WO2022117012A1

WO2022117012A1 - Spirocyclic jak inhibitor, pharmaceutical composition containing same, and application thereof

Info

Publication number: WO2022117012A1
Application number: PCT/CN2021/134880
Authority: WO
Inventors: 吕志俭; 李佳; 苏明波; 高安慧
Original assignee: 百极弘烨（广东）医药科技有限公司; 百极弘烨(南通)医药科技有限公司
Priority date: 2020-12-02
Filing date: 2021-12-01
Publication date: 2022-06-09
Also published as: CN116783198A

Abstract

The present invention relates to a spirocyclic JAK inhibitor, a pharmaceutical composition containing same, and an application thereof. Specifically, the present invention relates to a compound as shown in formula I or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug, or solvate thereof, and also relates to a pharmaceutical composition of the compound and using the compound as an JAK inhibitor, and a medical use of the compound in the preparation of a drug for preventing and/or treating a disease related to JAK, especially JAK1.

Description

Spirocyclic JAK inhibitor, pharmaceutical composition containing same and use thereof

technical field

The invention belongs to the field of medicinal chemistry, and particularly relates to a spirocyclic JAK inhibitor, a pharmaceutical composition containing the same, and applications.

Background technique

Protein kinases (PKs) are a group of enzymes that constitute one of the largest human enzyme families that regulate a variety of important biological processes including, inter alia, cellular kinases that catalyze protein, lipid, sugar, nucleoside and other cellular metabolism phosphorylation and plays a key role in all aspects of eukaryotic cell physiology. Aberrant kinase activity has been shown to be involved in a number of human diseases, including cancer, autoimmune and inflammatory diseases.

Janus kinases (JAKs) are cytoplasmic tyrosine kinases that transduce cytokine signals from membrane receptors to STAT transcription factors, which play an important role in the process of cytokine signaling. The JAK family includes four members, JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAKs typically associate in pairs with cytokine receptors as homodimers or heterodimers. Cytokines bind to their receptors, causing dimerization of the receptor molecules, and receptor-coupled JAKs approach each other and are activated by phosphorylation of interacting tyrosine residues. The JAK family transmits cytokine-mediated signals into cells through the JAK-STAT (signal transducer and activator of transcription) pathway.

Signal Transducer and Activator of Transcription (STAT) are a group of cytoplasmic proteins that can bind to DNA in the regulatory region of target genes. As the downstream substrates of JAKs, STATs can be activated by tyrosine phosphorylation under the stimulation of external signals, and then transferred to the nucleus to regulate gene transcription. When cytokines bind to their receptors, JAK family members autophosphorylate and/or transphosphorylate each other, followed by phosphorylation by STATs, which then migrate into the nucleus to regulate transcription.

Many abnormal immune responses, such as allergies, asthma, (allogeneic) transplant rejection, rheumatoid arthritis, autoimmune diseases such as amyotrophic lateral sclerosis and multiple sclerosis, myelodysplastic disorders, leukemias and lymphomas Such as hematological malignancies, their regulation is related to the JAK/STAT signaling pathway.

Research shows that blocking signal transduction at the level of JAK kinases holds promise for the development of treatments for inflammatory diseases, autoimmune diseases, myeloproliferative diseases and cancer. Inhibition of JAK kinases also aids in the treatment of skin immune diseases such as psoriasis and skin sensitization. Already on the market are Pfizer's Toficitinib, for the treatment of rheumatoid arthritis; and Incyte's ruxolitinib, for the treatment of myelofibrosis and acute graft-versus-host disease.

However, some existing JAK enzyme inhibitors also have some obvious toxic side effects. For example, some JAK inhibitors are prone to cause the following side effects: infection, including pneumonia, viral infection (such as herpes zoster infection), bacterial infection, actinomycetes Infections (mycobacterial infections), fungal infections, decreased immunity (eg, decreased NK cells), and anemia. In the United States, it even gets a Black box for some serious side effects, including, for example, acute tuberculosis, invasive fungal infections, bacterial infections, and some lymphomas or other tumors. Studies have shown that the existing JAK inhibitors often have inhibitory activities on JAK1 and JAK3, and most of these side effects are related to the inhibition of the activity of JAK3.

However, studies have shown that JAKs family kinases are responsible for regulating numerous signaling pathways. Since JAK1 and JAK3 are components of a common γ-chain cytokine receptor complex, it is difficult to develop inhibitors that are highly selective for JAK1.

JAK1 plays a key role in the regulation of biological responses, and JAK1 is widely expressed and associated with several major cytokine receptor families. It is involved through the IL-2 receptor gamma subunit family (IL-2, IL-4, IL-7R, IL-9R, IL-15R and IL-21R), the IL-4 receptor family (IL-4R, IL-21R) -13R), signaling of members of the gp130 receptor family and class II cytokine receptors, including the IL-10 receptor family and both the Type I and Type II IFN receptor families.

In summary, there is an urgent need in the art to develop inhibitors of Janus kinases or related kinases, especially inhibitors with high selectivity for JAK1.

SUMMARY OF THE INVENTION

The present invention provides an inhibitor of JAK or related kinases, especially an inhibitor with high selectivity to JAK1.

The first aspect of the present invention provides a compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,

In the formula,

R1, _R2 and _R3 are each independently selected from the group consisting _of substituted or unsubstituted H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amido , sulfonamido, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R _a ;

Or R ₁ and R ₂ together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl; Wherein, described substitution refers to be replaced by one or more R _a ;

B is independently selected from the group consisting of bond, -( _CH2 ) _r- , C(=O), _NRb , C(=O)O-,

-(CH ₂ ) _p -R _c , O, S, SO, SO ₂ ; R _c is selected from: C(=O)O-,

wherein, R _is independently selected from the group consisting of H, C1-C6 alkyl;

wherein, the H atoms in -(CH ₂ ) _r - and -(CH ₂ ) _p - may be optionally substituted by one or more _Ra ;

C is selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R _a ;

r and p are each independently 1, 2, 3, 4;

m, n, k and l are each independently 0, 1, 2, 3, and m+n≥1, k+l≥1;

The H in the moiety can be optionally substituted with one or more _Ra ;

wherein each R is independently selected from the group consisting of substituted _or unsubstituted groups: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl and C6-C12 aryl; wherein, the substitution described in R _a refers to being substituted by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2- C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

In another preferred embodiment, the compound represented by formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,

In the formula,

Or R ₁ and R ₂ together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein , the substitution refers to being substituted by one or more R _a ;

-(CH ₂ ) _p -R _c , O, S, SO, SO ₂ ; R _c is selected from: C(=O)O-,

C is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R _a ;

r and p are each independently 1, 2, 3, 4;

m, n, k and l are each independently 0, 1, 2, 3, and m+n≥1, k+l≥1;

The H in the moiety can be optionally substituted with one or more _Ra ;

In another preferred embodiment, each R _a is independently selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, Formyl, formamido, C1-C6 alkyl, halogenated C1-C6 alkyl, (CH ₂ ) _t G, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl, wherein t is 1, 2 or 3; G is selected from: 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,

Partially selected from:

where q is 0, 1, 2, 3, 4 or 5;

_Ra is defined as above.

