CN116783198A - Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor - Google Patents

Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor Download PDF

Info

Publication number
CN116783198A
CN116783198A CN202180080571.9A CN202180080571A CN116783198A CN 116783198 A CN116783198 A CN 116783198A CN 202180080571 A CN202180080571 A CN 202180080571A CN 116783198 A CN116783198 A CN 116783198A
Authority
CN
China
Prior art keywords
group
compound
pharmaceutically acceptable
substitution
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202180080571.9A
Other languages
Chinese (zh)
Inventor
吕志俭
李佳
苏明波
高安慧
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Baiji Hongye Nantong Pharmaceutical Technology Co ltd
Baiji Hongye Guangdong Pharmaceutical Technology Co ltd
Original Assignee
Baiji Hongye Nantong Pharmaceutical Technology Co ltd
Baiji Hongye Guangdong Pharmaceutical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Baiji Hongye Nantong Pharmaceutical Technology Co ltd, Baiji Hongye Guangdong Pharmaceutical Technology Co ltd filed Critical Baiji Hongye Nantong Pharmaceutical Technology Co ltd
Publication of CN116783198A publication Critical patent/CN116783198A/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention relates to a spiro JAK inhibitor, a pharmaceutical composition containing the spiro JAK inhibitor and application of the spiro JAK inhibitor. Specifically, the invention relates to a compound shown in a formula I or a stereoisomer or an optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, a pharmaceutical composition of the compound and a medical application of the compound serving as a JAK inhibitor in preparing medicaments for preventing and/or treating JAK, especially JAK1 related diseases.

