, hydroxyl, C ₁ with or without substituents A hydrocarbon group of _-4 , i is an integer between 0 and 3; B is O; c is an integer between 1 and 10 (preferably between 1 and 6).

In another preferred embodiment, A is C(=O)X1, wherein X1 is deleted or selected from (CR ₁₂ R ₁₃ ) _e O, and (CR ₁₂ R ₁₃ ) _e S, wherein e is between 0 and 2 Integer, R ₁₂ , R ₁₃ , R ₁₄ are each independently hydrogen or C _1-4 alkyl; W is O, NR ₁₇ , -X2C(=O)X3, or missing, wherein R ₁₇ is H, or a band C _1-4 hydrocarbon group with or without substituent; Y is CHX4(CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are each independently selected from H, hydroxy, with or without substituent Hydrocarbon group of C _1-4 , h is an integer between 0 and 3, X4 is cyano, nitro, or hydroxyl; Z is (CR ₂₄ R ₂₅ ) _i , wherein R ₂₄ and R ₂₅ are each independently selected from H , hydroxyl, C _1-4 hydrocarbon group with or without substituents, i is an integer between 0 and 15; B is O; c is between 0 and 10 (preferably between 0 and 6) Integer.

In another preferred embodiment, any of the substituents is selected from the following group: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C1-C6 alkoxy, unsubstituted or halogenated Substituted C2-C6 alkoxyalkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C2-C6 alkylcarbonyl, unsubstituted or halogenated C1-C6 alkylene- Hydroxy, unsubstituted or C1-C6 alkyl substituted amine group.

In another preferred example, A is C(=O); Y is (CR ₂₂ R ₂₃ ) _h , wherein R ₂₂ and R ₂₃ are independently selected from H, hydroxyl and CN, and h is between 1 and 3 Integer; preferably, R ₂₂ is H, R ₂₃ is CN, and h is 1.

In another preferred embodiment, the compound structure is shown in formula I':

Wherein, the definition of each group in formula I' is as described above.

In another preferred embodiment, the compound structure is shown in formula I":

Wherein, the definitions of each group in the formula I" are as described above.

表示单键。In another preferred embodiment, in formula I, I' or formula I",

Represents a single key.

In another preferred example, the X is C (=O).

In another preferred example, R ₁ is selected from the group consisting of: H, and C _1-4 alkyl groups with or without substituents.

In another preferred example, R ₂ and R ₅ are each independently selected from: hydrogen, and C _1-4 alkyl groups with or without substituents.

In another preferred example, R ₃ is selected from the group consisting of: hydrogen, and C _1-4 alkyl groups with or without substituents.

In another preferred embodiment, R ₆ is selected from: hydrogen, C _1-4 alkyl with or without substituent, OR ₂₉ wherein R ₂₉ is selected from H, C ₁ with or without substituent _-6 alkyl.

In another preferred embodiment, R ₈ is selected from: hydrogen, C _1-4 alkyl group with or without substituent, and NR ₂₈ R ₂₉ , wherein R ₂₈ R ₂₉ is H, or with or without Substituted C _1-4 hydrocarbyl.

In another preferred example, R ₈ is selected from: hydrogen, halogen, and C _1-4 alkyl with or without substituents.

In another preferred embodiment, R ₉ is selected from: hydrogen, halogen, and C _1-4 alkyl with or without substituents.

In another preferred example, R ₁₀ is selected from: hydrogen, halogen, cyano, nitro, and C _1-4 alkyl with or without substituents.

In another preferred embodiment, R ₄ is selected from H, cyano group, C _1-6 alkyl group with or without substituent.

In a second aspect of the present invention, a pharmaceutical composition is provided, which comprises the compound described in the first aspect or a pharmaceutically acceptable salt, prodrug thereof, and a pharmaceutically acceptable carrier.

In another preferred embodiment, the effective amount refers to a therapeutically effective amount or an inhibitory effective amount, preferably 0.01-99.99%.

In another preferred embodiment, the pharmaceutical composition further comprises another one or more antitumor agents.

In another preferred embodiment, the pharmaceutical composition degrades JAK3.

In another preferred embodiment, the pharmaceutical composition is used to treat diseases related to the activity or expression of JAK3.

The third aspect of the present invention provides the use of the compound as described in the first aspect of the present invention for:

(a) preparing a medicine for treating diseases related to the activity or expression of JAK3;

(b) preparing a JAK3 targeted degrader;

(c) non-therapeutic degradation of JAK3 in vitro;

(d) non-therapeutic inhibition of tumor cell proliferation in vitro; and/or

(e) Treatment of diseases associated with JAK3 activity or expression.

In another preferred example, the disease related to the activity or expression of JAK3 is a tumor or an autoimmune disease.

In another preferred embodiment, the disease related to JAK3 activity or expression level is selected from the group consisting of organ transplant rejection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis) , cancer, asthma, atopic dermatitis, type 1 diabetes and diabetic complications, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, lymphoma, multiple myeloma , alopecia areata, and vitiligo.

The fourth aspect of the present invention provides a preparation method of the compound of formula I as described in the first aspect of the present invention, comprising the steps:

(a) in an inert solvent, react with the compound of formula IV and the compound of formula II to obtain the compound of formula I;

In the above formulas, the definitions of each group are as described above, and M ₁ is a leaving group.