In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate has the structure shown in formula II:

where q is 0, 1, 2, 3, 4 or 5;

R ₁ , R ₂ , R ₃ , _Ra , B and C are as defined above.

In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, B is selected from the following group: C(=O)O-,

Wherein, the definition of R _b is as described above.

In another preferred example, in the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, C is selected from the group consisting of substituted or unsubstituted groups: 3 -8-membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, C6-C10 aryl; wherein, the substitution refers to being substituted by one or more R _a ;

_Ra is defined as above.

In another preferred embodiment, C is selected from the group consisting of substituted or unsubstituted groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, Linyl, phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to substitution by one or more R _a ; R _a is as defined above.

In another preferred embodiment,

Selected from:

where q is 0, 1, 2, 3, 4 or 5;

_Ra is defined as above.

In another preferred embodiment, B is selected from: -NH-,

-NH-C(=O)-, optionally, each hydrogen in the above groups is replaced by a C1-C6 alkyl group.

In another preferred example, C is selected from: H, methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothienyl, benzoyl furanyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from fluorine, chlorine, bromine, nitro, cyano, Hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, aminosulfonyl (or sulfonamido).

In another preferred example, C is selected from: H, methoxy, phenyl, methyl, ethyl,

cyclopropyl,

cyclohexyl,

Naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl group, methoxy group, methyl formate group, trifluoromethyl group, phenyl group, aminosulfonyl group (or sulfonamido group).

In another preferred embodiment, C is selected from: H, methyl, methoxy,

phenyl,

In another preferred embodiment, R ₁ is hydrogen.

In another preferred embodiment, R ₂ is hydrogen.

In another preferred embodiment, R ₃ is hydrogen.

In another preferred embodiment,

selected from

In another preferred embodiment, the compound has the structure shown in formula II:

where q is 0, 1, 2, 3, 4 or 5;

R ₁ , R ₂ , R ₃ , _Ra , B and C are as defined above.

In another preferred embodiment, each C1-C6 alkyl group is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl.

In another preferred embodiment, each C1-C6 alkoxy group is independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy , tert-butoxy.

In another preferred embodiment, each C2-C6 alkenyl group is independently selected from vinyl, propenyl, and allyl.

In another preferred embodiment, each C2-C6 alkynyl group is independently selected from ethynyl and propynyl.

In another preferred embodiment, each 3- to 10-membered heterocycloalkyl group is independently selected from tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, and morpholinyl.

In another preferred embodiment, each C3-C10 cycloalkyl group is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

In another preferred embodiment, each 5-12-membered heteroaryl group is independently selected from pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indole base, benzothienyl, benzofuranyl.

In another preferred embodiment, each C6-C12 aryl group is independently selected from phenyl and naphthyl.

In another preferred example, in formula I, R ₁ , R ₂ , R ₃ , R _a , B and C are specific groups corresponding to the specific compounds in the examples.

In another preferred embodiment, the compound or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, the compound is selected from the following group:

In another preferred embodiment, the compound of formula I is selected from the compounds shown in the examples.

The second aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate; and acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further includes a drug selected from the group consisting of:

PD-1 inhibitors (eg, nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10 , BAT1306, AK105, LZM 009 or biosimilars of the above drugs, etc.), PD-L1 inhibitors (such as durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F 520, GR1405, MSB2311 or biosimilars of the above drugs, etc.), CD20 antibodies (such as rituximab, obinutuzumab, Ofatumumab, veltuzumab, tositumumab, 131I-tositumumab, tiimumab, 90Y-tiimumab, 90In-tiimumab, tiimumab ( ibritumomab tiuxetan), etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM01) , ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocaltinib), PI3K inhibitors (such as idelaris, Duvelisib, Dactolisib, Taselisib, Bimiralisib, Omipalisib, Buparlisib, etc.), BTK inhibitors (such as ibrutinib, Tirabrutinib, acalatinib, zanubrutinib, Vecabrutinib, etc.), EGFR inhibitors (such as afatinib, gefitinib, erlotinib) Inhibitors such as Sorafenib, pazopanib, regorafenib, sertratinib, Ningetinib, cabozantinib, sunitinib, donafenib, etc.), HDAC inhibitors (such as Givinostat, Tucidinostat, vortex) Notatum, Fimepinostat, Droxinostat, Entinostat, Darxilast, Quisinostat, Tycodinaline, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, Milciclib, Trilaciclib, Lerociclib, etc.) , MEK inhibitors (such as selumetinib (AZD6244), trametinib (GSK1120212), PD0325901, U0126, Pim asertib (AS-703026), PD184352 (CI-1040, etc.), mTOR inhibitors (eg, Vistusertib, etc.), SHP2 inhibitors (eg, RMC-4630, JAB-3068, TNO155, etc.), or a combination thereof.

The third aspect of the present invention provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound described in the first aspect of the present invention or its stereoisomer or optical isomer, The pharmaceutically acceptable salts, prodrugs or solvates are mixed to form a pharmaceutical composition.

In another preferred embodiment, the compounds of the present invention can be prepared into powders, tablets, granules, capsules, solutions, emulsions, suspensions and the like.

In another preferred embodiment, the pharmaceutical composition is used to treat or prevent diseases related to the activity or expression level of JAK kinase.

In another preferred embodiment, the pharmaceutical composition is used as a JAK kinase inhibitor, preferably as a JAK1 kinase inhibitor.

The fourth aspect of the present invention provides the use of the compound described in the first aspect or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof for preparing treatment or prevention Medicines or pharmaceutical compositions for diseases associated with the activity or expression of JAK kinases.

In another preferred embodiment, the disease is selected from the group consisting of cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, Rheumatoid Arthritis, Skin Disorders, Multiple Sclerosis, Rheumatoid Arthritis, Psoriatic Arthritis, Inflammatory Bowel Disease, Myasthenia Gravis, Psoriasis.

Wherein, the cancer is selected from the group consisting of prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoid hyperplasia, pancreatic cancer, leukemia, lymphoma, and multiple myeloma.

In another preferred example, the disease related to the activity or expression level of the JAK kinase is a JAK1-related disorder.

Wherein, the JAK1-related disorder is preferably selected from the group consisting of type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis , Crohn's disease and alopecia areata.

In another preferred embodiment, there is provided a use of the compound described in the first aspect or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, for the preparation of inhibiting JAK A drug or pharmaceutical composition with kinase activity; wherein, the JAK kinase is preferably a JAK1 kinase.

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

Through extensive and in-depth research, the inventors have unexpectedly discovered a new JAK inhibitor for the first time, which has a novel structure, good biological activity and excellent selectivity against JAK1. Specifically, for the compounds of the present invention, the selectivity represented by the ratio of JAK2/JAK1 or the ratio represented by the ratio of JAK3/JAK1 or the ratio of TYK2/JAK1 is increased by an average of about 10-fold (most compounds are increased by about 20- 100 times). Therefore, the side effects associated with the inhibition of JAK3 by the compounds of the present invention are significantly reduced, and the safety is significantly improved. The present invention has been completed on this basis.

the term

In the present invention, unless otherwise specified, the terms used have the ordinary meanings known to those skilled in the art.