Description

Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a spiro JAK inhibitor, a pharmaceutical composition containing the spiro JAK inhibitor and application of the spiro JAK inhibitor.
Background
Protein Kinases (PKs) are a group of enzymes that regulate a variety of important biological processes, including in particular cellular kinases that catalyze the phosphorylation of proteins, lipids, sugars, nucleosides, and other cellular metabolites and play a key role in all aspects of eukaryotic cell physiology, which constitute one of the largest families of enzymes in humans. Abnormal kinase activity has been shown to be involved in many human diseases including cancer, autoimmune diseases 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 cytokine signaling. The JAK family includes four members JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK 2). JAKs are typically associated in pairs with cytokine receptors as homodimers or heterodimers. Cytokines bind to their receptors, causing dimerization of the receptor molecules, and JAKs coupled to the receptors come close to each other and are activated by the phosphorylation of interacting tyrosine residues. The JAK family transmits cytokine-mediated signals into cells through the JAK-STAT (signal transduction and transcription activator) pathway.
Signal transduction and transcription activators (Signal Transducer and Activator of Transcription, STAT) are a group of cytoplasmic proteins that bind to target gene regulatory region DNA. As a downstream substrate of JAKs, STATs can be activated by tyrosine phosphorylation under stimulation of an external signal, and then transferred into the transcription of nuclear regulatory genes. When cytokines bind to their receptors, JAK family members autophosphorylate and/or transphosphorylate each other, followed by stat phosphorylation and then migrate into the nucleus to regulate transcription.
Many abnormal immune responses, such as autoimmune diseases like allergy, asthma, (allograft) transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, hematological malignancies like myeloproliferative disorders, leukemia and lymphoma, are all associated with JAK/STAT signaling pathways.
Studies have shown that blocking signal transduction at the JAK kinase level offers promise for the development of therapeutic approaches to inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer. Inhibition of JAK kinases also contributes to the treatment of skin immune diseases such as psoriasis and skin sensitization. Toficitinib (Fascitinib) with a pyroxene has been marketed for the treatment of rheumatoid arthritis; and Incyte's ruxotinib for treating myelofibrosis and acute graft versus host disease.
However, some JAK enzyme inhibitors currently available also have some significant toxic side effects, for example, some JAK inhibitors are prone to cause the following side effects: infections including pneumonia, viral infections (e.g. herpes zoster infection), bacterial infections, actinomycete infections (mycobacterial infections), fungal infections, reduced immunity (e.g. NK cytopenia) and anaemia. In the united states, black boxes are alerted even by a portion of serious side effects including, for example, acute tuberculosis, invasive fungal infections, bacterial infections, and a portion of lymphomas or other tumors. Studies have shown that currently available JAK inhibitors tend to have inhibitory activity against both JAK1 and JAK3, and that most of these side effects are associated with inhibited JAK3 activity.
However, studies have shown that JAKs family kinases are responsible for regulating numerous signaling pathways. Since JAK1 and JAK3 are part of the common gamma-chain cytokine receptor complex, this has resulted in great difficulty in developing inhibitors with high selectivity for JAK 1.
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 in signaling through members of 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-13R), the gp130 receptor family and the class II cytokine receptors (including the IL-10 receptor family and both the type I and type II IFN receptor families).
In view of the foregoing, there is a strong need in the art to develop inhibitors of Janus kinases or related kinases, particularly inhibitors with high selectivity for JAK 1.
Disclosure of Invention
The present invention provides inhibitors of JAK or related kinases, particularly inhibitors having high selectivity for JAK 1.
In a first aspect of the present invention there is provided a compound of formula I or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, prodrug or solvate thereof,
In the method, in the process of the invention,
R 1 、R 2 and R is 3 Each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, amino, nitro, hydroxy, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formylAmino, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
or R is 1 And R is 2 Together with the atoms to which they are attached, constitute a substituted or unsubstituted group of radicals: 5-6 membered aryl or heteroaryl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl; wherein said substitution means by one or more R a Substitution;
b is independently selected from the group consisting of: bond, - (CH) 2 ) r -、C(＝O)、N-R b 、C(＝O)O-、 -(CH 2 ) p -R c 、O、S、SO、SO 2 ；R c Selected from: c (=O) O-, C (=O) O-Wherein R is b Independently selected from the group consisting of: H. C1-C6 alkyl;
wherein- (CH) 2 ) r -and- (CH) 2 ) p The H atom in-can optionally be replaced by one or more R a Substitution;
c is selected from the group consisting of substituted or unsubstituted: H. C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
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 is not less than 1, k+l is not less than 1;
h in the moiety may optionally be substituted with one or more R a Substitution;
wherein each R a Independently selected from the group consisting of substituted or unsubstituted: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-C10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl; wherein R is a By substitution is meant substitution with one or more groups selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-to 10-cycloalkyl, 5-to 12-membered heteroaryl and C6-C12-aryl.
In another preferred embodiment, the compound of formula I or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof,
In the method, in the process of the invention,
R 1 、R 2 and R is 3 Each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, amino, nitro, hydroxy, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-C10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
or R is 1 And R is 2 To which are attached atoms oneTo constitute the substituted or unsubstituted group: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein said substitution means by one or more R a Substitution;
b is independently selected from the group consisting of: bond, - (CH) 2 ) r -、C(＝O)、N-R b 、C(＝O)O-、 -(CH 2 ) p -R c 、O、S、SO、SO 2 ；R c Selected from: c (=O) O-, C (=O) O-Wherein R is b Independently selected from the group consisting of: H. C1-C6 alkyl;
wherein- (CH) 2 ) r -and- (CH) 2 ) p The H atom in-can optionally be replaced by one or more R a Substitution;
c is selected from the group consisting of substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
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 is not less than 1, k+l is not less than 1;
h in the moiety may optionally be substituted with one or more R a Substitution;
wherein each R a Independently selected from the group consisting of substituted or unsubstituted: halogen, amino, nitroHydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, 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 R is a By substitution is meant substitution with one or more groups selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-to 10-cycloalkyl, 5-to 12-membered heteroaryl and C6-C12-aryl.
In another preferred embodiment, each R a Independently selected from the group consisting of: halogen, amino, nitro, hydroxy, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, halogenated C1-C6 alkyl, (CH) 2 ) t G. C1-C6 alkoxy, haloC 1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 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 a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof,the moiety is selected from:
wherein q is 0, 1, 2, 3, 4 or 5;
R a is defined as above.
In another preferred embodiment, the compound or stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof has a structure shown in formula II:
wherein q is 0, 1, 2, 3, 4 or 5;
R 1 、R 2 、R 3 、R a the definitions of B and C are as described above.
In another preferred embodiment, the compound or stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, B is selected from the group consisting of: c (=O) O-, C (=O) O-Wherein R is b Is defined above.
In another preferred embodiment, the compound or stereoisomer, or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, C is selected from the group consisting of substituted or unsubstituted: 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; wherein said substitution means by one or more R a Substitution;
R a is defined as above.
In another preferred embodiment, C is selected from the group consisting of substituted or unsubstituted: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein the substitution means by one or more R a Substitution; r is R a Is defined as above.
In a further preferred embodiment of the present invention,selected from:
wherein q is 0, 1, 2, 3, 4 or 5;
R a is defined as above.
In another preferred embodiment, B is selected from: -NH-,-NH-C (=o) -, optionally each hydrogen in the above groups being substituted by a C1-C6 alkyl group.
In another preferred embodiment, C is selected from: H. methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothienyl, benzofuranyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, sulfamoyl (or sulfonamide).
In another preferred embodiment, C is selected from: H. methoxy, phenyl, methyl, ethyl,Cyclopropyl group,Cyclohexyl group,Naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, sulfamoyl (or sulfonamide).
In another preferred embodiment, C is selected from: H. methyl, methoxy, Phenyl group,
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 a further preferred embodiment of the present invention,selected from the group consisting of
In another preferred embodiment, the compound has the structure shown in formula II:
wherein q is 0, 1, 2, 3, 4 or 5;
R 1 、R 2 、R 3 、R a the definitions of B and C are as described above.
In another preferred embodiment, each C1-C6 alkyl is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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 is independently selected from ethenyl, propenyl, allyl.
In another preferred embodiment, each C2-C6 alkynyl is independently selected from ethynyl, propynyl.
In another preferred embodiment, each 3-10 membered heterocycloalkyl is independently selected from tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl.
In another preferred embodiment, each C3-C10 cycloalkyl is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.
In another preferred embodiment, each 5-12 membered heteroaryl is independently selected from the group consisting of pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, benzothienyl, benzofuranyl.
In another preferred embodiment, each C6-C12 aryl is independently selected from phenyl, naphthyl.
In another preferred embodiment, in formula I, R 1 、R 2 、R 3 、R a And B and C are specific groups corresponding to specific compounds in the examples.
In another preferred embodiment, the compound or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof is selected from the group consisting of:
in another preferred embodiment, the compound of formula I is selected from the compounds shown in the examples.
In a second aspect of the invention there is provided a pharmaceutical composition comprising a compound of the first aspect or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, prodrug or solvate thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of:
PD-1 inhibitors (such as nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT1306, AK105, LZM 009, or biological analogues of the above, etc.), PD-L1 inhibitors (such as Devacizumab, emamizumab, avstumab (avelumab), CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or biological analogues of the above, etc.), CD20 antibodies (such as rituximab, obabine You Tuozhu monoclonal antibody, ofatuzumab, veltuzumab, toximomab, 131I-toximomab, temozolomab, 90Y-temozolomab, 90 In-temozolomab, temozolomab (ibritumomab tiuxetan), etc.), CD47 antibodies (e.g., hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK inhibitors (e.g., ceritinib, ai Leti, buntinib, latinib, okatinib), PI3K inhibitors (e.g., aitiritinib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitors (e.g., ibrutinib, tirabutenib, acartinib, etc.), EGFR inhibitors (e.g., africtinib, gefitinib, erlotinib, lapatinib, dactinib, ecritinib, katinib, qtinib, uvalatinib, etc.), utinib, natinib, uvalatinib, uvalnemab, utinib, UK inhibitors (e.g., nacritinib, qeritinib, qerib, etc.), altinib, qeritinib, etc. Pazopanib, regorafenib, selatinib, nisrotinib, cabozantinib, sunitinib, dorafinib, and the like), HDAC inhibitors (e.g., givinostat, tucidinostat, vorinostat, fimepinostat, droxinostat, entinostat, darsitpristine, quesinostat, tacroline, and the like), CDK inhibitors (e.g., pamazetinib, rebamiptinib, abemaciclib, milciclib, trilaciclib, lerociclib, and the like), MEK inhibitors (e.g., semantenib (AZD 6244), trametinib (GSK 1120212), PD0325901, U0126, pimasertib (AS-703026), PD184352 (CI-1040, and the like), mTOR inhibitors (e.g., vistuertib, and the like), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, and the like), or combinations thereof.
In a third aspect of the present invention, there is provided a method of preparing a pharmaceutical composition comprising the steps of: mixing a pharmaceutically acceptable carrier with a compound of the first aspect of the invention or a stereoisomer or optical isomer thereof, a pharmaceutically acceptable salt, prodrug or solvate thereof, thereby forming a pharmaceutical composition.
In another preferred embodiment, the compounds of the present invention may be formulated into powders, tablets, granules, capsules, solutions, emulsions, suspensions, and the like.
In another preferred embodiment, the pharmaceutical composition is used for treating or preventing a disease associated with the activity or expression of JAK kinase.
In another preferred embodiment, the pharmaceutical composition is used as a JAK kinase inhibitor, preferably as a JAK1 kinase inhibitor.
In a fourth aspect, the present invention provides a compound according to the first aspect or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof for use in the preparation of a medicament or a pharmaceutical composition for the treatment or prevention of a disease associated with the activity or expression of JAK kinase.
In another preferred embodiment, the disease is selected from the group consisting of: cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases, autoimmune diseases of humans or animals, 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 lymphoproliferative disorders, pancreatic cancer, leukemia, lymphoma, multiple myeloma.
In another preferred embodiment, the disease associated with the activity or expression level of JAK kinase is a JAK 1-related disorder.
Wherein the JAK 1-associated disorder is preferably selected from the group consisting of: type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease and alopecia areata.
In another preferred embodiment, there is provided the use of a compound of the first aspect, or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, for the preparation of a medicament or pharmaceutical composition for inhibiting JAK kinase activity; wherein the JAK kinase is preferably a JAK1 kinase.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The present inventors have found, for the first time, through extensive and intensive studies, a novel JAK inhibitor which is novel in structure and has excellent bioactivity and extremely excellent selectivity against JAK 1. Specifically, the selectivity of the compounds of the present invention represented by the ratio of JAK2/JAK1 or the selectivity represented by the ratio of JAK3/JAK1 or the ratio of TYK2/JAK1 is increased about 10-fold on average (most compounds are increased about 20-100-fold). Thus, the side effects of the compounds of the invention associated with JAK3 inhibition are extremely reduced, while safety will be significantly improved. The present invention has been completed on the basis of this finding.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. That is, when the linking group-L1-as exemplified in the present invention does not indicate the linking direction, the linking direction may be in the same direction as the reading order from left to right, or may be in the opposite direction to the above. As will be illustrated by way of example, The linking group-L1-is-C-D-, if-C-D-is formed by linking the ring A and the ring B in the same direction as the reading sequence from left to rightif-C-D-is formed by connecting rings A and B in a direction opposite to the above-mentioned direction
The term "optional" or "optionally" means 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 where it does not.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "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 a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
As used herein, the term "alkenyl" includes straight or branched alkenyl groups. For example C 2 -C 6 Alkenyl refers to straight or branched alkenyl groups having 2 to 6 carbon atoms such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.
Such as the bookAs used herein, the term "alkynyl" includes straight or branched chain alkynyl groups. For example C 2 -C 6 Alkynyl refers to straight or branched chain alkynyl groups 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 double bonds) containing a specified number of C atoms, e.g. "C3-C10 cycloalkyl" refers to cycloalkyl groups having 3-10 (preferably 3, 4, 5, 6, 7 or 8) carbon atoms. It may be a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like. But also in the form of a bicyclic ring, for example a bridged or spiro ring. In the present invention, cycloalkyl is intended to include substituted cycloalkyl.
