CN105732636B - Heteroaromatic compounds and their use in medicine - Google Patents

Heteroaromatic compounds and their use in medicine Download PDF

Info

Publication number
CN105732636B
CN105732636B CN201511016911.4A CN201511016911A CN105732636B CN 105732636 B CN105732636 B CN 105732636B CN 201511016911 A CN201511016911 A CN 201511016911A CN 105732636 B CN105732636 B CN 105732636B
Authority
CN
China
Prior art keywords
alkyl
radical
substituted
compound
cyano
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.)
Active
Application number
CN201511016911.4A
Other languages
Chinese (zh)
Other versions
CN105732636A (en
Inventor
刘兵
黄九忠
任兴业
李志�
张英俊
郑常春
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.)
Guangdong HEC Pharmaceutical
Original Assignee
Dongguan Dongyangguang Medicine Research And Development Co ltd
Sunshine Lake Pharma 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 Dongguan Dongyangguang Medicine Research And Development Co ltd, Sunshine Lake Pharma Co Ltd filed Critical Dongguan Dongyangguang Medicine Research And Development Co ltd
Publication of CN105732636A publication Critical patent/CN105732636A/en
Application granted granted Critical
Publication of CN105732636B publication Critical patent/CN105732636B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention discloses a heteroaromatic compound and application thereof in medicines; specifically, the invention provides a kind of heteroaromatic compounds or stereoisomers, geometric isomers, tautomers, racemates, nitrogen oxides, hydrates, solvates, metabolites and pharmaceutically acceptable salts or prodrugs thereof, which are used for treating autoimmune diseases or proliferative diseases. The invention also discloses a pharmaceutical composition containing the compound and application of the compound or the pharmaceutical composition thereof in preparing medicines for treating autoimmune diseases or proliferative diseases.

Description

Heteroaromatic compounds and their use in medicine
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a heteroaromatic compound with protein kinase inhibitory activity and a pharmaceutical composition containing the heteroaromatic compound. The invention also relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention in medicine.
Background
Janus kinases (JAKs) belong to the tyrosine kinase family, consisting of JAK1, JAK2, JAK3 and TYK 2. JAKs play an important role in cytokine signaling. JAK1, JAK2 and TYK2 can inhibit multiple gene expression, whereas JAK3 only plays a role in granulocytes. Cytokine receptors typically function as heterodimers and are therefore not generally a JAK kinase interacting with cytokine receptors.
Each JAK associates preferentially with the intracytoplasmic portion of a discrete cytokine receptor (annu. rev. immunol.1998,16, pp.293-322). JAKs are activated upon ligand binding and initiate signaling by phosphorylating cytokine receptors, which themselves lack intrinsic kinase activity. This phosphorylation creates docking sites on the receptor for other molecules called STAT proteins (signal transducers and activators of transcription), and phosphorylated JAKs bind to a variety of STAT proteins. STAT proteins, or STATs, are DNA binding proteins that are activated by phosphorylation of tyrosine residues and function both as signaling molecules and transcription factors, and ultimately bind to specific DNA sequences present in the promoters of cytokine-responsive genes (J.allergy Clin. Immunol., Leonard, et al,2000,105: 877-888).
Genetic biological studies have shown that JAK1 functions by interacting with cytokine receptors such as IFNalpha, IFNgamma, IL-2, IL-6, and JAK1 knockout mice die due to loss of LIF receptor signaling. The characteristic tissues of JAK1 knockout mice are observed, and JAK1 is found to play an important role in cell pathways such as IFN, IL-10, IL-2/IL-4, IL-6 and the like.
Genetic biological studies have shown a link between JAK2 and the single chain, IL-3 and interferon gamma cytokine receptor families. In response, JAK2 knockout mice died of anemia. Kinase-mediated JAK2 mutations are associated with myeloproliferative disorders in humans, including polycythemia vera, idiopathic thrombocythemia, chronic idiopathic myelofibrosis, myelogenic tissue transformation with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, and the like.
JAK3 specifically acts on the gamma cytokine receptor chain, which is present in cytokine receptors such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. JAK3 plays an important role in the growth, proliferation and mutation of lymphocytes, and serious immune deficiency can be caused by abnormality. It has now been examined that JAK3 protein levels in XSCID populations are severely reduced or are deficient in their common gamma chain gene, showing that the immunosuppressive effect is due to blocking signaling through the JAK3 pathway. Animal studies have shown that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but also constitutively requires JAK3 to maintain T cell function. Based on their role in regulating lymphocytes, JAK3 and JAK 3-mediated pathways are used to modulate the indications for immunosuppression. JAK3 has been implicated in the mediation of many abnormal immune responses, such as allergy, asthma, autoimmune diseases such as suppression of transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, and solid and hematologic malignancies such as leukemia, lymphoma.
JAK3 inhibitors are useful therapeutics as immunosuppressive agents for: organ transplantation, xenotransplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and other conditions where immunosuppression is appropriate.
Non-hematopoietic expression of JAK3 has also been reported, although the functional significance is unclear (J.Immunol.,2002,168: 2475-2482). Since bone marrow transplantation for SCID is curative (Blood,2004,103:2009-2018), it seems unlikely that JAK3 has the necessary non-redundant function in other tissues or organs. Therefore, in contrast to other targets for immunosuppressive drugs, the restricted distribution of JAK3 is attractive. Active agents acting on molecular targets with expression limited to the immune system may lead to optimal efficacy: the toxicity ratio. Thus, in theory, targeting JAK3 would provide immunosuppression in situations where it is needed (i.e., on cells actively involved in the immune response) without causing any effect outside of these cell populations. Although in various STATs-/-Defective immune responses have been described in strains (J.Investig.Med.,1996,44: 304-311; Curr.Opin.cell biol.,1997,9:233-239), but the widespread distribution of STATs and the fact that these molecules lack enzymatic activity that can be targeted with small molecule inhibitors have contributed to their non-selectivity as key targets for immunosuppression.
TYK2 acts on the receptor complexes of type I interferons, IL-6, IL-10, IL-12, IL-23 and other cytokines. In agreement, primary cells derived from TYK 2-deficient humans present obstacles to signaling in type I interferons, IL-6, IL-10, IL-12, IL-23.
Thus, there is a need for compounds that inhibit the protein kinase JAK, thereby providing treatment for diseases such as autoimmune diseases, inflammatory diseases, and cancer.
Disclosure of Invention
The compound of the invention has an inhibitory effect on the activity of protein kinase. It is further desirable that the compounds of the present invention have multiple inhibitory functions and may inhibit JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M. In particular, the compounds and pharmaceutically acceptable pharmaceutical compositions thereof of the present invention are effective as JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M inhibitors.
In one aspect, the invention relates to a compound that is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (I):
Figure BDA0000892466340000021
wherein:
r is the following subformula:
Figure BDA0000892466340000022
wherein each R is1a、R1b、R1cAnd R1dIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C1-6Alkyl, hydroxy substituted C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl radical, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group;
each R2And R3Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, carboxyl or nitro;
each RaAnd RbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C1-6An alkyl group; or R on the same carbon atomaAnd RbTogether form oxo (═ O);
m is 0,1, 2,3, 4, 5 or 6;
each R4And R5Independently of one another is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6alkyl-C (═ O) -, cyano-substituted C1-6alkyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, C5-6alkyl-O-C (═ O) -, cyano-substituted C1-6alkyl-O-C (═ O) -, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C1-6Alkylamino substituted C3-8Cycloalkenyl radical, C1-6alkyl-NH-C (═ O) -or cyano-substituted C1-6alkyl-NH-C (═ O) -; or R4、R5And together with the N atom to which they are attached form a 3-12 atom composed ring, with the proviso that said 3-12 atom composed ring is not pyrazole optionally substituted with methyl or triazole optionally substituted with methyl;
each R6And R7Independently of one another is hydrogen, deuterium, C1-8Alkyl, cyano-substituted C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C2-10heterocyclyl-C (═ O) -C1-6Alkyl-, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group; or R6、R7And together with the N atom to which they are attached form a ring of 3 to 12 atoms;
each R8Independently of one another is hydrogen, C1-6Alkyl, cyano-substituted C1-6Alkyl, halo C1-6Alkyl radical, C3-8Cycloalkyl or C2-10A heterocyclic group;
each R9、R10And R11Independently of one another is hydrogen, deuterium, C1-6Alkyl or cyano-substituted C1-6An alkyl group;
n is 1,2,3, 4, 5 or 6;
R12is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group;
each X is independently-CH2-, -NH-, -O-, -S (═ O) -, or-S (═ O)2-；
Each Y is independently-CH2-, -NH-or-N (CH)3)-；
Each r, s or u is independently 0,1, 2 or 3;
each t, p, q or w is independently 1,2 or 3;
each R13Independently hydrogen, deuterium, cyano-substituted C1-6Alkyl or cyano-substituted C1-6alkyl-C (═ O) -;
each sub-formula (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv) and (xv) is independently optionally substituted by one or more R14Substitution;
each R14Independently hydrogen, deuterium, oxo (═ O), cyano-substituted C1-6Alkyl radical, R15-C(＝O)-、R16-S(＝O)2-、C1-6Alkylamino, cyano-substituted C1-6Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, R18-C(＝O)-N(R17)-C1-6Alkyl-, R18-C(＝O)-N(R17)-C1-8alkyl-C (═ O) -, R18-S(＝O)2-N(R17)-C1-6Alkyl-, R18-S(＝O)2-N(R17)-C1-8alkyl-C (═ O) -, R20R19N-C(＝O)-C1-6Alkyl-, R20R19N-S(＝O)2-C1-6Alkyl-, R20R19N-S(＝O)2-C1-8alkyl-C (═ O) -, C6-10Aryl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10aryl-C (═ O) -C1-6Alkyl-, C6-10aryl-S (═ O)2-C1-6Alkyl-, C1-9heteroaryl-C (═ O) -C1-6Alkyl-, C1-9heteroaryl-S (═ O)2-C1-6Alkyl-, C2-10heterocyclyl-C (═ O) -C1-6Alkyl-or C2-10heterocyclyl-S (═ O)2-C1-6Alkyl-;
each R15、R16And R18Independently is C1-8Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, cyano-substituted C1-8Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino C1-6Alkyl radical, C1-8Alkoxy, cyano-substituted C1-6Alkoxy radical, C6-10Aryl radical, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl group, C1-9Heteroaryl C1-6Alkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl or C2-10Heterocyclyl radical C1-6An alkyl group;
each R17、R19And R20Independently of one another is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-6Alkyl, halo C1-6Alkyl radical, C3-8Cycloalkyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group; or R19、R20And together with the N atom to which they are simultaneously attached form a ring of 3 to 12 atoms;
wherein each of said 3-12 atom rings is independently of the sub-structure:
Figure BDA0000892466340000031
Figure BDA0000892466340000041
each v, y, f and g is independently 0,1, 2 or 3;
each K is independently-NH-, -O-, -S (═ O) -, or-S (═ O)2-；
L is-CH2-、-NH-、-N(CH3) -or-N (CH)2CH3)-；
Each J is independently-CH2-, -NH-, -O-, -S (═ O) -, or-S (═ O)2-; and
wherein each of the hydroxyl group, carboxyl group and C1-6Alkyl radical, C1-8Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C1-8Alkoxy radical, C1-6Alkylamino radical, C1-6Alkylthio radical, C1-6Alkylsulfonyl, hydroxy-substituted C1-6Alkyl, cyano-substituted C1-6Alkyl, cyano-substituted C1-8Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, cyano-substituted C1-6Alkoxy, cyano-substituted C1-6Alkylamino radical, C1-6alkyl-C (═ O) -, cyano-substituted C1-6alkyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, C5-6alkyl-O-C (═ O) -, cyano-substituted C1-6alkyl-O-C (═ O) -, C1-6alkyl-NH-C (═ O) -, cyano-substituted C1-6alkyl-NH-C (═ O) -, 3-12-atom ring, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, C1-6Alkylamino substituted C3-8Cycloalkenyl radical, C2-10Heterocyclic group, C6-10Aryl radical, C1-9Heteroaryl group, C3-8Cycloalkyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C2-10heterocyclyl-C (═ O) -C1-6Alkyl-, C6-10Aryl radical C1-6Alkyl radical, C1-9Heteroaryl C1-6Alkyl radical, R15-C(＝O)-、R16-S(＝O)2-、R18-C(＝O)-N(R17)-C1-6Alkyl-, R18-C(＝O)-N(R17)-C1-8alkyl-C (═ O) -, R18-S(＝O)2-N(R17)-C1-6Alkyl-, R18-S(＝O)2-N(R17)-C1-8alkyl-C (═ O) -, R20R19N-C(＝O)-C1-6Alkyl-, R20R19N-S(＝O)2-C1-6Alkyl-, R20R19N-S(＝O)2-C1-8alkyl-C (═ O) -, C6-10aryl-C (═ O) -C1-6Alkyl-, C6-10aryl-S (═ O)2-C1-6Alkyl-, C1-9heteroaryl-C (═ O) -C1-6Alkyl-, C1-9heteroaryl-S (═ O)2-C1-6Alkyl-, C2-10heterocyclyl-C (═ O) -C1-6Alkyl-and C2-10heterocyclyl-S (═ O)2-C1-6Alkyl-independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, amino, nitro, carboxy, oxo (═ O), C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6Alkylamino, cyano-substituted C1-6Alkylamino radical, C1-6Alkoxy, cyano-substituted C1-6Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
In some of these embodiments, R is of the following subformula:
Figure BDA0000892466340000042
Figure BDA0000892466340000051
Figure BDA0000892466340000061
wherein each m, n, R1a、R1b、R1c、R1d、Ra、Rb、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13And R14Have the meaning as described in the present invention.
In some embodiments, the present invention relates to a compound of formula (Ia) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound of formula (Ia):
Figure BDA0000892466340000062
wherein each m, R1a、Ra、Rb、R2、R3、R4And R5Have the meaning as described in the present invention.
In some embodiments, the present invention relates to a compound of formula (Ib), or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound of formula (Ib):
Figure BDA0000892466340000063
wherein each R1b、R2、R3、R6And R7Have the meaning as described in the present invention.
In some of these embodiments, R is1aIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C1-3Alkyl, hydroxy substituted C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio or C1-3An alkylsulfonyl group.
In some of these embodiments, R is1aIs hydrogen, deuterium,Fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxy-substituted propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, ethylaminoethyl, methylthio, ethylthio, methylsulfonyl or ethylsulfonyl.
In some of these embodiments, R is1bIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C1-3Alkyl, hydroxy substituted C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio radical, C1-3Alkylsulfonyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is1bIs hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxy-substituted propyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, ethylaminoethyl, methylthio, ethylthio, methylsulfonyl, ethylsulfonyl, benzyl, phenethyl, triazolylmethyl, triazolylethyl, imidazolylmethyl, imidazolylethyl, pyrazolyl methyl or pyrazolyl ethyl.
In some of these embodiments, each R is2And R3Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, carboxyl or nitro.
In some of these embodiments, each R isaIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C1-3An alkyl group.
In some of these embodiments, each R isbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino or C1-3An alkyl group.
In some embodiments, R is on the same carbon atomaAnd RbTogether form oxo (═ O).
In some of these embodiments, m is 0,1, 2,3, 4, 5 or 6.
In some of these embodiments, R is4Is hydrogen, deuterium, C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3alkyl-C (═ O) -, cyano-substituted C1-3alkyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, cyano-substituted C1-3alkyl-O-C (═ O) -, C3-6Cycloalkyl radical, C3-6Cycloalkenyl radical, C1-3Alkylamino substituted C3-6Cycloalkenyl radical, C1-3alkyl-NH-C (═ O) -or cyano-substituted C1-3alkyl-NH-C (═ O) -.
In some of these embodiments, R is4Is hydrogen, deuterium, methyl, ethyl, propyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, C1-3alkyl-C (═ O) -, cyano-substituted methyl-C (═ O) -, cyano-substituted ethyl-C (═ O) -, cyano-substituted propyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, cyano-substituted methyl-O-C (═ O) -, cyano-substituted ethyl-O-C (═ O) -, cyano-substituted propyl-O-C (═ O) -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, C1-3alkyl-NH-C (═ O) -or cyano-substituted C1-3alkyl-NH-C (═ O) -.
In some of these embodiments, R is5Is hydrogen, deuterium, C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3alkyl-C (═ O) -, cyano-substituted C1-3alkyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, cyano-substituted C1-3alkyl-O-C (═ O) -, C3-6Cycloalkyl radical, C3-6Cycloalkenyl radical, C1-3Alkylamino substituted C3-6Cycloalkenyl radical, C1-3alkyl-NH-C (═ O) -or cyano-substituted C1-3alkyl-NH-C (═ O) -.
In some of these embodiments, R is5Is hydrogen, deuterium, methyl, ethyl, propyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, C1-3alkyl-C (═ O) -, cyano-substituted methyl-C (═ O) -, cyano-substituted ethyl-C (═ O) -, cyano-substituted propyl-C (═ O) -, C1-3alkyl-O-C (═ O) -, cyano-substituted methyl-O-C (═ O) -, cyano-substituted ethyl-O-C (═ O) -, cyano-substituted propyl-O-C (═ O) -, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, C1-3alkyl-NH-C (═ O) -or cyano-substituted C1-3alkyl-NH-C (═ O) -.
In some of these embodiments, R is4Is of the sub-structure:
Figure BDA0000892466340000071
in some of these embodiments, R is5Is of the sub-structure:
Figure BDA0000892466340000072
in some of these embodiments, R is4、R5And together with the N atom to which they are attached form the following subformula:
Figure BDA0000892466340000073
Figure BDA0000892466340000081
in some of these embodiments, R is6Is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C2-6heterocyclyl-C (═ O) -C1-4Alkyl-, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is6Hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, cyanomethyl-substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, phenyl, cyanomethyl-substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, C2-6Heterocyclyl radical C1-3Alkyl, azetidinyl-C (═ O) -C1-3Alkyl-, cyano-substituted azetidinyl-C (═ O) -C1-3Alkyl-, pyrrolidinyl-C (═ O) -C1-3Alkyl-, benzyl-, cyano-substituted benzyl, phenethyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is7Is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C2-6heterocyclyl-C (═ O) -C1-4Alkyl-, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is7Is hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methylCyano-substituted ethyl, cyano-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, cyanomethyl-substituted azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, phenyl, cyanomethyl-substituted phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, Czethylyl, cyclopentylethyl, cyclohexylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclopentylethyl2-6Heterocyclyl radical C1-3Alkyl, azetidinyl-C (═ O) -C1-3Alkyl-, cyano-substituted azetidinyl-C (═ O) -C1-3Alkyl-, pyrrolidinyl-C (═ O) -C1-3Alkyl-, benzyl-, cyano-substituted benzyl, phenethyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is6、R7And together with the N atom to which they are attached form the following subformula:
Figure BDA0000892466340000082
Figure BDA0000892466340000091
in some of these embodiments, R is1b、R6And R7Each C described in (1)1-3Alkyl, hydroxy substituted C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio radical, C1-3Alkylsulfonyl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl C1-3Alkyl radical, C1-6Alkyl, cyano-substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl and C2-6heterocyclyl-C (═ O) -C1-4Alkyl-independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, amino, nitro, carboxy, oxo (═ O), C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3Alkylamino, cyano-substituted C1-3Alkylamino radical, C1-3Alkoxy, cyano-substituted C1-3Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
Some of these embodiments are represented by R6、R7Each sub-formula formed with the N atom to which they are attached is independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, amino, nitro, carboxy, oxo (═ O), C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3Alkylamino, cyano-substituted C1-3Alkylamino radical, C1-3Alkoxy, cyano-substituted C1-3Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
In some embodiments, the present invention relates to a compound of formula (Ic) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of the compound of formula (Ic):
Figure BDA0000892466340000092
wherein each of Y, t, u and R14Have the meaning as described in the present invention.
In some embodiments, the present invention relates to a compound of formula (Id) or a stereoisomer, a geometric isomer, a tautomer, a racemate, a nitrogen oxide, a hydrate, a solvate, a metabolite, and a pharmaceutically acceptable salt or prodrug of a compound of formula (Id):
Figure BDA0000892466340000101
wherein each of p, q and R14Have the meaning as described in the present invention.
In some of these embodiments, R is14Is hydrogen, deuterium, cyano-substituted C1-3Alkyl radical, R15-C(＝O)-、R16-S(＝O)2-、C2-4Alkenyl radical, C2-4Alkynyl, R18-C(＝O)-N(R17)-C1-6Alkyl-, R18-C(＝O)-N(R17)-C1-6alkyl-C (═ O) -, R18-S(＝O)2-N(R17)-C1-3Alkyl-, R18-S(＝O)2-N(R17)-C1-6alkyl-C (═ O) -, R20R19N-C(＝O)-C1-4Alkyl-, R20R19N-S(＝O)2-C1-3Alkyl-, R20R19N-S(＝O)2-C1-6alkyl-C (═ O) -, C6-10Aryl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10aryl-C (═ O) -C1-3Alkyl-, C6-10aryl-S (═ O)2-C1-3Alkyl-, C1-5heteroaryl-C (═ O) -C1-3Alkyl-, C1-5heteroaryl-S (═ O)2-C1-3Alkyl-, C2-6heterocyclyl-C (═ O) -C1-3Alkyl-or C2-6heterocyclyl-S (═ O)2-C1-3Alkyl-;
wherein each R15、R16、R17、R18、R19And R20Have the meaning as described in the present invention.
In some of these embodiments, each R is15Independently is C1-6Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, cyano-substituted C1-6Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl radical, C1-6Alkoxy, cyano-substituted C1-3Alkoxy radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In some of these embodiments, each R is16Independently is C1-6Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, cyano-substituted C1-6Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl radical, C1-6Alkoxy, cyano-substituted C1-3Alkoxy radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In some of these embodiments, each R is18Independently is C1-6Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, cyano-substituted C1-6Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl radical, C1-6Alkoxy, cyano-substituted C1-3Alkoxy radical, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl or C2-6Heterocyclyl radical C1-3An alkyl group.
In some of these embodiments, each R is17Independently of one another is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-3Alkyl, halo C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, each R is19Independently of one another is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-3Alkyl, halo C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, each R is20Independently of one another is hydrogen, deuterium, C1-6Alkyl, cyano-substituted C1-3Alkyl, halo C1-3Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group.
In some of these embodiments, R is19、R20Optionally together with the N atom to which they are simultaneously attached, form the sub-structural formula:
Figure BDA0000892466340000102
Figure BDA0000892466340000111
in some of these embodiments, R is14、R15、R16、R17、R18、R19And R20Each C described in (1)1-6Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, cyano or the likeSubstituted C1-3Alkyl, cyano-substituted C1-6Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl radical, C1-6Alkoxy, cyano-substituted C1-3Alkoxy radical, R15-C(＝O)-、R16-S(＝O)2-、R18-C(＝O)-N(R17)-C1-6Alkyl-, R18-C(＝O)-N(R17)-C1-6alkyl-C (═ O) -, R18-S(＝O)2-N(R17)-C1-3Alkyl-, R18-S(＝O)2-N(R17)-C1-6alkyl-C (═ O) -, R20R19N-C(＝O)-C1-4Alkyl-, R20R19N-S(＝O)2-C1-3Alkyl-, R20R19N-S(＝O)2-C1-6alkyl-C (═ O) -, C6-10Aryl radical, C6-10Aryl radical C1-3Alkyl radical, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl radical, C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl radical, C2-6Heterocyclic group, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10aryl-C (═ O) -C1-3Alkyl-, C6-10aryl-S (═ O)2-C1-3Alkyl-, C1-5heteroaryl-C (═ O) -C1-3Alkyl-, C1-5heteroaryl-S (═ O)2-C1-3Alkyl-, C2-6heterocyclyl-C (═ O) -C1-3Alkyl-and C2-6heterocyclyl-S (═ O)2-C1-3Alkyl-independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, amino, nitro, carboxy, oxo (═ O), C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3Alkylamino, cyano-substituted C1-3Alkylamino radical, C1-3Alkoxy, cyano-substituted C1-3Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
Some of these embodiments are represented by R19、R20Each sub-formula formed together with the N atom to which they are simultaneously attached is independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, amino, nitro, carboxy, oxo (═ O), C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3Alkylamino, cyano-substituted C1-3Alkylamino radical, C1-3Alkoxy, cyano-substituted C1-3Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
In some of these embodiments, R is14Is hydrogen, deuterium, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, R15-C(＝O)-、R16-S(＝O)2-、C2-4Alkenyl radical, C2-4Alkynyl, R18-C(＝O)-N(R17)-C1-3Alkyl-, R18-C(＝O)-N(R17)-C1-4alkyl-C (═ O) -, R18-S(＝O)2-N(R17)-C1-3Alkyl-, R18-S(＝O)2-N(R17)-C1-4alkyl-C (═ O) -, R20R19N-C(＝O)-C1-4Alkyl-, R20R19N-S(＝O)2-C1-3Alkyl-, NH2-S(＝O)2-C1-4alkyl-C (═ O) -, benzyl, phenethyl, azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thiomorpholinylethyl, 1-oxothiomorpholinylmethyl, 1-oxothiomorpholinylethyl, 1-dioxothiomorpholinylmethyl, 1-dioxothiomorpholinylethyl, azetidinyl-C (═ O) -methyl-, azetidinyl-C (═ O) -ethyl-, cyano-substituted azetidinyl-C (═ O) -ethyl-, (O-n-butyl-C (═ O) -ethyl-), pyrrolidinyl-C (═ O) -methyl-, pyrrolidinyl-C (═ O) -ethyl-, piperidinyl-C (═ O) -methyl-, piperidinyl-C (═ O) -ethyl-, piperazinyl-C (═ O)-methyl-, piperazinyl-C (═ O) -ethyl-, morpholinyl-C (═ O) -methyl-, morpholinyl-C (═ O) -ethyl-, azetidinyl-S (═ O)2-methyl-, azetidinyl-S (═ O)2-ethyl-, cyano-substituted azetidinyl-S (═ O)2-ethyl-, pyrrolidinyl-S (═ O)2-methyl-, pyrrolidinyl-S (═ O)2-ethyl-, piperidinyl-S (═ O)2-methyl-, piperidinyl-S (═ O)2-ethyl-, piperazinyl-S (═ O)2-methyl-, piperazinyl-S (═ O)2-ethyl-, morpholinyl-S (═ O)2-methyl-or morpholinyl-S (═ O)2-ethyl-;
wherein each R15、R16、R17、R18、R19And R20Have the meaning as described in the present invention.
In some of these embodiments, each R is15Independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH3、-CH(CH2CH3)2、-C(CH3)2CH2CH3、-CH(CH3)CH(CH3)2、-CH2CH2CH(CH3)2、-CH2CH(CH3)CH2CH3、-CH2C(CH3)3Vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano-substituted C1-3Alkoxy, phenyl, aminosulfonyl-substituted phenyl, cyanomethoxy-substituted phenyl, benzyl, cyano-substituted benzyl, aminosulfonyl-substituted benzyl, phenethyl, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,Cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, azetidinylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, thiomorpholinylmethyl, thiomorpholinylethyl, 1-oxothiomorpholinylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinylmethyl, 1-oxothiomorpholinylethyl, 1-dioxothiomorpholinylmethyl or 1, 1-dioxothiomorpholinylethyl.
In some of these embodiments, each R is16Independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH3、-CH(CH2CH3)2、-C(CH3)2CH2CH3、-CH(CH3)CH(CH3)2、-CH2CH2CH(CH3)2、-CH2CH(CH3)CH2CH3、-CH2C(CH3)3Vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano-substituted C1-3Alkoxy, phenyl, aminosulfonyl-substituted phenyl, cyanomethoxy-substituted phenyl, benzyl, cyano-substituted benzyl, aminosulfonyl-substituted benzyl, phenethyl, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, azetidinyl, azetidinylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, ethyl, cyclopropylmethyl, cyclopentylethyl, cyclopent, Thiomorpholinylmethyl, thiomorpholinylethyl, 1-oxothiomorpholinylmethyl, 1-oxothiomorpholinylethyl, 1-dioxothiomorpholinylmethyl or 1, 1-dioxothiomorpholinylethyl.
In some of these embodiments, each R is18Independently methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH2CH2CH2CH2CH3、-CH(CH3)CH2CH2CH3、-CH(CH2CH3)2、-C(CH3)2CH2CH3、-CH(CH3)CH(CH3)2、-CH2CH2CH(CH3)2、-CH2CH(CH3)CH2CH3、-CH2C(CH3)3Vinyl, propenyl, ethynyl, propynyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, amino C1-3Alkyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, cyano-substituted C1-3Alkoxy, phenyl, aminosulfonyl substituted phenyl, cyanomethoxyPhenyl substituted by radicals, benzyl substituted by cyano, benzyl substituted by aminosulfonyl, phenethyl, C1-5Heteroaryl group, C1-5Heteroaryl C1-3Alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, azetidinyl, azetidinylmethyl, cyano-substituted azetidinylmethyl, azetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl, 3-oxomorpholinylmethyl, 3-oxomorpholinylethyl, ethyl, cyclopropylmethyl, cyclopentylethyl, cyclopent, Thiomorpholinylmethyl, thiomorpholinylethyl, 1-oxothiomorpholinylmethyl, 1-oxothiomorpholinylethyl, 1-dioxothiomorpholinylmethyl or 1, 1-dioxothiomorpholinylethyl.
In some of these embodiments, each R is17Independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl or haloC1-3An alkyl group.
In some of these embodiments, each R is19Independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl or haloC1-3An alkyl group.
In some of these embodiments, each R is20Independently hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyano-substituted methyl, cyano-substituted ethyl, cyano-substituted propyl, cyano-substituted isopropyl or haloC1-3An alkyl group.
In another aspect, the present invention relates to a compound that is a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (II):
Figure BDA0000892466340000131
wherein:
R21is hydrogen, deuterium, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl or cyano-substituted C1-6An alkyl group;
R22is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl or R25R26N-C(＝O)-；
R23Is R28-C(＝O)-N(R27)-、R28-S(＝O)2-N(R27)-、C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkenyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl or C1-9Heteroaryl C1-6An alkyl group;
each R24Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C1-6Alkyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6Alkoxy or C1-6An alkylamino group;
each R25、R26And R27Independently hydrogen, deuterium or C1-6An alkyl group;
each R28Independently of one another is hydrogen, deuterium, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, cyano-substituted C1-6Alkyl, hydroxy substituted C1-6Alkyl or halo C1-6An alkyl group; and
wherein each C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, halo C1-6Alkyl, hydroxy substituted C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, R25R26N-C(＝O)-、R28-C(＝O)-N(R27)-、R28-S(＝O)2-N(R27)-、C3-8Cycloalkyl radical C1-6Alkyl radical, C3-8Cycloalkenyl radical C1-6Alkyl radical, C2-10Heterocyclyl radical C1-6Alkyl radical, C6-10Aryl radical C1-6Alkyl and C1-9Heteroaryl C1-6Alkyl is independently optionally substituted with one or more substituents selected from deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, amino, nitro, carboxy, oxo (═ O), C1-6Alkyl, halo C1-6Alkyl, amino C1-6Alkyl, cyano-substituted C1-6Alkyl radical, C1-6Alkylamino, cyano-substituted C1-6Alkylamino radical, C1-6Alkoxy, cyano-substituted C1-6Alkoxy, NH2-S(＝O)2-or NH2-C (═ O) -, is substituted.
In some of these embodiments, R is21Is hydrogen, deuterium, C1-3Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl or cyano-substituted C1-3An alkyl group.
In some of these embodiments, R is22Is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C1-3Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl or R25R26N-C(＝O)-；
Wherein R is25And R26Have the meaning as described in the present invention.
In some of these embodiments, R is23Is R28-C(＝O)-N(R27)-、R28-S(＝O)2-N(R27)-、C3-6Cycloalkyl radical C1-3Alkyl radical, C3-6Cycloalkenyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3Alkyl radical, wherein said C2-6Heterocyclyl radical C1-3Alkyl is optionally oxo (═ O);
wherein R is27And R28Have the meaning as described in the present invention.
In some of these embodiments, each R is24Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, nitro, carboxyl, C1-3Alkyl, halo C1-3Alkyl, hydroxy substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-3Alkoxy or C1-3An alkylamino group.
In some of these embodiments, each R is25、R26And R27Independently hydrogen, deuterium or C1-4An alkyl group.
In some of these embodiments, each R is28Independently of one another is hydrogen, deuterium, C1-3Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, cyano-substituted C1-3Alkyl, hydroxy substituted C1-3Alkyl or halo C1-3An alkyl group.
In another aspect, the present invention includes, but is in no way limited to, compounds having one of the following structures or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:
Figure BDA0000892466340000141
Figure BDA0000892466340000151
Figure BDA0000892466340000161
Figure BDA0000892466340000171
Figure BDA0000892466340000181
Figure BDA0000892466340000191
Figure BDA0000892466340000201
Figure BDA0000892466340000211
Figure BDA0000892466340000221
one aspect of the invention relates to pharmaceutical compositions comprising a compound described herein.
In some embodiments, the pharmaceutical compositions of the present invention further comprise at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
In some embodiments, the pharmaceutical composition of the present invention further comprises an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.
Another aspect of the invention relates to the use of a compound of the invention or a pharmaceutical composition comprising a compound of the invention for the preparation of a medicament for the prevention, treatment or treatment of an autoimmune disease or a proliferative disease in a patient, and for lessening the severity thereof.
In some embodiments, the autoimmune disease described herein is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, and lymphoma.
In some embodiments, the proliferative disease of the invention is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the CNS (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
In another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for the preparation of a medicament for inhibiting or modulating protein kinase activity in a biological sample, said use comprising contacting said biological sample with a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention.
In some of these embodiments, the protein kinase is JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M.
In one aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (I), (Ia), (Ib), (Ic), (Id) or (II).
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I), (Ia), (Ib), (Ic), (Id) or (II).
The invention also encompasses the use of the compounds of the invention and pharmaceutically acceptable salts thereof for the manufacture of a pharmaceutical product for the treatment of autoimmune diseases or proliferative diseases, including those described herein. The compounds of the invention are also useful in the manufacture of a pharmaceutical product for alleviating, preventing, controlling or treating a condition mediated by JAK1, JAK2, JAK3, BTK, EGFR or EGFR T790M.
The present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I), (Ia), (Ib), (Ic), (Id) or (II) in combination with at least one pharmaceutically acceptable carrier, adjuvant or diluent.
The invention also encompasses a method of treating an autoimmune disease or a proliferative disease, or a condition responsive thereto, in a subject, comprising treating the subject with a therapeutically effective amount of a compound represented by formula (I), (Ia), (Ib), (Ic), (Id), or (II).
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, racemates, nitroxides, hydrates, solvates, metabolites, metabolic precursors, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes materials or compositions which must be compatible chemically or toxicologically, with the other components comprising the formulation, and with the mammal being treated.
Salts of the compounds of the present invention also include, but are not necessarily pharmaceutically acceptable salts of intermediates used in the preparation or purification of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (II) or isolated enantiomers of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (II).
Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, glycolate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, ethanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, dihydro, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H，3H，11C，13C，14C，15N，17O，18O，18F，31P，32P，35S，36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H，14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and13C. the isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I), (Ia), (Ib), (Ic), (Id) or (II) can be prepared by conventional techniques known to those skilled in the art or by the use of suitable isotopically labelled reagents as described in the examples and preparations of the present invention in place of the original used unlabelled reagent.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. Should be takenDeuterium in the context of the present invention is understood to be a substituent of a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
The foregoing has outlined only certain aspects of the present invention but is not limited in that these and other aspects will be more fully described in the following detailed description.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to one or to more than one (i.e., to at least one) of the objects. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer that has two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and mixtures of non-corresponding isomers (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)ndEd.Robert E.Gawley,Jeffrey Aube,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tablesof Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can interconvert by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, oxo (═ O), alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, cyano-substituted alkylamido, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocycloyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-C6Alkyl "or" C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in one embodiment, the alkyl group contains 1 to 8 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" denotes a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon. Unless otherwise specified, an alkylene group contains 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) Allyl (CH)3-CH ═ CH —), and the like.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C ≡ CH), 1-propynyl (-C)≡C-CH3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "alkoxyalkyl" means an alkyl group substituted with one or more alkoxy groups, wherein the alkyl group and alkoxy group have the meaning as described herein, examples of which include, but are not limited to, methoxymethyl, methoxyethyl, ethoxyethyl, and the like.
The term "alkoxyalkoxy" denotes an alkoxy group substituted with one or more alkoxy groups having the meaning as described herein, examples of which include, but are not limited to, methoxymethoxy, methoxyethoxy, methoxypropoxy, ethoxymethoxy, ethoxyethoxy and the like.
The terms "haloalkyl", "haloalkenyl" or "haloalkoxy" respectively denote alkyl, alkenyl or alkoxy groups substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy, -CH2Cl，-CH2CF3，-CH2CH2CF3And the like.
The term "cyano-substituted alk (oxy) yl" means that the alk (oxy) yl group is substituted with one or more cyano groups, examples of which include, but are not limited to, -CH2CN，-CH2CH2CN，-CH2CH2CH2CN，-OCH2CN，-OCH2CH2CN，-OCH2CH2CH2CN，-OCH(CN)CH3And the like.
The term "hydroxy-substituted alk (oxy) yl" means that the alk (oxy) yl group is substituted with one or more hydroxy groups, examples of which include, but are not limited to, -CH2OH，-CH2CH2OH，-CH2CH2CH2OH，-OCH2OH，-OCH2CH2OH，-OCH2CH2CH2OH，-OCH(OH)CH3And the like.
The term "alkylthio" refers to C1-10A linear or branched alkyl group is attached to a divalent sulfur atom, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, methylthio (CH)3S-), ethylthio, and the like.
The term "alkylsulfonyl" refers to alkyl-S (═ O)2-, wherein alkyl has the meaning as indicated in the present invention. Thus, examples include, but are not limited to CH3-S(＝O)2-，CH3-CH2-S(＝O)2-，CH3-CH2-CH2-S(＝O)2-，(CH3)2CH-S(＝O)2-and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
The term "cycloalkenyl" refers to a monocyclic, bicyclic, or tricyclic hydrocarbon ring having one or more carbon-carbon double bonds, which is not aromatic in general, and typically has the indicated number of ring-forming carbon atoms (i.e., C)3-8Cycloalkenyl refers to cycloalkenyl having 3,4, 5, 6, 7, or 8 carbon atoms as ring members). Cycloalkenyl groups can be attached to the rest of the molecule through any ring atom unless such attachment would violate valence requirements. The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, and the like.
The term "alkylamino substituted cycloalkenyl" refers to cycloalkenyl groups substituted with one or more alkylamino groups, wherein cycloalkenyl and alkylamino groups have the meaning as described herein, which may independently be unsubstituted or substituted with one or more substituents described herein. Examples include, but are not limited to, methylamino substituted cyclobutenyl, ethylamino substituted cyclobutenyl, or
Figure BDA0000892466340000281
The term "cycloalkylalkyl" denotes an alkyl group substituted with one or more cycloalkyl groups, wherein the alkyl group and the cycloalkyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, (1-oxo) -thiomorpholinyl, (1, 1-dioxo) -thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl, 2-oxa-5-azabicyclo [ 2.2.1.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxoA thiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In one embodiment, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 5 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Examples of heterocyclic groups consisting of 5 atomsIncluding, but not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH2Examples of the substitution of the-group by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiroheterobicyclic or fused heterobicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: 2-oxa-5-azabicyclo [2.2.1] hept-5-yl. Said heterocyclyl group of 7 to 12 atoms may be optionally substituted by one or more substituents as described herein.
In yet another embodiment, heterocyclyl refers to heterocycloalkyl. The term "heterocycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, or oxygen atoms.
The term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention. Examples include, but are not limited to, thiomorpholin-4-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-ylmethyl, pyrrolidin-2-ylmethyl, morpholin-4-ylmethyl and the like.
The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).
The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as depicted in formula a, one saturated bridged ring system (rings B and B') is referred to as a "fused bicyclic ring", while ring a and ring B share a carbon atom in two saturated ring systems, referred to as a "spiro ring" or a "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
Figure BDA0000892466340000301
The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms.
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "arylalkyl" or "aralkyl" means an alkyl group substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meaning described herein, examples of which include, but are not limited to, benzyl, phenethyl, p-toluylethyl, and the like.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.
The term "heteroarylalkyl" means that the alkyl group is substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl group have the meaning as set forth herein, examples of which include, but are not limited to, pyridin-2-ylethyl, thiazol-2-ylmethyl, imidazol-2-ylethyl, pyrimidin-2-ylpropyl, and the like.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO2H。
The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "cyano-substituted alkylamino" denotes an alkylamino group substituted with one or more cyano groups, examples of which include, but are not limited to, -NHCH2CN，-N(CH3)CH2CN，-NHCH2CH2CN，-NHCH2CH2CH2CN，-N(CH3)CH(CN)CH3And the like.
The term "hydroxy-substituted alkylamino" denotes an alkylamino group substituted with one or more hydroxy groups, examples of which include, but are not limited to, -NHCH2OH，-N(CH3)CH2OH，-NHCH2CH2OH，-NHCH2CH2CH2OH，-N(CH3)CH(OH)CH3And the like.
The term "alkylaminoalkyl" denotes an alkyl group substituted with one or more alkylamino groups, wherein alkyl and alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, N-methylaminomethyl, N-ethylaminomethyl, N, N-dimethylaminoethyl, N, N-diethylaminoethyl, and the like.
The term "aminoalkyl" includes C substituted with one or more amino groups1-10A straight or branched alkyl group. In some of these embodiments, aminoalkyl is C substituted with one or more amino groups1-6Examples of "lower aminoalkyl" radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl, and aminohexyl.
The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" refers to a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC)Boc), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyloxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005。
The term "prodrug" as used herein, represents a compound that is converted in vivo to a compound of formula (I), (Ia), (Ib), (Ic), (Id) or (II). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward dB.Roche, ed., Bioreproducible Carriers in Drug designs, American pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and pharmaceutical Applications, Nature Review Drug Discovery,2008,7, 255-.
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
The term "treating" or "treatment" as used herein refers, in some embodiments, to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
As used herein, "inflammatory disease" refers to any disease, disorder or condition of excessive inflammatory symptoms, host tissue damage or loss of tissue function due to excessive or uncontrolled inflammatory response. "inflammatory disease" also refers to a pathological condition mediated by leukocyte influx and/or neutrophil chemotaxis.
As used herein, "inflammation" refers to a local protective response caused by tissue damage or destruction that serves to destroy, dilute, or separate (sequester) harmful substances from damaged tissue. Inflammation is significantly linked to leukocyte influx and/or neutrophil chemotaxis. Inflammation can result from infection by pathogenic organisms and viruses, as well as from non-infectious means, such as trauma or reperfusion following myocardial infarction or stroke, immune and autoimmune responses to foreign antigens. Thus, inflammatory diseases that may be treated with the disclosed compounds include: diseases associated with specific defense system reactions as well as non-specific defense system reactions.
As used herein, "autoimmune disease" or "autoimmune disease" refers to any disease of the collection of tissue damage associated with humoral or cell-mediated responses to the body's own components. Examples of autoimmune diseases include lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid diseases, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia and lymphoma.
As used herein, "arthritic disease" refers to any disease characterized by inflammatory injury to the joints attributable to various etiologies. As used herein, "dermatitis" refers to any of a large family of skin diseases characterized by skin inflammation attributable to various etiologies. As used herein, "transplant rejection" refers to any immune response against a transplanted tissue, such as an organ or cell (e.g., bone marrow), characterized by loss of function of the transplanted or surrounding tissue, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the invention include methods for treating diseases associated with inflammatory cell activation.
The terms "cancer" and "cancerous" refer to or describe the physiological condition in a patient that is often characterized by uncontrolled cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma (carcinoma), lymphoma, blastoma, sarcoma, and leukemia, or lymphoproliferative disorder (lymphoproliferative disorders). More specific examples of such cancers include squamous cell cancer (such as epithelial squamous cell cancer), lung cancer (including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer (livercancer), bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer (kidney or renal cancer), prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma (hepatic carcinoma), anal cancer, penile cancer and head and neck cancer.
The term "biological specimen" as used herein refers to a specimen outside a living body, including, but in no way limited to, cell culture or cell extraction; biopsy material obtained from a mammal or an extract thereof; blood, saliva, urine, feces, semen, tears, or other living tissue liquid material and extracts thereof. Inhibiting or modulating kinase activity in a biological sample, particularly BLK, JAK1, JAK2, JAK3, BTK, BMX, TEC, ITK, TXK, HER2, HER4, EGFR, or EGFR T790M kinase activity, can be used for a variety of uses well known to those skilled in the art. Such uses include, but are in no way limited to, blood transfusion, organ transplantation, biological specimen storage, and biological identification.
Pharmaceutical compositions of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof. The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of a protein kinase in a biological sample or patient.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, if appropriate, in the form of a pharmaceutically acceptable derivative thereof. Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The pharmaceutical compositions disclosed herein can be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (II) can be extracted and then administered to a patient in powder or syrup form. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (Id), or (II). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds. Such dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, granules, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients.
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. sup. 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).
Use of the Compounds and compositions of the invention
The present invention provides methods of using the disclosed compounds and pharmaceutical compositions for treating, preventing, or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK2, or a disease or disorder mediated or otherwise affected by JAK kinase behavior, including JAK1, JAK2, JAK3, or TYK 2.
The JAK kinase can be a wild-type and/or a mutation of JAK1, JAK2, JAK3, or TYK2 kinase.
In one embodiment, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for treating, preventing or ameliorating one or more symptoms of a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior or a disease or disorder mediated or otherwise affected by inappropriate JAK1 kinase behavior.
In another embodiment, the disease, disorder, or one or more symptoms of the disease or disorder is associated with inappropriate JAK2 kinase behavior or inappropriate JAK3 kinase behavior.
By "inappropriate JAK kinase behavior" is meant JAK kinase behavior that occurs in a particular patient that deviates from normal JAK kinase behavior. Inappropriate JAK kinase behavior can be expressed in the form of, for example, abnormal increases in activity, or deviations in the time point and control of JAK kinase behavior. This inappropriate kinase behavior results, for example, from inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinases. Accordingly, the present invention provides methods of treating these diseases and disorders.
Consistent with the above description, such diseases or disorders include, but are not limited to: myeloproliferative diseases, such as polycythemia vera (PCV), essential thrombocythemia, Idiopathic Myelofibrosis (IMF); leukemias, e.g., myeloid leukemias including Chronic Myeloid Leukemia (CML), imatinib-resistant CML forms, Acute Myeloid Leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as myeloma; cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, and renal cancer; and inflammatory diseases or disorders associated with immune dysfunction, immunodeficiency, immune modulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type I diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease including crohn's disease and Ulcerative Colitis (UC), Systemic Lupus Erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and Chronic Obstructive Pulmonary Disease (COPD), and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
In one aspect, the present invention provides a class of compounds disclosed herein or pharmaceutical compositions comprising a compound disclosed herein for use in the prevention and/or treatment of a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, or transplant rejection in a mammal (including a human).
In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of suffering from a disease disclosed herein, the method comprising administering a condition treating effective amount or a condition preventing effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In another aspect, the invention provides a method of treating a mammal suffering from or at risk of suffering from a proliferative disease, an autoimmune disease, an allergic disease, an inflammatory disease, or transplant rejection.
In one method of therapeutic aspects, the invention provides methods of treating and/or preventing a mammal susceptible to or suffering from a proliferative disease comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the proliferative disease is selected from cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.
In another aspect, the invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of a proliferative disease. In particular embodiments, the proliferative disease is selected from the group consisting of cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.
In another aspect, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of a proliferative disease. In particular examples, the proliferative disease is selected from cancer (e.g., a solid tumor such as uterine leiomyosarcoma or prostate cancer), polycythemia vera, essential thrombocythemia, myelofibrosis, leukemia (e.g., AML, CML, ALL or CLL), and multiple myeloma.
In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, said method comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the presently disclosed pharmaceutical compositions or compounds. In a particular example, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.
In another aspect, the invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of autoimmune diseases. In a particular embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.
In another aspect, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an autoimmune disease. In a particular embodiment, the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, sjogren's syndrome, psoriasis, type I diabetes, and inflammatory bowel disease.
In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an allergic disease, said method comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.
In another aspect, the present invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of allergic diseases. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.
In another aspect, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an allergic disease. In a particular embodiment, the allergic disease is selected from respiratory allergic disease, sinusitis, eczema and measles, food allergy and insect venom allergy.
In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
In another aspect, the invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of inflammatory diseases. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
In another aspect, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising a compound disclosed herein, for use in the preparation of a medicament for the treatment or prevention of an inflammatory disease. In particular embodiments, the inflammatory disease is selected from inflammatory bowel disease, crohn's disease, rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
In another aspect, the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from transplant rejection comprising administering a therapeutically effective amount or a prophylactically effective amount of one or more of the pharmaceutical compositions or compounds disclosed herein. In particular examples, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.
In another aspect, the invention provides a class of compounds disclosed herein for use in the treatment and/or prevention of transplant rejection. In particular embodiments, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.
In another aspect, the present invention provides a class of compounds disclosed herein, or pharmaceutical compositions comprising a compound disclosed herein, for use in the preparation of a medicament for treating or preventing transplant rejection. In particular examples, the transplant rejection is organ transplant rejection, tissue transplant rejection, and cell transplant rejection.
In a further aspect, the present invention provides a class of compounds disclosed herein for use as medicaments, in particular for use as medicaments for the treatment and/or prevention of the aforementioned diseases. Also provided is the use of a compound disclosed herein for the manufacture of a medicament for the treatment and/or prevention of the aforementioned diseases.
One particular embodiment of the present methods comprises administering to a subject having inflammation an effective amount of a compound disclosed herein for a time sufficient to reduce the level of inflammation in the subject, and preferably to stop the progression of the inflammation. Particular embodiments of the method comprise administering to a subject suffering from or susceptible to bone rheumatoid arthritis an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, inflammation of the joints of said subject, and preferably to stop the progression of said inflammation.
Another particular embodiment of the method comprises administering to a subject having a proliferative disease an effective amount of a compound of the disclosure for a time sufficient to reduce the level of the proliferative disease in the subject and preferably to stop the progression of the proliferative disease. Particular embodiments of the method comprise administering to a subject suffering from cancer an effective amount of a compound disclosed herein for a time sufficient to reduce or prevent, respectively, the signs of cancer in said subject, and preferably to stop the progression of said cancer.
Combination therapy
The compounds of the present invention may be administered as the sole active agent or may be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are identified as safe and effective for such combination administration.
In one aspect, the present invention provides a method of treating, preventing or ameliorating a disease or disorder, comprising administering a safe and effective amount of a combination comprising a compound disclosed herein and one or more therapeutically active agents2-a combination of an adrenoreceptor agonist, a corticosteroid, a non-steroidal GR agonist, non-steroidal anti-inflammatory drugs (NSAID's), phosphodiesterase 4(PDE4) inhibitor, an anticholinergic agent, an H1 antagonist, an antihistamine or a combination thereof.
Examples of other therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and antiproliferative agents; an anti-inflammatory agent; and an immunomodulator or immunosuppressant.
In another aspect, the invention provides products comprising a compound of the invention and at least one other therapeutic agent, formulated for simultaneous, separate or sequential administration in therapy. In one embodiment, the treatment is for a disease or condition mediated by JAK kinase activity. The products provided by the combined preparation include compositions comprising the disclosed compounds and other therapeutic agents in the same pharmaceutical composition, or in different forms, e.g., kits.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound disclosed herein and one or more additional therapeutic agents. In one embodiment, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient, carrier, adjuvant or vehicle as described above.
In another aspect, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound disclosed herein. In one embodiment, the kit comprises means for separately holding the compositions, such as a container, a separate bottle, or a separate foil box. An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
The invention also provides the use of a compound of the invention in the treatment of a disease or condition mediated by JAK kinase activity, wherein the patient has been previously (e.g. within 24 hours) treated with another therapeutic agent. The invention also provides the use of other therapeutic agents in the treatment of diseases and conditions mediated by JAK kinase activity, wherein a patient has been previously (e.g. within 24 hours) treated with a compound of the invention.
The compounds disclosed herein may also be advantageously used in combination with other compounds, or in combination with other therapeutic agents, especially antiproliferative agents. Such antiproliferative agents include, but are not limited to, aromatase inhibitors; an antiestrogen; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; (ii) histone deacetylase inhibitors; inducing finenessCompounds of the cellular differentiation process; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antineoplastic antimetabolite; a platinum compound; compounds that target/reduce protein or lipid kinase activity and other anti-angiogenic compounds; a compound that targets, reduces or inhibits protein or lipid phosphatase activity; gonadorelin agonists; an antiandrogen; methionine aminopeptidase inhibitors; a bisphosphonate; a biological response modifier; an anti-proliferative antibody; heparanase inhibitors; ras oncogenic subtype inhibitors; a telomerase inhibitor; a proteasome inhibitor; agents for treating hematological tumors; compounds that target, decrease or inhibit Flt-3 activity; an Hsp90 inhibitor; temozolomide
Figure BDA0000892466340000361
And calcium folinate.
"combination" means a fixed combination or a kit of parts for the combined administration in the form of a single dosage unit, wherein a compound disclosed in the invention and a combination partner may be administered separately at the same time or may be administered separately within certain time intervals, in particular such that the combination partners show a cooperative, e.g. synergistic, effect. The terms "co-administration" or "co-administration" and the like are intended to encompass administration of the selected combination partner to a single individual in need thereof (e.g., a patient), and are intended to encompass treatment regimens in which the substances are not necessarily administered by the same route of administration or simultaneously. The term "pharmaceutical combination" means a product obtained by mixing or combining more than one active ingredient and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, such as the compounds disclosed herein, and the combination partner are administered to the patient simultaneously, in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound disclosed herein, and the combination partner are both administered to a patient as separate entities simultaneously, together or sequentially with no specific time limits, wherein the mode of administration provides therapeutically effective levels of both compounds in the patient. The latter also applies to cocktail therapies, such as the administration of three or more active ingredients.
General synthetic procedure
In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (Ia), (Ib), (Ic), (Id) or (II). The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
In the examples described below, all temperatures are given in degrees celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin HaoLiyu chemical Co., Ltd., Qingdao Tenglong chemical reagent Co., Ltd., and Qingdao Kaihua factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants. The test conditions of the nuclear magnetic resonance hydrogen spectrum are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature3，d6-DMSO，CD3OD or d6Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quatet, quartet), m (multiplet ), br (broadpeded, broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for low resolution Mass Spectrometry (MS) data determination were: agilent 6120Quadrupole HPLC-MS (column model: Zorbax SB-C18,2.1X 30mm,3.5 μm,6min, flow rate 0.6mL/min, mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2Proportion in O)), at 210/254nm with UV detection, using electrospray ionization mode (ESI).
The purity of the compound is characterized in the following way: agilent 1260 preparative high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 preparative high performance liquid chromatography (Pre-HPLC) (column model: NOVASEP,50/80mm, DAC) with UV detection at 210nm/254 nm.
The following acronyms are used throughout the invention:
HPLC high performance liquid chromatography; h2O water; MeOH, CH3OH methanol; CD (compact disc)3OD deuterated methanol; EtOH, ethanol; HCOOH formic acid; CH (CH)3CN, MeCN acetonitrile; DCM, CH2Cl2Dichloromethane; CHCl3Chloroform, chloroform; CDCl3Deuterated chloroform; DMF N, N-dimethylformamide; DMAC N, N-dimethylacetamide; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; HOBT 1-hydroxybenzotriazole; HATU 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate; SEMCl 2- (trimethylsilyl) ethoxymethyl chloride; NBS N-bromosuccinimide; THF tetrahydrofuran; TFA trifluorideAcetic acid; PE, Petroleum ether; EtOAc ethyl acetate; NaOH sodium hydroxide; na (Na)2SO4Sodium sulfate; (Boc)2Di-tert-butyl O-dicarbonate; BOC, BOC tert-butoxycarbonyl; CBZ, CBZ benzyloxycarbonyl; con.hcl concentrated hydrochloric acid; NH (NH)4Cl ammonium chloride; h2Hydrogen gas.
Synthesis method 1
Figure BDA0000892466340000381
The target compound 8 can be prepared by a first synthesis method, wherein R is1a、R2、R3、R4And R5Have the meaning as described in the present invention. The compound 2 is obtained by protecting the compound 1 with di-tert-butyl dicarbonate, and the compound 2 and R4NH2The method comprises the following steps of obtaining an amide compound 3 under the action of a condensation reagent, deprotecting the compound 3 to obtain a compound 4, reacting the compound 4 with a compound 5 under the catalysis of alkali or acid to obtain a compound 6, reducing the compound 6 to obtain a compound 7, and condensing the compound 7 with acid to obtain a target compound 8.
Synthesis method II
Figure BDA0000892466340000382
The target compound 14 can be prepared by a second synthesis method, wherein R is1a、R2、R3、R4And R5Have the meaning as described in the present invention. Esterifying the compound 9 to obtain a compound 10, reacting the compound 10 with strong base, adding an electrophilic reagent to obtain a compound 11, hydrolyzing the compound 11 under the condition of concentrated hydrochloric acid to obtain a compound 2, and reacting the compound 2 with amine R4-NH-R5Condensation to obtain a compound 12, deprotection of the compound 12 to obtain a compound 13, and reaction of the compound 13 with a compound 5 to obtain a target compound 14.
Synthesis method III
Figure BDA0000892466340000391
The target compound 17 can be prepared by a third synthesis method, wherein R is1b、R2、R3、R6And R7Have the meaning as described in the present invention. Reacting the compound 15 with the compound 5 under the action of alkali to obtain a compound 16, and reacting the compound 16 with amine R6-NH-R7Condensation to give the target compound 17.
Synthesis method IV
Figure BDA0000892466340000392
The target compound 22 can be prepared by a synthesis method IV, wherein R is1d、R2、R3、R8And R12Have the meaning as described in the present invention. Reacting the compound 18 with the compound 5 under the action of alkali to obtain a compound 19, and reacting the compound 19 with an amine R8-NH2Condensation reaction to obtain compound 20, reduction of compound 20 with borane or lithium aluminum hydride to obtain compound 21, compound 21 and carboxylic acid R12Reaction with-COOH gave the title compound 22.
Synthesis method five
Figure BDA0000892466340000393
Target compound 26 can be prepared by synthesis method five, wherein PG is a protecting group, such as Boc or Cbz; p, q and R14Have the meaning as described in the present invention. The compound 23 reacts with the compound 5 to obtain a compound 24, the compound 24 is deprotected to obtain a compound 25, and the compound 25 is subjected to condensation reaction or alkylation reaction to obtain a target compound 26.
Synthesis method VI
Figure BDA0000892466340000401
Target compound 30 can be prepared by synthesis method six, wherein PG is a protecting group, such as Boc or Cbz; r, s and R14Have the meaning as described in the present invention. Compound 27 reacts with compound 5 to give compound 28, compound 28 is deprotected to give compound 29, and compound 29 is subjected to condensation reaction or alkylation reaction to give target compound 30.
Synthesis method seven
Figure BDA0000892466340000402
Target compound 34 can be prepared by synthesis method seven, wherein PG is a protecting group, such as Boc or Cbz; w and R13Have the meaning as described in the present invention. Reacting the compound 31 with the compound 5 to obtain a compound 32, deprotecting the compound 32 to obtain a compound 33, and subjecting the compound 33 to condensation reaction or alkylation reaction to obtain a target compound 34.
Synthesis method eight
Figure BDA0000892466340000411
The target compounds 43 and 46 can be prepared by a synthesis method eight, wherein R14Have the meaning as described in the present invention. Esterifying a compound 35 to obtain a compound 36, reacting the compound 36 with a compound 37 to obtain a compound 38, reacting the compound 38 with bromoacetonitrile under the action of strong alkali to obtain a compound 39, reducing a cyano group by the compound 39 to obtain a compound 40, reacting the compound 40 in the presence of potassium tert-butoxide to obtain a compound 41, carrying out alkylation reaction on the compound 41 to obtain a compound 42, and deprotecting the compound 42 to obtain a target compound 43.
Reducing the compound 41 by borane or lithium aluminum hydride to obtain a compound 44, carrying out alkylation reaction or condensation reaction on the compound 44 to obtain a compound 45, and deprotecting the compound 45 to obtain a target compound 46.
Examples
Example 1(R) -N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -2-cyano-N-methylacetamide
Figure BDA0000892466340000412
Step 1: synthesis of Compound (R) -1- (tert-Butoxycarbonyl) pyrrolidine-2-carboxylic acid
D-proline (10.0g,86.80mmol) was dissolved in tetrahydrofuran (16mL) and water (40mL) at room temperature, sodium bicarbonate (18.2g,217.14mmol) and di-tert-butyl dicarbonate (27.3mL,130.20mmol) were added in this order, the reaction was allowed to react overnight at room temperature, quenched with water (50mL), extracted with ethyl acetate (150 mL. times.3), and extracted with anhydrous Na2SO4Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 9.3g of a colorless oil, yield: 50 percent.
MS(ESI,pos.ion)m/z:160.1[M-t-Bu+2]+.
Step 2: synthesis of Compound (R) -t-butyl 2- (methylcarbamoyl) pyrrolidine-1-carboxylate
(R) -1- (tert-butoxycarbonyl) pyrrolidine-2-carboxylic acid (1.30g,6.03mmol) was dissolved in dichloromethane (15mL) at room temperature, triethylamine (2.1mL,15.1mmol), EDCI (1.73g,9.06mmol), HOBT (1.22g,9.06mmol) and methylamine hydrochloride (611.82mg,9.06mmol) were added in this order, reacted at room temperature for 16h, quenched with saturated aqueous ammonium chloride (10mL), dichloromethane (15mL × 3) extracted, the organic phase was combined and washed with saturated ammonium chloride solution (50mL), dried over anhydrous sodium sulfate, concentrated and isolated by column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 800mg of a white solid, yield: 58 percent.
MS(ESI,pos.ion)m/z:229.2[M+1]+.
And step 3: synthesis of compound (R) -N-methyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxamide
(R) -tert-butyl 2- (methylcarbamoyl) pyrrolidine-1-carboxylate (1.0g,4.38mmol) was dissolved in dichloromethane (5mL) at room temperature, trifluoroacetic acid (1mL) was added, and after stirring at room temperature for 2 hours, the starting material disappeared, and the solvent was directly concentrated to conduct the next reaction.
The deprotected product (300mg,2.34mmol) was taken and N, N-dimethylacetamide (6mL), 4-chloropyrrolo [2,3-d ] was added]Pyrimidine (358.6mg,2.34mmol), potassium carbonate (968.76mg,7.02mmol), oil bath reaction at 90 ℃ for 5h, quenching with water (15mL), extraction with dichloromethane (15 mL. times.3),with anhydrous Na2SO4Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 280mg of white solid, yield: 49 percent.
MS(ESI,pos.ion)m/z:246.2[M+1]+.
And 4, step 4: synthesis of compound (R) -1- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) -N-methylmethanamine
Reacting (R) -N-methyl-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-2-carboxamide (180mg,0.73mmol) was dissolved in anhydrous tetrahydrofuran (7mL), slowly added with lithium aluminum hydride (139.7mg,3.07mmol) in portions, refluxed for 13 hours, quenched with methanol (5mL) added dropwise under ice bath, filtered, concentrated for column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 10/1), yielding 72mg of a colorless oil, yield: and 43 percent.
MS(ESI,pos.ion)m/z:434.2[M+1]+.
And 5: synthesis of compound (R) -N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -2-cyano-N-methylacetamide
Reacting (R) -1- (1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidin-2-yl) -N-methyl methylamine (70mg,0.30mmol) was dissolved in N, N-dimethylformamide (3mL), triethylamine (104.5 μ L,0.75mmol), EDCI (86.26mg,0.45mmol), HOBT (60.75mg,0.75mmol) and cyanoacetic acid (37.35mg,0.45mmol) were sequentially reacted at room temperature overnight, directly concentrated for column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 30/1), and preparative thin layer chromatography gave 31mg of a light yellow solid, yield: 35 percent.
MS(ESI,pos.ion)m/z:299.2[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.28(d,J＝4.0Hz,1H),7.11(dd,J＝3.4Hz,15.0Hz,1H),6.61(dd,J＝3.4Hz,14.6Hz,1H),4.52-4.84(m,1H),4.01-4.33(m,1H),3.83-4.05(m,3H),3.3(d,2H),3.12-3.19(d,3H),2.19(m,2H),1.98(m,2H).
Example 2(S) -N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -2-cyanoacetamide
Figure BDA0000892466340000421
Step 1: synthesis of Compound (S) -tert-butyl-2- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate
L-prolinol-1-carboxylic acid tert-butyl ester (5.0g,24.8mmol) was dissolved in dichloromethane (50mL) at 0 ℃, triethylamine (5.16mL,38.2mmol) was added, methanesulfonyl chloride (2.94mL,38.2mmol) was slowly added dropwise, the mixture was allowed to stand at room temperature overnight with stirring, the reaction solution was washed with a saturated ammonium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 6.0g of a colorless oil, yield: 87 percent.
MS(ESI,pos.ion)m/z:224.1[M-t-Bu+2]+.
Step 2: synthesis of compound (S) -tert-butyl-2- (azidomethyl) pyrrolidine-1-carboxylic acid ester
To (S) -tert-butyl-2- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylic acid ester (724mg,2.60mmol) was added DMF (3mL) to dissolve, sodium azide (253.5mg,3.9mmol) was added, reaction at 80 ℃ for 16h, addition of saturated aqueous ammonium chloride (10mL) to quench, dichloromethane (15mL × 3) extraction, drying over anhydrous sodium sulfate, concentration for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 580mg of a light yellow oil, yield: 99 percent.
MS(ESI,pos.ion)m/z:171.1[M-t-Bu+2]+.
And step 3: synthesis of Compound (S) -t-butyl-2- (aminomethyl) pyrrolidine-1-carboxylate
To a solution of (S) -tert-butyl-2- (azidomethyl) pyrrolidine-1-carboxylate (624mg,2.6mmol) in methanol (15mL) at room temperature was added palladium on carbon (10%, 65mg) and the reaction was carried out at room temperature for 1h, whereupon the starting material disappeared, filtered and concentrated to give a colorless oil which was directly subjected to the next reaction.
MS(ESI,pos.ion)m/z:201.2[M+1]+.
And 4, step 4: synthesis of Compound (S) -tert-butyl-2- ((2-cyanoacetamide) methyl) pyrrolidine-1-carboxylate
Preparation of cyanoacetyl chloride: to a solution of cyanoacetic acid (331.5mg,3.9mmol) in dichloromethane (6mL) was added DMF (3 drops), cooled to 0 deg.C, and oxalyl chloride (370. mu.L, 3.9mmol) was added dropwise slowly, stirred at room temperature for 30min, and concentrated to a brown oil.
The (S) -tert-butyl-2- (aminomethyl) pyrrolidine-1-carboxylic acid ester obtained in the previous step (crude, 2.6mmol) was dissolved in dichloromethane (6mL), triethylamine (723 μ L,5.2mmol) was added to cool to 0 ℃, freshly prepared cyanoacetyl chloride was dissolved in dichloromethane (3mL), slowly added dropwise to the reaction solution, reacted at room temperature for 1h, quenched with saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 153mg of a pale yellow solid, yield: 22 percent. MS (ESI, pos. ion) M/z 268.2[ M + 1]]+.
And 5: synthesis of the compound (S) -N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -2-cyanoacetamide
(S) -tert-butyl-2- ((2-cyanoacetamide) methyl) pyrrolidine-1-carboxylate (153mg,0.57mmol) was dissolved in dichloromethane (6mL), trifluoroacetic acid (212.3. mu.L, 2.85mmol) was added, stirring at room temperature for 2.5h, and concentration was carried out for the next reaction.
Dissolving in isopropanol (6mL), adding 4-chloropyrrolo [2,3-d ] pyrimidine (107.10mg,0.70mmol), triethylamine (322.7 μ L,2.32mmol) in that order, refluxing at 90 ℃ for 5.5h, concentrating directly for column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), and isolating by preparative chromatography to give 47mg of a white solid, yield: 20 percent.
MS(ESI,pos.ion)m/z:285.2[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.15(s,1H),7.11(d,J＝4.0Hz,1H),6.78(d,J＝4.0Hz,1H),4.67(m,1H),4.01(m,1H),3.86(m,1H),3.54(m,2H),2.00-2.31(m,4H),1.31(m,2H).
Example 3(S) -2-cyano-N- ((4, 4-difluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -N-methylacetamide
Figure BDA0000892466340000431
Step 1: synthesis of Compound (S) -1- (tert-Butoxycarbonyl) -4-oxopyrrolidine-2-carboxylic acid
(2S) -4-oxopyrrolidine-2-carboxylic acid (5.00g,30.20mmol) was dissolved in tetrahydrofuran (150mL) and triethylamine (15mL) and Boc were added sequentially2O (7mL), stirred at room temperature overnight. After evaporation of tetrahydrofuran under reduced pressure, hydrochloric acid (1M) was added to acidify to pH 2, ethyl acetate (200 mL. times.3) was extracted, the organic phase was washed with water (150mL), washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried thoroughly before being used directly in the next synthesis.
Step 2: synthesis of Compound (S) -1-tert-butyl-2-methyl-4-oxopyrrolidine-1, 2-dicarboxylic acid diethyl ester
(S) -1- (tert-Butoxycarbonyl) -4-oxopyrrolidine-2-carboxylic acid (3125mg,13.63mmol) was dissolved in N, N-dimethylformamide (20mL), sodium bicarbonate (5.73g,68.16mmol) was added, iodomethane (1.70mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous sodium chloride (30mL), extracted with ethyl acetate (200mL × 3), the organic phase was washed with water (150mL), washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give 2.50g of the product, yield: 75 percent.
And step 3: synthesis of compound (S) -1-tert-butyl-2-methyl-4, 4-difluoropyrrolidine-1, 2-dicarboxylic acid diethyl ester
Diethyl (S) -1-tert-butyl-2-methyl-4-oxopyrrolidine-1, 2-dicarboxylate (703mg,2.89mmol) was dissolved in dichloromethane (40mL), cooled to 0 ℃, diethylthiotrifluoride (1.91mL,14.45mmol) was added dropwise, stirred for 2h, concentrated under reduced pressure, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give 0.90g of product, yield: 100 percent.
MS(ESI,pos.ion)m/z:266.2[M+1]+.
And 4, step 4: synthesis of compound (S) -tert-butyl-4, 4-difluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylate
Diethyl (S) -1-tert-butyl-2-methyl-4, 4-difluoropyrrolidine-1, 2-dicarboxylate (800mg,3.02mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0 deg.C, and then lithium borohydride (0.70g) was added to slowly return to room temperature for reaction overnight. The reaction was quenched with water (100mL), extracted with ethyl acetate (150 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure for use in the next step.
And 5: synthesis of Compound (S) -tert-butyl-4, 4-difluoro-2- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate
(S) -tert-butyl 4, 4-difluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylate (700mg,2.95mmol) was dissolved in dichloromethane (50mL), cooled to 0 deg.C, and triethylamine (4.10mL) and methanesulfonyl chloride (1.20mL) were added dropwise in that order, and the reaction was allowed to return to room temperature for 1 h. The reaction was quenched with water (50mL), extracted with dichloromethane (50 mL. times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure for direct use in the next step.
Step 6: synthesis of compound (S) -tert-butyl-4, 4-difluoro-2- ((methylamino) methyl) pyrrolidine-1-carboxylate
(S) -tert-butyl 4, 4-difluoro-2- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate (600mg,1.90mmol) was dissolved in tetrahydrofuran (40mL), aqueous methylamine (40%, 30mL) was added, and the reaction was allowed to proceed overnight at 80 ℃ with tube sealing. Concentrating under reduced pressure, and performing column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), yielding 0.40g of product, yield: 80 percent.
MS(ESI,pos.ion)m/z:251.3[M+1]+.
And 7: synthesis of compound (S) -tert-butyl 2- ((2-cyano-N-methylacetamido) methyl) -4, 4-difluoropyrrolidine-1-carboxylate
(S) -tert-butyl 4, 4-difluoro-2- ((methylamino) methyl) pyrrolidine-1-carboxylate (300mg,1.20mmol), cyanoacetic acid (1.02g,12.1mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.20g,6.28mmol) and 1-hydroxybenzotriazole (0.80g,5.92mmol) were dissolved in dichloromethane (30mL), cooled to 0 deg.C, triethylamine (1.70mL) was added dropwise, and the reaction was allowed to return to room temperature overnight. Extraction with ethyl acetate (100mL × 3), washing of the organic phase with water (50mL), washing with saturated sodium chloride solution (100mL), drying over anhydrous sodium sulfate, concentration under reduced pressure, and column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) gave 0.29g of product, yield: 76 percent.
MS(ESI,pos.ion)m/z:318.3[M+1]+.
And 8: synthesis of compound (S) -2-cyano-N- ((4, 4-difluoropyrrol-2-yl) methyl) -N-methylacetamide
(S) -tert-butyl 2- ((2-cyano-N-methylacetamido) methyl) -4, 4-difluoropyrrolidine-1-carboxylate (0.29g,0.91mmol) was dissolved in dichloromethane (20mL), cooled to 0 deg.C, trifluoroacetic acid (10mL) was added dropwise, allowed to slowly return to room temperature for 3h, concentrated under reduced pressure and dried thoroughly for the next reaction.
And step 9: synthesis of compound (S) -2-cyano-N- ((4, 4-difluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) -N-methylacetamide
(S) -2-cyano-N- ((4, 4-difluoropyrrol-2-yl) methyl) -N-methylacetamide (0.20g,0.91mmol) and 4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidine (0.42g,2.7mmol) was dissolved in isopropanol (40mL), 2 drops of concentrated HCl were added dropwise, and the reaction was heated under reflux overnight. Concentrating under reduced pressure, and performing column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 120mg of solid, two-step overall yield: 39 percent.
MS(ESI,pos.ion)m/z:335.0[M+1]+；
1H NMR(400MHz,MeOH-d4):(exists as rotamers)δ(ppm)8.20-8.14(s,1H),7.13-7.10(s,1H),4.31-4.25(m,1H),4.08-4.01(m,1H),3.99-3.84(m,1H),3.58-3.51(m,3H),2.70-2.50(m,2H).
Example 4(S) -2- ((2- (((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) amino) -3, 4-diketosquaraine-1-yl) amino) acetonitrile
Figure BDA0000892466340000451
Step 1: synthesis of compound diethyl squarate
Squaric acid (1.00g,8.77mmol) was dissolved in absolute ethanol (20mL) and heated at reflux for 12 h. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 1.50g of a colorless liquid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:171.2[M+1]+.
Step 2: synthesis of compound 2- ((2-ethoxy-3, 4-diketo squaric acid-1-yl) amino) acetonitrile
Triethylamine (1.64g,16.20mmol) was added dropwise to a solution of diethyl squarate (1.38g,8.10mmol) and 2-aminoacetonitrile hydrochloride (500mg,5.40mmol) in anhydrous ethanol (20mL) and reacted at room temperature for 6 hours. Concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 793.8mg of a light yellow solid, yield: 82 percent.
MS(ESI,pos.ion)m/z:181.2[M+1]+.
And step 3: synthesis of Compound (S) -tert-butyl 2- ((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate
Methanesulfonyl chloride (740.0mg,6.46mmol) was added dropwise to a solution of (S) -2- (hydroxymethyl) pyrrolidine-1-tert-butyl methyl ester (1.00g,4.97mmol) and triethylamine (754.9mg,7.46mmol) in dichloromethane (20mL) and reacted at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), and purified to obtain 877.2mg of a pale yellow oil, yield: and 63 percent. MS (ESI, pos. ion) M/z 224.2[ M- (t-Bu) +2]+.
And 4, step 4: synthesis of compound (S) -2- (azidomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Sodium azide (296.4mg,4.56mmol) was added to a solution of tert-butyl (S) -2- ((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate (850mg,3.04mmol) in DMF (10mL) and the reaction was heated at 80 ℃ overnight. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (30mL), extracted with dichloromethane (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), purified to give 311.4mg of a pale yellow oil, yield: 45 percent.
MS(ESI,pos.ion)m/z:171.2[M-(t-Bu)+2]+.
And 5: synthesis of Compound (S) -tert-butyl 2- (aminomethyl) pyrrolidine-1-carboxylate
Palladium on carbon (10%, 93mg) was added to a solution of (S) -tert-butyl 2- (azidomethyl) pyrrolidine-1-carboxylate (310mg,1.37mmol) in MeOH (10mL)In H2The reaction was stirred at room temperature for 6 hours under ambient atmosphere. After the reaction was completed, filtration was carried out, and the filtrate was concentrated under reduced pressure to obtain 275mg of a colorless oily substance which was directly put into the next step without further purification.
MS(ESI,pos.ion)m/z:146.2[M-(t-Bu)+2]+.
Step 6: synthesis of Compound (S) -tert-butyl 2- (((2- ((cyanomethyl) amino) -3, 4-diketosquaraine-1-yl) amino) methyl) pyrrole-1-carboxylate
Triethylamine (156.8mg,1.55mmol) was added to a solution of 2- ((2-ethoxy-3, 4-diketosquaric acid-1-yl) amino) acetonitrile (214.4mg,1.19mmol) and tert-butyl (S) -2- (aminomethyl) pyrrolidine-1-carboxylate (275mg,1.37mmol) in EtOH (20mL) and reacted at room temperature for 3 hours. Concentrating the reaction solution under reduced pressure, and separating the obtained residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), purification afforded 268.6mg of a light yellow solid, yield: 67%.
MS(ESI,pos.ion)m/z:279.2[M-(t-Bu)+2]+.
And 7: synthesis of Compound (S) -2- ((2- (((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-2-yl) methyl) amino) -3, 4-diketosquaraine-1-yl) amino) acetonitrile
Trifluoroacetic acid (456.1mg,4.00mmol) was added to a solution of tert-butyl (S) -2- (((2- ((cyanomethyl) amino) -3, 4-diketosquaraine-1-yl) amino) methyl) pyrrole-1-carboxylate (268.6mg,0.80mmol) in DCM (20mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in isopropanol (20mL), 4-chloropyrrolopyrimidine (245.7mg,1.60mmol) and triethylamine (323.8mg,3.20mmol) were added, and the reaction mixture was heated at 90 ℃ for 9 hours. Concentrating the reaction solution under reduced pressure, and separating the obtained residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 73.4mg white solid, yield: 26 percent.
MS(ESI,pos.ion)m/z:352.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.80(s,1H),8.18(s,1H),7.18(s,1H),6.65(s,1H),4.87-4.95(m,1H),4.71(d,J＝6.0Hz,1H),4.51-4.63(m,1H),4.09-4.26(m,2H),3.89-3.98(m,2H),3.77-3.83(m,2H),1.99-2.11(m,4H).
Example 5N- (cyanomethyl) -N-methyl-3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxamide
Figure BDA0000892466340000461
Step 1: synthesis of compound pyrrolidine-3-carboxylic acid methyl ester
Thionyl chloride (12.00mL,165.40mmol) was slowly added dropwise to a mixture of pyrrolidine-3-carboxylic acid (9.10g,79.00mmol) in methanol (120mL) under ice bath, and after the addition was completed, the reaction mixture was transferred to an oil bath for 6h at 42 ℃. Concentration under reduced pressure gave an oil which was not purified and used directly in the next reaction.
Step 2: synthesis of compound methyl 1-tert-butoxycarbonylpyrrolidine-3-carboxylate
Triethylamine (35.00mL,251.00mmol) was added to a solution of methyl pyrrolidine-3-carboxylate (13.50g,81.50mmol) in dichloromethane (120mL) under ice-cooling, and the mixture was reacted at room temperature for 2 hours after completion of the dropwise addition. Di-tert-butyl carbonate (25.2mL,118.00mmol) was slowly added to the above mixture under ice-cooling and reacted at room temperature overnight. The reaction was quenched with saturated ammonium chloride solution (200mL), extracted with dichloromethane (300mL × 4), the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 18.70g of a pale yellow oil, yield: 99 percent.
MS(ESI,pos.ion)m/z:252.1[M+Na]+；
1H NMR(400MHz,CDCl3):δ(ppm)3.60(s,3H),3.55-3.18(m,4H),3.01-2.88(m,1H),2.02(d,J＝5.8Hz,2H),1.35(s,9H).
And step 3: synthesis of Compound 1-t-butyl 3-methyl 3- (methylthio) tetrahydropyrrole-1, 3-dicarboxylate
Under nitrogen protection, a solution of n-butyllithium in n-hexane (2.4M,7.30mL,18.00mmol) was slowly added dropwise to a solution of anhydrous diisopropylamine (2.70mL,19.00mmol) in anhydrous tetrahydrofuran (30mL) and reacted at-40 ℃ for 1h to prepare lithium diisopropylamide. A solution of methyl 1-tert-butoxycarbonylpyrrolidine-3-carboxylate (2.10g,9.20mmol) in anhydrous tetrahydrofuran (30mL) was slowly added dropwise to the freshly prepared lithium diisopropylamide solution, reacted at-78 ℃ for 1.5h, then added dropwise with dimethyl disulfide (2.0mL,22.60 mmol), reacted at-78 ℃ for 30min, and slowly warmed to room temperature for 18 h. Saturated ammonium chloride solution (200mL) was added, stirred for 5 minutes, extracted with ethyl acetate (400mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 1.20g yellow oil, yield: 48 percent.
MS(ESI,pos.ion)m/z:176.1[M-t-Bu+2]+.
And 4, step 4: synthesis of compound methyl 3- (methylthio) tetrahydropyrrole-3-carboxylate trifluoroacetate
Trifluoroacetic acid (10mL) was added dropwise to a solution of 1-tert-butyl 3-methyl 3- (methylthio) pyrrolidine-1, 3-dicarboxylate (1.20g,4.40mmol) in dichloromethane (20mL) under ice-bath, reacted at room temperature for 6h, concentrated under reduced pressure, and used in the next reaction without purification.
And 5: synthesis of compound methyl 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxylate
Methyl 3- (methylthio) pyrrolidine-3-carboxylate trifluoroacetate (0.90g,3.31mmol) was dissolved in N, N-dimethylformamide (10mL), N-diisopropylethylamine (6mL,34.4mmol) was slowly added dropwise, and after 1 hour of reaction at room temperature, 4-chloropyrrolopyrimidine (0.75g,4.9mmol) was added and reacted at 80 ℃ overnight. Quenching the reaction with water (100mL), extracting with dichloromethane (100 mL. times.3), washing with brine, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 50/1), yielding 1.20g of a yellow oily solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:293.0[M+1]+.
Step 6: synthesis of compound 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxylic acid
3- (methylthio) -1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) tetrahydropyrrole-3-carboxylic acid methyl ester (1.00g,3.42mmol) was dissolved in methanol (20mL) solution and a mixture of lithium hydroxide (0.25g,10.44mmol) and water (6mL) was added. Stirring at room temperature for 12h, removing methanol under reduced pressure, adjusting pH to 6 with hydrochloric acid (6M), and adding dichloromethane (15)0 mL. times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 200mg of an oil. Concentrating the aqueous layer under reduced pressure to obtain a solid, adding CH2Cl2Soaking in/MeOH (20mL/20mL), filtering, and concentrating the filtrate under reduced pressure to give 600mg of a solid, yield: 84 percent.
MS(ESI,pos.ion)m/z:279.1[M+1]+.
And 7: synthesis of compound N- (cyanomethyl) -N-methyl-3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxamide
Oxalyl chloride (0.15mL,1.7mmol) and catalytic amount of N, N-dimethylformamide (0.10mL) were slowly added dropwise to 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] under ice-bath]Pyrimidin-4-yl) tetrahydropyrrole-3-carboxylic acid (0.15g,0.54mmol) in anhydrous dichloromethane (30mL) was reacted at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (25mL), and then added dropwise slowly to a solution of 2- (methylamino) acetonitrile (0.12g,1.07mmol) and triethylamine (0.40mL,3.00mmol) in anhydrous dichloromethane (10mL) and reacted at room temperature overnight. Diluting with water (35mL), extracting with dichloromethane (35 mL. times.3), drying with anhydrous sodium sulfate, removing solvent, and separating the concentrated solution by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1) to give a yellow solid, and the crude product was further purified by preparative high performance liquid chromatography to give 8mg of a white solid, yield: 4.5 percent.
MS(ESI,pos.ion)m/z:331.1[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.30(s,1H),7.42(s,1H),6.99(d,J＝19.7Hz,1H),4.53-4.20(m,4H),3.46(d,J＝22.5Hz,3H),2.72(dd,J＝67.1,45.1Hz,2H),2.18(s,3H),1.36-1.32(m,2H).
Example 6N- (cyanomethyl) -N-methyl-2- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxamide
Figure BDA0000892466340000471
Step 1: synthesis of compound 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine
Under ice-water bath, 4-chloropyrrolo [2,3-d ] is added]Sodium hydride (60%, 1.04g,26.0mmol) was added to a solution of pyrimidine (2.0g,13mmol) in DMF (15mL), stirred at room temperature for 1h, SEMCl (3.5mL,20mmol) was slowly added dropwise to the reaction solution in a water bath, the reaction was kept mild, the dropwise addition was continued for about 10 min, and the reaction was stirred at room temperature overnight. Quenched by slowly dropping water (20mL), extracted with dichloromethane (25 mL. times.3), and extracted with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 3/1) afforded 2.0g of a colourless oil, yield: and 55 percent.
MS(ESI,pos.ion)m/z:284.1[M+1]+.
Step 2: synthesis of compound methyl 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
To 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d at room temperature]To a solution of pyrimidine (1.0g,3.5mmol) in DMF (8mL) were added potassium carbonate (2.9g,21mmol) and L-proline methyl ester (451.5mg,3.5mmol) in that order, reacted in an oil bath at 80 ℃ for 4h, quenched with water (20mL), extracted with dichloromethane (25 mL. times.3), and quenched with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 3/1) gave 850mg of a colourless oil, yield: and 64 percent.
MS(ESI,pos.ion)m/z:377.2[M+1]+.
And step 3: synthesis of compound methyl 2-methylsulfanyl-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
To a solution of diisopropylamine (1.46mL,10mmol) in THF (20mL) at-15 deg.C under nitrogen was added n-butyllithium (1.4M,3.8mL), stirred at this temperature for 10 minutes, cooled to-78 deg.C, and after 30 minutes, 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] was added]A solution of methyl pyrimidin-4-yl) pyrrolidine-2-carboxylate (850mg,2.26mmol) in THF (12mL) was slowly added dropwise to the reaction mixture, and the reaction was continued at-78 ℃ for 1 h; dimethyldithio (409.7. mu.L, 4.63mmol) was added and the reaction was allowed to warm to room temperature naturally overnight. Adding saturated ammonium chloride solution (15mL) to quench, and adding dichloromethane (15mL in a prepared form3) Extracting with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1) gave 560mg of a yellow oil in yield: 59 percent.
MS(ESI,pos.ion)m/z:423.2[M+1]+；
1H NMR(600MHz,CDCl3):δ(ppm)8.36(s,1H),7.12(d,J＝3.7Hz,1H),6.62(d,J＝3.7Hz,1H),5.59(d,J＝3.4Hz,2H),4.18(m,2H),3.73(s,3H),3.54(m,2H),2.54(m,2H),2.41(m,1H),2.29(m,1H),2.23(s,3H),0.92(t,J＝6.0Hz,2H),-0.04(s,9H).
And 4, step 4: synthesis of compound methyl 2-methylthio-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
Reacting 2-methylthio-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-yl) pyrrolidine-2-carboxylic acid methyl ester (490mg,1.16mmol) was dissolved in dichloromethane (10mL), and hydrogen chloride dioxane solution (4M,5mL) was added, stirred overnight at room temperature, and concentrated to give a white solid. Tetrahydrofuran (10mL) was added and sodium hydroxide solution (1M) was added to adjust the pH>8, stirred at room temperature for 4h, extracted with dichloromethane (15 mL. times.3), and extracted with anhydrous Na2SO4Drying, removal of the solvent, column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 1/1) afforded 180mg of a light yellow solid, yield: 38 percent.
MS(ESI,pos.ion)m/z:293.2[M+1]+.
And 5: synthesis of compound 2-methylthio-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylic acid
Methyl 2-methylsulfanyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate (130mg,0.44mmol) was dissolved in concentrated hydrochloric acid (5mL), reacted at 80 ℃ for 7H, the solvent was directly concentrated, toluene taken with water to give 123mg of a brown solid, yield: 99 percent.
MS(ESI,pos.ion)m/z:279.1[M+1]+.
Step 6: synthesis of the compound N- (cyanomethyl) -N-methyl-2- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxamide
2-methylthio-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-2-carboxylic acid(120mg,0.43mmol) was dissolved in N, N-dimethylformamide (3mL), triethylamine (180. mu.L, 1.29mmol), EDCI (164.4mg,0.85mmol), HOBT (116mg,0.86mol) and 2-methylaminoacetonitrile hydrochloride (91mg,0.86mmol) were added successively, stirred at room temperature overnight, quenched with water (15mL), extracted with dichloromethane (15 mL. times.3), and extracted with anhydrous Na2SO4Drying, and performing column chromatography on the concentrated solution (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 11mg of a colorless oil, yield: 17 percent.
MS(ESI,pos.ion)m/z:331.2[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.14(s,1H),7.10(s,1H),6.59(s,1H),4.43(s,2H),3.72(t,J＝6.6Hz,2H),3.06(s,3H),2.69(m,2H),2.11(s,3H),2.07(m,2H).
Example 7N- (3-cyanobenzyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Figure BDA0000892466340000491
Step 1: synthesis of compound pyrrolidine-3-carboxylic acid ethyl ester
Concentrated hydrochloric acid (2mL) was added to a solution of pyrrolidine-3-carboxylic acid (600mg,5.93mmol) in EtOH (30mL) and heated at reflux overnight. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 1.87g of a pale yellow liquid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:144.3[M+1]+.
Step 2: synthesis of Compound ethyl 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylate
Potassium carbonate (10.83g,78.36mmol) was added to pyrrolidine-3-carboxylic acid ethyl ester (1.87g,13.06mmol) and 4-chloro-7H-pyrrolo [2,3-d ]]Pyridine (3.01g,19.59mmol) in isopropanol (30mL) under reflux overnight, concentrating under reduced pressure after the reaction is complete, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), purification afforded 2.16g of white solid, yield: and 64 percent. MS (ESI, pos. ion) M/z 261.1[ M + 1]]+.
And step 3: synthesis of Compound 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid
A solution of sodium hydroxide (0.66g,16.60mmol) in water (2mL) was added to 1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid ethyl ester (2.16g,8.30mmol) in EtOH (40mL) was reacted at room temperature for 3 hours. After the reaction was completed, EtOH was removed by concentration under reduced pressure, pH was adjusted to about 6 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain 1.80g of a white solid, which was directly put into the next step without further purification. MS (ESI, pos.ion) M/z 233.1[ M + 1]]+.
And 4, step 4: synthesis of compound N- (3-cyanobenzyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
3- (aminomethyl) benzonitrile (170mg,1.29mmol), HOBT (232mg,1.72mmol), EDCI (330.0mg,1.72mmol) and diisopropylethylamine (445.0mg,3.45mmol) were added to 1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (200.00mg,0.86mmol) was dissolved in DMF (20mL) and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was quenched by addition of water (30mL), extracted with dichloromethane (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 210.0mg of white solid, yield: 70 percent.
MS(ESI,pos.ion)m/z:347.0[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.61(s,1H),8.65(t,J＝5.7Hz,1H),8.10(s,1H),7.72-7.74(m,2H),7.61-7.63(m,1H),7.53-7.57(m,1H),7.12(d,J＝2.3Hz,1H),6.58(d,J＝1.6Hz,1H),4.37(d,J＝5.9Hz,2H),3.75-4.02(m,4H),3.17-3.21(m,1H),2.16-2.27(m,2H).
Example 81- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carbonyl) pyrrolidine-3-carbonitrile
Figure BDA0000892466340000492
3-Cyanopyrrolidine hydrochloride (128.00mg,0.97mmol), HOBT (174.00mg,1.29mmol), EDCI (247.0mg,1.29mmol) anddiisopropylethylamine (333.0mg,2.58mmol) was added to 1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (150.00mg,0.65mmol) was dissolved in DMF (20mL) and reacted at room temperature overnight. After completion of the reaction, the reaction mixture was quenched by addition of water (30mL), extracted with dichloromethane (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 104.1mg of a white solid, yield: 52 percent.
MS(ESI,pos.ion)m/z:311.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)12.28(s,1H),8.22(d,J＝2.1Hz,1H),7.30(s,1H),6.76(s,1H),3.79-3.97(m,5H),3.63-3.71(m,2H),3.52-3.58(m,1H),3.37-3.48(m,2H),2.12-2.38(m,4H).
Example 9N-isopropyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Figure BDA0000892466340000501
Diisopropylamine (101mg,1.71mmol), HOBt (116mg,0.86mmol) and EDCI (165mg,0.86mmol) were added to 1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (100mg,0.43mmol) was dissolved in DMF (5mL) and reacted at room temperature for 17 hours. After completion of the reaction, the reaction mixture was quenched by addition of water (20mL), extracted with dichloromethane (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 93.1mg of a white solid, yield: 79 percent.
MS(ESI,pos.ion)m/z:274.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.56(s,1H),8.08(s,1H),7.89(d,J＝7.5Hz,1H),7.10-7.11(m,1H),6.55-6.56(m,1H),3.82-3.96(m,3H),3.72(s,2H),3.01-3.05(m,1H),2.09-2.19(m,2H),1.08(d,J＝6.6Hz,6H).
Example 10N- (2-cyanoethyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Figure BDA0000892466340000502
3-aminopropionitrile (29mg,0.41mmol), HOBT (93mg,0.69mmol), EDCI (132mg,0.69mmol) and triethylamine (139mg,1.37mmol) were added to 1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (80mg,0.34mmol) was dissolved in DMF (5mL) and reacted at room temperature for 17 hours. After completion of the reaction, the reaction mixture was quenched by adding water (20mL), extracted with dichloromethane (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 66.7mg of white solid, yield: 68 percent.
MS(ESI,pos.ion)m/z:285.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.61(s,1H),8.46(t,J＝5.6Hz,1H),8.09(s,1H),7.12-7.13(m,1H),6.57(d,J＝2.3Hz,1H),3.75-3.99(m,4H),3.52(s,1H),3.11-3.18(m,2H),2.68(t,J＝6.5Hz,2H),2.13-2.23(m,2H).
Example 11N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyanoacetamide
Figure BDA0000892466340000511
Step 1: synthesis of Compound 1- (t-Butoxycarbonyl) pyrrolidine-3-carboxylic acid
To a solution of 3-pyrrolidinecarboxylic acid (5.0g,43.43mmol) in tetrahydrofuran (30mL) was added sodium hydroxide solution (2M,60mL) and di-tert-butyl carbonate (10.45g,47.88mmol) in this order under ice-cooling, followed by stirring at room temperature for 12 hours. The tetrahydrofuran was evaporated under reduced pressure, the reaction residue was adjusted to pH 2-3 with a saturated citric acid solution, extracted with ethyl acetate (150 mL. times.3), dried and concentrated to give 7.4g of a pale yellow oil, yield: 79 percent.
MS(ESI,pos.ion)m/z:160.07[M-t-Bu+2]+.
Step 2: synthesis of Compound 3- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
To 1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (4.0g,19mmol) was added borane tetrahydrofuran solution (1M,54mL) slowly under ice-bath, stirred at room temperature overnight, quenched by adding methanol (10mL) slowly, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 2.4g colorless oil, yield: 70 percent.
MS(ESI,pos.ion)m/z:146.09[M-t-Bu+2]+.
And step 3: synthesis of Compound 3- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Tert-butyl 3- (hydroxymethyl) pyrrolidine-1-carboxylate (5.0g,24.8mmol) was dissolved in dichloromethane (60mL) at 0 ℃, triethylamine (5.16mL,38.2mmol) was added, methanesulfonyl chloride (2.94mL,38.2mmol) was slowly added dropwise, the mixture was allowed to stand at room temperature overnight with stirring, the reaction solution was washed with a saturated ammonium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 6.0g of a colorless oil, yield: 87 percent.
MS(ESI,pos.ion)m/z:146.09[M-t-Bu+2]+.
And 4, step 4: synthesis of compound 3- (azidomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
To tert-butyl 3- (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate (724mg,2.6mmol) was added DMF (3mL) to dissolve at room temperature, sodium azide (253.5mg,3.9mmol) was added, reaction was carried out at 80 ℃ for 16h, water was added to quench, saturated aqueous ammonium chloride (10mL) was added to quench, dichloromethane (15mL × 3) was extracted, dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 580mg of a light yellow oil, yield: 99 percent.
MS(ESI,pos.ion)m/z:171.05[M-t-Bu+2]+.
And 5: synthesis of Compound 3- (aminomethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
To a solution of tert-butyl 3- (azidomethyl) pyrrolidine-1-carboxylate (624mg,2.6mmol) in methanol (15mL) at room temperature was added palladium on carbon (10%, 275.6mg) and the reaction was carried out at room temperature for 1h, whereupon the starting material disappeared, and it was filtered and concentrated to give a colorless oil which was directly subjected to the next reaction.
MS(ESI,pos.ion)m/z:145.06[M-t-Bu+2]+.
Step 6: synthesis of compound t-butyl 3- ((2-cyanoacetyl) methyl) pyrrolidine-1-carboxylate
Preparation of cyanoacetyl chloride: to a solution of cyanoacetic acid (331.5mg,3.9mmol) in dichloromethane (6mL) was added DMF (3 drops), cooled to 0 deg.C, and oxalyl chloride (370. mu.L, 3.9mmol) was added dropwise slowly, stirred at room temperature for 30min, and concentrated to a brown oil.
The tert-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (crude, 2.6mmol) obtained in the previous step was dissolved in dichloromethane (6mL), triethylamine (723 μ L,5.2mmol) was added, cooled to 0 ℃, freshly prepared cyanoacetyl chloride was dissolved in dichloromethane (3mL), slowly added dropwise to the reaction solution, reacted at room temperature for 1h, quenched with saturated sodium bicarbonate solution (10mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), to give 153mg of a pale yellow solid, yield: 22 percent.
MS(ESI,pos.ion)m/z:212.07[M-t-Bu+2]+.
And 7: synthesis of compound N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyanoacetamide
Tert-butyl 3- ((2-cyanoacetyl) methyl) pyrrolidine-1-carboxylate (153mg,0.57mmol) was dissolved in dichloromethane (6mL), trifluoroacetic acid (212.3 μ L,2.85mmol) was added, stirred at room temperature for 2.5h, and concentrated for the next reaction; dissolving in isopropanol (6mL), adding 4-chloropyrrolo [2,3-d ] pyrimidine (107.10mg,0.70mmol) and triethylamine (323 μ L,2.32mmol) in that order, refluxing at 90 ℃ for 5.5h, concentrating directly for column chromatography (eluent: DCM/MeOH (v/v) ═ 30/1), and isolating by preparative chromatography to give 7mg of a white solid, yield: 2.7 percent.
MS(ESI,pos.ion)m/z:285.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)11.63(s,1H),8.47(t,J＝5.1Hz,1H),8.08(s,1H),7.17(d,J＝59.5Hz,1H),6.59(s,1H),3.93(dt,J＝92.7,25.9Hz,2H),3.68(s,2H),3.45(dd,J＝33.6,3.1Hz,2H),3.22(m,2H),2.43(d,J＝40.6Hz,1H),2.04(m,1H),1.74(s,1H).
Example 12N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyano-N-methylacetamide
Figure BDA0000892466340000521
Step 1: synthesis of Compound 1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid
4-chloropyrrolo [2,3-d ] is reacted]Pyrimidine (1.0g,6.50mmol), 3-pyrrolidinecarboxylic acid (902mg,7.83mmol), potassium carbonate (2.70g,20.00mmol) and N, N-dimethylacetamide (10mL) were mixed in a reaction flask, heated at 100 ℃ for reaction for 11 hours, stirred on silica gel, and subjected to column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 4.0g of a yellow solid, yield: 260% (containing inorganic salts).
MS(ESI,pos.ion)m/z:233.1[M+1]+.
Step 2: synthesis of compound N-methyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (100mg,0.43mmol) was dissolved in N, N-dimethylformamide (5mL), EDCI (164.3mg,0.86mmol), HOBT (116.1mg,0.86mmol), triethylamine (120. mu.L, 0.86mmol) and methylamine hydrochloride (57mg,0.85mmol) were added in this order, and the mixture was stirred at room temperature overnight. Quenched by addition of saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL × 3), combined organic phases washed with saturated aqueous ammonium chloride (50mL), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 50mg of a white solid, yield: 48 percent.
MS(ESI,pos.ion)m/z:246.2[M+1]+.
And step 3: synthesis of the compound 1- (1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) -N-methylmethanamine
Reacting N-methyl-1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxamide (150mg,0.61mmol) was dissolved in anhydrous tetrahydrofuran (8mL) and addedRefluxing lithium aluminum hydride (116mg,3.06mmol) for 5 hr, adding methanol to quench, filtering with diatomaceous earth, concentrating the filtrate, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 110mg of a gray solid, yield: 78 percent.
MS(ESI,pos.ion)m/z:232.2[M+1]+.
And 4, step 4: synthesis of compound N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyano-N-methylacetamide
1- (1- (7H-pyrrolo [2, 3-d))]Pyrimidin-4-yl) pyrrolidin-3-yl) -N-methyl methylamine (150mg,0.65mmol) was dissolved in N, N-dimethylformamide (6mL), EDCI (247.5mg,1.29mmol), HOBT (175mg,1.30mmol), triethylamine (180 μ L,1.29mmol) and cyanoacetic acid (110.16mg,1.30mmol) were added in this order, stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL × 3), the organic phases were combined and washed with saturated aqueous ammonium chloride (50mL), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 30/1), and preparative thin layer chromatography gave 38mg of a light yellow solid in yield: 20 percent.
MS(ESI,pos.ion)m/z:299.3[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.62(s,1H),8.07(m,1H),7.11(m,1H),6.56(m,1H),4.06(s,2H),3.68-3.85(m,5H),2.98(s,3H),2.90(m,1H),2.61(m,1H),2.06(m,1H),1.72(m,1H).
Example 13N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyano-N-cyclopropylacetamide
Figure BDA0000892466340000531
Step 1: synthesis of compound N-cyclopropyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (100mg,0.43mmol) was dissolved in N, N-dimethylformamide (5mL), EDCI (164.3mg,0.86mmol), HOBT (116.1mg,0.86mmol), triethylamine (120. mu.L, 0.86mmol) and cyclopropylamine (59. mu.L, 0.85mmol) were added in this order, and the mixture was stirred at room temperature overnight. After addition of a saturated aqueous ammonium chloride solution (10mL), quenching, extraction with dichloromethane (15mL × 3), organic phases were combined and washed with a saturated aqueous ammonium chloride solution (50mL), dried over anhydrous sodium sulfate, and concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), yielding 30mg of a white solid, yield: 26 percent.
MS(ESI,pos.ion)m/z:272.3[M+1]+.
Step 2: synthesis of the Compound N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) cyclopropylamine
Reacting N-cyclopropyl-1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxamide (50mg,0.18mmol) was dissolved in borane tetrahydrofuran solution (1M,5mL), the reaction was refluxed overnight, quenched with methanol (3mL), concentrated, dissolved with methanol (5mL), added with sodium hydroxide solution (1M,1mL), refluxed for 2 hours, added with silica gel to mix with the sample, and subjected to column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 20/1), yielding 35mg of a light yellow oil, yield: 74 percent.
MS(ESI,pos.ion)m/z:258.1[M+1]+.
And step 3: synthesis of compound N- ((1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidin-3-yl) methyl) -2-cyano-N-cyclopropylacetamide
Reacting N- ((1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidin-3-yl) methyl) cyclopropylamine (200mg,0.78mmol) was dissolved in N, N-dimethylformamide (6mL), EDCI (296.8mg,1.55mmol), HOBT (209.8mg,1.55mmol), triethylamine (216 μ L,1.55mmol) and cyanoacetic acid (132.1mg,1.55mmol) were added in this order, stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL × 3), the organic phases were combined and washed with saturated aqueous ammonium chloride (50mL), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 30/1), and preparative thin layer chromatography gave 12mg of a light yellow solid in yield: 4.8 percent.
MS(ESI,pos.ion)m/z:325.1[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)11.62(s,1H),8.07(s,1H),7.11(m,1H),6.56(m,1H),4.27(s,2H),3.66-3.89(m,4H),2.81(m,1H),2.63(m,1H),2.08(m,1H),1.72(m,1H),1.22(m,2H),0.82(m,4H).
Example 14N- (cyanomethyl) -3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxamide
Figure BDA0000892466340000541
3- (methylthio) -1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (0.15g,0.54mmol), aminoacetonitrile hydrochloride (75mg,0.81mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.21g,1.07mmol), 1-hydroxybenzotriazole (0.15g,1.09mmol) and triethylamine (0.30mL,2.00mmol) were reacted in N, N-dimethylformamide (5mL) overnight at room temperature. Quenching the reaction with water (20mL), extracting with dichloromethane (20 mL. times.4), drying the organic layer over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 70mg of a yellow sticky mass, which was purified by preparative thin layer chromatography to yield 6mg of a solid.
MS(ESI,pos.ion)m/z:317.1[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.15(s,2H),8.15(s,1H),7.21(d,J＝3.4Hz,1H),6.79(d,J＝3.0Hz,1H),5.50(s,11H),4.87(s,58H),4.23(s,3H),4.23(s,2H),3.88-3.52(m,7H),3.36(s,15H),3.32(dt,J＝3.1,1.6Hz,14H),3.22(q,J＝7.3Hz,9H),2.69(d,J＝26.4Hz,2H),2.38(dd,J＝28.8,5.8Hz,2H),2.17(s,3H),2.17(s,4H),2.04(dd,J＝12.0,6.2Hz,1H),1.42(s,10H),1.32(dd,J＝16.0,8.6Hz,30H),0.91(s,12H).
Example 15N- (cyanomethyl) -N-cyclopropyl-3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxamide
Figure BDA0000892466340000542
Oxalyl chloride (0.15mL,1.70mmol) and a catalytic amount of N, N-dimethylformamide (0.10mL) were slowly added dropwise to 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] under ice-bath]Pyrimidin-4-yl) tetrahydropyrrole-3-carboxylic acid (0)15g,0.54mmol) in anhydrous dichloromethane (30mL) at room temperature for 10h, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (25 mL). Then, the mixture was added dropwise slowly to a solution of 2- (methylamino) acetonitrile (114mg,1.07mmol) and triethylamine (0.40mL,3.00mmol) in anhydrous dichloromethane (10mL) and reacted at room temperature overnight. Diluting with water (35mL), extracting with dichloromethane (35 mL. times.3), drying with anhydrous sodium sulfate, removing solvent, and separating the concentrated solution by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 20mg of a white solid.
MS(ESI,pos.ion)m/z:357.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)11.65(s,1H),8.11(s,1H),7.15(d,J＝2.5Hz,1H),6.57(s,1H),4.48(s,2H),3.98(m,2H),2.04(s,3H),1.36-1.25(m,5H),0.88(tt,J＝21.8,8.3Hz,4H).
Example 16N- (2-cyanoethyl) -N-cyclopentyl-3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) tetrahydropyrrole-3-carboxamide
Figure BDA0000892466340000551
Oxalyl chloride (0.60mL,7.00mmol) and a catalytic amount of N, N-dimethylformamide (0.10mL) were slowly added dropwise to 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] under ice-bath]Pyrimidin-4-yl) tetrahydropyrrole-3-carboxylic acid (0.40g,1.44mmol) was dissolved in anhydrous dichloromethane (30mL) and reacted at room temperature for 10 hours, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in anhydrous dichloromethane (25 mL). Then, 3- (cyclopentylamino) propionitrile (0.40g,2.89mmol) and triethylamine (1.0mL,7.10mmol) were added dropwise slowly to a solution of anhydrous dichloromethane (20mL) and reacted at room temperature overnight. Diluting with water (35mL), extracting with dichloromethane (35 mL. times.3), drying with anhydrous sodium sulfate, removing solvent, and separating the concentrated solution by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1) to give the crude product, which was further purified by high performance liquid chromatography to give 4mg of a white solid. MS (ESI, pos. ion) M/z 399.2[ M + 1]]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.26(s,1H),7.41(s,1H),6.98(d,J＝3.5Hz,1H),4.43-4.09(m,2H),3.62-3.45(m,2H),2.98-2.54(m,4H),2.21(s,3H),2.04(dd,J＝8.1,4.5Hz,2H),1.85(s,2H),1.66(d,J＝31.7Hz,4H),1.33(dd,J＝8.5,4.5Hz,3H).
Example 171- (3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carbonyl) pyrrolidine-3-carbonitrile
Figure BDA0000892466340000552
Step 1: synthesis of compound methyl 1-tert-butoxycarbonylpyrrolidine-3-thiomethyl-3-carboxylate
N-butyllithium (2.4M,24.00mL) was slowly added dropwise to a solution of diisopropylamine (7.77g,76.80mmol) in anhydrous THF (70mL) at-78 ℃ under nitrogen, and after stirring the reaction at this temperature for 30min, a solution of methyl 1-tert-butoxycarbonylpyrrolidine-3-carboxylate (8.00g,34.89mmol) in anhydrous THF (10mL) was slowly added dropwise and the reaction was stirred at this temperature for 1.5 h. After dimethyl disulfide (6.57g,69.70mmol) was slowly added dropwise to the reaction solution, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature overnight. After the reaction is finished, adding saturated NH into the reaction liquid4The reaction was quenched with Cl solution (10mL), concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), purified to give 6.00g of a light yellow liquid, yield: 62 percent.
MS(ESI,pos.ion)m/z:298.2[M+23]+.
Step 2: synthesis of compound methyl 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylate
After TFA (24.80g,217.50mmol) was slowly added dropwise to a solution of methyl 1-t-butoxycarbonylpyrrolidine-3-thiomethyl-3-carboxylate (6.00g,21.79mmol) in DCM (30mL) and reacted at room temperature for 4 hours, the reaction mixture was concentrated under reduced pressure to give methyl pyrrolidine-3-thiomethyl-3-carboxylate as a pale yellow oil, which was dissolved in DMF (50mL), triethylamine (15.40g,152.00mmol) was slowly added dropwise, and the reaction mixture was stirred at room temperature for 0.5 hours, followed by addition of 4-chloropyrrolopyrimidine (3.35g,21.80mmol) and reaction at 80 ℃ overnight. After the reaction, slowly cooling to room temperature, adding water (30mL) to quench the reaction, and mixing the reaction productsThe material was extracted with dichloromethane (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), purification afforded 4.70g of a light yellow solid, yield: 74 percent.
MS(ESI,pos.ion)m/z:293.1[M+1]+.
And step 3: synthesis of compound 3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid
A solution of NaOH (6.42g,161mmol) in water (5mL) was slowly added dropwise to 3- (methylthio) -1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid methyl ester (4.70g,16.07mmol) in MeOH (30mL) was reacted overnight at room temperature. After completion of the reaction, MeOH was removed by concentration under reduced pressure, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the residue obtained by distillation under reduced pressure was separated by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 8/1), purification afforded 3.40g of a light yellow solid, yield: 76 percent.
MS(ESI,pos.ion)m/z:279.1[M+1]+.
And 4, step 4: synthesis of Compound 1- (3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carbonyl) pyrrolidine-3-carbonitrile
Oxalyl chloride (1.82g,14.37mmol) was slowly added dropwise to 3-methylsulfanyl-1- (7H-pyrrolo [2,3-d ] at 0 deg.C]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (80mg,0.29mmol) in anhydrous DCM (5mL) with 2 drops of DMF as catalyst, slowly warmed to room temperature after the addition, stirred at room temperature for reaction for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in anhydrous DCM (5mL), to which cyanocyclopentane hydrochloride (37mg,0.29mmol) and triethylamine (145mg,1.44mmol) in anhydrous DCM (5mL) were slowly added dropwise at 0 deg.C, and slowly warmed to room temperature after the addition, and the reaction was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 18/1), purification afforded 30mg of white solid, yield: 29 percent.
MS(ESI,pos.ion)m/z:357.2[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)11.65(s,1H),8.11(s,1H),7.15(s,1H),6.58(s,1H),3.69-4.20(m,8H),3.55(s,1H),2.55(s,1H),2.13-2.35(m,3H),2.03(s,3H).
Example 182- (1- (3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carbonyl) pyrrolidin-3-yl) acetonitrile
Figure BDA0000892466340000561
Step 1: synthesis of Compound 2- (pyrrolidin-3-yl) acetonitrile trifluoroacetate
Trifluoroacetic acid (542mg,4.75mmol) was slowly added dropwise to a solution of tert-butyl 3-cyanomethylpyrrolidine-1-carboxylate (100mg,0.48mmol) in DCM (5mL) at 0 ℃ and the temperature was slowly raised to room temperature after the addition of the dropwise thereto, followed by stirring at room temperature for 5 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 110mg of a yellow-brown liquid, which was used in the next reaction without purification.
MS(ESI,pos.ion)m/z:111.2[M+1]+.
Step 2: synthesis of Compound 2- (1- (3- (methylthio) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carbonyl) pyrrolidin-3-yl) acetonitrile
Oxalyl chloride (1.60g,12.60mmol) was slowly added dropwise to 3-methylsulfanyl-1- (7H-pyrrolo [2,3-d ] at 0 deg.C]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (70mg,0.25mmol) in anhydrous DCM (3mL) with 2 drops of DMF as catalyst, slowly warmed to room temperature after the addition, stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give a residue, which was dissolved in anhydrous DCM (3mL), and a solution of 2- (pyrrolidin-3-yl) acetonitrile trifluoroacetate salt (82.00mg,0.75mmol) and triethylamine (204mg,2.02mmol) in anhydrous DCM (5mL) was slowly added dropwise at 0 ℃ and slowly warmed to room temperature after the addition was completed, and the reaction was stirred at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 40mg of white solid, yield: and 43 percent. MS (ESI, pos. ion) M/z 371.2[ M + 1]]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.19(s,1H),8.32(s,1H),7.10(d,J＝3.4Hz,1H),6.60(d,J＝3.3Hz,1H),4.07-4.23(m,5H),3.62-3.84(m,3H),2.48-2.67(m,7H),2.11(d,J＝1.8Hz,3H).
Example 19N- (cyanomethyl) -3-fluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Figure BDA0000892466340000571
Step 1: synthesis of compound 1-benzyl-3-fluoropyrrolidine-3-methyl formate
Trifluoroacetic acid (0.30g,2.59mmol) was slowly added dropwise to a solution of methyl 2-fluoroacrylate (1.50g,14.41mmol) and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (3.80g,16.00mmol) in DCM (20mL) at 0 deg.C, after dropwise addition, the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature for 12 h. After completion of the reaction, concentration was performed under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), and purified to obtain 2.59g of a colorless liquid, yield: 76 percent.
MS(ESI,pos.ion)m/z:238.2[M+1]+.
Step 2: synthesis of compound 3-fluoropyrrolidine-3-methyl formate
Pd/C (10%, 0.52g) was added to a solution of methyl 1-benzyl-3-fluoropyrrolidine-3-carboxylate (2.59g,10.91mmol) in MeOH (30mL), H2And reacting at room temperature for 8h under the atmosphere. After the reaction, the solid was filtered off, and the filtrate was concentrated under reduced pressure to give 1.54g of a colorless liquid, which was directly charged into the next step without further purification.
MS(ESI,pos.ion)m/z:148.1[M+1]+.
And step 3: synthesis of compound methyl 3-fluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylate
Triethylamine (1.24g,12.23mmol) was added to a solution of methyl 3-fluoropyrrolidine-3-carboxylate (0.60g,4.08mmol) and 4-chloropyrrolopyrimidine (0.75g,4.89mmol) in isopropanol (10mL), and the reaction was heated at 80 ℃ overnight. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 25/1), and purified to obtain 680mg of a white solid, yield: and 63 percent.
MS(ESI,pos.ion)m/z:265.1[M+1]+.
And 4, step 4: synthesis of compound 3-fluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid
A solution of NaOH (0.294g,12.27mmol) in water (1mL) was added dropwise to 3-fluoro-1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid methyl ester (0.670g,2.54mmol) in MeOH (15mL) and reacted overnight at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the residue obtained by distillation under reduced pressure was separated by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 8/1), purification afforded 0.61g of a white solid, yield: 97 percent.
MS(ESI,pos.ion)m/z:251.1[M+1]+.
And 5: synthesis of compound N- (cyanomethyl) -3-fluoro-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Triethylamine (0.49g,4.79mmol) was added to 3-fluoro-1- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (0.20g,0.80mmol), HOBT (0.216g,1.60mmol), EDCI (0.31g,1.60mmol) and aminoacetonitrile hydrochloride (0.11g,1.19mmol) in DMF (10mL) were reacted at room temperature overnight. After the reaction was complete, the reaction was quenched by addition of water (10mL), extracted with dichloromethane (20 mL. times.2), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 85mg of a white solid, yield: 37 percent.
MS(ESI,pos.ion)m/z:289.1[M+1]+；
1H NMR(600MHz,DMSO-d6):δ(ppm)11.69(s,1H),9.29(t,J＝4.7Hz,1H),8.13(s,1H),7.16-7.17(m,1H),6.61-6.62(m,1H),4.25(d,J＝5.5Hz,2H),4.12-4.22(m,3H),3.87(s,1H),2.54-2.62(m,1H),2.40-2.46(m,1H).
Example 20N- (cyanomethyl) -3- (hydroxymethyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Figure BDA0000892466340000581
Step 1: synthesis of methyl 2- (((tert-butyldimethylsilyl) oxy) meth) acrylate, a compound
Tert-butyldimethylsilyl chloride (4.14g,27.47mmol) was added to a solution of ethyl 2-hydroxymethylacrylate (3.19g,27.47mmol) and imidazole (1.87g,27.47mmol) in anhydrous DMF (25mL) and reacted at room temperature overnight. After the reaction is finished, H is added2Quenched with O (15mL), extracted with dichloromethane (40 mL. times.2), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1), purified to give 3.64g of a colorless liquid, yield: 58 percent.
MS(ESI,pos.ion)m/z:231.1[M+1]+.
Step 2: synthesis of Compound methyl 1-benzyl-3- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidine-3-carboxylate
After TFA (324mg,2.84mmol) was added dropwise to a solution of methyl 2- (((tert-butyldimethylsilyl) oxy) methyl) acrylate (3.64g,15.80mmol) and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (4.16g,17.54mmol) in DCM (20mL) at 0 deg.C, the temperature was slowly raised to room temperature and the reaction was allowed to proceed at room temperature overnight. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), and purified to obtain 3.28g of a colorless liquid, yield: 57 percent.
MS(ESI,pos.ion)m/z:364.2[M+1]+.
And step 3: synthesis of Compound methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidine-3-carboxylate
Palladium on carbon (10%, 280mg) was added to a solution of methyl 1-benzyl-3- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidine-3-carboxylate (1.40g,3.85mmol) in anhydrous MeOH (20mL) in H2The reaction was carried out overnight at room temperature under ambient conditions. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.05g of a colorless liquid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:274.2[M+1]+.
Step 4 Synthesis of Compound methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylate
Triethylamine (1.55g,15.36mmol) was added to a solution of methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) pyrrolidine-3-carboxylate (1.05g,3.84mmol) and 4-chloropyrrolopyrimidine (884mg,5.76mmol) in DMF (14mL) and reacted at 80 ℃ overnight. After the reaction is finished, H is added2Quenched with O (10mL), extracted with ethyl acetate (20 mL. times.2), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtration and concentration under reduced pressure, the residue obtained was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) and purified to give 1.31g of a white solid, yield: 87 percent.
MS(ESI,pos.ion)m/z:391.2[M+1]+.
And 5: synthesis of the Compound 3- (((tert-butyldimethylsilyl) oxy) methyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylic acid
A solution of sodium hydroxide (409mg,10.24mmol) in water (1mL) was added to a solution of methyl 3- (((tert-butyldimethylsilyl) oxy) methyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxylate (400mg,1.02mmol) in MeOH (8mL) and reacted overnight at room temperature. After the reaction, the pH was adjusted to about 6 with concentrated hydrochloric acid, and the mixture was distilled under reduced pressure to obtain 400mg of a white solid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:377.2[M+1]+.
Step 6: synthesis of the compound 3- (((tert-butyldimethylsilyl) oxy) methyl) -N- (cyanomethyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Oxalyl chloride (3.37g,26.56mmol) was added dropwise to 3- (((tert-butyldimethylsilyl) oxy) methyl) -1- (7H-pyrrolo [2,3-d ] at 0 deg.C]Pyrimidin-4-yl) pyrrolidine-3-carboxylic acid (200mg,0.53mmol) in anhydrous DCM (5mL) with 2 drops of DMF as catalyst, slowly warmed to room temperature after the addition, stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in anhydrous DCM (5mL), and aminoacetonitrile hydrochloride (72mg,0.80mmol) and triethylamine (3) were slowly added dropwise thereto at 0 deg.C22mg,3.19mmol) in dry DCM (5mL) and slowly warmed to room temperature over the addition of dropwise, stirring the reaction at room temperature overnight. After completion of the reaction, saturated brine (10mL) was added and the organic layer was washed with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 110mg of a light yellow solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:415.3[M+1]+.
And 7: synthesis of compound N- (cyanomethyl) -3- (hydroxymethyl) -1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-3-carboxamide
Tetrabutylammonium fluoride (1M,0.32mL,0.32mmol) was slowly added dropwise to 3- (((tert-butyldimethylsilyl) oxy) methyl) -N- (cyanomethyl) -1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) pyrrolidine-3-carboxamide (110mg,0.27mmol) in THF (5mL) was reacted at room temperature for 8 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 18mg of white solid, yield: 23 percent.
MS(ESI,pos.ion)m/z:301.2[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.09(s,1H),7.10(d,J＝3.5Hz,1H),6.70(d,J＝2.6Hz,1H),4.17-4.24(m,3H),3.91(s,3H),3.78(q,J＝11.2Hz,2H),2.40(s,1H),2.22(m,1H).
Example 214- (2, 6-diazaspiro [3.4] octan-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
Figure BDA0000892466340000591
Step 1: synthesis of Compound 6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
Potassium carbonate (779mg,5.64mmol) was added to 2, 6-diazaspiro [3.4]]octane-2-Carbonic acid tert-butyl ester (400mg,1.88mmol) in N, N-dimethylacetamide (15mL) was reacted by heating at 45 ℃ for 0.5 hour, followed by addition of 4-chloropyrrolopyrimidine (374mg, 2.4)4mmol), the reaction was heated at 95 ℃ for 6 hours. After completion of the reaction, water (30mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), purification afforded 524mg of white solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:330.3[M+1]+.
Step 2: synthesis of compound 4- (2, 6-diazaspiro [3.4] octane-6-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
An ethyl acetate solution of hydrogen chloride (4.0M,8mL) was added dropwise to a solution of tert-butyl 6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octane-2-carbonate (500mg,1.52mmol) in ethyl acetate (16mL) at room temperature, and the reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 542.51mg of a white solid, yield: 99 percent.
MS(ESI,pos.ion)m/z:230.2[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)7.83(s,1H),7.00(d,J＝3.6Hz,1H),6.41(d,J＝3.2Hz,1H),3.68-3.88(m,8H),2.20(s,2H).
Example 223- (6- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-2-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000601
N, N-diisopropylethylamine (147mg,1.14mmol) was added to 4- (2, 6-diazaspiro [3.4]]Octane-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (172mg,0.57mmol) and 1-cyanoacetyl-3, 5-dimethylpyrazole (140mg,0.86mmol) in 1, 4-dioxane (3mL) were reacted by heating at 100 ℃ for 2.5 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 78.3mg of white solid, yield: 46 percent.
MS(ESI,pos.ion)m/z:297.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.61(s,1H),8.09(s,1H),7.13(t,J＝4.0Hz,1H),6.59(s,1H),4.09-4.19(m,2H),3.88-3.98(m,4H),3.70-3.79(m,4H),2.20(s,2H).
Example 234- (2, 7-diazaspiro [4.4] nonan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
Figure BDA0000892466340000602
Step 1: synthesis of compound t-butyl 7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate
Potassium carbonate (734mg,5.31mmol) was added to 2, 7-diazaspiro [4.4]]Nonane-2-carboxylic acid tert-butyl ester (400mg,1.77mmol) in N, N-dimethylacetamide (15mL) was heated at 45 ℃ for 0.5 hours, followed by addition of 4-chloropyrrolopyrimidine (353mg,2.30mmol) and heating at 95 ℃ for 6 hours. After completion of the reaction, water (30mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), purification afforded 596.43mg of white solid, yield: 98 percent.
MS(ESI,pos.ion)m/z:344.3[M+1]+.
Step 2: synthesis of compound 4- (2, 7-diazaspiro [4.4] nonan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
A solution of hydrogen chloride in ethyl acetate (4.0M,8mL) was added dropwise to a solution of tert-butyl 7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (500mg,1.46mmol) in ethyl acetate (16mL) at room temperature and the reaction was heated at 65 ℃ for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain 519mg of a white solid, yield: 99 percent.
MS(ESI,pos.ion)m/z:244.20[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.10(s,1H),7.11(d,J＝4Hz,1H),6.71(d,J＝4Hz,1H),3.82-3.94(m,4H),3.18-3.22(m,2H),3.02-3.10(m,2H),2.12-2.13(m,2H),1.95-2.03(m,2H).
Example 243- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000611
N, N-diisopropylethylamine (886mg,6.86mmol) was slowly added dropwise to 4- (2, 7-diazaspiro [4.4] at 0 deg.C]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (309.91mg,0.98mmol) in DMF (7mL) was reacted with stirring at 0 ℃ for 0.5 hours, cyanoacetic acid (166mg,1.96mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (745mg,1.96mmol) were added in that order, and the reaction mixture was reacted with stirring at room temperature for 30 hours. After completion of the reaction, the reaction was quenched by addition of water (20mL), extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 77.1mg of white solid, yield: 25 percent.
MS(ESI,pos.ion)m/z:311.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.58(s,1H),8.08(t,J＝2.4Hz,1H),7.12(t,J＝2.8Hz,1H),6.59(t,J＝1.6Hz,1H),3.93(d,J＝14.0Hz,2H),3.67-3.84(m,4H),3.55(t,J＝7.0Hz,1H),3.38-3.49(m,3H),1.88-2.00(m,4H).
Example 254- (2, 7-diazaspiro [4.5] decan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Figure BDA0000892466340000612
Step 1: synthesis of compound 7-benzyloxycarbonyl-2-tert-butoxycarbonyl-2, 7-diazaspiro [4.5] decane
To tert-butyl 2, 7-diazaspiro [4.5] decane-2-carboxylate oxalate (300mg,1.05mmol) were added tetrahydrofuran (5mL), water (2mL), potassium carbonate (363.2mg,2.63mmol) and benzyl chloroformate (224 μ L,1.57mmol) in this order at room temperature, stirred at room temperature for 4h, quenched by addition of saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15mL × 3), dried over anhydrous sodium sulfate, concentrated for column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give 320mg of a white solid, yield: 81 percent.
MS(ESI,pos.ion)m/z:319.2[M-t-Bu+2]+.
Step 2: synthesis of compound 2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decane-7-benzyloxycarbonyl
Reacting 7-benzyloxycarbonyl-2-tert-butoxycarbonyl-2, 7-diazaspiro [4.5] at room temperature]Decane (320mg,0.86mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (0.5mL) was added, stirring was carried out at room temperature for 4h, after the reaction was completed, concentration was carried out directly to obtain a pale yellow oil, and N, N-dimethylacetamide (6mL), potassium carbonate (475.7mg,3.42mmol) and 4-chloropyrrolo [2,3-d ] were added in this order]Pyrimidine (156.98mg,1.03mmol), reacted at 90 ℃ for 8h, quenched by addition of saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15 mL. times.3), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: CH: eluent: C)2Cl2MeOH (v/v) ═ 30/1), yielding 325mg of a light yellow solid, yield: 97 percent.
MS(ESI,pos.ion)m/z:392.2[M+1]+.
And step 3: synthesis of compound 4- (2, 7-diazaspiro [4.5] decan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Reacting 2- (7H-pyrrolo [2,3-d ] at room temperature]Pyrimidin-4-yl) -2, 7-diazaspiro [4.5]Decane-7-benzyloxycarbonyl (325mg,0.83mmol) was dissolved in methanol (6mL), palladium on carbon (10%, 88.6mg) was added, the reaction was carried out at 50 ℃ for 10 hours, and after the completion of the reaction, filtration and concentration were carried out to obtain a pale yellow oily substance, which was subjected to column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), yielding 230mg of white solid, yield: 99 percent.
MS(ESI,pos.ion)m/z:258.3[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)10.07(s,br,1H),8.29(s,1H),7.01(d,J＝4.0Hz,1H),6.59(d,J＝4.0Hz,1H),3.85(m,3H),3.57(m,1H),3.49(s,1H),2.71-2.87(m,4H),2.03(m,1H),1.83(m,1H),1.61(m,4H).
Example 263- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decan-7-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000621
4- (2, 7-diazaspiro [4.5] decan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine (100mg,0.40mmol) was dissolved in N, N-dimethylformamide (6mL) at room temperature, HOBT (81mg,0.60mmol), EDCI (115mg,0.6mmol) and cyanoacetic acid (51mg,0.60mmol) were added in this order, reacted at room temperature for 18H, quenched with saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15 mL. times.3), dried over anhydrous sodium sulfate, concentrated, and chromatographed to give 47mg of a white solid, yield: 37 percent.
MS(ESI,pos.ion)m/z:325.1[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)8.08(s,1H),7.09and 7.12(d,J＝4Hz,1H),6.69and 6.72(d,J＝4Hz,1H),4.0(s,2H),3.85(m,1H),3.77(m,1H),3.60(m,3H),3.50(m,2H),3.39(m,1H),1.79(m,6H).
Example 274- (2, 7-diazaspiro [4.5] decan-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
Figure BDA0000892466340000622
Step 1: synthesis of Compound 7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decane-2-carboxylic acid tert-butyl ester
To 2, 7-diazaspiro [4.5] at room temperature]Decane-2-carboxylic acid tert-butyl ester oxalate (200mg,0.70mmol) was added to N, N-dimethylacetamide (6mL), potassium carbonate (463.68mg,3.36mmol) and 4-chloropyrrolo [2,3-d ] in this order]Pyrimidine (128.84mg,0.84mmol), reacted at 90 ℃ for 8h, quenched by addition of saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15 mL. times.3), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: CH: chromatography)2Cl2MeOH (v/v) ═ 30/1), yielding 234mg of a light yellow oil, yield: 94 percent.
MS(ESI,pos.ion)m/z:358.3[M+1]+.
Step 2: synthesis of Compound 4- (2, 7-diazaspiro [4.5] decan-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride
Reacting 7- (7H-pyrrolo [2,3-d ] at room temperature]Pyrimidin-4-yl) -2, 7-diazaspiro [4.5]decane-2-Carbonic acid tert-butyl ester (234mg,0.66mmol) was dissolved in dichloromethane (3mL), a solution of hydrogen chloride in ethyl acetate (4M, 819. mu.L, 3.27mmol) was added, the reaction was carried out at room temperature for 3 hours, after the completion of the reaction, a white solid was obtained by concentration, neutralized with a saturated solution of sodium hydrogencarbonate (5mL), concentrated with silica gel and sample-stirred, and subjected to column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), yielding 144mg of a white solid, yield: 86 percent.
MS(ESI,pos.ion)m/z:258.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.13(s,1H),7.18(d,J＝4Hz,1H),6.70(d,J＝4Hz,1H),3.95-3.99(m,4H),3.46(m,2H),3.37(m,1H),3.08(m,1H),1.68-2.06(m,6H).
Example 283- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decan-2-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000631
4- (2, 7-diazaspiro [4.5] decan-7-yl) -7H-pyrrolo [2,3-d ] pyrimidine dihydrochloride (120mg,0.47mmol) was dissolved in N, N-dimethylformamide (5mL) at room temperature, HOBT (95.85mg,0.71mmol), EDCI (136.11mg,0.71mmol), cyanoacetic acid (60mg,0.71mmol) and triethylamine (98.8. mu.L, 0.71mmol) were added in this order, reacted at room temperature for 18H, quenched with saturated aqueous ammonium chloride (10mL), extracted with dichloromethane (15 mL. times.3), dried over anhydrous sodium sulfate, concentrated, and chromatographed to give 50mg of a white solid, yield: 33 percent.
MS(ESI,pos.ion)m/z:325.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.12and 8.15(s,1H),7.14and 7.16(d,J＝4Hz,1H),6.55and 6.60(d,J＝4Hz,1H),4.30(m,1H),4.10(m,1H),2.97(m,1H),3.46-3.85(m,5H),3.14-3.23(m,2H),1.92(m,2H),1.82(m,4H).
Example 293- (7- (5-fluoro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000632
Step 1: synthesis of compound 4-chloro-5-fluoro-7H-pyrrolo [2,3-d ] pyrimidine
4-chloropyrrolo [2,3-d ] pyrimidine (153mg,1.0mmol) was dissolved in acetonitrile (7.5mL) at room temperature, acetic acid (1.5mL) and 1-chloromethyl-4-fluoro-1, 4-diazidobicyclo [2.2.2] octane bistetrafluoroborate (531.39mg,1.5mmol) were added in this order, oil-bath reaction was carried out at 70 ℃ for 19h, the reaction was stopped, cooled to room temperature, quenched by addition of saturated sodium bicarbonate solution (10mL), ethyl acetate (15mL × 3) was extracted, dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 86mg of a gray solid, yield: 50 percent.
MS(ESI,pos.ion)m/z:172.1[M+1]+.
Step 2: synthesis of Compound 7- (5-fluoro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester
4-chloro-5-fluoro-7H-pyrrolo [2,3-d ] is reacted at room temperature]Pyrimidine (86mg,0.50mmol) was dissolved in N, N-dimethylacetamide (3mL), and 2, 7-diazaspiro [4, 4] was added sequentially]Nonane-2-carboxylic acid tert-butyl ester (49mg,0.22mmol) and potassium carbonate (89.76mg,0.66mmol) were reacted at 90 ℃ for 5h, quenched with water (6mL), extracted with dichloromethane (15 mL. times.3), and purified over anhydrous Na2SO4Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)2Cl2MeOH (v/v /) ═ 30/1) to give 59mg of yellow solid, yield: 41 percent.
MS(ESI,pos.ion)m/z:362.3[M+1]+.
And step 3: synthesis of compound 3- (7- (5-fluoro-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-carbonylpropionitrile
At room temperature, 7- (5-fluoro-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [4.4]Nonane-2-carboxylic acid tert-butyl ester (49mg,0.14 mmo)L) was dissolved in dichloromethane (5mL), trifluoroacetic acid (0.25mL) was added, and the mixture was stirred at room temperature for 5 hours and directly concentrated to give a yellow oil, N-dimethylformamide (5mL) was added to dissolve it, triethylamine (55.6 μ L,0.40mmol), EDCI (38.2mg,0.20mmol), HOBT (27mg,0.20mmol) and cyanoacetic acid (17.3mg,0.20mmol) were sequentially added, and the mixture was reacted at room temperature overnight, directly concentrated, and the solvent was removed, and the concentrate was subjected to column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 30/1), yielding 11mg of a white solid, yield: 24 percent.
MS(ESI,pos.ion)m/z:329.20[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.52(s,1H),8.10(d,J＝2.4Hz,1H),7.14(d,1H),3.92-3.96(d,2H),3.41-3.79(m,8H),1.99(m,4H).
Example 303- (7- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000641
Step 1: synthesis of Compound 7- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester
4-chloro-5-methyl-7H-pyrrolo [2,3-d ] is reacted at room temperature]Pyrimidine (80mg,0.48mmol), 2, 7-diazaspiro [4.4]]Tert-butyl nonane-2-carboxylate (90mg,0.40mmol) and potassium carbonate (166mg,1.20mmol) were added to N, N-dimethylacetamide (5mL) and heated at 90 ℃ for reaction overnight. Cooling to room temperature, quenching with water (50mL), extracting with ethyl acetate (50 mL. times.3), drying the organic layer with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the concentrated solution by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 142mg of a white solid, yield: 100 percent.
MS(ESI,pos.ion)m/z:358.3[M+1]+.
Step 2: synthesis of compound 5-methyl-4- (2, 7-diazaspiro [4.4] nonan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine hydrochloride
A mixture of tert-butyl 7- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (142mg,0.40mmol) and ethyl acetate (3mL) was stirred in an ice bath for 15 minutes, cooled thoroughly, and a solution of hydrogen chloride in ethyl acetate (4M,4mL) was slowly added dropwise, stirred in an ice bath for 30 minutes, and stirred at room temperature for 6.5 hours. Concentration under reduced pressure gave 130mg of a white solid which was used directly in the next reaction.
And step 3: synthesis of compound 3- (7- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-carbonylpropionitrile
Reacting 5-methyl-4- (2, 7-diazaspiro [4.4] at room temperature]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (132mg,0.40mmol) was dissolved in N, N-dimethylformamide (6mL), hydroxybenzotriazole (81mg,0.60mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (115mg,0.60mmol), cyanoacetic acid (51mg,0.6mmol) and triethylamine (1.60mmol,0.22mL) were sequentially added thereto, reacted overnight at room temperature, quenched with water (50mL), extracted with dichloromethane (50 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column chromatography (eluent: CH: eluent: 50 mL. times.3)2Cl2MeOH (v/v) ═ 15/1), yielding 67mg of a white solid, which was then separated by preparative thin layer chromatography (developing solvent: CH (CH)2Cl2MeOH (v/v) ═ 12/1), yielding 59mg of a white solid, two-step overall yield: 46 percent.
MS(ESI,pos.ion)m/z:325.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.14-8.04(m,1H),8.04-7.92(m,2H),7.78-7.66(m,2H),7.22-6.96(m,1H),6.77-6.59(m,1H),3.85-3.48(m,6H),2.17-2.02(m,3H),1.41-1.29(m,3H).
Example 314- (2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -2-oxoethyl) benzonitrile
Figure BDA0000892466340000651
4- (2, 7-diazaspiro [4.4] at room temperature]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (82mg,0.26mmol) was dissolved in N, N-dimethylformamide (6mL), and 1-hydroxybenzotriazole (53mg,0.39mmol) was added in sequencel), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75mg,0.39mmol), 4-cyanophenylacetic acid (63mg,0.39mmol) and triethylamine (1.04mmol,0.15mL) were reacted at room temperature for 18 hours, quenched by addition of water (50mL), extracted with dichloromethane (100mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 20/1), yielding 100mg of a white solid, yield: 98 percent.
MS(ESI,pos.ion)m/z:387.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.60(s,1H),8.09(d,J＝3.9Hz,1H),7.76(dd,J＝15.0,8.2Hz,2H),7.44(dd,J＝10.5,8.3Hz,2H),7.13(d,J＝3.1Hz,1H),6.59(d,J＝1.7Hz,1H),3.79(s,1H),3.75(s,1H),3.68(t,J＝6.7Hz,2H),3.44(dt,J＝18.5,7.0Hz,2H),1.95(dd,J＝21.0,13.8Hz,4H),1.24(s,4H).
Example 324- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carbonyl) benzenesulfonamide
Figure BDA0000892466340000652
4- (2, 7-diazaspiro [4.4] at room temperature]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (82mg,0.26mmol) is dissolved in N, N-dimethylformamide (6mL), 1-hydroxybenzotriazole (53mg,0.39mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (75mg,0.39mmol), 4-p-carboxybenzenesulfonamide (79mg,0.39mmol) and triethylamine (1.04mmol,0.15mL) are added in sequence, the mixture is reacted at room temperature overnight, water (10mL) is added for quenching, dichloromethane (50 mL. times.3) is used for extraction, anhydrous sodium sulfate is dried, reduced pressure concentration is carried out, and column chromatography separation is carried out on the concentrated solution (eluent: CH: eluent: C, N-dimethylformamide)2Cl2MeOH (v/v) ═ 15/1), yielding 88mg of a white solid, yield: 80 percent.
MS(ESI,pos.ion)m/z:427.2[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.14-8.04(m,1H),8.04-7.92(m,2H),7.78-7.66(m,2H),7.22-6.96(m,1H),6.77-6.59(m,1H),3.85-3.48(m,6H),2.17-2.02(m,3H),1.41-1.29(m,3H).
Example 333- (2- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decan-7-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000653
Step 1: synthesis of Compound 2, 7-diazaspiro [4.5] decane-7-benzyloxycarbonyl-2-carboxylic acid tert-butyl ester
Mixing 2, 7-diazaspiro [4.5]]Tert-butyl decane-2-carboxylate oxalate (400mg,1.40mmol) and potassium carbonate (1.16g,8.40mmol) were dissolved in a mixed solvent of THF (15mL) and water (3mL), followed by addition of benzyl chloroformate (1.43g,8.40mmol), and the mixture was stirred at room temperature for 8 hours. After the reaction is finished, adding saturated NaHCO into the reaction liquid3The reaction was quenched with solution (20mL), extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1), purified to give 445.6mg of a colorless liquid, yield: 85 percent.
MS(ESI,pos.ion)m/z:319.3[M-t-Bu+2]+.
Step 2: synthesis of compound 2, 7-diazaspiro [4.5] decane-7-carboxylic acid benzyl ester hydrochloride
A solution of hydrogen chloride in ethyl acetate (4M,20mL) was added dropwise to tert-butyl 2, 7-diazaspiro [4.5] decane-7-benzyloxycarbonyl-2-carboxylate (445.6mg,1.19mmol) at room temperature, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 847.9mg of a colorless liquid, which was used in the next reaction without purification.
MS(ESI,pos.ion)m/z:275.2[M+1]+.
And step 3: synthesis of benzyl 2- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decane-7-carboxylate, a compound
Potassium carbonate (497.6mg,3.60mmol) was added to 2, 7-diazaspiro [4.5]]decane-7-Carboxylic acid benzyl ester hydrochloride (225.0mg,0.72mmol) in DMAC (8mL) was reacted by heating at 45 ℃ for 0.5 hour, followed by addition of 4-chloropyrrolopyrimidine (157.5mg,0.94mmol) and reaction at 90 ℃ for 7.5 hoursThen (c) is performed. After completion of the reaction, water (20mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 110.9mg white solid, yield: 38 percent.
MS(ESI,pos.ion)m/z:406.2[M+1]+.
And 4, step 4: synthesis of compound 5-methyl-4- (2, 7-diazaspiro [4.5] decan-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Palladium on carbon (10%, 77.0mg) was added to 2- (5-methyl-7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) -2, 7-diazaspiro [4.5]Benzyl decane-7-carboxylate (110.9mg,0.27mmol) in MeOH (6mL) in H2The reaction was heated to 45 ℃ in the atmosphere for 17 hours. After the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure to obtain 62.0mg of a white solid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:272.1[M+1]+.
And 5: synthesis of the compound 3- (2- (5-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.5] decan-7-yl) -3-carbonylpropionitrile
Reacting 5-methyl-4- (2, 7-diazaspiro [4.5]]Decan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine (62.0mg,0.23mmol), cyanoacetic acid (39.1mg,0.46mmol) and HATU (174.9mg,0.46mmol) were dissolved in DMF (5mL) and N, N-diisopropylethylamine (89.2mg,0.69mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, water (20mL) was added to the reaction solution to quench the reaction, ethyl acetate (20 mL. times.3) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), yielding 18.5mg of a white solid, yield: 24 percent.
MS(ESI,pos.ion)m/z:339.3[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.35(s,1H),8.07(s,1H),6.98(s,1H),4.09(d,J＝4.5Hz,1H),3.74-3.84(m,3H),3.40-3.53(m,6H),2.31-2.35(m,3H),1.87(s,1H),1.54-1.69(m,5H).
Example 343- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000671
Step 1: synthesis of compound 2, 6-diazaspiro [3.4] octane-6-benzyloxycarbonyl-2-carboxylic acid tert-butyl ester
Mixing 2, 6-diazaspiro [3.4]]Octane-2-carboxylic acid tert-butyl ester (160mg,0.75mmol) and potassium carbonate (207.3mg,1.50mmol) were dissolved in a mixed solvent of THF (8mL) and water (2mL), followed by addition of benzyl chloroformate (192.8mg,1.13mmol), and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, water (10mL) was added to the reaction solution to quench the reaction, ethyl acetate (15 mL. times.3) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1), purified to give 209.1mg of a colorless liquid, yield: 80 percent.
MS(ESI,pos.ion)m/z:291.2[M-(t-Bu)+2]+.
Step 2: synthesis of compound 2, 6-diazaspiro [3.4] octane-6-benzyl formate hydrochloride
An ethyl acetate solution of hydrogen chloride (4M,4mL) was added dropwise to a solution of tert-butyl 2, 6-diazaspiro [3.4] octane-6-benzyloxycarbonyl-2-carboxylate (209mg,0.60mmol) in ethyl acetate (3mL) at room temperature, and the reaction was stirred at room temperature for 4 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 218.8mg of a colorless liquid, which was used in the next reaction without purification.
MS(ESI,pos.ion)m/z:247.3[M+1]+.
And step 3: synthesis of benzyl 2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octane-6-carboxylate, a compound
Potassium carbonate (497.6mg,3.60mmol) was added to 2, 6-diazaspiro [3.4]]octane-6-Carboxylic acid benzyl ester hydrochloride (218.8mg,0.77mmol) in N, N-dimethylacetamide (10mL) was reacted by heating at 45 ℃ for 0.5 hour, followed by addition of4-Chloropyrrolopyrimidine (119.8mg,0.78mmol) was added and the reaction was heated at 95 ℃ for 6 hours. After completion of the reaction, water (20mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 18/1), purification afforded 191.1mg of white solid, yield: 88 percent.
MS(ESI,pos.ion)m/z:364.2[M+1]+.
And 4, step 4: synthesis of compound 4- (2, 6-diazaspiro [3.4] octane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Palladium on carbon (10%, 37.6mg) was added to 2- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) -2, 6-diazaspiro [3.4]Benzyl octane-6-carboxylate (188mg,0.52mmol) in MeOH (10mL) in H2The reaction was heated to 45 ℃ for 5 hours in the atmosphere. After the reaction, filtration was carried out, and the filtrate was concentrated under reduced pressure to obtain 185.3mg of a pale yellow solid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:230.2[M+1]+.
And 5: synthesis of compound 3- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 6-diazaspiro [3.4] octan-6-yl) -3-carbonylpropionitrile
N, N-diisopropylethylamine (76.3mg,0.59mmol) was added to 4- (2, 6-diazaspiro [3.4]]Octane-6-yl) -7H-pyrrolo [2,3-d]Pyrimidine (90.0mg,0.39mmol) and 1-cyanoacetyl-3, 5-dimethylpyrazole (96.3mg,0.59mmol) in 1, 4-dioxane (8mL) were reacted by heating at 100 ℃ for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 31.4mg of white solid, yield: 27 percent.
MS(ESI,pos.ion)m/z:297.3[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.66(s,1H),8.12(m,J＝2.0Hz,1H),7.15-7.17(m,1H),6.37-6.40(m,1H),4.19-4.23(m,4H),3.95(s,2H),3.68(s,1H),3.59(s,1H),3.50(t,J＝6.9Hz,1H),3.41(t,J＝7.0Hz,1H),2.22(t,J＝6.9Hz,1H),2.13(t,J＝7.0Hz,1H).
Example 353- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 5-diazaspiro [3.4] octan-5-yl) -3-carbonylpropionitrile
Figure BDA0000892466340000681
Step 1: synthesis of compound tert-butyl 2, 5-diazaspiro [3.4] octane-5-benzyloxycarbonyl-2-carboxylate
Mixing 2, 5-diazaspiro [3.4]]Octane-2-carboxylic acid tert-butyl ester oxalate (400mg,1.55mmol) and potassium carbonate (1.29g,9.30mmol) were dissolved in a mixed solvent of THF (16mL) and water (4mL), followed by addition of benzyl chloroformate (1.59g,9.30mmol), and the mixture was stirred at room temperature for reaction for 22 hours. After completion of the reaction, water (20mL) was added to the reaction solution to quench the reaction, ethyl acetate (30 mL. times.3) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1), purified to give 353.7mg of a colorless liquid, yield: 66 percent.
MS(ESI,pos.ion)m/z:291.2[M-(t-Bu)+2]+.
Step 2: synthesis of benzyl 2, 5-diazaspiro [3.4] octane-5-carboxylate as a Compound
An ethyl acetate solution of hydrogen chloride (4M,16mL) was added dropwise to a solution of tert-butyl 2, 5-diazaspiro [3.4] octane-5-benzyloxycarbonyl-2-carboxylate (353.7mg,1.02mmol) in ethyl acetate (8mL) at room temperature, and the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 315mg of a white solid, which was used in the next reaction without purification.
MS(ESI,pos.ion)m/z:247.1[M+1]+.
And step 3: synthesis of benzyl 2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 5-diazaspiro [3.4] octane-5-carboxylate, a compound
Potassium carbonate (2.04g,3.84mmol) was added to 2, 5-diazaspiro [3.4]]Benzyl octane-5-carboxylate (315.0mg,1.28mmol) in N, N-dimethylacetamide (15mL) was heated at 45 ℃ for 0.5 hour, 4-chloropyrrolopyrimidine (254.9mg,1.66mmol) was added, and the mixture was heated at 95 ℃ for 6 hoursThen (c) is performed. After completion of the reaction, water (20mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (30 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 12/1), purification afforded 284.6mg of white solid, yield: 61 percent.
MS(ESI,pos.ion)m/z:364.2[M+1]+.
And 4, step 4: synthesis of compound 4- (2, 5-diazaspiro [3.4] octane-2-yl) -7H-pyrrolo [2,3-d ] pyrimidine
Palladium on carbon (10%, 56.9mg) was added to 2- (7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) -2, 5-diazaspiro [3.4]Benzyl octane-5-carboxylate (284.6mg,0.78mmol) in MeOH (15mL) in H2The reaction was heated to 45 ℃ in the atmosphere for 24 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 220.1mg of a white solid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:230.1[M+1]+.
And 5: synthesis of compound 3- (2- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 5-diazaspiro [3.4] octan-5-yl) -3-carbonylpropionitrile
N, N-diisopropylethylamine (620.4mg,4.80mmol) was added to 4- (2, 5-diazaspiro [3.4]]Octane-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine (220.1mg,0.96mmol) and 1-cyanoacetyl-3, 5-dimethylpyrazole (235mg,1.44mmol) in 1, 4-dioxane (8mL) were reacted by heating at 100 ℃ for 10 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 49mg of white solid, yield: 17 percent.
MS(ESI,pos.ion)m/z:297.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.66(s,1H),8.12(s,1H),7.15(s,1H),6.37(s,1H),4.88(s,2H),4.00(m,6H),2.29(m,2H),1.83(m,2H).
Example 362- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -1-acetylmorpholine
Figure BDA0000892466340000691
Step 1: synthesis of compound 2-chloro-1-acetylmorpholine
Chloroacetyl chloride (24mmol,1.92mL) was slowly added dropwise to a mixture of morpholine (20mmol,1.74mL) and triethylamine (30mmol,4.18mL) in anhydrous tetrahydrofuran (40mL) while cooling on ice for 4h and at room temperature overnight. Quenching with water (100mL), removing tetrahydrofuran under reduced pressure, extracting with dichloromethane (100mL × 3), drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 50/1), yielding 3.24g of yellow oil, yield: 100 percent.
MS(ESI,pos.ion)m/z:164.1[M+1]+.
Step 2: synthesis of compound 2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -1-acetylmorpholine
4- (2, 7-diazaspiro [4.4] at room temperature]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (95mg,0.30mmol) was dissolved in N, N-dimethylacetamide (5mL), potassium carbonate (83mg,0.60mmol) and 2-chloro-1-acetylmorpholine (98mg,0.60mmol) were added, respectively, and reacted at 90 ℃ overnight, quenched with water (50mL), extracted with dichloromethane (50 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column chromatography (eluent: CH: eluent: 1-acetylmorpholine)2Cl2MeOH (v/v) ═ 15/1) to give a white solid, which was further purified by preparative thin layer chromatography to give 50mg of a white solid, yield: 45 percent.
MS(ESI,pos.ion)m/z:371.3[M+1]+.
Example 374- (2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -2-oxoethyl) morpholin-3-one
Figure BDA0000892466340000692
Step 1: synthesis of benzyl 2- (3-oxomorpholine) acetate compound
Under the protection of nitrogen, under ice bath, the mixture is preparedSodium hydride (1.05g,26.30mmol) was added portionwise to a solution of 3-morpholinone (2.20g,22.00mmol) in N, N-dimethylformamide (22mL) and reacted at room temperature for 1 h. Benzyl 2-bromoacetate (24mmol,3.8mL) was added thereto, and the reaction mixture was stirred at room temperature for reaction for 2 hours. Quenching with water (100mL), extracting with ethyl acetate (100 mL. times.3), washing the organic layer with water (100mL) and saturated brine (100mL), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating the concentrated solution by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), yielding 3.40g of product, yield: and 63 percent.
MS(ESI,pos.ion)m/z:250.2[M+1]+.
Step 2: synthesis of Compound 2- (3-oxomorpholine) acetic acid
Palladium hydroxide on carbon (20%, 1.00g) was added to a solution of benzyl 2- (3-oxomorpholine) acetate (3.4g,13.64mmol) in methanol (50mL) at room temperature. The reaction was stirred at room temperature for 2h under hydrogen atmosphere, filtered through celite and the filtrate was concentrated under reduced pressure to give 1.70g of product, yield: 78 percent.1H NMR(400MHz,DMSO-d6):δ(ppm)4.05(d,J＝11.8Hz,4H),3.93-3.76(m,2H),3.45-3.33(m,2H).
And step 3: synthesis of the compound 4- (2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -2-oxoethyl) morpholin-3-one
4- (2, 7-diazaspiro [4.4] at room temperature]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (85mg,0.27mmol) was dissolved in N, N-dimethylformamide (5mL), 2- (3-oxomorpholine) acetic acid (65mg,0.40mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (80mg,0.40mmol), hydroxybenzotriazole (58mg,0.40mmol) and triethylamine (1.07mmol, 25. mu.L) were added, the mixture was reacted overnight at room temperature, quenched with water (50mL), extracted with dichloromethane (50 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was subjected to column chromatography (eluent: CH. times.3)2Cl2MeOH (v/v) ═ 15/1) to give a white solid, which was further purified by preparative thin layer chromatography to give 45mg of a white solid, yield: 44 percent.
MS(ESI,pos.ion)m/z:385.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.10(d,J＝2.5Hz,1H),7.15-7.06(m,1H),6.71(d,J＝3.6Hz,1H),4.30-4.23(m,1H),4.21-4.16(m,2H),3.98-3.91(m,3H),3.75-3.58(m,3H),3.55-3.46(m,3H),2.18-2.02(m,4H),1.34-1.23(m,4H).
Example 381- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) ethanone
Figure BDA0000892466340000701
Triethylamine (100mg,1.00mmol) was added to 4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (80mg,0.25mmol) and acetic anhydride (520mg,0.51mmol) in dichloromethane (6mL) were added and the reaction mixture was stirred at room temperature for 17 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 18mg of white solid, yield: 25 percent.
MS(ESI,pos.ion)m/z:286.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.11(d,J＝2.9Hz,1H),7.11(dd,J＝3.4,2.6Hz,1H),6.66(dd,J＝3.5,2.2Hz,1H),3.92(s,2H),3.74-3.78(m,2H),3.65-3.69(m,1H),3.54-3.56(m,2H),3.46(d,J＝8.9Hz,1H),3.37(s,1H),2.02-2.11(m,6H).
Example 391- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) propenone
Figure BDA0000892466340000702
Acryloyl chloride (23mg,0.21mmol) was added to 4- (2, 7-diazaspiro [4.4] at 0 deg.C]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (80mg,0.25mmol) and triethylamine (51mg,0.50mmol) in dichloromethane (8mL) was added, and the reaction mixture was stirred at room temperature for 17 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 5/1), purification afforded 22.00mg of white solid, yield: 29 percent.
MS(ESI,pos.ion)m/z:298.2[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.19(s,1H),8.24(d,J＝4.0Hz,1H),7.05(t,J＝3.6Hz,1H),6.52(d,J＝3.2Hz,1H),6.35-6.47(m,2H),5.64-5.71(m,1H),4.89(s,1H),3.96(s,1H),3.52-3.84(m,5H),3.07-3.13(m,2H),2.01-2.09(m,4H).
Example 402- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetonitrile
Figure BDA0000892466340000711
Triethylamine (77mg,0.76mmol) was added to 4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (60mg,0.19mmol) and bromoacetonitrile (30mg,0.25mmol) in MeOH (6mL) were added and the reaction mixture was stirred at room temperature for 17 h. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 45mg of white solid, yield: 84 percent.
MS(ESI,pos.ion)m/z:283.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.10(s,1H),7.10(d,J＝3.6Hz,1H),6.68(d,J＝3.6Hz,1H),3.85(s,3H),3.77(s,3H),2.76-2.89(m,3H),2.68-2.70(m,1H),1.94-2.13(m,4H).
Example 411- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -2-hydroxyacetophenone
Figure BDA0000892466340000712
4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine dihydrochloride (60mg,0.19mmol), 2-hydroxyacetic acid (24mg,0.32mmol), HOBt (51mg,0.38mmol) and EDCI (72mg,0.38mmol) were dissolved in DMF (5mL), and triethylamine (96mg,0.95mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, water (20mL) was added to the reaction solution to quench the reaction, and methylene chloride was added(20 mL. times.3) and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 12mg of white solid, yield: 21 percent.
MS(ESI,pos.ion)m/z:302.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.57(s,1H),8.07(s,1H),7.10-7.12(m,1H),6.59-6.60(m,1H),4.54-4.55(m,1H),4.01(dd,J＝21.3,5.0Hz,2H),3.84(s,1H),3.69(s,1H),3.46-3.51(m,6H),1.98-2.01(m,4H).
Example 427- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylic acid tert-butyl ester
Figure BDA0000892466340000721
Reacting 2, 7-diazaspiro [4.4] at room temperature]Tert-butyl nonane-2-carboxylate (236mg,1.05mmol) and potassium carbonate (450mg,3.20mmol) were added to N, N-dimethylacetamide (10mL), heated at 45 ℃ for reaction for 0.5h, cooled to room temperature, and then 4-chloropyrrolopyrimidine (250mg,1.60mmol) was added, and the mixture was heated at 95 ℃ with stirring for reaction for 12 h. Cooling to room temperature, quenching the reaction with water (50mL), extracting with dichloromethane (100 mL. times.3), drying the organic layer over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 270mg of a white solid, yield: 75 percent.
MS(ESI,pos.ion)m/z:344.3[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.57(s,1H),8.08(s,1H),7.11(s,1H),6.59(s,1H),3.76(d,J＝57.8Hz,6H),3.27(d,J＝7.1Hz,2H),1.94(d,J＝34.7Hz,5H),1.41(d,J＝7.1Hz,9H).
Example 431- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3, 3-dimethylbut-1-one
Figure BDA0000892466340000722
4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine trifluoroacetate (60mg,0.13mmol), 3-dimethyl-1-butanoic acid (22mg,0.19mmol), HOBt (34mg,0.26mmol) and EDCI (48mg,0.26mmol) were dissolved in DMF (5mL), and triethylamine (51mg,0.51mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched by addition of water (20mL), extracted with dichloromethane (20 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 38.50mg of white solid, yield: 89 percent. MS (ESI, pos.ion) M/z 342.2[ M + 1]]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.58(s,1H),8.08(s,1H),7.11(s,1H),6.58(s,1H),3.57-3.84(m,5H),3.40-3.50(m,3H),2.14(d,J＝12.1Hz,2H),1.84-1.97(m,4H),1.00(d,J＝10.8Hz,9H).
Example 442- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- (2,2, 2-trifluoroethyl) propionamide
Figure BDA0000892466340000723
Step 1: synthesis of the Compound Ethyl 2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) propionate
Ethyl 2-bromoacetate (54mg,0.30mmol) was added to 4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine trifluoroacetate (102mg,0.22mmol) and triethylamine (87mg,0.09mmol) in DCM/DMF (9mL, v/v. 8/1) were mixed and reacted at rt overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 43.10mg of a light yellow solid, yield: 58 percent.
MS(ESI,pos.ion)m/z:344.20[M+1]+.
Step 2: synthesis of the compound 2- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- (2,2, 2-trifluoroethyl) propionamide
NaOH (52mg,1.30mmol) in water (0.5mL) was added to 2- (7- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -2, 7-diazaspiro [4.4]Nonan-2-yl) propionic acid ethyl ester (43mg,0.13mmol) in THF (5mL) was reacted at room temperature for 24 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in DMF (8mL), and 2,2, 2-trifluoroethylamine hydrochloride (3mg,0.25mmol), HOBt (34mg,0.25mmol), EDCI (48mg,0.25mmol) and triethylamine (76mg,0.75mmol) were added in this order, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched by addition of water (20mL), extracted with dichloromethane (20 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 8mg of white solid, yield: 16 percent.
MS(ESI,pos.ion)m/z:397.2[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.09(s,1H),7.10(d,J＝2.7Hz,1H),6.70(d,J＝3.3Hz,1H),3.84-4.00(m,4H),3.67-3.70(m,2H),3.21(q,J＝7.3Hz,1H),3.05-3.06(m,1H),2.75-2.82(m,2H),2.65-2.66(m,1H),2.05-2.13(m,2H),1.91-1.97(m,2H),1.30-1.35(m,3H).
Example 45N- (4- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -4-oxobutyl) acetamide
Figure BDA0000892466340000731
Step 1: synthesis of compound 4-acetamido butyric acid
Acetic anhydride (79mg,0.78mmol) was added to a solution of 4-aminobutyric acid (80mg,0.78mmol) in methanol (4mL) and reacted at room temperature overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: CH) 2Cl2MeOH (v/v) ═ 20/1), purification afforded 60mg of white solid, yield: 53 percent.
MS(ESI,pos.ion)m/z:146.2[M+1]+.
Step 2: synthesis of the Compound N- (4- (7- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) -4-oxobutyl) acetamide
4- (2, 7-diazaspiro [4.4]]Nonan-2-yl) -7H-pyrrolo [2,3-d]Pyrimidine trifluoroacetate (52mg,0.11mmol), 4-acetamidobutyric acid (32mg,0.22mmol), HOBT (29mg,0.22mmol) and EDCI (42mg,0.22mmol) were dissolved in DMF (5mL) and triethylamine (44mg,0.44mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was quenched by addition of water (20mL), extracted with dichloromethane (20 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 14mg of white solid, yield: 34 percent. MS (ESI, pos. ion) M/z 371.2[ M +1 ]]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.12(d,J＝2.1Hz,1H),7.16(d,J＝2.9Hz,1H),6.76(t,J＝3.7Hz,1H),3.49-3.71(m,7H),3.20-3.25(m,2H),2.37-2.43(m,2H),2.03-2.15(m,5H),1.95(d,J＝21.1Hz,3H),1.80-1.84(m,2H).
Example 462- (6-carbonyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) acetonitrile
Figure BDA0000892466340000741
Step 1: synthesis of the compound 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine
Sodium hydride (60%, 5.08g,127mmol) was added portionwise to 4-chloro-7H-pyrrolo [2,3-d ] at-5 deg.C]After pyrimidine (15g,97.67mmol) in anhydrous DMF (30mL) and stirring the reaction solution at the temperature for 2.5h, 2- (trimethylsilyl) ethoxymethyl chloride (19.54g,117.21mmol) was slowly added dropwise, after the dropwise addition, the reaction solution was stirred at the temperature overnight, then the reaction solution was reacted at room temperature for 24h, after the reaction was completed, water (30mL) was added to quench the reaction, the reaction mixture was extracted with ethyl acetate (50 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtration, concentration under reduced pressure and column chromatography of the residue on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) purified to give 20.61g of a white solid, yield: 74 percent.
MS(ESI,pos.ion)m/z:284.2[M+1]+.
Step 2: synthesis of compound pyrrolidine-2-carboxylic acid ethyl ester hydrochloride
Concentrated hydrochloric acid (2mL) was added to a solution of pyrrolidine-2-carboxylic acid (1.60g,13.90mmol) in ethanol (30mL) and heated at reflux overnight. After the reaction, the reaction mixture was concentrated under reduced pressure to obtain 2.51g of a colorless liquid, which was directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:144.3[M+1]+.
And step 3: synthesis of the Compound ethyl 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
Triethylamine (2.80g,28.00mmol) was added to a solution of pyrrolidine-2-carboxylic acid ethyl ester hydrochloride (2.51g,14.00mmol) in isopropanol (30mL) and reacted at room temperature for 0.5H, followed by addition of 4-chloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine (2.60g,9.20mmol) and heating of the reaction to reflux overnight. After completion of the reaction, concentration was performed under reduced pressure, and the obtained residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), and purified to obtain 2.60g of a white solid, yield: 72 percent.
MS(ESI,pos.ion)m/z:391.2[M+1]+.
And 4, step 4: synthesis of the compound ethyl 2- (acetonitrile) -1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
N-butyllithium (2.4M,14.00mL) was slowly added dropwise to a solution of diisopropylamine (3.60g,36.00mmol) in anhydrous THF (5mL) at-78 deg.C under nitrogen, the reaction was stirred at this temperature for 15min, and 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] was slowly added dropwise]A solution of pyrimidin-4-yl) pyrrolidine-2-carboxylic acid ethyl ester (2.60g,6.66mmol) in anhydrous THF (2mL) was added dropwise and the reaction stirred at this temperature for 0.5 h. Bromoacetonitrile (2.40g,20.00mmol) was slowly added dropwise to the reaction solution, and then the temperature was slowly raised to room temperature, and the reaction was stirred at room temperature overnight. Reaction ofAfter completion, saturated NH was added to the reaction solution4The reaction was quenched with Cl solution (1mL), concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) and purified to give 716.00mg of a light yellow liquid, yield: 25 percent.
MS(ESI,pos.ion)m/z:430.2[M+1]+.
And 5: synthesis of the Compound ethyl 2- (2-aminoethyl) -1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) pyrrolidine-2-carboxylate
A methanolic solution of ammonia (7.0M,7mL) was added with Raney nickel (14mg,0.16mmol) sequentially to 2- (acetonitrile) -1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-yl) pyrrolidine-2-carboxylic acid ethyl ester (716mg,1.67mmol) in MeOH (15mL), H2Hydrogenation reaction is carried out for 5h at 40 ℃ under the atmosphere. After the reaction, the solid was filtered off, the filtrate was concentrated under reduced pressure, and the residue obtained was separated by silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 288mg of white solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:434.2[M+1]+.
Step 6: synthesis of the compound 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-6-one
Potassium tert-butoxide (149mg,1.33mmol) was added to 2- (2-aminoethyl) -1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ]]Pyrimidin-4-yl) pyrrolidine-2-carboxylic acid ethyl ester (288mg,0.66mmol) in toluene (8mL) was heated at reflux overnight. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 185mg of white solid, yield: 72 percent.
MS(ESI,pos.ion)m/z:388.2[M+1]+.
And 7: synthesis of the compound 2- (6-carbonyl-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) acetonitrile
Sodium hydride (60%, 51mg,1.29mmol) was portionwise at-15 deg.CAdding 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) -1, 7-diazaspiro [4.4]Nonan-6-one (10mg,0.26mmol) in dry DMF (5mL) and the reaction stirred at this temperature for 2 h. Bromoacetonitrile (155mg,1.29mmol) was added thereto, the reaction was stirred at that temperature for 0.5 hour, then slowly warmed to room temperature, stirred at room temperature for 48 hours, quenched by slowly adding water (10mL), extracted with dichloromethane (15 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1), purified to give 38mg of a yellow-brown liquid, yield: 35 percent.
MS(ESI,pos.ion)m/z:427.2[M+1]+.
And 8: synthesis of Compound 2- (6-carbonyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) acetonitrile
Trifluoroacetic acid (41mg,0.36mmol) was slowly added 2- (6-carbonyl-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] at room temperature]Pyrimidin-4-yl) -1, 7-diazaspiro [4.4]Nonan-7-yl) acetonitrile (38mg,0.09mmol) in dichloromethane (5mL) was reacted at room temperature for 24 h. After completion of the reaction, the reaction solution was made alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 18mg of a white solid, yield: 68 percent.
MS(ESI,pos.ion)m/z:297.2[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.15(s,1H),7.10(d,J＝3.6Hz,1H),6.68(d,J＝3.6Hz,1H),4.58-4.61(m,2H),4.27(d,J＝17.4Hz,1H),4.15-4.19(m,1H),4.03-4.07(m,1H),3.84-3.88(m,1H),3.59-3.64(m,1H),2.63-2.68(m,1H),2.06-2.32(m,4H).
Example 472- (6-carbonyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) propionitrile
Figure BDA0000892466340000751
Step 1: synthesis of the compound 2- (6-carbonyl-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) propionitrile
Sodium hydride (60%, 40mg,1.00mmol) was added portionwise to 1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] at-15 deg.C]Pyrimidin-4-yl) -1, 7-diazaspiro [4.4]Nonan-6-one (78mg,0.20mmol) and potassium iodide (33mg,0.20mmol) in dry DMF (5mL) was stirred at this temperature for 2 h. Then 3-bromopropionitrile (268mg,2.00mmol) was added thereto, the reaction was stirred at this temperature for 0.5 hour, the temperature was slowly raised to room temperature, the reaction was stirred at room temperature for 48 hours, water (10mL) was slowly added to the reaction solution to quench the reaction, dichloromethane (15 mL. times.3) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering and concentrating under reduced pressure to obtain 110.00mg of yellow-brown liquid which is directly used in the next step without further purification.
MS(ESI,pos.ion)m/z:441.3[M+1]+.
Step 2: synthesis of compound 2- (6-carbonyl-1- (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) -1, 7-diazaspiro [4.4] nonan-7-yl) propionitrile
Trifluoroacetic acid (229mg,2.00mmol) was added slowly to 2- (6-carbonyl-1- (7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] at room temperature]Pyrimidin-4-yl) -1, 7-diazaspiro [4.4]Nonan-7-yl) propionitrile (110mg,0.25mmol) in dichloromethane (5mL) was reacted at room temperature for 24 h. After completion of the reaction, the reaction solution was made alkaline with saturated sodium bicarbonate solution, extracted with dichloromethane (15 mL. times.3), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and separating the residue by silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 15/1), purification afforded 8mg of white solid, yield: 13 percent.
MS(ESI,pos.ion)m/z:311.3[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.12(s,1H),7.10(d,J＝3.6Hz,1H),6.68(d,J＝3.6Hz,1H),4.16-4.24(m,2H),4.05-4.07(m,1H),3.85-3.86(m,1H),3.59-3.70(m,2H),2.77-2.89(m,3H),2.06-2.29(m,5H).
Example 482-cyano-N- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) acetamide
Figure BDA0000892466340000761
Step 1: synthesis of Compound (3-aminophenyl) benzyl carbamate
M-phenylenediamine (5.0g,50.0mmol) was dissolved in methylene chloride (100mL), cooled to 0 deg.C, N-diisopropylethylamine (25.00mL) and benzyl chloroformate (3.20mL) were added dropwise, and the mixture was allowed to slowly return to room temperature and stirred overnight. Concentrated under reduced pressure and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 9.00g of product, yield: 74 percent.
MS(ESI,pos.ion)m/z:243.2[M+1]+.
Step 2: synthesis of Compound (3- (methylamino) phenyl) carbamic acid benzyl ester
Benzyl (3-aminophenyl) carbamate (2.00g,8.25mmol) was dissolved in N, N-dimethylformamide (20mL), sodium bicarbonate (2.08g,24.7mmol) and iodomethane (0.50mL,8.02mmol) were added, the reaction was stirred at room temperature for 3h, quenched with saturated aqueous sodium chloride (150mL), extracted with ethyl acetate (200mL × 3), washed with organic phase water (150mL), washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: PE/v) ═ 10/1) to give 1.80g of product, yield: 85 percent.
MS(ESI,pos.ion)m/z:257.2[M+1]+.
And step 3: synthesis of benzyl 3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) carbamate
Benzyl (3- (methylamino) phenyl) carbamate (0.66g,2.60mmol) and 4-chloro-7H-pyrrolo [2, 3-d)]Pyrimidine (0.40g,2.60mmol) was dissolved in isopropanol (50mL), 3 drops of concentrated HCl were added, and the mixture was heated under stirring and reflux overnight. Concentrating under reduced pressure, and performing column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 0.70g of product in yield：70％。
MS(ESI,pos.ion)m/z:374.3[M+1]+.
And 4, step 4: compound N1-methyl-N1- (7H-pyrrolo [2, 3-d)]Synthesis of pyrimidin-4-yl) benzene-1, 3-diamines
Benzyl (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) carbamate (0.50g,1.34mmol) was dissolved in methanol (50mL), palladium on carbon (10%, 0.10g) was added, the reaction was purged three times, and the reaction was stirred under hydrogen balloon pressure for 3H. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure and used directly for the next reaction.
And 5: synthesis of Compound 2-cyano-N- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) acetamide
Cyanoacetic acid (0.90g,10.45mmol) was dissolved in tetrahydrofuran (50mL), a catalytic amount of N, N-dimethylformamide (0.1mL) was added dropwise, cooled to 0 deg.C, oxalyl chloride (2.70mL,31.34mmol) was slowly added dropwise, the reaction was allowed to return to room temperature and stirred for 1h, concentrated under reduced pressure, dried and then dissolved in tetrahydrofuran (50mL) for further use.
Will N1-methyl-N1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) benzene-1, 3-diamine (0.50g,2.00mmol) was dissolved in tetrahydrofuran (50mL), triethylamine (6.00mL) was added, cooled to 0 deg.C, and the freshly prepared acid chloride solution was added dropwise, slowly returned to room temperature and reacted for 5 h. Quenching the reaction with saturated sodium bicarbonate solution (30mL), extracting with dichloromethane (30 mL. times.3), drying over anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 0.40g of solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:307.1[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)8.27(s,1H),7.67-7.66(m,1H),7.62(s,1H),7.58-7.47(m,1H),7.16-7.15(m,1H),6.83(d,J＝4.0,1H),3.60(s,3H),3.37-3.32(m,2H).
Example 494- (4-fluoro-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzyl) morpholin-3-one
Figure BDA0000892466340000771
Step 1: synthesis of compound (3-amino-4-fluorophenyl) methanol
The compound 3-amino-4-fluoro-benzoic acid (3.00g,19.34mmol) was dissolved in tetrahydrofuran (50mL), cooled to 0 deg.C, lithium aluminum hydride (3.67g,96.69mmol) was added and the solution was heated to reflux overnight. The reaction was quenched with methanol (20mL), filtered, and the filtrate was directly concentrated and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give 2.20g of the product, yield: 81 percent.
MS(ESI,pos.ion)m/z:142.2[M+1]+.
Step 2: synthesis of Compound (4-fluoro-3- (methylamino) phenyl) methanol
Compound (3-amino-4-fluorophenyl) methanol (2.00g,14.17mmol) was dissolved in N, N-dimethylformamide (20mL), cooled to 0 deg.C, sodium bicarbonate (3.57g,42.5mmol) was added, methyl iodide (0.85mL,13.6mmol) was added dropwise, and the solution was allowed to return to room temperature overnight. The reaction was quenched with saturated aqueous sodium chloride (100mL), extracted with ethyl acetate (100mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 1.50g of the product, yield: 68 percent.
MS(ESI,pos.ion)m/z:156.0[M+1]+.
And step 3: synthesis of Compound (4-fluoro-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) methanol
(4-fluoro-3- (methylamino) phenyl) methanol (1.20g,7.73mmol) was dissolved in isopropanol (50mL) and 4-chloro-7H-pyrrolo [2,3-d ] added]Pyrimidine (1.20g,7.84mmol), stirring, adding dropwise 3 drops of concentrated hydrochloric acid, and heating and refluxing for reaction overnight. Concentrating under reduced pressure, and performing column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 20/1), yielding 1.10g of product, yield: 52 percent.
MS(ESI,pos.ion)m/z:273.2[M+1]+.
And 4, step 4: synthesis of compound N- (5- (bromomethyl) -2-fluorophenyl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
(4-fluoro-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) methanol (800mg,2.94mmol) was dissolved in dichloromethane (50mL), cooled to 0 deg.C, phosphorus tribromide (0.55mL,5.88mmol) was added dropwise, and the reaction was allowed to return to room temperature and stirred overnight. The reaction was quenched by addition of saturated aqueous sodium chloride (100mL), extracted with dichloromethane (100 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was used directly in the next step.
And 5: synthesis of compound 4- (4-fluoro-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) benzyl) morpholin-3-one
Morpholin-3-one (1.51g,14.92mmol) is dissolved in N, N-dimethylformamide (20mL), cooled to 0 deg.C, sodium hydride (60%, 0.90g,2.25mmol) is added, after stirring reaction at 0 deg.C for 1H, N- (5- (bromomethyl) -2-fluorophenyl) -N-methyl-7H-pyrrolo [2,3-d ] is added]Pyrimidin-4-amine (0.50g,1.49mmol), allowed to react overnight at room temperature, quenched with saturated aqueous sodium chloride (100mL), extracted with ethyl acetate (100 mL. times.3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), yielding 200mg of solid, yield: 40 percent.
MS(ESI,pos.ion)m/z:356.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)8.31(s,1H),7.48-7.43(m,2H),7.36-7.31(m,1H),6.92(d,J＝4.0Hz,1H),4.64(s,2H),4.15(s,2H),3.84(t,J＝4.0,4.0Hz,2H),3.60(s,3H),3.39-3.33(m,2H).
Example 504- ((3-Acrylamidophenyl) amino) -N-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carboxamide
Figure BDA0000892466340000781
Step 1: synthesis of compound 5-bromo-4-chloro-7H-pyrrolo [2,3-d ] pyrimidine
The compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine (14.1g,91.8mmol) was dissolved in chloroform (200mL) and NBS (17.17g,96.4mmol) was added slowly. The reaction was heated at reflux for 2h, cooled to room temperature, filtered to remove solids, and the filtrate was concentrated to give 18.1g of a grey solid, yield: 85 percent.
MS(ESI,pos.ion)m/z:234.0[M+1]+.
Step 2: synthesis of compound 4-chloro-7H-pyrrolo [2,3-d ] pyrimidine-5-carboxylic acid
The compound 5-bromo-4-chloro-7H-pyrrolo [2,3-d]Pyrimidine (3g,12.9mmol) in dry THF (50mL), N2Protection n-butyllithium (2.4M,16.2mL,38.7mmol) was slowly injected at-78 ℃ and reacted for 1h at-78 ℃. Then introducing CO into the reaction system2The reaction was continued at-78 ℃ for 1 h. The reaction temperature was slowly raised back to room temperature and the reaction was continued at room temperature for 12 h. Water (20mL) was added to quench and the reaction was adjusted to pH 3-4 with HCl (1M). Filtration gave 1.53g of a solid, yield: 60 percent.
MS(ESI,pos.ion)m/z:198.1[M+1]+.
And step 3: synthesis of compound 4-chloro-N-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-formamide
The compound 4-chloro-7H-pyrrolo [2,3-d]Pyrimidine-5-carboxylic acid (198mg,1mmol) was dissolved in dichloromethane (15mL), catalytic amounts of DMF (1 drop) were added, oxalyl chloride (381mg,3mmol) was added at 0 deg.C, and the reaction was carried out at 0 deg.C for 0.5h and room temperature for 1 h. And (4) spin-drying the solvent to obtain an acyl chloride crude product for later use. Isopropylamine (89mg,1.5mmol) was dissolved in dichloromethane (10mL), and a solution of the crude acid chloride in dichloromethane (5mL) was added at 0 deg.C and reacted at room temperature overnight. Saturated NH4Cl solution (15mL) quenched, extracted with dichloromethane (15 mL. times.3), Na2SO4Drying, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), yielding 155mg of a yellow solid, yield: 65 percent.
MS(ESI,pos.ion)m/z:239.15[M+1]+.
And 4, step 4: synthesis of benzyl 3- ((5- (isopropylformamide) -7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) carbamate
The compound 4-chloro-N-isopropyl-7H-pyrrolo [2,3-d]Pyrimidine-5-carboxamide (200mg,0.84mmol) and the compound benzyl (3-aminophenyl) carbamate (224mg,0.92mmol) were dissolved in isopropanol (200mL), concentrated hydrochloric acid (3 drops) was added, and the reaction was heated under reflux overnight. Evaporating solvent, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), yielding 152mg of product, yield: 41 percent.
MS(ESI,pos.ion)m/z:445.20[M+1]+.
And 5: synthesis of compound 4- ((3-aminophenyl) amino) -N-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carboxamide
Compound (3- ((5- (isopropylformamide) -7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) amino) phenyl) carbamic acid benzyl ester (152mg,0.34mmol) was dissolved in methanol (10mL), palladium on carbon (30mg) was added, the reaction was performed at room temperature for 6 hours under a hydrogen atmosphere, the filtrate was filtered, evaporated to dryness, and separated by column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 10/1), yielding 101mg of product, yield: 95 percent.
MS(ESI,pos.ion)m/z:311.0[M+1]+.
Step 6: synthesis of compound 4- ((3-acrylamidophenyl) amino) -N-isopropyl-7H-pyrrolo [2,3-d ] pyrimidine-5-carboxamide
The compound 4- ((3-aminophenyl) amino) -N-isopropyl-7H-pyrrolo [2,3-d]Pyrimidine-5-carboxamide (50mg,0.16mmol) was dissolved in DMF (5mL), and triethylamine (24mg,0.24mmol), HOBT (32mg,0.24mmol) and EDCI (46mg,0.24mmol) were added and reacted at room temperature for 10 h. Diluting with water (20mL), extracting with dichloromethane (15 mL. times.3), Na2SO4Drying, evaporating solvent, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), yielding 25mg of white solid, yield: 35 percent.
MS(ESI,pos.ion)m/z:365.20[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)12.34(d,J＝8.3Hz,1H),10.20(s,1H),8.71-8.25(m,1H),8.17(d,J＝2.1Hz,1H),8.00(d,J＝1.7Hz,1H),7.74(d,J＝7.8Hz,1H),7.48(d,J＝7.8Hz,1H),7.28(dd,J＝27.2,19.1Hz,1H),6.48(dd,J＝16.9,10.2Hz,1H),6.27(dd,J＝17.0,1.7Hz,1H),5.77(d,J＝1.8Hz,1H),5.46-5.24(m,1H),4.22(td,J＝13.6,6.8Hz,1H),4.18-4.08(m,1H),1.42-1.12(m,6H).
Example 51N- (3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amino) phenyl) acrylamide
Figure BDA0000892466340000791
Will N1-methyl-N1- (7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl) benzene-1, 3-diamine (0.32g,1.34mmol), acrylic acid (1.02g,14.2mmol), EDCI (1.2g,6.28mmol) and HOBT (0.8g,5.9mmol) were dissolved in dichloromethane (30mL), cooled to 0 ℃, triethylamine (1.7mL,12.2mmol) was added dropwise, returned to room temperature for 12h, diluted with ethyl acetate (20mL), washed with organic phase water (15mL), washed with saturated aqueous sodium chloride solution (15mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, column chromatography (eluent: CH (CH)2Cl2MeOH (v/v) ═ 30/1), yielding 100mg of a light yellow solid, yield: 25 percent.
MS(ESI,pos.ion)m/z:294.1[M+1]+；
1H NMR(600MHz,MeOH-d4):δ(ppm)8.27(s,1H),7.80-7.68(m,2H),7.49(t,J＝8.0Hz,1H),7.14(d,J＝6.9Hz,1H),6.86-6.75(m,1H),6.40(ddd,J＝18.8,17.0,5.9Hz,3H),5.79(dd,J＝9.9,1.8Hz,2H),4.92(d,J＝3.5Hz,1H),3.61(s,3H).
By analogy with the synthetic methods of the examples of the present invention, and the synthetic methods described in the present invention, with appropriate alternative starting materials, the compounds shown in table 1 were prepared:
table 1 name and characterization data for the compounds
Figure BDA0000892466340000792
Figure BDA0000892466340000801
Figure BDA0000892466340000811
Figure BDA0000892466340000821
Figure BDA0000892466340000831
Biological activity
Biological example 1 JAK1/2/3 in vitro Activity test method one
(1) Detecting the inhibition effect of the compound on JAK1/2/3 enzyme by using Caliper Mobility Shift Assay; (2) preparing a 1-time kinase reaction solution: 50mM HEPES, pH 7.5, 0.0015% Brij-35, 10mM MgCl22mM DTT; (3) preparing a reaction termination solution: 100mM HEPES, pH 7.5, 0.0015% Brij-35, 0.2% Coating Reagent #3(Caliper, cat # 760050), 50mM EDTA; (4) enzyme formulation (JAK 1/2/3): preparing enzyme solution with reaction system diluent, wherein the final enzyme preparation concentration is JAK1(30nM), JAK2(2nM) and JAK 3(4 nM); (5) preparing a substrate: the diluted reaction system solution was used to prepare a substrate solution, the final concentration of the substrate being shown in Table 2.
TABLE 2 Final substrate formulation concentrations
Figure BDA0000892466340000832
According to the optimization result of the experimental method, a 384-well plate (Corning, Cat.No.3573, Lot.No.12608008) is adopted for the experiment to detect, and JAK1/2/3 enzyme concentrations are prepared into JAK1(75nM), JAK2(5nM), JAK 3(10nM), and final concentrations are JAK1(30nM), JAK2(2nM) and JAK 3(4 nM); the concentration of a substrate Peptide FAM-P22 is prepared to be 7.5 mu M, and the final reaction concentration is 3 mu M; the ATP preparation concentrations were JAK1 (225. mu.M), JAK2 (50. mu.M), JAK3 (15.5. mu.M), and the final concentrations were JAK1 (90. mu.M), JAK2 (20. mu.M), JAK3 (6.2. mu.M); the concentration of Peptide D (sequence 5-FAM-C6-KKHTDDGYMPMSPGVA-NH2) is prepared to be 7.5 mu M, and the final reaction concentration is 3 mu M; both the enzyme and the substrate were prepared using 1-fold kinase reaction solution. The reaction system is shown in Table 3.
Table 3 Compound vs JAK1/2/3 enzyme IC50Detection system
Figure BDA0000892466340000841
The detection is carried out by adopting a 384-well plate, a test sample well, a positive control well and a negative control well are arranged in the experiment, each sample utilizes a double-well to detect the inhibition effect of the compound on the JAK1/2/3 enzyme concentration under 8 concentrations, an enzyme and substrate reaction well is used as a positive control, and no reaction is carried outEnzyme wells (kinase reaction solution) served as negative controls. After adding corresponding samples, buffer solution and enzyme into each hole in sequence according to the table 3, incubating in a constant temperature box at 25 ℃ (RT) for 10min, adding prepared Peptide solution into each hole, incubating at the constant temperature of 28 ℃ for 60min, adding reaction termination solution, detecting by using a Caliper EZ Reader at the excitation wavelength of FP485 nm/525 nm, and reading data to obtain the conversion rate. The inhibition of JAK1/2/3 enzyme was plotted at different concentrations of compound using Graph Pad Prism 5 software to calculate IC50The results are shown in Table 4.
Enzyme (JAK1/2/3) inhibition data for the compounds of Table 4
Figure BDA0000892466340000842
The data in table 4 show that the compounds of the present invention have a strong inhibitory effect on JAK1, JAK2 or JAK3, or on JAK1, JAK2 and JAK3 at the same time. The examples in table 4 are typical representations of the compounds of the present invention, which make it possible to deduce the activity of other structurally similar compounds.
Biological example 2 method for testing JAK1/2/3 in vitro Activity
(1) The inhibition effect of the Lance Assay compound on JAK1/2/3 enzyme is adopted; (2) preparing a kinase buffer solution: 50mM HEPES pH 7.5, 1mM EGTA, 10mM MgCl22mM DTT and 0.01% Tween-20; (3) preparing a reaction termination solution: 1 × Detection Buffer dissolves 40mM EDTA; (4) preparing a detection mixed solution: diluting Eu-anti-phosphotyrosine antibody (PT66) to 8nM by using 1 XLANCE DetectionBuffer; (5) the detection is carried out by adopting a white 384-well plate, and the reaction system is as follows:
table 5 Compound vs JAK1/2/3 enzyme IC50Detection system
Figure BDA0000892466340000843
The test sample hole, the positive control hole and the negative control hole are arranged in the experiment, each sample utilizes the double-compound hole to detect the inhibition effect of the compound under 8 concentrations on the JAK1/2/3 enzyme concentration, and utilizesJAK enzyme and substrate-free reaction wells were used as positive controls, and enzyme-free wells (kinase reaction solution) were used as negative controls. Adding corresponding sample, buffer solution and enzyme into each well in the order of Table 5, incubating in a thermostat at 25 deg.C (RT) for 5min, adding prepared Eu-anti-phosphorus-tyrosine Antibody (PT66) into each well, incubating at 25 deg.C for 60min, and performing enzyme digestion by using enzyme
Figure BDA0000892466340000853
And detecting by a Multilabel Reader at the FP excitation wavelength of 320 nm/665 nm, and reading data.
The assay results are expressed as a percentage of the activity measured for the test compound and the control compound as (test compound activity/control compound activity) × 100, and the percentage of the inhibitory activity of the test compound and the control compound as 100- (test compound activity/control compound activity) × 100 is determined. Calculating the average value of the measured results by using Hill equation curve fitting, drawing an inhibition/concentration-reaction curve, and calculating IC by nonlinear regression analysis of the inhibition/concentration-reaction curve50Value, EC50Value and hill coefficient (nH). The hill equation is:
Figure BDA0000892466340000851
where Y is the specific activity, a is the left asymptote of the curve, D is the right asymptote of the curve, C is the compound concentration50＝IC50Or EC50And nH is the slope factor. The result analysis adopts Hill software and is suitable for
Figure BDA0000892466340000855
Business software of
Figure BDA0000892466340000854
4.0 the data generated were compared for verification and the results are shown in table 6.
Enzyme (JAK1/2/3) inhibition data for the compounds of Table 6
Figure BDA0000892466340000852
The data in table 6 show that the compounds of the present invention have a strong inhibitory effect on JAK1, JAK2 or JAK3, or simultaneously on JAK1, JAK2 and JAK 3. The examples in table 6 are typical representations of the compounds of the present invention, which make it possible to deduce the activity of other structurally similar compounds.

Claims (5)

1. A compound of formula (Ia), formula (Ib) or a pharmaceutically acceptable salt of a compound of formula (Ia), formula (Ib):
Figure FDA0002369900870000011
wherein:
R1ais hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C1-3Alkyl, hydroxy substituted C1-3Alkyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Alkoxy radical C1-3Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio or C1-3An alkylsulfonyl group;
R1bis hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C1-3Alkyl, hydroxy substituted C1-3Alkyl radical, C2-4Alkynyl, C1-3Alkoxy radical, C1-3Alkoxy radical C1-4Alkyl radical, C1-3Alkylamino radical C1-3Alkyl radical, C1-3Alkylthio radical, C1-3Alkylsulfonyl radical, C6-10Aryl radical C1-3Alkyl or C1-5Heteroaryl C1-3An alkyl group;
each R2And R3Independently hydrogen, deuterium, fluorine, chlorine, bromine or iodine;
each RaAnd RbIndependently hydrogen, deuterium, fluorine, chlorine, bromine, iodine or C1-3An alkyl group;
m is 1, 2,3 or 4;
R4is hydrogen, deuterium or C1-3An alkyl group;
R5is cyano-substituted C1-3Alkyl, cyano-substituted C1-3alkyl-C (═ O) -, cyano-substituted C1-3alkyl-O-C (═ O) -, C3-6Cycloalkyl radical, C3-6Cycloalkenyl radical, C1-3Alkylamino substituted C3-6Cycloalkenyl or cyano-substituted C1-3alkyl-NH-C (═ O) -; wherein said cycloalkyl, cycloalkylene and alkylamino are independently C optionally substituted with one or more groups selected from cyano, cyano1-3Alkyl, cyano-substituted C1-3Alkylamino or cyano-substituted C1-3Substituted by a substituent of alkoxy;
or R4、R5And together with the N atom to which they are attached form the following subformula:
Figure FDA0002369900870000012
R6is hydrogen, deuterium, C1-6Alkyl radical, C3-6Cycloalkyl or C6-10Aryl radical C1-3Alkyl, wherein the aryl is phenyl;
R7is cyano-substituted C1-4Alkyl radical, C3-6Cycloalkyl radical, C2-6Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl or C6-10Aryl radical C1-3An alkyl group; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are independently C optionally substituted by one or more groups selected from cyano, cyano1-3Alkyl, cyano-substituted C1-3Alkylamino or cyano-substituted C1-3Substituted by a substituent of alkoxy;
or R6、R7And together with the N atom to which they are attached form the following subformula:
Figure FDA0002369900870000013
2. a compound which is a compound having one of the following structures or a pharmaceutically acceptable salt of a compound having one of the following structures:
Figure FDA0002369900870000021
Figure FDA0002369900870000031
Figure FDA0002369900870000041
3. a pharmaceutical composition comprising a compound of any one of claims 1-2, said pharmaceutical composition further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle; or/and
the pharmaceutical composition further comprising an additional therapeutic agent selected from the group consisting of a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, and an agent for treating autoimmune disease.
4. Use of a compound of any one of claims 1-2 or a pharmaceutical composition of claim 3 for the manufacture of a medicament for preventing, treating, or ameliorating an autoimmune disease or a proliferative disease in a patient, wherein the autoimmune disease is lupus, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, psoriasis, type I diabetes, complications due to organ transplantation, foreign body transplantation, diabetes, asthma, atopic dermatitis, autoimmune thyroid disease, ulcerative colitis, crohn's disease, alzheimer's disease, leukemia, or lymphoma; the proliferative disease is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, head and neck cancer, prostate cancer, pancreatic cancer, cancer of the central nervous system, glioblastoma, myeloproliferative disease, atherosclerosis or pulmonary fibrosis.
5. Use of a compound of any one of claims 1-2 or a pharmaceutical composition of claim 3 for the preparation of a medicament for inhibiting or modulating the activity of a protein kinase in a biological specimen, the use comprising contacting the biological specimen with a compound of any one of claims 1-2 or a pharmaceutical composition of claim 3, the protein kinase being JAK1, JAK2, or JAK 3.
CN201511016911.4A 2014-12-30 2015-12-28 Heteroaromatic compounds and their use in medicine Active CN105732636B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410840212 2014-12-30
CN2014108402120 2014-12-30

Publications (2)

Publication Number Publication Date
CN105732636A CN105732636A (en) 2016-07-06
CN105732636B true CN105732636B (en) 2020-04-21

Family

ID=56296400

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201511016911.4A Active CN105732636B (en) 2014-12-30 2015-12-28 Heteroaromatic compounds and their use in medicine

Country Status (1)

Country Link
CN (1) CN105732636B (en)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016161160A1 (en) 2015-04-03 2016-10-06 Kalyra Pharmaceuticals, Inc. Spirocyclic compounds
HUE060733T2 (en) * 2015-07-31 2023-04-28 Taiho Pharmaceutical Co Ltd Pyrrolo[2,3-d]pyrimidine compound or salt thereof
BR112018012707A2 (en) * 2015-12-22 2019-01-29 Vitae Pharmaceuticals Inc menin-mll interaction inhibitors
CN107098908B (en) * 2016-02-23 2021-01-08 欣凯医药科技(上海)有限公司 Preparation method and application of pyrrolopyrimidine compound
ES2947636T3 (en) 2016-03-16 2023-08-14 Kura Oncology Inc Substituted thieno[2,3-d]pyrimidine derivatives as inhibitors of menin-MLL and methods of use
IL298381A (en) 2016-06-10 2023-01-01 Vitae Pharmaceuticals Llc Inhibitors of the menin-mll interaction
TWI738864B (en) * 2016-09-14 2021-09-11 比利時商健生藥品公司 Spiro bicyclic inhibitors of menin-mll interaction
SI3512857T1 (en) 2016-09-14 2021-07-30 Janssen Pharmaceutica Nv Spiro bicyclic inhibitors of menin-mll interaction
AU2017339890A1 (en) * 2016-10-05 2019-04-11 Recurium Ip Holdings, Llc Spirocyclic compounds
KR20180051220A (en) * 2016-11-08 2018-05-16 주식회사 대웅제약 Novel pyrrolopyrimidine derivatives and pharmaceutical composition comprising the same
ES2901227T3 (en) 2016-12-15 2022-03-21 Janssen Pharmaceutica Nv Azepane inhibitors of menin-MLL interaction
WO2018134352A1 (en) * 2017-01-20 2018-07-26 Leo Pharma A/S Bicyclic amines as novel jak kinase inhibitors
US11649251B2 (en) 2017-09-20 2023-05-16 Kura Oncology, Inc. Substituted inhibitors of menin-MLL and methods of use
KR20190063745A (en) * 2017-11-30 2019-06-10 (주)인핸스드바이오 NEW COMPOUNDS FOR INHIBITING BINDING BETWEEN p34 PROTEIN AND NEDD4-1 PROTEIN AND USE THEREOF
US11396517B1 (en) 2017-12-20 2022-07-26 Janssen Pharmaceutica Nv Exo-aza spiro inhibitors of menin-MLL interaction
CN111574442A (en) * 2017-12-29 2020-08-25 杭州阿诺生物医药科技有限公司 Preparation method of indoleamine 2, 3-dioxygenase inhibitor
CN110156674A (en) * 2018-02-13 2019-08-23 中国科学院上海有机化学研究所 A kind of spiro-compound as indoles amine -2,3- dioxygenase inhibitor
US20210323977A1 (en) * 2018-08-28 2021-10-21 Hoffmann-La Roche Inc. Pyrrolidinyl amide compounds for the treatment of autoimmune disease
EP3858813A4 (en) * 2018-09-27 2022-06-22 Shenzhen Chipscreen Biosciences Co., Ltd. Quinolone derivative having indoleamine-2,3-dioxygenase inhibited activity
CN113993585A (en) * 2019-03-27 2022-01-28 英矽智能科技知识产权有限公司 Bicyclic JAK inhibitors and uses thereof
CN112794855B (en) * 2019-11-13 2023-07-28 中国药科大学 Preparation method and application of N-aryl pyrimidine-4-amine derivative
WO2022117012A1 (en) * 2020-12-02 2022-06-09 百极弘烨（广东）医药科技有限公司 Spirocyclic jak inhibitor, pharmaceutical composition containing same, and application thereof
CN114805399B (en) * 2021-01-29 2023-09-26 成都先导药物开发股份有限公司 JAK1 inhibitor and preparation method thereof
US11919901B2 (en) 2021-05-14 2024-03-05 Syndax Pharmaceuticals, Inc. Inhibitors of the menin-MLL interaction

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101679440A (en) * 2007-04-02 2010-03-24 帕劳制药股份有限公司 Pyrrolopyrimidine derivatives as jak3 inhibitors
CN102372717A (en) * 2010-08-20 2012-03-14 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compound and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101679440A (en) * 2007-04-02 2010-03-24 帕劳制药股份有限公司 Pyrrolopyrimidine derivatives as jak3 inhibitors
CN102372717A (en) * 2010-08-20 2012-03-14 和记黄埔医药（上海）有限公司 Pyrrolopyrimidine compound and use thereof

Also Published As

Publication number Publication date
CN105732636A (en) 2016-07-06

Similar Documents

Publication Publication Date Title
CN105732636B (en) Heteroaromatic compounds and their use in medicine
CN112105419B (en) Condensed ring compound
JP7041198B2 (en) 5-Chloro-2-difluoromethoxyphenylpyrazolopyrimidine compound which is a JAK inhibitor
TWI548636B (en) Pyrrolo[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyrazinyl and pyrrolo[2,3-d]pyridinyl acrylamides
CN105732637B (en) Heteroaromatic compounds and their use in medicine
TWI675833B (en) Biaryl inhibitors of bruton's tyrosine kinase
JP2021169491A (en) Fused ring compounds
CN104125959B (en) Heteroaryl pyridone and aza-pyridone compounds as inhibitors of BTK activity
CN110003178B (en) Diheteroaryl compounds and uses thereof
CN114456175A (en) Pyrrolotriazine compounds as TAM inhibitors
CN115835908A (en) Bicyclic heterocycles as FGFR inhibitors
CN115448923A (en) Pyrimido-cyclic compounds, process for their preparation and their use
CN105566321B (en) Heteroaromatic compounds and their use in medicine
CN106336413B (en) Compounds as JAK inhibitors and uses thereof
KR20230035036A (en) Dual kinase-bromodomain inhibitors
CN114302886A (en) Triazolopyridazine derivative, preparation method, pharmaceutical composition and application thereof
CN115867346A (en) Kinase inhibitors
TW202024072A (en) 1,5-naphthyridin-4(1h)-one derivatives as pi3kbeta inhibitors
WO2023006013A1 (en) Novel parp7 inhibitor and use thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right
TR01 Transfer of patent right

Effective date of registration: 20200609

Address after: 523808 Guangdong city of Dongguan province Hubei Songshan Industrial Park Industrial Road No. 1

Patentee after: SUNSHINE LAKE PHARMA Co.,Ltd.

Address before: 523808 Guangdong city of Dongguan province Hubei Songshan Industrial Park Industrial Road No. 1

Co-patentee before: DONGGUAN HEC PHARM R&D Co.,Ltd.

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.

CP03 Change of name, title or address
CP03 Change of name, title or address

Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.