When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. That is, when the linking group -L1- listed in the present invention does not indicate its linking direction, its linking direction can be linked in the same direction as the reading order from left to right, or it can be linked in the opposite direction to the above-mentioned direction. to connect. An example is as follows,

The linking group -L1- is -CD-, if -CD- connects ring A and ring B in the same direction as the reading order from left to right

If -CD- is formed by connecting ring A and ring B in the opposite direction to the above

The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .

As used herein, when used in reference to a specifically recited value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the terms "containing" or "including (including)" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of," or "consisting of."

As used herein, the term "alkyl" includes straight or branched chain alkyl groups. For example C ₁ -C ₆ alkyl means straight or branched chain alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl Wait.

As used herein, the term "alkenyl" includes straight or branched chain alkenyl groups. For example C ₂ -C ₆ alkenyl refers to straight or branched alkenyl having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 -butenyl, or similar groups.

As used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example, C2 _- _C6alkynyl refers to a straight or branched chain alkynyl group having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, or the like.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group (saturated or containing a double bond) containing the specified number of C atoms, eg "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3-10 (preferably 3, 4, 5, 6, 7 or 8) carbon atoms. It may be a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. Bicyclic forms, such as bridged or spiro forms, are also possible. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.

As used herein, the term "C1-C6alkoxy" refers to a straight or branched chain alkoxy group having 1-6 carbon atoms; it has the formula C1-C6alkyl-O- or -C1-C5alkane Alkyl-O-C1-C5 alkyl (eg, _-CH2 -O- _CH2CH3 , _-CH2 _- _O- ( _CH2 ) _2CH3 , -CH2CH2 _- O _- _CH2CH3 ₎ Structure, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

As used herein, "heterocyclyl" refers to a saturated or partially saturated cyclic group having heteroatoms selected from N, S, and O, and "3-10 membered heterocyclyl" refers to A saturated or partially saturated cyclic group having 3-10 atoms and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. In the present invention, heterocyclyl and heterocycloalkyl have the same meaning and can be used interchangeably. It may be monocyclic or bicyclic, eg bridged or spirocyclic. The 3-10-membered heterocyclic(alkyl) group is preferably a 3-8-membered heterocyclic(alkyl) group, more preferably a 6-8-membered heterocyclic(alkyl) group. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, and the like.

As used herein, "aryl" refers to an aromatic ring group containing no heteroatoms in the ring, and "C6-C12 aryl" refers to an aromatic ring group having 6 to 12 carbon atoms that contains no heteroatoms in the ring , the aryl group can be fused to a heteroaryl group, a heterocyclic group or a cycloalkyl ring, wherein the ring connected with the parent structure is an aryl ring. Such as phenyl (ie, six-membered aromatic ring), naphthyl, etc., wherein six-membered aryl is also intended to include six-membered aryl and 5-6 membered cycloalkyl and six-membered aryl and 5-6 membered heterocycloalkyl . The C6-C12 aryl group is preferably a C6-C10 aryl group. Aryl groups can be optionally substituted or unsubstituted.

As used herein, "heteroaryl" refers to a cyclic aromatic group having 1-3 atoms that are heteroatoms selected from the following groups of N, S, and O, and "5-12 membered heteroaryl" refers to a group having 5-12 atoms A cyclic aromatic group of atoms wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or a fused ring form. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups can be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio , alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamido, Formyl, formamide, carboxyl and carboxylate, etc.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl and Br.

In the present invention, the term "amido" refers to a group with the structure -CONRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as above defined. R and R' can be the same or different in the dialkylamine moiety. Examples of amide groups include, but are not limited to: _-CONH2 , -CONHCH3, _-CONHCH2CH3 , -CON _(CH3)2 _, _-CONH _cyclopropyl , -CONH cyclobutyl, -CONH cyclopentyl, - CONH cyclohexyl, -CONCH ₃ cyclopropyl, -CONCH ₃ cyclobutyl, -CONCH ₃ cyclopentyl, -CONCH ₃ cyclohexyl.

In the present invention, the term "sulfonamido" refers to a group with the structure -SO ₂ NRR', wherein R and R' can independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of sulfonamido groups include, but are not limited to _: _-SO2NH2 , _-SO2NHCH3 , _-SO2NHCH2CH3 , _-SO2N ₍ _CH3 ₎ ₂ , _{-SO2NHcyclopropyl} , _-SO ₂ NH cyclobutyl, -SO ₂ NH cyclopentyl, -SO ₂ NH cyclohexyl, -SO ₂ NCH ₃ cyclopropyl, -SO ₂ NCH ₃ cyclobutyl, -SO ₂ NCH ₃ cyclopentyl, -SO ₂ NCH ₃ cyclohexyl.

In the present invention, the term "formyl" refers to a group comprising -CHO.

In the present invention, the term "carboxamido" refers to containing

The group, carboxamido is also intended to include substituted carboxamido, having the formula

wherein each R independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, as defined above. Each R may be the same or different.

In the present invention, "amino" means having the structure -N-RR', where R and R' each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above , R and R' can be the same or different. Examples of amino groups include, but are not limited to: _-NH2 , _-NHCH3 , -NHCH2CH3, -N( _CH3 ₎ ₂ , -NHcyclopropyl, -NHcyclobutyl, _{-NHcyclopentyl} , -NH Cyclohexyl, -NCH ₃ cyclopropyl, -NCH ₃ cyclobutyl, -NCH ₃ cyclopentyl, -NCH ₃ cyclohexyl.

In the present invention, "sulfoxide" means having -S(O)-R, R independently representing hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above. Examples of sulfoxide groups include, but are not limited to: -S(O) _-CH3 , -S(O)-CH2CH3, -S(O)-CH ₍ _CH3 ₎ ₂ .

In the present invention, "sulfone" means having -S(O) ₂ -R, R independently representing hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above. Examples of sulfone groups include, but are not limited to: -S(O) ₂ - _CH3 , -S(O) ₂ - _CH2CH3 , -S(O) ₂ - _CH ( _CH3 ) ₂ .

In the present invention, "ester group" means having the structure -C(O)-OR or RC(O)-O-, wherein R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl , Heterocyclyl, as defined above. Examples of ester groups include, but are not limited to: -C(O)-O- _CH3 , -C(O)-O- _CH2CH3 , _-C (O)-O _- _CH2CH2CH3 , _-C (O)-O-CH(CH ₃ ) ₂ , -OC(O)-CH ₃ , -OC(O)-CH ₂ CH ₃ , -OC(O)-CH ₂ CH ₂ CH ₃ , -OC(O )-CH(CH ₃ ) ₂ .

In the present invention, the term "substituted" refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, a substituted group may have at any substitutable position of the group a substituent selected from a particular group, which may be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.

Unless specifically stated that the group described in the present invention is "substituted or unsubstituted", the group of the present invention can be substituted by a substituent selected from the following group: deuterium, halogen, cyano, nitro, hydroxyl , amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl base, C6-C12 aryl.

In the present invention, the term "plurality" refers independently to 2, 3, 4, 5.

Unless otherwise specified, the structural formulas described herein are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example, those containing asymmetric R, S configuration of the center, (Z), (E) isomer of double bond, etc. Accordingly, individual stereochemical isomers or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.