In another preferred embodiment, the method further comprises the steps of:

(b) in an inert solvent, the compound of formula III and the compound of formula V are reacted to obtain the compound of formula II, wherein M ₁ and M ₂ are leaving groups.

The fifth aspect of the present invention provides a method for degrading JAK3, comprising the steps of: administering an effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof as described in the first aspect of the present invention to a target, or The subject is administered an inhibitory effective amount of the pharmaceutical composition according to the fourth aspect of the invention.

In another preferred embodiment, the degradation is non-therapeutic in vitro.

In another preferred embodiment, when an effective amount of the compound of formula I according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof is administered to the target, the effective amount for inhibition is 0.001-500 nmol/L, It is preferably 0.01-200 nmol/L.

The sixth aspect of the present invention provides a method for treating a disease related to the activity or expression of JAK3, the method comprising: administering a therapeutically effective amount of the compound of formula I according to the first aspect of the present invention to a treatment subject, Or the pharmaceutical composition according to the fourth invention of the present invention.

In another preferred example, the subject is a mammal; preferably, the mammal is a human.

In another preferred example, the disease related to the activity or expression of JAK3 is a tumor or an autoimmune disease.

In another preferred embodiment, the disease related to JAK3 activity or expression level is selected from the group consisting of organ transplant rejection, xenograft rejection, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis) , cancer, asthma, atopic dermatitis, type 1 diabetes and diabetic complications, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, lymphoma, multiple myeloma , alopecia areata, and vitiligo.

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (eg, the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, it is not repeated here.

Detailed ways

After extensive and in-depth research, the inventors prepared a class of compounds with the structure shown in formula I, and found that they have JAK3 degradation activity. In addition, the compound can degrade JAK3 at a very low concentration, and the activity is quite excellent, so it can be used to treat diseases such as tumors related to the activity or expression of JAK3. The present invention has been completed on this basis.

The present invention provides a new class of compounds and their use in degrading tyrosine protein kinase JAK3. The compounds of the present invention are capable of degrading JAK3, and can be used as JAK3 degraders to exert immunomodulatory effects, as well as for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Atopic dermatitis, keratoconjunctivitis sicca, and Crohn's disease.

the term

In the present invention, the term "C _1-8 hydrocarbon group" refers to a functional group containing only carbon and hydrogen atoms, wherein the number of carbon atoms is 1-8. Hydrocarbyl can be regarded as the free radical left after the corresponding hydrocarbon loses a hydrogen atom, which can be alkyl, cycloalkyl, alkenyl or alkynyl, etc.; its structure can be straight chain, branched chain or cyclic; it can be It is aliphatic and can also be aromatic.

The term "C _1-6 alkyl" refers to straight or branched chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, or similar groups.

The term "alkoxy" as used herein includes O-alkyl, wherein "alkyl" is as defined above.

The term "halo" as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo.

The compounds of the present invention may contain double bonds. When such double bonds are contained, the compounds of the present invention exist in cis, trans, or mixtures thereof.

Halogen as used herein includes fluorine, chlorine, bromine and iodine.

Unless otherwise indicated, alkyl groups and the alkyl portion of an alkoxy group as referred to herein may be straight chain, branched chain, or cyclic.

In the present invention, the term "cyclic hydrocarbon group" refers to a functional group containing both carbon and hydrogen atoms. Including cycloalkyl, cycloalkenyl (containing at least one carbon-carbon double bond) and aryl. They can be monocyclic, bicyclic and polycyclic. They can be spiro rings or fused rings.

In the present invention, the term "heterocyclic hydrocarbon group" refers to a functional group containing carbon, hydrogen and at least one heteroatom other than carbon and hydrogen. Including heterocycloalkyl, heterocycloalkenyl (containing at least one carbon-carbon double bond) and heteroaryl. One or more of the ring-forming atoms in the ring is a heteroatom. Heteroatoms can be O, N, and S atoms, and various combinations thereof. They can be monocyclic, bicyclic and polycyclic. They can be spiro rings or fused rings.

In the present invention, the term "substituent" includes but is not limited to fluorine, chlorine, bromine, cyano, hydroxyl, amino, C _1-6 hydrocarbyloxy, C _1-6 halohydrocarbyl, C _1-6 acyl, C _{1 -6} Sulfonyl.

The term "hydrocarbyloxy" as used herein refers to an O-hydrocarbyl group, wherein "hydrocarbyl" is as defined above.

The term "hydrocarbyloxycarbonyl" as used herein refers to a C(=O)O-hydrocarbyl group, wherein "hydrocarbyl" is as defined above.

The term "amino" as used herein refers to N(H or hydrocarbyl 1) (H or hydrocarbyl 2), wherein "hydrocarbyl" is as defined above.

The term "aminocarbonyl" as used herein refers to a C(=O)-amine group, wherein "amine" is as defined above.

The term "amido" as used herein refers to an N(H or hydrocarbyl)-C(=O)-hydrocarbyl group, wherein "hydrocarbyl" is as defined above.

In the present invention, the terms "comprising", "comprising" or "including" mean that the various ingredients can be used together in the mixture or composition of the present invention. Thus, the terms "consisting essentially of" and "consisting of" are encompassed by the term "comprising".

