CN109705191B - IAP inhibitors and their use in medicine - Google Patents

IAP inhibitors and their use in medicine Download PDF

Info

Publication number
CN109705191B
CN109705191B CN201811241130.9A CN201811241130A CN109705191B CN 109705191 B CN109705191 B CN 109705191B CN 201811241130 A CN201811241130 A CN 201811241130A CN 109705191 B CN109705191 B CN 109705191B
Authority
CN
China
Prior art keywords
independently
compound
amino
butyl
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201811241130.9A
Other languages
Chinese (zh)
Other versions
CN109705191A (en
Inventor
寇玉辉
谢洪明
张英俊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangdong HEC Pharmaceutical
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Publication of CN109705191A publication Critical patent/CN109705191A/en
Application granted granted Critical
Publication of CN109705191B publication Critical patent/CN109705191B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention belongs to the field of medicines, and relates to a novel compound for inhibiting IAP and application thereof. In particular, the present invention relates to a compound that is useful as an IAP inhibitor, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug thereof. The invention also relates to the use of said compounds and pharmaceutical compositions thereof as medicaments, in particular for the preparation of medicaments for the treatment or prevention of proliferative diseases.

Description

IAP inhibitors and their use in medicine
Technical Field
The present invention relates to a novel compound that inhibits IAP (inhibitor of apoptosis proteins), a salt thereof, a pharmaceutical composition thereof, and a method for producing the same. The invention further relates to the use of these compounds and their salts, their pharmaceutical compositions for the manufacture of medicaments for the treatment of proliferative diseases, in particular for the treatment of cancer.
Background
Apoptosis (programmed cell death) plays an important role in the development and homeostasis of all multicellular organisms. Alterations in the apoptotic pathway are involved in many types of human pathologies, including developmental disorders, cancer, autoimmune diseases, and neurodegenerative disorders. One mode of action of chemotherapeutic drugs is cell death through apoptosis.
Apoptosis is conserved between different species and is mainly performed by activated caspases (caspases), a family of cysteine proteases with aspartate specificity in their matrix. Once activated, the effector caspases cause proteolytic cleavage of a broad spectrum of cellular targets, which ultimately leads to cell death. In normal, viable cells that have not received apoptotic stimuli, most caspases remain inactive. If caspases are abnormally activated, their proteolytic activity can be inhibited by a family of evolutionarily conserved proteins called IAPs (inhibitors of apoptosis proteins).
IAP family proteins inhibit apoptosis by preventing activation of precursor caspases and inhibiting the enzymatic activity of mature caspases. IAPs have been described in organisms (from drosophila to humans) and are known to be overexpressed in many human cancers. IAPs prevent apoptosis by interacting directly with and neutralizing caspases. The prototype IAPs-XIAP and cIAP have three functional domains, referred to as BIR1, 2 and 3 domains, respectively. It is believed that by inhibiting caspases, the BIR domain causes an anti-apoptotic effect, thereby inhibiting apoptosis. Overexpression of XIAP in tumor cells has been shown to provide protection against various pro-apoptotic stimuli and to increase tolerance to chemotherapy. For patients with acute myeloid leukemia, a strong correlation between XIAP protein levels and survival has been demonstrated.
Smac has been reported to neutralize XIAP by binding to the peptide binding pocket on the surface of BIR3, therein abrogating the apoptotic inhibitory effect of XIAP. Smac interacts with essentially all IAPs that have been tested to date, including XIAP, c-IAP1, c-IAP2, ML-IAP and survivin. Thus, Smac appears to be a major regulator of apoptosis in mammals. It has been shown that Smac can increase not only the proteolytic activation of precursor caspases, but also the enzymatic activity of mature caspases, both of which depend on their ability to physically interact with IAPs.
Therefore, there is a need for compounds that mimic Smac for use as therapeutic agents in the treatment of proliferative diseases, particularly cancer. WO2005097791 and WO2008016893 disclose a series of IAP inhibitor compounds useful for the treatment of cancer, including compounds of the structure:
Figure BDA0001839332310000011
the present invention relates to a novel compound that inhibits IAP. The compounds are useful for treating proliferative diseases, including cancer.
Disclosure of Invention
The excellent characteristics of some parameters of the compound of the invention, such as half-life period, clearance rate, selectivity, bioavailability, chemical stability, metabolic stability, membrane permeability, solubility and the like, can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance and the like.
In one aspect, the present invention provides a compound having a structure represented by formula (I), (II), (III) or (IV), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of the compound having the structure represented by formula (I), (II), (III) or (IV),
Figure BDA0001839332310000021
wherein,
n1 is 1,2,3,4, 5, 6 or 7;
each n2 is independently 0, 1,2,3,4, 5, 6, or 7;
each n3 is independently 0, 1,2,3,4, 5, 6, 7, 8, or 9;
each m is independently 0, 1,2,3,4 or 5;
q is 1,2,3 or 4;
u is 1 or 2;
Q2is a covalent bond or-CH2-；
Cy is the following subformula:
Figure BDA0001839332310000022
wherein each t1Independently 1,2,3 or 4;
each t2Independently 1 or 2;
each t3Independently 0, 1,2 or 3;
wherein each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v), and (Cy-vi) is independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, and amino;
each R1、R2、R3、R3aAnd R5Independently H, D, alkyl, alkenyl, alkynyl, or carbocyclyl, wherein said alkyl, alkenyl, alkynyl, and carbocyclyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, phenyl, and amino;
each R4Independently H, D or alkyl;
each R0Independently D, F, Cl, Br, oxo (═ O), cyano, hydroxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, heterocyclyl, -S (═ O) -R10、-S(＝O)2-R10、-COOR8Aryl, alkoxy or alkyl; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, heterocyclyl, aryl, alkoxy, alkyl, 3-7 membered carbocycle, and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, and amino;
each R6Independently is H, D, F, Cl, Br, alkyl, hydroxy, amino, cyano, or alkoxy, wherein said alkyl, amino, and alkoxy are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, and amino;
each R7Independently H, D, alkyl, F, Cl, Br, or amino;
each R8、R9Independently H, D, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino; and
each R10Independently amino, alkyl, cycloalkylHeterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or 3-to 10-membered carbocyclyl wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and 3-10 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino;
each R4Independently H, D or C1-6An alkyl group; and
each R7Independently H, D, C1-6Alkyl, F, Cl, Br or amino.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Each of propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl is independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino;
each R4Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; and
each R7Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, F, Cl, Br or amino.
In some embodiments, each R is0Independently is D, F, Cl, Br, oxo (═ O), cyano, hydroxy, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered heterocyclyl, -S (═ O) -R10、-S(＝O)2-R10、-COOR8、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino;
each R8、R9Independently H, D, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino; and
each R10Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is0Independently D, F, Cl, Br, oxo (═ O), cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, -NR8R9、-S(＝O)-R10、-S(＝O)2-R10、-COOR8Phenoxy, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, carboxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; or, two R0And together with the carbon atoms to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, oxirane, oxetane, azaCyclopropane, 1, 3-dioxolane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine, tetrahydropyran, or tetrahydrofuran; wherein said hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, ethylene oxide, oxetane, aziridine, 1, 3-dioxolane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine, tetrahydropyran, and tetrahydrofuran are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, phenoxy, pyrrolidinyl, piperidine, tetrahydrofuranyl, hydroxy, cyclohexyl, and tetrahydrofuranyl, Isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl, and amino;
each R8And R9Independently H, D, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl; wherein said methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, and phenyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, phenyl, and amino; and
each R10Independently amino, methyl, ethyl, propylCyclopropyl, cyclohexyl, cyclopentyl, piperidinyl or phenyl; wherein said amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, phenyl, and amino.
In some embodiments, each R is6Independently H, D, F, Cl, Br, C1-6Alkyl, hydroxy, amino, cyano or C1-6Alkoxy, wherein said C1-6Alkyl, amino and C1-6Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino.
In some embodiments, each R is6Independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxy, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, hexacyclic, hydroxy, amino, n-propyl, n-butyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyridinyl, dioxanyl, and the like, Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and amino。
In some embodiments, Cy is the following subformula:
Figure BDA0001839332310000051
wherein each sub-formula (Cy-1), (Cy-2), (Cy-3), (Cy-4), (Cy-5), Cy-6), (Cy-7), (Cy-8), (Cy-9), Cy-10) is independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and amino.
In another aspect, the present invention provides a compound having a structure according to formula (VII), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure according to formula (VII),
Figure BDA0001839332310000052
wherein,
each R1、R2、R3、R3aAnd R5Independently H, D, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or 3-to 10-membered carbocyclyl wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and 3-10 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino;
each R4Independently H, D or C1-6An alkyl group;
each R7Independently H, D, alkyl, F, Cl, Br, or amino;
Figure BDA0001839332310000061
wherein each T1And T2Independently is a bond, -CR12R13-、-CR12R13-O-、-O-CR12R13-、-NR11-CR12R13-、-CR12R13-NR11、-CR12R13)2-、-(CR12R13)3-、-NR11-, -O-or-S-;
T3is-CR12R13-、-NR11-, -O-or-S-;
each R11Independently H, D, C1-6Alkyl, hydroxy, amino, cyano, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl or C6-10An aryl group;
each R12、R13Independently H, D, F, Cl, Br, hydroxy, oxo, amino, cyano, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl or C1-6An alkoxy group;
each R6Independently H, D, F, Cl, Br, C1-6Alkyl, hydroxy, amino, cyano or C1-6Alkoxy, wherein said C1-6Alkyl, amino and C1-6Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino;
wherein each subformula Y-1a, Y-2a, Y-3a, Y-4a and Y-5a can be independently and optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, oxo, amino, cyano, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl and C1-6Substituted by a substituent of alkoxy.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl or phenyl, wherein said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and phenyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino;
each R4Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
each R7Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, F, Cl, Br or amino;
Figure BDA0001839332310000062
Figure BDA0001839332310000071
wherein each R is11Independently H, D, methyl, ethyl, n-propyl, isopropyl, hydroxy, amino, cyano, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuryl, piperidinyl, or phenyl;
each R12、R13Independently is H, D, F, Cl, Br, hydroxy, oxo, amino, cyano, methyl, ethyl,N-propyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuryl, piperidinyl, methoxy, ethoxy, n-propoxy or isopropoxy;
each R6Independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxy, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, or tert-butoxy;
wherein each subformula Y1a, Y2a, Y3a, Y4a, Y5a, Y6a, Y7a, Y8a, Y9a, Y10a, Y11a, Y12a, Y13a, Y14a, Y15a, Y16a, Y17a, Y18a, Y19a and Y20a may be independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuranyl, piperidinyl, methoxy, ethoxy, n-propoxy or isopropoxy.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof.
In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a proliferative disease.
Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitroxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are within the scope of the present invention.
In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions which must be compatible with chemical or toxicological considerations, in connection with the other components which make up the formulation and 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 the compounds of formula (I), (II), (III) or (IV) or isolated enantiomers of the compounds of formula (I), (II), (III) or (IV).
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. Those 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 referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
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.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, 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 diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); principles of Asymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.
Unless otherwise defined herein, for any variable that occurs more than one time in any substituent or compound or any general structure described herein, its definition on each occurrence is independent of, and does not affect, its definition occurring anywhere else. Furthermore, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. A stable compound is one that can be isolated from the reaction mixture in a useful purity.
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, such as compounds of the general formula above, or as specifically exemplified, sub-classified and encompassed within the examples. It is understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the terms "substituted" or "substituted" mean that one or more hydrogen atoms in a given structure are replaced with a particular substituent. In some embodiments, "optionally substituted" means that the group may be substituted or unsubstituted. 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 can be, but not limited to, D, F, Cl, Br, hydroxyl, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, amino, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that specific items expressed between the same symbols do not affect each other in different groups or that specific items expressed between the same symbols in the same groups do not affect each other. For example, the structural formula "- (R)0)n1”、“-(R0)n2"and structural formula" - (R)0)n3' between three R0The specific options of (a) are not affected; structure "- (R)0)n1In each R0Are not affected by 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 "C1-6Alkyl "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 "C" used alone as a prefixm-n"group" means any group having m to n carbon atoms.
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. In some embodiments, the alkyl group contains 1 to 10 carbon atoms; in some embodiments, 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. In some specific structures, when an alkyl group is explicitly represented as a linking group, then the alkyl group represents a linked alkylene group, e.g., formula (C)6-10Aryl group) - (C1-6C in alkyl) -, C1-6Alkyl is understood to mean C1-6An alkylene group.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl (Et-CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl (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) 2-ethyl-1-butyl (-CH)2CH(CH2CH3)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 "amino" refers to "-NH2”。
The term "hydroxy" refers to "-OH".
The term "cyano" refers to "-CN" or "-C ≡ N".
The term "halogen" refers to F, Cl, Br or I.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 10 carbon atoms; in one embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) Propenyl (-CHCH)3) Isopropenyl (-C (CH)3)＝CH2) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, in one embodiment, the alkynyl group contains 2-10 carbon atoms; alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (-C.ident.C-CH)3) And so on.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. 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 terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a mono-, bi-or tricyclic ring containing 3 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur and oxygen, and which may be fully saturated or contain one or more degrees of unsaturation, but not one aromatic ring. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. In some embodiments, heterocyclyl is 3-7 memberedA heterocyclic group of (a); in other embodiments, the heterocyclyl is a 4-7 membered heterocyclyl; in other embodiments, heterocyclyl is a 3-6 membered heterocyclyl; in other embodiments, heterocyclyl is a 4-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a 5-6 membered heterocyclyl; in other embodiments, the heterocyclyl is a 5-membered heterocyclyl; in other embodiments, the heterocyclyl is a 6-membered heterocyclyl; in other embodiments, the heterocyclyl is a 7-membered heterocyclyl. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, 1, 3-dioxolyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, 1, 4-oxazepanyl, thiepanyl, oxazepanyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, 1, 3-dioxolyl, 2-dioxolanyl, dithiopyranyl, 4-oxazepanyl, tetrahydropyranyl, dioxanyl, piperidinyl, thiapanyl, and oxazepanyl