As used herein, the term "tautomer" means that structural isomers having different energies can exceed a low energy barrier, thereby interconverting. For example, proton tautomers (ie, protonation) include interconversion by migration of protons, such as 1H-indazole and 2H-indazole. Valence tautomers include interconversion by some bonding electron recombination.

As used herein, the term "solvate" refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a complex in specified proportions.

Active ingredient

As used herein, "compounds of the present invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of compounds of formula I.

The compound of formula I of the present invention has the following structure,

In the formula, R ₁ , R ₂ , R ₃ , B, C, m, n, k and l are as defined above.

Preferably, the compound of formula I has the structure described in formula II,

In the formula, R ₁ , R ₂ , R ₃ , R _a , q, B and C are as defined above.

Preferably, in formula I-II, B is selected from the following group: C(=O)O-,

Wherein, R _b is defined as above.

Preferably, in formula I-II, C is selected from the group consisting of substituted or unsubstituted groups: 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, C6-C10 aryl Preferably, C is selected from the group consisting of substituted or unsubstituted groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl , phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution refers to being substituted by one or more R _a ;

_Ra is defined as above.

The salts that the compounds of the present invention may form are also within the scope of the present invention. Unless otherwise specified, compounds in the present invention are understood to include their salts. As used herein, the term "salt" refers to salts formed with inorganic or organic acids and bases in the acid or basic form. In addition, when a compound of the present invention contains a basic moiety, which includes, but is not limited to, pyridine or imidazole, and when it contains an acidic moiety, including, but is not limited to, a carboxylic acid, the zwitterion ("inner salt") that may be formed is contained in within the scope of the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, eg, in isolation or purification steps in the manufacturing process. The compounds of the present invention may form salts, for example, by reacting Compound I with an amount, eg, an equivalent, of an acid or base, salting out in a medium, or lyophilizing in an aqueous solution.

The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (eg with acetic acid or trihaloacetic acids such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates , benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentane propionate, diglycolate, lauryl sulfate, Ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodate, isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalic acid Salts, pectates, persulfates, phenylpropionates (such as 3-phenylpropionate), phosphates, picrates, pivalates, propionates, salicylates, succinates, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonates, dodecanoates, and the like.

Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts formed from organic bases (eg, organic amines) such as benzathine, dicyclohexylamine , Hepamine (salt with N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl, and dipentyl sulfate), long-chain halides (eg, decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides) and iodides), aralkyl halides (such as benzyl and phenyl bromides), and the like.

Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" as used herein refers to a compound that undergoes chemical transformation through a metabolic or chemical process to yield the compound, salt, or solvate of the present invention in the treatment of a related disease. The compounds of the present invention include solvates, such as hydrates.

The compounds, salts or solvates of the present invention may exist in tautomeric forms (eg amides and imine ethers). All of these tautomers are part of the present invention.

Stereoisomers of all compounds (eg, those due to asymmetric carbon atoms that may exist for various substitutions), including their enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist concurrently with other isomers (eg, as a pure or substantially pure optical isomer with specific activity), or may be mixtures such as Racemates, or mixtures with all other stereoisomers or a part thereof. The chiral center of the present invention has two configurations, S or R, as defined by the 1974 recommendation of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic form can be resolved by physical methods, such as fractional crystallization, or by derivatization to diastereomer separation crystallization, or by chiral column chromatography. The individual optical isomers can be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by crystallization.

The compound in the present invention, the compound obtained by successively preparing, isolating and purifying the compound whose weight content is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), is described in the text List. Herein such "very pure" compounds of the invention are also intended to be part of the invention.

All configurational isomers of the compounds of the present invention are contemplated, whether in admixture, pure or very pure form. The definition of compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as carbocyclic and heterocyclic cis and trans isomers.

Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.

Specific functional groups and chemical term definitions are detailed below. For purposes of the present invention, chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. Definitions of specific functional groups are also described therein. In addition, basic principles of organic chemistry and specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, which is incorporated by reference in its entirety.

Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention covers all compounds including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, Spin mixtures and other mixtures. Additionally asymmetric carbon atoms may represent substituents such as alkyl groups. All isomers, as well as mixtures thereof, are encompassed by the present invention.

In accordance with the present invention, a mixture of isomers may contain isomers in various ratios. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: All ratios of 2, 99:1, or 100:0, isomers are within the scope of the present invention. Similar ratios readily understood by those of ordinary skill in the art, as well as ratios that are mixtures of more complex isomers, are also within the scope of the invention.

The present invention also includes isotopically labeled compounds, equivalent to the original compounds disclosed herein. In practice, however, it usually occurs that one or more atoms are replaced by atoms with different atomic weights or mass numbers. Examples of isotopes that may be listed as compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, respectively , ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the aforementioned compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as radioisotopes ^of3H ^and14C , are also among them and are useful in drug and substrate tissue distribution experiments. Tritium, ie ³ H and carbon-14, ie ¹⁴ C, are relatively easy to prepare and detect. Is the first choice among isotopes. In addition, heavier isotopic substitutions such as deuterium, ie, ² H, may be preferred in some cases due to their good metabolic stability in certain therapeutics, such as increased half-life or reduced dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by substituting readily available isotopically-labeled reagents for non-isotopically labeled reagents using the protocols disclosed in the Examples.

If a synthesis of a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis, or by derivatization with a chiral auxiliary, separation of the resulting diastereomeric mixture, and removal of the chiral auxiliary to obtain pure enantiomer. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, a suitable optically active acid or base can be used to form diastereomeric salts with it, and then the diastereomeric salts can be formed by separation crystallization or chromatography, etc. Separation by conventional means then yields the pure enantiomer.

As described herein, the compounds of the present invention may be taken with any number of substituents or functional groups to extend their encompassing scope. In general, whether the term "substituted" appears before or after the term "optional", the general formula for including substituents in the formulations of the present invention refers to the replacement of a hydrogen radical with the specified structural substituent. When multiples of a particular structure are substituted at positions with multiples of the specified substituents, the substituents may be the same or different at each position. The term "substituted" as used herein includes all permissible substitutions of organic compounds. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, for example, the heteroatom nitrogen may have hydrogen substituents or any permissible organic compound described above to supplement its valence. Furthermore, the present invention is not intended to limit in any way the permissible substituted organic compounds. The present invention contemplates that the combination of substituents and variable groups is well suited for the treatment of diseases in the form of stable compounds. As used herein, the term "stable" refers to a compound that is stable enough to be detected for a sufficient period of time to maintain the structural integrity of the compound, preferably for a sufficient period of time, and is used herein for the above-mentioned purposes.

The metabolites of the compounds involved in the present application and their pharmaceutically acceptable salts, as well as prodrugs that can be converted into the structures of the compounds involved in the present application and their pharmaceutically acceptable salts in vivo, are also included in the claims of the present application middle.

Preparation method of compound

Methods for the preparation of compounds of formula I are described in the following schemes and examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise specified. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate the reaction or to avoid unwanted side reaction products.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (eg, 0°C to 150°C, preferably 10°C to 100°C). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.