In the present invention, the term "pharmaceutically acceptable" ingredients refers to substances that are suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergy), ie, have a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject depends on the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to prespecify the exact effective amount. However, for a given situation, routine experimentation can be used to determine the effective amount, as is the judgment of the clinician.

As used herein, unless otherwise specified, the term "substituted" refers to the replacement of one or more hydrogen atoms on a group with a substituent selected from the group consisting of halogen, unsubstituted or halogenated C _1-6 alkyl, Unsubstituted or halogenated _C2-6 acyl, unsubstituted or halogenated _C1-6 alkyl-hydroxy.

Unless otherwise specified, in the present invention, all occurrences of compounds are intended to include all possible optical isomers, such as single chiral compounds, or mixtures of various chiral compounds (ie, racemates). In all compounds of the present invention, each chiral carbon atom can optionally be in the R configuration or the S configuration, or a mixture of the R and S configurations.

As used herein, the term "compounds of the present invention" refers to compounds of formula I. The term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the present invention with acids. Acids suitable for forming salts include, but are not limited to, inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, formic, acetic, propionic, oxalic, malonic, succinic, fumaric, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.

Compounds and their pharmaceutically acceptable salts

The present invention relates to a compound of formula I or a pharmaceutically acceptable salt thereof;

in:

表示单键；

represents a single key;

表示单键或双键；

Indicates a single bond or a double bond;

A is absent or selected from C(=O), C(=O)X1-, SOX1-, _{SO2X1-, C1-8 hydrocarbyl} with or without substituents, with or without substituents C _1-8 cyclic hydrocarbon group, and C _1-8 heterocyclic hydrocarbon group with or without substituent; wherein X1 is absent or selected from (CR ₁₂ R ₁₃ ) _e O, (CR ₁₂ R ₁₃ ) _e S and NR ₁₄ ; wherein R ₁₂ , R ₁₃ , and R ₁₄ are each independently selected from H, a C _1-8 hydrocarbon group with or without a substituent, and a C _1-8 ring with or without a substituent Hydrocarbyl, and C _1-8 heterocyclic hydrocarbon groups with or without substituents, e is an integer between 0 and 3;

W is absent or selected from O, NR ₁₇ , -X2C(=O)X3, -X2S(=O) _g X3; wherein R ₁₇ is H, C _1-8 hydrocarbyl with or without substituents, with C _1-8 cyclic hydrocarbon groups with or without substituents, C _1-8 heterocyclic hydrocarbon groups with or without substituents; wherein X2, X3 are each independently absent or selected from O, S, NR ₁₈ ; wherein g is an integer from 0 to 2; wherein R ₁₈ is H, a C _1-8 hydrocarbyl group with or without a substituent, a C _1-8 cyclic hydrocarbyl group with or without a substituent, C _1-8 heterocyclic hydrocarbon groups with or without substituents;

Y is ( _CR22R23 ) _h , _CHX4 ( _CR22R23 ) _h , CX4=CH( _{CR22R23 ) h} or ( _{CR22R23 ) h} ; wherein h is an integer between 0 and ₃₀ ; wherein R ₂₂ and R ₂₃ are each independently selected from H, cyano group, hydroxyl group, amino group, C _1-8 hydrocarbon group with or without substituent group, and C _1-8 ring group with or without substituent group Hydrocarbyl, C _1-8 heterocyclic hydrocarbyl with or without substituents, C _1-8 hydrocarbyloxy with or without substituents; wherein X4=H, halogen, cyano, nitro , hydroxyl, with or without substituent C _1-8 hydrocarbyloxy, with or without substituent C _1-8 hydrocarbyloxycarbonyl, with or without substituent C _1-8 amino, With or without substituent C _1-8 ester group, with or without substituent C _1-8 aminocarbonyl, with or without substituent C _1-8 hydrocarbyl, with or without substituent A substituted C _1-8 cyclic hydrocarbon group, with or without a substituent C _1-8 heterocyclic hydrocarbon group;

Z is (CR ₂₄ R ₂₅ ) _i , CHX5(CR ₂₄ R ₂₅ ) _i , CX5=CH(CR ₂₄ R ₂₅ ) _i or C≡C(CR ₂₄ R ₂₅ ) _i ; where i is between 0 and 30 Integer; wherein R ₂₄ , R ₂₅ are each independently selected from H, cyano, hydroxyl, amino, C _1-8 hydrocarbyl with or without substituent, with or without substituent C _1-8 Cyclic hydrocarbon group, with or without substituent C _1-8 heterocyclic hydrocarbon group, with or without substituent C _1-8 hydrocarbonoxy group; wherein X5=H, halogen, cyano, nitro, hydroxyl, With or without substituent C _1-8 hydrocarbyloxy, with or without substituent C _1-8 hydrocarbyloxycarbonyl, with or without substituent C _1-8 amino, with or without substituent C _1-8 ester group, with or without substituent C _1-8 aminocarbonyl, with or without substituent C _1-8 hydrocarbyl, with or without substituent base C _1-8 cyclic hydrocarbon group, with or without substituent C _1-8 heterocyclic hydrocarbon group;

B is absent or selected from O, C=O, S, NR ₁₅ , -NR ₁₅ C(=O)-, -C(=O)NR ₁₅ -, -C(=O)O-, OC(=O) O-, -NR ₁₅ C(=O)O-, -OC(=O)NR ₁₅ -, -NR ₁₅ C(=O)NR ₁₆ -, C _1-12 with or without substituents Hydrocarbon group, C _1-12 cyclic hydrocarbon group with or without substituent, and C _1-12 heterocyclic hydrocarbon group with or without substituent; wherein R ₁₅ and R ₁₆ are each independently selected from H , C _1-8 hydrocarbon groups with or without substituents, C _1-8 cyclic hydrocarbon groups with or without substituents, and C _1-8 heterocyclic groups with or without substituents Cyclohydrocarbyl;

X is selected from CR ₁₉ R ₂₀ , C(=O), S(=O), SO ₂ , NR ₂₁ ; wherein R ₁₉ and R ₂₀ are each independently selected from H, cyano, hydroxyl, amino, with or without C _1-8 hydrocarbyl with substituents, C _1-8 cyclohydrocarbyl with or without substituents, C _1-8 heterocyclic hydrocarbyl with or without substituents, with or without substituents Unsubstituted C _1-8 hydrocarbyloxy; wherein R ₂₁ is selected from H, C _1-8 hydrocarbyl with or without substituent, C _1- with or without substituent ₈ cyclic hydrocarbon group, C _1-8 heterocyclic hydrocarbon group with or without substituent;

R ₁ , R ₆ , R ₁₀ are each independently selected from H, C _1-8 hydrocarbon group with or without substituent, cyclic hydrocarbon group with or without substituent, with or without substituent Heterocyclic hydrocarbon group, C _1-6 acyl group with or without substituent;

R ₂ and R ₂ are each independently selected from: hydrogen, OR ₃₃ , NR ₃₄ R ₃₅ , cyano, halogen, C _1-8 hydrocarbon groups with or without substituents, with or without substituents Cyclic hydrocarbon group, heterocyclic hydrocarbon group with or without substituent, C _1-6 acyl group with or without substituent, amide group with or without substituent; wherein R ₅₃ , R ₃₄ , R ₃₅ is each independently selected from H, C _1-8 hydrocarbon group with or without substituent, cyclic hydrocarbon group with or without substituent, and heterocyclic hydrocarbon group with or without substituent;

R ₃ , R ₇ , R ₈ , R ₆ are each independently selected from: H, OR ₂₇ , NR ₂₈ R ₂₉ , cyano, halogen, nitro, C _1-8 hydrocarbyl with or without substituents, Cyclohydrocarbyl with or without substituents, heterocyclic hydrocarbyl with or without substituents, X6S(=O)kR ₃₀ , X6C(=O)R ₃₁ ; wherein _k is between 0 and 2 an integer of ; wherein R ₂₇ , R ₂₈ , R ₂₉ , R ₃₀ , R ₃₁ are independently selected from H, C _1-8 hydrocarbon groups with or without substituents, cyclic hydrocarbon groups, and heterocyclic hydrocarbon groups; wherein X6 is missing Or selected from O, S, NR ₃₀ ; wherein R ₂₂ is H, C _1-8 hydrocarbyl with or without substituents, cyclic hydrocarbyl with or without substituents, and with or without substituents Substituted heterocyclic hydrocarbon groups;

R ₄ is selected from H, cyano group, carboxyl group, C _1-8 hydrocarbon group with or without substituent group, hydrocarbon oxycarbonyl group with or without substituent group;

a is an integer between 0 and 5 (such as 1, 2, 3, 4, 5);

b is an integer between 0 and 3 (such as 1, 2, 3);

c is an integer between 0 and 30 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9);

d is an integer between 0 and 9 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9).

The integers described herein may be 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 unless otherwise specified.

In another preferred embodiment, each C1-8 cyclic hydrocarbon group is preferably a C3-8 cyclic hydrocarbon group (eg, a C3-8 cycloalkyl group).

In another preferred embodiment, each C1-8 heterocyclic hydrocarbon group is preferably a C3-8 heterocyclic hydrocarbon group (eg, a 4-10 membered heterocycloalkyl group containing 3-8 carbon atoms).

In a preferred embodiment of the present invention, the compound is selected from the group consisting of:

The compounds of the present invention may form pharmaceutically acceptable salts with inorganic acids, organic acids or bases. Described inorganic acid includes but not limited to hydrochloric acid, hydrobromic acid, nitric acid, perchloric acid, sulfuric acid or phosphoric acid etc.; Described organic acid includes but not limited to methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzene Sulfonic acid, p-toluenesulfonic acid, fumaric acid, oxalic acid, acetic acid, maleic acid, ascorbic acid, lactic acid, tartaric acid, malonic acid, glycolic acid, succinic acid and propionic acid, etc.; the bases include but are not limited to inorganic acids salts and amines.

The term pharmaceutically acceptable salts refers to those salts which, according to medical judgment, are suitable for use in contact with human and mammalian tissues without undue toxicity, irritation, allergic response, and the like. Pharmaceutically acceptable salts are well known in the art.

The present invention also encompasses pharmaceutical compositions containing prodrugs of compounds of formula I. Prodrugs include compounds in which the precursor molecule is covalently bound to the free carboxyl group of the compound of formula I through a carbonate, carbamate, amide, alkylester, phosphate, phosphoramidate bond, on hydroxyl, amino or amine groups.