As used herein, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms; having the formula C1-C6 alkyl-O-or-C1-C5 alkyl-O-C1-C5 alkyl (e.g., -CH) 2 -O-CH 2 CH 3 、-CH 2 -O-(CH 2 ) 2 CH 3 、-CH 2 CH 2 -O-CH 2 CH 3 ) Structure such as 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, the heterocyclic group and the heterocycloalkyl group have the same meaning and are used interchangeably. It may be a single ring or may be in the form of a double ring, for example in the form of a bridged or spiro ring. The 3-to 10-membered heterocyclic (alk) yl group is preferably a 3-to 8-membered heterocyclic (alk) yl group, more preferably a 6-to 8-membered heterocyclic (alk) yl 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 cyclic group containing no heteroatoms in the ring, and "C6-C12 aryl" refers to an aromatic cyclic group containing 6 to 12 carbon atoms containing no heteroatoms in the ring, which may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring. Such as phenyl (i.e., six-membered aromatic ring), naphthyl, and the like, wherein six-membered aryl is also intended to include six-membered aryl-5-6 membered cycloalkyl and six-membered aryl-5-6 membered heterocycloalkyl. The C6-C12 aryl group is preferably a C6-C10 aryl group. Aryl groups may 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 N, S and O, and "5-12 membered heteroaryl" refers to a cyclic aromatic group having 5-12 atoms and wherein 1-3 atoms are heteroatoms selected from the following groups N, S and O. It may be a single ring or may be in the form of a fused ring. 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 may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring. Heteroaryl groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, amido, sulfonamide, formyl, carboxamide, carboxyl, carboxylate and the like.
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 "amide" refers to a group with the structure-CONRR ', wherein R and R' may independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as defined above. R and R' may be the same or in the dialkylamine fragmentDifferent. Examples of amide groups include, but are not limited to: -CONH 2 、-CONHCH 3 、-CONHCH 2 CH 3 、-CON(CH 3 ) 2 -CONH cyclopropyl, -CONH cyclobutyl, -CONH cyclopentyl, -CONH cyclohexyl, -CONCH 3 Cyclopropyl, -CONCH 3 Cyclobutyl, -CONCH 3 Cyclopentyl, -CONCH 3 And a cyclohexyl group.
In the present invention, the term "sulfonamide" refers to a compound having the structure-SO 2 The group NRR 'wherein R and R' may independently represent hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, as defined above. R and R' may be the same or different in the dialkylamine fragment. Examples of sulfonamide groups include, but are not limited to: -SO 2 NH 2 、-SO 2 NHCH 3 、-SO 2 NHCH 2 CH 3 、-SO 2 N(CH 3 ) 2 、-SO 2 NH cyclopropyl, -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 And a cyclohexyl group.
In the present invention, the term "formyl" refers to a group comprising-CHO.
In the present invention, the term "carboxamide group" is meant to includeThe carboxamide group is also intended to comprise a substituted carboxamide group having the formulaWherein R each independently represents hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heteroarylCyclic groups, as defined above. Each R may be the same or different.
In the present invention, "amino" means having a structure of-N-RR ', R and R ' each independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above, and R ' may be the same or different. Examples of amino groups include, but are not limited to: -NH 2 、-NHCH 3 、-NHCH 2 CH 3 、-N(CH 3 ) 2 -NH cyclopropyl, -NH cyclobutyl, -NH cyclopentyl, -NH cyclohexyl, -NCH 3 Cyclopropyl, -NCH 3 Cyclobutyl, -NCH 3 Cyclopentyl, -NCH 3 And a cyclohexyl group.
In the present invention, "sulfoxide group" means having-S (O) -R, R independently represents hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above. Examples of sulfoxide groups include, but are not limited to: -S (O) -CH 3 、-S(O)-CH 2 CH 3 、-S(O)-CH(CH 3 ) 2 。
In the present invention, "sulfone group" means having-S (O) 2 -R, R independently represent hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, as defined above. Examples of sulfone groups include, but are not limited to: s (O) 2 -CH 3 、-S(O) 2 -CH 2 CH 3 、-S(O) 2 -CH(CH 3 ) 2 。
In the present invention, "ester" means having the structure-C (O) -O-R or R-C (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-CH 3 、-C(O)-O-CH 2 CH 3 、-C(O)-O-CH 2 CH 2 CH 3 、-C(O)-O-CH(CH 3 ) 2 、-O-C(O)-CH 3 、-O-C(O)-CH 2 CH 3 、-O-C(O)-CH 2 CH 2 CH 3 、-O-C(O)-CH(CH 3 ) 2 。
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable.
Unless otherwise indicated as "substituted or unsubstituted", the radicals according to the invention may be substituted by substituents selected from the group consisting of: deuterium, halogen, cyano, nitro, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl.
In the present invention, the term "plurality" independently means 2, 3, 4, 5.
Unless otherwise specified, the structural formulae described herein are intended to include all isomeric forms (e.g., enantiomers, diastereomers and geometric isomers (or conformational isomers)): for example R, S configuration containing asymmetric centers, the (Z), (E) isomers of double bonds, etc. Thus, individual stereochemical isomers of the compounds of the invention or mixtures of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof are all within the scope of the invention.
As used herein, the term "tautomer" means that structural isomers having different energies may exceed the low energy barrier, thereby interconverting. For example, proton tautomers (i.e., proton transfer) include tautomers by proton transfer, such as 1H-indazole and 2H-indazole. Valence tautomers include tautomers that undergo interconversion by recombination of some of the bond-forming electrons.
As used herein, the term "solvate" refers to a compound of the invention that coordinates to a solvent molecule to form a complex in a specific ratio.
Active ingredient
As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I.
The compounds of formula I of the present invention have the following structure,
wherein R is 1 、R 2 、R 3 The definitions of B, C, m, n, k and l are as described above.
Preferably, the compound of formula I has the structure described in formula II,
wherein R is 1 、R 2 、R 3 、R a The definitions of q, B and C are as described above.
Preferably, in formulas I-II, B is selected from the group consisting of: c (=O) O-, C (=O) O-Wherein R is b Is defined as above.
Preferably, in formulae I-II, C is selected from the group consisting of substituted or unsubstituted: 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; preferably, C is selected from substituted or unsubstitutedThe following groups: cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydropyranyl, piperazinyl, piperidinyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, imidazolyl, pyrazolyl, furanyl, thiazolyl, pyrrolyl, indolyl, naphthyl, wherein said substitution is by one or more R a Substitution;
R a is defined as above.
Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.
The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalene sulfonate (e.g., 2-naphthalene sulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like.
Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hydrabamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, 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 (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.
Prodrugs and solvates of the compounds of the invention are also within the scope of coverage. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. 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 (e.g., amides and imine ethers). All of these tautomers are part of the present invention.
Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may 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 recrystallization.
The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.
All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics,75 th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.
Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.
According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.
The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes, respectively, such as 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g 3 H and 14 radioisotopes of C are also useful in, among other things, tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium 3 H and carbon-14, i.e 14 C, their preparation and detection are relatively easy. Is the first choice in isotopes. Furthermore, heavier paritySubstitution of elements, e.g. deuterium, i.e 2 H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.
If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.
As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention recognizes that the combination of substituents and variable groups is very good in the treatment of diseases in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof of the present application, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof of the present application are also encompassed by the claims of the present application.
Process for the preparation of compounds
The following schemes and examples describe methods for preparing compounds of formula I. The starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of the steps of the reaction scheme may be altered to promote the reaction or to avoid unwanted side reaction products.
Typically, in the preparation scheme, each reaction is carried out in an inert solvent at a temperature ranging from room temperature to reflux temperature (e.g., 0 ℃ to 150 ℃, preferably 10 ℃ to 100 ℃). The reaction time is usually 0.1 hours to 60 hours, preferably 0.5 to 48 hours.
Preferably, the compounds of the present application can be prepared as follows
In the presence of a catalyst (such as HATU, potassium carbonate, etc.) in an inert solvent (such as DCM, DMF, etc.), the compound I' is reacted to give the compound I