Preferably, the compounds of the present invention can be prepared by the following steps

In an inert solvent (such as DCM, DMF, etc.), in the presence of a catalyst (such as HATU, potassium carbonate, etc.), compound I' reacts to obtain compound I

In the formula,

R ₁ , R ₂ , R ₃ , m, n, k and l are as defined above;

R is selected from the group consisting of substituted or unsubstituted groups: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 Cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl;

B' is selected from the group consisting of amino, hydroxyl, carboxyl, sulfonic acid,

-CO-NH-R';

C' is selected from: amino group, hydroxyl group, carboxyl group, sulfonic acid group,

CO-O-R', -CO-NH-R';

Wherein, R' is selected from substituted or unsubstituted following groups: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl, 5 -12-membered heteroaryl, C6-C12 aryl;

The substitution refers to substitution with one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.

The starting materials and reagents used in the synthesis method of the compounds of the present invention can be purchased commercially or synthesized by methods reported in the literature.

Pharmaceutical compositions and methods of administration

Since the compounds of the present invention have excellent inhibitory activity against JAK kinases, the compounds of the present invention or stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates thereof, and containing the compounds of the present invention are the main activities The pharmaceutical composition of ingredients can be used to prevent and/or treat (stabilize, alleviate or cure) JAK kinase-related diseases (eg, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis) , Crohn's disease, myasthenia gravis, cancer (including prostate, kidney, liver, breast, lung, thyroid, Kaposi's sarcoma, giant lymphoid hyperplasia, pancreatic cancer, leukemia, lymphoma or multiple myeloma, etc.)).

The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharmaceutically acceptable excipient or carrier. 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 10-200 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel 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 are capable of admixture 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 Tween)

), 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, parenteral (intravenous, intramuscular, or subcutaneous).

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 hydroxymethylcellulose, alginates, 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, and the like.

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.

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

When administered in combination, the pharmaceutical composition also includes one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (eg, eg, JAK inhibitors). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (eg, JAK inhibitors) can be used simultaneously, separately or sequentially with the compounds of the invention Prevention and/or treatment of diseases related to the activity or expression of JAK kinases.

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 20 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 are:

1. The compound of the present invention has a novel structure and excellent JAK kinase inhibitory effect;

2. The compounds of the present invention can be used as JAK kinase inhibitors, especially as highly selective inhibitors of JAK1.

3. The compounds of the present invention have better pharmacokinetic properties and efficacy, such as better druggability, low toxicity and side effects, and good bioavailability.

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. The experimental methods without specific conditions in the following examples 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.

The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Example

General Materials and Test Methods:

Methods for synthesizing the compounds of the present invention are shown in the Schemes, Methods and Examples below. Starting materials are commercially available or can be prepared according to known methods in the art or described herein. The compounds of the present invention can be illustrated by the specific examples shown below. However, these specific embodiments should not be construed as the only species of the invention. These examples further detail the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations of conditions and procedures can be used to prepare these compounds.

All temperatures are in degrees Celsius unless otherwise stated.

The percentages for the yields are all mass percentages.

All parts are by volume and all percentages are by volume unless otherwise indicated.

Thin layer chromatography (PTLC) preparations were performed on 20 x 20 cm plates (500 micron thick silica gel). Silica gel chromatography was performed using a Biotage flash chromatography system.

¹ H NMR was performed on a Bruker Ascend™ 400 spectrometer, 400 MHz, 298 K, and the chemical shifts (ppm) of the residual protons in the deuterated reagent are given as references:

CDCl ₃ δ=7.26ppm, CD ₃ ODδ=3.30ppm, DMSO-d ₆ δ=2.50ppm

LCMS chromatography was performed using an Agilent Technologies 1260 Link 6100 quadrupole spectrometer. For LC mobile phase 0.1% formic acid-water (A) and 0.1% formic acid-acetonitrile (B), eluent gradient: 0-5.5 min 0-95% B, 5.5-6 min 95% B, 6-8 min 0% B with SB-Aq 50 mm x 2.1 mm x 3.5 µm capillary column.

Mass spectrometry (MS) was determined by electrospray ion mass spectrometry (ESI).

HPLC mass spectrometry analysis conditions:

LC1:

Column: SB-Aq 50mm×2.1mm×3.5μm;

Temperature: 40℃;

Eluent: 100:0 to 5:95 v/v 0.1% formic acid-water/0.1% formic acid-acetonitrile, 8 minutes;

Flow: 1.0mL/min, inject 5μL;

Detection: VWD, 210nm&254nm;

MS: mass range 100-100 amu; positive ion electrospray ionization.

Abbreviation list:

AcOH=acetic acid

Alk is alkyl

AR is aryl

Boc = tert-butoxycarbonyl

bs = broad peak

CH ₂ Cl ₂ = dichloromethane

d = double peak

dd = double doublet

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

DCM = dichloromethane

DMF=N,N-dimethylformamide

DMSO = dimethyl sulfoxide

EA = ethyl acetate

ESI = Electrospray Ionization

Et = ethyl

EtOAc = ethyl acetate

EtOH = Ethanol

h = hours

HOAc=acetic acid

LiOH = Lithium Hydroxide

m = multiple

Me = methyl

MeCN=acetonitrile

MeOH = methanol

MgSO ₄ = magnesium sulfate

min = minutes

MS = Mass Spectrometry

NaCl = sodium chloride

NaOH = sodium hydroxide

Na ₂ SO ₄ = sodium sulfate

NMR = nuclear magnetic resonance spectroscopy

PE = petroleum ether

PG = protecting group

Ph = phenyl

rt = room temperature

s = single peak

t = triplet

TFA = trifluoroacetic acid

THF = tetrahydrofuran

Synthesis of Example 1 A1:

The first step: ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetate (A1-2)

Under nitrogen protection, 1,4-cyclohexanedione monoethylene glycol ketal (A1-1, 10.0 g, 64.0 mmol) was added to anhydrous THF (100 ml), stirred in an ice bath for 5 min, and sodium hydrogen (3.07 g) was added in batches. , 76.8mmol, 60%dispersion in mineral oil), continue to stir in ice bath for 0.5h, then slowly add triethyl phosphonoacetate (14.78g, 65.9mmol) in THF solution (50ml), after dripping, it naturally rises to room temperature to continue Stir for 2h. After TLC confirmed that the reaction was complete, water was added to quench, THF was concentrated, EA was added for extraction, the organic layer was collected, dried over anhydrous sodium sulfate, and EA was concentrated to obtain a yellow liquid 2-(1,4-dioxaspiro[4.5]decane-8). - subunit) ethyl acetate (A1-2, 14.38 g, crude), used directly in the next step without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 5.69 (s, 1H), 4.17 (q, J=8.0 Hz, 2H), 4.00 (s, 4H), 3.04-3.01 (m, 2H), 2.42-2.39 ( m, 2H), 1.82-1.77 (m, 4H), 1.30 (t, J=8.0 Hz, 3H).

The second step: ethyl 2-(8-nitromethyl-1,4-dioxaspiro[4.5]dec-8-yl)acetate (A1-3)

Ethyl 2-(1,4-dioxaspiro[4.5]dec-8-ylidene)acetate (A1-2, 14.38g, 63.6mmol) was added to THF (100ml), followed by tetrabutylfluoride Ammonium (18.29 g, 70 mmol, 70 mL, 1M in THF), nitromethane (5.82 g, 95.40 mmol), the temperature was raised to 80°C, and the reaction was stirred for 16 h. After TLC confirmed the completion of the reaction, THF was concentrated, EA and deionized water were added, and the liquids were extracted and separated. The organic layer was dried over anhydrous sodium sulfate, and EA was concentrated to obtain a yellow liquid 2-(8-(nitromethyl)-1,4). - Ethyl dioxaspiro[4.5]dec-8-yl)acetate (A1-3, 16.68 g, crude), used directly in the next step without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 4.75(s, 2H), 4.21-4.15(q, J=8.0Hz, 2H), 3.97(s, 4H), 2.58(s, 2H), 1.74-1.72( m, 8H), 1.31-1.25 (m, 3H).

The third step: 1,4-dioxa-10- ^azabispiro [ ^4.2.48.25 ]tetradecane-11-one (A1-4)

Ethyl 2-(8-nitromethyl-1,4-dioxaspiro[4.5]dec-8-yl)acetate (A1-3, 16.68g) was added to methanol (150ml) followed by Raney nickel , pass hydrogen into the reaction at 45°C for 48h. After monitoring the completion of the reaction by LCMS, filter and concentrate methanol to obtain 1,4-dioxa-10- ^azabispiro [ ^4.2.48.25 ]tetradec-11-one (A1-4, 11.98g, crude), used directly in the next step without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 5.65(s, 1H), 3.97(s, 4H), 3.22(s, 2H), 2.26(s, 2H), 1.77-1.74(m, 4H), 1.69- 1.66 (m, 4H).

The fourth step: 1,4-dioxa-10-azaspiro[ ^4.2.48.25 ]tetradecane ( ^A1-5 )

Under nitrogen, 1,4-dioxa-10- ^azabispiro [ ^4.2.48.25 ]tetradec-11-one (A1-4, 2g, 9.47mmol) was added to dry THF (30ml) , stirred for 5 min, slowly added borane THF solution (47.4 ml, 47.4 mmol, 1 M), warmed to 70 °C, and stirred for 16 h. After confirming that the reaction was complete by LCMS, it was cooled to room temperature, quenched by slowly adding methanol, and the solvent was concentrated to obtain oily 1,4-dioxa- ¹⁰ -azaspiro[ ^4.2.48.25 ]tetradecane (A1- 5, 1.8 g, crude), used directly in the next step without purification.

Step 5: 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa- ¹⁰ -azaspiro[ ^4.2.48.25 ]tetradecane (A1-6)

1,4-dioxa-10-azaspiro[ ^4.2.48.25 ]tetradecane ( ^A1-5 , 1.8 g, 9.13 mmol) and 4-chloro-7H-pyrrolo[2,3- d] Pyrimidine (1.4g, 9.13mmol) was added to DMF (30ml), then N,N-diisopropylethylamine (2.36g, 18.3mmol) was added, the temperature was raised to 100°C, and stirred for 16h. After confirming that the reaction was complete by LCMS, it was cooled to room temperature, filtered with suction, the filter cake was collected, and dried under reduced pressure to obtain 10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4- Dioxa-10-azaspiro[ ^4.2.48.25 ]tetradecane ( ^A1-6 , 2.26 g, crude) was used in the next step without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ 10.16 (br, 1H), 8.33 (s, 1H), 7.05 (d, J=3.48Hz, 1H), 6.59 (d, J=3.52Hz, 1H), 3.99 – 3.96 (m, 6H), 3.73 (s, 2H), 2.00 – 1.92 (m, 2H), 1.78 – 1.71 (m, 8H).

The sixth step: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-aza-spiro[4.5]dec-8-one (A1-7)

10-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,4-dioxa-10-azaspiro[ ^4.2.48.25 ]tetradecane ( ^A1-6 , 2.26g, 7.20mmol) was added to THF (30ml), concentrated hydrochloric acid (10ml) was added dropwise, and the mixture was stirred at room temperature for 16h. After confirming the completion of the reaction by LCMS, 6mol/L NaOH solution was added dropwise to adjust pH=7～8, suction filtration, the filter cake was collected, and dried under reduced pressure to obtain off-white solid 2-(7H-pyrrolo[2,3-d]pyrimidine -4-yl)-2-aza-spiro[4.5]decan-8-one (A1-7, 1.89 g, crude) was used in the next step without purification. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.63 (br, 1H), 8.35 (s, 1H), 7.09 (d, J=4Hz, 1H), 6.61 (d, J=4.0Hz, 1H), 4.05 ( s, 2H), 3.89 (s, 2H), 2.48 (t, J=8.0Hz, 4H), 2.12 (t, J=8.0Hz, 2H), 2.07–1.96 (m, 4H).

Step 7: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1)

2-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-one (A1-7, 1 g, 3.70 mmol) was added to absolute ethanol (30 ml) ), then add 7mol/L NH ₃ in MeOH solution (29.6ml, 0.21mol) and isopropyl titanate (2.1g, 7.40mmol), stir at room temperature for 6h, then add sodium borohydride (210mg, 5.56mmol) in batches ) and continued stirring for 16h. After confirming that the reaction was complete by LCMS, ammonia water (17 ml) was added to quench the reaction, stirred at room temperature for 15 min, suction filtered, and the filtrate was collected. After concentration, EA was added and stirred for 10 min. MS (ESI) m/z: calcd 272.19 (M+H), found 272.10; ¹ H NMR (400 MHz, DMSO- _d6 ) δ 11.55 (br, 1H), 8.06 (s, 1H), 7.09 (d, J = 3.32Hz, 1H), 6.57(s, 1H), 3.79(s, 2H), 3.49(s, 2H), 2.71-2.68(m, 1H), 1.87(s, 2H), 1.72-1.69(m, 2H), 1.64-1.61 (m, 2H), 1.43 (s, 2H), 1.33-1.27 (m, 2H).

Example 2 Synthesis of N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)acetamide (A2):

Under nitrogen protection, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1, 4 mg, 14.8 μmol) was added to MeCN (1 ml) ), sodium bicarbonate (2 mg, 23.8 μmol) was added, cooled to 0°C and stirred for 5 min, and then the MeCN solution of acetyl chloride (1.1 mg, 14.8 μmmol) was added dropwise, and the mixture was stirred in an ice bath for 1 h. After LCMS confirmed the completion of the reaction, MeCN was concentrated, and the residue was purified by preparative plate to obtain A2 (3 mg, yield 64.9%) as a white solid. MS (ESI) m/z: calcd 314.20 (M+H), found 314.00; ¹ H NMR (400 MHz, MeOH- _d4 ) δ 8.08 (s, 1H), 7.10 (d, J=3.56 Hz, 1H) ,6.71(d,J＝3.56Hz,1H),3.91(br,2H),3.73-3.63(m,3H),2.06-2.04(m,2H),1.95(s,3H),1.88-1.85(m , 2H), 1.79-1.75 (m, 2H), 1.65-1.59 (m, 2H), 1.53-1.45 (m, 2H).

Example 3 Synthesis of N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)benzenesulfonamide (A3:

Under nitrogen protection, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1, 10 mg, 36.9 μmol) was added to DMF (2 ml) ), stir to dissolve, add potassium carbonate (6.1 mg, 44.2 μmol), and then dropwise add a solution of benzenesulfonyl chloride (7.8 mg, 44.2 μmol) in DMF (0.5 ml), and stir at room temperature for 1 h. After LCMS confirmed that the reaction was complete, EA and deionized water were added for extraction, the organic phase was collected, EA was concentrated, and the residue was purified by reverse-phase column to obtain white solid A3 (5 mg, yield 33.1%). MS (ESI) m/z: calcd 412.18 (M+H), found 412.20; ¹ H NMR (400MHz, DMSO- _d6 ) δ 12.65 (br, 1H), 8.27 (d, J=8.0Hz, 1H), 7.84(d,J=8.0Hz,2H),7.71(d,J=8.0Hz,1H),7.66-7.58(m,3H),7.43(br,1H),6.88(br,1H),3.99(br , 1H), 3.63 (br, 3H), 3.02 (br, 1H), 1.92-1.85 (m, 2H), 1.61-1.59 (m, 4H), 1.39-1.32 (m, 4H).

Example 4 N-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-yl)-3-bromo-5-nitrobenzene Synthesis of formamide (A4):

Under nitrogen protection, 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[4.5]dec-8-amine (A1, 15 mg, 55.3 μmol) and 3-bromo- 5-Nitrobenzoic acid (13.5mg, 55.3μmol) was added to a mixed solvent of DCM (2ml) and DMF (0.5ml), then HATU (21mg, 55.3μmol) was added, stirred in an ice bath for 5min, then N was added dropwise, A solution of N-diisopropylethylamine (7.1 mg, 55.3 μmol) in DCM (1 ml) was stirred in an ice bath for 0.5 h. After LCMS confirmed the completion of the reaction, dichloromethane and deionized water were added, the organic layer was collected, dried over anhydrous Na ₂ SO ₄ , concentrated in DCM, and the residue was purified by reverse phase column to obtain white solid A4 (11 mg, yield 40.0%) . MS (ESI) m/z: calcd 499.11, 501.11 (M+H), found 499.21, 501.22; ¹ H NMR (400 MHz, DMSO- _d6 ) δ 12.66 (br, 1H), 8.74 (d, J=8.0 Hz ,1H),8.66-8.65(m,1H),8.56(d,J=1.48Hz,1H),8.49-8.48(m,1H),8.30(d,J=4.0Hz,1H),7.45(s, 1H), 6.94 (s, 1H), 4.04-3.87 (m, 5H), 2.05-1.75 (m, 6H), 1.59-1.52 (m, 4H).

Referring to the preparation of the experimental procedures of Examples 2-4, and using different acylating reagents, Examples 5-75 were obtained, as shown in Table 1 below.

Table 1

Example 76 N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-yl)-2-chloro-4-nitro Synthesis of benzamide (76)

The first step: 6-oxo-2-azaspiro[3.3]heptane (A76-01)

2-Boc-6-oxo-2-azaspiro[3.3]heptane (200 mg, 0.95 mmol) was added to DCM (2 mL), trifluoroacetic acid (2 mL) was added under nitrogen protection, and the mixture was stirred at room temperature for 3.0 h. After confirming that the reaction was complete by LCMS, the reaction solution was directly rotated to dryness to obtain 6-oxo-2-azaspiro[3.3]heptane trifluoroacetate (A76-01, 215mg, crude) as a yellow oil, which was used directly without purification. Next step. MS(ESI) m/z: calcd 112.07(M+H), found 112.14.

Step 2: 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02)

6-oxo-2-azaspiro[3.3]heptane trifluoroacetate (A76-01, 215 mg, 0.95 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (148 mg, 0.96 mmol) was added to N-methylpyrrolidone (4 ml), then potassium carbonate (900 mg, 6.5 mmol) was added, the temperature was raised to 80° C. and stirred for 14 h. After confirming that the reaction was complete by LCMS, it was cooled to room temperature, filtered with suction, and the filter cake was collected and dried under reduced pressure to obtain 6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl as an off-white solid. )-2-azaspiro[3.3]heptane (A76-02, 40 mg, crude) was used in the next step without purification.

The third step: 2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03)

6-oxo-2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]heptane (A76-02, 40 mg, 0.18 mmol) was added to absolute ethanol (2ml), then add 7mol/L NH ₃ in MeOH solution (2ml, 14mmol) and isopropyl titanate (105mg, 0.37mmol), stir at room temperature for 6h, then add sodium borohydride (67mg, 1.8mmol), continue Stir for 16h. After confirming that the reaction was complete by LCMS, ammonia water (2 mL) was added to quench the reaction, stirred at room temperature for 15 min, suction filtered, and the filtrate was collected. - Pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03, 35 mg, crude), used directly in the next step without further treatment. MS (ESI) m/z: calcd 229.13 (M+H), found 229.10.

Step 4: N-(2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6yl)-4-chloro-2-nitro Benzamide (A76)

2-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-azaspiro[3.3]hept-6-amine (A76-03, 35 mg, 0.15 mmol) and 4-chloro-2 - Nitrobenzoic acid (30 mg, 0.15 mmol) was added to DMF (1 ml), then HATU (57 mg, 0.15 mmol) was added, stirred in an ice bath for 5 min, and then N,N-diisopropylethylamine (19.35 mg) was added dropwise , 0.15 mmol) in DMF (0.5 mL), and continued to stir in an ice bath for 1 h. After confirming that the reaction was complete by LCMS, the reaction solution was directly purified by reverse-phase column to obtain A76 as a white solid (20 mg, yield 32.3%). MS (ESI) m/z: calcd 413.11 (M+H), found 413.10; ¹ H NMR (400 MHz, DMSO- _d6 ) δ 12.64 (s, 1H), 8.97 (d, J=6.9 Hz, 1H), 8.30(s, 1H), 8.19(s, 1H), 7.91(d, J=8.2Hz, 1H), 7.67(d, J=8.2Hz, 1H), 7.45(s, 1H), 6.70(s, 1H ), 4.53(m, 4H), 4.26-4.22(m, 1H), 2.78-2.64(m, 2H), 2.35-2.30(m, 2H).

Effect example 1: biological test method

JAK kinase activity is measured using a homogeneous time-resolved fluorescence technique. Reactions for this method were in 384 shallow well plates and the total reaction volume was 10 μL. Mixture of kinase protein, compound, ATP and substrate in reaction buffer of 50 mM Hepes (pH 7.0), NaN ₃ 0.02%, BSA 0.01%, 0.1 mM Orthocanadate, 5 mM MgCl ₂ , 1 mM DTT After 1 hour of reaction, an antibody capable of recognizing phosphorylation of the substrate, a dye XL-615 and a detection buffer (Cisbio) containing EDTA were added to the system. The reaction signal of the kinase was detected by the multi-well plate detector of PE Company. The parameter settings are excitation light 320nm, emission light 615nm and 665nm. The activity of JAK is indirectly reflected by the signal ratio of 665nm and 615nm. In the reaction, background wells without enzyme and holoenzyme activity wells without compound were set.