Preparation of compounds

Preparation

The preparation method of the compound of formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.

The following reaction schemes illustrate the preparation of compounds of the present invention. Unless otherwise indicated, A, B, W, Y, Z, X, a, b, c, d, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ in the reaction scheme and subsequent discussion , R ₇ , R ₈ , R ₉ , R ₁₀ are as defined above.

In general, compounds of formula I can be obtained from formula III as described in the following schemes:

In compound II, when W is ether, it can be prepared by direct nucleophilic substitution with an intermediate containing a leaving group under the action of formula III (W1=OH), or by Mitsunobu reaction and alcohol reaction; when When W is ester, carbamate (NHCO ₂ ), it can be prepared by reacting with acid chloride, activated ester (amide), carboxylic acid, isocyanate by formula III (W1=OH) under the action of alkali; when W is amine, it can be prepared by reacting with acid chloride, activated ester (amide), carboxylic acid and isocyanate It can be prepared by direct nucleophilic substitution with an intermediate containing a leaving group under the action of formula III (W1=NH ₂ ), or by reductive amination reaction of formula III (W1=NH ₂ ) with an aldehyde/ketone. ; When W is amide, alkoxycarbonyl amine (OCONH) and urea, it can be prepared by reacting with corresponding acid chloride, activated ester (amide), carboxylic acid and isocyanate under the action of base by using formula III (W1=NH ₂ ).

In compound I, when A is connected with nitrogen atom by C-N bond, it can be prepared by direct substitution or reductive amination; when A is connected with nitrogen atom by way of amide, urea, carbamate, sulfonamide and sulfamide, it can be prepared by direct substitution or reductive amination. The corresponding acid chlorides, activated esters (amides), carboxylic acids, isocyanates, sulfonyl chlorides, sulfuryl chlorides were prepared.

Generally, according to the connection of structures A and W, compound I can also be obtained by first connecting formula IV to the intermediate chain, and then reacting with formula III. The chemical synthesis method used is the same as above.

Compounds of formula III, IV can be obtained by known synthetic methods or are readily commercially available.

Use of compounds of formula I

The compound of formula I can be used for one or more of the following purposes:

(a) preparing a medicine for treating diseases related to the activity or expression of JAK3;

(b) preparing a JAK3 targeted degrader;

(c) non-therapeutic degradation of JAK3 in vitro;

(d) non-therapeutic inhibition of tumor cell proliferation in vitro; and/or

(e) Treating diseases associated with JAK3 activity or expression (eg, autoimmune diseases).

In another preferred example, the disease related to the activity or expression level of JAK3 is organ transplant rejection, xenotransplantation, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, psoriasis (psoriasis), cancer, asthma, Atopic dermatitis, type I diabetes and diabetic complications, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, lymphoma, multiple myeloma, alopecia areata, vitiligo, etc. .

The compound of formula I of the present invention can be used to prepare a pharmaceutical composition comprising: (i) an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof; and (ii) a pharmaceutically acceptable Carrier.

In another preferred embodiment, the effective amount refers to a therapeutically effective amount or an inhibitory effective amount.

The compounds of formula I of the present invention can also be used in methods of inhibiting or degrading JAK3, either non-therapeutic or therapeutic in vitro.

In another preferred embodiment, when an inhibitory effective amount of the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof is administered to the inhibited object, the inhibitory effective amount is 0.001-500 nmol/L, preferably 0.01 -200nmol/L.

In particular, the present invention also provides a method for treating a disease related to the activity or expression of JAK3, the method comprising: administering a therapeutically effective amount of the compound of formula I to the subject, or the compound of formula I as an active ingredient pharmaceutical composition.

Pharmaceutical compositions and methods of administration

Since the compound of the present invention can significantly degrade JAK3 to exert its inhibitory activity against JAK3, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are mainly The pharmaceutical composition of the active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression level of JAK3. According to the prior art, the compounds of the present invention can be used to treat diseases including tumors and the like.

The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount. The "safe and effective amount" refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein means that the components of the composition 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 include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as

), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium fatty acid, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, 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 in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

Besides these inert diluents, the compositions can also contain 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 such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and 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 non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

Dosage forms for topical administration of the compounds of this invention 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 that may be required if necessary.

The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is The administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.

The main advantages of the present invention include:

1. A compound of formula I is provided.

2. Provided is a JAK3 degrading agent with novel structure and its preparation and application. The inhibitor can degrade JAK3 at a very low concentration.

3. A pharmaceutical composition for treating diseases related to JAK3 activity is provided.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise specified.

Example 1 Preparation of compound 3

first step:

2.14g of 6-bromohexanoyl chloride and 1.37g of pomalidomide were dissolved in 50ml of THF (tetrahydrofuran), stirred and refluxed for 8h, cooled to room temperature, concentrated and dried under vacuum at 40°C to obtain 2.19g of compound (1). MS (ESI): 450 [M+H] ⁺ .