In the method, in the process of the application,
R 1 、R 2 、R 3 the definitions of m, n, k and l are as described above;
r is selected from the group consisting of substituted or unsubstituted: C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl;
B' is selected from the group consisting of: amino, hydroxy, carboxyl, sulfonic acid group,-CO-NH-R'；
C' is selected from: amino, hydroxy, carboxyl, sulfonic acid group,CO-O-R'、-CO-NH-R'；
Wherein R' is selected from the group consisting of substituted or unsubstituted: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocyclyl, C3-to C10-cycloalkyl, 5-to 12-membered heteroaryl, C6-to C12-aryl;
the substitution means substitution with one or more groups selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-to 10-cycloalkyl, 5-to 12-membered heteroaryl and C6-C12-aryl.
Starting materials and reagents used in the methods of synthesizing the compounds of the invention are commercially available or are synthesized by methods reported in the literature.
Pharmaceutical compositions and methods of administration
Since the compound of the present invention has excellent JAK kinase inhibitory activity, the compound of the present invention or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) JAK kinase-associated diseases (for example, skin diseases, rheumatoid arthritis, multiple sclerosis, type I diabetes, psoriatic arthritis, juvenile arthritis, crohn's disease, myasthenia gravis, cancers (including prostate cancer, kidney cancer, liver cancer, breast cancer, lung cancer, thyroid cancer, kaposi's sarcoma, giant lymphoproliferative diseases, pancreatic cancer, leukemia, lymphoma or multiple myeloma, etc.)).
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention within a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-200mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., JAK inhibitors).
When administered in combination, the pharmaceutical compositions also include combinations with one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., JAK inhibitors). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds (e.g., JAK inhibitors) may be used simultaneously, separately or sequentially with the compounds of the invention for preventing and/or treating diseases associated with the activity or expression level of JAK kinase.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 20 to 500mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention has the main advantages that:
1. the compound disclosed by the invention is novel in structure and has an excellent JAK kinase inhibition effect;
2. the compounds of the present invention are useful as JAK kinase inhibitors, particularly as highly selective inhibitors of JAK 1.
3. The compound has better pharmacokinetic property and drug effect, such as better drug forming property, low toxic and side effect, good bioavailability and the like.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Examples
General materials and test methods:
the synthetic methods of the compounds of the present invention are shown in the schemes, methods and examples below. The starting materials are commercially available or may be prepared according to known methods described in the art or herein. The compounds of the present invention are illustrated by the specific examples shown below. However, these specific embodiments should not be construed as the only kind of the invention. These examples further illustrate the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known variations of conditions and procedures may be used to prepare these compounds.
All temperatures are in degrees celsius unless otherwise indicated.
The percentages for the yields are mass percentages.
All parts are parts by volume and all percentages are percentages by volume unless otherwise indicated.
Thin Layer Chromatography (PTLC) was performed on a 20X 20cm plate (500 μm thick silica gel). Silica gel chromatography was performed using a Biotage flash chromatography system.
1 H NMR was performed with a Bruker AscendTM400 spectrometer, 400mhz,298k, and the chemical shift (ppm) of residual protons in deuterated reagent gave a reference:
CDCl 3 δ＝7.26ppm，CD 3 ODδ＝3.30ppm，DMSO-d 6 δ＝2.50ppm
LCMS chromatography uses agilent technology 1260 linked 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 capillary column of 50 mm. Times.2.1 mm. Times.3.5. Mu.m.
Mass Spectrometry (MS) was determined by electrospray ion mass spectrometry (ESI).
HPLC mass spectrometry conditions:
LC1：
column: SB-Aq50 mm. Times.2.1 mm. Times.3.5. Mu.m;
temperature: 40 ℃;
eluent: 100:0 to 5:95 v/v 0.1% formic acid-water/0.1% formic acid-acetonitrile for 8 minutes;
flow rate: 1.0mL/min, 5. Mu.L;
and (3) detection: VWD,210nm &254nm;
MS: the mass range is 100-100amu; positive ion electrospray ionization.
Abbreviation table:
AcOH = acetic acid
Alk is an alkyl group
AR is aryl
Boc=t-butoxycarbonyl group
bs=broad peak
CH 2 Cl 2 =dichloromethane
d=bimodal
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 group
EtOAc = ethyl acetate
Etoh=ethanol
h=h
Hoac=acetic acid
Lioh=lithium hydroxide
m = multiple
Me=methyl group
Mecn=acetonitrile
Meoh=methanol
MgSO 4 =magnesium sulfate
min = min
Ms=mass spectrum
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: 2- (1, 4-dioxaspiro [4.5] dec-8-ylidene) acetic acid ethyl ester (A1-2)
1, 4-cyclohexanedione monoethyl glycol ketal (A1-1, 10.0g,64.0 mmol) was added to anhydrous THF (100 ml) under nitrogen protection, stirred in an ice bath for 5min, sodium hydrogen (3.07g,76.8mmol,60%dispersion in mineral oil) was added in portions, stirring in an ice bath was continued for 0.5h, then a solution of triethyl phosphonoacetate (14.78 g,65.9 mmol) in THF (50 ml) was slowly added, and after dropping naturally warmed to room temperature and stirring continued for 2h. After TLC confirmed the completion of the reaction, water quenching, concentrating THF, extracting with EA, collecting the organic layer, drying over anhydrous sodium sulfate, concentrating EA to give 2- (1, 4-dioxaspiro [4.5] as a yellow liquid]Decyl-8-subunit) ethyl acetate (A1-2, 14.38g, trude) was used directly in the next step without purification. 1 H NMR(400MHz,CDCl 3 )δ5.69(s,1H),4.17(q,J＝8.0Hz,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＝8.0Hz,3H)。
And a second step of: 2- (8-Nitromethyl-1, 4-dioxaspiro [4.5] dec-8-yl) acetic acid ethyl ester (A1-3)
2- (1, 4-dioxaspiro [4.5] ]Ethyl dec-8-ylidene acetate (A1-2, 14.38g,63.6 mmol) was added to THF (100 ml), followed by tetrabutylammonium fluoride (18.29g,70mmol,70mL,1M in THF) and nitromethane (5.82 g,95.40 mmol) in this order, and the temperature was raised to 80℃and the reaction was stirred for 16h. After TLC confirmed the completion of the reaction, THF was concentrated, EA and deionized water were added, the separated solution was extracted, and the organic layer was dried over anhydrous sodium sulfate, and EA was concentrated to give 2- (8- (nitromethyl) -1, 4-dioxaspiro [4.5 ] as a yellow liquid]Decyl-8-yl) ethyl acetate (A1-3, 16.68g, crude) was used directly in the next step without purification. 1 H NMR(400MHz,CDCl 3 )δ4.75(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)。
And a third step of: 1, 4-dioxa-10-azadispiro [4.2.4 8 .2 5 ]Tetradecan-11-one (A1-4)
2- (8-Nitromethyl-1, 4-dioxaspiro [4.5 ]]Decyl-8-yl) ethyl acetate (A1-3, 16.68 g) was added to methanol (150 ml), then Raney nickel was added and reacted at 45℃for 48h with hydrogen. After completion of the LCMS monitoring reaction, the reaction mixture was filtered and the methanol was concentrated to give 1, 4-dioxa-10-azadispiro [4.2.4 ] 8 .2 5 ]Tetradecan-11-one (A1-4, 11.98g, crop) was used directly in the next step without purification. 1 H NMR(400MHz,CDCl 3 )δ5.65(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)。
Fourth step: 1, 4-dioxa-10-azaspiro [4.2.4 8 .2 5 ]Tetradecane (A1-5)
Nitrogen protection, 1, 4-dioxa-10-azadispiro [4.2.4 8 .2 5 ]Tetradecan-11-one (A1-4, 2g,9.47 mmol) was added to dry THF (30 ml) and stirred for 5min, borane THF solution (47.4 ml,47.4mmol, 1M) was slowly added, warmed to 70℃and stirred for 16h. After completion of the reaction by LCMS, the reaction mixture was cooled to room temperature, quenched by slow addition of methanol, and the solvent was concentrated to give 1, 4-dioxa-10-azaspiro [4.2.4 ] as an oil 8 .2 5 ]Tetradecane (A1-5, 1.8g, crude) was used directly without purificationNext, the process is performed.
Fifth step: 10- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -1, 4-dioxa-10-azaspiro [4.2.4 8 .2 5 ]Tetradecane (A1-6)
1, 4-dioxa-10-azaspiro [4.2.4 8 .2 5 ]Tetradecane (A1-5, 1.8g,9.13 mmol) and 4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidine (1.4 g,9.13 mmol) was added to DMF (30 ml), followed by N, N-diisopropylethylamine (2.36 g,18.3 mmol), warmed to 100℃and stirred for 16h. After completion of the reaction, LCMS was confirmed, cooled to room temperature, suction filtered, the cake was collected, and suction dried under reduced pressure to give 10- (7H-pyrrolo [2, 3-d) as an off-white solid]Pyrimidin-4-yl) -1, 4-dioxa-10-azaspiro [4.2.4 8 .2 5 ]Tetradecane (A1-6, 2.26g, crude) was used directly in the next step without purification. 1 H NMR(400MHz,CDCl 3 )δ10.16(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)。
Sixth step: 2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-aza-spiro [4.5] decan-8-one (A1-7)
10- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -1, 4-dioxa-10-azaspiro [4.2.4 8 .2 5 ]Tetradecane (A1-6, 2.26g,7.20 mmol) was added to THF (30 ml), concentrated hydrochloric acid (10 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 16h. After the completion of the reaction, 6mol/L NaOH solution is added dropwise to adjust the pH value to be 7-8, the filtration is carried out, a filter cake is collected, and the filtration is carried out under reduced pressure and dried to obtain an off-white solid 2- (7H-pyrrolo [2, 3-d) ]Pyrimidin-4-yl) -2-aza-spiro [4.5]Decan-8-one (A1-7, 1.89g, crop) was used directly in the next step without purification. 1 H NMR(400MHz,CDCl 3 )δ10.63(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)。
Seventh step: 2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-azaspiro [4.5] decan-8-amine (A1)
2- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2-azaspiro [4.5]Decan-8-one (A1-7, 1g,3.70 mmol) was added to absolute ethanol (30 ml), followed by 7mol/L NH 3 (MeOH) (29.6 ml,0.21 mol) and isopropyl titanate (2.1 g,7.40 mmol), stirred at room temperature for 6h, then sodium borohydride (210 mg,5.56 mmol) was added in portions and stirring was continued for 16h. After LCMS confirmed the completion of the reaction, the reaction was quenched by addition of aqueous ammonia (17 ml), stirred at room temperature for 15min, suction filtered, the filtrate collected, concentrated, added with EA, stirred for 10min, suction filtered, the filter cake collected, and dried in vacuo to give an off-white solid A1 (900 mg). MS (ESI) M/z calcd 272.19 (M+H), found 272.10; 1 H NMR(400MHz,DMSO- d6 )δ11.55(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):
nitrogen protection, 2- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2-azaspiro [4.5]Decan-8-amine (A1, 4mg, 14.8. Mu. Mol) was added to MeCN (1 ml), sodium bicarbonate (2 mg, 23.8. Mu. Mol) was added, and the mixture was cooled to 0℃and stirred for 5min, and then a MeCN solution of acetyl chloride (1.1 mg, 14.8. Mu. Mmol) was added dropwise thereto, and ice-bath stirring was continued for 1h. After LCMS confirmed the reaction was complete, meCN was concentrated and the residue was purified by prep. to give A2 as a white solid (3 mg, 64.9% yield). MS (ESI) M/z calcd314.20 (M+H), found 314.00; 1 H NMR(400MHz,MeOH- d4 )δ8.08(s,1H),7.10(d,J＝3.56Hz,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:
nitrogen protection, 2- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2-azaspiro [4.5]Decan-8-amine (A1, 10mg, 36.9. Mu. Mol) was added to DMF (2 ml), dissolved by stirring, potassium carbonate (6.1 mg, 44.2. Mu. Mol) was added, followed by dropwise addition of a solution of benzenesulfonyl chloride (7.8 mg, 44.2. Mu. Mol) in DMF (0.5 ml) and stirring at room temperature for 1h. After LCMS confirmed completion of the reaction, 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 give A3 as a white solid (5 mg, yield 33.1%). MS (ESI) M/z calcd 412.18 (M+H), found 412.20; 1 H NMR(400MHz,DMSO- d6 )δ12.65(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 synthesis of N-2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-azaspiro [4.5] dec-8-yl) -3-bromo-5-nitrobenzamide (A4):
nitrogen protection, 2- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2-azaspiro [4.5]Decan-8-amine (A1, 15mg, 55.3. Mu. Mol) and 3-bromo-5-nitrobenzoic acid (13.5 mg, 55.3. Mu. Mol) were added to a mixture of DCM (2 ml) and DMF (0.5 ml), HATU (21 mg, 55.3. Mu. Mol) was added and stirred in an ice bath for 5min, then a solution of N, N-diisopropylethylamine (7.1 mg, 55.3. Mu. Mol) in DCM (1 ml) was added dropwise and stirred in an ice bath for 0.5h. After LCMS confirmed the reaction was complete, dichloromethane and deionized water were added and the organic layer was collected, anhydrous Na 2 SO 4 Dried, concentrated DCM and the residue purified by reverse phase column to give a white solid A4 (11 mg, 40.0% yield). MS (ESI) M/z calcd 499.11, 501.11 (M+H), found 499.21, 501.22; 1 H NMR(400MHz,DMSO- d6 )δ12.66(br,1H),8.74(d,J＝8.0Hz,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)。
prepared with reference to the experimental procedure of examples 2-4, with different acylating reagents, gave examples 5-75, as shown in table 1 below.
TABLE 1
EXAMPLE 76 Synthesis of N- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-azaspiro [3.3] hept-6-yl) -2-chloro-4-nitrobenzamide (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 and stirred at room temperature for 3.0h. After LCMS confirmed the reaction was complete, the reaction mixture was directly dried by spin to give 6-oxo-2-azaspiro [3.3] heptane trifluoroacetate (a 76-01, 215mg, crude) as a yellow oil, which was used directly in the next step without purification. MS (ESI) M/z calcd 112.07 (M+H), found 112.14.
And a second step of: 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, 215mg,0.95 mmol) and 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (148 mg,0.96 mmol) were added to N-methylpyrrolidone (4 ml), followed by potassium carbonate (900 mg,6.5 mmol), and the mixture was stirred for 14H at 80 ℃. After LCMS confirmed completion of the reaction, cooled to room temperature, suction filtered, the filter cake was collected, and suction dried under reduced pressure to give 6-oxo-2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-azaspiro [3.3] heptane (a 76-02, 40mg, crude) as an off-white solid, which was used directly in the next step without purification.
And a third step of: 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, 40mg,0.18 mmol) was added to absolute ethanol (2 ml), followed by 7mol/L NH 3 Is stirred at room temperature for 6h with isopropyl titanate (105 mg,0.37 mmol) and MeOH (2 ml,14 mmol) and sodium borohydride (67 mg,1.8 mmol) is added and stirring is continued for 16h. After completion of the reaction by LCMS, the reaction was quenched by adding ammonia (2 mL), stirring at room temperature for 15min, suction filtration, collecting the filtrate, concentrating, adding EA for dissolution, suction filtration, collecting the filtrate, and spin-drying under reduced pressure to give 2- (7H-pyrrolo [2, 3-d) as a pale yellow oil]Pyrimidin-4-yl) -2-azaspiro [3.3]Hept-6-amine (A76-03, 35mg, trude) was used directly in the next step without further treatment. MS (ESI) M/z calcd 229.13 (M+H), found 229.10.
Fourth step: n- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2-azaspiro [3.3] hept-6-yl) -4-chloro-2-nitrobenzamide (A76)
2- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2-azaspiro [3.3]Hept-6-amine (A76-03, 35mg,0.15 mmol) and 4-chloro-2-nitrobenzoic acid (30 mg,0.15 mmol) were added to DMF (1 ml), HATU (57 mg,0.15 mmol) was added thereto, stirred in an ice bath for 5min, and then N, N-diisopropylethylamine (19.35 mg, A solution of 0.15mmol of DMF (0.5 mL) was stirred in an ice bath for 1h. After LCMS confirmed the reaction was complete, the reaction was directly purified by reverse phase column to give 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(400MHz,DMSO- d6 )δ12.64(s,1H),8.97(d,J＝6.9Hz,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 testing method
The method for measuring and activating JAK kinase uses homogeneous time-resolved fluorescence technology. The reaction of this method was carried out in 384 shallow well plates in a total reaction volume of 10. Mu.L. A mixture of kinase protein, compound, ATP and substrate was incubated at 50mM Hepes (pH 7.0), naN 3 0.02%, BSA 0.01%, 0.1mM orthovanadate (orthovanadate), 5mM MgCl 2 1mM DTT in reaction buffer, after 1 hour of reaction, an antibody recognizing substrate phosphorylation and dye XL-615 and EDTA-containing detection buffer (Cisbio) were added to the system. The reaction signal of the kinase was detected by a multi-well plate detector from PE company. The parameter settings are excitation light 320nm, emission light 615nm and 665nm. JAK viability is indirectly reflected by the ratio of 665nm to 615nm signals. The reaction was set with background wells without enzyme and wells with total enzyme activity without compound.
Compound arrestin IC 50 The value of (2) is calculated by the formula: y=100/(1+10 ((log ic 50-X)) HillSlope).
In the JAK1 reaction system, the ATP concentration was 2. Mu.M, and the JAK1 protein concentration was 0.2 ng/. Mu.L.
In the JAK2 reaction system, the ATP concentration was 2. Mu.M, and the JAK1 protein concentration was 0.01 ng/. Mu.L.
In the JAK3 reaction system, the ATP concentration was 2. Mu.M, and the JAK1 protein concentration was 0.04 ng/. Mu.L.
In the TYK2 reaction system, the ATP concentration was 2. Mu.M, and the JAK1 protein concentration was 0.2 ng/. Mu.L.
The test data are divided into the following: a: IC 50 <10nM；B:IC 50 11-100nM；C:IC 50 101-1000nM；D:IC 50 1001-10000nM；E:IC 50 >10000nM。
The test results are shown in Table 2.
TABLE 2
The experimental results suggest that:
(1) The compounds of formula I of the present application exhibit very excellent JAK inhibiting activity, in particular JAK1 activity. The compounds of the application may have IC50 values as low as 10nM or less, so that daily doses of typically 10mg to 30mg are extremely effective in inhibiting JAK, particularly JAK1, in subjects (such as patients, particularly rheumatoid arthritis or psoriasis patients) weighing about 70 kg.
(2) The compounds of formula I of the present application exhibit very excellent JAK selectivity, i.e., a ratio of IC50 of JAK3/JAK1, a ratio of IC50 of JAK2/JAK1, a ratio of IC50 of TYK2/JAK1 is increased by about 10-fold (mostly about 20-100-fold), which is far superior to drugs currently on the market.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