The _IC50 value of compound inhibitory protein was obtained by the formula: Y=100/(1+10^((LogIC50-X)*HillSlope)).

In the JAK1 reaction system, the concentration of ATP was 2 μM, and the concentration of JAK1 protein was 0.2 ng/μL.

In the JAK2 reaction system, the concentration of ATP was 2 μM, and the concentration of JAK1 protein was 0.01 ng/μL.

In the JAK3 reaction system, the concentration of ATP was 2 μM, and the concentration of JAK1 protein was 0.04 ng/μL.

In the TYK2 reaction system, the concentration of ATP was 2 μM, and the concentration of JAK1 protein was 0.2 ng/μL.

The test data are divided into the following categories: A: IC ₅₀ <10nM; B: IC ₅₀ 11-100 nM; C: IC ₅₀ 101-1000 nM; D: IC ₅₀ 1001-10000 nM; E: IC ₅₀ >10000 nM.

The test results are shown in Table 2.

Table 2

The above experimental results suggest that:

(1) The compounds of formula I of the present invention exhibit very excellent JAK inhibitory activity, especially JAK1 activity. The IC50 value of the compounds of the present invention can be as low as 10 nM or lower, so that for a subject weighing about 70 kg (such as a patient, especially a patient with rheumatoid arthritis or psoriasis), a daily dose of 10 mg-30 mg is usually sufficient. Extremely potent inhibition of JAK, especially JAK1.

(2) The compound of formula I of the present invention exhibits very excellent JAK selectivity, that is, the ratio of IC50 of JAK3/JAK1, the ratio of IC50 of JAK2/JAK1, and the ratio of IC50 of TYK2/JAK1 are increased by about 10 times (mostly About 20-100 times), far superior to the currently marketed drugs.

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

A compound shown in formula I or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate,

In the formula,

R1, R2 and R3 are each independently selected from the group consisting of substituted or unsubstituted H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfone, sulfoxide, amido , sulfonamido, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;

Or R 1 and R 2 together with the atoms to which they are attached form a substituted or unsubstituted group of the following groups: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein , the substitution refers to being substituted by one or more R a ;

B is independently selected from the group consisting of bond, -( CH2 ) r- , C(=O), NRb , C(=O)O-,
-(CH 2 ) p -R c , O, S, SO, SO 2 ; R c is selected from: C(=O)O-,
wherein, R is independently selected from the group consisting of H, C1-C6 alkyl;

wherein, the H atoms in -(CH 2 ) r - and -(CH 2 ) p - may be optionally substituted by one or more Ra ;

C is selected from the group consisting of substituted or unsubstituted groups: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3 -C10 cycloalkyl, 5-12-membered heteroaryl, C6-C12 aryl; wherein, the substitution refers to being substituted by one or more R a ;

r and p are each independently 1, 2, 3, 4;

m, n, k and l are each independently 0, 1, 2, 3, and m+n≥1, k+l≥1;

The H in the moiety can be optionally substituted with one or more Ra ;

wherein each R is independently selected from the group consisting of substituted or unsubstituted groups: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12-membered heteroaryl and C6-C12 aryl; wherein, the substitution described in R a refers to being substituted by one or more groups selected from the group consisting of halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amido, sulfonamide, ester, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2- C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl.
The compound of claim 1 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, characterized in that:
Partially selected from:

where q is 0, 1, 2, 3, 4 or 5;

R a is defined as in claim 1 .
The compound of claim 1 or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that it has the structure shown in formula II:

where q is 0, 1, 2, 3, 4 or 5;

R 1 , R 2 , R 3 , Ra , B and C are as defined in claim 1 .
The compound of claim 1, or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein B is selected from the group consisting of C(=O)O- ,
Wherein, the definition of R b is as described in claim 1 .
The compound of claim 1 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein C is selected from the group consisting of substituted or unsubstituted groups: 3-8-membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10-membered heteroaryl, C6-C10 aryl; wherein, the substitution refers to being substituted by one or more R a ;

R a is defined as in claim 1 .
The compound of claim 1 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound satisfies one or more of the following conditions ,

(1)
Selected from:

wherein, q is 0, 1, 2, 3, 4 or 5; R a is defined as described in claim 1;

(2) B is selected from: -NH-,
-NH-C(=O)-; optionally, each hydrogen in the above groups is replaced by C1-C6 alkyl;

(3) C is selected from: H, methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothienyl, benzofuranyl, pyrimidine wherein, optionally, C is substituted with a substituent selected from: fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl , methyl, methoxy, methyl formate, trifluoromethyl, phenyl, sulfonamide;

Preferably, C is selected from: H, methoxy, phenyl, methyl,
cyclopropyl,
cyclohexyl,
Naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl group, methoxy group, methyl formate group, trifluoromethyl group, phenyl group, sulfonamide group;

More preferably, C is selected from: H, methyl, methoxy,

phenyl,

(4) R 1 is hydrogen;

(5) R 2 is hydrogen;

(6) R 3 is hydrogen;

Particularly,
selected from
The compound according to any one of claims 1-5, or its stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, wherein in the compound, each substituted The base satisfies one or more of the following conditions,

Each C1-C6 alkyl group is independently selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl;

Each C1-C6 alkoxy group is independently selected from: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy;

Each C2-C6 alkenyl group is independently selected from: vinyl, propenyl, allyl;

Each C2-C6alkynyl group is independently selected from: ethynyl, propynyl;

Each 3-10 membered heterocycloalkyl is independently selected from: tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl;

Each C3-C10 cycloalkyl group is independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

Each 5-12 membered heteroaryl group is independently selected from: pyrrolyl, furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, benzothienyl , benzofuranyl;

Each C6-C12 aryl group is independently selected from: phenyl, naphthyl.
The compound of claim 1 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, wherein the compound is selected from the group consisting of:
A pharmaceutical composition, characterized in that it comprises the compound of any one of claims 1-8 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate; and a pharmaceutically acceptable carrier;

In particular, the pharmaceutical composition is used for the treatment or prevention of diseases related to the activity or expression of JAK kinases;

More particularly, the pharmaceutical composition is used as a JAK kinase inhibitor, preferably a JAK1 kinase inhibitor.
A use of a compound as claimed in any one of claims 1 to 8 or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate, characterized in that,

It is used for preparing medicine or pharmaceutical composition for treating or preventing diseases related to the activity or expression level of JAK kinase; or, it is used for preparing medicine or pharmaceutical composition for inhibiting the activity of JAK kinase, and the JAK kinase is preferably JAK1 kinase ;

In particular, the disease is selected from the group consisting of cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, rheumatoid joints inflammation, skin disorders, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, psoriasis; wherein the cancer is preferably selected from the group consisting of prostate cancer, kidney cancer, liver cancer, Breast cancer, lung cancer, thyroid cancer, Kaposi's sarcoma, giant lymphoid hyperplasia, pancreatic cancer, leukemia, lymphoma, multiple myeloma;

In particular, the disease related to the activity or expression level of JAK kinase is a JAK1-related disorder; wherein, the JAK1-related disorder is preferably selected from the group consisting of type I diabetes, lupus, multiple sclerosis, rheumatoid Arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, Crohn's disease and alopecia areata.