CN105732637B - Heteroaromatic compounds and their use in medicine - Google Patents

Heteroaromatic compounds and their use in medicine Download PDF

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CN105732637B
CN105732637B CN201511020679.1A CN201511020679A CN105732637B CN 105732637 B CN105732637 B CN 105732637B CN 201511020679 A CN201511020679 A CN 201511020679A CN 105732637 B CN105732637 B CN 105732637B
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compound
cancer
disease
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CN105732637A (en
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刘兵
黄九忠
任兴业
李志�
龙伯华
张英俊
郑常春
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Guangdong HEC Pharmaceutical
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Dongguan Dongyangguang Medicine Research And Development Co ltd
Sunshine Lake Pharma Co Ltd
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    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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 pharmaceutically 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 of the 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 BDA0000892394300000021
wherein:
x is CH or N;
r is R1、-C(＝O)-R2、-C(＝O)-(CRaRb)m-R3、-(CRaRb)m-C(＝O)-R3、-(CRaRb)m-R4、-C(＝O)-N(Rc)-(CRaRb)n-R5、-S(＝O)2-R6、-S(＝O)2-N(Rc)-(CRaRb)n-R7OR-C (═ O) -OR7；
R1Is C3-6Cycloalkyl radical, C4-6Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C1-5A heteroaryl group;
R2is C6-8Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl or C6-10Aryl with the proviso that when R2In the case of pyrrolidinyl, by at least one R2xSubstitution;
each R2xIndependently is deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, amino, carboxy, -C (═ O) -NH2、-S(＝O)2-NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy-or cyano-substituted C1-6An alkylamino group;
each R3Independently is C6-8Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C1-5A heteroaryl group;
R4is C3-6Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C1-5Heteroaryl with the proviso that when R4When it is phenyl, at least one R4xSubstitution;
each R4xIndependently from deuterium, chlorine, bromine, iodine, cyano, nitro, amino, carboxyl, -C (═ O) -NH2、-S(＝O)2-NH2、-S(＝O)2-C2-10Heterocyclic group, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy-or cyano-substituted C1-6An alkylamino group;
R5is C3-6Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C4-5A heteroaryl group;
R6is C3-6Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C1-5Heteroaryl with the proviso that R6Is not 5-methyl-isoxazol-4-yl;
each R7Independently is C3-6Cycloalkyl radical, C2-10Heterocyclic group, C3-6Cycloalkenyl radical, C6-10Aryl or C1-5A heteroaryl group;
each RaAnd RbIndependently is H, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, amino, carboxyl or C1-3An alkyl group;
each RcIndependently H, C1-3Alkyl or cyano-substituted C1-3An alkyl group;
each m is independently 1,2,3, 4, 5 or 6;
each n is independently 0,1, 2,3, 4, 5 or 6;
each R1、R2、R3、R4、R5、R6And R7Independently optionally substituted by one or more RxSubstitution;
each RxIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy, cyano-substituted C1-6Alkylamino radical, C2-10Heterocyclyl or C2-10Heterocyclyloxy, wherein said C is2-10Heterocyclyl and C2-10Heterocyclyloxy is independently optionally substituted with one or more RySubstitution; and
each RyIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy-or cyano-substituted C1-6An alkylamino group.
In some of these embodiments, each R iscIndependently H, methyl, ethyl, propyl, isopropyl, cyanomethyl, cyanoethyl or cyano-substituted propyl.
In some of these embodiments, each R isxIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2、C1-4Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-4Alkoxy, cyano-substituted C1-4Alkylamino radical, C2-6Heterocyclyl or C2-6Heterocyclyloxy, wherein said C is2-6Heterocyclyl and C2-6Heterocyclyloxy is independently optionally substituted with one or more RySubstitution; wherein R isyHave the meaning as described in the present invention.
In some of these embodiments, each R isyIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2、C1-4Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-4Alkoxy-or cyano-substituted C1-4An alkylamino group.
In some of these embodiments, R is R1、-C(＝O)-R2、-C(＝O)-(CH2)m-R3、-(CH2)m-C(＝O)-R3、-(CH2)m-R4、-C(＝O)-N(Rc)-(CH2)n-R5、-S(＝O)2-R6、-S(＝O)2-N(Rc)-(CH2)n-R7OR-C (═ O) -OR7；
Wherein each m, n, Rc、R1、R2、R3、R4、R5、R6And R7Have the meaning as described in the present invention.
In some of these embodiments, R is1Is phenyl, cyclobutyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl; r1Optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, R is2Is phenyl; r2Optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, each R is3Independently is phenyl; each R3Independently optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, R is4Is represented by 1,2,3, 4 or 5R4xSubstituted phenyl; further, R4Optionally substituted by one or more RxSubstitution; wherein R isxAnd R4xHave the meaning as described in the present invention.
In some of these embodiments, R is5Is phenyl; r5Optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, R is6Is phenyl; r6Optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, each R is7Independently is phenyl; each R7Independently optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, R is2Is of the sub-structure:
Figure BDA0000892394300000031
Figure BDA0000892394300000041
Figure BDA0000892394300000042
R2optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, each R is3Independently the sub-formulae:
Figure BDA0000892394300000043
Figure BDA0000892394300000044
each R3Independently optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, R is4Is of the sub-structure:
Figure BDA0000892394300000045
Figure BDA0000892394300000046
R4optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, R is5Is of the sub-structure:
Figure BDA0000892394300000047
Figure BDA0000892394300000051
Figure BDA0000892394300000052
R5optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, R is6Is of the sub-structure:
Figure BDA0000892394300000053
Figure BDA0000892394300000054
R6optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, each R is7Independently the sub-formulae:
Figure BDA0000892394300000055
Figure BDA0000892394300000056
each R7Independently optionally substituted by one or more RxSubstitution;
wherein Y, Z, t, R, s, p, RxAnd R2xHave the meaning as described in the present invention.
In some of these embodiments, each Y is independently-CH2-, -NH-, -O-, -S (═ O) -, or-S (═ O)2-；
Each Z is independently-NH-, -O-, -S (═ O) -or-S (═ O)2-；
Each t is independently 0,1, 2 or 3;
each r is independently 0,1 or 2;
each s is independently 1 or 2;
each p is independently 1 or 2.
In some of these embodiments, R is2xIs deuterium, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, carboxyl, -C (═ O) -NH2、-S(＝O)2-NH2、C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-3Alkoxy-or cyano-substituted C1-3An alkylamino group.
In some of these embodiments, R is4xIs deuterium, chlorine, bromine, iodine, cyano, nitro, amino, carboxyl, -C (═ O) -NH2、-S(＝O)2-NH2、-S(＝O)2-C2-6Heterocyclic group, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-3Alkoxy-or cyano-substituted C1-3An alkylamino group.
In some of these embodiments, each R is1、R2、R3、R4、R5、R6And R7Independently optionally substituted by one or more RxSubstitution; wherein R isxHave the meaning as described in the present invention.
In some of these embodiments, each R isxIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2Methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamino, dimethylamino, ethylamino, propylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-4Alkoxy, cyano-substituted C1-3Alkylamino, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, tetrahydrofuranyloxy or tetrahydropyranyloxy, wherein said piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1-dioxothiomorpholinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, tetrahydrofuranyloxy or tetrahydropyranyloxy are independently optionally substituted with one or more RySubstitution; wherein R isyHave the meaning as described in the present invention.
In some of these embodiments, each R isyIndependently deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo (═ O), -C (═ O) -NH2、-S(＝O)2-NH2、C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-3Alkoxy-or cyano-substituted C1-3An alkylamino group.
In still other embodiments, R is1Is of the sub-structure:
Figure BDA0000892394300000061
in still other embodiments, R is2Is of the sub-structure:
Figure BDA0000892394300000062
Figure BDA0000892394300000071
in still other embodiments, each R is3Independently the sub-formulae:
Figure BDA0000892394300000072
in still other embodiments, R is4Is of the sub-structure:
Figure BDA0000892394300000081
in still other embodiments, each R is2、R3、R4、R5、R6And R7Independently the sub-formulae:
Figure BDA0000892394300000082
Figure BDA0000892394300000091
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 BDA0000892394300000092
wherein:
R11is deuterium, bromine, iodine, cyano, hydroxy, nitro, carboxy, -C (═ O) -NR12R13、-S(＝O)2-NR12R13、C1-3Alkyl, halo C1-3Alkyl, amino C1-3Alkyl radical, C1-4Alkylamino radical C1-4Alkyl, (C)1-4Alkyl radical)2N-C1-4Alkyl-, hydroxy-substituted C1-3Alkyl, cyano-substituted C1-3Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, C3-6Cycloalkylamino, C6-10Arylamino, C1-5Heteroarylamino, -N (R)14)-C(＝O)-R15、-N(R14)-S(＝O)2-R15、C3-6Cycloalkyl radical, C3-6Cycloalkenyl radical, C2-8Heterocyclic group, C6-10Aryl radical, C1-5Heteroaryl group, C3-6Cycloalkyl radical C1-3Alkyl radical, C3-6Cycloalkyl radical C1-3Alkoxy radical, C3-6Cycloalkenyl radical C1-3Alkyl radical, C3-6Cycloalkenyl radical C1-3Alkoxy radical, C2-6Heterocyclyl radical C1-3Alkyl radical, C2-6Heterocyclyl radical C1-6Alkoxy radical, C6-10Aryl radical C1-3Alkyl radical, C6-10Aryl radical C1-3Alkoxy radical, C1-5Heteroaryl C1-3Alkyl or C1-5Heteroaryl C1-3An alkoxy group;
each R12And R13Independently is H, deuterium or C1-3An alkyl group;
each R14Independently is H, deuterium or C1-3An alkyl group;
each R15Independently is H, deuterium or C1-4An alkyl group; and
R11optionally substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo, -C (═ O) -NH2、-S(＝O)2-NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy, cyano-substituted C1-6Alkylamino radical, C2-8Heterocyclyl or C2-8Heterocyclyloxy substituted with a substituent.
In some of these embodiments, R is11Optionally substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, iodo, cyano, hydroxy, nitro, amino, carboxy, oxo, -C (═ O) -NH2、-S(＝O)2-NH2、C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Alkylamino, halogeno C1-3Alkyl, halo C1-3Alkoxy, hydroxy-substituted C1-3Alkyl, hydroxy substituted C1-3Alkoxy, cyano-substituted C1-3Alkyl, cyano-substituted C1-3Alkoxy, cyano-substituted C1-3Alkylamino radical, C2-6Heterocyclyl or C2-6Heterocyclyloxy substituted with a substituent.
In some of these embodiments, R is11Is deuterium, bromine, iodine, cyano, hydroxy, nitro, carboxy, -C (═ O) -NH2、-S(＝O)2NH2Methoxy, ethoxy, methylamino, ethylamino, -NH-C (═ O) -CH3、-NH-C(＝O)-CH2CH3、(CH3)2N-CH2-、(CH3)2N-CH2-CH2-、(CH3CH2)2N-CH2-、(CH3CH2)2N-CH2-CH2Morpholinylmethyl, morpholinylethyl, morpholinylpropyl, morpholinylmethoxy, morpholinylethoxy, morpholinylpropoxy, phenylamino, (4-morpholinylphenyl) amino, pyrazolylamino, N-methylpyrazolylamino, imidazolylamino, pyridylamino or pyrimidylamino.
In yet another aspect, the present invention relates to a compound that is a compound of formula (III) or a stereoisomer, geometric isomer, tautomer, racemate, nitrogen oxide, hydrate, solvate, metabolite, or pharmaceutically acceptable salt or prodrug of a compound of formula (III):
Figure BDA0000892394300000101
wherein:
each of E, G, M and J is independently N or CR16；
K is-O-, -S-or-N (R)17)-；
Each R16Independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, -C (═ O) -NH2、-S(＝O)2-NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino, halogeno C1-6Alkyl, halo C1-6Alkoxy, hydroxy-substituted C1-6Alkyl, hydroxy substituted C1-6Alkoxy, cyano-substituted C1-6Alkyl, cyano-substituted C1-6Alkoxy-or cyano-substituted C1-6An alkylamino group; and
R17is hydrogen, deuterium or C1-6An 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, racemates, nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs of compounds having one of the following structures:
Figure BDA0000892394300000102
Figure BDA0000892394300000111
Figure BDA0000892394300000121
one aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention.
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), (II) or (III).
Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds encompassed by formula (I), (II) or (III).
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 medicament for alleviating, preventing, managing 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), (II) or (III) 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), (II) or (III).
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 compounds of formula (I), (II) or (III) or isolated enantiomers of compounds of formula (I), (II) or (III).
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), (II) or (III) can be prepared by conventional techniques known to those skilled in the art or as described in the examples and preparations of this inventionPrepared by substituting a suitable isotopically labelled reagent for 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. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I), (II) or (III). 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. Racemic products are alsoThe separation can be 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:A PracticalApproach(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, 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, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, 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" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 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 "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 by one or more alkoxy groups, wherein the alkoxy groups have the meaning as described herein.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group 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 alkyl" denotes an alkyl group substituted with one or more cyano groups, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CH2CN，-CH2CH2CN，-CH2CH2CH2CN, and the like.
The term "cyano-substituted alkoxy" denotes an alkoxy group substituted with one or more cyano groups, wherein the alkoxy group has, for exampleWithin the meaning of the present invention, such examples include, but are not limited to, -OCH2CN，-OCH2CH2CN，-OCH2CH2CH2CN，-OCH(CN)CH3And the like.
The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, -CH2OH，-CH2CH2OH，-CH2CH2CH2OH and the like.
The term "hydroxy-substituted alkoxy" denotes an alkoxy group substituted with one or more hydroxy groups, wherein the alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -OCH2OH，-OCH2CH2OH，-OCH2CH2CH2OH，-OCH(OH)CH3And 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" denotes a mono-or polyvalent, partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond. In one embodiment, cycloalkenyl groups contain 3 to 12 carbon atoms; in another embodiment, cycloalkenyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkenyl groups contain 3 to 6 carbon atoms. The cycloalkenyl groups can be independently unsubstituted or substituted with one or more substituents described herein. Examples of thisIncluding, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
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 term "cycloalkylalkoxy" denotes an alkoxy group substituted with one or more cycloalkyl groups, wherein the alkoxy group and the cycloalkyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropylmethoxy, cyclopropylethoxy, cyclobutylmethoxy, cyclobutylethoxy, cyclopentylmethoxy, cyclopentylethoxy, cyclohexylmethoxy, cyclohexylethoxy and the like.
The term "cycloalkenylalkyl" denotes an alkyl group substituted with one or more cycloalkenyl groups, wherein the alkyl group and cycloalkenyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, cyclopentadienylpropyl, cyclobutenylisopropyl, and the like.
The term "cycloalkenylalkoxy" denotes an alkoxy group substituted with one or more cycloalkenyl groups, wherein the alkoxy group and cycloalkenyl group have the meaning as described herein, examples of which include, but are not limited to, cyclopropenylmethoxy, cyclobutenylmethoxy, cyclopentenylethoxy, cyclopentylpropyloxy, 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) -. Of ringsThe sulfur atom may optionally be oxidized to 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-dioxothiomorpholinyl. 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 replaced by-C (O) -include, but are not limited toLimited 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 5-atom heterocyclic groups include, but are 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, dioxanylDithianyl, thioxane. 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 term "heterocyclylalkoxy" refers to a heterocyclyl-substituted alkoxy group in which the oxygen atom is attached to the rest of the molecule; wherein the heterocyclyl and alkoxy groups have the meaning as indicated in the present invention. Examples of such include, but are not limited to, thiomorpholin-4-ylmethoxy, tetrahydrofuran-3-ylmethoxy, oxetan-3-ylmethoxy, pyrrolidin-2-ylmethoxy, morpholin-4-ylethoxy, morpholin-4-ylpropoxy, and the like.
The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups as defined herein attached to and linked by an oxygen atom to the rest of the molecule, wherein the heterocyclyl group has the meaning as described herein, examples of which include, but are not limited to, morpholinyloxy, piperidinyloxy, pyrrolidinyloxy, tetrahydrofuryloxy (tetrahydrofuran-2-yloxy, tetrahydrofuran-3-yloxy) 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 below, 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 BDA0000892394300000191
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 a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic, wherein each ring comprises 3 to 7 atoms in the ring and has 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 "arylalkoxy" means an alkoxy group substituted with one or more aryl groups, wherein the alkoxy and aryl groups have the meaning described herein, and examples include, but are not limited to, phenylmethoxy, phenylethoxy, and the like.
The term "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the aryl group has the meaning described herein, examples of which include, but are not limited to, phenoxy, p-tolyloxy, p-ethylbenzene oxy, 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 is aromatic and at least one ring contains one or more heteroatoms, wherein each ring 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 an alkyl group is substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl groups have the meaning as set forth herein. The term "heteroarylalkoxy" means that an alkoxy group is substituted with one or more heteroaryl groups, wherein the alkoxy group and heteroaryl groups have the meaning as described herein.
The term "carboxyl group"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 "cycloalkylamino" means that the amino group is substituted with one or two cycloalkyl groups.
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 "arylamino" or "arylamino" means that an amino group is substituted with one or two aryl groups, examples of which include, but are not limited to, N-phenylamino. In some embodiments, the aromatic ring on the arylamino group may be further substituted.
The term "heteroarylamino" means that the amino group is substituted with one or two heteroaryl groups, and the heteroaryl ring on the heteroarylamino group can be further substituted with a substituent as described herein, examples of which include, but are not limited to, pyrazolylamino, N-methylpyrazolylamino, imidazolylamino, pyridylamino or pyrimidylamino.
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 "alkylaminoalkyl" refers to an aminoalkyl group in which the hydrogen of the amino group is replaced by one or two alkyl groups. Examples include, but are not limited to, methylaminomethyl, dimethylaminomethyl, methylaminoethyl, dimethylaminoethyl, ethylaminomethyl, diethylaminomethyl, ethylaminoethyl, propylaminomethyl, butylaminomethyl.
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" means 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, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (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), (II) or (III). 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 novelderly Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrug, Design and clinical applications, Nature Review Discovery,2008,7,255 and 270, and S.J.Her et al, Prodrugs of pharmaceuticals and pharmaceuticals, Journal of chemical Chemistry,2008,51,2328 and 5.
"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: berg, s.me et al, descriptive pharmaceutically 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), (II), or (III) 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), (II), or (III). 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; compounds that induce a 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 BDA0000892394300000251
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 methods described herein, wherein the substituents are as defined in formula (I), (II) or (III), unless otherwise indicated. 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.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. 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. mu. mu.L)m,6min, flow rate of 0.6mL/min, mobile phase: 5% -95% (CH containing 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; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; HOBT 1-hydroxybenzotriazole; SEMCl2- (trimethylsilyl) ethoxymethyl chloride; THF tetrahydrofuran; PE petroleum ether; EtOAc ethyl acetate; na (Na)2SO4Sodium sulfate; Pd/C palladium/carbon; POCl3Phosphorus oxychloride; NaIO4/RuCl3Sodium periodate/ruthenium trichloride; sodium NaH hydride; NH (NH)3·H2O ammonia water; CNCH2COOH cyanoacetic acid; h hours; min for the next minute.
Synthesis method 1
Figure BDA0000892394300000271
The target compound 8 can be prepared by a first synthesis method, wherein R isxHave the meaning as described in the present invention. Reacting the compound 1 with paratoluensulfonyl chloride to obtain a compound 2; reacting the compound 2 with the compound 3 to obtain a compound 4; deprotection of compound 4 affords compound 5; deprotection of compound 5 affords compound 6; the compound 6 reacts with the compound 7 to obtain a target compound 8.
Synthesis method II
Figure BDA0000892394300000272
The target compound 10 can be prepared by synthesis method two, wherein Y, t and RxHave the meaning as described in the present invention. The compound 6 reacts with the compound 9 to obtain the target compound 10.
Synthesis method III
Figure BDA0000892394300000273
The target compound 12 can be prepared by synthesis method three, wherein Rx has the meaning as described in the present invention. The compound 6 reacts with the compound 11 to obtain a target compound 12.
Synthesis method IV
Figure BDA0000892394300000281
The target compound 16 can be prepared by the fourth synthesis method. Carrying out esterification reaction on the compound 13 to obtain a compound 14; compound 14 with NH in the presence of triethylamine2CH2CN reacts to obtain a compound 15; the compound 15 reacts with the compound 6 to obtain the target compound 16.
Synthesis method five
Figure BDA0000892394300000282
The target compound 19 can be prepared by a fifth synthetic method, wherein RLIs a leaving group such as halogen; each of m and R4Have the meaning as described in the present invention. The compound 6 reacts with the compound 17 to obtain the target compound 19.
The target compound 20 can be prepared by a synthesis method five, wherein RLIs a leaving group such as halogen; each of m and R3Have the meaning as described in the present invention. Compound 6 reacts with compound 18 to give the target compound 20.
Synthesis method VI
Figure BDA0000892394300000291
The target compound 29 can be prepared by synthesis method six, wherein E, G and M have the meanings as described in the invention. Reacting the compound 21 with the compound 22 to obtain a compound 23; compound 23 and POCl3Reacting to obtain a compound 24; reacting the compound 24 with the compound 3 to obtain a compound 25; compound 25 in NaIO4/RuCl3Reacting in the presence of a catalyst to obtain a compound 26; compound 26 in NH3·H2Cyclizing in the presence of O to obtain a compound 27; compound 27 is reacted with H under Pd/C catalysis2Reacting to obtain a compound 28; compound 28 and CNCH2The COOH reaction gave the title compound 29.
Synthesis method seven
Figure BDA0000892394300000292
The target compound 36 can be prepared by synthesis method seven, wherein E, G and M have the meanings as described in the invention. Reacting the compound 21 with the compound 30 to obtain a compound 31; compound 31 and POCl3Reacting to obtain a compound 32; reacting the compound 32 with the compound 3 to obtain a compound 33; reacting the compound 33 with hydrazine hydrate to obtain a compound 34; compound 34 with H under Pd/C catalysis2Reacting to obtain a compound 35; compound 35 and CNCH2The COOH reaction gave the title compound 36.
Examples
Example 14- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidine-1-carbonyl) benzonitrile
Figure BDA0000892394300000301
Step 1: synthesis of compound 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidine
4-Chloropyrrolo [2,3-d ] pyrimidine (5.00g,32.56mmol) and p-toluenesulfonic acid chloride (6.83g,35.82mmol) were dissolved in acetone (50mL), and a solution of sodium hydroxide (1.56g,39.07mmol) in water (20mL) was slowly added dropwise to the reaction mixture at 0 ℃ and, after completion of the addition, the reaction was stirred at room temperature for 8 hours. After completion of the reaction, the reaction solution was filtered, and the cake was washed with a mixed solvent of acetone/water (10mL, v/v. 1/1) and then dried to obtain 9.39g of a white solid, yield: 93.71 percent.
MS(ESI,pos.ion)m/z:308.2[M+1]+.
Step 2: synthesis of the compound N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
(3R,4R) -1-benzyl-4-methyl-3-methylamino-piperidine (1g,4.58mmol) and potassium carbonate (3.80g,27.48mmol) were charged in succession with 4-chloro-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d ]]A solution of pyrimidine (2.82g,9.16mmol) in water (45mL) was stirred at 105 ℃ for 18 h. After the reaction, the mixture is filtered and chromatographed by a silica gel column (eluent: CH)2Cl2/CH3OH (v/v) ═ 20/1), purification afforded 1.54g of white solid, yield: 68.75 percent.
MS(ESI,pos.ion)m/z:490.1[M+1]+.
And step 3: synthesis of Compound N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Potassium tert-butoxide (1.77g,15.75mmol) was charged with N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7-p-toluenesulfonyl-7H-pyrrolo [2,3-d]The reaction was stirred at room temperature for 2 hours in a solution of pyrimidin-4-amine (1.54g,3.15mmol) in tetrahydrofuran (24 mL). After the reaction, water (50mL) was added to the reaction solution to quench the reaction, ethyl acetate (100mL) was extracted, the organic phases were combined and anhydrous Na was used2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 20/1), purification afforded 1.01g of white solid, yield: 95.28 percent.
MS(ESI,pos.ion)m/z:336.2[M+1]+.
And 4, step 4: synthesis of compound N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Hydrogen and oxygen are mixedPalladium (20%, 2.0g) and trifluoroacetic acid (1.36g,11.92mmol) were added sequentially to N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-amine (2.0g,5.96mmol) in methanol (15mL) in H2The reaction was stirred at room temperature for 1.5 hours under ambient atmosphere. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 867.7mg of a white solid.
MS(ESI,pos.ion)m/z:246.3[M+1]+.
And 5: synthesis of compound 4- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [3,4-d ] pyrimidin-4-yl) amine) piperidine-1-carbonyl) benzonitrile
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (182.0mg,0.74mmol), p-cyanobenzoic acid (217.8mg,1.48mmol) and 2- (7-azobenzotriazol) -N, N' -tetramethyluronium hexafluorophosphate (562.7mg,1.48mmol) were dissolved in DMF (10mL), then N, N-diisopropylethylamine (382.6mg,2.96mmol) was added, and the mixture was stirred at room temperature for reaction for 2 hours. After completion of the reaction, water (20mL) was added to the reaction mixture to quench the reaction, ethyl acetate (60mL) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 52.9mg of white solid, yield: 19.69 percent.
MS(ESI,pos.ion)m/z:375.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.91(s,1H),8.20(s,1H),7.86-7.96(m,2H),7.59-7.63(m,2H),7.23(s,1H),6.68(s,1H),5.76(s,1H),4.87-4.97(m,1H),4.11-4.14(m,1H),3.85-3.91(m,2H),3.17-3.28(m,3H),2.43-2.44(m,1H),1.78(s,1H),1.56(s,1H),1.24(s,1H),1.04(d,J＝6.8Hz,3H).
Example 23- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidine-1-carbonyl) benzenesulfonamide
Figure BDA0000892394300000311
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidine-4Amine (114.0mg,0.46mmol), m-sulfonamide benzoic acid (185.1mg,0.92mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (349.8mg,0.92mmol) were dissolved in DMF (8mL), N, N-diisopropylethylamine (237.8mg,1.84mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (20mL) was added to the reaction mixture to quench the reaction, ethyl acetate (60mL) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 46.0mg of white solid, yield: 23.34 percent.
MS(ESI,pos.ion)m/z:429.1[M+1]+；
1H NMR(400MHz,MeOH-d4):δ(ppm)7.99-8.14(m,3H),7.70(s,2H),7.14(s,1H),6.62-6.70(m,1H),3.94-4.23(m,2H),3.60-3.65(m,1H),3.49-3.54(m,3H),3.37(s,1H),2.53(s,1H),1.92(s,1H),1.68(s,1H),1.30-1.34(m,1H),1.13(d,J＝7.2Hz,3H).
Example 31- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidine-1-carbonyl) -3-cyanoazetidine
Figure BDA0000892394300000312
3-cyanoazetidine hydrochloride (162.4mg,1.377mmol) and N, N-diisopropylethylamine (389.0mg,3.01mmol) were added to a solution of triphosgene (69.6mg,0.51mmol) in dichloromethane (12mL), the reaction stirred at room temperature for 1H, then N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] was added]Pyrimidin-4-amine (336mg,1.37mmol) was added slowly dropwise to a solution of N, N-diisopropylethylamine (195.2mg,1.51mmol) in dichloromethane (8mL) and reacted at room temperature for 48 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)2Cl2/CH3OH (v/v) ═ 14/1), purification afforded 47.7mg of white solid, yield: 9.85 percent.
MS(ESI,pos.ion)m/z:354.3[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)10.83(s,1H),8.28(s,1H),7.07(d,J＝3.6Hz,1H),6.55(d,J＝3.6Hz,1H),5.08(s,1H),4.18-4.29(m,4H),3.61-3.71(m,2H),3.36-3.45(m,4H),2.45-2.51(m,1H),2.25(s,3H),1.85-1.93(m,1H),1.63-1.71(m,1H),1.08(d,J＝7.1Hz,3H).
Example 41- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidine-1-carbonyl) -3-cyanoazacyclopentane
Figure BDA0000892394300000321
3-cyanoazacyclopentane hydrochloride (172.4mg,1.3030mmol) and N, N-diisopropylethylamine (369.6mg,2.86mmol) were added to a solution of triphosgene (142.4mg,0.48mmol) in dichloromethane (15mL), the reaction stirred at room temperature for 1H, then N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] was added]Pyrimidin-4-amine (320mg,1.30mmol) was added slowly dropwise to a solution of N, N-diisopropylethylamine (184.8mg,1.43mmol) in dichloromethane (8mL) and reacted at room temperature for 2 days. After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: CH)2Cl2/CH3OH (v/v) ═ 14/1), purification afforded 90.1mg of white solid, yield: 18.86 percent. MS (ESI, pos. ion) M/z 368.3[ M + 1]]+；
1H NMR(400MHz,CDCl3):δ(ppm)11.06(s,1H),8.24(s,1H),7.04(d,J＝3.6Hz,1H),6.52(d,J＝3.5Hz,1H),5.03(s,1H),3.72-3.82(m,1H),3.46-3.63(m,5H),3.38(d,J＝2.3Hz,3H),3.00-3.08(m,1H),2.49(s,3H),2.10-2.24(m,2H),2.03(s,1H),1.86-1.93(m,1H),1.62-1.66(m,1H),1.05(dd,J＝7.1,1.5Hz,3H).
Example 52- (1, 1-Sulfur dioxide-morpholino) -1- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidin-1-yl) ethanone
Figure BDA0000892394300000322
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (236.0mg,0.96mmol), 2- (1, 1-thiomorpholine) acetic acid (278.0mg,1.44mmol), HOBT(260.0mg,1.92mmol) and EDCI (368.0mg,1.92mmol) were dissolved in DMF (10mL) and N, N-diisopropylethylamine (373.0mg,2.87mmol) 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 (30mL), extracted with dichloromethane (150mL), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 91.0mg of white solid, yield: 22.49 percent.
MS(ESI,pos.ion)m/z:421.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)1.01-1.08(m,3H),1.24(s,1H),1.56-1.79(m,2H),2.37-2.40(m,1H),2.86-2.91(m,3H),3.04-3.17(m,5H),3.27(s,2H),3.40-3.59(m,3H),3.66-3.96(m,2H),6.57(d,J＝8.4Hz,1H),7.14(d,J＝2.5Hz,1H),8.10(s,1H),11.64(s,1H).
Example 64- (2- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidin-1-yl) -2-acetyl) morpholin-3-one
Figure BDA0000892394300000323
Mixing N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (330.0mg,1.35mmol), 2- (3-oxomorpholine) acetic acid (321.0mg,2.02mmol), HOBT (363.0mg,2.69mmol) and EDCI (515.0mg,2.69mmol) were dissolved in DMF (25mL) and N, N-diisopropylethylamine (521.0mg,4.03mmol) 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 (30mL), extracted with dichloromethane (150mL), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 18/1), purification afforded 248.1mg of white solid, yield: 47.73 percent.
MS(ESI,pos.ion)m/z:387.3[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.66(s,1H),8.12(d,J＝7.3Hz,1H),7.15(s,1H),6.57(s,1H),4.22-4.34(m,2H),4.06(s,1H),3.98-4.00(m,1H),3.89-3.93(m,1H),3.82-3.85(m,2H),3.66-3.73(m,2H),3.42-3.50(m,3H),3.27(s,3H),2.40(s,1H),1.60-1.82(m,2H),1.23-1.26(m,1H),1.02(d,J＝7.1Hz,3H).
Example 7 (3R,4R) -N- (cyanomethylene) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidine-1-carboxamide
Figure BDA0000892394300000331
A solution of aminoacetonitrile hydrochloride (75.9mg,0.82mmol) and N, N-diisopropylethylamine (232.63mg,1.80mmol) in dichloromethane (5mL) was added slowly dropwise to a solution of triphosgene (80.1mg,0.27mmol) in dichloromethane (3mL), the reaction stirred at room temperature for 1H, then N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d ] was added]Pyrimidin-4-amine (200mg,0.82mmol) was added slowly dropwise to a solution of N, N-diisopropylethylamine (116.32mg,0.90mmol) in dichloromethane (5mL) and reacted at room temperature for 19 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)2Cl2/CH3OH (v/v) ═ 8/1), purification afforded 52.1mg of white solid, yield: 19.40 percent.
MS(ESI,pos.ion)m/z:328.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)8.12(s,1H),7.11(t,J＝4.0Hz,1H),6.66(t,J＝3.2Hz,1H),4.10(s,2H),3.73-3.88(m,2H),3.48-3.63(m,2H),3.43(s,3H),3.24-3.25(m,1H),2.43-2.47(m,1H),1.86-1.91(m,1H),1.69-1.74(m,1H),1.10(d,J＝7.2Hz,3H).
Example 84- (2- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidin-1-yl) -2-acetyl) benzonitrile
Figure BDA0000892394300000332
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (93.0mg,0.38mmol), p-cyanophenylacetic acid (133.1mg,0.76mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (289.0mg,0.76mmol) was dissolved in DMF (6mL), then N, N-diisopropylethylamine (196.4mg,1.52mmol) was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (10mL) was added to the reaction mixture to quench the reaction, ethyl acetate (60mL) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 10/1), purification afforded 120.8mg of white solid, yield: 81.84 percent.
MS(ESI,pos.ion)m/z:389.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.69(s,1H),8.09(s,1H),7.79(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.46(d,J＝8.0Hz,1H),7.39(d,J＝8.0Hz,1H),7.13(s,1H),6.48(d,J＝25.0Hz,1H),3.77-4.06(m,4H),3.50-3.69(m,2H),3.23(s,3H),2.35-2.36(m,1H),1.99(s,1H),1.67-1.69(m,1H),1.52-1.56(m,1H),1.00(d,J＝6.8Hz,3H).
Example 94- (4- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidin-1-yl) -4-butanoyl) morpholin-3-one
Figure BDA0000892394300000341
Step 1: synthesis of compound ethyl 4- (3-oxomorpholine) butyrate
NaH (60%, 474mg,11.86mmol) was added to a solution of 3-morpholinone (600mg,5.93mmol) and ethyl bromobutyrate (2.32g,11.86mmol) in anhydrous DMF (15mL) at 0 deg.C and reacted overnight at room temperature. After completion of the reaction, the reaction was quenched by addition of water (30mL), extracted with EtOAc (150mL), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give 309mg of a colorless liquid, yield: 24.20 percent.
MS(ESI,pos.ion)m/z:216.3[M+1]+.
Step 2: synthesis of compound 4- (3-oxomorpholine) butyric acid
A solution of NaOH (287mg,7.18mmol) in water (2mL) was added to a solution of ethyl 4- (3-oxomorpholine) butyrate (309mg,1.44mmol) in ethanol (10mL) and allowed to react overnight at room temperature. After the reaction was completed, ethanol was removed by concentration under reduced pressure, the pH was adjusted to about 6 with concentrated hydrochloric acid, filtered, and the filter cake was dried to obtain 250mg of a white solid, which was directly put into the next step without further purification.
MS(ESI,pos.ion)m/z:188.2[M+1]+.
And step 3: synthesis of the compound 4- (4- ((3R,4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d ] pyrimidin-4-yl) amine) piperidin-1-yl) -4-butyryl) morpholin-3-one
Reacting N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (218mg,0.89mmol), 4- (3-oxomorpholine) butanoic acid (249.0mg,1.33mmol), HOBT (240.0mg,1.78mmol) and EDCI (340.0mg,1.78mmol) were dissolved in DMF (25mL), N-diisopropylethylamine (459.0mg,3.56mmol) was added and the mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was quenched by addition of water (30mL), extracted with dichloromethane (150mL), and the combined organic phases were extracted with anhydrous Na2SO4Drying, filtering, concentrating under reduced pressure, and subjecting the obtained residue to silica gel column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 15/1), purification afforded 55mg of white solid, yield: 14.90 percent.
MS(ESI,pos.ion)m/z:415.2[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)11.90(s,1H),8.17(s,1H),7.21(s,1H),6.64(s,1H),3.94-4.02(m,2H),3.74-3.83(m,4H),3.46-3.68(m,6H),3.26-3.29(m,3H),2.29-2.39(m,3H),1.71-1.79(m,3H),1.19-1.23(m,2H),1.03(d,J＝7.0Hz,3H).
Example 10 (3R,4R) - (R) -tetrahydrofuran-3-yl 4-methyl-3- (methyl (1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amine) piperidine-1-carboxylate
Figure BDA0000892394300000342
Step 1: synthesis of compound 4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidine
Reacting 4-chloro-1H-pyrazolo [3,4-d]Pyrimidine (1.00g,6.47mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (1.35g,8.09mmol) were dissolved in a mixed solvent of THF (15mL) and DMF (8mL), then N, N-diisopropylethylamine (1.05g,8.09mmol) was added and the mixture was stirred at-20 ℃ for 1 hour. After completion of the reaction, the reaction mixture was quenched by addition of water (20mL), extracted with dichloromethane (90mL), and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 15/1) to give 935.1mg of a colorless liquid, yield: 50.82 percent.
MS(ESI,pos.ion)m/z:285.1[M+1]+.
Step 2: synthesis of the compound N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
4-chloro-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3,4-d]Pyrimidine (830mg,3.51mmol) and (3R,4R) -1-benzyl-4-methyl-3-methylamino-piperidine (590mg,2.70mmol) were dissolved in DMF (10mL) and N, N-diisopropylethylamine (1.40g,10.80mmol) was added and the mixture was stirred at 60 ℃ for 17 h. After completion of the reaction, water (20mL) was added to the reaction mixture to quench the reaction, ethyl acetate (90mL) was extracted, and the combined organic phases were extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give 1.21g of a brown yellow liquid, yield: 96.03 percent.
MS(ESI,pos.ion)m/z:467.4[M+1]+.
And step 3: synthesis of Compound N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-1H-pyrazolo [3,4-d ] pyrimidin-4-amine
An ethyl acetate solution of hydrogen chloride (4.0M,16mL) was added dropwise to N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-pyrazolo [3, 4-d) at room temperature]The reaction was heated at 40 ℃ for 2.5 hours to a solution of pyrimidin-4-amine (1.21g,2.59mmol) in ethyl acetate (8 mL). After the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:CH2Cl2MeOH (v/v) ═ 15/1), purification afforded 824.8mg of a light yellow solid, yield: 94.65 percent.
MS(ESI,pos.ion)m/z:337.3[M+1]+.
And 4, step 4: synthesis of compound N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-amine
Palladium hydroxide on carbon (20%, 829mg) and trifluoroacetic acid (561mg,4.92mmol) were added sequentially to N- ((3R,4R) -1-benzyl-4-methylpiperidin-3-yl) -N-methyl-1H-pyrazolo [3,4-d]Pyrimidin-4-amine (829mg,2.46mmol) in MeOH (25mL) in H2The reaction was heated at 50 ℃ for 17 hours in an atmosphere. Filtering after the reaction is finished, concentrating the filtrate under reduced pressure, and performing silica gel column chromatography (eluent: CH) on the obtained residue2Cl2MeOH (v/v) ═ 10/1), purification afforded 507.2mg of light yellow liquid, yield: 83.71 percent.
MS(ESI,pos.ion)m/z:247.2[M+1]+.
And 5: synthesis of Compound (3R,4R) - (R) -tetrahydrofuran-3-yl 4-methyl-3- (methyl (1H-pyrazolo [3,4-d ] pyrimidin-4-yl) amine) piperidine-1-carboxylate
(R) - (-) -3-Hydroxytetrahydrofuran (156.0mg,1.77mmol) was added to a solution of N, N' -carbonyldiimidazole (249.7mg,1.54mmol) in THF (10mL), and the mixture was stirred at room temperature for 0.5 hour, followed by addition of triethylamine (3.35g,33.11mmol), and addition of N-methyl-N- ((3R,4R) -4-methylpiperidin-3-yl) -1H-pyrazolo [3,4-d ]]A solution of pyrimidin-4-amine (190.0mg,0.77mmol) in THF (10mL) was stirred at 60 ℃ for 48 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) ═ 10/1), purification afforded 87.3mg of white solid, yield: 31.46 percent.
MS(ESI,pos.ion)m/z:361.1[M+1]+；
1H NMR(400MHz,DMSO-d6):δ(ppm)0.97(d,J＝6.8Hz,3H),1.23(s,1H),1.54-1.59(m,1H),1.71(s,1H),1.89-1.91(m,1H),2.08(s,1H),2.32(s,1H),3.32(s,3H),3.47(s,2H),3.58-3.75(m,6H),5.14(s,1H),8.17(s,2H),8.23(s,1H),13.50(s,1H).
Example 113- (3- ((2-methoxy-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) (methyl) amino) -4-methylpiperidin-1-yl) -3-carbonylpropionitrile
Figure BDA0000892394300000351
Step 1: synthesis of compound 2, 4-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidine
At 0 deg.C, to 2, 4-dichloro-7H-pyrrolo [2,3-d ]]To a mixture of pyrimidine (500mg,2.67mmol) and sodium hydride (60%, 126.16mg,3.20mmol) was added N, N-dimethylformamide (15mL), stirred at 0 ℃ for 1h, SEMCl (516.5. mu.L, 2.95mmol) was slowly added, reacted at room temperature for 1h, then 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) ═ 5/1) afforded 680mg of a colourless oil, yield: 79.6 percent. MS (ESI, pos. ion) M/z 318.1[ M + 1]]+.
Step 2: synthesis of the compound N- (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
2, 4-dichloro-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]A mixture of pyrimidine (100mg,0.51mmol), 3-methylamino-4-methyl-1-benzylpiperidine (68.55mg,0.31mmol), potassium carbonate (256.68mg,1.86mmol) and tetrahydrofuran/water (2mL/2mL) was placed in a sealed tube and reacted at 110 ℃ for 24 h. Quenched by addition of saturated brine (10mL), extracted with dichloromethane (15 mL. times.3), and extracted with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 2/1) gave 86mg of a colourless oil, yield: 54.7 percent.
MS(ESI,pos.ion)m/z:500.3[M+1]+.
And step 3: synthesis of the compound N- (1-benzyl-4-methylpiperidin-3-yl) -2-methoxy-N-methyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine
At room temperature, N- (1-benzyl-4-methylpiperidin-3-yl) -2-chloro-N-methyl-7- ((2- (trimethyl)Silyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (50mg,0.1mmol) was dissolved in methanol (7mL), sodium methoxide (54.1mg,1.0mmol) was added, the mixture was refluxed for 12 hours, quenched by slowly adding water (10mL), extracted with dichloromethane (15 mL. times.3), and extracted with anhydrous Na2SO4Drying, removal of the solvent and column chromatography of the concentrate (eluent: PE/EtOAc (v/v) ═ 1/1) gave 50mg of a colourless oil, yield: 99 percent.
MS(ESI,pos.ion)m/z:496.40[M+1]+.
And 4, step 4: synthesis of Compound N- (1-benzyl-4-methylpiperidin-3-yl) -2-methoxy-N-methyl-7H-pyrrolo [2,3-d ] pyrimidin-4-amine
Reacting N- (1-benzyl-4-methylpiperidin-3-yl) -2-methoxy-N-methyl-7- ((2- (trimethylsilyl) ethoxy) methyl) -7H-pyrrolo [2,3-d]Pyrimidin-4-amine (100mg,0.20mmol) was dissolved in dichloromethane (3mL), trifluoroacetic acid (0.25mL) was added, stirring at room temperature for 8h, concentration was performed, tetrahydrofuran (3mL) was added for dissolution, sodium hydroxide solution (4M,0.2mL) was added, stirring at room temperature overnight, extraction was performed with ethyl acetate (15 mL. times.3), and anhydrous Na was added2SO4Drying, removing solvent, and performing column chromatography on the concentrated solution (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 68mg of a light yellow oil, yield: 93.2 percent.
MS(ESI,pos.ion)m/z:366.30[M+1]+.
And 5: synthesis of compound 3- (3- ((2-methoxy-7H-pyrrolo [2,3-d ] pyrimidin-4-yl) (methyl) amino) -4-methylpiperidin-1-yl) -3-carbonylpropionitrile
Reacting N- (1-benzyl-4-methylpiperidin-3-yl) -2-methoxy-N-methyl-7H-pyrrolo [2,3-d]Dissolving pyrimidin-4-amine (68mg,0.19mmol) in methanol (5mL), adding palladium hydroxide (20%, 13mg), reacting in an oil bath at 50 ℃ for 5h, filtering, and concentrating; dissolving in N, N-dimethylformamide (3mL), sequentially adding triethylamine (77.4 μ L,0.56mmol), EDCI (53.3mg, 0.28mmol), HOBT (37.7mg,0.28mol) and cyanoacetic acid (23.7mg,0.28mmol), stirring at room temperature overnight, concentrating to remove solvent, and separating by column chromatography (eluent: CH)2Cl2MeOH (v/v) ═ 30/1), yielding 11mg of a colorless oil, yield: 17.4 percent.
MS(ESI,pos.ion)m/z:343.3[M+1]+；
1H NMR(400MHz,CDCl3):δ(ppm)6.90(m,1H),6.55(m,1H),5.05(m,1H),3.99(m,2H),3.92(s,3H),3.87(m,1H),3.62-3.74(m,2H),3.48(m,1H),3.40(d,3H),2.53(m,1H),1.94(m,1H),1.79(m,1H),1.12(dd,J＝7.2Hz,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 compound name and characterization data
Figure BDA0000892394300000371
Figure BDA0000892394300000381
Biological activity
Biological example 1
Reagents and manufacturers required for the experiment:
JAK3, Carna, cat # 08-046; LANCE Detection Buffer,10X, PerkinElmer, cat # CR 97-100; TopSealTMA, Perkinelmer, cat # 6005185.
The compounds of the invention were biologically tested using the following methods:
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 × LANCE Detection Buffer;
5. the detection is carried out by adopting a white 384-well plate, and the reaction system is as follows:
TABLE 2 Compound vs JAK1/2/3 enzyme IC50Detection system
Figure BDA0000892394300000391
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, JAK enzyme and substrate-free reaction wells are used as positive controls, and enzyme-free wells (kinase reaction liquid) are used as negative controls. Adding corresponding sample, buffer solution and enzyme into each well in the order of Table 2, 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 BDA0000892394300000392
The Multilabel Reader detects and reads data at FP 320nM excitation/665 nM emission wavelength.
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 BDA0000892394300000393
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 BDA0000892394300000394
Business software of
Figure BDA0000892394300000395
4.0 the data generated were compared for verification and the results are shown in table 3.
Enzyme (JAK1/2/3) inhibition data for the compounds of Table 3
Figure BDA0000892394300000396
The data in table 3 show that the compound of the present invention has strong inhibitory effect on JAK1, JAK2 or JAK3 kinase; or the compound has stronger inhibition effect on JAK1, JAK2 and JAK3 kinases; the examples in table 3 are typical representations of the compounds of the present invention, which make it possible to deduce the activity of other structurally similar compounds.

Claims (4)

1. 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 FDA0002369942690000011
2. a pharmaceutical composition comprising a compound of claim 1, the pharmaceutical composition further comprising at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle; or/and
the pharmaceutical composition 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.
3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 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.
4. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 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 the compound of claim 1 or the pharmaceutical composition of claim 2, the protein kinase being JAK1, JAK2, or JAK 3.
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