Step 2:

1g of compound (1), 1.28g of compound (2) and 2.6g of DIPEA (N,N-diisopropylethylamine) were dissolved in 50ml of DMF (N,N-dimethylformamide), stirred at 80°C for 6h, The mixture was cooled to room temperature, concentrated and subjected to column chromatography to obtain 810 mg of compound (3), yield: 65.6%. MS (ESI): 615 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD) δ 8.61 (d, J=8Hz, 1H), 8.11 (s, 1H), 7.72 (m, 1H), 7.54 (d, J=8Hz, 1H), 7.10 ( d, J=4Hz, 1H), 6.63 (s, 1H), 5.14 (dd, J=12, 4Hz, 1H), 3.48 (br, 3H), 3.37 (s, 1H), 2.50-3.10 (m, 10H) ), 2.32 (m, 1H), 2.16 (m, 1H), 1.25-2.00 (m, 9H), 1.03 (d, J=8Hz, 3H).

Example 2 Preparation of compound 7

first step:

Dissolve 100 mg of 4-hydroxythalidomide, 96 mg of triethylene glycol monobenzyl ether, and 100 mg of triphenylphosphine in 10 ml of anhydrous THF, drop 95 mg of DIAD (diisopropyl azodicarboxylate), and react at room temperature for 2 h. THF was removed under reduced pressure, and 110 mg of compound (4) was obtained after purification by column chromatography. MS (ESI): 497 [M+H] ⁺ .

Step 2:

100 mg of compound (4) and 100 mg of 10% Pd-C were added to 10 ml of methanol, and hydrogenated at room temperature overnight. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography to obtain 40 mg of compound (5). MS (ESI): 407 [M+H] ⁺ .

third step:

30 mg of compound (5) was dissolved in 5 ml of dichloromethane, 47 mg of Dess-martin oxidant was added, and the reaction was carried out at room temperature for 3 h. Add saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ , stir for 5 min, separate the organic layer, dry over anhydrous Na ₂ S ₂ O ₃ , and concentrate to dryness to obtain compound (6), which is directly used in the next step. .

After compound (6) was dissolved in 7 ml of dichloromethane, 36 mg of raw material (2) and 23 mg of NaBH(OAc) ₃ were added, the reaction was carried out at room temperature overnight, the dichloromethane was evaporated under reduced pressure, and the compound (7) was obtained after purification by column chromatography, 20 mg. MS (ESI): 634 [M+H] ⁺ . ¹ H NMR (hydrochloride, 400 MHz, D ₂ O) δ 8.09 (d, J=1.6 Hz, 1H), 7.45-7.62 (m, 1H), 7.18 (dd, J=12.0, 7.2 Hz, 1H), 7.07(m, 2H), 6.54-6.70(m, 1H), 4.90-5.08(m, 2H), 4.12(m, 2H), 3.30-3.85(m, 14H), 3.20(s, 3H), 2.73( m, 2H), 2.42 (m, 2H), 2.09 (m, 2H), 1.73 (m, 1H), 1.00 (d, J=8.0 Hz, 3H).

Example 3 Preparation of compound 10

first step:

174 mg of benzyl 2-(2-(2-bromoethoxy)ethoxy)acetate, 100 mg of potassium carbonate, 20 mg of potassium iodide and 100 mg of pomalidomide were added to 20 ml of DMF (N,N-dimethylformamide) , 80 ℃ reaction overnight. The reaction solution was purified by column chromatography to obtain 113 mg of compound (8). MS (ESI): 510 [M+H] ⁺ .

Step 2:

100 mg of compound (8) and 100 mg of 10% Pd-C were added to 10 ml of methanol, and hydrogenated at room temperature overnight. After filtration, the filtrate was concentrated, and the residue was purified by column chromatography to obtain 73 mg of compound (9). MS (ESI negative ion): 418 [MH] ⁻ .

third step:

50 mg of compound (9) and 30 mg of raw material (2) were dissolved in 5 ml of dichloromethane, and 20 mg of HOBt (1-hydroxybenzotriazole) and EDC (1-(3-dimethylaminopropyl)-3-ethyl) were added. carbodiimide hydrochloride) 40 mg, reacted at room temperature overnight. Dichloromethane was evaporated under reduced pressure and purified by column chromatography to obtain compound (10), 50 mg. MS (ESI): 647 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl3) δ 10.63 (br, 1H), 9.84 (br, 1H), 8.22 (d, J=1.2Hz, 1H), 7.43 (t, J=7.6Hz, 1H), 7.06 ( dd, J=7.2, 1.2Hz, 1H), 6.97 (d, J=2.8Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 6.51 (d, J=3.6Hz, 1H), 6.42 ( m, 1H), 5.12 (br, 1H), 4.91 (m, 1H), 4.55 (br, 2H), 3.89 (m, 4H), 3.64 (s, 3H), 3.51 (br, 2H), 3.38 (m , 3H), 2.50-3.01(m, 6H), 2.25(br, 1H), 2.10(m, 1H), 1.86(br, 1H), 1.64(br, 1H), 0.96(d, J=6.8Hz, 3H).

Example 4 Preparation of compound 13

first step:

200 mg of raw material (2) was dissolved in 20 ml of dichloromethane, 100 mg of triethylamine and 180 mg of 5-benzyloxypentanesulfonyl chloride were added, and the reaction was carried out at room temperature overnight. The solvent was evaporated under reduced pressure, and 187 mg of compound (11) was obtained after purification by column chromatography. MS (ESI): 486 [M+H] ⁺ .