  1. A compound of formula I or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof,
    in the method, in the process of the invention,
    R 1 、R 2 and R is 3 Each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, amino, nitro, hydroxy, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-C10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
    or R is 1 And R is 2 Together with the atoms to which they are attached, constitute a substituted or unsubstituted group of radicals: 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, C3-C10 cycloalkyl; wherein said substitution means by one or more R a Substitution;
    b is independently selected from the group consisting of: bond, - (CH) 2 ) r -、C(＝O)、N-R b 、C(＝O)O-、 -(CH 2 ) p -R c 、O、S、SO、SO 2 ；R c Selected from: c (=O) O-, C (=O) O-Wherein R is b Independently selected from the group consisting of: H. C1-C6 alkyl;
    wherein- (CH) 2 ) r -and- (CH) 2 ) p The H atom in-can optionally be replaced by one or more R a Substitution;
    c is selected from the group consisting of substituted or unsubstituted: H. C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-C10 cycloalkyl, 5-to 12-membered heteroaryl, C6-C12 aryl; wherein said substitution means by one or more R a Substitution;
    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 is not less than 1, k+l is not less than 1;
    h in the moiety may optionally be substituted with one or more R a Substitution;
    wherein each R a Independently selected from the group consisting of substituted or unsubstituted: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-C10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl and C6-C12 aryl; wherein R is a By substitution is meant substitution with one or more groups selected from the group consisting of: halogen, amino, nitro, hydroxyl, mercapto, cyano, carboxyl, sulfone, sulfoxide, amide, sulfonamide, ester, formyl, carboxamide, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-to 10-membered heterocycloalkyl, C3-to 10-cycloalkyl, 5-to 12-membered heteroaryl and C6-C12-aryl.
  2. A compound of claim 1, or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, The moiety is selected from:
    wherein q is 0, 1, 2, 3, 4 or 5;
    R a is defined as in claim 1.
  3. A compound according to claim 1, or a stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof, having the structure of formula II:
    wherein q is 0, 1, 2, 3, 4 or 5;
    R 1 、R 2 、R 3 、R a the definitions of B and C are as defined in claim 1.
  4. A compound according to 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-, C (=O) O-Wherein R is b Is defined as in claim 1.
  5. The compound of claim 1 or a stereoisomer thereofOr an optical isomer, a pharmaceutically acceptable salt, prodrug or solvate, characterized in that C is selected from the group consisting of substituted or unsubstituted: 3-8 membered heterocycloalkyl, C3-C8 cycloalkyl, 5-10 membered heteroaryl, C6-C10 aryl; wherein said substitution means by one or more R a Substitution;
    R a is defined as in claim 1.
  6. 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 is R a Is as defined in claim 1;
    (2) B is selected from: -NH-,-NH-C (=o) -; optionally, each hydrogen in the above groups is substituted with a C1-C6 alkyl group;
    (3) C is selected from: H. methoxy, phenyl, methyl, ethyl, thiazolyl, pyridyl, cyclopropyl, pyrazinyl, cyclohexyl, benzothienyl, benzofuranyl, pyrimidinyl, naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, sulfonamide;
    preferably, C is selected from: H. methoxy, phenyl, methyl,Cyclopropyl group,Cyclohexyl group,Naphthyl, cyclobutyl, cyclopentyl, cycloheptyl; wherein, optionally, C is substituted with a substituent selected from the group consisting of: fluorine, chlorine, bromine, nitro, cyano, hydroxy, ethynyl, methyl, methoxy, methyl formate, trifluoromethyl, phenyl, sulfonamide;
    more preferably, C is selected from: H. methyl, methoxy, Phenyl group,
    (4)R 1 Is hydrogen;
    (5)R 2 is hydrogen;
    (6)R 3 is hydrogen;
    in particular the number of the elements to be processed,selected from the group consisting of
  7. The compound of any one of claim 1 to 5, or a stereoisomer, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, or a solvate thereof, wherein each substituent satisfies one or more of the following conditions,
    Each C1-C6 alkyl is independently selected from: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl;
    each C1-C6 alkoxy is independently selected from: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy;
    each C2-C6 alkenyl is independently selected from: ethenyl, propenyl, allyl;
    each C2-C6 alkynyl 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 is independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;
    each 5-12 membered heteroaryl is independently selected from: pyrrolyl, furanyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, indolyl, benzothienyl, benzofuranyl;
    each C6-C12 aryl is independently selected from: phenyl and naphthyl.
  8. 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:
  9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a stereoisomer or optical isomer, a pharmaceutically acceptable salt, prodrug or solvate thereof; and a pharmaceutically acceptable carrier;
    in particular, the pharmaceutical composition is useful for treating or preventing diseases associated with the activity or expression of JAK kinase;
    more particularly, the pharmaceutical composition is useful as a JAK kinase inhibitor, preferably as a JAK1 kinase inhibitor.
  10. The use of a compound according to any one of claim 1 to 8, or a stereoisomer or an optical isomer, a pharmaceutically acceptable salt, a prodrug or a solvate thereof,
    it is used for preparing a medicament or a pharmaceutical composition for treating or preventing diseases related to the activity or expression amount of JAK kinase; alternatively, it is used for the preparation of a medicament or pharmaceutical composition for inhibiting JAK kinase activity, preferably JAK1 kinase;
    in particular, the disease is selected from the group consisting of: cancer, myeloproliferative diseases, inflammation, immune diseases, organ transplantation, viral diseases, cardiovascular diseases or metabolic diseases, autoimmune diseases of humans or animals, rheumatoid arthritis, 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 lymphoproliferative disorders, pancreatic cancer, leukemia, lymphoma, multiple myeloma;
    In particular, the disease associated with the activity or expression level of JAK kinase is a JAK 1-related disorder; wherein the JAK 1-associated disorder is preferably selected from the group consisting of: type I diabetes, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease and alopecia areata.
CN202180080571.9A 2020-12-02 2021-12-01 Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor Pending CN116783198A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN202011399496 2020-12-02
CN2020113994966 2020-12-02
PCT/CN2021/134880 WO2022117012A1 (en) 2020-12-02 2021-12-01 Spirocyclic jak inhibitor, pharmaceutical composition containing same, and application thereof