Figure BDA0001839332310000101
Radical, diaza
Figure BDA0001839332310000111
Radical, S-N-aza
Figure BDA0001839332310000112
Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]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-oxo-azepanyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholinyl, and the like. SaidHeterocyclyl groups may be optionally substituted with one or more substituents described herein.
The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In some embodiments, "carbocyclyl" or "carbocycle" is C3-10Carbocyclyl or 3-10 membered carbocycle; in other embodiments, "carbocyclyl" or "carbocycle" is C3-7Carbocyclyl or 3-7 membered carbocycle; in other embodiments, "carbocyclyl" or "carbocycle" is C4-7Carbocyclyl or a 4-7 membered carbocyclic ring; in still other embodiments, "carbocyclyl" or "carbocycle" is C4-6In yet other embodiments, "carbocyclyl" or "carbocycle" is C3-6Carbocyclyl or 3-6 membered carbocycle. Such examples further include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl (1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl), cyclopentadienyl (2, 4-cyclopentadienyl, 1, 3-cyclopentadienyl), cyclohexyl, cyclohexenyl (1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl), cyclohexadienyl (1, 3-cyclohexadienyl, 1, 4-cyclohexadienyl), cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl group may be optionally substituted with one or more substituents described herein.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In some embodiments, cycloalkyl contains 3 to 6 carbon atoms, i.e., C3-6A cycloalkyl group. Specific examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "aryl" denotes a compound containing 6 to 14 ring atomsOr monocyclic, bicyclic and tricyclic carbon ring systems of 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. In some embodiments, the aryl group contains 6 to 10 carbon atoms, i.e., C6-10And (4) an aryl group. Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms (heteroatoms comprise nitrogen, phosphorus, oxygen or sulfur), wherein each ring system contains a ring of 5 to 7 atoms and has 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". In some embodiments, the heteroaryl group is a 5-6 membered heteroaryl; in other embodiments, the heteroaryl group is a 5-membered heteroaryl; in other embodiments, the heteroaryl group is a 6 membered heteroaryl. 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), and the like, 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 "aryloxy" means that the aryl group is attached to the rest of the molecule through an oxygen atom. Wherein the aryl group has the meaning as described in the present invention. In one embodiment, the aryloxy group contains 6 to 10 carbon atoms, i.e., C6-10An aryloxy group. Examples of aryloxy groups include, but are not limited to: phenoxy, naphthoxy, and the like. The aryloxy group may be optionally substituted with one or more substituents described herein.
The term "haloalkyl" denotes an alkyl group substituted with one or more halogens. In some embodiments, haloalkyl group represents a haloalkyl group containing 1-6 carbon atoms, i.e., C1-6A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-4 carbon atoms, i.e., C1-4A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-3 carbon atoms, i.e., C1-3A haloalkyl group. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, 1, 2-dichloroethyl, 1, 2-difluoroethyl, and the like.
The term "hydroxyalkyl" denotes an alkyl group substituted with one or more hydroxyl groups. In some embodiments, a hydroxyalkyl group represents a hydroxyalkyl group containing 1-6 carbon atoms, i.e., C1-6A hydroxyalkyl group; in still other embodiments, the hydroxyalkyl group represents a haloalkyl group containing 1 to 4 carbon atoms, i.e., C1-4A hydroxyalkyl group; in still other embodiments, the hydroxyalkyl group represents a hydroxyalkyl group containing 1 to 3 carbon atoms, i.e., C1-3A hydroxyalkyl group. Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, 1, 2-dihydroxyethyl, 1-hydroxypropyl, 2-dihydroxyethyl-hydroxypropyl, 2-hydroxy-2 methylpropyl, hydroxybutyl, and the like.
The term "alkoxyalkyl" denotes an alkyl group substituted with one or more alkoxy groups. In some embodiments, the alkoxyalkyl group is represented by one C1-6Alkoxy-substituted C1-6Alkyl radicals, i.e. C1-6Alkoxy radical C1-6An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-4Alkoxy-substituted C1-4Alkyl radicals, i.e. C1-4Alkoxy radical C1-4An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-3Alkoxy-substituted C1-3Alkyl radicals, i.e. C1-3Alkoxy radical C1-3An alkyl group; in other embodiments, the alkoxyalkyl group is represented by a C1-3Alkoxy-substituted C1-4Alkyl radicals, i.e. C1-3Alkoxy radical C1-4An alkyl group. Examples include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, methoxypropyl, and the like.
The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogens. In some embodiments, the haloalkoxy group represents a haloalkyl group containing 1 to 6 carbon atoms, i.e., C1-6A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-4 carbon atoms, i.e., C1-4A haloalkyl group; in still other embodiments, haloalkyl groups represent haloalkyl containing 1-3 carbon atoms, i.e., C1-3A haloalkyl group. Examples include, but are not limited to, trifluoromethoxy, difluoromethoxy, monofluoro-substituted methoxy, 1, 2-difluoroethoxy, and the like.
As described herein, the substituent (R)0)n1The ring system formed by a ring bound to the center (as shown in formula f) represents n1 substituents R0The substitution can be made at any substitutable or any reasonable position on the ring. For example, formula f represents any possible substituted position on the ring which may be substituted by n1 substituents R0And (4) substitution.
Figure BDA0001839332310000121
As described herein, unless otherwise specified, a ring substituent may be attached to the rest of the molecule through any available position on the ring. For example, piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl.
Unless otherwise indicated, the structural formulae depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational) isomers): such as the R, S configuration containing an asymmetric center, the (Z), (E) isomers of the double bond, and the conformational isomers of (Z), (E). Thus, individual stereochemical isomers of the compounds of the present invention or mixtures of enantiomers, diastereomers, or geometric isomers (or conformers) thereof are within the scope of the present invention.
Unless otherwise indicated, the structural formulae depicted herein and the compounds depicted herein include all isomeric forms (e.g., enantiomeric, diastereomeric, geometric or conformational isomers), nitroxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs. Thus, compounds that are individual stereochemically isomeric forms, enantiomeric forms, diastereomeric forms, geometric forms, conformational forms, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts and prodrugs of the compounds of the present invention are also within the scope of the present invention. In addition, unless otherwise indicated, the structural formulae of the compounds described herein include isotopically enriched concentrations of one or more different atoms.
The term "protecting group" or "Pg" refers to a substituent that when reacted with other functional groups, is typically 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-butyloxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylideneMethoxycarbonyl (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). 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.
For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.Symphosis Series, Edward B.Roche, ed., Bioreversible Carriers in Drug designs, American Pharmaceutical Association and Pergamon Press,1987, J.Rautio et al, Prodrugs in Design and Clinical Applications, Nature Review Delivery, 2008,7,255 and 270, S.J.Herer 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.
The definition and convention of stereochemistry in the present invention is generally used with reference to the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York,1994.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including, but in no way limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefix D, L or R, S is used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l or (+), (-) are used to designate the sign of the rotation of plane polarized light of the compound, with (-) or l indicating that the compound is left-handed and the prefix (+) or d indicating that the compound is right-handed. The chemical structures of these stereoisomers are identical, but their stereo structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is commonly referred to as a mixture of enantiomers. 50:50 is called a racemic mixture or racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" refer to a mixture of two enantiomers in equimolar amounts, lacking optical activity.
"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.
The term "tautomer" or "tautomeric form" means that isomers of structures of different energies may be interconverted through a low energy barrier. For example, proton tautomers (i.e., prototropic tautomers) include tautomers that move through protons, such as keto-enol and imine-enamine isomerizations. Valence (valence) tautomers include tautomers that recombine into bond electrons.
"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 having two or more chiral centers 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.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodidesSalts, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. 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.
The "hydrate" of the present invention means an association of solvent molecules with water.
"nitroxide" in the context of the present invention means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
"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.
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) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.
In another aspect, the invention relates to intermediates for the preparation of compounds encompassed by formula (I), (II), (III) or (IV).
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I), (II), (III) or (IV).
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and pharmaceutically acceptable adjuvants thereof. In some embodiments, adjuvants of the present invention include, but are not limited to, carriers, excipients, diluents, vehicles, or combinations thereof. In some embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel, or spray dosage form.
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 a compound of formula (I), (II), (III) or (IV). 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, for each designated deuterium atom, 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), at least) The isotopic enrichment factor of (a). 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).
Description of the Compounds of the invention
The compound can effectively inhibit the proliferation of tumor cells as an IAP inhibitor, and can be used for preparing medicaments for preventing and treating cancers.
In one aspect, the present invention provides a compound having a structure represented by formula (I), (II), (III) or (IV), or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug of a compound having a structure represented by formula (I), (II), (III) or (IV),
Figure BDA0001839332310000151
Figure BDA0001839332310000161
wherein,
n1 is 1,2,3,4, 5, 6 or 7;
each n2 is independently 0, 1,2,3,4, 5, 6, or 7;
each n3 is independently 0, 1,2,3,4, 5, 6, 7, 8, or 9;
each m is independently 0, 1,2,3,4 or 5;
q is 1,2,3 or 4;
u is 1 or 2;
Q2is a covalent bond or-CH2-；
Cy is the following subformula:
Figure BDA0001839332310000162
wherein each t1Independently 1,2,3 or 4;
each t2Independently 1 or 2;
each t3Independently 0, 1,2 or 3;
wherein each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v), and (Cy-vi) is independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, and amino;
each R1、R2、R3、R3aAnd R5Independently H, D, alkyl, alkenyl, alkynyl, or carbocyclyl, wherein said alkyl, alkenyl, alkynyl, and carbocyclyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, phenyl, and amino;
each R4Independently H, D or alkyl;
each R0Independently D, F, Cl, Br, oxo (═ O), cyano, hydroxy, haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, -NR8R9Aryloxy, heterocyclyl, -S (═ O) -R10、-S(＝O)2-R10、-COOR8Aryl, alkoxy or alkyl; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said haloalkyl, hydroxyalkyl, haloalkoxy, alkoxyalkyl, aryloxy, heterocyclyl, aryl, alkoxy, alkyl, 3-7 membered carbocycle, and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl, and amino;
each R6Independently is H, D, F, Cl, Br, alkyl, hydroxy, amino, cyano, or alkoxy, wherein said alkyl, amino, and alkoxy are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, and amino;
each R7Independently H, D, alkyl, F, Cl, Br, or amino;
each R8、R9Independently H, D, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino; and
each R10Independently amino, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said amino, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, alkyl, cycloalkyl, heterocyclyl, alkoxy, aryl and amino.
In some embodiments, each subformula (Cy-i), (Cy-ii), (Cy-iii), (Cy-iv), (Cy-v), and (Cy-vi) is independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxyl, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or 3-to 10-membered carbocyclyl wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and 3-10 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino;
each R4Independently H, D or C1-6An alkyl group;
each R0Independently is D, F, Cl, Br, oxo (═ O), cyano, hydroxy, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy group, 3-to 7-membered heterocyclic group、-S(＝O)-R10、-S(＝O)2-R10、-COOR8、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino;
each R6Independently H, D, F, Cl, Br, C1-6Alkyl, hydroxy, amino, cyano or C1-6Alkoxy, wherein said C1-6Alkyl, amino and C1-6Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino;
each R7Independently H, D, C1-6Alkyl, F, Cl, Br or amino;
each R8、R9Independently H, D, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino; and
each R10Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or 3-to 10-membered carbocyclyl wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and 3-10 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino;
each R4Independently H, D or C1-6An alkyl group; and
each R7Independently H, D, C1-6Alkyl, F, Cl, Br or amino.
In some embodiments, each R is1、R2、R3、R3aIndependently H, D, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl or 3-6 membered carbocyclyl wherein said C is1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl and 3-6 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino.
In some embodiments, each R is4Independently H, D or C1-4An alkyl group.
In some embodiments, each R is5Independently H, D, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl or 3-6 membered carbocyclyl, whereinC is1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl and 3-6 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino.
In some embodiments, each R is1、R2、R3、R3aIndependently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Each of propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl is independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino.
In some embodiments, each R is4Independently H, D, methyl, ethyl, n-propylAlkyl, isopropyl, n-butyl, isobutyl or tert-butyl.
In some embodiments, each R is5Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl or cyclohexadienyl, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH ═ CH2、-CH＝CH-CH3、-CH2-CH＝CH2、-CH＝CH-CH2CH3-、-CH2-CH＝CH2-CH3、-(CH2)2-CH＝CH2、-C(CH3)＝CH2-CH3Each of propargyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclohexadienyl is independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino.
In some embodiments, each R is7Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, F, Cl, Br or amino.
In some embodiments, each R is0Independently is D, F, Cl, Br, oxo (═ O), cyano, hydroxy, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered heterocyclyl, -S (═ O) -R10、-S(＝O)2-R10、-COOR8、C6-10Aryl radical, C1-6Alkoxy or C1-6An alkyl group; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Haloalkoxy, C1-6Alkoxy radical C1-6Alkyl radical, C6-10Aryloxy group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-6Alkoxy radical, C1-6Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is8、R9Independently H, D, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino; and
each R10Independently of one another is amino, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl or 5-6 membered heteroaryl; wherein said amino group, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each independently optionally substituted by 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy radical, C6-10Aryl and amino.
In some embodiments, each R is0Independently is D, F, Cl, Br, oxo (═ O), cyano, hydroxy, C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C1-4Haloalkoxy, C1-4Alkoxy radical C1-4Alkyl, -NR8R9、C6-10Aryloxy, 3-7 membered heterocyclyl, -S (═ O) -R10、-S(＝O)2-R10、-COOR8、C6-10Aryl radical, C1-4Alkoxy or C1-4An alkyl group; or, two R0And the carbon atoms to which they are attached together form a 3-7 membered carbocyclic ring or a 3-7 membered heterocyclic ring; wherein said C1-4Haloalkyl, C1-4Hydroxyalkyl radical, C1-4Haloalkoxy, C1-4Alkoxy radical C1-4Alkyl radical, C6-10Aryloxy group, 3-to 7-membered heterocyclic group, C6-10Aryl radical, C1-4Alkoxy radical, C1-4Alkyl, 3-7 membered carbocycle and 3-7 membered heterocycle are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino.
In some embodiments, each R is0Independently D, F, Cl, Br, oxo (═ O), cyano, hydroxy, amino, trifluoromethyl, trifluoromethoxy, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, -NR8R9、-S(＝O)-R10、-S(＝O)2-R10、-COOR8Phenoxy, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, carboxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl; or, two R0And together with the carbon atoms to which they are attached form cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, oxirane, oxetane, aziridine, 1, 3-dioxanCyclopentane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine, tetrahydropyran, or tetrahydrofuran; wherein said hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxy, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, morpholinyl, piperazinyl, imidazolidinyl, phenyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, ethylene oxide, oxetane, aziridine, 1, 3-dioxolane, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyridine, tetrahydropyran, and tetrahydrofuran are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, phenoxy, pyrrolidinyl, piperidine, tetrahydrofuranyl, hydroxy, cyclohexyl, and tetrahydrofuranyl, Isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl, and amino.
In some embodiments, each R is8、R9Independently H, D, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl; wherein said methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl and phenyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, phenyl and amino.
In some embodiments, each R is10Independently of ammoniaA group selected from methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, and phenyl; wherein said amino, methyl, ethyl, propyl, cyclopropyl, cyclohexyl, cyclopentyl, piperidinyl, or phenyl are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, phenyl, and amino.
In some embodiments, each R is6Independently H, D, F, Cl, Br, C-6Alkyl, hydroxy, amino, cyano or C1-6Alkoxy, wherein said C1-6Alkyl, amino and C1-6Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino.
In some embodiments, each R is6Independently H, D, F, Cl, Br, C1-4Alkyl, hydroxy, amino, cyano or C1-4Alkoxy, wherein said C1-4Alkyl, amino and C1-4Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino.
In some embodiments, each R is6Independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxyl, amino, cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, wherein said methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, amino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyl, tert-butyl, amino, methoxy, ethoxy, n-propoxy, isopropoxy, tert-butyl, hydroxyl, amino, or amino, or amino, or amino, or amino, or amino, or amino, or amino, or aminoEach of n-butoxy, iso-butoxy and tert-butoxy is independently optionally substituted with 1,2,3 or 4 substituents selected from the group consisting of D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy and amino.
In some embodiments, Cy is the following subformula:
Figure BDA0001839332310000201
wherein each sub-formula (Cy-1), (Cy-2), (Cy-3), (Cy-4), (Cy-5), Cy-6), (Cy-7), (Cy-8), (Cy-9), Cy-10) is independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and amino.
In some embodiments, the present invention provides a compound of the structure of formula (V), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of the structure of formula (V),
Figure BDA0001839332310000211
wherein R is0、R6、R7M and n1 have the definitions as described herein.
In some embodiments, the present invention provides a compound of the structure of formula (VI), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of the structure of formula (VI),
Figure BDA0001839332310000212
wherein R is0And n1 has the definitions as set forth herein.
In another aspect, the present invention provides a compound having a structure according to formula (VII), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound having a structure according to formula (VII),
Figure BDA0001839332310000213
wherein,
each R1、R2、R3、R3aAnd R5Independently H, D, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl or 3-to 10-membered carbocyclyl wherein said C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and 3-10 membered carbocyclyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy, phenyl and amino;
each R4Independently H, D or C1-6An alkyl group;
each R7Independently H, D, alkyl, F, Cl, Br, or amino;
Figure BDA0001839332310000221
wherein each T1And T2Independently is a bond-CR12R13-、-CR12R13-O-、-O-CR12R13-、-NR11-CR12R13-、-CR12R13-NR11、-CR12R13)2-、-(CR12R13)3-、-NR11-, -O-or-S-;
T3is-CR12R13-、-NR11-, -O-or-S-;
each R11Independently H, D, C1-6Alkyl, hydroxy, amino, cyano, C1-6Alkoxy radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl or C6-10An aryl group;
each R12、R13Independently H, D, F, Cl, Br, hydroxy, oxo, amino, cyano, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl or C1-6An alkoxy group;
each R6Independently H, D, F, Cl, Br, C1-6Alkyl, hydroxy, amino, cyano or C1-6Alkoxy, wherein said C1-6Alkyl, amino and C1-6Each alkoxy is independently optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, C1-4Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C1-4Alkoxy and amino;
wherein each subformula Y-1a, Y-2a, Y-3a, Y-4a and Y-5a can be independently and optionally substituted by 1,2,3 or 4 groups selected from D, F, Cl, Br, hydroxy, oxo, amino, cyano, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl and C1-6Substituted by a substituent of alkoxy.
In some embodiments, each R is1、R2、R3、R3aAnd R5Independently H, D, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl or phenyl, wherein said methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl or phenyl isAlkenyl, cyclohexenyl and phenyl are each independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyrimidinyl, dioxanyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl and amino;
each R4Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
each R7Independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, F, Cl, Br or amino;
Figure BDA0001839332310000222
Figure BDA0001839332310000231
wherein each R is11Independently H, D, methyl, ethyl, n-propyl, isopropyl, hydroxy, amino, cyano, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuryl, piperidinyl, or phenyl;
each R12、R13Independently H, D, F, Cl, Br, hydroxy, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuryl, piperidinyl, methoxy, ethoxy, n-propoxy, or isopropoxy;
each R6Independently H, D, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, hydroxy, amino,Cyano, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy;
wherein each subformula Y1a, Y2a, Y3a, Y4a, Y5a, Y6a, Y7a, Y8a, Y9a, Y10a, Y11a, Y12a, Y13a, Y14a, Y15a, Y16a, Y17a, Y18a, Y19a and Y20a may be independently optionally substituted with 1,2,3 or 4 substituents selected from D, F, Cl, Br, hydroxy, oxo, amino, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, pyrrolyl, piperazinyl, morpholinyl, tetrahydrofuranyl, piperidinyl, methoxy, ethoxy, n-propoxy or isopropoxy.
In some embodiments, the present invention provides a structure according to formula (VIII), or a stereoisomer, geometric isomer, tautomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of a compound of formula (VIII),
Figure BDA0001839332310000232
wherein,
Figure BDA0001839332310000233
having the definitions as described in the present invention.
In another aspect, the present invention provides a compound having the structure of one of, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure BDA0001839332310000241
Figure BDA0001839332310000251
Figure BDA0001839332310000261
Figure BDA0001839332310000271
in another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and pharmaceutically acceptable adjuvants thereof.
In another aspect, the invention provides the use of a compound of the invention or a pharmaceutical composition of the invention in the manufacture of a medicament for the prevention or treatment of a proliferative disease. In another aspect, the invention provides a compound of the invention or a pharmaceutical composition of the invention for use in the prevention or treatment of a proliferative disease.
In one aspect, the invention provides a method for treating or preventing a proliferative disorder, the method comprising administering to a patient having a proliferative disorder a pharmaceutically acceptable therapeutically effective amount of a compound of the invention or a pharmaceutical composition of the invention.
In some embodiments, the proliferative disease described herein is cancer.
In some embodiments, the cancers of the present invention include, but are not limited to, rectal cancer, renal cancer, ovarian cancer, pancreatic cancer, prostate cancer, breast cancer, melanoma, glioblastoma, acute myeloid leukemia, small cell lung cancer, non-small cell lung cancer, rhabdomyosarcoma, basal cell carcinoma, and the like.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
Nitroxides of the compounds of the present invention are also included within the scope of the present invention. The nitroxides of the compounds of the present invention may be prepared by oxidation of the corresponding nitrogen-containing basic species using a common oxidizing agent (e.g. hydrogen peroxide) in the presence of an acid such as acetic acid at elevated temperature, or by reaction with a peracid in a suitable solvent, for example peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
If the compounds of the invention are basic, the desired salts may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or using organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluenesulfonic acid, ethanesulfonic acid, and the like.
If the compounds of the invention are acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali or alkaline earth metal hydroxides, and the like. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine, piperazine and the like, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
Compounds of the invention and pharmaceutical compositions, formulations and administrations thereof
According to another aspect, a feature of the pharmaceutical composition of the invention includes a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), a compound listed in the present invention, or a compound of the examples. The amount of compound in the compositions of the invention is effective to treat or ameliorate a proliferative disease, including cancer, in a subject.
As described herein, the pharmaceutically acceptable compositions of the present invention further comprise pharmaceutically acceptable adjuvants, as used herein, including any solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, and the like, as appropriate for the particular target dosage form. As described in the following documents: 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. Annu 1999, Marcel Dekker, New York, taken together with The disclosure of this document, indicates that different adjuvants can be used In The preparation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except insofar as any conventional adjuvant is incompatible with the compounds of the present invention, e.g., any adverse biological effect produced or interaction in a deleterious manner with any other component of a pharmaceutically acceptable composition, their use is contemplated by the present invention.
When useful in therapy, a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and pharmaceutically acceptable salts thereof, may be administered as a raw chemical, and may also be provided as the active ingredient of a pharmaceutical composition. Accordingly, the present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention, particularly a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable adjuvants, including but not limited to carriers, diluents, or excipients, and the like. The term "therapeutically effective amount" as used herein refers to the total amount of each active component sufficient to show meaningful patient benefit (e.g., cancer cell reduction). When the active ingredient alone is used for separate administration, the term refers only to that ingredient. When used in combination, the term refers to the combined amounts of the active ingredients that, when combined, administered sequentially or simultaneously, result in a therapeutic effect. The compounds of the invention, especially the compounds of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) and their pharmaceutically acceptable salts are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. According to another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation which comprises mixing a compound of the present invention, especially a compound of formula (I), (II), (III), (IV), (V) or (VI), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and which are effective for their intended use.
The amount of active ingredient that is combined with one or more adjuvants to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. The amount of active ingredient in a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the rate of excretion of the compound used, the time of treatment and the age, sex, body weight and condition of the patient. Preferred unit dosage forms are those containing a daily or divided dose or suitable fraction thereof of the active ingredient described herein above. Treatment can be initiated with small doses, which are clearly below the optimal dose of the compound. Thereafter, the dosage is increased in smaller increments until the optimum effect is achieved in this case. In general, the compounds are most desirably administered at concentration levels that generally provide effective results in antitumor terms without causing any harmful or toxic side effects.
The pharmaceutical compositions comprise from about 1% to about 95%, preferably from about 20% to about 90% of the active ingredient. The pharmaceutical compositions of the present invention may be, for example, in unit dosage form such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
The dose of a compound of formula I or a pharmaceutically acceptable salt thereof administered to a patient, e.g., a human of about 70kg body weight, is preferably from about 3mg to about 10g, more preferably from about 10mg to about 1.5g, most preferably from about 100mg to about 1000mg per person per day, preferably divided into 1 to 3 single doses which may, for example, be of the same size. The dosage of children is half of that of adults.
The pharmaceutical compositions provided herein comprise a therapeutically effective amount of one or more compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) provided herein for preventing, treating, or ameliorating one or more symptoms of a hyperproliferative disease or disorder associated with caspase activity, including caspase-9 activity. Such diseases or disorders include, but are not limited to, hyperproliferative diseases, autoimmune diseases, psoriasis, hyperplasia, and restenosis.
The pharmaceutical compositions are suitable for administration by any suitable route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by mixing the active ingredient with a carrier or excipient. Oral administration or injection administration is preferred.
In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For example, tablets are prepared by making a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into tablets. The powdered mixture is prepared by mixing the appropriately comminuted compound with a diluent or base as described above, optionally with a binder (for example carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone), a dissolution inhibitor (for example paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (for example bentonite, kaolin or dicalcium phosphate). The powdered mixture may be granulated by wetting with a binder such as syrup, starch slurry, acacia slurry (acadia mucilage) or a solution of cellulosic or polymeric material and pressure sieving. An alternative to granulation is to pass the powder mixture through a tablet press, with the result that poorly formed agglomerates are broken up into granules. The granules may be lubricated by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the dies of the tablet press. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure may also be combined with a free-flowing inert carrier and compressed into tablets without going through a granulation or pre-compression step. Transparent or opaque protective coating materials may be provided which consist of a shellac coating, a sugar coating or a coating of a polymeric material and a waxy polishing coating (wax). Dyes may be added to these coatings to distinguish different unit doses.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example, such formulations which are suitable for oral administration may include flavouring agents.
Use of the Compounds and pharmaceutical compositions of the invention
Features of the pharmaceutical compositions of the invention include a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), a compound of the invention as set out in the examples, or a compound of the examples, and a pharmaceutically acceptable adjuvant, e.g., carrier, adjuvant or vehicle, etc. The compounds in the compositions of the invention are useful in the prevention and treatment of proliferative diseases.
The proliferative disease is primarily a neoplastic disease (or cancer) (and/or any metastases). The compounds of the present invention or pharmaceutical compositions thereof can be used for the preparation of a medicament particularly useful for the treatment of cancer, including tumors, such as skin cancer, breast cancer, brain cancer, neck cancer, testicular cancer, and the like. It is particularly useful for the treatment of metastatic or malignant tumors. More particularly, cancers that may be treated by the compositions and methods of the present invention include, but are not limited to, the following tumor types: such as astrocytic, breast, neck, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid cancers, as well as sarcomas. More particularly, these compounds are useful in the treatment of: cancer in the heart region: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancer: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, hamartoma, mesothelioma; cancer in the gastrointestinal tract: esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, reoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract cancer: renal cancer (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urinary tract cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); cancer of the liver site: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bone-related cancers: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrosarcoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell chordoma, osteochondromatoma (osteoectochondromy wart), benign chondroma, chondroblastoma-like fibroma (chondroblastoma), osteoid osteoma, and giant cell tumor; cancers of the nervous system: cranial cancers (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meningeal cancers (meningioma, meningiosarcoma (menigiospora), glioma), brain cancers (astrocytoma, neuroblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynecological cancer: uterine cancer (endometrial cancer), cervical cancer (neck cancer, pre-neoplastic cervical dysplasia), ovarian cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors (granulosa-thecal tumors), sertoli cell tumors, dysgerminoma, malignant teratoma), vulval cancer (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (rhabdomyosarcoma), fallopian tube tumor (carcinoma), hematologic cancer: leukemia (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, pre-tumor cervical dysplasia, cervical cancer (cervical cancer, pre-malignant cyst-cervical cancer), uterine cancer-cervical cancer (serous cyst adenocarcinoma, mucinous cyst adenocarcinoma, sarcoidosis, dysgerminoma, malignant teratoma), vulval cancer (squamous cell carcinoma, botryoid sarcoma, fallopian tube tumor (carcinoma), hemangioma), hematologic cancer, leukemia, Non-hodgkin lymphoma (malignant lymphoma); skin cancer: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal cancer, neuroblastoma. Thus, the term "cancer cell" as provided herein includes cells having any or related of the above-identified conditions.
In the broad sense of the present invention, a proliferative disease may also be a hyperproliferative condition such as leukemia, hyperplasia, fibrosis (especially pulmonary fibrosis, but also other types of fibrosis such as renal fibrosis), angiogenesis, psoriasis, atherosclerosis and smooth muscle hyperplasia in blood vessels such as stenosis or restenosis following angioplasty.
When referring to a tumor, a tumor disease, a cancer or a cancer, additionally or alternatively metastases at the original organ or tissue and/or any other site are implied, irrespective of the site of the tumor and/or metastases.
The compounds of the present invention may be administered alone or in combination with other anti-cancer agents, such as compounds that inhibit tumor angiogenesis, e.g., protease inhibitors, epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, and the like; cytotoxic drugs such as antimetabolites, e.g., purine and pyrimidine mimetic antimetabolites; antimitotic agents such as microtubule stabilizing agents and antimitotic alkaloids; a platinum coordination complex; anti-tumor antibiotics; alkylating agents such as nitrogen mustards and nitrosoureas; endocrine drugs such as adrenocorticosteroids, androgens, antiandrogens, estrogens, antiestrogens, aromatase inhibitors, gonadotropin-releasing hormone agonists and somatostatin analogues and compounds targeting enzymes or receptors that are overexpressed and/or involved in specific metabolic pathways that are upregulated in tumor cells, for example inhibitors of ATP and GTP phosphodiesterase, inhibitors of histone deacetylase, inhibitors of protein kinases such as serine, threonine and tyrosine kinases, for example, Abelson protein tyrosine kinase and various growth factors, their receptors and kinase inhibitors such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors, platelet derived growth factor receptor kinase inhibitors, and the like; methionine aminopeptidase inhibitors, proteasome inhibitors, and cyclooxygenase inhibitors, e.g., cyclooxygenase-1 or-2 inhibitors.
In some embodiments, when administered in combination, there are two modes: 1) the compound or the pharmaceutical composition and other combinable active medicaments are respectively prepared into separate preparations, and the two preparations can be the same or different and can be used sequentially or simultaneously; when used sequentially, the first medicament does not lose its effective effect in vivo when the second medicament is administered; 2) the compound or pharmaceutical composition of the present invention and other active agents that can be combined are formulated into a single formulation and administered simultaneously.
The invention further relates to a method of promoting apoptosis in rapidly proliferating cells comprising contacting the rapidly proliferating cells with an apoptosis-promoting effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII) of the invention that binds to the Smac binding site of the XIAP and/or cIAP protein.
In another embodiment of the invention, a compound or composition of the invention may be administered with a chemotherapeutic agent and/or with radiation therapy, immunotherapy and/or photodynamic therapy to promote apoptosis and enhance the effectiveness of said chemotherapy, radiation therapy, immunotherapy and/or photodynamic therapy.
An "effective amount" or "effective dose" of a compound or pharmaceutically acceptable composition of the invention refers to an amount effective to treat or reduce the severity of one or more of the conditions mentioned herein. The compounds and compositions according to the methods of the present invention can be administered in any amount and by any route effective to treat or reduce the severity of the disease. The exact amount necessary will vary depending on the patient, depending on the race, age, general condition of the patient, severity of infection, particular factors, mode of administration, and the like. The compound or composition may be administered in combination with one or more other therapeutic agents, as discussed herein.
General Synthesis of Compounds of the invention
In general, the compounds of the invention can be prepared by the processes described herein, unless otherwise indicated, wherein the substituents are as defined in formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII). 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 Lingkai medicine, Aldrich Chemical Company, Inc., 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 Chemicals Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaseiki chemical plant.
The anhydrous tetrahydrofuran is obtained by refluxing and drying the metallic sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, N, N-dimethylacetamide and petroleum ether were used dried over anhydrous sodium sulfate in advance.
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. Nuclear magnetic resonance spectroscopy with CDC13Or DMSO-d6As solvent (reported in ppm) TMS (0ppm) or chloroform (7.25ppm) was used as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet ), m (multiplet, multiplet), br (broad ), dd (doublet of doublets), dt (doublet of triplets ). Coupling constants are expressed in hertz (Hz).
Low resolution Mass Spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315B DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.
Low resolution Mass Spectral (MS) data were determined by Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature maintained at 30 ℃), a G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was used for the LC-MS spectrometer.
Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1X 30mm, 5 μm. The injection volume is determined by the sample concentration; the flow rate is 0.6 mL/min; peaks of HPLC were recorded by UV-Vis wavelength at 210nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase a) and 0.1% formic acid in ultrapure water (phase B).
Compound purification was assessed by Agilent 1100 series High Performance Liquid Chromatography (HPLC) with UV detection at 210nm and 254nm, a Zorbax SB-C18 column, 2.1X 30mm, 4 μm, 10min, flow rate 0.6mL/min, 5-95% (0.1% formic acid in acetonitrile) in (0.1% formic acid in water), the column temperature was maintained at 40 ℃.
The following acronyms are used throughout the invention:
HCl/EA hydrochloric acid in ethyl acetate
PE Petroleum Ether
EA, EtOAc ethyl acetate
HCl hydrochloric acid
MeOH methanol
EtOH ethanol
DCM dichloromethane
NH4Cl ammonium chloride
TFAA trifluoroacetic anhydride
LiOH.H2O-lithium hydroxide monohydrate
NaOH sodium hydroxide
I2Iodine
NH4F ammonium fluoride
KHCO3Potassium bicarbonate
CuBr2Copper bromide
(Boc)2Di-tert-butyl O dicarbonate
CDMT 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine
ACN acetonitrile
BOC-L-Proline N-tert-butyloxycarbonyl-L-Proline
TFA trifluoroacetic acid
H2O water
DMT-MM 4- (4, 6-dimethoxytriazine) -4-methylmorpholine chloride
SOCl2Thionyl chloride
EDC.HCl 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride
HBTU benzotriazole-N, N, N ', N' -tetramethyluronium hexafluorophosphate
DMF N, N-dimethylformamide
DIPEA N, N-diisopropylethylamine
THF tetrahydrofuran
NaCl sodium chloride
AlCl3Aluminium trichloride
DEG C
min for
h hours
mL, mL
mmol millimole
g
mg of
N mol/l
rt Room temperature
N2Nitrogen gas
TLC thin layer chromatography
HPLC high performance liquid chromatography
The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Cy, R unless otherwise stated1、R3、R3a、R4、R5、R6、R7、R0、m、u、q、n3、n2、n1、Q2Having the definitions as described in the present invention.
Synthesis scheme 1
Figure BDA0001839332310000331
Compounds of formula (II-A) can be prepared by the methods described in FIG. 1To obtain wherein RAIs C1-4Alkyl, preferably methyl, ethyl; rBAs the alkali metal, potassium and sodium are preferred. Reacting the compound of formula (II-1) under acidic conditions (e.g., HCl, etc.) in a suitable solvent (e.g., ethyl acetate) to provide a compound of formula (II-2); a compound of the formula (II-2) with RAEsterification of the OH compound in a suitable solvent (e.g., thionyl chloride, etc.) to give a compound of formula (II-3); carrying out condensation reaction on the compound of the formula (II-3) and the compound of the formula (1) to obtain a compound of a formula (II-4); the compound of formula (II-4) is subjected to basic conditions (such as lithium hydroxide) to obtain a compound of formula (II-5); the compound of formula (II-5) and the compound of formula (II-b) are subjected to a condensation reaction in the presence of a condensation reagent (e.g., DMT-MM, etc.) under basic conditions (e.g., N-methylmorpholine) to give a compound of formula (II-a); deamination of the compound of formula (II-a) under acidic conditions (e.g., HCl/EA solution, etc.) affords the compound of formula (II-A).
Synthesis scheme 2
Figure BDA0001839332310000341
The compounds of formula (IV-A) can be prepared by the methods described in FIG. 2. The compound of formula (IV-1) and the compound of formula (IV-2) are subjected to a condensation reaction in the presence of a condensation reagent (e.g., DMT-MM, etc.) under basic conditions (e.g., N-methylmorpholine) to give a compound of formula (IV-a); deamination of the compound of formula (IV-a) under acidic conditions (e.g., trifluoroacetic acid, etc.) affords the compound of formula (IV-A).
Synthesis scheme 3
Figure BDA0001839332310000351
The compounds of formula (I-A) can be prepared by the methods described in FIG. 3. The compound of formula (IV-2) is condensed with the compound of formula (I-b) in the presence of a condensing agent (e.g., DMT-MM, etc.) under basic conditions (e.g., N-methylmorpholine) to give the compound of formula (II-a); deamination of the compound of formula (II-a) under acidic conditions (e.g., HCl/EA solution, etc.) affords the compound of formula (I-A).
Synthesis scheme 4
Figure BDA0001839332310000352
The compounds may be prepared by the methods described in FIG. 4. The compound of formula (IV-2) is condensed with the compound of formula (III-b) in the presence of a condensing agent (e.g., DMT-MM, etc.) under basic conditions (e.g., N-methylmorpholine) to give a compound of formula (II-a); deamination of the compound of formula (II-a) under acidic conditions (e.g., HCl/EA solution, etc.) affords the compound of formula (III-A).
Synthesis scheme 5
Figure BDA0001839332310000361
The compounds of formula (VII) can be prepared by the methods described in FIG. 5. Condensation of a compound of formula (I-V2) with a compound of formula (I-b1) in the presence of a condensation reagent (e.g., DMT-MM, etc.) under basic conditions (e.g., N-methylmorpholine) to provide a compound of formula (I-a 1); deamination of the compound of formula (I-a1) under acidic conditions (e.g., HCl/EA solution, etc.) affords the compound of formula (VII).
Intermediate Synthesis scheme 1
Figure BDA0001839332310000362
Compounds of formula (I-b) can be prepared by the methods described in intermediate synthesis scheme 1, wherein RAIs C1-4Alkyl, preferably methyl, ethyl; x is halogen, preferably chlorine or bromine. The compound of the formula (I-b-1) is reacted with Lawesson's reagent in a proper solvent (ethylene glycol dimethyl ether) to obtain a compound of the formula (I-b-2); cyclizing the compound of the formula (I-b-2) and the compound of the formula (I-b-3) to obtain a compound of the formula (I-b-4); the compound of the formula (I-b-4) is subjected to reduction elimination reaction under acidic condition to obtain the compound of the formula (I-b-5)A compound; hydrolyzing the compound of formula (I-b-5) under basic conditions (e.g., lithium hydroxide) to provide a compound of formula (I-b-6); a compound of formula (I-b-6) and a compound NH (OCH)3)CH3Obtaining a compound shown as a formula (I-b-7) under the action of HBTU and DIPEA; reacting the compound of the formula (I-b-7) with a Grignard reagent (I-b-8) compound to obtain a compound of the formula (I-b-9); deamination protection of the compound of formula (I-b-9) under acidic conditions gives the compound of formula (I-b).
Examples
Example 1: (R) -1- ((R) -6- ((R) -2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carbonyl) -5-azaspiro [2.4] heptan-5-yl) -2- (methylamino) propan-1-one
Figure BDA0001839332310000371
Step 1: (S) -5-azaspiro [2.4] heptane-6-carboxylic acid
Potassium (S) -5- (tert-Butoxycarbonyl) -5-azaspiro [2.4] heptane-6-carboxylate (1.60g,5.73mmol) was added to HCl/EA (4N) (9.5mL) and stirred at rt. TLC monitored the starting material reaction complete. The reaction solution was spin-dried to obtain 0.9g of a white solid.
MS(ESI,pos.ion)m/z:142.1(M+H)+。
Step 2: (S) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester hydrochloride
(S) -5-azaspiro [2.4]Heptane-6-carboxylic acid (5.73mmol) was added to MeOH (10mL) at-8 deg.C, low temperature, SOCl2(0.7mL,10mmol) was added slowly and over 10min, the reaction was set at-1 ℃ for 1.5h, and after rt 20min, the temperature was raised to 50 ℃ for reaction. TLC monitored the starting material reaction complete. The reaction mixture was then dried by suction to give 1.2g of a white solid, which was directly used in the next reaction step.
MS(ESI,pos.ion)m/z:156.1(M+H)+。
And step 3: (S) -5- ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionyl) -5-azaspiro [2.4] heptane-6-carboxylic acid methyl ester
(S) -5-azaspiro [2.4]Methyl heptane-6-carboxylate hydrochloride (195mg,1.0174mmol), (S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionic acid (230mg,1.1317mmol), ethyl 2-oxime cyanoacetate (98mg,0.68961mmol), DCM (5mL) were added successively to reactIn a bottle. EDC.HCl (683mg,3.563mmol) was added in 4 portions at-5 deg.C, over 20min, after 5min DIPEA (0.95mL,5.7mmol) was added slowly over about 15min, after 10-15min rt was stirred. TLC monitored the starting material reaction complete. NH (NH)4The Cl solution was quenched by addition, extracted 3 times with DCM, the organic phases were combined, dried, concentrated and passed through a column with PE/EA ═ 8:1 as eluent to give 205mg of white solid in 59% yield.
MS(ESI,pos.ion)m/z:341.2(M+H)+。
And 4, step 4: (S) -5- ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionyl) -5-azaspiro [2.4] heptane-6-carboxylic acid
(S) -5- ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionyl) -5-azaspiro [2.4]Heptane-6-carboxylic acid methyl ester (205mg,0.6022mmol), dioxane (2mL), lioh2O (78mg,1.859mmol) in H2In O (2mL), rt was stirred. TLC monitored the starting material reaction complete. Acetic acid was added to adjust PH to 3-4, EA extracted 3 times, the organic phases were combined, dried, and spin dried to give 180mg of a clear oil in 91% yield.
MS(ESI,pos.ion)m/z:327.2(M+H)+。
And 5: ((S) -1- ((S) -6- ((S) -2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carbonyl) -5-azaspiro [2.4] heptan-5-yl) -1-oxapropan-2-yl) (methyl) carbamic acid tert-butyl ester
(S) - (4-fluorophenyl) (2- (pyrrolidin-2-yl) thiazol-4-yl) methanone (169mg,0.5403mmol), DMT-MM (186mg,0.67216mmol), (S-5- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionyl) -5-azaspiro [2.4]Heptane-6-carboxylic acid (130mg,0.3983mmol) was added to EA (6mL) and the temperature was lowered to-1 ℃. After 5min, N-methylmorpholine (0.21mL,1.9mmol) was added slowly, over 40-45 min. After 30min, rt stirred and TLC monitored the starting material reaction was complete. NH (NH)4The Cl was quenched by addition of EA, extracted 3 times, the organic phases were combined, dried, concentrated, and passed through a column with PE/EA ═ 3:1 as eluent to give 168mg of white solid in 60% yield.
MS(ESI,pos.ion)m/z:585.2(M+H)+。
Step 6: (S) -1- ((S) -6- ((S) -2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carbonyl) -5-azaspiro [2.4] heptan-5-yl) -2- (methylamino) propan-1-one
Tert-butyl ((S) -1- ((S) -6- ((S) -2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carbonyl) -5-azaspiro [2.4] heptan-5-yl) -1-oxapropan-2-yl) (methyl) carbamate (260mg,0.4447mmol) was added to HCl/EA (4N) (9mL), rt stirred, TLC monitored for completion of the starting reaction. The reaction was concentrated and passed through a column with DCM/MeOH ═ 10:1 as eluent to give 90mg of a white solid in 41% yield.
1H NMR(400MHz,CDCl3)δ8.28(dd,J＝8.7,5.6Hz,2H),8.14(s,1H),7.14(t,J＝8.7Hz,2H),5.61(dd,J＝7.7,2.0Hz,1H),4.91(dd,J＝8.4,5.1Hz,1H),3.93(dd,J＝17.2,8.8Hz,1H),3.69(m,1H),3.59(d,J＝9.4Hz,1H),3.51(d,J＝9.5Hz,1H),3.37(q,J＝6.7Hz,1H),2.36(s,3H),2.27(m,7H),1.28(m,3H),0.71–0.55(m,4H)。
13C NMR(151MHz,CDCl3)δ185.41,173.23,172.76,170.78,166.60,164.91,154.04,133.50(d,J＝9.2Hz),131.02,128.92,128.26,115.47,115.32,68.29,58.71,58.42,56.62,54.79,47.25,36.76,31.56,24.75,21.42,18.05,14.17,11.63,10.89。
MS(ESI,pos.ion)m/z:485.5(M+H)+。
HPLC 97.2％。
Example 2: (S) -N- ((S) -1-cycloheptyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide isomer 1; (S) -N- ((R) -1-cycloheptyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide isomer 2
Figure BDA0001839332310000381
Step 1: (S) -2- ((tert-butyloxycarbonyl) (methyl) amino) propionic acid
(2S) -2- (methylamino) propionic acid (8.25g,80.0mmol) was dissolved in-4 deg.C low temperature NaOH (1N) (100mL) with stirring, acetone (50mL), (Boc)2O (23mL,100mmol) was added slowly and over 30-40 min. After 1-1.5h, rt is stirred. TLC monitored the starting material reaction complete. Acetic acidAdjusting pH to 4-5, extracting with EA for 3 times, drying, concentrating, and drying to obtain transparent oil. Part of the solid precipitated and PE/EA recrystallized. Suction drying gave 10.1g of a white solid. The yield thereof was found to be 62%.
MS(ESI,neg.ion)m/z:202.1(M-H)-。
Step 2: (S) -2-amino-2-cyclohexylacetic acid methyl ester hydrochloride
Cyclohexylglycine (11.2g,71.2mmol), MeOH (40mL) were added sequentially to the reaction flask. Low temperature at-12 ℃ SOCl2(8.2mL,110mmol) was added slowly and after 15-20min, the turbid liquid became clear. Setting the temperature at 0 ℃ for reaction for 1.5h, and after rt 20min, heating to 50 ℃ for reaction. TLC monitored the starting material reaction complete. Suction dried to give 15.5g of a white solid in quantitative yield.
MS(ESI,pos.ion)m/z:172.2(M+H)+。
And step 3: (S) -2- ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionamido) -2-cyclohexylacetic acid methyl ester
(S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionic acid (1.02g,5.02mmol), (S) -2-amino-2-cyclohexylacetic acid methyl ester hydrochloride (1.25g,6.02mmol), EA (26mL), CDMT (0.98g,5.6mmol) were added to the reaction flask in this order. N-methylmorpholine (1.9mL,17mmol) was added slowly at-3 ℃ over about 5 min. Rt stirred after 5 min. TLC monitored the starting material reaction complete. The reaction solution was filtered, and the filtrate was washed 5 times with EA, and then with saturated sodium bicarbonate, 10% acetic acid, and sodium chloride solution in this order. Concentration and column chromatography PE/EA 10:1 as eluent gave 1.6g of a colourless oil in 90% yield.
MS(ESI,pos.ion)m/z:379.3(M+Na)+。
1H NMR(400MHz,d6-DMSO)δ7.93(d,J＝38.8Hz,1H),4.53(d,J＝45.1Hz,1H),4.15(s,1H),3.62(s,3H),2.75(s,3H),1.66(d,J＝12.4Hz,3H),1.59(d,J＝10.4Hz,2H),1.52(d,J＝12.2Hz,1H),1.37(s,9H),1.28–1.11(m,6H),1.10–1.00(m,2H)。
And 4, step 4: (S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionamide) -2-cyclohexylacetic acid
(S) -methyl 2- ((S) -2- ((tert-Butoxycarbonyl) (methyl) amino) propionamido) -2-cyclohexylacetate (1580mg,4.432mmol) propyl was addedKetone (15 mL). Set 0 ℃ and LiOH.H2O (1250mg,29.79mmol) in water (15mL) was added over 5-10 min. TLC monitored the starting material reaction complete. Concentrating the reaction solution, adding water, extracting with EA for 3 times, drying, concentrating, PE/EA, and recrystallizing at low temperature. Suction dried to give 1.95g of a white solid. The yield was quantified.
MS(ESI,pos.ion)m/z:297.1(M+H)+。
1H NMR(400MHz,d6-DMSO)δ7.69(d,J＝67.9Hz,1H),4.58(s,1H),4.11(d,J＝6.5Hz,1H),2.75(s,3H),1.62(dd,J＝37.4,10.7Hz,6H),1.38(s,9H),1.20(m,5H),1.09–0.92(m,3H)。
And 5: 2-bromo-3, 4-dihydronaphthalen-1 (2H) -ones
3, 4-dihydro-1 (2H) -naphthalenone (2.22g,15.2mmol), EtOH (50mL), CuBr2(6.22g,27.8mmol) was added to the reaction flask. The reaction was heated in an oil bath at 40 ℃ and TLC monitored for complete reaction of the starting materials. The heating was stopped. Filtering by using kieselguhr, concentrating, and passing through a column, wherein the PE/EA is 100: 1-40: 1, 3.3g of a white solid was obtained. The yield thereof was found to be 97%.
MS(ESI,pos.ion)m/z:225.0,227.0(M+H)+。
1H NMR(400MHz,CDCl3)δ8.09(d,J＝7.8Hz,1H),7.52(td,J＝7.6,1.1Hz,1H),7.34(t,J＝7.6Hz,1H),7.31–7.24(m,1H),4.75(m,1H),3.31(m,1H),2.92(dt,J＝17.1,4.4Hz,1H),2.59–2.40(m,2H)。
Step 6: (2S) -2- (1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) pyrrolidine-1, 2-dicarboxylic acid 1-tert-butyl ester
2-bromo-3, 4-dihydronaphthalen-1 (2H) -one (648mg,2.8790mmol), ACN (12mL), DIPEA (0.73mL,4.4mmol), and BOC-L-Proline (795mg,3.6934mmol) were added sequentially to the reaction flask, and heated in a 50 deg.C oil bath with stirring. TLC monitored the starting material reaction complete. NH (NH)4Cl solution was added, DCM was extracted 3 times, the organic phases were combined, dried and concentrated. Column chromatography with PE/EA 10:1 as eluent gave 755mg of clear oil in 73% yield.
MS(ESI,pos.ion)m/z:382.1(M+Na)+。
1H NMR(400MHz,CDCl3)δ7.99(t,J＝8.4Hz,1H),7.50(dd,J＝12.2,6.8Hz,1H),7.32(dd,J＝13.1,7.0Hz,1H),7.26(s,1H),5.66–5.49(m,1H),4.50–4.33(m,1H),3.51(m,2H),3.28–3.03(m,2H),2.32(m,4H),2.09(m,1H),1.92(m,1H),1.45(m,9H)。
And 7: 2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
(2S) -2- (1-oxo-1, 2,3, 4-tetrahydronaphthalen-2-yl) pyrrolidine-1, 2-dicarbonate 1-tert-butyl ester (3340mg, 9.293mmol), ammonium acetate (4200mg,54.487mmol) and toluene (50mL) were added to the reaction flask in this order. The reaction is heated and stirred in an oil bath at 115 ℃ and refluxed. TLC monitored the starting material reaction complete. Adding water into the reaction solution, extracting with EA for 3 times, combining organic phases, drying, concentrating, and passing through a column, wherein the PE/EA is 4: 1 as eluent, gave a mixture of diastereomers in the form of an off-white solid, 2.7g, 88% yield.
MS(ESI,pos.ion)m/z:340.1(M+H)+。
1H NMR(400MHz,CDCl3)δ7.30(s,1H),7.16(dd,J＝16.6,7.8Hz,2H),7.05(t,J＝7.0Hz,1H),4.99(d,J＝5.1Hz,1H),3.42(s,2H),2.97(d,J＝5.2Hz,2H),2.81(m,2H),2.17(m,2H),1.91(d,J＝26.2Hz,2H),1.54–1.43(m,9H)。
And 8: 2- (pyrrolidin-2-yl) -4, 5-dihydro-1H-naphtho [1,2-d ] imidazole
Tert-butyl 2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidine-1-carboxylate (980mg,2.887mmol) was added to DCM (10 mL). The mixture was cooled to-4 deg.C and TFA (3.1mL,42mmol) was added slowly over 10 min. And (7) stirring at rt. TLC monitored the starting material reaction complete. The reaction was concentrated and 800mg of white solid was drained and the yield was determined. Normal phase HPLC analysis the ratio of the diastereomer content was 63: 36.
MS(ESI,pos.ion)m/z:240.1(M+H)+。
And step 9: isomer 1 and isomer 2 of tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate
2- (pyrrolidin-2-yl) -4, 5-dihydro-1H-naphtho [1,2-d]Imidazole (354mg,0.8136mmol), (S) -2- ((S) -2- ((tert-butoxycarbonyl) (methyl) amino) propionamide) -2-cyclohexylacetic acid (517mg,1.057mmol), DMT-MM (294mg,1.0624 m)mol), EA (8mL), N-methylmorpholine (0.25mL,2.3mmol) was added slowly at-1 deg.C, over 60 min. After 20min, the temperature is raised to 19 ℃ and stirred. TLC monitored the starting material reaction complete. NH (NH)4The Cl solution was added to quench the reaction. EA extraction 3 times, combined organic phases, dried, concentrated, column filtered, PE/EA ═ 1: and 1 is an eluent. Obtaining: target compound isomer 1, 233mg, white foam solid, yield 28%; isomer 2, 187mg of the title compound, clear oil, yield 22%.
Isomer 1: MS (ESI, pos.ion) M/z 564.3(M + H)+。
Isomer 2: MS (ESI, pos.ion) M/z 564.3(M + H)+。
Step 10: isomer 1 of (S) -N- ((S) -1-cyclohexyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Isomer 1 of tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (562mg,0.9970mmol) was added to DCM (20 mL). The temperature of the mixture was reduced to-2 deg.C, TFA (4mL) was added, the addition was completed in 5-10min, and after about 5min rt was stirred. TLC monitored the starting material reaction complete. Spin-dry and send to preparative HPLC to give 190mg of white solid in 41% yield.
1H NMR(400MHz,CDCl3)δ7.86(d,J＝5.0Hz,1H),7.73(d,J＝8.6Hz,1H),7.23–7.08(m,2H),7.04(m,1H),5.22(dd,J＝7.9,4.2Hz,1H),4.57(t,J＝8.0Hz,0.5H),4.24(t,J＝6.9Hz,0.5H),3.92(dd,J＝17.0,7.5Hz,0.5H),3.73–3.62(m,1H),3.49(dd,J＝14.4,5.7Hz,0.5H),3.08(ddd,J＝28.7,23.7,16.4Hz,2H),2.98–2.82(m,3H),2.77(d,J＝6.7Hz,1H),2.50(s,1H),2.41(s,2H),2.31(dd,J＝11.6,7.2Hz,1H),2.16(dd,J＝12.3,7.7Hz,1H),2.12–2.04(m,1H),2.01–1.85(m,3H),1.84–1.50(m,8H),1.25(s,3H)。
13C NMR(151MHz,CDCl3)δ177.00,175.02,172.39,169.87,128.00,126.77,125.60,120.58,60.53,56.23,54.81(d,J＝2.8Hz),48.05,45.98,40.88,35.24(d,J＝8.9Hz),32.03,29.80,28.47,26.34,26.05(dd,J＝27.1,11.9Hz),25.47,22.80,22.32,19.81。
MS(ESI,pos.ion)m/z:464.2(M+H)+。
HPLC 97.6％。
Step 11: isomer 2 of (S) -N- ((S) -1-cyclohexyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Isomer 2 of tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- (2- (4, 5-dihydro-1H-naphtho [1,2-d ] imidazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (410mg,0.7273mmol) was added to DCM (15 mL). The mixture was cooled to-2 deg.C, TFA (3mL) was added, and the addition was completed in 5-10min, after about 5min rt stirred. TLC monitored the starting material reaction complete. Spin-dry and send to preparative HPLC to give 200mg of white solid in 59% yield.
1H NMR(400MHz,CDCl3)δ7.78(d,J＝6.2Hz,1H),7.51(s,1H),7.19–7.11(m,2H),7.03(t,J＝7.4Hz,1H),5.37(d,J＝6.6Hz,1H),4.29(t,J＝7.7Hz,1H),4.06(t,J＝7.4Hz,1H),3.61(dd,J＝16.8,8.9Hz,1H),3.06(q,J＝6.9Hz,1H),2.99(t,J＝7.8Hz,2H),2.81(t,J＝7.8Hz,2H),2.69(d,J＝7.4Hz,1H),2.31(s,3H),2.21–2.07(m,3H),1.90(d,J＝13.1Hz,2H),1.85–1.64(m,7H),1.40(m,2H),1.33(s,3H)。
13C NMR(151MHz,CDCl3)δ176.66,171.58,147.62,134.02,128.07,126.61,125.43,119.98,60.32,56.63,55.66,47.54,39.84,35.10,32.06,30.52,29.93,29.75,29.29,26.27,25.99(d,J＝11.9Hz),24.49,22.82,19.36,14.25。
MS(ESI,pos.ion)m/z:464.2(M+H)+。
HPLC 93.6％。
Example 3(S) -N- ((S) -1-cyclohexyl-2- ((2S,4R) -4-fluoro-2- (4- (4-Fluorobenzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Figure BDA0001839332310000411
Step 1: (2S,4R) -1-tert-butyl 2-methyl 4-fluoropyrrolidinyl-1, 2-dicarboxylate
(2S,4S) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (14.7g,59.9mmol) and DCM (90mL) were added to the reaction flask in that order. N is a radical of2Stirring at-62 deg.C under protection, slowly adding diethylaminosulfur trifluoride (20.5mL,155mmol), and finishing adding for 15-20 min. After 90-100min, rt stirring. TLC monitored the starting material reaction complete. Adding NaCl solution at low temperature, discharging gas violently, standing for layering, collecting organic phase, extracting with EA for 3 times, and concentrating. Column chromatography, PE/EA is 10:1 as eluent, 12g of oil was obtained in 80% yield.
Step 2: (2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyrrolidine-2-carboxylic acid
(2S,4R) -1-tert-butyl 2-methyl 4-fluoropyrrolidinyl-1, 2-dicarboxylate (5400mg,21.839mmol) and THF (30mL) were added to the reaction flask in that order. Low temperature at-8 ℃ LiOH2O (4360mg,103.9mmol) in H2O (30mL) solution was added and rt was stirred. TLC monitored the starting material reaction complete. Concentrating, adding concentrated hydrochloric acid at low temperature, extracting with EA (pH 3-4) for 4 times, mixing organic phases, drying, and concentrating to obtain oily substance 3.28g with yield of 64%.
MS(ESI,pos.ion)m/z:256.1(M+Na)+。
And step 3: (2S,4R) -2-carbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
(2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyrrolidine-2-carboxylic acid (800mg,3.4299mmol), N-methylmorpholine (0.59mL,5.4mmol), THF (10mL) were added to the reaction flask in that order. Isobutyl chloroformate (1mL,7.915mmol) was slowly added to the reaction mixture at-15 ℃ for 10 min. Turbidity, after 80-90min, NH3.H2O (25-28%) (1.6mL) was added slowly over 1 h. After 15min, rt stirred. TLC monitored the starting material reaction complete. Concentration, addition of saturated sodium bicarbonate solution, extraction with EA for 3 times, drying, concentration, recrystallization with PE/EA to give 800mg of a pale yellow transparent oil in quantitative yield.
MS(ESI,pos.ion)m/z:255.1(M+Na)+。
1H NMR(400MHz,CDCl3)δ6.91(s,0.5H),6.33–5.85(m,1H),5.29–5.06(m,1H),4.94(s,0.5H),4.38(d,J＝56.3Hz,1H),3.89(d,J＝6.7Hz,1H),3.63–3.35(m,1H),2.50(m,2H),2.21(m,1H),1.44(s,9H)。
And 4, step 4: (2S,4R) -2-Thiocarbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester
(2S,4R) -2-carbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (850mg,3.6598mmol), Lawson' S reagent (1.3g,3.2mmol) were added to ethylene glycol dimethyl ether (8mL) and stirred at rt. TLC monitored the starting material reaction complete. Saturated sodium bicarbonate solution was added, EA extracted 3 times, dried, concentrated, column filtered, PE/EA ═ 4: 1 as eluent, 620mg of a pale yellow solid was obtained in 68% yield.
MS(ESI,pos.ion)m/z:271.0(M+Na)+。
1H NMR(400MHz,CDCl3)δ8.45(s,0.5H),8.12–7.64(m,1.5H),5.19(d,J＝52.9Hz,1H),4.82(t,J＝8.2Hz,1H),4.04–3.80(m,1H),3.58(ddd,J＝36.6,13.1,2.7Hz,1H),2.60(d,J＝36.9Hz,1.5H),1.96(m,0.5H),1.44(s,9H)。
And 5: 2- ((2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyrrolidin-2-yl) -4-hydroxy-4, 5-dihydrothiazole-4-carboxylic acid ethyl ester
KHCO3(2.04g,20.4mmol), (2S,4R) -2-thiocarbamoyl-4-fluoropyrrolidine-1-carboxylic acid tert-butyl ester (620mg,2.4968mmol) was added to ethylene glycol dimethyl ether (15mL), N2Protection, rt stirring for 5 min. Ethyl-3-bromo-2-oxo-propionate (1.3mL,8.1mmol) was added slowly at-1 deg.C, over 20min, and stirred at rt. TLC monitored the starting material reaction complete. Concentration of the reaction solution, NH4Cl solution is added, EA is extracted for 3 times, and the mixture is combined, dried and spin-dried to obtain 1g of brown oily matter, and the yield is quantified and the mixture is directly put into the next reaction.
MS(ESI,pos.ion)m/z:363.0(M+H)+。
Step 6: 2- ((2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyrrolidin-2-yl) thiazole-4-carboxylic acid ethyl ester
Ethyl 2- ((2S,4R) -1- (tert-butoxycarbonyl) -4-fluoropyrrolidin-2-yl) -4-hydroxy-4, 5-dihydrothiazole-4-carboxylate (2.5mmol), DME (15mL) were added to the reaction flask in this order, and N, 4R, 4-fluoropyrrolidin-2-yl-4-carboxylate (N2Protection at-1 deg.C, pyridine (1.8mL,22mmol) was added slowly over 2-3 min. After 5-10min, TFAA (1.55mL,11.2mmol) was added slowly, over 25-30 min. Triethylamine (a)0.69mL,5.0mmol) was added slowly over about 30 min. The reaction was allowed to proceed overnight. TLC monitored the starting material reaction complete. Concentrating, passing through a column, and enabling PE/EA to be 5: and 1 is an eluent. 535mg of a pale yellow solid are obtained in 62% yield.
MS(ESI,pos.ion)m/z:345.2(M+H)+。
1H NMR(400MHz,CDCl3)δ8.09(s,1H),5.35(s,1H),5.24(d,J＝52.4Hz,1H),4.40(d,J＝6.8Hz,2H),3.88(m,0.5H),3.76–3.54(m,1.5H),2.84(s,1H),2.40(dd,J＝95.5,38.1Hz,1H),1.45(s,3H),1.38(t,J＝7.0Hz,4H),1.29(s,6H)。
And 7: 2- ((2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyridin-2-yl) thiazole-4-carboxylic acid
Ethyl 2- ((2S,4R) -1- (tert-butoxycarbonyl) -4-fluoropyrrolidin-2-yl) thiazole-4-carboxylate (535mg,1.553mmol), THF (5mL), LiOH2O (346mg,8.246mmol) in H2O (5mL) solution was added to the reaction flask in order and rt was stirred. TLC monitored the starting material reaction complete. The reaction was concentrated at-3 ℃ and 1N HCl was adjusted to PH 3-4 to gradually precipitate a solid, which was filtered and dried to yield 356mg of a pale yellow solid in 72% yield. MS (ESI, pos.ion) M/z 339.0(M + Na)+。
And 8: (2S,4R) -4-fluoro-2- (4- (methoxy (methyl) carbamoyl) thiazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
2- ((2S,4R) -1- (tert-Butoxycarbonyl) -4-fluoropyridin-2-yl) thiazole-4-carboxylic acid (356mg,1.125mmol), HBTU (657mg,1.7324mmol) and DMF (8mL) were added sequentially to the reaction flask. The mixture was cooled to-1 deg.C and DIPEA (0.95mL,5.7mmol) and methoxymethyl amine hydrochloride (193mg,1.98mmol) were added. And (7) stirring at rt. TLC monitored the starting material reaction complete. NH (NH)4The Cl solution was added to quench the reaction. EA extraction 3 times, organic phases combined, NaCl solution washed 2 times, dried, concentrated, PE/EA 2.5: 1 as eluent, 350mg of white solid was obtained, yield 86%.
MS(ESI,pos.ion)m/z:382.2(M+Na)+。
1H NMR(400MHz,CDCl3)δ7.93(s,1H),5.25(d,J＝52.7Hz,2H),4.16–3.90(m,1H),3.76(s,3H),3.64(dd,J＝36.9,14.3Hz,1H),3.40(s,3H),2.78(s,3H),2.62–2.24(m,1H),1.45(s,3.5H),1.30(s,6.5H)。
And step 9: (2S,4R) -4-fluoro-2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
Tert-butyl (2S,4R) -4-fluoro-2- (4- (methoxy (methyl) carbamoyl) thiazol-2-yl) pyrrolidine-1-carboxylate (430mg,0.9572mmol) was dissolved in THF (12 mL). N is a radical of2Protecting, cooling to-22 deg.C, slowly adding 4-fluorophenyl magnesium bromide tetrahydrofuran solution (1N,7mL) for 1h, heating, and stirring at-11 deg.C. TLC monitored the starting material reaction complete. Saturated NH4Adding 18mL of Cl solution into the reaction solution, extracting with EA for 3 times, combining organic phases, drying, concentrating, and using column PE/EA-10: 1 as an eluent. 220mg of oil are obtained in a yield of 60%.
MS(ESI,pos.ion)m/z:417.0(M+Na)+。
1H NMR(400MHz,CDCl3)δ8.27(s,2H),8.18(s,1H),7.14(t,J＝7.8Hz,2H),5.33(m,2H),4.14–3.89(m,1H),3.67(dd,J＝35.8,14.0Hz,1H),2.83(d,J＝11.9Hz,1H),2.41(dd,J＝55.8,45.2Hz,1H),1.47(s,4H),1.31(s,5H)。
Step 10: (4-fluorophenyl) (2- ((2S,4R) -4-fluoropyrrolidin-2-yl) thiazol-4-yl) methanone
Tert-butyl (2S,4R) -4-fluoro-2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidine-1-carboxylate (290mg,0.7353mmol), HCl/EA (4N) (5mL) were added sequentially, stirred at rt, and TLC monitored for completion of the starting reaction. The reaction solution was spin-dried to obtain 230mg of a white solid. The yield was quantified.
MS(ESI,pos.ion)m/z:295.1(M+H)+。
Step 11: ((S) -1- (((S) -1-cyclohexyl-2- ((2S,4R) -4-fluoro-2- (4- (4-Benzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamic acid tert-butyl ester
(4-fluorophenyl) (2- ((2S,4R) -4-fluoropyrrolidin-2-yl) thiazol-4-yl) methanone (78mg,0.2650mmol), (2S) -2- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino group)]Propionyl group]Amino group]-2-cyclohexyl-acetic acid (158mg,0.4614mmol), DMT-MM (103mg,0.37222mmol), EA (3mL) was added to the flask, and N-methylmorpholine (0.095mL,0.86mmol) was added slowly over 10min at-1 deg.C. rt stirringTLC monitored the starting material reaction was complete. NH (NH)4Cl was added to quench the reaction. EA extraction 3 times, combined organic phase, dried, concentrated, column. EA/ETOH ═ 5: and 1 is an eluent. 98mg of a white solid are obtained as a mixture of isomers 1 and 2 in a ratio of 1:2 with a total yield of 60%.
MS(ESI,pos.ion)m/z:619.2(M+H)+。
Step 12: (S) -N- ((S) -1-cyclohexyl-2- ((2S,4R) -4-fluoro-2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidinyl-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- ((2S,4R) -4-fluoro-2- (4- (4-benzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (180mg,0.2909mmol) (isomer mixture), HCl/EA (4N) (4mL), rt stirring. TLC monitored the starting material reaction complete. Spin dry, 150mg crude. Preparative HPLC gave 80mg of the main product as a white solid in 53% yield. MS (ESI, pos. ion) M/z 519.2(M + H)+。
1H NMR(400MHz,CDCl3)δ8.27(dd,J＝8.8,5.5Hz,2H),8.20(s,1H),7.68(d,J＝9.3Hz,1H),7.15(t,J＝8.7Hz,2H),5.66(t,J＝8.1Hz,1H),5.44(s,1H),5.34–5.11(m,1H),4.63–4.55(m,1H),4.42(dd,J＝19.8,12.5Hz,1H),3.92–3.76(m,1H),3.08(q,J＝6.9Hz,1H),2.86–2.64(m,2H),2.37(s,3H),1.66(m 7H),1.31(s,3H),0.88(m,4H)。
13C NMR(101MHz,CDCl3)δ175.03,171.76,170.48,153.69,133.39(d,J＝9.2Hz),129.03,115.58,115.36,92.39,90.59,60.50,56.98,54.88,54.05,53.75(d,J＝12.2Hz),40.96,38.66,38.45,35.24,32.07,29.86(t,J＝7.8Hz),29.49,28.41(d,J＝12.9Hz),26.23,25.92(d,J＝7.0Hz),22.83,19.82,14.23。
HPLC 96.6％。
Synthesis of examples 17 to 19
The appropriate starting materials were selected, examples 17-19 were synthesized according to the synthesis scheme of example 2, with the following characterization data:
Figure BDA0001839332310000441
synthesis of examples 10 and 14
Example 10 was synthesized according to the synthesis scheme of example 4, with the following characterization data:
Figure BDA0001839332310000442
syntheses of examples 4-9, examples 11-13, examples 15-16, and examples 20-38
The synthesis of examples 4-9, examples 11-13, examples 15-16, examples 20-38, reference example 1 or synthesis scheme 3, was carried out by selecting the appropriate starting materials.
Figure BDA0001839332310000451
Figure BDA0001839332310000461
Figure BDA0001839332310000471
Figure BDA0001839332310000481
Example 39: (S) -N- ((S) -1-cyclohexyl-2- ((S) -2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidinyl-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Figure BDA0001839332310000482
Step 1: 3- (5-bromo-2-fluorophenyl) propionic acid
Triethylamine (8.3mL,60mmol) was slowly added to formic acid (5.9mL,160mmol) at-5 ℃ for 10-15 min. After 15min, 5-bromo-2-fluoro-benzaldehyde (4.1g,20mmol), 2-dimethyl-1, 3-dioxane-4, 6-dione (3.2g,22mmol) were added in sequence. The reaction solution was heated in an oil bath at 100 ℃. TLC monitored the starting material reaction complete. The reaction mixture was heated to a stop, ice water was added, and the mixture was acidified to pH 3 with 1N HCl to precipitate a white solid, which was then dried by suction to 4.17g, yielding 84%.
MS(ESI,pos.ion)m/z:247.0,249.0(M)+。
1H NMR(400MHz,CDCl3)δ7.40–7.28(m,2H),6.91(t,J＝9.1Hz,1H),2.95(t,J＝7.7Hz,2H),2.68(t,J＝7.7Hz,2H).
Step 2: 3- (5-bromo-2-fluorophenyl) propionyl chloride
3- (5-bromo-2-fluorophenyl) propionic acid (4.17g,16.9mmol), DMF (0.75mL), DCM (25mL) were added sequentially to a reaction flask, oxalyl chloride (3.7mL,44mmol) was added slowly at low temperature of 0 ℃ over 30min, rt stirred for 1h, spun dry to give 4.5g of oil, which was directly put to the next reaction.
And step 3: 7-bromo-4-fluoro-2, 3-dihydro-1H-inden-1-one
AlCl3(3.07g,23.0mmol) and DCM (25mL) were added to the flask in sequence. A solution of 3- (5-bromo-2-fluorophenyl) propionyl chloride (16.9mmol) in DCM (25mL) was added slowly at-15 deg.C and over 25 min. After 5min, the reaction was carried out in an oil bath at 40 ℃. TLC monitored the starting material reaction complete. Adding ice water into the reaction solution to quench the reaction, collecting an organic phase, extracting an aqueous phase with DCM for 2 times, drying, concentrating, and passing through a column, wherein PE/EA is 10:1 as eluent, 3.68g of white solid was obtained. The yield thereof was found to be 95%.
MS(ESI,pos.ion)m/z:229.0,230.9(M)+。
1H NMR(400MHz,CDCl3)δ7.49(dd,J＝8.5,4.1Hz,1H),7.13(t,J＝8.2Hz,1H),3.12–3.07(m,2H),2.80–2.75(m,2H).
And 4, step 4: 4-bromo-7-fluoro-2, 3-dihydro-1H-indene
7-bromo-4-fluoro-2, 3-dihydro-1H-inden-1-one (3.68g,16.1mmol), NH4F (3.62g,97.7mmol), TFA (25mL,336.6mmol) were added sequentially to the reaction flask. Triethylsilane (15.5mL,97.0mmol) was added slowly at-5 ℃ and over 25 min. After rt 5min, oil bath at 50 ℃ overnight. TLC monitored the starting material reaction complete. Concentrating the reaction solution, and adding carbonAdding sodium hydrogen carbonate solution, extracting with EA for 3 times, combining organic phases, drying, concentrating, and passing through a column, wherein PE/EA is 30: 1 as eluent, 1.7g of transparent liquid is obtained, yield 50%.
1H NMR(400MHz,CDCl3)δ7.26–7.21(m,1H),6.75(dd,J＝15.1,6.6Hz,1H),3.04(t,J＝7.5Hz,2H),2.95(t,J＝7.5Hz,2H),2.13(p,J＝7.6Hz,2H).
And 5: (7-fluoro-2, 3-dihydro-1H-inden-4-yl) magnesium bromide
N2Next, magnesium turnings (310mg,12.755mmol), I2(38mg,0.1497mmol) and THF (10mL) were added to the reaction flask in that order. Heated in an oil bath at 30 ℃ and 4-bromo-7-fluoro-2, 3-dihydro-1H-indene (1700mg,7.9048mmol) in THF (4mL) was added slowly over 40 min. After 1h, the Grignard reagent was prepared for use.
Step 6: (S) -2- (4- (methoxy (methyl) carbamoyl) thiazol-2-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
(S) -2- (1- (tert-butoxycarbonyl) pyrrolidin-2-yl) thiazole-4-carboxylic acid 180mg,0.6032mmol), HBTU (343mg,0.904mmol), and DMF (5mL) were sequentially added to the reaction flask. The mixture was cooled to-1 deg.C and DIPEA (0.51mL,3.1mmol), methoxymethyl amine hydrochloride (130mg,1.33mmol) were added sequentially and stirred at rt. TLC monitored the starting material reaction complete. Concentration of the reaction solution, NH4Adding Cl solution, extracting with EA for 3 times, combining organic phases, drying and concentrating. Column chromatography, PE/EA is 3:1 as eluent, 190mg of oil was obtained in 92% yield.
MS(ESI,pos.ion)m/z:342.2(M+H)+。
1H NMR(600MHz,CDCl3)δ7.94(s,1H),5.26–5.09(m,1H),3.75(s,3H),3.57(d,J＝18.6Hz,1H),3.50(d,J＝8.5Hz,1H),3.41(s,3H),2.26(m,2H),1.92(t,J＝7.1Hz,2H),1.46(s,3H),1.30(s,6H).
And 7: (S) -2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidinyl-1-carboxylic acid tert-butyl ester
N2Under protection, (S) -tert-butyl 2- (4- (methoxy (methyl) carbamoyl) thiazol-2-yl) pyrrolidine-1-carboxylate (550mg,1.611mmol) was added to THF (10 mL). Cooling the mixture to-22 deg.C, brominating (7-fluoro-2, 3-dihydro-1H-inden-4-yl)Magnesium (homemade) (7.5mmol, 13mL) was added slowly over about 70 min. TLC monitored the starting material reaction complete. Saturated ammonium chloride solution was added, EA extracted 3 times, the organic phases combined, dried, concentrated, and column PE/EA 10:1 as eluent to give 535mg of a pale yellow oil in 79% yield.
MS(ESI,pos.ion)m/z:417.2(M+H)+。
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.79(s,1H),6.90(t,J＝8.4Hz,1H),5.21(d,J＝28.4Hz,1H),3.69–3.38(m,2H),3.18(t,J＝7.4Hz,2H),2.95(t,J＝7.4Hz,2H),2.28(d,J＝21.3Hz,2H),2.11(p,J＝7.5Hz,2H),1.94(dd,J＝13.1,6.8Hz,2H),1.48(s,4H),1.35(s,5H).
And 8: (S) - (7-fluoro-2, 3-dihydro-1H-inden-4-yl) (2- (pyrrolidin-2-yl) thiazol-4-yl) methanone
(S) -tert-butyl 2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidinyl-1-carboxylate (475mg,1.140mmol), HCl/EA (4N,8.5mL) was added to the reaction flask and stirred at rt. TLC monitored the starting material reaction complete. The reaction solution was spin dried to give 400mg of a pale yellow solid in quantitative yield.
MS(ESI,pos.ion)m/z:317.1(M+H)+。
And step 9: ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamic acid tert-butyl ester
(S) - (7-fluoro-2, 3-dihydro-1H-inden-4-yl) (2- (pyrrolidin-2-yl) thiazol-4-yl) methanone (446mg,1.410mmol), DMT-MM (512mg,1.8502mmol), (2R) -2- [ [ (2S) -2- [ tert-butoxycarbonyl (methyl) amino group)]Propionyl group]Amino group]-2-cyclohexyl-acetic acid (622mg,1.817mmol), EA (18mL) were added sequentially to the reaction flask. And (3) carrying out low-temperature bath at the temperature of-1 ℃, after 5min, slowly adding N-methylmorpholine (0.55mL,5.0mmol), completing the addition for about 60min, heating up to rt, stirring, and monitoring the completion of the raw material reaction by TLC. NH (NH)4The Cl solution was quenched by addition, EA extracted 3 times, the organic phases were combined, dried, concentrated, and chromatographed on a column, PE/EA ═ 4: 1 as eluent, 690mg of white solid was obtained in 76% yield.
MS(ESI,pos.ion)m/z:641.3(M+H)+。
1H NMR(600MHz,CDCl3)δ8.02(s,1H),7.82(dd,J＝8.4,5.1Hz,1H),6.90(t,J＝8.4Hz,1H),6.74(m,1H),5.51(dd,J＝8.0,2.2Hz,1H),4.65–4.58(m,1H),3.88–3.82(m,1H),3.79–3.73(m,1H),3.18(m,2H),2.95(t,J＝7.5Hz,2H),2.78(s,3H),2.44–2.37(m,1H),2.31–2.22(m,1H),2.12(m,4H),1.75–1.57(m,7H),1.46(s,9H),1.32(d,J＝7.1Hz,3H),1.20–1.01(m,5H)。
Step 10: (S) -N- ((S) -1-cyclohexyl-2- ((S) -2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide
Tert-butyl ((S) -1- (((S) -1-cyclohexyl-2- ((S) -2- (4- (7-fluoro-2, 3-dihydro-1H-indene-4-carbonyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) amino) -1-oxopropan-2-yl) (methyl) carbamate (630mg,0.9831mmol), HCl/EA (4N) (11mL) were added to the reaction flask and stirred at rt. A white solid gradually precipitated. The reaction solution was spin dried and sent to preparative HPLC to give 430mg of a white solid. The yield thereof was found to be 81%.
1H NMR(400MHz,CDCl3)δ8.03(s,1H),7.84(dd,J＝8.4,5.1Hz,1H),7.69(d,J＝9.2Hz,1H),6.91(t,J＝8.5Hz,1H),5.52(dd,J＝7.8,2.3Hz,1H),4.62(dd,J＝9.1,6.3Hz,1H),3.92(dd,J＝16.9,8.7Hz,1H),3.83–3.74(m,1H),3.27–3.13(m,2H),3.06(q,J＝6.9Hz,1H),2.96(t,J＝7.5Hz,2H),2.39(s,4H),2.32–2.22(m,1H),2.19–2.05(m,4H),1.67(m,7H),1.31(m,3H),1.11(m,5H)。
13C NMR(151MHz,CDCl3)δ187.53,175.11,172.42,171.56,162.53,160.85,154.71,151.08(d,J＝7.3Hz),131.89(dd,J＝32.2,13.4Hz),130.22(d,J＝3.1Hz),128.01,112.69,112.54,60.52,58.78,54.63,47.69,40.94,35.29,33.91,31.65,30.19,29.82,28.45,28.19,26.23,26.11,25.93,25.38,24.71,19.84。
MS(ESI,pos.ion)m/z:541.3(M+H)+。
HPLC 97.7％。
Synthesis of examples 40 to 57
By selecting the appropriate starting materials, examples 41-57 were synthesized according to the synthesis scheme of example 39, with the following characterization data:
Figure BDA0001839332310000511
Figure BDA0001839332310000521
Figure BDA0001839332310000531
examples of biological Activity test
Example A test Compounds for in vitro Activity
The first step, the used experimental reagent and the test article are as follows:
McCoy's 5a medium, DMEM medium, and diabody (penicillin-streptomycin) were purchased from Hyclone;
fetal Bovine Serum (FBS) was purchased from Gibco;
dimethyl sulfoxide (DMSO) purchased from Sigma;
CCK8 kit was purchased from synneus of japan;
cell lines MDA-MB-231 and SKOV3 were purchased from ATCC.
Secondly, the experimental steps are as follows:
1. cell plating
a. Preparing complete culture medium, and mixing completely.
The complete medium for culturing the cells MDA-MB-231 was: 10% FBS + 1% diabody + 89% DMEM;
the complete medium for culturing cell SKOV3 was: 10% FBS + 1% diabody + 89% McCoy's 5 a;
b. recovering the cells, and selecting cell strains with good growth state after two generations.
c. The cell culture flask was removed from the incubator and checked for the cell name, culture medium type and cell number marked on the flask.
d. The cell suspension was pipetted into the centrifuge tube and centrifuged at 800-.
e. The cell supernatant in the centrifuge tube was aspirated.
f. Add the appropriate volume of medium to the centrifuge tube and gently blow it to resuspend the cells evenly.
g. Counting was performed using a Vi-Cell XR cytometer.
h. The cell suspension was adjusted to the appropriate concentration.
i. The cell suspension was added to a 96-well bottom transmural white plate at 100. mu.l/well. Marking the detailed information of cell name, plate density, date, etc., and placing the culture plate in CO2The incubator was overnight.
2. Preparation and addition of test samples:
a. compounds were formulated in DMSO into 10mM stock solutions
Preparation of 2mM compound 20. mu.l each of 10mM compound was diluted to 2mM in 80. mu.l DMSO.
c. The compounds were diluted stepwise 3-fold with DMSO at 2mM maximum concentration to give 10 concentration gradients.
3. Adding a test sample:
a. 0.5. mu.l of the corresponding compound plate was removed and added to the overnight-cultured cell culture plate.
b. Incubate at 37 ℃ for 72 hours.
4. Detection and analysis
After 72 hours of incubation, the original medium was discarded, 100. mu.l of complete medium containing 10% CCK-8 was added and incubated in an incubator at 37 ℃ for 1-2 hours, and the absorbance (A) of each well was measured at 450nm using a microplate reader.
5. Data analysis method
The inhibition rate of the drug on the growth of tumor cells was calculated according to the following formula:
tumor cell growth inhibition rate [ (Ac-As)/(Ac-Ab) ]. times.100
As the absorbance of the sample (cell + CCK-8+ test Compound)
Ac absorbance of negative control (cell + CCK-8+ DMSO)
Ab blank absorbance (Medium + CCK-8+ DMSO)
And data were analyzed and plotted using Graph Pad Prism 5 software.
The data processing software calculated the IC50 values for each compound at 72 hours.
Thirdly, the experimental results are as follows:
TABLE 1
Compound (I) MDA-MB-231,IC50(nM) Compound (I) MDA-MB-231,IC50(nM)
Example 3 41.00 Example 15 55.00
Example 4 10.00 Example 16 20.00
Example 5 7.00 Example 20 70.00
Example 6 45.00 Example 25 36.00
Example 7 10.00 Example 29 15.00
Example 10 90.00 Example 35 6.00
Example 11 100.00 Example 37 121.00
Example 12 30.00 Example 39 41.00
Fourthly, experimental conclusion:
the compound has good inhibitory effect on MDA-MB-231 cells.
Example B detection of the pharmacokinetics of the Compounds
The first step, the used experimental reagent and the test article are as follows:
propranolol (internal standard)), methanol, ammonium acetate, K2EDTA, formic acid, acetonitrile, MTBE (methyl tert-butyl ether),
KolliphorHS15 (polyethylene glycol 12 hydroxystearate), DMSO (dimethyl sulfoxide) are all commercially available.
SD rat: male, 180-.
Secondly, the experimental steps are as follows:
1. preparation of test article
The test solutions were prepared from 5% DMSO + 5% KolliphorHS15+ 90% physiological saline, and were adjusted to the solubility of each compound so that the compound was completely dissolved.
2. The animal experimental design is shown in Table 2
TABLE 2
Figure BDA0001839332310000551
3. The animal dose is shown in Table 3
TABLE 3
Group of Sex Number of animals Dosage to be administered Concentration of drug administration Volume of administration
IV Male sex 3 1mg/kg 0.5mg/mL 2mL/kg
IG Male sex 3 5mg/kg 0.5mg/mL 10mL/kg
4. Solution preparation
(1) Preparation of a stock solution of a test article: accurately weighing a proper amount of a test sample, dissolving the test sample in DMSO, diluting the test sample to 1mg/mL by using acetonitrile, and shaking up the test sample to obtain the test sample. Storing at-20 deg.C for use.
(2) Preparing an internal standard substance solution: a certain amount of 1mg/mL Propranol stock solution was precisely aspirated and diluted to 100ng/mL with water.
5. Sample analysis
Processing a sample by adopting a liquid-liquid extraction method, carrying out chromatographic separation, carrying out quantitative analysis on the sample by a triple quadrupole tandem mass spectrometer in a multiple reactive ion monitoring (MRM) mode, and calculating the concentration of the result by using instrument quantitative software.
6. Plasma sample pretreatment
Accurately sucking 30 μ L of plasma sample, adding 250 μ L of internal standard, and mixing by vortex. Extracting with 1mL MTBE once, centrifuging at 13000rpm at 4 deg.C for 2min, sucking 800 μ L supernatant, volatilizing in a 96-well nitrogen blower, re-dissolving the residue with 150 μ L methanol: 50, vortex mixing, and injecting with 8 μ L sample.
7. Preparation of Standard samples
Accurately sucking a proper amount of compound stock solution, and adding acetonitrile to dilute to prepare a standard series solution. Accurately sucking 20 mu L of each standard series solution, adding 180 mu L of blank plasma, uniformly mixing by vortex, preparing plasma samples with plasma concentrations of 3,5, 10, 30, 100, 300, 1000, 3000, 5000 and 10000ng/mL, performing double-sample analysis on each concentration according to 3.5.1.
8. Analytical method
The LC/MS method was used to determine the amount of test compound in rat plasma after administration of the different compounds.
9. Data processing
Pharmacokinetic parameters were calculated using WinNonlin 6.1 software, a non-compartmental model method.
Thirdly, the experimental results are as follows:
TABLE 4 PK parameters for the compounds of the invention
Figure BDA0001839332310000561
Fourth, conclusion of experiment
The results of the experiments in Table 4 show that the compounds of the present invention have a good bioavailability compared to comparative compound 1. (remark: chemical name of comparative Compound 1 shows (S) -N- ((S) -1-cyclohexyl-2- ((S) -2- (4- (4-fluorobenzoyl) thiazol-2-yl) pyrrolidin-1-yl) -2-oxoethyl) -2- (methylamino) propionamide)
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and alterations to the above embodiments without departing from the principle and spirit of the present invention, the scope of which is defined by the appended claims and their equivalents.

Claims (5)

1. A compound has a structure shown as a formula (I) or (III), or a stereoisomer or pharmaceutically acceptable salt of the compound with the structure shown as the formula (I) or (III),
Figure 630793DEST_PATH_IMAGE001
(I)，
Figure 847011DEST_PATH_IMAGE002
(III)，
wherein,
n1 is 1,2 or 3;
n3 is 0, 1,2 or 3;
each m is independently 0, 1,2,3,4 or 5;
each R1And R3Independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
each R2And R3aIndependently is H or D;
each R5Independently is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
each R4Independently is H or D;
each R0Independently is D, F, Cl, Br, oxo (= O), cyano, hydroxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, -S (= O) -R10、-S(=O)2-R10Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy; or, two R0And together with the carbon atoms between which they are attached form a cyclopropane, cyclobutane, cyclopentane, cyclohexane or cycloheptane; wherein said cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane are each independently optionally substituted with 1,2,3, or 4 substituents selected from D, F, Cl, Br, and hydroxyl;
each R6Independently H, D, F, Cl or Br;
each R7Independently is H or D; and
each R10Independently methyl, ethyl or propyl.
2. A compound having a structure described by formula (VII), or a stereoisomer or a pharmaceutically acceptable salt of the compound having the structure described by formula (VII),
Figure 542566DEST_PATH_IMAGE003
(VII)，
wherein,
each R1And R3Independently methyl, ethyl, n-propyl or isopropyl;
each R2And R3aIndependently is H or D;
R5is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
each R4Independently is H or D;
each R7Independently is H or D;
Figure 957367DEST_PATH_IMAGE004
is composed of
Figure 899915DEST_PATH_IMAGE005
，
Wherein,
each R12、R13Independently H, D, F, Cl or Br;
each R6Independently H, D, F, Cl or Br.
3. The compound has one of the following structures, or a stereoisomer or pharmaceutically acceptable salt thereof,
Figure 150899DEST_PATH_IMAGE006
Figure 571516DEST_PATH_IMAGE007
Figure 106402DEST_PATH_IMAGE008
Figure 764392DEST_PATH_IMAGE009
Figure 689623DEST_PATH_IMAGE010
Figure 976248DEST_PATH_IMAGE011
Figure 116373DEST_PATH_IMAGE012
Figure 400724DEST_PATH_IMAGE013
Figure 875568DEST_PATH_IMAGE014
Figure 637987DEST_PATH_IMAGE015
Figure 632619DEST_PATH_IMAGE016
Figure 150188DEST_PATH_IMAGE017
Figure 50011DEST_PATH_IMAGE018
Figure 429171DEST_PATH_IMAGE019
Figure 465260DEST_PATH_IMAGE020
Figure 153731DEST_PATH_IMAGE021
Figure 356829DEST_PATH_IMAGE022
Figure 461051DEST_PATH_IMAGE023
Figure 679542DEST_PATH_IMAGE024
Figure 289647DEST_PATH_IMAGE025
Figure 898482DEST_PATH_IMAGE026
Figure 134292DEST_PATH_IMAGE027
Figure 144973DEST_PATH_IMAGE028
Figure 925978DEST_PATH_IMAGE029
Figure 84427DEST_PATH_IMAGE030
Figure 530452DEST_PATH_IMAGE031
Figure 474268DEST_PATH_IMAGE032
Figure 613126DEST_PATH_IMAGE033
Figure 258871DEST_PATH_IMAGE034
。
4. a pharmaceutical composition comprising a compound according to any one of claims 1 to 3 and pharmaceutically acceptable adjuvants thereof.
5. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to claim 4 in the manufacture of a medicament for the prevention or treatment of a proliferative disease, wherein the proliferative disease is cancer.
CN201811241130.9A 2017-10-25 2018-10-24 IAP inhibitors and their use in medicine Active CN109705191B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2017110064198 2017-10-25
CN201711006419 2017-10-25

Publications (2)

Publication Number Publication Date
CN109705191A CN109705191A (en) 2019-05-03
CN109705191B true CN109705191B (en) 2022-04-29

Family

ID=66254657

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201811241130.9A Active CN109705191B (en) 2017-10-25 2018-10-24 IAP inhibitors and their use in medicine

Country Status (1)

Country Link
CN (1) CN109705191B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021220178A1 (en) * 2020-04-29 2021-11-04 Cominnex Zrt. Iap antagonists and their therapeutic applications

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UY33236A (en) * 2010-02-25 2011-09-30 Novartis Ag DIMERIC INHIBITORS OF THE IAP
UY33794A (en) * 2010-12-13 2012-07-31 Novartis Ag DIMERIC INHIBITORS OF THE IAP
NO2755614T3 (en) * 2012-01-03 2018-03-31
CN104558102A (en) * 2013-10-18 2015-04-29 中国人民解放军军事医学科学院毒物药物研究所 Anti-apoptosis protein inhibitor and application thereof
GB201506871D0 (en) * 2015-04-22 2015-06-03 Glaxosmithkline Ip Dev Ltd Novel compounds

Also Published As

Publication number Publication date
CN109705191A (en) 2019-05-03

Similar Documents

Publication Publication Date Title
CN109400625B (en) Fused bicyclic compound and application thereof in medicine
CN113135924B (en) Pyrimidine derivatives and their use in medicine
IL293962A (en) Kras mutant protein inhibitors
KR101961500B1 (en) Serine/threonine kinase inhibitors
JP7105781B2 (en) Benzimidazole derivatives, methods of preparation and their use
CN111936475A (en) Immunomodulator, composition and preparation method thereof
JP6437452B2 (en) Bicyclic aromatic carboxamide compounds useful as Pim kinase inhibitors
CA3157361A1 (en) Bicyclic heterocycles as fgfr inhibitors
CN111315749A (en) Novel dihydroisoxazole compounds and their use in the treatment of hepatitis b
JP2017518276A (en) Polyfluoro-substituted compounds as breton-type tyrosine kinase (BTK) inhibitors
US11548868B2 (en) Heterocyclic compounds, compositions comprising heterocyclic compound, and methods of use thereof
WO2014113191A1 (en) Hedgehog pathway signaling inhibitors and therapeutic applications thereof
CN116178391A (en) Forward allosteric modulators of muscarinic acetylcholine receptor M4
KR20150129010A (en) Ido inhibitors
CN105732637B (en) Heteroaromatic compounds and their use in medicine
CN114423751B (en) Novel heterocyclic compounds useful as selective AURORA a inhibitors
EP3350185A1 (en) 1-phenylpyrrolidin-2-one derivatives as perk inhibitors
CN112574235A (en) RET inhibitor, pharmaceutical composition and application thereof
CN112442050A (en) RET inhibitor, pharmaceutical composition and application thereof
JP2022517085A (en) Halogenated allylamine compounds and their applications
CN111518100A (en) Cyclopropenoarylbenzofuran substituted nitrogen heteroaryl compound and application thereof
CN108948019B (en) Focal adhesion kinase inhibitors and uses thereof
CN109705191B (en) IAP inhibitors and their use in medicine
CN114805311A (en) Spirocyclic indenes
US20190374526A1 (en) Substituted Heterocyclic Compounds as Inhibitors of PRDM9

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant
CP03 Change of name, title or address
CP03 Change of name, title or address

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

Patentee after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd.

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

Patentee before: SUNSHINE LAKE PHARMA Co.,Ltd.