Step 2:

180 mg of compound (11) and 180 mg of 10% Pd-C were added to 20 ml of methanol, and hydrogenated at room temperature overnight. Filtration, concentration of the filtrate, and purification by column chromatography gave compound (12) 134 mg. MS (ESI): 396 [M+H] ⁺ .

third step:

50 mg of 4-hydroxythalidomide, 50 mg of triphenylphosphine and 50 mg of compound (12) were dissolved in 5 ml of anhydrous tetrahydrofuran, 50 mg of DIAD (diisopropyl azodicarboxylate) was added dropwise, and the reaction was carried out at room temperature for 3 h. The tetrahydrofuran was removed under reduced pressure and purified by column chromatography to obtain 33 mg of compound (13). MS (ESI): 652 [M+H] ⁺ . ¹ H NMR (HCl, 400 MHz, D ₂ O) δ 8.11 (d, J=2.0 Hz, 1H), 7.43-7.61 (m, 1H), 7.20 (dd, J=11.6, 6.8 Hz, 1H) , 7.08(m, 2H), 6.60-6.71(m, 1H), 5.02(m, 2H), 4.54(m, 1H), 4.02(m, 2H), 3.85(m, 2H), 3.18(s, 3H ), 2.72-3.12 (m, 4H), 2.15-2.50 (m, 4H), 1.28-2.06 (m, 9H), 0.96 (d, J=7.6Hz, 3H).

Example 5 Preparation of compound 17

first step

4-Fluoxalidomide (2.00g) was added to 3-amino-1-propanol (10.00g), microwave reaction was carried out for 0.5 hours, the reaction solution was diluted with dichloromethane (50ml), followed by 0.5M dilute hydrochloric acid, Washed with water and saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column to obtain 0.60 g of compound 14 as a yellow solid, yield: 25%. MS (ESI): 331 [M+H] ⁺ .

second step

Compound 17 (200 mg) and diisopropylethylamine (150 mg) were dissolved in dichloromethane (10 ml), and methanesulfonyl chloride (80 mg) was added dropwise. After the addition, the reaction solution was continued to stir overnight. The reaction solution was washed with 0.5M dilute hydrochloric acid and saturated brine, the organic phase was concentrated under reduced pressure, the residue was dissolved in anhydrous N,N-dimethylformamide (10ml), tofacitinib free base 16 (226mg) was added on ice Under cooling in a water bath, 60% sodium hydride (40 mg) was added in portions, slowly warmed to room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel preparative plate to obtain 16 mg of compound 17 as a yellow solid, yield: 4.2%. MS (ESI): 626[M+H] ⁺ .

Similarly, the following compounds were prepared by a method similar to the above example:

Example 6 Detection of the activity of compounds to degrade JAK3 protein by Western blot

Cell line: Jurkat cell line was cultured in an incubator at 37° C., 5% CO ₂ , and saturated humidity with RPMI1640 containing 10% calf serum.

The DMSO control group and the compound intervention group (10 μM) were set. After 24 hours of treatment, the cells were collected and 100 μL of pre-cooled cell lysate was added, lysed on ice for 30 min, and the total cell protein was extracted. Quantitative. Routine gel preparation, sample loading, electrophoresis, then transfer to membrane, block, add rabbit anti-human JAK3 (1:500), incubate overnight at 4°C, and add horseradish peroxidase-labeled goat anti-rabbit IgG (1:500) after rinsing. 5000), after rinsing, the color of ECL developer solution was developed, scanned and imaged by Bio-Rad gel imaging system, and processed and analyzed by computer software. Glyceraldehyde phosphate dehydrogenase (GAPDH) was used as an internal control.

The grayscale analysis of each band was performed using Image J software to calculate the degradation rate of the compound to degrade JAK3 protein.

The degradation activities of the compounds on JAK3 protein in Jurkat cells are shown in the following table:

Compound number degradative activity Compound number degradative activity 3 ++++ twenty two ++++ 7 +++ twenty three ++++ 10 +++ twenty four +++ 14 +++ 25 +++ 15 ++++ 26 ++++ 18 +++ 27 ++++ 19 +++ 28 +++ 20 +++ 29 +++ twenty one +++ 30 ++++

Remarks: In the above table, "-" means no degradation activity, "+" means the degradation rate is 10%-30%, "++" means the degradation rate is 30%-50%, "+++" means the degradation rate 50%-90%, "++++" means the degradation rate is greater than 90%.

Example 7 CCK8 method to detect the inhibitory effect of the compound on the proliferation of Jurkat cells (human leukemia T lymphocytes)

The inhibitory effect of compounds on Jurkat cell proliferation was determined by CCK8 assay in vitro. Specific steps are as follows:

Jurkat cells were cultured in 1640 medium with 10% calf serum, seeded in a 96-well plate, 2×10 ⁵ cells/well, and placed in a 37°C, 5% CO ₂ incubator. The compounds were dissolved in dimethyl sulfoxide (DMSO) to obtain a solution with a concentration of 10 mM, then diluted with phosphate buffer to the desired concentration, and added to the above 96-well plates respectively, with 2 wells for each concentration, 10 μl per well, and 10 μl per well. Each concentration was tested in two parallels. The corresponding serial dilutions in DMSO were added to the plate as a control.

After culturing the above 96-well plate in a 37°C, 5% CO ₂ cell incubator for 48 hours, 10 μl of CCK8 solution was added to each well, and the incubation was continued in the incubator for 1 to 4 hours. The absorbance value at 465 nm was measured.

Relative cell viability after compound treatment was calculated from light absorbance values.

The _IC50 of compounds on Jurkat cells was calculated by software.

The in vitro proliferation inhibitory effects of the synthesized compounds on Jurkat cells are shown in Table 1:

Table 1

Compound number IC₅₀(μM) 3 20 7 100 10 60 14 10 15 8

The above results indicated that the synthesized compounds possessed a good inhibitory activity against Jurkat cells.

Example 8 In vivo anti-rheumatoid arthritis activity of compound (15)

The anti-rheumatoid arthritis effect of compound (15) was determined in vivo with Wistar rat rheumatoid arthritis induced by whole Freund's adjuvant as a model. Specific steps are as follows:

1) Test sample

Sample: Compound (15).

2) Preparation method

Sample: Compound (15), dissolved with physiological saline injection during preparation

3) Animals and Adjuvants

24 Wistar rats, male, weighing 170-200 g.

Adjuvant: Complete Freund's Adjuvant (CFA), Sigma.

4) Test method

The Wistar rats were randomly divided into 4 groups with 6 rats in each group. They were blank control group, model group, compound (15) group (20 mg/kg ip administration), and tofacitinib positive control group (20 mg/kg po administration). Rheumatoid arthritis was induced by intradermal injection of 0.15 mL of CFA into the left hind paw of rats. The rats were given administration on the 11th day after modeling, once a day, and ended on the 20th day. After the treatment, the left hind paw volume was measured, and the paw swelling inhibition rate was calculated.

5) Test results

The inhibition rate of compound (15) on full Freund's adjuvant-induced rheumatoid arthritis in rats is shown in Table 2:

Table 2

group Foot swelling inhibition rate (%) Blank control group - model group - Compound (15) 49 Positive control (tofacitinib) 29

The above in vivo experimental results show that compound (15) has good anti-rheumatoid arthritis activity in vivo, and the activity is significantly higher than that of the positive control drug tofacitinib.

All documents mentioned herein are incorporated by reference in this application as if each document were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (8)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof:

wherein:

represents a single bond;

represents a single bond;

a is absent or selected from C (═ O) X1; wherein X1 is (CR)₁₂R₁₃)_eO; wherein R is₁₂、R₁₃Each independently is H, e is an integer between 0 and 3;

w is absent or selected from O, NR₁₇X2C (═ O) X3; wherein R is₁₇Is H; wherein X3 is NR₁₈And X2 is absent, R₁₈Is H;

y is (CR)₂₂R₂₃)_h(ii) a Wherein h is an integer between 0 and 6; wherein R is₂₂、R₂₃Each independently is H;

z is (CR)₂₄R₂₅)_i(ii) a Wherein i is an integer between 0 and 6; wherein R is₂₄、R₂₅Each independently is H;

b is absent or is O;

x is C (═ O);

R₁is hydrogen; r₆Is methyl; r₁₀Is hydrogen; r₂Is hydrogen; r₅Is methyl;

R₃、R₇、R₈、R₉each independently is hydrogen; r₄Is hydrogen;

a is 5; b is 3; c is an integer between 0 and 6; d is 1.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

in said formula I, A is absent; w is X2C (═ O) X3 where X3 is NR₁₈And X2 is absent; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, H is an integer between 1 and 6; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is an integer between 1 and 6; c is 0; or

In said formula I, A is absent; w is absent or is O; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, and H is an integer from 0 to 3; b is O; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is an integer between 0 and 3; c is an integer between 1 and 6; or

Wherein a is C (═ O) X1, where X1 is (CR)₁₂R₁₃)_eO; wherein R is₁₂、R₁₃Each independently is H, e is 1; w is NR₁₇Wherein R is₁₇Is H; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, and H is an integer from 0 to 3; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is an integer between 0 and 3; b is O; c is an integer between 1 and 4; or

In said formula I, A is absent; w is NR₁₇Wherein R is₁₇Is H; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, and H is an integer from 0 to 3; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is an integer between 0 and 4; b is O; c is an integer between 1 and 6; or

In said formula I, A is absent; deletion of W; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, H is 0; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is 0; b is O; c is an integer between 1 and 6.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula I, a is absent; w is X2C (═ O) X3, where X3 is NH and X2 is absent; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, H is an integer between 1 and 6; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is 0(ii) a c is 0.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is absent; deletion of W; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, and H is an integer from 0 to 3; b is O; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is an integer between 0 and 3; c is an integer between 1 and 6.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein a is absent; deletion of W; y is (CR)₂₂R₂₃)_hWherein R is₂₂、R₂₃Each independently is H, H is 0; z is (CR)₂₄R₂₅)_iWherein R is₂₄、R₂₅Each independently is H, i is 0; b is O; c is an integer between 1 and 4.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, for:

(a) preparing a medicament for treating diseases related to the activity or expression amount of JAK 3;

(b) preparing a JAK3 targeted degradation agent;

(c) non-therapeutically degrading JAK3 in vitro; and/or

(d) Non-therapeutically inhibiting tumor cell proliferation in vitro.

8. A method of degrading JAK3 in vitro, the method comprising: administering to a subject an effective amount of a compound of formula I as described in claim 1 or a pharmaceutically acceptable salt thereof.