Publications (1)

Publication Number Publication Date
CN116783198A true CN116783198A (en) 2023-09-19

Family

ID=81852954

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202180080571.9A Pending CN116783198A (en) 2020-12-02 2021-12-01 Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor

Country Status (2)

Country Link
CN (1) CN116783198A (en)
WO (1) WO2022117012A1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105732636B (en) * 2014-12-30 2020-04-21 广东东阳光药业有限公司 Heteroaromatic compounds and their use in medicine
US10799507B2 (en) * 2017-02-03 2020-10-13 Leo Pharma A/S 5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5-azaspiro[2.5]octane-8-carboxylic acid derivatives as novel JAK kinase inhibitors

Also Published As

Publication number Publication date
WO2022117012A1 (en) 2022-06-09

Similar Documents

Publication Publication Date Title
CA2969090C (en) Triazolopyrimidine compounds and uses thereof
US20230118795A1 (en) Aryl or heteroaryl pyridone or pyrimidine derivative, preparation method and use thereof
WO2021228161A1 (en) Alkoxlyalkyl-substituted heterocyclic inhibitor, preparation method therefor, and use thereof
CN115335379A (en) Spiro-containing quinazoline compounds
RU2633694C2 (en) Dyetherned phenylaminopyrimidine and pharmaceutical composition containing such connection
WO2022199586A1 (en) Pyrimidopyridine inhibitor, preparation method therefor, and use thereof
WO2021238817A1 (en) Macrocyclic jak inhibitor and use thereof
WO2021249563A1 (en) Aryl or heteroaryl pyridone or pyrimidone derivative, preparation method therefor and application thereof
CA2658404A1 (en) Selective antagonists of a2a adenosine receptors
CA3150284A1 (en) Aza-quinoline compounds and uses thereof
WO2022095909A1 (en) Compound used as ntrk inhibitor and application thereof
CN111718332B (en) 2-substituted pyrazol amino-4-substituted amino-5-pyrimidine formamide compound, composition and application thereof
AU2019339994B2 (en) Furo[3,4-b]pyrrole-containing BTK inhibitor
EP3854793A1 (en) Aromatic heterocyclic compound with kinase inhibitory activity
CN109476643B (en) Pyrazolylaminobenzimidazole derivatives as JAK inhibitors
CN110938070A (en) Heteroaromatic compound with kinase inhibition activity
CN117916234A (en) Compounds as TYK2/JAK1 pseudo-kinase domain inhibitors and methods of synthesis and use
CN116783198A (en) Spirocyclic JAK inhibitor, pharmaceutical composition containing same and application of spiro JAK inhibitor
CN115215869A (en) Substituted tricyclic inhibitor and preparation method and application thereof
CN115215844A (en) Substituted pyrimido-ring inhibitor and preparation method and application thereof
CN113583020B (en) JAK2 inhibitor and application
EP4159738A1 (en) Macrocyclic jak inhibitor and uses thereof
CN117820305A (en) Heterocyclic substituted quinazoline and preparation method and application thereof
EP4310081A1 (en) Ctla-4 small molecule degradation agent and application thereof
CN116813646A (en) Substituted bridged ring inhibitors and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination