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HK1208866B - Aryl and heteroaryl fused lactams - Google Patents

Aryl and heteroaryl fused lactams Download PDF

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Publication number
HK1208866B
HK1208866B HK15109626.6A HK15109626A HK1208866B HK 1208866 B HK1208866 B HK 1208866B HK 15109626 A HK15109626 A HK 15109626A HK 1208866 B HK1208866 B HK 1208866B
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Hong Kong
Prior art keywords
alkyl
optionally substituted
membered heteroaryl
halogen
group
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Application number
HK15109626.6A
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Chinese (zh)
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HK1208866A1 (en
Inventor
M．P．爱德华兹
R．A．孔普夫
P-P．孔
I．J．麦卡尔平
S.宁科维奇
E．Y．芮
S．C．萨顿
J．H．塔特洛克
M．J．威思
L．R．曾德尔
Original Assignee
辉瑞大药厂
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Priority claimed from PCT/IB2013/060682 external-priority patent/WO2014097041A1/en
Publication of HK1208866A1 publication Critical patent/HK1208866A1/en
Publication of HK1208866B publication Critical patent/HK1208866B/en

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Description

Aryl and heteroaryl fused lactams
CROSS-REFERENCE TO RELATED APPLICATIONS
The priority benefit of U.S. provisional application No.61/740,596, filed on 21/12/2012 of the present application, is incorporated herein in its entirety.
Technical Field
The present invention relates to compounds of formulae (I) - (IV) and pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds and salts, and uses thereof. The compounds, salts and compositions of the invention are useful for treating or ameliorating abnormal cell proliferative disorders, such as cancer.
Background
Epigenetic changes play an important role in regulating cellular processes including cell proliferation, cell differentiation, and cell survival. Epigenetic silencing of tumor suppressor genes and activation of oncogenes can occur through CpG island methylation patterns, histone modifications, and DNA binding protein dysregulation. Polycomb genes (Polycomb genes) are a group of epigenetic effectors. EZH2 (enhancer of zeste isoform 2) is the catalytic component of Polycomb suppressor Complex 2(Polycomb resolver Complex 2) (PRC2), which Polycomb suppressor Complex 2 is a conserved multi-subunit Complex that suppresses gene transcription by making lysine 27(H3K27) on histone H3. EZH2 plays a key role in regulating gene expression patterns that regulate cell fate decisions such as differentiation and self-renewal. EZH2 is overexpressed in some cancer cells, where it is associated with cell differentiation, cell invasion, chemoresistance, and metastasis.
High EZH2 expression correlates with poor prognosis, advanced and advanced stages in several cancer types. The cancer types include breast, colorectal, endometrial, gastric, liver, renal, lung, melanoma, ovarian, pancreatic, prostate, and bladder cancer. See Crea et al crit. rev. oncol. hematonol.2012, 83: 184-; see also Kleer et al Proc.Natl.Acad.Sci.USA 2003, 100: 11606-11; mimori et al eur.j.surg.oncol.2005, 31: 376 to 80; bachmann et al j.clin.oncol.2006, 24: 268-273; matsukawa et al Cancer Sci.2006, 97: 484-491; lab of Sasaki et al invest.2008, 88: 873-882; sudo et al Br.J. cancer 2005, 92(9): 1754-; breuer et al, Neoplasia 2004, 6: 736-43; lu et al Cancer Res.2007, 67: 1757-; ougholkov et al, clin. cancer res.2008, 14: 6790-6796; varambally et al Nature 2002, 419: 624-629; wagener et al int.j. cancer 2008, 123: 1545-; and Weikert et al int.j.mol.med.2005, 16: 349-353.
Recurrent somatic mutations in EZH2 were identified in diffuse large B-cell lymphoma (DLBCL) and Follicular Lymphoma (FL). Mutations that alter EZH2 tyrosine 641 (e.g., Y641C, Y641F, Y641N, Y641S, and Y641H) have been reported to be observed in up to 22% of growing center B-cell DLBCL and 7% FL. Morin et al nat. genetics 2010 Feb; 42(2):181-185. Mutations of alanine 677(a677) and alanine 687(a687) have also been reported. McCAbe et al proc.natl.acad.sci.usa 2012, 109: 2989 and 2994; majer et al FEBSletters 2012, 586: 3448-3451. Activation mutations of EZH2 suggest that substrate specificity is altered, resulting in elevated levels of trimethylated H3K27(H3K27me 3).
Accordingly, compounds that inhibit wild-type and/or mutant forms of EZH2 are contemplated for use in the treatment of cancer.
SUMMARY
The present invention provides, in part, novel compounds and pharmaceutically acceptable salts thereof that can modulate EZH2 activity to achieve biological functions, including (but not limited to): inhibiting cell proliferation and cell invasion, inhibiting metastasis, inducing apoptosis, or inhibiting angiogenesis. The invention also provides pharmaceutical compositions and medicaments comprising a compound or salt of the invention, alone or in combination with other therapeutic agents or palliatives. The invention also provides, in part, methods of preparing the novel compounds, salts and compositions thereof, and methods of use thereof.
In one aspect, the present invention provides a compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
u is N or CR3；
V is N or CR4；
L is C1-C4An alkylene linker;
m is a bond or-O-;
R1is C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R21Substitution;
R2selected from H, C1-C8Alkyl radical, C1-C8Alkoxy, -OR6、-NR7R8、-C(O)NR7R8、-SO2NR7R8、-NR7SO2R8、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C 1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R22Is substituted, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Substitution;
R3is H, C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R23Substitution;
R4selected from H, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, - (C)1-C4Alkyl) Rz、-ORx、-CN、-C(O)Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORy、-NRxSO2Ry、-NRxSO2NRxRy、-OC(O)Rxand-OC (O) NRxRy；
RxAnd RyEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
Rzeach independently selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl、C6-C12Aryl and 5-12 membered heteroaryl; and is
Wherein R is4、RxOr RyThe C in (1)1-C8Alkyl and (C)1-C4Alkyl) RzThe C in (1)1-C4Each alkyl group is optionally substituted with one or more R24Is substituted, and R4、Rx、Ry、RzOr RxAnd RySaid C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R 34Substitution;
R5each independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10Wherein said C is1-C4Alkyl or C1-C4Each alkoxy group is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10；
R6Is- (CR)11R12)n-R13；
R7And R8Each independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
R7And R8May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is7Or R8The C in (1)1-C8Each alkyl group is optionally substituted with one or more R27Is substituted, and R7、R8Or R7And R8Said C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R37Substitution;
R9and R10Each independently is H or C1-C4An alkyl group; or
R9And R10May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is9Or R10The C in (1)1-C4Alkyl and R9And R10Each of said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R11And R12Each independently is H, halogen or C1-C4Alkyl radical, wherein said C1-C4Each alkyl group is optionally substituted with one or more R22Substitution;
R13is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Substitution;
m is 0 to 4;
n is 0 to 4;
R21、R22、R23and R24Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Re、-CO2Re、-C(O)NReRf、-ORe、-SRe、-SORe、-SO2Re、-SO2NReRf、-NO2、-NReRf、-NReC(O)Rf、-NReC(O)NReRf、-NReC(O)ORf、-NReSO2Rf、-NReSO2NReRf、-OC(O)Re、-OC(O)NReRf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Reand RfEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
ReAnd RfMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is21、R22、R23、R24、Re、RfOr ReAnd RfSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C 1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R27Each independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C4Alkoxy radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R32、R34And R37Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Rc、-CO2Rc、-C(O)NRcRd、-ORc、-SRc、-SORc、-SO2Rc、-SO2NRcRd、-NO2、-NRcRd、-NRcC(O)Rd、-NRcC(O)NRcRd、-NRcC(O)ORd、-NRcSO2Rd、-NRcSO2NRcRd、-OC(O)Rc、-OC(O)NRcRd、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Rcand RdEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
RcAnd RdMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is32、R34、R37、Rc、RdOr RcAnd RdSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
X and Z are independently selected from H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, halogen, CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Raor-OC (O) NRaRb；
Wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Ra、-OC(O)NRaRb、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Raand RbEach independently is H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl, wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, C1-C4Alkyl, -OR14、-NR14 2、-CO2R14、-C(O)NR14 2、-SO2R14and-SO2NR14 2Wherein R is14Each independently is H or C1-C4An alkyl group; or
RaAnd RbMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S, Wherein said heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2(ii) a And is
Y is H, halogen, -OH or C1-C4An alkoxy group.
In some aspects, the compound of formula (I) is a compound of formula (I-A), (I-B), or (I-C):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5L, M, M, X, Y and Z are as defined for formula (I).
In another aspect, the invention provides a compound of formula (II):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、U、V、R5M, X, Y and Z are as defined for formula (I).
In some aspects, the compound of formula (II) is a compound of formula (II-A), (II-B), or (II-C):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
In another aspect, the invention provides a compound of formula (III):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、U、V、R5M, X, Y and Z are as defined for formula (I).
In some aspects, the compound of formula (III) is a compound of formula (III-A), (III-B), or (III-C):
or a pharmaceutically acceptable salt thereof,
Wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
In another aspect, the invention provides a compound of formula (IV):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、U、V、R5M, X, Y and Z are as defined for formula (I)。
In some aspects, the compound of formula (IV) is a compound of formula (IV-A), (IV-B), or (IV-C):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of one of the formulae described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides methods of treatment and uses comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof.
In one aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with an anti-neoplastic agent in an amount effective to treat the abnormal cell growth. In some embodiments, the antineoplastic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic drugs, anti-hormonal agents, and anti-androgens.
In a common embodiment of the methods provided herein, the abnormal cell growth is cancer. In some embodiments, the provided methods result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasion; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.
In another aspect, the present invention provides a method of treating an EZH 2-mediated disease in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disease. The compounds and salts of the present invention inhibit the wild type and some mutant forms of human histone transferase EZH 2.
In another aspect, the invention provides a compound of one of the formulae described herein, or a pharmaceutically acceptable salt thereof, for use in treating abnormal cell growth in a subject.
In another aspect, the invention provides the use of a compound of one of the formulae described herein, or a pharmaceutically acceptable salt thereof, in the treatment of abnormal cell growth in a subject.
In another aspect, the invention provides the use of a compound of one of the formulae described herein or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of abnormal cell growth.
In a common embodiment, the abnormal cell growth is cancer and the subject is a human.
In some embodiments, the methods described herein further comprise administering to the subject an amount of an anti-cancer therapeutic or ameliorative agent, said amounts together being effective to treat said abnormal cell growth. In some such embodiments, the one or more anti-cancer therapeutic agents are selected from the group consisting of an antineoplastic agent, an anti-angiogenic agent, a signal transduction inhibitor, and an antiproliferative agent, in amounts that together are effective to treat the abnormal cell growth.
In other embodiments, the uses described herein include the use of a compound of one of the formulae described herein or a pharmaceutically acceptable salt thereof in combination with one or more substances selected from the group consisting of an anti-neoplastic agent, an anti-angiogenic agent, a signal transduction inhibitor, and an antiproliferative agent.
In some embodiments, the agents described herein are suitable for use in combination with one or more substances selected from the group consisting of anti-neoplastic agents, anti-angiogenic agents, signal transduction inhibitors, and antiproliferative agents.
Each of the embodiments of the compounds of the invention described below may be combined with one or more other embodiments of the compounds of the invention described herein, which are incompatible with the embodiment with which it is combined. Furthermore, the embodiments of the present invention described below each focus on a pharmaceutically acceptable salt of the compound of the present invention within its scope. Thus, the meaning of the phrase "or a pharmaceutically acceptable salt thereof" is to describe all compounds described herein.
Detailed Description
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples thereof contained herein. It should be understood that: the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should additionally be understood that: terms used herein are to be given their commonly used meanings as are well known in the relevant art, unless specifically defined herein.
As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise. For example, "a substituent includes one or more substituents.
"alkyl" refers to a saturated monovalent aliphatic hydrocarbon group including straight and branched chain groups having the indicated number of carbon atoms. The alkyl substituents typically contain 1 to 20 carbon atoms ("C)1-C20Alkyl group), preferably 1 to 12 carbon atoms ("C")1-C12Alkyl group "), more preferably 1 to 8 carbon atoms (" C ")1-C8Alkyl "), or 1 to 6 carbon atomsSeed (' C)1-C6Alkyl group "), or 1 to 4 carbon atoms (" C)1-C4Alkyl "). Examples of alkyl groups include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like. Alkyl groups may be substituted or unsubstituted. In particular, an alkyl group may be substituted with one or more halo groups (depending on the total number of hydrogen atoms present in the alkyl moiety), unless specifically indicated otherwise. Thus C 1-C4Alkyl includes haloalkyl, such as trifluoromethyl or difluoroethyl (i.e. CF)3and-CH2CHF2)。
The optionally substituted alkyl groups described herein may be substituted with one or more substituents independently selected unless otherwise indicated. The total number of substituents can be equal to the total number of hydrogen atoms on the alkyl moiety, provided that the substitution is chemically reasonable. Optionally substituted alkyl typically contains 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, preferably 1 to 4 optional substituents, or more preferably 1 to 3 optional substituents.
Suitable optional substituents for alkyl groups include (but are not limited to): c3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, halogen, ═ O (oxo), ═ S (thio), ═ N-CN, ═ N-ORX、＝NRX、-CN、-C(O)Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORx、-NRxSO2Ry、-NRxSO2NRxRy、-ORx、-OC(O)Rxand-OC (O) NRxRy(ii) a Wherein R isxAnd RyEach independently is H, C1-C8Alkyl radical、C1-C8Acyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl, or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S; rxAnd RyEach optionally substituted with 1-3 substituents independently selected from halogen, ═ O, ═ S, ═ N-CN, ═ N-OR ', -NR ', -CN, -c (O) R ', -CO 2R'、-C(O)NR'2、-SR'、-SOR'、-SO2R'、-SO2NR'2、-NO2、-NR'2、-NR'C(O)R'、-NR'C(O)NR'2、-NR'C(O)OR'、-NR'SO2R'、-NR'SO2NR'2-, -OR ', -OC (O) R ' and-OC (O) NR '2Wherein R' is each independently H, C1-C8Alkyl radical, C1-C8Acyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or C5-C12A heteroaryl group; and wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted as further defined herein.
Typical substituents on alkyl groups include halogen, -OH, C1-C4Alkoxy, -O-C6-C12Aryl, -CN, ═ O, -COORx、-OC(O)Rx、-C(O)NRxRy、-NRxC(O)Ry、-NRxRy、C3-C8Cycloalkyl radical, C6-C12Aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl; wherein R isxAnd RyEach independently is H or C1-C4Alkyl, or RxAnd RyMay form, together with the N to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which is optionally substitutedComprises 1, 2 or 3 additional heteroatoms selected from O, N and S; wherein said C3-C8Cycloalkyl radical, C6-C12Aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some embodiments, alkyl is optionally substituted with one or more substituents, and preferably with 1 to 3 substituents independently selected from halogen, -OH, C 1-C4Alkoxy, -O-C6-C12Aryl, -CN, ═ O, -COORx、-OC(O)Rx、-C(O)NRxRy、-NRxC(O)Ry、-NRxRy、C3-C8Cycloalkyl radical, C6-C12Aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl; wherein R isxAnd RyEach independently is H or C1-C4Alkyl, or RxAnd RyMay form, together with the N to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S; and said C is3-C8Cycloalkyl radical, C6-C12Aryl, 5-12 membered heteroaryl, and 3-12 membered heterocyclyl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In other embodiments, alkyl is optionally substituted with one or more substituents, and preferably with 1 to 3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NRxRy、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; wherein R isxAnd RyEach independently is H or C1-C4Alkyl, or RxAnd RyMay form, together with the N to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S; and wherein said cycloalkyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some cases, substituted alkyl groups may be specifically named according to the substituent. For example, "haloalkyl" refers to an alkyl group having the indicated number of carbon atoms, typically containing 1 to 6 carbon atoms and 1, 2, or 3 halogen atoms (i.e., "C"), substituted with one or more halogen substituents1-C6Haloalkyl "), thus, C1-C6Haloalkyl includes trifluoromethyl (-CF)3) And difluoromethyl (-CF)2H)。
Similarly, "hydroxyalkyl" refers to an alkyl group having the indicated number of carbon atoms substituted with one or more hydroxyl substituents, typically containing 1 to 6 carbon atoms and 1, 2, or 3 hydroxyl groups (i.e., "C")1-C6Hydroxyalkyl "). Thus, C1-C6Hydroxyalkyl includes hydroxymethyl (-CH)2OH) and 2-hydroxyethyl(-CH2CH2OH)。
"alkoxyalkyl" refers to an alkyl group having the indicated number of carbon atoms substituted with one or more alkoxy substituents. Alkoxyalkyl typically contains 1-6 carbon atoms in the alkyl moiety and is substituted with 1, 2 or 3C1-C4Alkoxy substituents. Alkoxyalkyl is sometimes referred to herein as C1-C4alkoxy-C1-C6An alkyl group.
"aminoalkyl" refers to an alkyl group having the indicated number of carbon atoms substituted with one or more substituted or unsubstituted amino groups (as otherwise defined herein). Aminoalkyl typically contains 1 to 6 carbon atoms in the alkyl moiety and is substituted with 1, 2, or 3 amino substituents. Thus, C1-C6Aminoalkyl radicals include, for example, aminomethyl (-CH)2NH2) N, N-dimethylamino-ethyl (-CH)2CH2N(CH3)2) 3- (N-cyclopropylamino) propyl (-CH)2CH2CH2NH-cPr) and N-pyrrolidinylethyl (-CH)2CH2-N-pyrrolidinyl).
"alkenyl" refers to an alkyl group, as defined herein, that is composed of at least two carbon atoms and at least one carbon-carbon double bond. Typically, alkenyl groups have 2 to 20 carbon atoms ("C)2-C20Alkenyl "), preferably 2 to 12 carbon atoms (" C ")2-C12Alkenyl "), more preferably 2 to 8 carbon atoms (" C ")2-C8Alkenyl "), or 2 to 6 carbon atoms (" C)2-C6Alkenyl), or 2 to 4 carbon atoms ("C)2-C4Alkenyl "). Representative examples include (but are not limited to): vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. Alkenyl groups may be unsubstituted or substituted with the same groups described herein as suitable for alkyl.
"alkynyl" refers to an alkyl group, as defined herein, consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Alkynyl having 2 to 20 carbon atoms ("C) 2-C20Alkynyl), preferably 2 to 12 carbon atoms ("C")2-C12Alkynyl), more preferably 2 to 8 carbon atoms ("C")2-C8Alkynyl "), or 2 to 6 carbon atoms (" C)2-C6Alkynyl "), or 2 to 4 carbon atoms (" C)2-C4Alkynyl "). Typical examples include (but are not limited to): ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl and the like. Alkynyl groups may be unsubstituted or substituted with the same groups described herein as suitable for alkyl.
As used herein, "alkylene" refers to a divalent hydrocarbon group having the indicated number of carbon atoms to which two other groups may be bonded. Sometimes it is referred to as- (CH)2)n-, where n is 1 to 8 and preferably n is 1 to 4. In the indicated cases, the alkylene groups may also be substituted with other groups and may include one or more unsaturations (i.e., alkenylene or alkynylene moieties) or rings. The open valences of the alkylene groups need not be located at opposite ends of the chain. thus-CH (Me) -and-C (Me)2Also included within the scope of the term "alkylene" are cyclic groups (e.g. cyclopropa-1, 1-diyl) and unsaturated groups (e.g. ethenyl (-CH ═ CH-) or propenyl (-CH-)2-CH ═ CH-)) is also the same. Where an alkylene group is described as being optionally substituted, the substituent includes substituents typically present on alkyl groups as described herein.
"Heteroalkylene" means an alkylene group as described above in which one or more of the multiple non-contiguous carbon atoms of the alkylene chain is replaced by-N (R) -, -O-or-S (O)q-substituted, wherein R is H or C1-C4Alkyl and q is 0-2. For example, the group-O- (CH)2)1-4-is "C2-C5"-heteroalkylene, wherein one of the carbon atoms of the corresponding alkylene is substituted with O.
"alkoxy" refers to a monovalent-O-alkyl group in which the alkyl portion has the indicated number of carbon atoms. Alkoxy groups typically contain 1 to 8 carbon atoms ("C)1-C8Alkoxy ") or 1 to 6 carbon atoms (" C)1-C6Alkoxy ") or 1 to 4 carbon atoms (" C)1-C4Alkoxy "). E.g. C1-C4Alkoxy radicals including-OCH3、-OCH2CH3、-OCH(CH3)2、-OC(CH3)3And the like. Such alkoxy groups may also be referred to herein as methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. An alkoxy group may be unsubstituted or substituted on the alkyl moiety with the same groups described herein as suitable for alkyl. In particular, the alkoxy group may be substituted with one or more halo groups (up to the total number of hydrogen atoms present in the alkyl moiety). Thus C1-C4Alkoxy groups include haloalkoxy groups, such as trifluoromethoxy and 2, 2-difluoroethoxy (i.e., -OCF)3and-OCH2CHF2)。
Similarly, "thioalkoxy" refers to a monovalent-S-alkyl group in which the alkyl moiety has the indicated number of carbon atoms and may be optionally substituted on the alkyl moiety with the same groups described herein as suitable for alkyl. E.g. C 1-C4Thioalkoxy groups including-SCH3and-SCH2CH3。
"cycloalkyl" means a non-aromatic, saturated or partially unsaturated carbocyclic ring system containing the indicated number of carbon atoms, which may be a monocyclic, bridged or fused bicyclic or polycyclic ring system, which is linked to the base molecule through a carbon atom of the cycloalkyl ring. Typically, cycloalkyl groups of the present invention contain 3 to 12 carbon atoms ("C)3-C12Cycloalkyl group "), preferably 3 to 8 carbon atoms (" C3-C8Cycloalkyl "). Representative examples include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptatriene, adamantane, and the like. Cycloalkyl groups may be unsubstituted or substituted with the same groups described herein as suitable for alkyl.
Examples of exemplary cycloalkyl rings include (but are not limited to):
"cycloalkylalkyl" may be used to describe a cycloalkyl ring, typically C3-C8Cycloalkyl radicals linked through an alkylene group, typically C1-C4The alkylene group is attached to the base molecule. Cycloalkylalkyl is described by the total number of carbon atoms in the carbocyclic ring and the linking group, and typically contains 4-12 carbon atoms ("C)4-C12Cycloalkylalkyl "). Thus, cyclopropylmethyl is C4-cycloalkylalkyl, and cyclohexylethyl is C 8-cycloalkylalkyl. Cycloalkylalkyl groups may be unsubstituted or substituted on the cycloalkyl and/or alkylene moieties with the same groups described herein as being suitable for alkyl groups.
The terms "heterocyclyl", "heterocyclic" or "heteroalicyclic" are used interchangeably herein to refer to a non-aromatic, saturated or partially unsaturated ring system containing the indicated number of ring atoms, including as ring members at least one heteroatom selected from N, O and S, wherein the heterocyclic ring is bonded to the base molecule through the ring atoms (which may be C or N). The heterocyclic ring may be fused to one or more other heterocyclic or carbocyclic rings, which fused rings may be saturated, partially unsaturated or aromatic. Preferably, the heterocyclic ring comprises from 1 to 4 heteroatoms selected from N, O and S, more preferably from 1 to 2 ring heteroatoms as ring members, provided that such heterocyclic ring does not comprise two linked oxygen atoms. The heterocyclyl group may be unsubstituted or substituted with the same groups described herein as suitable for alkyl, aryl or heteroaryl. In addition, the ring N atom may be optionally substituted with groups suitable for amines (e.g., alkyl, acyl, carbamoyl, sulfonyl substituents, etc.), and the ring S atom may be optionally substituted with l or 2 oxo groups (i.e., S (O)) qWherein q is 0, 1 or 2). Preferred heterocycles comprise 3-12 membered heterocyclyl groups as defined herein.
Illustrative examples of saturated heterocyclic groups include (but are not limited to):
illustrative examples of partially unsaturated heterocyclyl groups include (but are not limited to):
illustrative examples of bridged and fused heterocyclic groups include (but are not limited to):
in a common embodiment, heterocyclyl contains 3-12 ring members (including carbon and non-carbon heteroatoms), preferably 4-6 ring members. In certain preferred embodiments, the substituents comprising 3-12 membered heterocyclic rings are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl rings, each of which may be optionally substituted on each particular substituent, so long as such substitution is chemically reasonable.
It will be understood that no more than two N, O or S atoms are typically attached sequentially, except where an oxo group is attached to N or S to form a nitro or sulfonyl group, or in the case of some heteroaromatic rings, for example, triazines, triazoles, tetrazoles, oxadiazoles, thiadiazoles and the like.
The term "heterocyclylalkyl" may be used to describe a heterocyclyl group of a specified size that is attached to a base molecule through an alkylene linker of a specified length. Typically. Such groups comprise optionally substituted 3-12 membered heterocyclic rings, which are interrupted by C 1-C4An alkylene linker is attached to the base molecule. Wherein such groups may be optionally substituted on the alkylene portion with the same groups described herein as suitable alkyl groups, as indicated, andand are substituted on the heterocyclic moiety with groups described as suitable for heterocycles.
"aryl" or "aromatic" refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having well-known aromatic character wherein at least one ring contains a fully conjugated pi-electron system. Typically, an aryl group contains 6 to 20 carbon atoms ("C)6-C20Aryl "), preferably 6 to 14 carbon atoms (" C ")6-C14Aryl group ") or more preferably 6 to 12 carbon atoms (" C)6-C12Aryl ") as a ring member. The fused aryl group may include an aromatic ring (e.g., a benzene ring) fused to another aromatic ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring. The point of attachment to the base molecule on such a fused aromatic ring system may be a C atom of an aromatic or non-aromatic portion of the ring system. Examples of the aryl group include phenyl, biphenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl and tetrahydronaphthyl, but are not limited thereto. The aryl group may be unsubstituted or substituted as described elsewhere herein.
Similarly, "heteroaryl" or "heteroaromatic" refers to a monocyclic or fused bicyclic or polycyclic ring system having well-known aromatic character (containing the indicated number of ring atoms and including at least one heteroatom selected from N, O and S as a ring member within the aromatic ring). The inclusion of heteroatoms imparts aromaticity in the 5-and 6-membered rings. Typically, heteroaryl groups contain 5 to 20 ring atoms ("5-20 membered heteroaryl"), preferably 5 to 14 ring atoms ("5-14 membered heteroaryl"), and more preferably 5 to 12 ring atoms ("5-12 membered heteroaryl"). The heteroaromatic ring retains aromaticity by bonding the ring atoms of the heteroaromatic ring to the base molecule. Thus, a 6-membered heteroaromatic ring may be bonded to the base molecule through a carbon atom in the ring, while a 5-membered heteroaromatic ring may be bonded to the base molecule through a carbon or nitrogen atom in the ring. Examples of unsubstituted heteroaryl groups generally include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, thialine, isoquinoline, purine, triazine, naphthyridine, and carbazole. In a generally preferred embodiment, the 5-6 membered heteroaryl is selected from the group consisting of pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridyl and pyrimidyl rings. Heteroaryl groups may be unsubstituted or substituted as described elsewhere herein.
Aryl, heteroaryl, and heterocyclyl moieties described herein as optionally substituted may be substituted with one or more substituents independently selected unless otherwise indicated. The total number of substituents may be equal to the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, so long as such substitutions are chemically reasonable and the aromaticity is maintained in the case of aryl and heteroaryl rings. An optionally substituted aryl, heteroaryl or heterocyclyl group typically contains 1-5 optional substituents, sometimes 1-4 optional substituents, preferably 1-3 optional substituents or more preferably 1-2 optional substituents.
Optional substituents suitable for the aryl, heteroaryl and heterocyclyl rings include, but are not limited to: c1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; and halogen, ═ O, -CN, -c (O) Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORx、-NRxSO2Ry、-NRxSO2NRxRy、-ORx、-OC(O)Rxand-OC (O) NRxRy(ii) a Wherein R isxAnd RyEach independently is H, C1-C8Alkyl radical, C1-C8Acyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl, or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S; r xAnd RyEach optionally substituted with 1-3 substituents independently selected from halogen, ═ O, ═ S, ═ N-CN, ═ N-OR ', -NR ', -CN, -c (O) R ', -CO2R'、-C(O)NR'2、-SR'、-SOR'、-SO2R'、-SO2NR'2、-NO2、-NR'2、-NR'C(O)R'、-NR'C(O)NR'2、-NR'C(O)OR'、-NR'SO2R'、-NR'SO2NR'2-, -OR ', -OC (O) R ' and-OC (O) NR '2Wherein R' is each independently H, C1-C8Alkyl radical, C1-C8Acyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl; and said C is1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted as defined in the further sections herein.
In typical embodiments, the optional substitution on the aryl, heteroaryl, and heterocyclyl rings includes one or more substituents and preferably 1 to 3 substituents independently selected from halogen, C1-C8Alkyl, -OH, C1-C8Alkoxy, -CN, ═ O, -C (O) Rx、-COORx、-OC(O)Rx、-C(O)NRxRy、-NRxC(O)Ry、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORy、-NRxSO2Ry、-NRxSO2NRxRy、-OC(O)Rx、-OC(O)NRxRy、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, -O- (C)3-C8Cycloalkyl), -O- (3-12 membered heterocyclyl), -O- (C)6-C12Aryl) and-O- (5-12 membered heteroaryl); wherein R isxAnd RyEach independently is H or C1-C4Alkyl, or RxAnd RyMay form, together with the N to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S; and wherein each is described as optionally substituted or as R xOr RySaid C constituting part1-C8Alkyl radical, C1-C8Alkoxy radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, -O- (C)3-C8Cycloalkyl), -O- (3-12 membered heterocyclyl), -O- (C)6-C12Aryl) and-O- (5-12 membered heteroaryl) are optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl), -N (C)1-C4Alkyl radical)2And N-pyrrolidinyl.
Illustrative examples of monocyclic heteroaryls include (but are not limited to):
illustrative examples of fused ring heteroaryls include (but are not limited to):
"arylalkyl" refers to an aryl group as described herein, which is attached to a base molecule through an alkylene or similar linker. Arylalkyl is described by the total number of carbon atoms in the ring and the carbon atoms of the linker. Thus, benzyl is C7Aryl alkyl, and phenyl ethyl is C8-arylalkyl. Typically, arylalkyl groups contain from 7 to 16 carbon atoms ("C)7-C16Arylalkyl ") wherein the aryl portion contains 6 to 12 carbon atoms and the alkylene portion contains 1 to 4 carbon atoms. Such a group may also be represented by-C1-C4alkylene-C6-C12And (4) an aryl group.
"heteroarylalkyl" refers to a heteroaryl group, as described above, that is attached to the base molecule through an alkylene linker, and differs from "arylalkyl" in that at least one ring atom of the aromatic moiety is a heteroatom selected from N, O and S. Heteroarylalkyl is sometimes described herein in terms of the total number of non-hydrogen atoms (i.e., C, N, S and O atoms) and the combined linking groups in the ring, excluding substituent groups. Thus, for example, pyridylmethyl may be referred to as "C 7"-heteroarylalkyl. Typically, unsubstituted heteroarylalkyl groups contain 6 to 20 non-hydrogen atoms (including C, N, S and O atoms), with the heteroaryl portion typically containing 5 to 12 atoms and the alkylene portion typically containing 1 to 4 carbon atoms. Such a group may also be represented by-C1-C4Alkylene-5-12 membered heteroaryl.
Similarly, "arylalkoxy" and "heteroarylalkoxy" refer to aryl and heteroaryl groups attached to a base molecule through a heteroalkylene linker (i.e., -O-alkylene-), where the groups are described in terms of the non-hydrogen atoms in the ring (i.e., C, N, S and O atoms) and the total number of linkers combined. Thus, -O-CH2-phenyl and-O-CH2The pyridyl radicals may each be referred to as C8Arylalkoxy and C8-heteroarylalkoxy.
If arylalkyl, arylalkoxy, heteroarylalkyl or heteroarylalkoxy is described as optionally substituted, the substituents may be on the divalent linking group or on the aryl or heteroaryl portion of the group. The substituents optionally present on the alkylene or heteroalkylene are generally the same as those described above for alkyl or alkoxy, while the substituents optionally present on the aryl or heteroaryl portion are generally the same as those described above for aryl or heteroaryl.
"hydroxy" means an-OH group.
"Acyloxy" refers to a monovalent group-OC (O) alkyl, wherein the alkyl portion has the indicated number of carbon atoms (typically C)1-C8Preferably C1-C6Or C1-C4) And may be optionally substituted with groups suitable for alkyl. Thus, C1-C4The acyloxy group includes-OC (O) C1-C4Alkyl substituents, e.g. -OC (O) CH3。
"acylamino" refers to a monovalent group-NHC (O) alkyl or-NRC (O) alkyl, where the alkyl moiety has the indicated number of carbon atoms (typically C)1-C8Preferably C1-C6Or C1-C4) And may be optionally substituted with groups suitable for alkyl. Thus C1-C4Acylamino groups include-NHC (O) C1-C4Alkyl substituents, e.g. -NHC (O) CH3。
"aryloxy" or "heteroaryloxy" refers to an optionally substituted-O-aryl or-O-heteroaryl, in each case aryl and heteroaryl as defined in the further sections herein.
"arylamino" or "heteroarylamino" refers to optionally substituted-NH-aryl, -NR-aryl, -NH-heteroaryl or-NR-heteroaryl, in each case aryl and heteroaryl as otherwise defined herein and R represents a substituent of a suitable amine, e.g., alkyl, acyl, carbamoyl or sulfonyl, and the like.
"cyano" refers to a-C.ident.N group.
"unsubstituted amino" refers to the group-NH2. Where an amino group is described as substituted or optionally substituted, the term includes the form-NRxRyWherein R isxAnd RyEach independently is H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, acyl, thioacyl, aryl, heteroaryl, cycloalkylalkyl, aralkyl, or heteroaralkyl, each having the indicated number of atoms and optionally substituted as described herein. For example, "alkylamino" refers to-NRxRyGroup, wherein RxAnd RyOne is an alkyl moiety and the other is H, "dialkylamino" means-NRxRyWherein R isxAnd RyAre all alkyl moieties wherein the alkyl moiety has the indicated number of carbon atoms (e.g., -NH-C1-C4Alkyl or-N (C)1-C4Alkyl radical)2). Typically, the alkyl substituent on the amine contains 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, or more preferably 1 to 4 carbon atoms. The term also includes RxAnd RyTogether with the N atom to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which may itself be optionally substituted as described herein for heterocyclyl or heteroaryl, and which may contain from 1 to 3 additional heteroatoms selected from N, O and S as ring members, with the proviso that such rings do not contain two linked oxygen atoms.
"halogen" or "halo" refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I). Preferably, halogen means fluorine or chlorine (F or Cl).
As used herein, "heteroform" sometimes refers to derivatives of groups such as alkyl, aryl, or acyl groups in which at least one carbon atom of a given carbocyclic group is replaced with a heteroatom selected from N, O and S. Thus, the heteroforms of alkyl, alkenyl, alkynyl, acyl, aryl, and arylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl, heteroaryl, and heteroarylalkyl, respectively. It will be understood that no more than two N, O or S atoms are typically attached in sequence, except where an oxo group is attached to N or S to form a nitro or sulfonyl group.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
The terms "optionally substituted" and "substituted or unsubstituted" may be used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., substituted), provided that such substitution is chemically reasonable, and that the total number of substituents that may be present, if not otherwise specifically indicated, is equal to the total number of hydrogen atoms present in the unsubstituted group being described. In the case where an optional substituent is bound via a double bond (e.g., an oxo (═ O) substituent), that group occupies two of the valencies, and thus may be reduced by 2 in total by the other substituents included. Where the optional substituents are independently selected from a series of alternatives, the selected groups may be the same or different.
In one aspect, the present invention provides a compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
u is N or CR3；
V is N or CR4；
L is C1-C4An alkylene linker;
m is a bond or-O-;
R1is C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R21Substitution;
R2selected from H, C1-C8Alkyl radical, C1-C8Alkoxy, -OR6、-NR7R8、-C(O)NR7R8、-SO2NR7R8、-NR7SO2R8、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R22Is substituted, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Substitution;
R3is H, C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R23Substitution;
R4selected from H, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, - (C)1-C4Alkyl radical)Rz、-ORx、-CN、-C(O)Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORy、-NRxSO2Ry、-NRxSO2NRxRy、-OC(O)Rxand-OC (O) NRxRy；
RxAnd RyEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
RzEach independently selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; and is
Wherein R is4、RxOr RyThe C in (1)1-C8Alkyl and (C)1-C4Alkyl) RzThe C in (1)1-C4Each alkyl group is optionally substituted with one or more R24Is substituted, and R4、Rx、Ry、RzOr RxAnd RySaid C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34Substitution;
R5each independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NR9R10And-C(O)NR9R10Wherein said C is1-C4Alkyl or C1-C4Each alkoxy group is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10；
R6Is- (CR)11R12)n-R13；
R7And R8Each independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
R7And R8May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is7Or R8The C in (1)1-C8Each alkyl group is optionally substituted with one or more R27Is substituted, and R7、R8Or R7And R8Said C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R 37Substitution;
R9and R10Each independently is H or C1-C4An alkyl group; or
R9And R10May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is9Or R10The C in (1)1-C4Alkyl and R9And R10Said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together are each optionally substituted by 1-3Substituted with substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R11And R12Each independently is H, halogen or C1-C4Alkyl radical, wherein said C1-C4Each alkyl group is optionally substituted with one or more R22Substitution;
R13is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Substitution;
m is 0 to 4;
n is 0 to 4;
R21、R22、R23and R24Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Re、-CO2Re、-C(O)NReRf、-ORe、-SRe、-SORe、-SO2Re、-SO2NReRf、-NO2、-NReRf、-NReC(O)Rf、-NReC(O)NReRf、-NReC(O)ORf、-NReSO2Rf、-NReSO2NReRf、-OC(O)Re、-OC(O)NReRf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Reand RfEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
ReAnd R fMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is21、R22、R23、R24、Re、RfOr ReAnd RfSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R27Each independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C4Alkoxy radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R32、R34And R37Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Rc、-CO2Rc、-C(O)NRcRd、-ORc、-SRc、-SORc、-SO2Rc、-SO2NRcRd、-NO2、-NRcRd、-NRcC(O)Rd、-NRcC(O)NRcRd、-NRcC(O)ORd、-NRcSO2Rd、-NRcSO2NRcRd、-OC(O)Rc、-OC(O)NRcRd、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Rcand R dEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
RcAnd RdMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is32、R34、R37、Rc、RdOr RcAnd RdSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
X and Z are independently selected from H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, halogen, CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Raor-OC (O) NRaRb；
Wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb,-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Ra、-OC(O)NRaRb、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Raand RbEach independently is H, C 1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl, wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, C1-C4Alkyl, -OR14、-NR14 2、-CO2R14、-C(O)NR14 2、-SO2R14and-SO2NR14 2Wherein R is14Each independently is H or C1-C4An alkyl group; or
RaAnd RbMay form together with the N atom to which they are attached a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally comprises 1, 2 or 3 additional heteroatoms selected from O, N and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2(ii) a And is
Y is H, halogen, -OH or C1-C4An alkoxy group.
In the compounds of formula (I), U and V are each independently selected from N and a substituted carbon atom (each CR)3And CR4) Such that the core ring comprising U and V may be differently a phenyl, pyridyl or pyridazinyl ring. In some of the formula (I)In embodiments, no more than 1 of U and V is N. In other embodiments of formula (I), U and V are both N. In other embodiments of formula (I), one of U and V is N. In other embodiments, neither U nor V is N.
In one embodiment of formula (I), U is CR3And V is CR4Such that the ring containing U and V is a benzene ring. In some such embodiments, R3Is H or F, preferably H.
In another embodiment of formula (I), U is N and V is CR4Such that the ring containing U and V is [4,3-c ]]-a fused pyridine ring.
In another embodiment of formula (I), U is CR3And V is N, such that the ring containing U and V is [3,2-c]-a fused pyridine ring. In some such embodiments, R3Is H or F, preferably H.
In the compounds of formula (I), L is C1-C4An alkylene linker. In a preferred embodiment, L is C2-C3An alkylene linker. In some specific embodiments, L is a methylene, ethylene, or propylene linker. In some preferred embodiments, L is an ethylene linker. In other preferred embodiments, L is a propylene linker.
In some embodiments of formula (I), L is C1-C4An alkylene linker, and m is 0, such that alkylene linker L is unsubstituted. In other embodiments, m is an integer from 1 to 4, such that the alkylene linker L is substituted with 1 to 4R5And (4) substituting the group. In a preferred embodiment, L is an ethylene linker and m is 0. In another preferred embodiment, L is a propylene linker and m is 0.
In the compounds of formula (I), M is a bond or-O-. In some preferred embodiments, M is a bond. In other preferred embodiments, M is-O-.
In some embodiments of formula (I), L is C1-C4An alkylene linker, and M is a bond. In some embodiments, L is C2-C3An alkylene linker, and M is a bond. In other embodiments, L is a methylene, ethylene, or propylene linker, and M is a bond. In some such embodiments, L is an ethylene linker and M is a bond. In other such embodiments, L is a propylene linker and M is a bond.
In further embodiments, L is C1-C4An alkylene linker, M is a bond, and M is 0, such that alkylene linker L is unsubstituted. In other embodiments, L is C1-C4An alkylene linker, M is a bond and M is an integer from 1 to 4, such that the alkylene linker L is substituted with 1 to 4R5And (4) substituting the group. In some such embodiments, L is C2-C3An alkylene linker. In other such embodiments, L is a methylene, ethylene, or propylene linker.
In some embodiments of formula (I), L is C1-C4An alkylene linker, and M is-O-. In some embodiments, L is C 2-C3An alkylene linker, and M is-O-. In other embodiments, L is a methylene, ethylene, or propylene linkage, and M is-O-. In some such embodiments, L is an ethylene linker and M is-O-. In other such embodiments, L is a propylene linker and M is-O-.
In further embodiments, L is C1-C4An alkylene linker, M is-O-, and M is 0, such that alkylene linker L is unsubstituted. In other embodiments, L is C1-C4An alkylene linker, M is-O-, and M is an integer from 1 to 4, such that the alkylene linker L is substituted with 1 to 4R5And (4) substituting the group. In some such embodiments, L is C2-C3An alkylene linker. In other such embodiments, L is a methylene, ethylene, or propylene linker.
In the formula (I)) In the compound of (1), R5Each independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10Wherein said C is1-C4Alkyl or C1-C4Each alkoxy group is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10。
When R is5comprising-NR9R10or-C (O) NR9R10When R is9And R10Each independently is H or C1-C4An alkyl group; or R 9And R10May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S. R9Or R10The C in (1)1-C4Alkyl and R9And R10Each of said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some embodiments, R5Each independently selected from halogen, -OH and C1-C4An alkyl group. In some such embodiments, R5Each is halogen, preferably fluorine. In one embodiment, m is 1, and R is5Is F. In another embodiment, m is 2, and R5Each is F. In some such embodiments, m is 2, R5Each is F, and R5The groups are disubstituted in pairs on one carbon atom of L. In other embodiments, m is 1 or 2, and R5Each independently selected from-OH, ═ O, C1-C4Alkyl and C1-C4Alkoxy, wherein said C1-C4Alkyl or C1-C4Alkoxy is in each case optionally substituted by 1 to 3 halogen, -OH or C1-C4Alkoxy substitution. In some embodiments, m is 1 or 2, and R5is-OH, methyl or methoxy.
In the compounds of formula (I), R1Is C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R21And (4) substitution. In some such embodiments, the C1-C8Alkyl or C1-C8Alkoxy is optionally substituted with 1-3R21And (4) substituting the group. In some such embodiments, R1Is C1-C4Alkyl or halogen, wherein said C1-C4Alkyl is optionally substituted with 1-3R21And (4) substituting the group. In other embodiments, R1Is unsubstituted C1-C4Alkyl or halogen.
In some embodiments of formula (I), R1Is halogen, preferably chlorine (Cl) or fluorine (F). In other embodiments of formula (I), R1Is C1-C8Alkyl radical, wherein said C1-C8Alkyl is optionally substituted with 1-3R21And (4) substituting the group. In some embodiments, R1Is optionally substituted C1-C4An alkyl group. In specific embodiments, R1Is unsubstituted C1-C4Alkyl, preferably methyl or ethyl. In specific embodiments, R1Is methyl, ethyl, chloro or fluoro. In a preferred embodiment, R1Is methyl. In other preferred embodiments, R1Is Cl.
In the compounds of formula (I), R2Independently selected from H, C1-C8Alkyl radical, C1-C8Alkoxy, -OR6、-NR7R8、-C(O)NR7R8、-SO2NR7R8、-NR7SO2R8、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C 6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R22Is substituted, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32And (4) substitution. In some embodiments, said C1-C8Alkyl or C1-C8Alkoxy is optionally substituted with 1-3R22Is substituted by radicals, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3R32And (4) substituting the group.
In one embodiment, R2Is C1-C8Alkyl radical, wherein said C1-C8Alkyl is optionally substituted by one or more R22And (4) substituting the group. In some embodiments, R2Is optionally substituted by 1-3R22Radical substituted C1-C8An alkyl group. In some such embodiments, R2Is optionally substituted by 1-3R22Substituted C1-C4An alkyl group. In specific embodiments, R2Is optionally substituted by 1-3R22Radical substituted C1-C4Alkyl radical, said R22The radicals are independently selected from halogen, -C (O) NReRf、-ORe、-NReRf、-NReC(O)Rfand-NReSO2RfWherein R iseAnd RfAs defined above for formula (I). In some such embodiments, ReAnd RfIndependently is H or C1-C4An alkyl group. In other embodiments, ReAnd RfTogether form a 4-6 membered heterocyclyl ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperizinyl (ii) an oxazinyl group, a morpholinyl group, or a thiomorpholinyl group, each of which is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some embodiments of formula (I), R2Is C1-C8Alkoxy, wherein said C1-C8Alkoxy is optionally substituted by one or more R22And (4) substituting the group. In some embodiments, R2Is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group. In other embodiments, R2Is optionally substituted by 1-4R22Radical substituted C1-C8An alkoxy group. In other embodiments, R2Is optionally substituted by 1-3R22Radical substituted C1-C8An alkoxy group.
In some such embodiments, R22Each independently is halogen or-OH, preferably fluorine or-OH. In a specific embodiment, said C1-C8Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy, each of which may be independently substituted by 1 to 5 fluorine or OH groups, up to the number of hydrogen atoms. In some embodiments, said C1-C8Alkoxy is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. In one embodiment, R 2Is isopropoxy. In another embodiment, R2Is an ethoxy group. In another embodiment, R2Is sec-butoxy.
In other embodiments, R2Is C independently substituted by 1-5 fluoro or-OH groups1-C8An alkoxy group. Wherein said C1-C8Embodiments in which the alkoxy group is substituted with at least one F are also referred to as C1-C8A fluoroalkoxy group. C1-C8Examples of fluoroalkoxy groups include, but are not limited to, the groups 1, 1-difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 1- (trifluoromethyl) ethoxy, 1,1,1- (trifluoroprop-2-yl) oxy, 3,3,4, 4-tetrafluorobutoxy, 3,3, 3-trifluoro-2-hydroxypropoxy, 1, 1-difluoroprop-2-yl) oxy, and 2, 2-difluoroethoxy.
In another embodiment, R2Is substituted by 1-5 substituents independently selected from halogen, -C (O) NReRfand-OReR of (A) to (B)22Radical substituted C1-C8Alkoxy radical, wherein ReAnd RfIndependently is H or C1-C4An alkyl group.
In another embodiment, R2is-OR6Wherein R is6Is- (CR)11R12)n-R13Wherein n is 0 to 4. In such compounds, R11And R12Each independently is H, halogen or C1-C4Alkyl radical, wherein said C1-C4Each alkyl group is optionally substituted with one or more R22And (4) substitution. Preferably, R11And R12Each independently of the other being H, halogen or unsubstituted C1-C4An alkyl group. In specific embodiments, R 11And R12Each independently is H or methyl. In the above embodiments, R13Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32And (4) substitution. In some such embodiments, n is 0, and R is13Is C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl OR 5-12 membered heteroaryl, such that-OR6Respectively comprise C3-C8Cycloalkoxy, 3-12 membered heterocyclyloxy, C6-C12Aryloxy or 5-12 membered heteroaryloxy, each of which may optionally be substituted with one or more R32And (4) substitution. In a common embodiment, n is 1 or 2, and R13Is 5-12 membered heteroaryl, optionally substituted with one or more R32And (4) substitution.
In another embodiment, R2Is selected from-NR7R8、-C(O)NR7R8、-SO2NR7R8and-NR7SO2R8Wherein R is7And R8Each independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or R7And R8May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S; wherein R is7Or R8The C in (1)1-C8Each alkyl group is optionally substituted with one or more R 27Is substituted, and R7、R8Or R7And R8Said C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R37And (4) substitution. In some such embodiments, R37Each independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2. In some such embodiments, when R2comprising-NR7R8、-C(O)NR7R8or-SO2NR7R8When R is7And R8Each independently is H or C1-C4An alkyl group.
In another embodiment of (I), R2Is a 5-12 membered heteroaryl group, wherein said heteroAryl is optionally substituted with one or more R32And (4) substitution. In some such embodiments, the 5-12 membered heteroaryl is optionally substituted with 1-3R32And (4) substituting the group.
In some embodiments, R2Is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl. In some such embodiments, the 5-6 membered heteroaryl is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, each of which may optionally be substituted with 1-3R32And (4) substituting the group. In other such embodiments, the 5-6 membered heteroaryl is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, each of which is optionally substituted with 1-3R 32And (4) substituting the group. In a preferred embodiment, the 5-6 membered heteroaryl is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, and pyrimidinyl, each of which is optionally substituted with 1-3R32And (4) substituting the group. In another preferred embodiment, the 5-6 membered heteroaryl is pyrazolyl or triazolyl, optionally substituted with 1-3R32And (4) substituting the group. In another preferred embodiment, the 5-6 membered heteroaryl is pyrazolyl, isoxazolyl, or triazolyl, each of which is optionally substituted with 1-3R32And (4) substituting the group.
In specific embodiments, R2May be selected from the group consisting of 5-6 membered heteroaryl, wherein the asterisk (—) indicates the point of attachment to the base molecule, and optionally the substituent R32May be present at any atom of the heteroaryl ring (N or C) bearing an H atom in its unsubstituted form:
wherein p is 0, 1, 2 or 3; q is 0, 1 or 2; r is 0 or 1; and s is 0, 1, 2, 3 or 4.
In other embodiments, R2May be selected from the group consisting of 5-membered heteroaryl, wherein the asterisk (—) indicates the point of attachment to the base molecule, and optionally the substituent R32May be present at any atom of a heteroaryl ring (N or C) bearing an H atom in its unsubstituted form (including tautomeric forms):
Wherein p is 0, 1, 2 or 3; q is 0, 1 or 2.
In specific embodiments, R2May be selected from the following 5-membered heteroaryl groups, wherein the asterisk (—) indicates the point of attachment to the base molecule:
in another embodiment, R2Is a 3-12 membered heterocyclyl, wherein said heterocyclyl is optionally substituted with one or more R32And (4) substitution. In some embodiments, the heterocyclyl is optionally substituted with 1-3R32And (4) substituting the group. In some such embodiments, the 3-12 membered heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-oxa-5-azabicyclo [2.2.1]Heptylalkyl, 3-oxa-8-azabicyclo [3.2.1]Octyl, dihydropyranyl, tetrahydrofuryl and tetrahydropyranyl, each optionally substituted with 1-3R32And (4) substituting the group.
In another embodiment, R2Is C6-C12Aryl, wherein said aryl is optionally substituted with one or more R32And (4) substitution. In some such embodiments, the aryl group is optionally substituted with 1-3R32And (4) substituting the group. In a particular embodiment, the aryl group is selected from phenyl, biphenylPhenyl, naphthyl, indanyl, indenyl and tetrahydronaphthyl, each optionally substituted with 1-3R32And (4) substituting the group.
In another embodiment, R 2Is optionally substituted by one or more R32Substituted C3-C8A cycloalkyl group. In some such embodiments, the C3-C8Cycloalkyl is optionally substituted with 1-3R32And (4) substituting the group. In a particular embodiment, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each of which is optionally substituted with 1-3R32And (4) substituting the group.
In the compounds of formula (I), R3Is H, C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R23And (4) substitution. In some embodiments, said C1-C8Alkyl or C1-C8Alkoxy is optionally substituted with 1-3R23And (4) substituting the group. In some embodiments, R3Is C1-C4Alkyl or C1-C4Alkoxy, optionally substituted with 1-3R23And (4) substituting the group. In some such embodiments, C1-C4Alkyl or C1-C4Alkoxy is each optionally substituted by 1 to 3R23Is substituted by the radicals R23The radicals being selected from halogen, -OH or C1-C4An alkoxy group. In specific embodiments, R3is-OMe. In other embodiments, R3Is H or halogen, preferably H or F. In a preferred embodiment, R3Is H. In other embodiments, R3Is F. In other embodiments, R3is-CN.
In the compounds of formula (I), R 4Selected from H, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, - (C)1-C4Alkyl) Rz、-ORx、-CN、-C(O)Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORy、-NRxSO2Ry、-NRxSO2NRxRy、-OC(O)Rxand-OC (O) NRxRyAs further defined above for formula (I).
RxAnd RyEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S.
RzEach independently selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl.
In each of the above embodiments, R4、RxOr RyThe C in (1)1-C8Alkyl and (C)1-C4Alkyl) RzThe C in (1)1-C4Each alkyl group is optionally substituted with one or more R24Is substituted, and R4、Rx、Ry、RzOr RxAnd RySaid C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34And (4) substitution.
In one embodiment, R4Is H,Halogen or-CN. In some such embodiments, R4Is H. In other such embodiments, R4Is halogen, preferably Cl or F. In other such embodiments, R4Is halogen, preferably Cl or F. In other such embodiments, R 4Is Cl or Br. In other such embodiments, R4is-CN.
In another embodiment, R4is-C (O) NRxRyWherein R isxAnd RyAs defined above for formula (I). In some such embodiments, RxAnd RyIndependently is H or C1-C4An alkyl group.
In another embodiment, R4Is optionally substituted by one or more R24Substituted C1-C8An alkyl group. In some such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C8An alkyl group. In other such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C4An alkyl group. In some such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C4Alkyl radical, said R24The groups are independently selected from-ORe、-NReRf、-NReC(O)Rf、-NReC(O)ORf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, each of which is further defined as in formula (I) and optionally substituted as described in formula (I).
In another embodiment, R4Is- (C)1-C4Alkyl) -RzWherein R iszIndependently selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein RzThe C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-to 12-memberedHeteroaryl is each optionally substituted with one or more R34And (4) substitution.
In one such embodiment, R 4Is- (C)1-C4Alkyl) RzWherein R iszIs a 3-12 membered heterocyclic group, and wherein RzSaid 3-12 membered heterocyclyl in (a) is optionally substituted with one or more R34And (4) substitution. In some such embodiments, RzSaid 3-12 membered heterocyclyl in (a) is optionally substituted with 1-3R34And (4) substituting the group.
In another embodiment, R4Is- (C)1-C4Alkyl) RzWherein R iszIs a 5-12 membered heterocyclic group, and wherein RzSaid 5-12 membered heterocyclyl in (a) is optionally substituted with one or more R34And (4) substitution. In some such embodiments, RzSaid 5-12 membered heterocyclyl in (a) is optionally substituted with 1-3R34And (4) substituting the group. In some embodiments, RzIs a 5-6 membered heteroaryl optionally substituted with 1-3R34And (4) substituting the group.
In some embodiments, when R4Is- (C)1-C4Alkyl) -RzWhen is formed as- (C)1-C4Alkyl) -RzConstituent of (C)1-C4Alkyl) linker is to RzUnsubstituted C1-C4Alkylene selected from methylene, ethylene, propylene or butylene. In some embodiments, the- (C)1-C4Alkyl) group optionally substituted with one or more R24And (4) substituting the group. In other embodiments, the- (C) is1-C4Alkyl) group is methylene, ethylene, propylene or butylene, optionally substituted with 1-3R24And (4) substituting the group.
In another embodiment of formula (I), R 4Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein R4The C in (1)3-C8Cycloalkyl, 3-12 membered heteroCyclic group, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34And (4) substitution.
In one such embodiment, R4Is optionally substituted by one or more R34Substituted 3-12 membered heterocyclyl. In some such embodiments, the 3-12 membered heterocyclyl is optionally substituted with 1-3R34And (4) substituting the group. In some embodiments, the 3-12 membered heterocyclyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, and thiomorpholinyl, each of which is optionally substituted with 1-3R34And (4) substituting the group.
In another embodiment, R4Is optionally substituted by one or more R34Substituted 5-12 membered heteroaryl. In some such embodiments, the 5-12 membered heteroaryl is optionally substituted with 1-3R34And (4) substituting the group. In some embodiments, R4Is optionally substituted by 1-3R34A group-substituted 5-6 membered heteroaryl.
In some embodiments, R4Or RzSaid 5-6 membered heteroaryl in (a) is selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each of which is optionally substituted with 1-3R 34And (4) substituting the group.
In specific embodiments of each formula herein, R4May be selected from the group consisting of 5-6 membered heteroaryl, wherein the asterisk (—) indicates the point of attachment to the base molecule, and optionally the substituent R34May be present at any atom of the heteroaryl ring (N or C) bearing an H atom in its unsubstituted form:
wherein p' is 0, 1, 2 or 3;
q' is 0, 1 or 2;
r' is 0 or 1; and is
s' is 0, 1, 2, 3 or 4.
In another embodiment, R4is-ORxWherein R isxSelected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein RxThe C in (1)1-C8Each alkyl group is optionally substituted with one or more R24Is substituted, and RxThe C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34And (4) substitution.
In the compounds of formula (I), R7And R8Each independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl. In such embodiments, R7Or R8The C in (1)1-C8Each alkyl group is optionally substituted with one or more R27Is substituted, and R7Or R8The C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R 37And (4) substitution. In some embodiments of formula (I), R7And R8Each independently is H or C1-C8Alkyl radical, wherein said C1-C8Alkyl is optionally substituted by one or more R27And (4) substitution. In some such embodiments, the C1-C8Alkyl is optionally substituted with 1-3R27And (4) substituting the group.
In other embodiments of formula (I), R7And R8Together with the N atom to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally comprises 1,2 or 3 additional heteroatoms selected from O, N and S. In such embodiments, R7And R8Said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together are each optionally substituted with one or more R37And (4) substitution.
In the compounds of formula (I), R21、R22、R23And R24Further as defined in formula (I) are each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Re、-CO2Re、-C(O)NReRf、-ORe、-SRe、-SORe、-SO2Re、-SO2NReRf、-NO2、-NReRf、-NReC(O)Rf、-NReC(O)NReRf、-NReC(O)ORf、-NReSO2Rf、-NReSO2NReRf、-OC(O)Re、-OC(O)NReRf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl.
In some embodiments of formula (I), ReAnd RfEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl.
In other embodiments of formula (I), ReAnd RfTogether with the N atom to which they are attached form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S.
R21、R22、R23、R24、Re、RfOr ReAnd RfSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl orEach of the 5-12 membered heteroaryl groups is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In specific embodiments, R21、R22、R23And R24Each independently selected from halogen, -ORe、-CN、-NReRf、-C(O)NReRf、-NReC(O)Rf、-SO2NReRfand-NReSO2RfWherein R iseAnd RfAs defined above for formula (I). In some such embodiments, ReAnd RfEach independently selected from H and C1-C4Alkyl radical, wherein said C1-C4Alkyl is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In other such embodiments, when R21、R22、R23Or R24comprising-NReRfor-C (O) NReRfWhen R iseAnd RfEach independently is H or C1-C4An alkyl group; or ReAnd RfMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally comprises 1, 2 or 3 additional heteroatoms selected from O, N and S, wherein the 3-12 membered heterocyclyl or 5-12 membered heteroaryl is each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In other embodiments of formula (I), R21、R22、R23And R24Each is an optionally substituted 3-12 membered heterocyclyl or an optionally substituted 5-12 membered heteroaryl. In some embodiments, the 3-12 membered heterocyclyl or the 5-12 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some embodiments, R21、R22、R23And R24Each independently selected from Cl, F, -OH, -OCH3、-OC2H5、-OCF3、-CN、C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、NHSO2CH3and-N (CH)3)SO2CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl. In some such embodiments, the 4-6 membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which may be optionally substituted as defined in formula (I). In other such embodiments, the 5-6 membered heteroaryl is optionally substituted pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, or pyrimidinyl. In some embodiments, the 4-6 membered heterocycle Cyclyl or said 5-6 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In the compounds of formula (I), R27Independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C4Alkoxy radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2. When R is27is-NR9R10When R is9And R10Each independently is H or C1-C4An alkyl group; or R9And R10May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S; wherein R is9Or R10The C in (1)1-C4Alkyl and R9And R10Each of said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In the compounds of formula (I), R32、R34And R37Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Rc、-CO2Rc、-C(O)NRcRd、-ORc、-SRc、-SORc、-SO2Rc、-SO2NRcRd、-NO2、-NRcRd、-NRcC(O)Rd、-NRcC(O)NRcRd、-NRcC(O)ORd、-NRcSO2Rd、-NRcSO2NRcRd、-OC(O)Rc、-OC(O)NRcRd、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; rcAnd RdEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or RcAnd RdMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S; wherein R is32、R34、R37、Rc、RdOr RcAnd RdSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some of theseIn an embodiment of (1), R32、R34And R37Each independently is halogen, C1-C8Alkyl, -CN, -C (O) NRcRd、-NRcRd、-NRcC(O)Rd、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl is optionally substituted by-OH, -C1-C4Alkoxy or halogen substitution, R cAnd RdEach independently is H or C1-C4Alkyl radical, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In specific embodiments, R32、R34And R37Each independently selected from-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted as defined in formula (I). In particular embodiments, the 4-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl is optionally substituted with one or more halogen, C1-C4Alkyl or C1-C4Alkoxy substitution. In other specific embodimentsSaid 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some such embodiments, the 4-6 membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which may be optionally substituted as defined for formula (I). In some such embodiments, the 5-6 membered heteroaryl is optionally substituted pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl, or pyrimidinyl. In other such embodiments, the 5-6 membered heteroaryl is optionally substituted pyridinyl or pyrimidinyl. In other such embodiments, the 5-6 membered heteroaryl is optionally substituted pyrazolyl or triazolyl.
In the compound of formula (I), X and Z are independently selected from H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, halo, -CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Raand-OC (O) NRaRb(ii) a Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl may be optionally substituted with 1-3 substituents independently selected from halogen, -CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Ra、-OC(O)NRaRb、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; wherein R isaAnd RbAs defined above for formula (I).
In some embodiments, X and Z are independently selected from C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, each of which may be optionally substituted as described above for formula (I). In other embodiments, X and Z are independently selected from-NRaRband-ORaWherein R isaAnd RbOptionally substituted as described above for formula (I). In a particular embodiment of formula (I), X and Z are each independently C1-C8Alkyl, preferably C1-C4Alkyl, wherein the alkyl is optionally substituted by halogen, -OH, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2And (4) substitution. In a preferred embodiment, X and Z are each independently C1-C4An alkyl group.
In the compounds of formula (I), Y is H, halogen, -OH or C 1-C4An alkoxy group. In particular embodiments, Y is H or F. In some such embodiments, Y is H. In other such embodiments, Y is F. In other embodiments, Y is OH. In other embodiments, Y is C1-C4An alkoxy group.
In the formula (I)) In a preferred embodiment, X and Z are each independently selected from C1-C8Alkyl, and Y is H or F. In a more preferred embodiment of formula (I), X and Z are each independently selected from C1-C4Alkyl, and Y is H.
In some embodiments, the compound of formula (I) is a compound of formula (I-A), (I-B), or (I-C):
wherein R is1、R2、R3、R4、R5L, M, M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (I) and combinations thereof also apply to the corresponding groups of formulae (I-A), (I-B) and (I-C).
In another aspect, the invention provides a compound of formula (II):
or a pharmaceutically acceptable salt thereof,
wherein:
u is N or CR3；
V is N or CR4；
R1Is C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R21Substitution;
R2selected from H, C1-C8Alkyl radical, C1-C8Alkoxy, -OR6、-NR7R8、-C(O)NR7R8、-SO2NR7R8、-NR7SO2R8、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C 1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R22Is substituted, and said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Substitution;
R3is H, C1-C8Alkyl radical, C1-C8Alkoxy, halogen, -OH, -CN or-NR7R8Wherein said C is1-C8Alkyl or C1-C8Each alkoxy group is optionally substituted with one or more R23Substitution;
R4selected from H, halogen, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, - (C)1-C4Alkyl) Rz、-ORx、-CN、-C(O)Rx、-CO2Rx、-C(O)NRxRy、-SRx、-SORx、-SO2Rx、-SO2NRxRy、-NO2、-NRxRy、-NRxC(O)Ry、-NRxC(O)NRxRy、-NRxC(O)ORy、-NRxSO2Ry、-NRxSO2NRxRy、-OC(O)Rxand-OC (O) NRxRy；
RxAnd RyEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl(ii) a Or RxAnd RyMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
Rzeach independently selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; and is
Wherein R is4、RxOr RyThe C in (1)1-C8Alkyl and (C)1-C4Alkyl) RzThe C in (1)1-C4Each alkyl group is optionally substituted with one or more R24Is substituted, and R4、Rx、Ry、RzOr RxAnd RySaid C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R 34Substitution;
R5each independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10Wherein said C is1-C4Alkyl or C1-C4Each alkoxy group is optionally substituted with 1-3 substituents independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10and-C (O) NR9R10；
R6Is- (CR)11R12)n-R13；
R7And R8Each independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
R7And R8Can be connected with themThe N atoms together form a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is7Or R8The C in (1)1-C8Each alkyl group is optionally substituted with one or more R27Is substituted, and R7、R8Or R7And R8Said C in (A) together3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R37Substitution;
R9and R10Each independently is H or C1-C4An alkyl group; or
R9And R10May form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally contains 1, 2 or 3 additional heteroatoms selected from O, N and S;
wherein R is9Or R10The C in (1)1-C4Alkyl and R9And R10Each of said 3-12 membered heterocyclyl or 5-12 membered heteroaryl together is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R11And R12Each independently is H, halogen or C1-C4Alkyl radical, wherein said C1-C4Each alkyl group is optionally substituted with one or more R22Substitution;
R13is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroarylEach optionally substituted by one or more R32Substitution;
m is 0 to 4;
n is 0 to 4;
R21、R22、R23and R24Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Re、-CO2Re、-C(O)NReRf、-ORe、-SRe、-SORe、-SO2Re、-SO2NReRf、-NO2、-NReRf、-NReC(O)Rf、-NReC(O)NReRf、-NReC(O)ORf、-NReSO2Rf、-NReSO2NReRf、-OC(O)Re、-OC(O)NReRf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Reand RfEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
ReAnd RfMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is21、R22、R23、R24、Re、RfOr ReAnd RfSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical、C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C 1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R27Each independently selected from halogen, -OH, C1-C4Alkoxy, -CN, -NR9R10、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C4Alkoxy radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
R32、R34And R37Each independently selected from halogen, C1-C8Alkyl, -CN, -O, -C (O) Rc、-CO2Rc、-C(O)NRcRd、-ORc、-SRc、-SORc、-SO2Rc、-SO2NRcRd、-NO2、-NRcRd、-NRcC(O)Rd、-NRcC(O)NRcRd、-NRcC(O)ORd、-NRcSO2Rd、-NRcSO2NRcRd、-OC(O)Rc、-OC(O)NRcRd、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Rcand RdEach independently selected from H, C1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl; or
RcAnd RdMay form, together with the N atom to which they are attached, a 3-12 membered heterocyclyl or 5-12 membered heteroaryl ring, each of which optionally contains 1, 2, or 3 additional heteroatoms selected from O, N and S;
wherein R is32、R34、R37、Rc、RdOr RcAnd RdSaid C in (A) together1-C8Alkyl radical, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with 1-3 substituents independently selected from halogen, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
X and Z are independently selected from H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl, 5-12 membered heteroaryl, halogen, CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Raor-OC (O) NRaRb；
Wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, -CN, -C (O) Ra、-CO2Ra、-C(O)NRaRb,-SRa、-SORa、-SO2Ra、-SO2NRaRb、-NO2、-NRaRb、-NRaC(O)Rb、-NRaC(O)NRaRb、-NRaC(O)ORa、-NRaSO2Rb、-NRaSO2NRaRb、-ORa、-OC(O)Ra、-OC(O)NRaRb、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl;
Raand RbEach independently is H, C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl, wherein said C1-C8Alkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl are each optionally substituted with one or more substituents independently selected from halogen, C1-C4Alkyl, -OR14、-NR14 2、-CO2R14、-C(O)NR14 2、-SO2R14and-SO2NR14 2Wherein R is14Each independently is H or C1-C4An alkyl group; or
RaAnd RbMay form together with the N atom to which they are attached a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, each of which optionally comprises 1, 2 or 3 additional heteroatoms selected from O, N and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, -OH, ═ O, C 1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2(ii) a And is
Y is H, halogen, -OH or C1-C4An alkoxy group.
The embodiments described herein with respect to formula (I) and combinations thereof also apply to the corresponding groups of formula (II).
In the compounds of the formula (II), U is N or CR3And V is N or CR4And U and V are independently selected.
In a common embodiment of formula (II), U is CR3And V is CR4Such that the ring containing U and V is a benzene ring. Such a 3, 4-dihydroisoquinolin-1 (2H) -one compound may be represented by the formula (II-A). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In another embodiment of formula (II), U is N and V is CR4Such that the ring containing U and V is [4,3-c ]]-a fused pyridine ring. Such a 3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one compound is sometimes represented by the formula (II-B).
In another embodiment of formula (II), U is CR3And V is N, such that the ring containing U and V is [3,2-c]-a fused pyridine ring. Such 7, 8-dihydro-1The 6-naphthyridin-5 (6H) -one compound is sometimes represented by the formula (II-C). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In a common embodiment of formula (II), m is 0 and R5Is absent. In some embodiments of formula (II), m is 1 or 2, and R is5Each independently selected from halogen, -OH and C1-C4An alkyl group. In some embodiments, m is 1 or 2, and R5Independently selected from F, -OH and methyl.
In some embodiments of formula (II), R1Is C1-C4Alkyl or halogen optionally substituted by 1-3R21And (4) substituting the group. In some such embodiments, R1Is halogen, preferably Cl or F. In other such embodiments, R1Is C1-C4Alkyl radical, wherein said C1-C4Alkyl is optionally substituted with 1-3R21And (4) substituting the group. In specific embodiments, R1Is unsubstituted C1-C4Alkyl, preferably methyl or ethyl. In specific embodiments, R1Is methyl, ethyl, chloro or fluoro. In a preferred embodiment, R1Is Cl. In other preferred embodiments, R1Is methyl.
In some embodiments of formula (II), R2Is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group. In other embodiments, R2Is optionally substituted by 1-5R22Radical substituted C1-C4An alkoxy group. In other embodiments, R2Is optionally substituted by 1-3R22Radical substituted C1-C4An alkoxy group. In some such embodiments, R 22Each independently selected from halogen or-OH, preferably F or-OH. In other such embodiments, R22Each independently selected from halogen, -C (O) NReRfand-OReWherein R iseAnd RfIndependently is H or C1-C4An alkyl group.
In a particular embodiment of formula (II), R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy, each of which may be independently substituted with 1 to 5 fluorine or OH groups (up to the number of hydrogen atoms). In some embodiments, R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. In one embodiment, R2Is isopropoxy. In another embodiment, R2Is an ethoxy group. In another embodiment, R2Is sec-butoxy.
In further embodiments of formula (II), R2Is C1-C8Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms)1-C8An alkoxy group. In some such embodiments, R2Is C1-C4Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms)1-C4An alkoxy group. In specific embodiments, R2Is 1, 1-difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 1- (trifluoromethyl) ethoxy, 1,1,1- (trifluoroprop-2-yl) oxy, 3,3,4, 4-tetrafluoro-butoxy, 3,3, 3-trifluoro-2-hydroxypropoxy, 1, 1-difluoroprop-2-yl) oxy or 2, 2-difluoroethoxy. In a preferred embodiment of formula (II), R 2Is C1-C4Alkoxy or C1-C4A fluoroalkoxy group.
In another embodiment of formula (II), R2Is a 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1-3R32And (4) substituting the group. In some embodiments, R2Is a 5-6 membered heteroaryl optionally substituted with 1-3R32And (4) substituting the group. In a preferred embodiment, R2Is a 5-6 membered heteroaryl selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl and pyrimidinyl, each optionally substituted with 1-3R32And (4) substituting the group. In some such embodiments, R2Is a pyrazolyl or triazolyl group, and the compound is a pyrazolyl or triazolyl group,optionally substituted with 1-3R32And (4) substituting the group. In some of the respective embodiments described above, R32Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution.
In other embodiments of formula (II), R2Is C1-C8Alkyl optionally substituted with 1-3R22And (4) substituting the group. In some such embodiments, R2Is optionally substituted by 1-3R22Substituted C1-C4An alkyl group. In specific embodiments, R22Each independently selected from halogen, -C (O) NR eRf、-ORe、-NReRf、-NReC(O)Rfand-NReSO2RfWherein R iseAnd RfAs defined above for formula (I).
In further embodiments of formula (II), R2Is OR6Wherein R is6Is- (CR)11R12)n-R13And n is 0 to 4. In such compounds, R11And R12Each independently is H, halogen or C1-C4Alkyl radical, wherein said C1-C4Each alkyl group is optionally substituted with one or more R22And (4) substitution. Preferably, R11And R12Each independently of the other being H, halogen or unsubstituted C1-C4An alkyl group. In specific embodiments, R11And R12Each independently is H or methyl. In thatIn the above embodiments, R13Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R32Preferably 1-3R32And (4) substitution. In some such embodiments, n is 0, and R is13Is C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl OR 5-12 membered heteroaryl, such that-OR6Respectively comprise C3-C8Cycloalkoxy, 3-12 membered heterocyclyloxy, C6-C12Aryloxy or 5-12 membered heteroaryloxy, each of which may optionally be substituted with one or more R32And preferably 1-3R32And (4) substitution. In other embodiments, n is 1 or 2, and R13Is 5-12 membered heteroaryl, optionally substituted with one or more R 32Preferably 1-3R32And (4) substitution. In some embodiments, when R2is-OR6When R is32Each independently selected from halogen and C1-C8Alkyl radical, wherein said C1-C8Each alkyl is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2。
In some embodiments of formula (II), R3Is H, C1-C8Alkyl radical, C1-C8Alkoxy or halogen. In specific embodiments, R3Is H or halogen, preferably H or F. In a preferred embodiment, R3Is H. In other embodiments, R3Is F.
In an embodiment of formula (II)In the embodiment, R4Is H, halogen or-CN. In some such embodiments, R4Is H. In other such embodiments, R4Is halogen, preferably Cl or F. In other such embodiments, R4Is Cl or Br. In other embodiments, R4is-CN.
In another embodiment of formula (II), R4Is optionally substituted by 1-3R24Substituted C1-C8An alkyl group. In some such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C4An alkyl group. In specific embodiments, R 24Each independently selected from halogen, -ORe、-NReRf、-NReC(O)Rf、-NReC(O)ORf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, each of which is further defined as in formula (I) and optionally substituted as described in formula (I).
In another embodiment of formula (II), R4Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein R4The C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34And (4) substitution.
In a preferred embodiment of formula (II), R4Is optionally substituted by one or more R34Substituted 5-12 membered heteroaryl. In some such embodiments, the 5-12 membered heteroaryl is optionally substituted with 1-3R34And (4) substituting the group. In some embodiments, R4Is optionally substituted by 1-3R34A group-substituted 5-6 membered heteroaryl. In some such embodiments, R4Selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, and the like,A thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl ring, each of which is optionally substituted with 1-3R34And (4) substituting the group.
In some embodiments, when R 4Is C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12When aryl or 5-12 membered heteroaryl, R34Each independently is halogen, C1-C8Alkyl, -CN, -C (O) NRcRd、-NRcRd、-NRcC(O)Rd、C3-C8Cycloalkyl radical, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl is optionally substituted by-OH, -C1-C4Alkoxy or halogen substituted, and RcAnd RdEach independently is H or C1-C4An alkyl group. In specific embodiments, R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution.
In a first preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally independently selected 1-3 halogens, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a second preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a third preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2Is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H;
R4is H or halogen;
R32each is independentSelected from halogen and C1-C8Alkyl, -ORc、-SRc、-SO2Rcand-NRcRdAnd R iscAnd RdEach independently is H or C1-C8An alkyl group; or
R32Each independently selected from halogen and C1-C8Alkyl radical, wherein said C1-C8Each alkyl is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
m is 0 and R5Is absent;
x and Z are independently C1-C4An alkyl group; and
y is H.
In a fourth preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is OR6；
R6Is- (CR)11R12)n-R13；
n is 0 or 1;
R13is a 3-12 membered heterocyclyl or 5-12 membered heteroaryl, wherein each of said 3-12 membered heterocyclyl or 5-12 membered heteroaryl is optionally substituted with 1-3R32Substitution; or
R13Is optionally substituted by 1-3R32A substituted 3-12 membered heterocyclyl; or
R13Is optionally substituted by 1-3R32Substituted 5-12 membered heteroaryl; or
R13Is optionally substituted by 1-3R32Substituted C3-C8A cycloalkyl group; or
R13Is optionally substituted by 1-3R32Substituted C 6-C12An aryl group;
R3is H;
R4is H or halogen;
R32each independently selected from halogen, C1-C8Alkyl, -ORc、-SRc、-SO2Rcand-NRcRdAnd R iscAnd RdEach independently is H or C1-C8An alkyl group; or
R32Each independently selected from halogen and C1-C8Alkyl radical, wherein said C1-C8Each alkyl is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
m is 0 and R5Is absent;
x and Z are independently C1-C4An alkyl group; and
y is H.
In a fifth preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is OR6；
R6Is- (CR)11R12)n-R13；
n is 0 or 1;
R13is optionally substituted by 1-3R32A substituted 3-12 membered heterocyclyl;
R3is H;
R4is H or halogen;
R32each independently selected from halogen and C1-C8Alkyl radical, wherein said C1-C8Each alkyl is optionally substituted with 1-3 substituents independently selected from halo, -OH, ═ O, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C6Haloalkyl, C1-C6Hydroxyalkyl radical, C1-C4alkoxy-C1-C6Alkyl, -CN, -NH2、-NH(C1-C4Alkyl) and-N (C)1-C4Alkyl radical)2；
m is 0 and R5Is absent;
X and Z are independently C1-C4An alkyl group; and
y is H.
In a sixth preferred embodiment of formula (II), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is C1-C4An alkoxy group;
R3is H;
R4is H or halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent;
x and Z are independently C1-C4An alkyl group; and
y is H.
In another embodiment of formula (II), U is N and V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In another embodiment of formula (II), U is N and V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In another embodiment of formula (II), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C 1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In another embodiment of formula (II), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R32each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In some particularly preferred embodiments of formula (II), the compound has a combination of 3, 4, 5, 6, 7, 8, 9 or 10 of the preferred features in each of the above-mentioned groups of preferred embodiments.
In some embodiments, the compound of formula (II) is a compound of formula (II-A), (II-B), or (II-C):
Or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (II) and combinations thereof also apply to the corresponding groups of formulae (II-A), (II-B) and (II-C).
In another aspect, the invention provides a compound of formula (III):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、U、V、R5M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (I) and combinations thereof also apply to the corresponding groups of formula (III).
In the compounds of the formula (III), U is N or CR3And V is N or CR4And U and V are independently selected.
In a common embodiment of formula (III), U is CR3And V is CR4Such that the ring containing U and V is a benzene ring. Such 2,3,4, 5-tetrahydro-1H-benzo [ c]Aza derivativesThe (E) -1-ketone compound is sometimes represented by the formula (III-A). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In another embodiment of the formula (III)In embodiments, U is N and V is CR4Such that the ring containing U and V is [4,3-c ]]-a fused pyridine ring. Such 6,7,8, 9-tetrahydro-5H-pyrido [4,3-c ]]Aza derivativesThe (E) -5-ketone compound is sometimes represented by the formula (III-B).
In another embodiment of formula (III), U is CR 3And V is N, such that the ring containing U and V is [3,2-c]-a fused pyridine ring. Such 6,7,8, 9-tetrahydro-5H-pyrido [3,2-c]Aza derivativesThe (E) -5-ketone compound is sometimes represented by the formula (III-C). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In a common embodiment of formula (III), m is 0 and R5Is absent. In some embodiments of formula (III), m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group. In some embodiments, m is 1 or 2, and R5Independently selected from F, -OH and methyl.
In some embodiments of formula (III), R1Is optionally substituted by 1-3R21Radical substituted C1-C4Alkyl or halogen. In some such embodiments, R1Is halogen, preferably Cl or F. In other such embodiments, R1Is C1-C4Alkyl radical, wherein said C1-C4Alkyl is optionally substituted with 1-3R21And (4) substituting the group. In specific embodiments, R1Is unsubstituted C1-C4Alkyl, preferably methyl or ethyl. In specific embodiments, R1Is methyl, ethyl, chloro or fluoro. In a preferred embodiment, R1Is Cl. In other preferred embodiments, R1Is methyl.
In some embodiments of formula (III), R 2Is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group. In other embodiments, R2Is optionally substituted by 1-5R22Radical substituted C1-C4An alkoxy group. In some such embodiments, R22Each independently selected from halogen or-OH, preferably F or-OH. In other such embodiments, R22Each independently selected from halogen, -C (O) NReRfand-OReWherein R iseAnd RfIndependently is H or C1-C4An alkyl group.
In a particular embodiment of formula (III), R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy, each of which may be independently substituted with 1 to 5 fluorine or OH groups (up to the number of hydrogen atoms). In some embodiments, R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. In one embodiment, R2Is isopropoxy. In another embodiment, R2Is an ethoxy group. In another embodiment, R2Is sec-butoxy.
In further embodiments of formula (III), R2Is C1-C8Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms)1-C8An alkoxy group. In some such embodiments, R2Is C1-C4Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms) 1-C4An alkoxy group. In specific embodiments, R2Is 1, 1-difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, 1- (trifluoromethyl) ethoxy, 1,1,1- (trifluoroprop-2-yl) oxy, 3,3,4, 4-tetrafluoro-butoxy, 3,3, 3-trifluoro-2-hydroxypropoxy, 1, 1-difluoroprop-2-yl) oxy or 2, 2-difluoroethoxy. In a preferred embodiment of formula (III), R2Is C1-C4Alkoxy or C1-C4A fluoroalkoxy group.
In another embodiment of formula (III), R2Is a 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1-3R32And (4) substituting the group. In some embodiments, R2Is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl. In a preferred embodiment, R2Is a 5-6 membered heteroaryl selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl and pyrimidinyl, each optionally substituted with 1-3R32And (4) substituting the group. In some such embodiments, R2Is optionally substituted by 1-3R32A radical substituted pyrazolyl or triazolyl. In some of the respective embodiments described above, R32Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution.
In other embodiments of formula (III), R2Is optionally substituted by 1-3R22Radical substituted C1-C8An alkyl group. In some such embodiments, R2Is optionally substituted by 1-3R22Substituted C1-C4An alkyl group. In specific embodiments, R22Each independently selected from halogen, -C (O) NReRf、-ORe、-NReRf、-NReC(O)Rfand-NReSO2RfWherein R iseAnd RfAs defined above for formula (I).
In some embodiments of formula (III), R3Is H, C1-C8Alkyl radical, C1-C8Alkoxy or halogen. In specific embodiments, R3Is H or halogen, preferably H or F. In a preferred embodiment, R3Is H. In other embodiments, R3Is F.
In one embodiment of formula (III), R4Is H, halogen or-CN. In some such embodiments, R4Is H. In other such embodiments, R4Is halogen, preferably Cl or F. In other such embodiments, R4Is Cl or Br. In other such embodiments, R4is-CN.
In another embodiment of formula (III), R4Is optionally substituted by 1-3R24Substituted C1-C8An alkyl group. In some such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C4An alkyl group. In specific embodiments, R24Each independently selected from halogen, -OR e、-NReRf、-NReC(O)Rf、-NReC(O)ORf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, each of which is further defined as in formula (I) and optionally substituted as described in formula (I).
In another embodiment of formula (III), R4Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein R4The C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substituted with one or more R34And (4) substitution.
In a preferred embodiment of formula (III), R4Is optionally substituted by one or more R34Substituted 5-12 membered heteroaryl. In some such embodiments, the 5-12 membered heteroaryl is optionally substituted with 1-3R34And (4) substituting the group.In some embodiments, R4Is optionally substituted by 1-3R34A group-substituted 5-6 membered heteroaryl. In some such embodiments, R4Selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl rings, each of which is optionally substituted with 1 to 3R34And (4) substituting the group.
In some embodiments, when R4Is C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C 6-C12When aryl or 5-12 membered heteroaryl, R34Each independently is halogen, C1-C8Alkyl, -CN, -C (O) NRcRd、-NRcRd、-NRcC(O)Rd、C3-C8Cycloalkyl radical, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl is optionally substituted by-OH, -C1-C4Alkoxy or halogen substituted, and RcAnd RdEach independently is H or C1-C4An alkyl group. In specific embodiments, R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by halogen, C1-C4Alkyl or C1-C4Alkoxy substitution.
In a preferred embodiment of formula (III), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a second preferred embodiment of formula (III), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a third preferred embodiment of formula (III), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2Is optionally covered by1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a fourth preferred embodiment of formula (III), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a fifth preferred embodiment of formula (III), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a sixth preferred embodiment of formula (III), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R32each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In some particularly preferred embodiments of formula (III), the compound has a combination of 3,4, 5, 6, 7, 8, 9 or 10 of the preferred features in each of the groups described above.
In some aspects, the compound of formula (III) is a compound of formula (III-A), (III-B), or (III-C):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (III) and combinations thereof also apply to the corresponding groups of formulae (III-A), (III-B) and (III-C).
In another aspect, the invention provides a compound of formula (IV):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、U、V、R5M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (I) and combinations thereof also apply to the corresponding groups of formula (IV).
In the compounds of the formula (IV), U is N or CR3And V is N or CR4And U and V are independently selected.
In a common embodiment of formula (IV), U is CR3And V is CR4Such that the ring comprising U and V is a phenyl ring. Such 3, 4-dihydrobenzo [ f ][1,4]OxazazemThe (2H) -5-keto compound is sometimes represented by the formula (IV-A). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In another embodiment of formula (IV), U is N and V is CR4Such that the ring containing U and V is [4,3-c ]]-a fused pyridine ring. Such 3, 4-dihydropyrido [4,3-f ]][1,4]OxazazemThe (2H) -5-keto compound is sometimes represented by the formula (IV-B).
In another embodiment of formula (IV), U is CR3And V is N, such that the ring containing U and V is [3,2-c]-a fused pyridine ring. Such 3, 4-dihydropyrido [3,2-f ]][1,4]OxazazemThe (2H) -5-keto compound is sometimes represented by the formula (IV-C). In some such embodiments, R3Is H or halogen, preferably H or F, and more preferably H.
In a common embodiment of formula (IV), m is 0 and R5Is absent. In some embodiments of formula (IV), m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group. In some embodiments, m is 1 or 2, and R5Independently selected from F, -OH and methyl.
In some embodiments of formula (IV), R1Is optionally substituted by 1-3R21Radical substituted C1-C4Alkyl or halogen. In some such embodiments, R1Is halogen, preferably Cl or F. In other such embodiments, R 1Is C1-C4Alkyl radical, wherein said C1-C4Alkyl is optionally substituted with 1-3R21And (4) substituting the group. In specific embodiments, R1Is unsubstituted C1-C4Alkyl, preferably methyl or ethyl. In specific embodiments, R1Is methyl, ethyl, chloro or fluoro. In a preferred embodiment, R1Is Cl. In other preferred embodiments, R1Is methyl.
In some embodiments of formula (IV), R2Is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group. In other embodiments, R2Is optionally substituted by 1-5R22Radical substituted C1-C4An alkoxy group. In some such embodiments, R22Each independently selected from halogen or-OH, preferably F or-OH. In other such embodiments, R22Each independently selected from halogen, -C (O) NReRfand-OReWherein R iseAnd RfIndependently is H or C1-C4An alkyl group.
In a particular embodiment of formula (IV), R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy, each of which may be independently substituted with 1 to 5 fluorine or OH groups (up to the number of hydrogen atoms). In some embodiments, R2Is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy or tert-butoxy. In one embodiment, R 2Is isopropoxy. In another embodiment, R2Is an ethoxy group. In another embodiment, R2Is sec-butoxy.
In another embodiment of formula (IV), R2Is C1-C8Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms)1-C8An alkoxy group. In some such embodiments, R2Is C1-C4Fluoroalkoxy, i.e. C substituted by 1-5F (up to the number of hydrogen atoms)1-C4An alkoxy group. In specific embodiments, R2Is 1, 1-difluoromethoxy, trifluoromethoxy, 2,2, 2-trifluoroethoxy, or a salt thereof,1- (trifluoromethyl) ethoxy, 1,1,1- (trifluoropropan-2-yl) oxy, 3,3,4, 4-tetrafluoro-butoxy, 3,3, 3-trifluoro-2-hydroxypropoxy, 1, 1-difluoropropan-2-yl) oxy or 2, 2-difluoroethoxy. In a preferred embodiment of formula (IV), R2Is C1-C4Alkoxy or C1-C4A fluoroalkoxy group.
In another embodiment of formula (IV), R2Is a 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with 1-3R32And (4) substituting the group. In some embodiments, R2Is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl. In a preferred embodiment, R2Is a 5-6 membered heteroaryl selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, pyridinyl and pyrimidinyl, each optionally substituted with 1-3R 32And (4) substituting the group. In some such embodiments, R2Is optionally substituted by 1-3R32A radical substituted pyrazolyl radical. In some of the respective embodiments described above, R32Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted by halogen, C1-C4Alkyl or C1-C4Alkoxy substitution.
In other embodiments of formula (IV), R2Is optionally substituted by 1-3R22Radical substituted C1-C8An alkyl group. In some such embodiments, R2Is optionally substituted by 1-3R22Substituted C1-C4An alkyl group. In specific embodiments, R22Each independently selected from halogen, -C (O) NReRf、-ORe、-NReRf、-NReC(O)Rfand-NReSO2RfWherein R iseAnd RfAs defined above for formula (I).
In some embodiments of formula (IV), R3Is H, C1-C8Alkyl radical, C1-C8Alkoxy or halogen. In specific embodiments, R3Is H or halogen, preferably H or F. In a preferred embodiment, R3Is H. In other embodiments, R3Is F.
In one embodiment of formula (IV), R4Is H, halogen or-CN. In some such embodiments, R4Is H. In other such embodiments, R4Is halogen, preferably Cl or F. In other such embodiments, R 4Is Cl or Br. In other such embodiments, R4is-CN.
In another embodiment of formula (IV), R4Is optionally substituted by 1-3R24Substituted C1-C8An alkyl group. In some such embodiments, R4Is optionally substituted by 1-3R24Radical substituted C1-C4An alkyl group. In specific embodiments, R24Each independently selected from halogen, -ORe、-NReRf、-NReC(O)Rf、-NReC(O)ORf、C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, each of which is further defined as in formula (I) and optionally substituted as described herein by formula (I).
In another embodiment of formula (IV), R4Is selected from C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl and 5-12 membered heteroaryl, wherein R4C in (1)3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12Aryl or 5-12 membered heteroaryl are each optionally substitutedOne or more R34And (4) substitution.
In a preferred embodiment of formula (IV), R4Is optionally one or more R34Substituted 5-12 membered heteroaryl. In some such embodiments, the 5-12 membered heteroaryl is optionally substituted with 1-3R34And (4) substituting the group. In some embodiments, R4Is optionally substituted by 1-3R34A group-substituted 5-6 membered heteroaryl. In some such embodiments, R4Selected from pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thienyl, thiazolyl, isothiazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl rings, each of which is optionally substituted with 1 to 3R 34And (4) substituting the group.
In some embodiments, when R4Is C3-C8Cycloalkyl, 3-12 membered heterocyclyl, C6-C12When aryl or 5-12 membered heteroaryl, R34Each independently is halogen, C1-C8Alkyl, -CN, -C (O) NRcRd、-NRcRd、-NRcC(O)Rd、C3-C8Cycloalkyl radical, C6-C12Aryl and 5-12 membered heteroaryl, wherein said C1-C8Alkyl is optionally substituted by-OH, -C1-C4Alkoxy or halogen substituted, and RcAnd RdEach independently is H or C1-C4An alkyl group. In specific embodiments, R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionallyBy halogen, C1-C4Alkyl or C1-C4Alkoxy substitution.
In a preferred embodiment of formula (IV), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a second preferred embodiment of formula (IV), U is CR3And V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a third preferred embodiment of formula (IV)In which U is N and V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2Is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R34each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a fourth preferred embodiment of formula (IV), U is N and V is CR4And the compounds have a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R4is H, halogen or 5-12 membered heteroaryl, wherein said 5-12 membered heteroaryl is optionally substituted with 1-3R34Substituted by groups;
R32and R34Each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C 1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a fifth preferred embodiment of formula (IV), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-5R22Radical substituted C1-C8An alkoxy group;
R22each independently is halogen or-OH;
R3is H or F;
m is 0 and R5Is absent; or
m is 1 or 2, and R5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In a sixth preferred embodiment of formula (IV), U is CR3And V is N, and the compound has a combination of two or more of the following preferred features:
R1is C1-C4Alkyl or halogen;
R2is optionally substituted by 1-3R32A group-substituted 5-6 membered heteroaryl;
R3is H or F;
R32each independently is-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, wherein said 4-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl is optionally substituted with 1-3 independently selected halogen, C1-C4Alkyl or C1-C4Alkoxy substitution;
m is 0 and R5Is absent; or
m is a number of 1 or 2,and R is5Each independently selected from halogen, -OH and C1-C4An alkyl group;
x and Z are independently C1-C4An alkyl group; and
y is H or F.
In some particularly preferred embodiments of formula (IV), the compound has a combination of 3, 4, 5, 6, 7, 8, 9 or 10 of the preferred features in each of the groups described above.
In some aspects, of formula (IV) is a compound of formula (IV-A), (IV-B), or (IV-C):
or a pharmaceutically acceptable salt thereof,
wherein R is1、R2、R3、R4、R5M, X, Y and Z are as defined for formula (I).
The embodiments described herein with respect to formula (IV) and combinations thereof also apply to the corresponding groups of formulae (IV-A), (IV-B) and (IV-C).
"pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, as an active ingredient, with at least one pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to facilitate administration of the compound to a subject.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of one of the formulae described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and/or excipients.
In some embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent or demulcent. In some such embodiments, the at least one additional drug or agent is an anti-cancer agent as described below. In some such embodiments, the combination provides additive, greater than additive, or synergistic anti-cancer effects. In some such embodiments, the one or more additional anti-cancer therapeutic agents are selected from the group consisting of anti-neoplastic agents, anti-angiogenic agents, signal transduction inhibitors, and antiproliferative agents.
In one aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an antineoplastic agent, which together are effective to treat said abnormal cell growth. In some embodiments, the antineoplastic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic drugs, anti-hormonal drugs, and anti-androgens.
In a common embodiment of the methods provided herein, the abnormal cell growth is cancer. In some embodiments, the methods provided herein result in one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasion; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.
In another aspect, the present invention provides a method of treating an EZH 2-mediated disorder in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disorder.
In a preferred embodiment of the methods provided herein, the subject is a mammal, in particular a human.
Unless otherwise indicated, all references to compounds of the invention herein include references to their salts, solvates, hydrates and complexes, to solvates of their salts, hydrates and complexes (including polymorphs, stereoisomers and isotopically labeled versions thereof).
The compounds of the invention may exist in the form of pharmaceutically acceptable salts, such as acid addition salts and base addition salts of compounds of one of the formulae provided herein. The term "pharmaceutically acceptable salt" as used herein, refers to salts that retain the biological effectiveness and properties of the parent compound. Unless otherwise indicated, the term "pharmaceutically acceptable salt" as used herein includes salts of acidic or basic groups that may be present in the compounds of the formulae disclosed herein.
For example, the basic compounds of the present invention can form a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to an animal, it is often necessary in practice to initially isolate the pharmaceutically unacceptable salt of a compound of the present invention from the reaction mixture, then treat it with an alkaline agent to convert the pharmaceutically unacceptable salt simply back to the free base compound and then convert the free base to a pharmaceutically acceptable acid addition salt. Basic acid addition salts of the compounds of the present invention can be prepared by treating the basic compound with approximately equal amounts of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. The desired solid salt is obtained after evaporation of the solvent. Addition of a suitable mineral or organic acid to the solution also allows the desired acid salt to precipitate from the solution of the free base in an organic solvent.
The acid can be used to prepare non-toxic pharmaceutically acceptable acid addition salts of such basic compounds, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate [ i.e. 1,1' -methylene-bis (2-hydroxy-3-naphthoate) ].
Examples of salts include (but are not limited to): acetate, acrylate, benzenesulfonate, benzoate (e.g., chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1, 4-dicarboxylate, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, chloride, hexanoate, octanoate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, ethylenediaminetetraacetate, edisylate, propionamidoyl sulfate, ethanesulfonate, ethylsuccinate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycollate, hydroxyacetyl (glycollyl) p-aminobenzoate, heptanoate, hexyne-1, 6-dicarboxylate, hexylresorcinate (hexylresorcinonate), Hydrabamine, hydrobromide, hydrochloride, gamma-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, dodecanoate, malate, maleate, malonate, hydroxyphenylacetate, methanesulfonate, metaphosphate, methanesulfonate, methosulfate, biphosphate, mucate, naphthalenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), hexadecanoate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polyhemiuronate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, isothiosulfonate, lactate, lactobionate, laurate, malate, maleate, salicylate, glycolate, succinate, salicylate, and salicylate, Sulfates, sulfonates, sulfites, tannins, tartrates, 8-chlorotheophylline salts, tosylates, triethiododes and valerate.
Illustrative examples of suitable salts include: organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary and tertiary amines, cyclic amines (e.g., piperidine, morpholine, and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
The compounds of the present invention comprising a basic moiety (e.g., amino group) may form pharmaceutically acceptable salts with various amino acids in addition to the aforementioned acids.
The acidic compounds of the present invention are capable of forming basic salts with a variety of pharmacologically acceptable cations. Examples of such salts include alkali metal salts or alkaline earth metal salts, particularly sodium and potassium salts. All of these salts are prepared by conventional techniques. The chemical bases used as reagents to prepare the pharmaceutically acceptable basic salts of the invention are those that form non-toxic basic salts with the acidic compounds of the invention. These salts may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base (e.g. a primary, secondary or tertiary amine), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. These salts can also be prepared from: the corresponding acidic compound is treated with an aqueous solution containing the desired pharmacologically acceptable cation, and the resulting solution is then evaporated to dryness, preferably under reduced pressure. Alternatively, these salts can also be prepared from: the lower alkanol solution of the acidic compound is mixed together with the desired alkali metal alkoxide and the resulting solution is evaporated to dryness in the previous manner. In either case, it is preferred to use stoichiometric amounts of reagents in order to ensure complete reaction and maximum yield of the desired end product.
Chemical bases that can be used as reagents to make the pharmaceutically acceptable basic salts of the compounds of the invention acidic are those that form non-toxic basic salts with the compounds of the invention. Such non-toxic basic salts include, but are not limited to, those derived from: pharmacologically acceptable cations such as alkali metal cations (e.g. potassium and sodium) and alkaline earth metal cations (e.g. calcium and magnesium), ammonium or water-soluble amine addition salts (e.g. meglumine, basic salts of lower alkanolammonium and other pharmaceutically acceptable organic amines).
Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.
For a view of suitable Salts, see "Handbook of pharmaceutical Salts" published by Stahl and Wermuth: properties, Selection, and Use "(Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are well known to those skilled in the art.
The salts of the invention can be prepared according to methods familiar to those skilled in the art. Pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by mixing solutions of the compounds with the desired acid or base, as appropriate. The salt may precipitate out of solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the salt may vary from complete ionization to almost no ionization.
One skilled in the art will appreciate that treatment with a stoichiometric excess of a suitable acid can convert a compound of the present invention in free base form having basic functionality to an acid addition salt. The acid addition salts of the compounds of the present invention are reconverted to the corresponding free bases typically by treatment with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, in the presence of an aqueous solvent and at a temperature between about 0 ℃ and 100 ℃. The free base form can be isolated by conventional means, for example by extraction with an organic solvent. In addition, the acid addition salts which may exchange the compounds of the invention are treated with different solubilities of the salts, volatility or acidity of the acid or with ion exchange resins which are suitably charged. For example, the exchange may be affected by reacting a salt of a compound of the invention with a slight stoichiometric excess of an acid having a pK lower than that of the acid component of the starting salt. Typically this transition is carried out at a temperature between about 0 ℃ and the boiling point of the solvent used as the medium for this step. Typically base addition salts enable similar exchanges through the intermediation of the free base form.
The compounds of the present invention may exist in unsolvated as well as solvated forms. When the solvent or water is strongly bound, the complex will have a well-defined stoichiometry that is not governed by humidity. However, when solvents or water are weakly bound within the channel solvate and hygroscopic compound, the water/solvent content is dominated by humidity and dryness conditions. In such cases, the non-stoichiometry would be the benchmark. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvates, including crystallized solvents, of the invention may be isotopically substituted (e.g. D) 2O、d6-acetone, d6-DMSO) and solvates.
The scope of the invention also includes complexes, such as clathrate complexes, drug-host inclusion complexes, where the drug and host are present in stoichiometric or non-stoichiometric amounts, as opposed to the aforementioned solvates. Also included herein are complexes of drugs comprising organic and/or inorganic components that may be in two or more stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized or non-ionized. For an overview of such complexes see J PharmSci, 64(8), 1269-1288, Haleblian (8.1975), which is incorporated herein by reference in its entirety.
The invention also relates to prodrugs of compounds of the formula provided herein. Thus, certain derivatives of the compounds of the invention which may not be as potent or pharmacologically active as such may be converted to the compounds of the invention by, for example, water splitting when administered to a patient. Such derivatives are referred to as "prodrugs", and further information on the use of prodrugs can be found in the ' Pro-drugs as Novel Delivery Systems, volume 14, ACS Symposium Series (T Higuchi and WStella) and ' Bioreversible Carriers in Drug Design ', Pergamon Press, 1987(ed. e BRoche, American Pharmaceutical Association), which are incorporated herein by reference in their entirety.
Prodrugs of the invention may be produced, for example, by replacing suitable functional groups present in compounds of the invention with certain moieties of a "precursor moiety" familiar to those skilled in the art, which precursor moiety is described, for example, in "Design of produgs" (Elsevier, 1985) by HBundgaard, the entire contents of which are incorporated herein by reference.
Some non-limiting examples of prodrugs of the invention include:
(i) in the case where the compound contains a carboxylic acid function (-COOH), an ester thereof (e.g., hydrogen is (C)1-C8) Alkyl substitution);
(ii) in the case where the compound contains an alcohol functional group (-OH), an ether thereof (e.g., hydrogen is (C)1-C6) Alkanoyloxymethyl substitution); and
(iii) in which the compound contains a primary or secondary amino function (-NH)2or-NHR, where R ≠ H), amides thereof (e.g., one or two hydrogens substituted with a suitable metabolically labile group (e.g., amide, carbamate, urea, phosphonate, sulfonate, etc.).
Additional examples of substituents as in the preceding examples and examples of other prodrug forms can be found in the aforementioned references.
Finally, certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.
The scope of the present invention also includes metabolites of the compounds of the present invention, i.e., compounds that are formed in vivo after administration of the drug.
Of the formula provided hereinThe compounds may have asymmetric carbon atoms. The carbon-carbon bond of the compounds of the invention may be represented herein by the solid lineSolid wedgeOr a wedge of broken linesAnd (4) showing. The use of solid lines to represent asymmetric carbon atom bonds is intended to indicate that all possible stereoisomers of carbon atoms (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of solid or dashed wedges to indicate asymmetric carbon atom bonds is intended to indicate that only the stereoisomers shown are included. The compounds of the present invention may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to represent the asymmetric carbon atom bonds is intended to indicate that all possible stereoisomers are included. For example, unless otherwise specifically indicated, it is intended that the compounds of the present invention may exist in enantiomeric and diastereomeric forms, or as racemates and mixtures thereof. The use of a solid line to represent bonds to one or more asymmetric carbon atoms in a compound of the invention and a solid or dashed wedge to represent bonds to the remaining asymmetric carbon atoms in the same compound is intended to indicate that a mixture of diastereomers is present.
The compounds of the invention having a chiral center may exist as stereoisomers, such as racemates, enantiomers or diastereomers.
Stereoisomers of compounds of formula (la) herein may include cis-and trans-isomers, optical isomers (e.g., (R) and (S) enantiomers, diastereomers, geometric isomers, rotamers, atropisomers, conformational isomers and tautomers) of the compounds of the invention (including compounds exhibiting more than one type of isomerism); and mixtures thereof (e.g., racemic and diastereomeric pairs). Also included are acid addition salts or base addition salts in which the counterion is cycloactive (e.g., d-lactate or 1-lysine salt) or racemic (e.g., dl-tartrate or dl-arginine salt).
Upon crystallization of any racemate, there may be two distinct types of crystallization. The first form is the aforementioned racemic compound (true racemate), in which a homogeneous type crystal containing both enantiomers in equimolar amounts is produced. The second type is a racemic mixture or a crystal mass, in which equimolar amounts of the two forms of the crystal (each containing a single enantiomer) are produced.
The compounds of the present invention may exhibit phenomena of tautomerism and structural isomerism. For example, the compounds of the present invention may exist in several tautomeric forms (including the enol-imine and keto-enamine forms) and geometric isomers and mixtures thereof. The scope of the compounds of the present invention includes all such tautomeric forms. In solution the tautomers exist as mixtures of tautomeric groups. In the solid state, usually one tautomer predominates. Even though one tautomer may be described, the invention also includes all tautomers of the compounds of the provided formula.
In addition, some of the compounds of the present invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation about a single bond within the molecule is hindered or greatly retarded, as a result of asymmetric steric interactions of the remainder of the molecule with substituents located at either end of the single bond. The interconversion of atropisomers is sufficiently slow to allow separation and separation under predetermined conditions. The energy barrier for thermal racemization can be determined by steric hindrance of free rotation of one or more bonds forming the chiral axis.
In the case where the compounds of the present invention contain an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers can be isolated by conventional techniques familiar to those skilled in the art, such as chromatography and fractional crystallization.
Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or separation of the racemates (or racemates of salts or derivatives) using, for example, chiral High Performance Liquid Chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol or, in the case where the compound contains an acidic or basic moiety, an acid or base (e.g., tartaric acid or 1-phenylethylamine). The resulting mixture of diastereomers may be separated by chromatography and/or fractional crystallization and converted to the corresponding pure enantiomers by means familiar to those skilled in the art.
The enantiomerically enriched chiral compound of the invention (or chiral precursor thereof) is obtained by chromatography, typically HPLC, on an asymmetric resin using a mobile phase consisting of a hydrocarbon (typically heptane or hexane, containing from 0 to 50%, typically from 2 to 20% isopropanol) and from 0 to 5% of an alkylamine (typically 0.1% diethylamine).
The stereoisomeric crystal groups may be isolated by conventional techniques familiar to those skilled in the art, see, for example, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994), published by EL Eliel, the entire contents of which are incorporated herein by reference.
As used herein, "enantiomerically pure" describes a compound that exists in a single enantiomeric form and is represented by an enantiomeric excess (e.e). Preferably, where the compound is present in enantiomeric form, the enantiomer is present in an enantiomeric excess of greater than or equal to about 80%, more preferably in an enantiomeric excess of greater than or equal to about 90%, more preferably in an enantiomeric excess of greater than or equal to about 95%, more preferably in an enantiomeric excess of greater than or equal to about 98%, and most preferably in an enantiomeric excess of greater than or equal to about 99%. Similarly, "diastereomerically pure" as used herein describes a compound that exists in diastereomeric form and is represented by diastereomeric excess (d.e.). Preferably, where the compound is present in diastereomeric form, the diastereomeric excess is greater than or equal to about 80%, more preferably greater than or equal to about 90%, more preferably greater than or equal to about 95%, more preferably greater than or equal to about 98%, and most preferably greater than or equal to about 99%.
The invention also includes isotopically-labeled compounds, which are identical to those recited in one of the formulae provided herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
Isotopically-labeled compounds of the present invention can be prepared by conventional techniques well known to those skilled in the art or by procedures analogous to those described herein, by substituting a suitable isotopically-labeled reagent for an otherwise employed non-labeled reagent.
Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as (but not limited to):2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18f and36and (4) Cl. Certain isotopically-labeled compounds of the present invention (e.g., incorporated into a radioisotope (e.g., by way of example)3H and14C) compounds of (ii) can be used in drug and/or substrate tissue distribution assays. Tritium (i.e. tritium3H) And carbon 14 (i.e.14C) Isotopes are particularly preferred for their ease of preparation and detectability. In addition, by heavier isotopes (e.g. deuterium, i.e. hydrogen)2H) Substitution may provide certain therapeutic advantages (resulting from greater metabolic stability), such as increased in vivo half-life or reduced dosage requirements. And may therefore be preferred in some circumstances. Usually formed by Isotopically labeled compounds of the present invention can be prepared by carrying out the procedures disclosed in the schemes and/or in the examples and preparations by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The pharmaceutically acceptable compounds of the present invention may be administered as crystalline or amorphous products or mixtures thereof. The compounds of the invention can be obtained for example in the form of solid plugs, powders or films by processes such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave drying or radio frequency drying may be used for this purpose.
Methods of treatment and uses
The invention further provides methods of treatment and uses comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic agents or palliatives.
In one aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject an amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an anti-neoplastic agent, which together are effective to treat the abnormal cell growth. In some such embodiments, the antineoplastic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxic drugs, anti-hormonal drugs, and anti-androgens.
The compounds of the invention include any of the formulae described herein, i.e. compounds of formula I, II, III, IV, I-A, I-B, I-C, II-A, II-B, II-C, III-A, III-B, III-C, IV-A, IV-B or IV-C as provided and defined herein or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a method of treating abnormal cell growth in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to treat abnormal cell growth.
In another aspect, the present invention provides a method of inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.
In another aspect, the present invention provides a method of inhibiting cancer cell invasion in a subject, comprising administering to the subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell invasion.
In another aspect, the present invention provides a method of inducing apoptosis in a cancer cell in a subject, comprising administering to the subject an effective apoptosis-inducing amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a method of inducing apoptosis in a cancer cell in a subject comprising administering to the subject a therapeutically effective amount of a compound of one of the formulae described herein or a pharmaceutically acceptable salt thereof.
In a common specific embodiment of the methods provided herein, the abnormal cell growth is cancer, wherein the aforementioned cancer is selected from basal cell carcinoma, medulloblastoma, liver cancer, striated muscle cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous melanoma or intra-ocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anus, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, hodgkin's disease, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, carcinoma of the adrenal gland, carcinoma of the soft tissue, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, chronic or acute leukemia, lymphocytic lymphomas, carcinoma of the bladder, carcinoma of the kidney or ureter, carcinoma of the renal pelvis, carcinoma of the kidney, cancer of the Central Nervous System (CNS), primary CNS lymphoma, carcinoma of the central, Spinal axis cancer, brain stem glial cancer, pituitary gland adenocarcinoma, or a combination of one or more of the foregoing cancers.
In some embodiments, the compounds of the invention are selective for mutant forms of EZH2, such that H3K27 trimethylation, which is associated with some cancers, is inhibited. The methods and uses provided herein can be used to treat cancer, including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL).
The compounds of the invention are useful for the treatment of cancer, including, for example, tumors, such as brain, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, testicular, and thyroid cancers and sarcomas.
The term "therapeutically effective amount" as used herein means an amount of a compound that will provide some reduction in one or more of the symptoms of the condition being treated. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (l) Reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasion to some extent and/or (4) relieving to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer.
As used herein, "subject" refers to a human or animal subject. In some preferred embodiments, the subject is a human.
The term "treating" as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting or preventing the progression of the disorder or condition being treated or one or more symptoms thereof. The term "treatment" as used herein refers to the action of "treating" as defined above, unless otherwise indicated. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject.
The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application.
As used herein, "abnormal cell growth" refers to cell growth not associated with normal regulatory mechanisms (e.g., loss of contact inhibition) unless otherwise indicated. Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous), including abnormal growth of: (1) tumor cells (tumors) showing increased expression of EZH 2; (2) benign and malignant cells of other proliferative diseases in which EZH2 is overexpressed; (3) tumors that proliferate via activation of aberrant EZH 2; and (4) benign and malignant cells of other proliferative diseases, in which abnormal EZH2 activation occurs.
As used herein, "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth, including solid tumors, hematological cancers, myeloid cancers, or lymphoid cancers, named for the type of cells that form the tumor. Examples of solid tumors include, but are not limited to, sarcomas and carcinomas. Examples of hematological cancers include, but are not limited to, leukemia, lymphoma, and myeloid cancer. The term "cancer" includes, but is not limited to, primary cancers that originate at a specific part of the body, metastatic cancers that have begun to spread to other parts of the body, recurrence from the original primary cancer after remission, and secondary primary cancers (new primary cancers in people with a history of a first cancer of a different kind than the second cancer). The compounds of the invention inhibit EZH2 and are therefore all suitable for therapeutic use in mammals, particularly humans, as antiproliferative agents (e.g. cancer) or anti-cancer agents (e.g. effects against solid tumours). In particular, the compounds of the present invention are useful in the prevention and treatment of various hyperproliferative diseases of the human body, including malignant and benign abnormal cell growth.
The compounds, compositions, and methods provided herein can be used to treat cancers including (but not limited to) the following:
Circulatory systems, such as the heart (sarcocarcinoma [ angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma ], mucinous carcinoma, rhabdomyocarcinoma, fibrocarcinoma, lipocarcinoma and teratocarcinoma), the longitudinal diaphragm and pleura, and other organs in the thoracic cavity, vascular tissues associated with hemangiomas and tumors;
respiratory tract (e.g., nasal and middle ear, paranasal sinuses, larynx, trachea, bronchi and lung), such as Small Cell Lung Cancer (SCLC), non-small cell lung cancer (NSCLC), bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (small bronchial) cancer, bronchial adenocarcinoma, meat cancer, lymphoma, chondral defect cancer, mesothelial cancer;
the gastrointestinal system, such as the esophagus (e.g., squamous cell carcinoma, adenocarcinoma, smooth muscle carcinoma, lymphoma), stomach (e.g., carcinoma, lymphoma, smooth muscle carcinoma), stomach, pancreas (e.g., ductal adenocarcinoma, insulin carcinoma, glucagon carcinoma, gastrinoma, carcinoid tumor, pancreatic adenoma), small intestine (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Karposi's carcinoma, smooth muscle carcinoma, vascular carcinoma, lipoma, neurofibroma, fibrocarcinoma), large intestine (e.g., adenocarcinoma, tubular adenocarcinoma, villous adenocarcinoma, hamartoma, smooth muscle carcinoma);
urinary tract, such as kidney (adenocarcinoma, Wilms' carcinoma [ nephroblastoma ], lymphoma, leukemia), bladder and/or urethra (squamous cell carcinoma, metastatic cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoidosis), testis (seminoma, teratocarcinoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoidosis, interstitial cell carcinoma, fibrocarcinoma, fibroadenocarcinoma, adenomatoid tumors, lipoma);
Liver, such as hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, vascular carcinomatous carcinoma, hepatocellular adenoma, vascular carcinoma, pancreatic endocrine carcinoma (such as pheochromocytoma, insulin carcinoma, intestinal vasoactive polypeptide carcinoma, pancreatic islet cell carcinoma, and glucagonoma);
bone, such as osteoplastic cancer (sarcoidosis), fibroplasia, malignant fibrous histiocytic cancer, chondral sarcoidosis, ewings' sarcoidosis, malignant lymphoma (reticulocyte sarcoidosis), multiple myeloma, malignant giant cell chordoma cancer, osteochondral exostosis (osteochondral exostosis), benign osteochondral cancer, chondrocytic carcinoma, cartilage mucofibromatosis, osteoid bone cancer, and giant cell cancer;
nervous system, such as Central Nervous System (CNS) cancer, primary central nervous system lymphoma, head cancer (bone cancer, vascular cancer, granulomatous cancer, yellow cancer, osteitis deformans), cerebrospinal membrane (cerebrospinal membrane cancer, cerebrospinal membrane sarcoma, glial cancer), brain cancer (astrocytic cancer, neuroblastoma, glial cancer, ependymal cancer, blastocarcinomatous [ pineal cancer ], glioblastoma multiforme, oligodendroglial cancer, sphingomyeline cancer, retinal blastomatous, congenital tumor), spinal neurofibromatosis, cerebrospinal membrane cancer, glial cancer, sarcoma);
Reproductive systems, such as gynecology, uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumoral cervical dysplasia), ovaries (ovarian carcinoma [ serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma ], granulosa-and sheath cell tumors, Sertoli-Leydig cell tumors, malignant germ cell carcinoma, malignant teratocarcinoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibro-sarcomas, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoidosis (embryonal rhabdomyocarcinoma), fallopian tubes (fallopian tube carcinoma) and other sites associated with female genitalia: placenta, penis, prostate, testis and other sites associated with male genitalia;
blood systems, such as blood (myeloid leukemia [ acute and chronic ], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma [ malignant lymphoma ];
oral cavity, e.g., lips, tongue, gums, floor of mouth, jaw, other parts of mouth, parotid gland, other parts of salivary gland, tonsils, oropharynx, nasopharynx, piriformis, hypopharynx, and other sites within the lips, oral cavity, throat;
Skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, nevi dysplastic nevi, adipose carcinoma, vascular carcinoma, dermal fibrocarcinoma, and keloid;
adrenal gland: neuroblast cancer: and
other organizations, including: connective tissue and soft tissue, retroperitoneal cavity and peritoneum, eye, intraocular melanoma, adnexa, breast, head or/and neck, anal region, thyroid, parathyroid, adrenal gland and other endocrine glands and related tissues, secondary and unknown malignant tumors of lymph node, secondary malignant tumors of respiratory and digestive system and secondary malignant tumors of other parts.
More particularly, examples of cancer as used in the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), head or neck cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anus, stomach cancer, breast cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, Central Nervous System (CNS) cancer, primary Central Nervous System (CNS) lymphoma, non-hodgkin's lymphoma, spinal axis cancer, or a combination of one or more of the foregoing cancers.
More particularly, examples of cancer as used in the present invention include cancers selected from the group consisting of: lung cancer (NSCLC and SCLC), breast cancer, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, or a combination of one or more of the foregoing cancers.
In a specific embodiment of the invention, the non-cancerous condition includes such proliferative conditions as benign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasia of the prostate (e.g., BPH).
In another aspect, the invention provides a method of inhibiting cell proliferation comprising contacting a cell with an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, effective to inhibit cell proliferation.
In another aspect, the invention provides a method of inducing apoptosis in a cell comprising contacting the cell with an amount of a compound described herein effective to induce apoptosis in the cell.
By "contacting" is meant combining a compound or pharmaceutically acceptable salt of the invention and a cell expressing EZH2 in such a way that the compound can directly or indirectly affect the activity of EZH 2. The contacting can be performed in vitro (i.e., in an artificial environment, such as, but not limited to, in a test tube or culture medium) or in vivo (i.e., in vivo, such as, but not limited to, a mouse, rat, or rabbit).
In some embodiments, the cell is a cell line, such as a cancer cell line. In other embodiments, the cell is in a tissue or tumor, and the tissue or tumor can be in a subject, including a human.
Dosage forms and regimens
Administration of the compounds of the invention can be achieved using any method capable of delivering the compounds of the invention to the site of action. These methods include oral routes, intraduodenal routes of administration, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.
Dosage regimens may be adjusted to produce the best desired response. For example, a single large dose may be administered, several divided doses may be administered over time or the dose may be reduced or increased in proportion as indicated by the exigencies of the therapeutic situation. This is highly advantageous for formulating parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to the physically discrete units suitable as unitary dosages for the subject to be treated: each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention is governed by and directly depends on the inherent limitations of (a) the specific properties of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved and (b) the field of co-therapy of the active compound for sensitivity in an individual.
Thus, it will be apparent to those skilled in the art from this disclosure that the dosages and dosage regimens can be adjusted according to methods well known in the art of treatment. I.e., the maximum tolerated dose can be readily established, the effective amount to bring a detectable therapeutic benefit to the patient can also be determined, and the temporary need to administer various agents that can bring a detectable therapeutic benefit to the patient. Thus, while certain dosages and dosing regimens are exemplified herein, these examples in no way limit the dosages and dosing regimens that can be provided to a patient in practicing the invention.
It is noted that the dosage may vary with the type and severity of the condition to be alleviated and may include a single dose or multiple doses. It is further understood that for any particular mammal, the particular dosage regimen should be adjusted over time according to the individual needs and the professional judgment of the person administering or instructing the administration of the composition, and that the dosage ranges provided herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. For example, the dosage may be adjusted according to pharmacokinetic or pharmacodynamic parameters, which may include clinical manifestations (e.g., toxicity and/or experimental values). Thus, the present invention encompasses dose escalation in patients as measured by one of skill in the art. Determining suitable dosages and dosing regimens for administering chemotherapeutic agents is well known in the relevant art and will be understood to be covered by those skilled in the art once provided with the teachings disclosed herein.
The amount of a compound of the invention administered will depend on the severity of the subject, disorder or condition being treated, the rate of administration, the treatment of the compound of the invention, and the discretion of the prescribing physician. However, effective dosages will be in single or divided doses ranging from about 0.001mg/kg to about 100mg/kg body weight per day, preferably from about lmg/kg to about 35mg/kg body weight per day. For a 70kg human, the effective dose will be in the range of from about 0.05g to about 7g per day, preferably from about 0.1g to about 2.5g per day. In some instances, dosage levels below the lower limit of the aforesaid dosage range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the aforesaid larger doses are first divided into several small doses for administration throughout the day.
Formulations and routes of administration
As used herein, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the compound being administered.
The pharmaceutically acceptable carrier may comprise conventional pharmaceutical carriers or excipients. The choice of carrier and/or excipient will depend to a large extent on the following factors: for example, the particular mode of administration, the effect of the excipients on solubility and stability, and the characteristics of the dosage form.
Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (e.g., hydrates and solvates), and the pharmaceutical compositions may optionally contain additional ingredients such as flavoring agents, binders, excipients, and the like. Thus for oral administration, tablets containing various excipients (e.g., citric acid) may be employed with various disintegrants (e.g., starch, alginic acid and certain complex silicates) and with binders (e.g., sucrose, gelatin and acacia). Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. Additionally, lubricating agents (e.g., magnesium stearate, sodium lauryl sulfate, and talc) are commonly used for tableting. Solid compositions of a similar kind may also be used in soft and hard gelatin capsules. Non-limiting examples of starting materials therefore include lactose or milk sugar and high molecular weight polyethylene glycols. Where aqueous suspensions or elixirs are desired for oral use, the active compound therein may be combined with various sweetening or flavoring agents, coloring matter or pigments, optionally in admixture with emulsifying or suspending agents, and with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof.
The pharmaceutical compositions may be, for example, in a form suitable for oral administration (e.g. tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions), for parenteral injection (e.g. sterile solutions, suspensions or emulsions), for topical administration (e.g. ointments or creams) or for rectal administration (e.g. suppositories).
Exemplary parenteral administration forms include solutions or suspensions of the active compounds with sterile aqueous solutions, for example, aqueous propylene glycol or glucose solutions. Such dosage forms may be suitably buffered as desired.
The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages.
Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods of making them are described, for example, "Remington's Pharmaceutical Sciences," 19 th edition (Mack Publishing Company, 1995), which is incorporated by reference herein in its entirety.
The compounds of the present invention may be administered orally. Oral administration may involve swallowing so that the compound of the invention enters the gastrointestinal tract, or buccal or sublingual administration so that the compound of the invention enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid formulations such as tablets, microparticles, liquid or powder containing capsules, lozenge-shaped tablets (containing a liquid), chewable agents, multiparticulate and nanoparticle, gels, solid solutions, liposomes, films (including buccal patches), ovules, sprays and liquid formulations.
Liquid preparations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard gelatin capsules and typically include a carrier (for example, water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or a suitable oil) and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by reconstitution of, for example, solids derived from sachets.
The compounds of the present invention are also useful in fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986(2001), issued to Liang and Chen, which are incorporated herein by reference in their entirety.
For tablet dosage forms, depending on the dosage, the amount of drug may be from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form. In addition to the drug, tablets typically contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low carbon number alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally the amount of disintegrant will be estimated from 1 to 25 wt%, preferably from 5 to 20 wt% of the dosage form.
Binders are commonly used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous lactose, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
The tablets may also optionally contain surfactants (e.g., sodium lauryl sulfate and polysorbate 80) and glidants (e.g., silicon dioxide and talc). When present, the amount of surfactant typically comprises from 0.2 to 5 wt% of the tablet and the amount of glidant typically comprises from 0.2 to 1 wt% of the tablet.
Tablets also typically contain lubricating agents such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and mixtures of magnesium stearate and sodium lauryl sulfate. Typically the amount of lubricant is from 0.25 to 10 wt% of the tablet, preferably from 0.5 to 3 wt% of the tablet.
Other conventional ingredients include antioxidants, colors, flavors, preservatives and taste masking agents.
Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about 90 wt% binder, from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
The tablet blend can be directly compressed or rolled into tablets. Alternatively, the tablet blend or a portion of the tablet may be wet granulated, dry granulated or melt granulated, melt congealed or extruded prior to tableting. The final formulation may comprise one or more layers and may be coated or uncoated or encapsulated.
For details of tablet formulation, see "Pharmaceutical Dosage Forms: tablets, volume 1 "(H.Lieberman and L.Lachman, Marcel Dekker, N.Y., N.Y.,1980(ISBN 0-8247-6918-X)), the entire contents of which are incorporated herein by reference.
The oral solid preparation can be formulated as a real-time release and/or modified release preparation. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations.
Suitable modified release formulations are described in U.S. Pat. No. 6,106,864. Other suitable delivery techniques (e.g., high energy dispersion, penetration and drug-coated particles) are described in detail in Verma et al pharmaceutical technology On-line, 25(2), 1-14 (2001). For a description of achieving controlled release with chewing gum see WO 00/35298. The disclosures of these references are incorporated herein by reference in their entirety.
Parenteral administration
The compounds of the invention may also be administered directly into the bloodstream, intramuscularly or into internal organs. Suitable parenteral administration includes intravenous, intraarterial, intraperitoneal, intracerobrospinal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable parenteral administration devices include injection needles (including micro-needles), needle-less syringes and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers, preferably at a pH of from 3 to 9, but for some applications may be more suitably formulated as sterile non-aqueous solutions or in dry form with suitable carriers such as sterile pyrogen-free water being used.
Preparation of parenteral formulations under sterile conditions (e.g., by freeze-vacuum drying) can be readily accomplished using standard pharmaceutical techniques familiar to those skilled in the art.
The solubility of the compounds of the invention used to prepare parenteral solutions can be enhanced by suitable formulation techniques, such as the incorporation of solubilizing agents.
The parenteral formulations may be formulated as real-time release and/or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations. The compounds of the invention may thus be formulated as solid, semi-solid or thixotropic liquids for application as an implant depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
The compounds of the present invention may also be applied topically to the skin or mucosa (i.e., dermally or through the skin) and typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, sheets, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated, see, for example, J Pharm Sci, 88(10), 955-958 (10.1999) published by Finnin and Morgan, and other topical application modalities include electroporation, iontophoresis, sonophoresis, and micro-needle or needleless syringes (e.g., Powderject)TM，BiojectTMEtc.) delivery. The disclosures of these references are incorporated herein by reference in their entirety.
The topical formulations may be formulated as real-time release and/or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations.
The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either the compound of the invention alone, a mixture (e.g. a dry blend mixed with lactose) or a mixture of component particles (e.g. mixed with a phospholipid (e.g. lecithin)), with a dry powder inhaler, or as an aerosol with a pressurised container, pump, nebulizer (preferably with an electrohydrodynamic nebulizer to produce a fine mist), or a nebulizer with or without the use of a suitable propellant (e.g. 1,1,1,2,3,3, 3-heptafluoropropane). For intranasal administration, the powder may include a bioadhesive (e.g., chitosan or cyclodextrin).
The pressurized container, pump, spray, atomiser or spray may comprise a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol or alternative dispersing agents for suitable active compounds, a co-solvent or extended release agent, a propellant as a solvent and optionally a surfactant (e.g. sorbitan trioleate, oleic acid or oligolactic acid).
Prior to use in dry powder or suspension formulations, the drug product is micronised to a size suitable for inhalation delivery (typically less than 5 μm). This may be achieved by any suitable milling process (e.g. spiral jet milling, fluidized bed jet milling, supercritical fluid processing into nanoparticles, high pressure homogenization or spray drying).
Capsules (made, for example, from gelatin or HPMC), blister packs and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base (for example, lactose or starch) and a performance modifier (for example, L-leucine, mannitol or magnesium stearate). The lactose may be anhydrous or in the form of a monohydrate, preferably a monohydrate. Other suitable excipients include polydextrose, dextrose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
Suitable solution formulations for use in an electrohydrodynamically generated mist nebulizer may contain from 1 μ g to 20mg of a compound of the invention per actuation and the actuation volume may vary from 1 μ L to 100 μ L. Typical formulations include the compounds of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.
Suitable flavoring agents (e.g., menthol and levomenthol) or sweetening agents (e.g., saccharin or saccharin sodium) may be added to the aforementioned formulations of the invention for inhalation/intranasal administration.
Formulations for inhalation/intranasal administration may be formulated as real-time release and/or modified release formulations, for example with poly (DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations.
In the case of dry powder inhalers and aerosols, the dosage units are determined by means of a valve delivering a metered dose. The dosage units of the invention are typically arranged to administer a metered dose or "puff" containing a desired amount of a compound of the invention, and the total daily dose may be administered in a single dose throughout the day or more usually in divided doses.
The compounds of the invention may be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated as real-time release and/or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations.
The compounds of the invention may also be administered directly to the eye or ear, typically in the form of a fine powder suspension or drops of a solution of the compound of the invention in isotonic pH adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, implants of both biological degradability (e.g., gel sponge, collagen) and biological nondegradability (e.g., silicone), wafers, lenses and microparticles or vesicular systems (e.g., nonionic surfactant vesicles and liposomes). Polymers (e.g., crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymers, such as agarose gel (gelan gum), and preservatives (e.g., benzalkonium chloride) may be combined together.
Formulations for ocular/otic administration may be formulated as real-time release and/or modified release formulations. Modified release formulations include delayed, sustained, pulsed, controlled release, targeted and programmed release formulations.
Other techniques
The compounds of the present invention may be complexed with soluble macromolecular entities (e.g., cyclodextrins with suitable derivatives thereof or polyethylene glycol-containing polymers) in order to improve their solubility, dissolution rate, taste masking, bioavailability, and/or stability for any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. In the case of an alternative to direct complexation with the drug, the cyclodextrin may be used as an adjuvant, i.e. carrier, diluent or co-solvent. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which are found in PCT Publication nos. WO 91/11172, WO 94/02518 and WO 98/55148, the entire contents of which are incorporated herein by reference.
Dosage form
The amount of active compound administered will depend on the severity of the subject, disorder or condition being treated, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. However, an effective dose will typically range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human this corresponds to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more suitable, while in other cases still larger doses, typically divided into several smaller doses for administration throughout the day, may be employed without causing any harmful side effects.
Medicament box of accessory
Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which comprises a compound according to the invention, may suitably be combined in a kit form suitable for co-administration of the compositions. Thus, the kits of the invention comprise two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, and a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet. Examples of such kits are the familiar blister packs used for packaging tablets, capsules, etc.
The kits of the invention are particularly suitable for administration of different dosage forms, e.g. oral and parenteral, for administration of the individual compositions at different dosage intervals, or for adjustment of the individual compositions with respect to each other. To aid compliance, the kit typically contains instructions for administration and may be provided with a memory aid.
Combination therapy
The term "combination therapy" as used herein refers to the sequential or simultaneous administration of a compound of the invention and at least one additional drug or agent (e.g., an anti-cancer agent).
As indicated previously, the compounds of the present invention may be used in combination with one or more additional anti-cancer agents as described hereinafter. Where a combination therapy is used, one or more additional anti-cancer agents may be administered after or concurrently with the administration of a compound of the invention. In a specific embodiment, the compound of the invention is administered after the additional anti-cancer agent is administered to the mammal (e.g., a human). In another embodiment, the additional anti-cancer agent is administered after the compound of the invention is administered to the mammal. In another embodiment, the compound of the invention is administered at the same time the additional anti-cancer agent is administered to the mammal (e.g., human).
The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in a mammal, including a human, comprising an amount of a compound of the present invention as defined above (including hydrates, solvates and polymorphs of the aforementioned compound or a pharmaceutically acceptable salt thereof) in combination with one or more, preferably one to three, anticancer agents selected from the group consisting of an antiangiogenic agent and a signal transduction inhibitor, and a pharmaceutically acceptable carrier, wherein the amount of the active agents in combination with the amount of the anticancer agents in total has a therapeutic effect on the aforementioned abnormal cell growth.
In a specific embodiment of the invention, the anti-cancer agent used in combination with the compounds of the invention and the pharmaceutical compositions described herein is an anti-angiogenic agent (e.g., an agent that stops tumors from developing new blood vessels), examples of which include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiogenin inhibitors, PKC β inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (α -v/β -3) inhibitors, MMP-2 (matrix metalloproteinase-2) inhibitors, and MMP-9 (matrix metalloproteinase-9) inhibitors.
Preferred anti-angiogenic agents include: sunitinib (Sutent)TM) Bevacizumab (Avastin)TM) Axitinib (AG13736), SU 14813(Pfizer) and AG13958 (Pfizer).
Additional anti-angiogenic agents include: vatalanib (CGP 79787), Sorafenib (Nexavar)TM) Pegaptanib octasodium salt (Macugen)TM) Vandetanib (Zactima)TM) PF-0337210(Pfizer), SU 14843(Pfizer), AZD 2171(AstraZeneca), and ranibizumab (Lucentis)TM)、NeovastatTM(AE 941)、tetrathiomolybdata (CoprexaTM) AMG 706(Amgen), VEGF Trap (AVE0005), CEP 7055(Sanofi-Aventis), XL 880(Exelixis), tiratinib (BAY 57-9352) and CP-868,596 (Pfizer).
Other anti-angiogenic drugs include: enzastaurin (enzastaurin) (LY 317615), midostaurin (midostaurin) (CGP 41251), perifosine (KRX 0401), teprenone (Selbex)TM) And UCN0l (Kyowa Hakko).
Other examples of anti-angiogenic agents with which the compounds of the present invention may be used in combination with the pharmaceutical compositions described herein include: celecoxib (celecoxib) (Celebrex)TM) Parecoxib (parecoxib) (Dynastat)TM) Deracoxib (deracoxib) (SC 59046), lumiracoxib (Preige)TM) Valdecoxib (Bextra)TM) Rofecoxib (Vioxx)TM) Iguratimod (carram)TM) IP 75l (Invedus), SC-58125(Pharmacia) and etoricoxib (Arcoxib)TM)。
Other anti-angiogenic drugs include: exishulin (exisulind) (Aptosyn)TM) Salicylic acid salicylate (salsalate) (Amigesic)TM) Difluorinal (diflunisal) (Dolobid)TM) Ibuprofen (Motrin)TM) Ketoprofen (ketoprofen) (Orudis)TM) Nabumetone (nalumetone) (Relafen)TM) Piroxicam (Feldene)TM) Naproxen (naproxen) (Aleve)TM，NaprosynTM) Diammine phenolic acid (diclofenac) (Voltaren)TM) Indomethacin (indomethacin) (Indocin) TM) Sulindac (sulindac) (Clinoril)TM) Tolmetin (tolmetin) (Tolectin)TM) Etodolac (Lodine), etodolac (Lodine)TM) Ketorolac (ketorolac) (Tortadol)TM) With ao ShaOxaprozin (Daypro)TM)。
Other anti-angiogenic drugs include: ABT 510(Abbott), apremilast (apratastat) (TM1005), AZD 8955(AstraZeneca), and indolicin (Metastat)TM) And PCK 3145 (Procyon).
Other anti-angiogenic drugs include: abamectin A (acitretin) (Neottison)TM) Novel peptide plipidepsin (aplidine)TM) The compound comprises cecropin (cilnggtide) (EMD121974), combretastatin A4 phosphate (combretastatin A4) (CA4P), fenretinide (4HPR), halofuginone (tetrostatin)TM)、PanzemTM(2-methoxyestradiol), PF-03446962(Pfizer), remamastat (BMS 275291), and carbamazepine (cataxomab) (Removab)TM) Lenalidomide (Revlimid)TM) Squalamine (EVIZON)TM) Thalidomide (thalidomide)TM)、UkrainTM(NSC 631570)、VitaxinTM(MEDI 522) with zoledronic acid (Zomet)TM)。
In another embodiment, the anti-cancer agent is a so-called signal transduction inhibitor (e.g., a regulatory molecule that inhibits the fundamental effects of the survivors that govern cell growth, differentiation and communication within the cell). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More particularly, signal transduction inhibitors include (for example): farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1(EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors and so-called multi-targeted kinase inhibitors.
Preferred signal transduction inhibitors include: gefitinib (Ires)saTM) Cetuximab (Erbitux)TM) Erlotinib (Tarceva)TM) Trastuzumab (trastuzumab) (Herceptin)TM) Sutent (sultinib)TM) Imatinib (imatinib) (Gleevec)TM) And PD325901 (Pfizer).
Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the present invention and the pharmaceutical compositions described herein include: BMS 214662(Bristol-Myers Squibb), Ionafarnib (Sarasar)TM) Ten market Feitexol (AG 2037), matuzumab (matuzumab) (EMD 7200), nimotuzumab (TheraciM h-R3)TM) Panitumumab (Vectibix)TM)、Vandetanib(ZactimaTM) Pazopanib (SB 786034), ALT110 (alteras Therapeutics), BIBW 2992(Boehringer Ingelheim) and CervenTM(TP 38)。
Other examples of signal transduction inhibitors include: PF-2341066(Pfizer), PF-299804(Pfizer), canertinib (CI 1033), pertuzumab (pertuzumab) (Omnitarg)TM)、Lapatinib(TycerbTM) Pelitinib (EKB 569), miltefosine (miltefosine)TM)、BMS 599626(Bristol-Myers Squibb)、Lapuleucel-T(NeuvengeTM)、NeuVaxTM(E75 cancer vaccine), OsidemTM(IDM l), muritinib (mubritinib) (TAK-165), CP-724,714(Pfizer), panitumumab (Vectibix) TM) Lapatinib (Tycerb)TM) PF-299804(Pfizer), pelitinib (pelitinib) (EKB 569) and pertuzumab (pertuzumab) (Omnitarg)TM)。
Other examples of signal transduction inhibitors include: ARRY 142886(Array Biopharm), everolimus (Certican)TM) Azololimus (zotarolimus) (Endeavor)TM) Temsirolimus (Torsisel)TM) AP23573(ARIAD) and VX 680 (Vertex).
In addition, other signal transduction inhibitors include: XL 647(Exelixis), sorafenib (sorafenib) (Nexavar), LE-AON (Georgetown university) and GI-4000 (Globelmmune).
Other signal transduction inhibitors include: ABT 75l (abbott), alvocidib (flaperophilol), BMS387032(Bristol Myers), EM 1421(Erimos), indesulam (E7070), selicib (selicib) (CYC 200), BIO 112(Onc BIO), BMS387032 (Bristol-myerssquirb), PD 0332991(Pfizer), and AG024322 (Pfizer).
The present invention encompasses the use of the compounds of the present invention in combination with classical antineoplastic agents. Classical antineoplastic agents include, but are not limited to, hormonal modulators such as hormones, anti-hormones, androgen agonists, androgen antagonists and anti-estrogen therapeutic agents, Histone Deacetylase (HDAC) inhibitors, gene silencing agents or gene activators, ribonucleases, proteasomes, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors, tubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination complexes, gene therapy agents, antisense oligonucleic acid, Vascular Targeting Agents (VTA) and statins.
Examples of classical anti-neoplastic agents that may be used in combination therapy with a compound of the present invention, optionally in combination with one or more other agents, include (but are not limited to): glucocorticoids, e.g. dexamethasone, prednisone, prelysosone, meperisone, methylprednisolone, hydrocortisone, and progestins, e.g. medroxyprogesterone, megestrol, mipriprostone, RU-486, selective estrogen receptor inhibitors (SERM, e.g. tamoxifen, raloxifene, lasofoxifene, artomoxifene, arzoxifene, benzoxefen, raloxifene, lasofoxifene, prednimesulide, prednimisolone, prednimidoxinosone, hydrocortisone, and progestins, e.g. medroxyprogesterone, medroxyphene, and doxrofecofeneBazedoxifene (bazedoxifene), fimiphene (fismem)ifene), oxymetaxifene (ormeloxifene), ospemifene (ospemifene), timirifene (tesmilifene), toremifene (toremifene), trilostane (trilostane) and CHF 4227 (cheisii)), selective estrogen receptor down-regulator (SERD: such as fulvestrant (fulvestrant), exemestane (amostin), anastrozole (Arimidex), atamestane (atamestane), fadrozole (fadrozole), letrozole (fetarla), gonadol (GnRH: commonly known as luteinizing hormone releasing hormone [ LHRH ]) Agonists such as buserelin (buserelin) (Suprefact), goserelin (goserelin) (Zoladex), leuprorelin (leuprolin) (Lupron), triptorelin (triptorelin) (Trelstar), abarelix (abarelix) (pleenaxis), bicalutamide (Casodex), cyproterone (cyproterone), flunitramide (Eulexin), megestrol (megestrol), nilutamide (nilutamide) (Nilandron), oxathirone (ovaterone), dutasteride (epiandrosteride), finasteride (finasteride), Serenoa res, gol 00801, abarelix (abarelix), sertraline (sertralin), leuprorelin (propelleline), letrozole (letrozole), and combinations thereof.
Other examples of classical antineoplastic agents for use with the compounds of the present invention include (but are not limited to): cycloheptanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptides (FR901228 or FK228), G2M-777, MS-275, pivaloyl butyrate and PXD-101; onconase (ranpirnase), PS-341(MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan (belotecan), BN-80915(Roche), camptothecin, flutolanil (diflomotecan), indolocarban (edonarin), irinotecan (exatecan) (Daiichi), gimeran (gimatecan), 10-hydroxycamptothecin, irinotecan hydrochloride (irinotecan HCl) (Camptosar), lurtotecan (lurotecan), Orathecan (rubican), Supergen), SN-38, topotecan (topotecan), camptothecin, 10-hydroxybase, 9-aminocamphetamine, irinotecan (irinotecan), SN-38, indolocarbatecin (lanocorticin), topotecan (topotecan), doxorubicin (adriamycin), doxorubicin (adriamycin (doxorubicin), doxorubicin (doxorubicin), doxorubicin (L), and a), or a), a, Doxorubicin (doxorubicin), elsamitrucin (elsamitsumicin), epirubicin (epirubicin), etoposide (etoposide), idarubicin (idarubicin), garrubicin (galubicin), hydroxyurea, nemorubicin (nemorubicin), noratone (novaltron), pirarubicin (pirarubicin), pixantrone (pixantrone), procarbazine (procarbazine), fringenin (rebeccamycin), sobuzosin (sobuzoxazone), teflozin (taflunoside), valrubicin (valrubicin), nerocard (dexrazoxane), sina-N-oxide, cyclophosphamide, melamin (hexatamamine), AP-trystein (AP-5280), apraxin (apraxine), estramustine (gabapentin), sultaine (fenazamide), sultamide (fenazamide), sulbactam (fenazamide (sulbactam), sulbactam (bendazole (sulbactam), sulbactam (fenacin (sulbactam), sulbactam (sulbactam), sul, Glufosfamide (glufosfamide), ifosfamide (ifosfamide), KW-2170, lomustine (lomustine), macsfamide (mafosfamide), methyldichloroethylamine, melphalan (melphalan), mitomannitol (mitobronitol), dibromodulcitol (mitolactotol), mitomycin C (mitomycin C), chlordiazepoxide (mitoxatron), nimustine (nimustine), Raynaudimus (ranimustine), temozolomide (temozolomide), thiotepa (thiotepa) and platinum coordination alkylating compounds, such as cisbaminum chloride (cissplatin), Burserdin (Paraplatin) (carboplatin), EPTA (eptatin), lobaplatin (lobaplatin), nedaplatin (nedaplatin), saratin (santatin), and satoplatin (oxaliplatin), in combination with platinum (saroplatin).
The present invention also encompasses the use of the compounds of the present invention in combination with: dihydrofolate reductase inhibitors (e.g. methotrexate), NeuTrexin trimetrexauronate (trimetress g)lucuronate)), purine antagonists (e.g., 6-conceptylpurine riboxib, halopurine, 6-thioguanine, cladribine (cladribine), clofarabine (Clolar), fludarabine (fludarabine), nelarabine (nelarabine) and raltitrexed (raltrexed)), pyrimidine antagonists (e.g., 5-fluorouracil (5-FU), alima (pemetrexed disodium), LY231514, MTA), capecitabine (capecitabine) (Xeloda)TM) Massachusex, UemzarTM(gemcitabine, EliLilly), Tegafur (UFT Orzel or Uforal and including Tegafur), Gimestat and Tourett TS-1 composition), defluorinated ureter (doxifluorine), carmofur (carmofur), cytarabine (including octopamine (ocfosfate) type, stearate phosphate type, sustained release type and liposome type), enocitabine (enocitabine), 5-azacitidine (Vidaza), decitabine (decitabine) and ethynyl-cycib-ine and other antimetabolites (e.g. eflornithine (eflornithine), hydroxyglandins, leucovorin (leucovorin), nolatrexed (thlimatexaq), trequine (tripine), trimetrexate (trimetrexate), N- (5- [ N- (3, 4-dihydro-2-methyl-4-oxoazolin-6-ylmethyl) -N-methylamine. ]-2-thenoyl) -L-glutamic acid, AG-014699(Pfizer Inc.), ABT-472(Abbott laboratories), INO-1001(Inotek Pharmaceuticals), KU-0687(KuDOSPharmaceuticals), GPI 18180(Guilford Pharm Inc), and combinations thereof.
Other examples of classical anti-tumor cytotoxic agents used in combination therapy with a compound of the present invention, optionally in combination with one or more other agents, include (but are not limited to): abraxane (Abraxis Bioscience, Inc.), Batabulin (Amgen), EPO 906(Novartis), Vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin (bleomycin), mitomycin C, neocarzinostatin (Zinostatin), vinblastine, vincristine, vinblastine amide, vinorelbine (Navelbine), docetaxel (docetaxel), Ortataxel, paclitaxel (including Taxoprexin, a DHA/paclitaxel conjugate), cisplatin (carboplatin), carboplatin (Nedaplatin), Nedaplatin (Nedaplatin),Oxaliplatin (oxaloplatin), Satraplatin (Satraplatin), Camptosar, capecitabine (Xeloda), oxaliplatin (oxaloplatin), Taxotere, Canfosfamide (Telcyta) TM) DMXAA (Antisoma), ibandronic acid (ibandronic acid), L-asparaginase, and Pegasparnase (Oncapar)TM)、Efaproxiral(EfaproxynTM-radiotherapy)), bexarotene (Targretin)TM) Tesmilene (DPPE-enhances cytotoxic efficacy)), TheratopeTM(Biomira)，Tretinoin(VesanoidTM) Tirapazamine (Trizaone)TM) Motoxafin gold (motexafin gadolinum) (Xcytrin)TM)、CotaraTM(mAb), NBI-3001(Protox Therapeutics), polyglutamate-paclitaxel (XYotax)TM) And combinations thereof.
Additional examples of classical antineoplastic agents to be used in combination therapy with a compound of the present invention, optionally in combination with one or more other agents, include (but are not limited to): advexin (ING 201), TNFade (GeneVec, a compound that expresses TNF α in response to radiotherapy), RB94(Baylor College of Medicine), Genasense (Genasense) (Oblemsen, Genta), Combretastatin A4P (Combretastatin A4P) (CA4P), Oxi-4503, AVE-8062, ZD-6126, ZT-1027, Atorvastatin (Atorvastatin) (Lipitor, Pfizer Inc.), pravastatin (pravastatin) ((pravastatin) pravastatin, Bristol-Myers Squibb), lovastatin (Lovastatin) (mevastatin, Merck Inc.), Simvastatin (Simvastatin) (Zocor, Merck Inc.), Simvastatin (Fluvastatin) (leicol), Novartis), Cerivastatin (Cerivastatin) (Baycol, Bayer), Cerivastatin (Rosuvastatin) (scorotron, AstraZeneca), Lovastatin, Niacin (Niacin) (Advicor, Kos Pharmaceuticals), dolby (reducer), Lipitor (Lipitor), torsipropl (torcetrapib), and combinations thereof.
Another particular embodiment of the present invention of particular interest relates to a method of treating breast cancer in a human in need of such treatment comprising administering to said human an amount of a compound of the present invention in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of: trastuzumab (trastuzumab), tamoxifen (tamoxifen), docetaxel (docetaxel), paclitaxel (paclitaxel), capecitabine (capecitabine), gemcitabine (gemcitabine), vinorelbine (vinorelbine), exemestane (exemestane), letrozole (letrozole) and anastrozole (anastrozole).
In one embodiment, the invention provides a method of treating colorectal cancer in a mammal (e.g., a human) in need of such treatment by administering an amount of a compound of the invention in combination with one or more (preferably one to three) anti-cancer agents. Examples of specific anticancer agents include anticancer agents typically used in adjuvant chemotherapy, such as FOLFOX, 5-fluorouracil (5-FU) or capecitabine (Xeloda), leucovorin (leucovorin) in combination with platinum oxalate (oxaliplatin) (Eloxatin). Additional examples of specific anticancer agents include anticancer agents typically used in chemotherapy for metastatic disease, such as FOLFOX or FOLFOX combined with bevacizumab (avastatin), and FOLFIRI (5-FU or capecitabine), leucovorin (leucovorin) in combination with irinotecan (irinotecan) (Camptosar), and additional examples include 17-DMAG, ABX-EFR, AMG-706, AMT-2003, ANX-510(CoFactor), marine cyclic peptide (aplidine) (priapipid peptide novain), Aplidin, Aroplatin, axitinib (axitinib) (13736), AZD-0530, AZD-2171, BCG (Bevacizumab) (avastatin), BIO-184476, BIaxitinib (3555-55), Velcrotbms-145, BCG-145, Systemmazumab (BCG-145), Systemmazumab (Zymotuzumab), and so-Bytuzumab (Avastin), and so-Bevacizumab) (Avastin, Acinetobacter-145, Bytubm-145, Cyrtymetrix-145, Cymbob, Cymbox-145, Cymbox, and so-C, Capecitabine (capecitabine) (Xeloda), cetuximab (cetuximab) (Erbitux), clovarabine (clofarabine) (Clofarex), CMD-193, combretastatin (combretastatin), Cotara, CT-2106, CV-247, decitabine (decitabine) (Dacogen), E-7070, E-7820, indoxacarbacin (edotecarin), EMD-273066, enzastarin (enzastaurin) (LY-317615), epothilone B (epothilone B) (EPO-906), erlotinib (erlotinib) (Tarcuva), flazopiclone (flavopiridol), GCAN-101, gefitinib (gefitib) (Iressa 33, huC-DM (4), imatinib (Invitrob) (Gleiryt), gladiatinib (CPivene-25011), gladiatrizatin (HG-25011, gladiatrizotinib) (MBtaine-2506), glatirucaine (Ipexib, Ipombe-2506, Ipombe (Ipompex), Ipompezil (I, Ipom-b) (Messame, Ipompezil (I, Ipom-2506, Ipom-b, Ipombe, Ipompeb, Ipombe (Ipombe, Ipom-2501, Ipompeb, Ipombe, Ipom, Ipombe, Ipompeb, Ipombe, MEDI-522(Abregrin), Mitomycin (Mitomycin), MK-0457(VX-680), MLN-8054, NB-101l, NGR-TNF, NV-1020, orlistat (oblimersen) (Genasense, G3139), Oncovex, ONYX 015(CI-1042), platinum oxalate (Eloxiptin), panitumumab (ABX-EGF, Vectibix), pelitinib (pelitinib) (EKB-569), pemetrexed (pemetrexed) (alimata), PD-325901, PF-0337210, PF-1066, RAD-00l (Everolimus), RAV-12, Resveratrole, Rexin-G, S-1 (SN-1), Semilitilide (Szelisib), antimony-38 (sodium stanniocalcitum) (sodium glucosolani), Sussiumoside (Sussimus) (Sussimus 779), sunitinib (Sussimus 369), sunitinib (Sussimus) (Sussimus 14813), and Neissolimus (Sussimus) (SSnetovani) Tetrathiomolybdate, thalmide, TLK-286(Telcyta), topotecan (Hycamtin), trabectedin (Yondelis), vatalanib (PTK-787), vorinostat (vorinostat) (SAHA, Zolinza), WX-UK1 and ZYC300, wherein the amount of the active agent in combination with the amount of the anti-cancer agent is effective in treating colorectal cancer.
Another particular embodiment of the invention of particular interest relates to a method of treating renal cell carcinoma in a human in need of such treatment, comprising administering to said human an amount of a compound of the invention in combination with one or more (preferably one to three) anti-cancer agents selected from the group consisting of: acitinib (axitinib) (AG13736), capecitabine (capecitabine) (Xeloda), interferon alpha (interferon alpha), interleukin-2 (interleukin-2), bevacizumab (bevacizumab) (Avastin), gemcitabine (gemcitabine) (Gemzar), thalidomide (thalidomide), cetuximab (cetuximab) (Erbitux), vatalanib (vatalanib) (PTK-787), sunitinib (sunitinib) (Sutent)TM) AG-13736, SU-11248, Tarceva (Tarceva), Iressa, Lapatinib (Lapatinib) and Gleevec (Gleev)ec), wherein the amount of the active agent in combination with the amount of the anti-cancer agent is effective to treat renal cell carcinoma.
Another particular embodiment of the invention of particular interest relates to a method of treating melanoma in a human in need of such treatment comprising administering to the human an amount of a compound of the invention in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of: interferon alpha (interferon alpha), interleukin-2 (interleukin-2), temozolomide (temozolomide) (Temodar), docetaxel (docetaxel) (Taxotere), paclitaxel (paclitaxel), Dacarbazine (DTIC), carmustine (carmustine) (also called BCNU), Cisplatin, vinblastine (vinblastine), tamoxifen (tamoxifen), PD-325, 901, axitinib (axitinib) (AG13736), bevacizumab (Avastin), thalidomide (thalidomide), sorafenib (sorafanib), vatalanib (PTK-787), sunitinib (sunitinib) (tent-787) TM) CpG-7909, AG-13736, Iressa (Iressa), Lapatinib (Lapatinib) and Gleevec (Gleevec), wherein the amount of the active agent in combination with the amount of the anti-cancer agent is effective in treating melanoma.
Another particular embodiment of the invention of particular interest relates to a method of treating lung cancer in a human in need of such treatment comprising administering to said human an amount of a compound of the invention in combination with one or more (preferably one to three) anticancer agents selected from the group consisting of: capecitabine (Xeloda), axitinib (AG 13736), bevacizumab (bevacizumab) (Avastin), gemcitabine (gemcitabine) (Gemzar), docetaxel (docetaxel) (Taxotere), paclitaxel (paclitaxel), pemetrexed disodium (pemetrexed), Tarceva (Tarceva), Iressa (Iressa), Vinorelbine (Vinorelbine), Irinotecan (Irinotecan), etoposide (etoposide), Vinblastine (vinastatin), sunitinib (Sutent)TM) Combined with beradine (Paraplatin) (carboplatin), wherein the amount of the active agent and the amount of the anti-cancer agent are effective to treat lung cancer.
Synthesis method
The compounds of the present invention are prepared according to the exemplary methods provided herein and modifications thereof known to those skilled in the art. Various routes have been demonstrated for forming various fused lactam compounds. One general route for preparing the compounds of the invention involves ring-expanding a 5-membered ring oxime by Beckmann rearrangement to give a 6-membered ring lactam (method A). Similarly, 6-membered ring oximes can be subjected to ring expansion to give 7-membered ring lactams. Additional functional groups on the lactam precursor may be modified by conventional functional group manipulations, such as protection/deprotection, alkylation, acylation, activation, or coupling steps. Alternatively, the desired substituent is attached to the lactam-fused aromatic ring prior to ring expansion (e.g., method C). The pyrrolidone moiety can be installed by alkylating the lactam nitrogen atom under standard conditions, regardless of the sequence of steps. In some embodiments, it is desirable to modify the substituents on the fused aromatic ring after installation of the pyrrolidone (e.g., methods B and D).
An alternative route for preparing fused lactam starting materials involves rearranging quinoline or isoquinoline N-oxides to the corresponding unsaturated lactams (e.g., methods E and I). For example, reduction by hydrogenation gives a saturated lactam, which can be modified to install a pyrrolidone moiety and the desired functional group on the fused aromatic ring as described above. In some cases, it is desirable to install a reactive functional group, such as an aryl halide or triflate, on the fused aromatic ring. Such groups can be used as functional assemblies (handles) in different coupling reactions to install additional substituents.
For example, in method F, a Curtius rearrangement is performed on the acyl azide intermediate to install a Boc-protected amino functionality. Such groups may be used in coupling reactions, for example with activated carbonyl compounds, to give acylated products. The deprotected arylamino group can also be converted to various other functional groups by using an aryldiazonium ion as an intermediate. For example, using NaNO in the presence of CuBr2The diazonium ion is formed to yield the aryl bromide intermediate (method F). So that it canReaction of the diazonium ion of (a) with other copper salts, such as CuCl or CuCN, can be expected to give a chloro or cyano substituent, respectively. Can also be used by reacting with KI or HBF 4By reaction with H or by conversion of diazonium ions to iodide or fluoride2O and strong acids such as H2SO4The reaction at elevated temperature gives phenol. In other methods, aryl halides can be installed using well-known halogenation conditions. In method L, the aryl bromide is installed by reacting the phenol intermediate with NBS. Depending on the presence of another functional group, different sources of electrophilic halogen (e.g., Br) may be used2、I2、Cl2NBS, NIS, NCS) or by friedel-crafts halogenation or the like.
The aryl halide intermediates can be used for cross-coupling using a variety of metal mediated reactions. Suzuki (Suzuki) couplings with arylboronic acids or arylboronic esters can be used to form aryl-aryl linkages as shown in methods F and P. Similarly, aryl bromides may be used in various cross-coupling reactions, such as Stille (Stille) or sonogashira (sonigashira) reactions. In some cases, the aryl halide can be incorporated into the original starting material (e.g., method I) and used in a similar reaction.
Other reactive functional groups on the fused aryl ring can be modified by standard functional group transformations. For example, the ester substituent may be hydrolyzed and coupled with an amine, as shown in method G. Alternatively, esters or acids can be reduced to alcohols or converted to ketones or aldehydes. Such groups may themselves be further modified. For example, the alcohol intermediate may be alkylated to give an alkoxy or benzyloxy group. The alcohol may also be converted to a leaving group (e.g., mesylate, tosylate, halide), which may be replaced by a nucleophile such as an amine, thiol, alkoxide, phenoxide, etc., or subjected to Mitsunobu or other reactions, thereby significantly expanding the diversity of groups that can be installed. Similarly, ketones or aldehydes may be subjected to nucleophilic addition reactions, reductive alkylation, and the like.
Additional routes for forming fused lactams are provided in methods H and J. In each case, a suitably long masked alkylamino group is attached to the carbon atom ortho to the carboxylate on the aryl ring. Deprotection of the amine and ester groups leads to intramolecular cyclization to give the fused lactam. Similarly, in process U, a 5-membered cyclic lactam is formed by N-alkylation of a 2- (bromomethyl) -benzoate with a suitable aminomethyl-substituted pyridin-2 (1H) -one followed by internal amidation. In process V, the lactam ring is formed by reduction of the 2-cyanomethyl-benzoate to give the 2-aminomethyl-benzoate, which is likewise lactamized.
Various synthetic routes are provided for the preparation of benzoxazepinesCompounds, including, for example, forming carbon-oxygen or carbon-nitrogen bonds. In method K, intramolecular mitsunobu is used to form an oxazepine by installing a bond between the phenolic oxygen and the activated alcohol leaving group. In methods L and M, the amide bond of the lactam is formed by reacting the derivatized amine with activated benzoic acid. In Processes N and Q, oxaza is formed by base-catalyzed cyclization of an N-hydroxyethylfluorobenzamide intermediateAnd (4) a ring. Method O provides another route which involves lewis acid catalyzed lactamization of secondary amines on benzoates. In method R, oxazazepine is formed by base-catalyzed lactamization of 2-aminoethoxy-substituted aromatic compounds with ortho-carboxylic acid esters And (4) a ring. Such compounds are further functionalized, for example, by Suzuki coupling (method P) or similarly manipulating the functional groups described herein.
In some methods, suitable lactam intermediates are readily available and can be modified to install suitable substituents (e.g., methods S, T and W). In particular, the nitrogen atom of the lactam may be modified by N-alkylation with an appropriately protected pyridin-2 (1H) -one, such as 2-benzyloxy-3-chloromethyl-4, 6-dimethyl-pyridine, which protected group may be deprotected to give a substituted pyridin-2 (1H) -one.
These and other methods are exemplified for the purpose of making the examples provided herein. It will be appreciated by those skilled in the art that the selection of starting materials and the particular sequence of steps including, for example, the formation of lactam rings, the installation or manipulation of different substituents on the fused lactam or precursor thereof and the installation of pyrrolidone moieties may be varied by the selection of appropriate synthetic strategies.
Synthetic examples are provided throughout the following examples and tables 1 and 2. For exemplary compounds of the invention, WT EZH2 and mutant Y641N EZH2 EZH2IC50The values (μ M) are provided in Table 3.
The following abbreviations are used in the context of the examples: "Ac" means acetyl, "AcO" or "OAc" means acetoxy, "Ac 2O "refers to acetic anhydride," ACN "or" MeCN "refers to acetonitrile," AIBN "refers to azobisisobutyronitrile," BOC "," Boc "or" BOC "refers to N-tert-butyloxycarbonyl," Bn "refers to benzyl," BPO "refers to dibenzoyl peroxide," Bu "refers to butyl," iBu "refers to isobutyl," sBu "refers to sec-butyl," tBu "refers to tert-butyl," tBuOK "or" KOtBu "refers to potassium tert-butoxide," CDI "refers to carbonyldiimidazole," DCM "(CH)2Cl2) Refers to methylene chloride, "DEAD" refers to diethyl azodicarboxylate, "DIAD" refers to diisopropyl azodicarboxylate, "DIPEA" or "DIEA" refers to diisopropylethylamine, and "DBU" refers to 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene, "DIBAL-H" refers to diisobutylaluminum hydride, "DMA" refers to N, N-dimethylacetamide, "DMAP" refers to 4-dimethylaminopyridine, "DME" refers to dimethoxyethane, "DMF" refers to N, N-dimethylformamide, "DMS" refers to dimethyl formamideSulfur, "DMSO" refers to dimethylsulfoxide, "dppf" refers to (diphenylphosphino) ferrocene, "DPPP" refers to 1, 3-bis (diphenylphosphino) propane, "Et" refers to ethyl, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol, "HATU" refers to 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate, "HOAc" or "AcOH" refers to acetic acid, "i-Pr" or " iPr "refers to isopropyl," IPA "refers to isopropanol," KHMDS "refers to potassium hexamethyldisilazide (bis (trimethylsilyl) amino potassium)," LiHMDS "refers to lithium hexamethyldisilazide (bis (trimethylsilyl) amino lithium)," mCPBA "refers to m-chloroperoxy-benzoic acid," Me "refers to methyl," MeOH "refers to methanol," Ms "refers to methane sulfonate (often referred to as 'methane sulfonate')," MTBE "refers to methyl tert-butyl ether," NBS "refers to N-bromosuccinimide," NCS "refers to N-chlorosuccinimide," NIS "refers to N-iodosuccinimide," NMM "refers to N-methylmorpholine," NMP "refers to 1-methyl 2-pyrrolidone," Ph "refers to phenyl," RuPhos "refers to 2-dicyclohexylphosphino-2 ',6' -diisopropoxybiphenyl, "Selectfluor" refers to chloromethyl-4-fluoro-1, 4-diazoniabicyclo [2.2.2]Octane bis (tetrafluoro-borate), "TEA" means triethylamine, "TFA" means trifluoroacetic acid, "Tf" means trifluoromethanesulfonate (often referred to as 'trifluoromethanesulfonate'), "THF" means tetrahydrofuran, "TMS" means trimethylsilyl group, "TMSA" means trimethylsilyl azide, "TsCl" means tosyl chloride (often referred to as 'tosylate'), "SFC" means supercritical fluid chromatography, "TLC" means thin layer chromatography, "Rf" means a retained fraction, "" means about, "rt" means room temperature, "h" means hour, "min" means minute, "and" eq.
Preparation of synthetic intermediates
Compound F: 8-chloro-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid methyl ester
A mixture of 3, 5-dibromo-4-methyl-phenol (11.2g, 42.1mmol), 2-iodopropane (8.50mL, 85.0mmol), potassium carbonate (17.5g, 126mmol), and anhydrous DMF (100mL) was stirred at 80 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ether (300mL) and water (300 mL). The organic phase was separated, washed with brine (2 × 300mL), dried over sodium sulfate and concentrated in vacuo to give 1, 3-dibromo-5-isopropoxy-2-methyl-benzene (Cpd a, 12.8g, 99% yield) as an oil.
To a solution of 1, 3-dibromo-5-isopropoxy-2-methyl-benzene (Cpd A, 12.8g, 41.6mmol) in MeOH (250mL) in a 500mL Parr bottle was added KOAc (20.0g, 204mmol), DPPP (1.25g, 3.03mmol), and Pd (OAc)2(532mg, 2.38 mmol). The bottle was sealed, purged with nitrogen (3X) and CO (4X), charged with CO (160psi), and heated at 100 ℃. The internal pressure was raised to 190-200psi during heating. After heating at 100 ℃ overnight, the reaction mixture was cooled to room temperature. The vessel was vented and purged with nitrogen (2 ×). By passingThe pad was filtered of the precipitate and washed with MeOH. After concentration in vacuo, the resulting residue was partitioned between ethyl acetate (300mL) and water (300 mL). The organic phase was separated, washed with brine (1X 300mL), dried over sodium sulfate and concentrated in vacuo to give dimethyl 5-isopropoxy-2-methyl-isophthalate (Cpd B, 10.9g, 99% yield) as an oil.
To a solution of dimethyl 5-isopropoxy-2-methyl-isophthalate (Cpd B, 14.5g, 54.5mmol) in CCl4NBS (11.2g, 60.0mmol) was added to the solution (250 mL). After the mixture was stirred at 85 ℃ for 5 minutes, AIBN (2.69g, 16.4mmol) was added. The resulting reaction mixture was stirred at 85 ℃ for 1 hour. The reaction mixture was cooled in an ice bath and the precipitate was filtered and discarded. The resulting filtrate was concentrated in vacuo and purified by column chromatography (0-40%, EtOAc/heptane) to give dimethyl 2-bromomethyl-5-isopropoxy-isophthalate (CpdC, 17.5g, 93% yield) as a clear oilAnd curing when standing.
To a solution of dimethyl 2-bromomethyl-5-isopropoxy-isophthalate (Cpd C, 17.4g, 50.5mmol) in DMSO (200mL) was added NaCN (3.71g, 75.7mmol) in H2O (20mL) solution. The resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (500mL) and extracted with ethyl acetate (2X 300 mL). The combined organic phases were washed with brine (1 × 300mL), dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (0-40%, EtOAc/heptane) to give dimethyl 2- (cyanomethyl) -5- (propan-2-yloxy) benzene-1, 3-dicarboxylate (Cpd D, 12.8g, 87% yield) as a clear oil which solidified on standing.
Dimethyl 2- (cyanomethyl) -5- (propan-2-yloxy) benzene-1, 3-dicarboxylate (Cpd D, 1.04g, 3.57mmol) and cobalt (II) chloride hexahydrate (2.56g, 10.7mmol) were dissolved in MeOH (60mL) and cooled in an ice bath. Adding NaBH step by step4(853mg, 21.4mmol) and the reaction mixture was stirred at 0 ℃ for 0.5 h. Adding NH to the reaction mixture4Cl (saturated aqueous solution, 25mL), H2O (25mL) and EtOAc (50 mL). The reaction was allowed to stand at room temperature overnight. The residual solid was filtered and the aqueous layer was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (1 × 50mL), dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (0-60%, EtOAc/heptane) to give methyl 1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 644mg, 69% yield) as a white solid.1H NMR (400MHz, chloroform-d) 1.35(s, 3H)1.36(s, 3H)3.35(t, J ═ 6.57Hz, 2H)3.52(td, J ═ 6.57, 3.03Hz, 2H)3.91(s, 3H)4.61-4.72(m, 1H)5.91(br.s., 1H)7.62(d, J ═ 3.03Hz, 1H)7.83(d, J ═ 3.03Hz, 1H); MS 264.1[ M + H]。
To a solution of methyl 1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 400mg, 1.52mmol) in AcOH (5mL) was added NCS (416mg, 3.04 mmol). The reaction mixture was stirred at 100 ℃ overnight. The reaction mixture was concentrated in vacuo and washed with H 2O and NaHCO3The residue was diluted (saturated aqueous solution). The aqueous layer was extracted with EtOAc, thenThe organic layer was purified by column chromatography (50% EtOAc/heptane) to give the title compound (Cpd F, 180mg, 40%) as a white solid.1H NMR (400MHz, chloroform-d) 1.40(s, 3H)1.42(s, 3H)3.27-3.36(m, 2H)3.37-3.47(m, 2H)3.88-3.95(m, 3H)4.62(dt, J ═ 12.07, 6.13Hz, 1H)6.06(br.s., 1H)7.61(s, 1H); MS298.0[ M + H ]]。
Compound K: 2- (benzyloxy) -4- ({ [ tert-butyl (dimethyl) silyl ] oxy } methyl) -3- (chloromethyl) -6-methylpyridine
To a solution of-40 ℃ t-butyl (dimethyl) (prop-2-yn-1-yloxy) silane (1.70g, 10mmol) in THF (6mL) was added iPrMgCl. LiCl (8.46mL, 11mmol) dropwise, maintaining the internal temperature below-20 ℃. A solution of N-methoxy-N-methylacetamide (1.13g, 11.0mmol) in THF (4mL) was cooled to-10 deg.C and the alkyne solution was added to the Weinreb amide solution by cannula. The reaction mixture was stirred at-10 ℃ for 10 minutes. The reaction mixture was poured into saturated NH4A mixture of Cl and ice. The aqueous layer was extracted with EtOAc. The organic layer was washed with brine, Mg2SO4Drying, filtration and concentration in vacuo afforded 5- { [ tert-butyl (dimethyl) silyl ]Oxy } pent-3-yn-2-one (Cpd G, 1.5G, 64%) as an oil.
To a solution of 2-cyanoacetamide (1.74g, 20.7mmol) and tBuOK (2.32g, 20.7mmol) in DMSO (48mL) at 0 deg.C was added dropwise 5- { [ tert-butyl (dimethyl) silyl]Oxy } pent-3-yn-2-one (Cpd G, 4.4G, 21.0 mmol). The reaction mixture turned bright orange. The reaction mixture was stirred at 0 ℃ for 2 hours and then with NH4Cl (saturated aqueous solution) was quenched and diluted with water, resulting in the precipitation of a solid. The solid was collected by filtration and dried under vacuum to give 4- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (Cpd H, 5.0g, 86%) as a tan solid.
4- ({ [ tert-butyl (dimethyl) silyl) group]Oxy } methyl) -6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (Cpd H, 6.6g, 24mmol), Ag2A mixture of O (6.3g, 27mmol) and benzyl chloride (4.1g, 33mmol) in toluene (79mL) was heated at 100 ℃ for 21 h. By passingThe reaction mixture was filtered and then concentrated in vacuo. The residue was purified by column chromatography (0-30%, EtOAc/heptane) to give 2- (benzyloxy) -4- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) -6-methylpyridine-3-carbonitrile (Cpd I, 6.5g, 74%) as a tan solid.
To 0 ℃ 2- (benzyloxy) -4- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) -6-methylpyridine-3-carbonitrile (Cpd I, 1.0g, 2.8mmol) to a solution in MeOH (5mL) was added NaBH4(81mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo to give [2- (benzyloxy) -4- ({ [ tert-butyl (dimethyl) silyl)]Oxy } methyl) -6-methylpyridin-3-yl]Methanol (Cpd J, 147mg, 14%) as a solid.
To a solution of NCS (70.2mg, 0.515mmol) in DCM (2mL) at 0 deg.C was added DMS (34.9mg, 0.562 mmol). The reaction mixture was cooled to-40 ℃ and then [2- (benzyloxy) -4- ({ [ tert-butyl (dimethyl) silyl) group was added dropwise]Oxy } methyl) -6-methylpyridin-3-yl]A solution of methanol (Cpd J, 175mg, 0.468mmol) in DCM (1mL) was kept at an internal temperature below-30 ℃. Upon completion of the addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with brine, and MgSO4Dried, filtered and then concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc/heptane) to give the title compound (Cpd K, 120mg, 65%) as an oil.1H NMR (400MHz, chloroform-d) 7.50(d, J ═ 7.3Hz, 2H), 7.44-7.29(m, 3H), 6.94(s, 1H), 5.46(s, 2H), 4.83(s, 2H), 4.70(s, 2H), 2.47(s, 3H), 0.97(s, 9H), 0.14(s, 6H); MS 392[ M + H ] ]。
Compound P: 8-chloro-6-fluoro-7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one
A solution of 4-fluoro-3-methoxybenzoic acid (1.30g, 7.64mmol) and TEA (1.25mL, 8.97mmol) in sulfolane (6.0mL) was treated with HATU (3.25g, 8.55 mmol). After 10 min, aminoacetaldehyde dimethyl acetal (0.925mL, 8.58mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. Then using concentrated H2SO4The reaction mixture was treated (15mL) and stirred at 60 ℃ for 2 days. The reaction mixture was poured into ice and brought to pH 4 with 10M NaOH (. about.55 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to give 6-fluoro-7-methoxyisoquinolin-1 (2H) -one (Cpd L, 1.32g, 89%) as a white powder.
A suspension of 6-fluoro-7-methoxyisoquinolin-1 (2H) -one (Cpd L, 0.531g, 2.75mmol) and 10% Pd/C in EtOH (20mL) was suspended in H at room temperature2Stir vigorously in a hood (balloon) for 2 days. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 6-fluoro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd M, 430mg, 80%) as a white powder.
To a 0 ℃ solution of 6-fluoro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd M, 0.428g, 2.19mmol) in DCM (15mL) was added boron tribromide (1.0M in DCM, 6.00mL, 6.00 mmol). The reaction mixture was stirred for 1 hour, and then the reaction mixture was warmed to room temperature. After stirring for 4 hours, water (25mL) and EtOAc (100mL) were added and the mixture was stirred vigorously. The layers were separated and the organic layer was filtered and concentrated in vacuo to give 6-fluoro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd N, 355mg, 89%).
To a solution of 6-fluoro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd N, 0.110g, 0.607mmol) in DMF (1mL) was added N-chlorosuccinimide (0.0780g, 0.584 mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was diluted with water and the solution was extracted with DCM (× 3). The combined organic layers were concentrated in vacuo to give 8-chloro-6-fluoro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd O, 131mg, 100%) as a clear oil.
To a solution of 8-chloro-6-fluoro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (Cpd O, 131mg, 0.607mmol) in DMF (3.0mL) was added cesium carbonate (0.210g, 0.645mmol) and isopropyl iodide (0.0850mL, 0.850 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with EtOAc, washed with water (2 ×) and brine. The organic layer was concentrated in vacuo and the residue purified by column chromatography (40-100% EtOAc/heptane) to give the title compound (Cpd P, 62mg, 40%) as a white solid. MS 258[ M + H ].
A compound R: 8-chloro-4, 4-difluoro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one
To a solution of Cpd-a (0.451g, 2.15mmol) in acetonitrile (25mL) was added water (0.30mL) and 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [ 2.2.2% ]Octane ditetrafluoroborate (0.831g, 2.35 mmol). The reaction was stirred at room temperature for 72 h. The reaction mixture was poured into ethyl acetate, washed with 1:1 water/brine, then brine. The ethyl acetate layer was concentrated and the resulting pale yellow powder (Cpd-b) was dissolved in dichloromethane (15mL) and treated with methanesulfonic acid (0.90mL, 14 mmol). After 3h at room temperature, the reaction was diluted with dichloromethane and saturated NaHCO3And (4) washing with an aqueous solution. With Na2SO4The dichloromethane layer was dried, filtered and concentrated to give Cpd-c (0.269g, 56%) as a light orange powder.1H NMR(400MHz，DMSO-d6)10.89(br.s.，1H)，7.62(s，2H)，7.15(t，J＝5.68Hz，1H)，3.88(s，3H)；MS 228[M+H]+。
To a solution of 8-chloro-4-fluoro-7-methoxyisoquinolin-1 (2H) -one (Cpd-c, 0.267g, 1.17mmol) in acetonitrile (15mL) were added water (1.0mL) and 1- (chloromethyl) -4-fluoro-1, 4-diazoniabicyclo [ alpha ], [ beta ] -methyl-ethyl ester2.2.2]Octane ditetrafluoroborate (0.505g, 1.43 mmol). The reaction was stirred at room temperature for 2h, then concentrated in vacuo. The crude residue was dissolved in ethyl acetate and washed with 1:1 water/brine and then brine. The ethyl acetate layer was concentrated to give 8-chloro-4, 4-difluoro-3-hydroxy-7-methoxy-3, 4-dihydro-isoquinolin-1 (2H) -one (Cpd Q, 309mg, 99%) as a solid. The solid was dissolved in DCM (12.0mL) and treated with triethylsilane (1.00mL, 6.26mmol) and methanesulfonic acid (0.300mL, 4.26 mmol). After 8h at room temperature, the reaction mixture was decanted from the solid and saturated NaHCO was used 3Washing with water solution, and concentrating. The resulting residue was purified on silica gel (Biotage SNAP Ultra, 10g, gradient 40-90% ethyl acetate in heptane) to give Cpd R (0.038g, 13%) as a white solid.1H NMR(400MHz，DMSO-d6)8.52(br.s.，1H)，7.67(d，J＝8.59Hz，1H)，7.48(d，J＝8.84Hz，1H)，3.94(s，3H)，3.81(dt，J＝3.54，12.25Hz，2H)；MS 248[M+H]+。
Compound V: 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one
Sodium (23g, 0.99mol) was added stepwise to dry MeOH (800 mL). After addition, the mixture was stirred for 1 hour until the sodium was mostly dissolved. To the reaction mixture was added 2-chloro-4, 6-dimethylpyridine-3-carbonitrile (110g, 0.66 mol). The resulting mixture was heated at 70 ℃ and stirred for 4 hours. The suspension was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 10:1) to give 2-methoxy-4, 6-dimethylpyridine-3-carbonitrile (Cpd S, 103g, 100%) as a white solid.
LiAlH is added at room temperature4(48.0g, 1.27mol) MTBE (600mL) was added stepwise. To the suspension was added 2-methoxy-4, 6-dimethylpyridine-3-carbonitrile (Cpd S, 103g, 0.636mol) in MTBE/THF (1:1, 600mL) stepwise. The reaction mixture was stirred at room temperature for 1 hour, then quenched with water (75 mL).The precipitate was collected by filtration and the solid was washed with THF (3X 100 mL). The filtrate was concentrated in vacuo to give 1- (2-methoxy-4, 6-dimethylpyridin-3-yl) methylamine (Cpd T), which was used directly in the next step.
To a solution of 1- (2-methoxy-4, 6-dimethylpyridin-3-yl) methylamine (Cpd T) in THF (500mL) was added Boc stepwise2O (138.1g, 0.636 mol). After addition, the reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 10:1) to give [ (2-methoxy-4, 6-dimethylpyridin-3-yl) methyl group]Tert-butyl carbamate (Cpd U, 140g, 83% over two steps) as a white solid.
Reacting [ (2-methoxy-4, 6-dimethylpyridin-3-yl) methyl]A solution of tert-butyl carbamate (Cpd U, 140g, 0.52mol) in 6N HCl (500mL) was heated at 100 ℃ and stirred for 6 hours. The reaction mixture was concentrated and the residue recrystallized from EtOH to give the title compound (Cpd V, 77g, 55%) as the hydrochloride salt.1H NMR(400MHz，D2O)6.31(s，1H)，4.11(s，2H)，2.31-2.30(s，6H)；MS 175.1[M+Na]。
Compound Z: 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine
To a solution of 2-hydroxy-4, 6-dimethylpyridine-3-carbonitrile (85.0g, 0.574mol) and benzyl chloride (87.0g, 0.688mol) in toluene (800mL) was added Ag2O (146g, 0.631 mol). The reaction mixture was stirred at 110 ℃ overnight. By passingFiltering the reaction mixture with CH2Cl2The solid was washed. The filtrate was concentrated in vacuo and purified by column chromatography (petroleum ether/EtOAc) to give 2- (benzyloxy) -4, 6-dimethylpyridine-3-carbonitrile (Cpd W, 89g, 65%) as a white solid.
44.5g × 2 batches: to a stirred solution of 2- (benzyloxy) -4, 6-dimethylpyridine-3-carbonitrile (Cpd W, 44.5g, 187mmol) in CH at 0-5 deg.C2Cl2DIBAL-H (224mL, 224mmol, 1M in toluene) was added dropwise to the solution in (500 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with 1N HCl (200mL) and stirred vigorously for 30 minutes. The reaction mixture was neutralized with 4N NaOH (20mL), the biphasic mixture was filtered and CH was added2Cl2(500mL) washed. By CH2Cl2(200mL) the aqueous layer was extracted with Na2SO4The combined organic layers were dried and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc) to give 2- (benzyloxy) -4, 6-dimethylpyridine-3-carbaldehyde (Cpd X, 70g, 78%) as a yellow solid.
35g × 2 batches: to a solution of 2- (benzyloxy) -4, 6-dimethylpyridine-3-carbaldehyde (Cpd X, 35.0g, 145mmol) in CH at 0 deg.C3NaBH was added in portions to a solution in OH (1000mL)4(6.60g, 174 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and NaHCO3The residue was diluted (saturated aqueous solution). After the bubbling ceased, the aqueous solution was extracted with EtOAc (2X 500 mL). With Na2SO4The combined organic layers were dried, concentrated in vacuo, and purified by column chromatography (petroleum ether/EtOAc) to give [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ]Methanol (Cpd Y, 43g, 61%) as a colorless oil.
21.5g × 2 batches: at-40 ℃ in N2To [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl group in an atmosphere]Methanol (Cpd Y, 21.5g, 88.5mmol) in anhydrous CH2Cl2(400mL) to the solution SOCl was added2(16.0g, 133 mmol). The mixture was stirred at-40 ℃ for 30 minutes. The reaction mixture was poured into ice-water (300mL) and quenched with NaHCO3Adjusting the pH value of the (solid) solution to 7-8. Separating the mixture with CH2Cl2The aqueous layer was extracted (300 mL). The combined organic layers were washed with brine (300mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 100:1) to afford the titled compoundCompound (Cpd Z, 27.5g, 60%) as a white solid.1H NMR (400MHz, chloroform-d) 7.51-7.49(d, 2H), 7.41-7.37(t, 2H), 7.34-7.30(t, 1H), 6.62(s, 1H), 5.45(s, 2H), 4.73(s, 2H), 2.42(s, 3H), 2.37(s, 3H). MS 261.9[ M + H ]]。
Compound EE: 2- (benzyloxy) -3- (chloromethyl) -4-ethyl-6-methylpyridine
A solution of 2-cyano-acetamide (841mg, 10.0mmol) in DMSO (20mL) and potassium tert-butoxide (1.18g, 10.5mmol) was stirred at 23 ℃ for 30 minutes. The mixture was cooled to 0 ℃ and then pent-3-yn-2-one (1.1mL, 10mmol) was added and the reaction mixture stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride (3mL) and then diluted with water (10mL) resulting in the precipitation of a solid. The suspension was filtered and the solid was dried in vacuo to give 4-ethyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (Cpd AA, 1.2g, 71%) as a white solid.
A mixture of 4-ethyl-6-methyl-2-oxo-1, 2-dihydropyridine-3-carbonitrile (Cpd AA, 1.1g, 6.8mmol), (chloromethyl) benzene (1.1mL, 9.4mmol, 1.4 equiv.) and silver (I) oxide (1.8g, 7.7mmol) in dry toluene (22.7mL) was heated at 110 ℃ for 17 h. The reaction mixture was cooled to 23 ℃ and then passedAnd (5) filtering. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (heptane/EtOAc) to give 2- (benzyloxy) -4-ethyl-6-methylpyridine-3-carbonitrile (Cpd BB, 1.42g, 83%) as a colorless oil.
To a solution of 2- (benzyloxy) -4-ethyl-6-methylpyridine-3-carbonitrile (Cpd BB, 0.687g, 2.72mmol) in dichloromethane (9mL) at-5 deg.C was added a 1M solution of diisobutylaluminum hydride in dichloromethane (3mL, 3 mmol). After 3 hours, the reaction mixture was quenched with 1M aqueous hydrochloric acid (3mL)And then stirred for 15 minutes. Then 2M Rochelle (Rochelle) brine solution (3mL) was added byThe resulting mixture was filtered. The filtrate was concentrated in vacuo, the residue was extracted with ethyl acetate (40mL), washed with brine (10mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (heptane/EtOAc) to give 2- (benzyloxy) -4-ethyl-6-methylpyridine-3-carbaldehyde (Cpd CC, 323mg, 46%) as a colorless oil.
To a solution of 2- (benzyloxy) -4-ethyl-6-methylpyridine-3-carbaldehyde (Cpd CC, 323mg, 1.28mmol) in methanol (4.27mL) at 0 deg.C was added sodium borohydride (54mg, 1.41 mmol). After 1 hour, the reaction mixture was concentrated in vacuo and then diluted with ethyl acetate (20mL) and water (10 mL). The organic layer was washed with brine (5mL), then dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (heptane/EtOAc) to give [2- (benzyloxy) -4-ethyl-6-methylpyridin-3-yl ] methanol (Cpd DD, 280mg, 85% yield) as a colourless oil.
To a solution of N-chlorosuccinimide (81.5mg, 0.598mmol) in dichloromethane (2.47mL) at 0 deg.C was added dimethyl sulfide (48ul, 0.653 mmol). The reaction mixture was then cooled to-20 ℃ and [2- (benzyloxy) -4-ethyl-6-methylpyridin-3-yl ] was added dropwise]Methanol (Cpd DD, 140mg, 0.554mmol) in dichloromethane (1 mL). After 2 hours, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (heptane/EtOAc) to give the title compound (Cpd EE, 35mg, 23% yield) as a colourless oil.1H NMR (chloroform-d) 7.52(d, J ═ 7.3Hz, 2H), 7.29 to 7.44(m, 3H), 6.65(s, 1H), 5.46(s, 2H), 4.74(s, 2H), 2.72(q, J ═ 7.6Hz, 2H), 2.44(s, 3H), 1.28(t, J ═ 7.6Hz, 3H).
Compound HH: 3-bromo-2-methyl-6- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy ] benzoic acid methyl ester
A solution of 3-bromo-2-methylbenzoic acid (2.98g, 13.9mmol) in DMF (20mL) was treated with cesium carbonate (4.56g, 13.9mmol) and iodomethane (0.900mL, 14.4 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solution was poured into ethyl acetate. Wash with water (3 ×) and brine. The ethyl acetate layer was concentrated in vacuo to give methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.70g, 85% yield) as a clear oil.
A solution of methyl 3-bromo-2-methylbenzoate (Cpd FF, 2.40g, 10.5mmol) in trifluoroacetic acid (50mL) and trifluoroacetic anhydride (20mL) in a sealed tube was treated with potassium persulfate (3.12g, 11.5mmol) and dichloro (p-cymene) ruthenium (II) dimer (0.170g, 0.278 mmol). The reaction mixture was heated at 85 ℃ overnight. Volatiles were removed in vacuo and the resulting residue was dissolved in dichloromethane and water. By K3PO4(saturated aqueous solution) the aqueous phase was brought to pH 5. The layers were separated and the organic layer was purified by column chromatography (0-30% ethyl acetate/heptane) to give methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94g, 75%) as a clear oil.
A solution of methyl 3-bromo-6-hydroxy-2-methylbenzoate (Cpd GG, 1.94g, 7.90mmol) in DMF (25mL) was treated with cesium carbonate (3.45g, 10.0mmol) followed by 2- (2-bromoethoxy) tetrahydro-2H-pyran (2.06g, 9.84 mmol). The reaction mixture was heated at 55 ℃ for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water (2 ×) and brine. The organic layer was concentrated in vacuo to give a brown oil which was purified by column chromatography (0-25%, ethyl acetate/heptane) to give the title compound (Cpd HH, 2.11g, 67% yield) as a clear oil.1H NMR (400MHz, chloroform-d) 7.50(d, J ═ 8.80Hz, 1H), 6.72(d, J ═ 8.80Hz, 1H), 4.68(t, J ═ 3.36Hz, 1H), 4.13-4.18(m, 2H), 4.00(td, J ═ 4.77, 11.37Hz, 1H), 3.91(s, 3H), 3.86(ddd, J ═ 3.06, 8.59, 11.34Hz, 1H), 3.74-3.80(m, 1H), 3.49-3.56(m, 1H), 2.32(s, 3H), 1.78-1.89 (m, 1H)m，1H)，1.67-1.77(m，1H)，1.58-1.66(m，2H)，1.49-1.55(m，2H)。
Compound LL: ((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) (2-hydroxyethyl) carbamic acid tert-butyl ester
A mixture of 2-hydroxy-4, 6-dimethylnicotinonitrile (5.3g, 36mmol), benzyl chloride (5.7mL, 45mmol), silver (I) oxide (9.2g, 40mmol) and toluene (50mL) was heated in a sealed tube at 110 ℃ for 20 h. The mixture was cooled to room temperature and the solid was filtered and washed with dichloromethane. The filtrate was concentrated in vacuo and purified by column chromatography (40% EtOAc/heptane) to give 2- (benzyloxy) -4, 6-dimethylnicotinonitrile (Cpd II, 8.1g, 94% yield) as a white solid.
To a cooled (0 ℃ C.) solution of 2- (benzyloxy) -4, 6-dimethylnicotinonitrile (Cpd II, 8.1g, 34mmol) in dichloromethane (100mL) was added dropwise a solution of diisobutylaluminum hydride (1M in dichloromethane, 41mL, 41 mmol). The resulting mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was cooled to 0 ℃ and then carefully quenched by dropwise addition of 1N hydrochloric acid (75 mL). The solution was neutralized with 4N sodium hydroxide and then extracted with dichloromethane (2X 75 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to give 2- (benzyloxy) -4, 6-dimethylnicotinaldehyde (Cpd JJ, 6.4g, 78% yield) as an orange oil.
To a solution of 2- (benzyloxy) -4, 6-dimethylnicotinaldehyde (Cpd JJ, 6.4g, 27mmol) in methanol (100mL) was added 2-aminoethanol (8.34mL, 133 mmol). The reaction mixture was stirred at room temperature for 1 hour and then cooled to 0 ℃. Sodium cyanoborohydride (4.9g, 66mmol) was added in one portion and the reaction was slowly warmed to room temperature and stirred overnight. The methanol was removed in vacuo and the residue diluted with water (50mL) and extracted with dichloromethane (2X 50 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (EtOAc) to give 2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) amino) ethanol (Cpd KK, 4.2g, 55% yield) as a light yellow solid.
To a solution of 2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) amino) ethanol (Cpd KK, 3.0g, 10mmol) in dichloromethane (100mL) was added triethylamine (4.4mL, 32mmol) and di-tert-butyl dicarbonate (2.8g, 13 mmol). The reaction mixture was stirred at room temperature for 18 h, then diluted with water (50mL) and extracted with dichloromethane (2X 75 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound (Cpd LL, 4g, 98% yield) as a clear oil.1H NMR(400MHz，DMSO-d6)7.45(2H，d，J＝7.07Hz)，7.32-7.39(2H，m)，7.25-7.32(1H，m)，6.71(1H，s)，5.34(2H，s)，4.53(1H，br.s.)，4.47(2H，s)，3.23-3.30(2H，m)，2.92-3.06(2H，m)，2.33(3H，s)，2.23(3H，s)，1.36(9H，br.s.)；MS 387[M+H]。
Compound PP: 6-bromo-2-methyl-3- (prop-2-yloxy) benzoic acid methyl ester
To a solution of 3-hydroxy-2-methylbenzoic acid (6.00g, 40.0mmol) in DMF (40mL) was added K2CO3(11.4g, 82.8mmol) and 2-iodopropane (8.28g, 82.8 mmol). The reaction mixture was stirred at room temperature overnight and then heated at 70 ℃ for 3 hours. The reaction mixture was diluted with EtOAc and then passed throughAnd (5) filtering. The filtrate was washed with water and brine, and Na was added2SO4Dried, decanted, and concentrated in vacuo. The residue was purified by column chromatography (0-30%, EtOAc/heptane) to give propan-2-yl 2-methyl-3- (propan-2-yloxy) benzoate (Cpd MM, 4.0g, 40%) as a colorless oil.
To 2-methyl-3- (prop-2-yloxy) benzoic acid prop-2-yl To a solution of the ester (Cpd MM, 3.97g, 16.8mmol) in THF (40mL) was added 2N NaOH (25.2mL, 50.4 mmol). The reaction mixture became light yellow and was heated at 65 ℃ for 3 days. The reaction mixture was cooled to room temperature and then concentrated in vacuo. The residue was acidified with 10% HCl (aq) and then extracted with EtOAc. The organic layer was washed with brine, Na2SO4Drying, followed by concentration in vacuo, gave 2-methyl-3- (propan-2-yloxy) benzoic acid (Cpd NN, 4.0g, 100%) as an oil.
To a solution of 2-methyl-3- (propan-2-yloxy) benzoic acid (Cpd NN, 1.08g, 5.56mmol) in AcOH (5mL) was added Br2(888mg, 5.56 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give an oil. The crude oil was dissolved in MeOH (20mL) and H was added2SO4The resulting mixture was heated at 65 ℃ for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with water and brine, and Na was added2SO4Drying and concentration in vacuo gave 6-bromo-2-methyl-3- (propan-2-yloxy) benzoic acid (Cpd OO, 1.3g, 86%) as an oil which solidified to a tan solid on standing.
To a solution of 6-bromo-2-methyl-3- (propan-2-yloxy) benzoic acid (Cpd OO, 1.30g, 4.80mmol) in DCM (5mL) at 0 ℃ was added oxalyl chloride (810mg, 6.19mmol) followed by DMF (10 mL). The reaction mixture was stirred at 0 ℃ for 1.5 hours and then concentrated in vacuo. The residue was dissolved in MeOH (15mL) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organic layer was washed with brine, Na 2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (0-50%, EtOAc/heptane) to give the title compound (Cpd PP, 894mg, 65%) as an amber oil.1H NMR (400MHz, chloroform-d) 1.33(d, J ═ 6.11Hz, 6H)2.16(s, 3H)3.95(s, 3H)4.50(dt, J ═ 12.04, 6.08Hz, 1H)6.75(d, J ═ 8.80Hz, 1H)7.31(d, J ═ 8.80Hz, 1H); MS 287[ M + H]。
Compound QQ: 3-bromo-6-fluoro-2-methylbenzoic acid
To 0 deg.C 2-fluoro-6-methyl-benzoic acid (1.48g, 9.60mmol) in concentrated H2SO4NBS (1.79g, 10.1mmol) was added to the solution in (40 mL). The mixture was stirred at 0 ℃ for 3 hours. The reaction mixture was poured into ice water (200mL) and extracted with ether (2X 200 mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the title compound (compound QQ, 2.15g, 96% yield) as a solid.1H NMR (400MHz, chloroform-d) 7.64(dd, J ═ 8.84, 5.31Hz, 1H), 6.92(t, J ═ 8.84Hz, 1H), 2.54(s, 3H); MS 231.0[ M + H ]]。
Examples
General methods and representative examples
Method A
Example 1: 8-chloro-7- (difluoromethoxy) -2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -3, 4-dihydroisoquinolin-1 (2H) -one
Stirring of 6-methoxy-2, 3-dihydro-1H-inden-1-one (15.0g, 93.0mmol) and Et at RT 3N (28.2g, 279mmol) in MeOH (200mL) in NH2OH.HCl (12.8g, 186 mmol). After the addition, the resulting solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated in vacuo. To the residue was added EtOAc (300 mL). The solution was washed with water (2X 150mL), brine (150mL), and Na2SO4Dried and concentrated in vacuo to give (1E) -N-hydroxy-6-methoxy-2, 3-dihydro-1H-indene-1-imine (1a, 17g,>100%) in whiteAnd (3) a solid.
To (1E) -N-hydroxy-6-methoxy-2, 3-dihydro-1H-indene-1-imine (1a, 28.0g, 158mmol), DMAP (1.93g, 15.8mmol) and Et at 0 deg.C3A solution of N (63.8g, 632mmol) in dry DCM (200mL) was added MsCl (27.5g, 239mmol) dropwise. After the addition, the resulting solution was stirred at room temperature for 14 hours. With water (150mL), saturated NH4The reaction mixture was washed with Cl (130mL) and brine (130 mL). With Na2SO4The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 1:1) to give (1E) -6-methoxy-N- [ (methylsulfonyl) oxy]-2, 3-dihydro-1H-indene-1-imine (1b, 27g, 67%) as a yellow solid.
To a stirred mixture of (1E) -6-methoxy-N- [ (methylsulfonyl) oxy group at 0 deg.C]-2, 3-dihydro-1H-indene-1-imine (1b, 27g, 106mmol), BF 3MeOH (14% in MeOH, 16.8g, 170mmol) and TiCl4(32.3g, 170mmol) to a suspension in dry DCM (200mL) was added MsCl (20.9g, 183mmol) dropwise. After the addition, the resulting solution was stirred at room temperature for 14 hours. To the reaction mixture was added DCM (200mL) and saturated NaHCO3The solution was washed to pH 7. The organic layer was washed with brine (150mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (DCM/MeOH) to give 7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (1c, 22g, 100%) as a gray solid.
To 7-methoxy-3, 4-dihydroisoquinoline-1 (2H) -one (1c, 13.0g, 73.9mmol) in concentrated H at 0 deg.C2SO4To the mixture in (120mL) was added NCS (10.4g, 77.6mmol) stepwise. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured onto ice water (200 mL). With Na2CO3(s) basifying the solution to pH 8. The reaction mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with brine (300mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 1:1) to give 8-chloro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (1d, 7.8g, 50%) as a yellow solid.
To 0 ℃ in dry CH 8-chloro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (1d, 7.8g, 3.7mmol)2Cl2BBr was added dropwise to the solution in (120mL)3(11mL, 111 mmol). After addition, the mixture was stirred at room temperature overnight. To the reaction mixture was added dropwise H2O (200 mL). The mixture was extracted with EtOAc (8X 200mL) and Na2SO4Drying and vacuum concentrating. To the residue were added EtOAc (20mL) and petroleum ether (40 mL). The mixture was filtered and the solid was dried in vacuo to give 8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1e, 6.6g, 91%) as a brown solid.
A mixture of 8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1e, 5.6g, 28mmol) and diethylcarbamoyl chloride (4.3g, 31mmol) in pyridine (100mL) was stirred at 100 ℃ for 5 hours. Adding H to the reaction mixture2O (300 mL). The mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with 1N HCl (2X 300mL) and brine (300mL), and Na2SO4Drying and vacuum concentrating. The residue (EtOAc) was purified by column chromatography to give 8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl diethyl carbamate (1f, 7.6g, 90%) as a brown oil.
At 0 ℃ in N2To a suspension of NaH (2.2g, 54mmol, 60% in oil) in dry DMF (20mL) under a gas atmosphere was added dropwise a solution of 8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl diethyl carbamate (1f, 8.0g, 27mmol) in dry DMF (40 mL). The mixture was stirred at 0 ℃ for 15 minutes. 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 8.5g, 32.4mmol) was added. The mixture was stirred at room temperature overnight. Carefully add H dropwise to the reaction mixture 2O (200 mL). The mixture was extracted with EtOAc (2X 150 mL). The combined organic layers were washed with brine (4X 200 mL). With Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give diethyl carbamic acid 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl ester (1g,14g, 99%) as a yellow oil.
Diethylcarbamic acid 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A mixture of methyl } -8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl ester (1g, 14.0g, 26.8mmol) and NaOH (10.7g, 268mmol) in EtOH (200mL) was refluxed overnight. The reaction mixture was concentrated in vacuo. Adding H to the reaction mixture2O (200mL), the solution was acidified to pH 3 with 1N HCl. The reaction mixture was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with brine (300mL) and Na2SO4Drying and vacuum concentrating. To the residue were added EtOAc (20mL) and petroleum ether (100 mL). The mixture was filtered and the solid was dried in vacuo to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1H, 9.8g, 87%) as an off-white solid.
At-78 ℃ in N2To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl in a gas atmosphere]Methyl } -8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1H, 0.1g, 0.237mmol) and KOH (0.265g, 4.74mmol) in CH3CN/H2To a solution in O (10mL/1mL) was added [ bromo (difluoro) methyl group]Phosphonic acid diethyl ester (0.126g, 0.474 mmol). The resulting mixture was warmed to room temperature and stirred for 30 minutes. With EtOAc (20mL) and H2The mixture was diluted with O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with brine (10mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by preparative TLC (petroleum ether/EtOAc, 4:1) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-7- (difluoromethoxy) -3, 4-dihydroisoquinolin-1 (2H) -one (1i, 0.08g, 72%) as a yellow oil.
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl at room temperature]Methyl } -8-chloro-7- (difluoromethoxy) -3, 4-dihydroisoquinolin-1 (2H) -one (1i, 0.08g, 0.169mmol) in CH2Cl2To the solution in (10mL) was added TFA (10 mL). The resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give a residue, which was dissolved in CH2Cl2(20mL) followed by saturated NaHCO 3(5mL), brine (5mL), washed with Na2SO4Drying and vacuum concentrating. The residue was purified by preparative tlc (etoac) to give the title compound (example 1, 43.1mg, 67%) as a white solid.1H NMR (400MHz, methanol-d 4)7.36-7.34(m, 1H), 7.24-7.22(m, 1H), 7.00-6.63(m, 1H), 6.11(s, 1H), 4.76(s, 2H), 3.51-3.48(m, 2H), 2.90-2.87(m, 2H), 2.29(s, 3H), 2.25(s, 3H); MS 382.9[ M +1 ]]。
Method B
Example 53: 2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7-methoxy-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-6-carbonitrile
To 7-methoxy-3, 4-dihydroisoquinoline-1 (2H) -one (53a, 1.7g, 9.6mmol) in concentrated H at 0 deg.C2SO4To the mixture in (40mL) was added NIS (2.4g, 11mmol) stepwise. The mixture was stirred at room temperature for 14 hours. The mixture was cooled to 0 ℃ and basified to pH 8 with aqueous NaOH. The mixture was extracted with EtOAc (5X 60 mL). The combined organic layers were washed with brine (3X 60mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 1:1) to give 8-iodo-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (53b, 2.1g, 79%) as a yellow solid.
At 0 ℃ in N 2To a solution of 8-iodo-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (53b, 2.08mg, 5.22mmol) in anhydrous DMF (30mL) in a gas atmosphere was added NaH (420mg, 10.4mmol, 60% in oil) for 30 min. 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 1.89g, 7.83mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 14 hours. By H2The mixture was quenched with O (60mL) and EtOAc (4X 80mL) was extracted. The combined organic layers were washed with brine (2X 50mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by preparative HPLC to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-iodo-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (53c, 2.5g, 91%) as a yellow solid.
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl at room temperature]To a solution of methyl } -8-iodo-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (53c, 300mg, 0.568mmol) in NMP (8mL, dry) was added CuCN (152mg, 1.705 mmol). The resulting mixture was stirred at 190 ℃ for 3 hours. The mixture was cooled to room temperature and H was added2O (20mL) was added to the mixture. The mixture was diluted with EtOAc (5X 20 mL). The combined organic layers were washed with brine (3X 20mL) and Na 2SO4Drying and concentration in vacuo afforded a residue which was purified by column chromatography (petroleum ether/EtOAc, 3:1) to afford 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -7-methoxy-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-8-carbonitrile (53d, 0.568mmol, 100%) as a yellow solid.
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl at room temperature]Methyl } -7-methoxy-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-8-carbonitrile (53d, 0.568mmol) in CH2Cl2To the solution in (25mL) was added TFA (12 mL). The resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. MeOH (100mL) was added to the residue and stirred for 0.5 h. The mixture was filtered and the solid dried in vacuo to give the title compound (example 53, 15.9mg, 6.7%) as a yellow solid.1H NMR(400MHz，DMSO-d6)：d 11.58(s，1H)，7.70(s，1H)，7.61(s，1H)，5.89(s，1H)，4.58(s，2H)，3.96(s，3H)，3.51-3.48(t，2H)，2.83-2.80(t，2H)，2.16(s，3H)，2.12(s，3H)；MS 338.1[M+1]。
Method C
Example 58: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7- [ (1,1, 1-trifluoropropan-2-yl) oxy ] -3, 4-dihydroisoquinolin-1 (2H) -one
In a sealed tube, 8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1e, 120mg, 0.610mmol), methanesulfonic acid 1,1, 1-trifluoropropan-2-yl ester (526mg, 2.74mmol) and K2CO3A mixture of (420mg, 3.05mmol) in dry DMF (8mL) was stirred at 140 ℃ for 48 h. Adding H to the reaction mixture 2O (40 mL). The mixture was extracted with EtOAc (2X 20 mL). The combined organic layers were washed with brine (4X 30mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by preparative TLC (EtOAc, Rf. about.0.65) to give 8-chloro-7- [ (1,1, 1-trifluoropropan-2-yl) oxy]-3, 4-dihydroisoquinolin-1 (2H) -one (58a, 27mg, 15%) as a yellow oil.
At 0 ℃ in N2To 8-chloro-7- [ (1,1, 1-trifluoropropan-2-yl) oxy) in a gas atmosphere]To a solution of-3, 4-dihydroisoquinolin-1 (2H) -one (58a, 50mg, 0.17mmol) in dry DMF (6mL) was added NaH (60% in oil, 21mg, 0.51mmol) stepwise. The resulting mixture was stirred at 0 ℃ for 10 min, then 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 76mg, 0.29mmol) was added. The resulting mixture was stirred at room temperature overnight. Adding H to the reaction mixture2O (20 mL). The mixture was extracted with EtOAc (2X 10 mL). The combined organic layers were washed with brine (4X 15mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 6:1) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-7- [ (1,1, 1-trifluoropropan-2-yl) oxy)]-3, 4-dihydroisoquinolin-1 (2H) -one (58b, 70mg, 80%) as a colorless oil.
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl at room temperature]Methyl } -8-chloro-7- [ (1,1, 1-trifluoropropan-2-yl) oxy)]-3, 4-dihydroisoquinolin-1 (2H) -one (58b, 70mg, 0.14mmol) in CH2Cl2(5mL) inTo the solution was added TFA (1 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue (EtOAc) was purified by column chromatography to give the title compound (example 58, 20mg, 34%) as a white solid.1H NMR (400MHz, chloroform): 11.16(s, 1H), 7.08-7.05(d, 1H), 7.00-6.98(d, 1H), 5.94(s, 1H), 4.75(s, 2H), 4.57-4.54(t, 1H), 3.55(s, 2H), 2.77(s, 2H), 2.33-2.25(d, 6H), 1.55(s, 3H); MS 428.9[ M + H ]]。
Example 296: 1, 4-anhydro-3-deoxy-2-O- {5, 8-dichloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl } -L-threo-pentitol
Part 1 oxalyl chloride (34mL, 0.395mol) was added to a solution of 3-methoxy-2-nitrobenzoic acid (60g, 0.305mol) in dry dichloromethane (600mL) followed by N, N-dimethylformamide (0.6mL, 7.8mmol) and moderate evolution of gas started. The compound was stirred at room temperature for 2 hours and then concentrated in vacuo to remove volatiles. The crude acid chloride was dissolved in dry dichloromethane (150mL) and added dropwise to a cooled (5 ℃ C.) solution of aminoacetaldehyde diethyl acetal (48mL, 0.33mol) and triethylamine (52mL, 0.374mol) in dry dichloromethane (250 mL). The mixture was stirred at room temperature for 2 hours, then washed with saturated aqueous sodium bicarbonate (2X 100mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated to give N- (2, 2-diethoxyethyl) -3-methoxy-2-nitrobenzamide (296a, 92g, 97% yield) as a yellow solid. MS: 335[ M +1 ].
Reacting N- (2, 2-diethoxyethyl) -3-methoxy-A mixture of 2-nitrobenzamide (296a, 92g, 0.295mol) in concentrated sulfuric acid (1L) was stirred at 70 ℃ for 3 hours. After cooling to room temperature, the mixture was slowly poured into ice water (3L), resulting in the formation of a solid precipitate. The precipitate was collected by filtration. The filter cake was washed with water (1L) and dried to give 7-methoxy-8-nitroisoquinolin-1 (2H) -one (296b, 60g, 92% yield) as a brown solid.1H NMR(400MHz，DMSO-d6)7.92-7.89(d，J＝9.2Hz，1H)，7.81-7.79(d，J＝9.2Hz，1H)，7.18-7.15(t，J＝6.6Hz，1H)，6.66-6.64(d，J＝7.2Hz，1H)，3.95(s，3H)。
A suspension of 7-methoxy-8-nitroisoquinolin-1 (2H) -one (296b, 30g, 0.136mol) and 10% palladium on carbon (15g, 0.014mol) in ethanol (1L) was stirred at 40 ℃ under a hydrogen atmosphere (20psi) for 72H. The mixture was filtered through celite, the flask and filter pad were washed with ethanol (1L), and the combined filtrates were concentrated in vacuo to give 8-amino-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (296C, 24g, 92% yield) as a brown oil. MS:193[ M +1 ].
N-chlorosuccinimide (20g, 0.147mol) was added to a solution of 8-amino-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (296c, 24g, 0.125mol) in N, N-dimethylformamide (250mL), and stirred at room temperature overnight. The solution was partitioned between water (100mL) and ethyl acetate (5X 100 mL). The combined organic extracts were washed with brine (5 × 100mL), dried over sodium sulfate, and concentrated to dryness. The residue was triturated with acetonitrile (200mL) and the solid collected by filtration. After drying, 8-amino-5-chloro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (296d, 12.5g, 44% yield) was obtained as a blue solid. 1H NMR(400MHz，DMSO-d6)：7.84(s，1H)，6.93(s，1H)，3.80(s，3H)，3.29-3.25(m，2H)，2.81-2.78(t，J＝6.6Hz，2H)。
Isovaleronitrile (20mL, 0.149mol) was added dropwise to a heated (55 ℃ C.) suspension of copper (II) chloride (40g, 0.298mol) and lithium chloride (38g, 0.905mol) in acetonitrile (500 mL). The mixture at the temperature of stirring for 5 minutes, then one add 8-amino-5-chloro-7-methoxy-3, 4-two hydrogen isoquinoline-1 (2H) -ketone (296d, 20g, 0.089 mol). After the addition was complete, stirring was continued at 55 ℃ for 45 minutes. The reaction mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (300mL), and extracted with ethyl acetate (4X 200 mL). The combined organic layers were washed with aqueous ammonium chloride (200mL) and brine (100mL), dried over sodium sulfate, and concentrated in vacuo to give crude 5, 8-dichloro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (296e, 20g, 90% purity, 92% yield) as a brown solid. MS: 245[ M +1 ].
Di-tert-butyl dicarbonate (76g, 0.352mol) was added in one portion to a cooled (0 ℃ C.) solution of crude 5, 8-dichloro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one (296e, 20g, 0.082mol) and 4-dimethylaminopyridine (30g, 0.246mol) in N, N-dimethylformamide (200 mL). After the addition was complete, the solution was stirred at room temperature overnight and then partitioned between water (200mL) and ethyl acetate (5X 200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate 100:1-10: 1) to give tert-butyl 5, 8-dichloro-7-methoxy-1-oxo-3, 4-dihydroisoquinoline-2 (1H) -carboxylate (296f, 11g, 39% yield) as a light yellow solid. 1H NMR(400MHz，DMSO-d6)：7.50(s，1H)，4.00(s，3H)，3.86-3.83(t，J＝6.8Hz，2H)，2.99-2.96(t，J＝5.8Hz，2H)，1.54(s，9H)。
Boron tribromide (10mL) was added to a cooled (0 ℃ C.) solution of 5, 8-dichloro-7-methoxy-1-oxo-3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester (296f, 14.5g, 45.4mmol) in dry dichloromethane (100 mL). The mixture was stirred at room temperature overnight, then water (10mL) was added, resulting in the formation of a precipitate. The precipitate was collected by filtration, washed with water (500mL), and dried to give 5, 8-dichloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (296g, 9.2g, 95% yield) as a pale yellow solid.1H NMR(400MHz，DMSO-d6)：10.58(s，1H)，8.17(s，1H)，7.13(s，1H)，3.25-3.23(m，2H)，2.83-2.80(t，J＝6.2Hz，2H)。MS：232[M+1]。
Part 2 ice-cooled (2R) -oxetan-2-ylmethanol (2.00g, 27.0mmol) and imidazole (3.68g, 54.0mmol) in dry dichloromethaneTo the mixture in an alkane (60mL) was added tert-butyl (chloro) diphenylsilane (8.40mL, 32.4mmol) dropwise, resulting in the formation of a white precipitate. The mixture was stirred at 0 ℃ for 15 minutes, then the cooling bath was removed and stirring continued at room temperature for 1 hour. Aqueous ammonium chloride (2M, 100mL) was added and the layers separated. The aqueous layer was extracted with dichloromethane (100 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by silica gel chromatography (gradient elution with 0-30% ethyl acetate in heptane) to give tert-butyl [ (2S) -oxetan-2-ylmethoxy-l ]Diphenylsilane (296h, 8.40g, 99% yield) as an oil.1H NMR(400MHz，CDCl3)7.65-7.76(m，4H)，7.36-7.49(m，6H)，3.88(dd，J＝11.86，3.30Hz，1H)，3.74(dd，J＝11.80，4.71Hz，1H)，3.10-3.20(m，1H)，2.76(dd，J＝5.14，4.16Hz，1H)，2.63(dd，J＝5.14，2.69Hz，1H)，1.09(s，9H)。MS：330[M+1]。
Copper (I) cyanide (3.60g, 40.2mmol) was placed in a 3-neck flask under nitrogen and dried under vacuum with moderate heating using a heat gun. It was then cooled to room temperature under a nitrogen atmosphere. This procedure was repeated 3 times, then anhydrous tetrahydrofuran (80mL) was added. The resulting mixture was cooled to-78 deg.C, then vinylmagnesium bromide (1M in tetrahydrofuran, 88.5mL, 88.5mmol) was added dropwise while maintaining the internal temperature below-68 deg.C. The heterogeneous mixture was warmed to-20 ℃ and stirred at this temperature for 30 minutes. After cooling, the solution was returned to-78 ℃ and tert-butyl [ (2S) -oxetan-2-ylmethoxy-propane was added dropwise]Diphenylsilane (296h, 8.38g, 26.8 mmol). The mixture was stirred and allowed to warm gradually to room temperature overnight. 100mL of ammonium hydroxide/ammonium chloride (1/102M NH) was used4Cl) the reaction mixture was quenched and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (200mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (gradient elution with 0-20% ethyl acetate in heptane) to give (2S) -1- { [ tert-butyl (diphenyl) silyl]Oxy } pent-4-en-2-ol (296i, 5.68g, 62% yield) as a clear oil. 1H NMR(400MHz，CDCl3)7.65-7.71(m，4H)，7.36-7.49(m，6H)，5.75-5.87(m，1H)，5.03-5.14(m，2H)，3.76-3.85(m，1H)，3.66-3.72(m，1H)，3.54-3.61(m，1H)，2.45(d，J＝4.03Hz，1H)，2.23-2.30(m，2H)，1.09(s，9H)。MS：358[M+18]。
Reacting (2S) -1- { [ tert-butyl (diphenyl) silyl]A solution of oxy } pent-4-en-2-ol (296i, 5.60g, 16.4mmol) in dry tetrahydrofuran (30mL) was cooled to 0 deg.C and treated with tetrabutylammonium fluoride solution (1M in tetrahydrofuran, 18.3mL, 18.3 mmol). The mixture was stirred, warmed to room temperature over 1 hour, then concentrated and purified by silica gel chromatography (gradient elution with 0-100% ethyl acetate in heptane) to give (2S) -pent-4-ene-1, 2-diol (296j, 1.25g, 73% yield) as an oil.1H NMR(400MHz，CDCl3)5.83(ddt，J＝17.16，10.10，7.15，7.15Hz，1H)，5.08-5.21(m，2H)，3.73-3.83(m，1H)，3.67(d，J＝11.13Hz，1H)，3.48(dd，J＝10.94，7.40Hz，1H)，2.51(br.s.，1H)，2.42(br.s.，1H)，2.17-2.32(m，2H)。
A mixture of (2S) -pent-4-ene-1, 2-diol (296j, 1.20g, 11.7mmol) and sodium bicarbonate (2.96g, 35.2mmol) in dry acetonitrile (40mL) was stirred at room temperature for 10 minutes and then cooled to 0 ℃ with an ice bath. Iodine (8.95g, 35.2mmol) was added, washed with 1M aqueous sodium thiosulfate (100mL) and brine (100mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (gradient elution with 0-100% ethyl acetate in heptane) to give a mixture of (3S,5S) -5- (iodomethyl) tetrahydrofuran-3-ol and (3S,5R) -5- (iodomethyl) tetrahydrofuran-3-ol (296k, 2.19g, 82% yield).
A mixture of (3S,5S) -5- (iodomethyl) tetrahydrofuran-3-ol and (3S,5R) -5- (iodomethyl) tetrahydrofuran-3-ol (296k, 2.16g, 9.47mmol) was dissolved in anhydrous dimethylsulfoxide (40 mL). Potassium 4-nitrobenzoate (2.98g, 14.2mmol) and 18-crown-6 (3.76g, 14.2mmol) were added and the mixture was stirred at 90 ℃ overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (100mL) and water (100 mL). The organic phase was washed with water (100mL) and brine (100mL), dried over sodium sulfate, concentrated to dryness, purified by silica gel chromatography (gradient elution with 0-100% ethyl acetate in heptane), The product was obtained as a mixture of diastereomers: 4-Nitrobenzoic acid ((2S,4S) -4-hydroxytetrahydrofuran-2-yl) methyl ester and 4-nitrobenzoic acid ((2R,4S) -4-hydroxytetrahydrofuran-2-yl) methyl ester (296l, 1.13g, 45% yield) as solids.1H NMR(400MHz，CDCl3)8.21-8.33(m，4H)，4.46-4.64(m，3H)，4.36(dd，J＝11.68，6.66Hz，1H)，4.05(dd，J＝9.90，4.03Hz，0.76H)，3.93-3.99(m，0.24H)，3.80-3.88(m，1H)，2.34-2.45(m，0.25H)，2.08-2.17(m，0.77H)，1.81-1.96(m，1H)，1.57(br.s.，1H)。
4-Nitrobenzoic acid ((2S,4S) -4-hydroxytetrahydrofuran-2-yl) methyl ester and 4-nitrobenzoic acid ((2R,4S) -4-hydroxytetrahydrofuran-2-yl) methyl ester (296l, 700mg, 2.62mmol) were combined with triethylamine (1.10mL, 7.89mmol) in dry dichloromethane (12 mL). Methanesulfonyl chloride (400 μ L, 5.17mmol) was added, resulting in a moderate exotherm. After stirring at room temperature for 3 hours, the reaction mixture was partitioned between water (50mL) and dichloromethane (2X 50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (gradient elution with 20-100% ethyl acetate in heptane). The lower polarity peak was the desired single diastereomer, 4-nitrobenzoic acid ((2R,4S) -4- ((methylsulfonyl) oxy) tetrahydrofuran-2-yl) methyl ester (296m, 672mg, 74% yield).1H NMR(400MHz，CDCl3)8.26-8.33(m，2H)，8.17-8.25(m，2H)，5.34-5.43(m，1H)，4.50-4.60(m，2H)，4.34-4.43(m，1H)，4.13-4.20(m，1H)，4.05-4.12(m，1H)，3.07(s，3H)，2.47(dd，J＝14.24，5.81Hz，1H)，2.00-2.13(m，1H)。
A solution of ((2R,4S) -4- ((methylsulfonyl) oxy) tetrahydrofuran-2-yl) methyl 4-nitrobenzoate (296m, 300mg, 0.869mmol), 5, 8-dichloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (296g, 222mg, 0.956mmol), and cesium carbonate (566mg, 1.74mmol) in N, N-dimethylformamide (8mL) was heated to 100 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50mL), washed with water (2X 50mL) and brine (50mL), dried over sodium sulfate, concentrated to dryness, and purified by silica gel chromatography (gradient with 0-100% ethyl acetate in heptane) Elution) to give 2, 5-anhydro-3-deoxy-4-O- (5, 8-dichloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1-O- (4-nitrobenzoyl) -L-threo-pentitol (296n, 128mg, 31% yield) as a solid.1H NMR(400MHz，CDCl3)8.18-8.33(m，4H)，7.03(s，1H)，6.09(br.s.，1H)，4.99(td，J＝4.28，1.96Hz，1H)，4.56-4.62(m，2H)，4.42-4.52(m，1H)，4.27(d，J＝10.64Hz，1H)，4.02(dd，J＝10.58，4.34Hz，1H)，3.48(td，J＝6.36，3.91Hz，2H)，2.99-3.09(m，2H)，2.56(ddd，J＝14.24，8.19，6.42Hz，1H)，2.18(dd，J＝14.12，5.07Hz，1H)。MS：481[M+1]
A solution of potassium tert-butoxide in tetrahydrofuran (1.0M, 645. mu.L, 0.645mmol) was added dropwise to a cooled (0 ℃ C.) solution of 2, 5-anhydro-3-deoxy-4-O- (5, 8-dichloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -1-O- (4-nitrobenzoyl) -L-threo-pentitol (296N, 120mg, 0.249mmol) in anhydrous N, N-dimethylformamide (4 mL). After stirring for 30 min, a solution of 2- (benzyloxy) -3- (chloromethyl) -4, 6-lutidine (compound Z, 71mg, 0.273mmol) in dry N, N-dimethylformamide (1mL) was added and stirring continued at 0 ℃ for a further 30 min. The reaction mixture was diluted with ethyl acetate (50mL), washed with water (2X 50mL) and brine (50mL), dried over sodium sulfate, concentrated to dryness and purified by silica gel chromatography (gradient elution with 0-100% ethyl acetate in heptane) to give 1, 4-anhydro-2-O- (2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl)]Methyl } -5, 8-dichloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -3-deoxy-L-threo-pentitol (296o, 36mg, 26% yield) as a solid. 1H NMR(400MHz，CDCl3)7.45(d，J＝7.21Hz，2H)，7.29-7.40(m，3H)，6.94(s，1H)，6.62(s，1H)，5.43(s，2H)，4.92(br.s.，1H)，4.87(s，2H)，4.15-4.26(m，2H)，3.91(dd，J＝10.39，3.91Hz，1H)，3.75-3.84(m，1H)，3.66-3.75(m，1H)，3.25(t，J＝6.05Hz，2H)，2.69(t，J＝6.05Hz，2H)，2.42(s，3H)，2.34-2.40(m，1H)，2.32(s，3H)，2.03-2.16(m，2H)。MS：557[M+1]。
1, 4-anhydro-2-O- (2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -5, 8-dichloro-1-oxyA solution of the o-1, 2,3, 4-tetrahydroisoquinolin-7-yl) -3-deoxy-L-threo-pentitol (296o, 36mg, 0.065mmol) in trifluoroacetic acid (2mL) was stirred at room temperature for 3 hours. Volatiles were removed in vacuo and the residue was partitioned between ethyl acetate (20mL) and saturated aqueous sodium bicarbonate (20 mL). The aqueous layer was back-extracted with ethyl acetate (2X 20 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by silica gel chromatography (gradient elution with 0-10% methanol in ethyl acetate) to give 1, 4-anhydro-3-deoxy-2-O- {5, 8-dichloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl } -L-threo-pentitol (example 296, 12mg, 40% yield). After lyophilization, the solid was obtained.1H NMR (400MHz, methanol-d 4)7.14(s, 1H), 6.00(s, 1H), 4.93-5.02(m, 1H), 4.64(s, 2H), 3.95-4.06(m, 2H), 3.85(dd, J ═ 10.39, 4.28Hz, 1H), 3.56-3.64(m, 1H), 3.49-3.55(m, 1H), 3.38(t, J ═ 6.17Hz, 2H), 2.80(t, J ═ 6.24Hz, 2H), 2.36(ddd, J ═ 14.09, 7.79, 6.60Hz, 1H), 2.18(s, 3H), 2.14(s, 3H), 1.84(dd, J ═ 13.94, 5.50, 1H).
Method D
Example 253: 5, 8-dichloro-7- (3, 5-dimethyl-1, 2-oxazol-4-yl) -2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -3, 4-dihydroisoquinolin-1 (2H) -one
A mixture of 3-chloro-2-methylbenzoic acid (100g, 0.58mol), N-chlorosuccinimide (90g, 0.67mol) and palladium (II) acetate (14.7g, 65.7mmol) in N, N-dimethylformamide (1L) was stirred overnight at 110 ℃ under a nitrogen atmosphere. After cooling to room temperature, cesium carbonate (378g, 1.16mol) and iodoethane (317g, 2.03mol) were added and stirring was continued at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of water (1L) and methyl tert-butyl ether (800 mL). The solids were removed by filtration and the filtrate layer was separated. The aqueous layer was extracted with additional methyl tert-butyl ether (600 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (1.2L), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 50:1 petroleum ether/ethyl acetate) to give ethyl 3, 6-dichloro-2-methylbenzoate (253b, 110g,. about.80% pure, 80% yield) as a yellow oil.
A solution of 3, 6-dichloro-2-methylbenzoate (253b, 120g, 0.52mol) and N-bromosuccinimide (147g, 0.82mol) in chloroform (1L) was treated with azobisisobutyronitrile (25.3g, 0.15mol), and the mixture was refluxed overnight. After cooling to room temperature, the mixture was diluted with dichloromethane (800mL) and washed with water (1.2L). The aqueous layer was extracted with dichloromethane (800 mL). The combined organic extracts were washed with saturated aqueous ammonium chloride (1.5L), dried over sodium sulfate, and concentrated in vacuo to give ethyl 2- (bromomethyl) -3, 6-dichlorobenzoate (253c, 160g, 100% yield) which was used without further purification.
A solution of sodium cyanide (75.12g, 1.53mol) in water (300mL) was added dropwise to a solution of ethyl 2- (bromomethyl) -3, 6-dichlorobenzoate (253c, 320g, 1.03mol) in dimethyl sulfoxide (2.4L) at room temperature. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into a mixture of water (4L) and methyl tert-butyl ether (2L), and the layers were separated. The organic layer was washed with water (2L) and saturated aqueous sodium chloride (2L), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30:1 petroleum ether/ethyl acetate) to give ethyl 3, 6-dichloro-2- (cyanomethyl) benzoate (253d, 150g,. about.75% pure, 47% yield) as a yellow oil.
Cobalt (II) chloride hexahydrate (166g, 0.70mol) was added to a solution of ethyl 3, 6-dichloro-2- (cyanomethyl) benzoate (253d, 90g, 0.35mol) in ethanol (1.5L) at room temperature and the resulting mixture was cooled to 0 ℃. Sodium borohydride (66.3g, 1.74mol) was added in portions. The mixture was stirred at room temperature for 1 hour, then refluxed overnight. The resulting suspension was filtered and then refiltered. The solids in the filter cake were stirred in ethyl acetate (600mL) and then filtered. The process was repeated a second time. The combined filtrate was added to the original filtration residue, and the organic solution was washed with water (800mL) and saturated aqueous sodium chloride solution (800mL), dried over sodium sulfate, and concentrated in vacuo to give 5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253e, 29.3g, 39% yield) as an off-white solid.
To a solution of 5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253e, 40g, 0.186mol) in concentrated sulfuric acid (200mL) was added N-bromosuccinimide (49.7g, 0.279mol) in portions at 60 ℃. Stirring was continued for 2h at 60 ℃ and N-bromosuccinimide (5g, 28mmol) was added. After stirring at 60 ℃ for a further 1 h, the mixture was poured into ice water (500mL) and extracted with dichloromethane (3X 500 mL). The extract was washed with saturated aqueous sodium chloride (800mL), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in ethyl acetate (40mL) and petroleum ether (20mL), the resulting solid was collected by filtration and dried under vacuum to give 7-bromo-5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253f, 41g, 75% yield) as a yellow-white solid.
A solution of potassium tert-butoxide in tetrahydrofuran (1.0M, 190mL, 0.19mol) was added dropwise to a cooled (0 ℃ C.) solution of 7-bromo-5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253f, 47g, 0.16mol) in anhydrous N, N-dimethylformamide (500mL) under a nitrogen atmosphere. Stirring was continued for 5 min at 0 ℃ and then 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (compound Z, 40.2g, 0.15mol) was added in one portion. After stirring for 10 min at 0 deg.C, the mixture was treated with concentrated acetic acid (2mL) and poured into methyl tert-butyl ether (600 mL). The organic solution was washed with water (800mL) and saturated aqueous sodium chloride (800mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 30: 1-20: 1 petroleum ether/ethyl acetate) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ]Methyl } -7-bromo-5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253g, 50g, 64% yield) as an off-white solid.1H NMR(400MHz，DMSO-d6)：8.08(s，1H)，7.45-7.43(m，2H)，7.32-7.29(m，3H)，6.76(s，1H)，5.38(s，2H)，4.71(s，2H)，3.24(t，J＝6Hz，2H)，2.72(t，J＝6Hz，2H)，2.36(s，3H)，2.31(s，3H)。MS：521[M+1]。
A mixture of 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -7-bromo-5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253g, 500mg, 0.96mmol), 3, 5-dimethylisoxazole-4-boronic acid pinacol ester (320mg, 1.44mmol), cesium fluoride (437mg, 2.88mmol) and tetrakis (triphenylphosphine) palladium (0) (70.0mg, 0.06mmol) in dioxane (20mL) was degassed with nitrogen and then stirred at 100 ℃ for 18 hours. After cooling, the mixture was partitioned between water (15mL) and ethyl acetate (3X 20 mL). The combined organic layers were washed with saturated aqueous sodium chloride (20mL), dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting with 10:1 petroleum ether/ethyl acetate) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -5, 8-dichloro-7- (3, 5-dimethyl-1, 2-oxazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (253H,400mg, 78% yield) as a yellow oil.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A solution of methyl } -5, 8-dichloro-7- (3, 5-dimethyl-1, 2-oxazol-4-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (253H,400mg, 0.75mmol) in trifluoroacetic acid (10mL) was stirred at 45 ℃ for 3 hours and then concentrated in vacuo to remove volatiles. The residue was partitioned between dichloromethane (15mL) and saturated aqueous sodium bicarbonate (4X 20 mL). The organic layer was washed with saturated aqueous sodium chloride (20mL), dried over sodium sulfate, concentrated and purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5, 8-dichloro-7- (3, 5-dimethyl-1, 2-oxazol-4-yl) -2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ]-3, 4-dihydroisoquinolin-1 (2H) -one (example 253, 250mg, 75% yield) as a white solid.1H NMR(600MHz，DMSO-17mm)11.57(s，1H)，7.67(s，1H)，5.89(s，1H)，4.57(s，2H)，3.51(t，J＝6.33Hz，2H)，2.95(t，J＝6.33Hz，2H)，2.24(s，3H)，2.18(s，3H)，2.12(s，3H)，2.06(s，3H)。MS：446[M+1]。
Example 229: 5, 8-dichloro-7- (1, 4-dimethyl-1, 2, 3-triazol-5-yl) -2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -3, 4-dihydroisoquinolin-1 (2H) -one
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl in a microwave tube]To a mixture of methyl } -7-bromo-5, 8-dichloro-3, 4-dihydroisoquinolin-1 (2H) -one (253g, 500mg, 0.96mmol) and 1, 4-dimethyl-5- (tributylstannyl) -1H-1,2, 3-triazole (CAS:1047637-17-1, 754mg, 1.95mmol) was added 1, 4-dioxane (10mL), copper (I) iodide (28mg, 0.14mmol) and tetrakis (triphenylphosphine) palladium (0) (160mg, 0.14 mmol). The solution was degassed using a stream of argon and degassing was continued for 10 minutes. The microtube vials were sealed and the mixture was heated at 125 ℃ for 2 hours under microwave irradiation. TLC (1: 1 petroleum ether/ethyl acetate, Rf: 0.5) showed about 50% 253g remaining. However, reheating no longer confirms the presence of product. The mixture was diluted with methyl tert-butyl ether (100mL), washed with water (3X 100mL), dried over sodium sulfate and concentrated to dryness. The residue was purified by flash chromatography, eluting with petroleum ether/ethyl acetate 1:1, to give- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ]Methyl } -5, 8-dichloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (229a, 108mg, 21% yield) as a white solid.1H NMR(400MHz，DMSO-d6)：7.76(s，1H)，7.44(d，J＝1.35Hz，2H)，7.28-7.34(m，3H)，6.75(s，1H)，5.38(s，2H)，4.71(s，2H)，3.77(s，3H)，3.30-3.34(m，2H)，2.82(s，2H)，2.35(s，3H)，2.32(s，3H)，2.08(s，3H)。MS：446.1[M+1]。
The 229a solution (1.1g, 2.1mmol) was dissolved in trifluoroacetic acid (25mL) and stirred at 45 ℃ for 3 hours. TLC (10: 1 dichloromethane/methanol, Rf: 0.5) showed the reaction was complete. The mixture was concentrated, diluted with dichloromethane (30mL), washed with aqueous sodium bicarbonate (4X 50mL) and brine (2X 20mL), dried over sodium sulfate, and concentrated to dryness. The residue was purified by flash chromatography (eluting with 10:1 dichloromethane methanol) to give 5, 8-dichloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7-(1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (example 229, 514mg, 51% yield) as a white solid.1H NMR(400MHz，CDCl3)：11.73(s，1H)，7.31(s，1H)，5.95(s，1H)，4.77(s，2H)，3.85(s，3H)，3.77(t，J＝12.8Hz，2H)，3.06-3.02(m，2H)，2.38(s，3H)，2.29(s，3H)，2.21(s，3H)。MS：446.1[M+1]。
Example 66: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7- (1-methyl-1H-pyrazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
To a solution of 8-chloro-7-hydroxy-3, 4-dihydroisoquinolin-1 (2H) -one (1e, 535mg, 2.71mmol) in DCM (10mL) was added N-phenyltrifluoromethanesulfonimide (870mg, 2.44mmol) and Et3N (630mg, 6.23 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography to give trifluoromethanesulfonic acid 8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl ester (66a, 795mg, 89%) as a colorless oil which solidified upon standing.
To a solution of 8-chloro-1-oxo-1, 2,3, 4-tetrahydroisoquinolin-7-yl trifluoromethanesulfonate (66a, 300mg, 0.910mmol) in DMF (5mL) was added 1-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (205mg, 0.956mmol), PdCl2(dppf) -DCM (74.3mg, 0.0910mmol) and Na2CO3(289mg, 2.73 mmol). With N2The reaction mixture was degassed and stirred in a sealed tube at 80 ℃ for 2 days. The reaction mixture was adjusted to pH 7 and purified by preparative chromatography to give 8-chloro-7- (1-methyl-1H-pyrazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (66b, 48mg, 20%) as an oil.
8-chloro-7- (1-methyl-1H-pyrazol-5-yl) -3,a solution of 4-dihydroisoquinolin-1 (2H) -one (66b, 48.0, 0.180mmol), 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 71.7mg, 0.274mmol) and KHMDS (182mg, 0.915mmol) in 1, 4-dioxane (5mL) was heated at 80 deg.C overnight. Adding H to the reaction mixture2O (10mL), extraction of the solution with EtOAc (10mL), concentration of the organic layer in vacuo, and purification of the residue by preparative chromatography to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-7- (1-methyl-1H-pyrazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (66c, 60mg, 67%) as a colorless oil.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A solution of methyl } -8-chloro-7- (1-methyl-1H-pyrazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (66c, 60mg, 0.12mmol) in TFA (3mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was purified by preparative chromatography to give the title compound (example 66, 8.5mg, 17%) as a white solid.1H NMR(700MHz，DMSO-d6)11.56(br.s，1H)7.44(d，J＝7.70Hz，1H)7.35(d，J＝7.70Hz，1H)7.50(d，J＝1.76Hz，1H)6.29(d，J＝1.76Hz，1H)5.90(s，1H)4.60(s，2H)3.61(s，3H)3.46-3.50(m，2H)2.91(t，J＝5.83Hz，2H)2.19(s，3H)2.14(s，3H)；MS397.0[M+1]。
Method E
Example 76: 2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -N, N, 8-trimethyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxamide
8-methylisoquinoline 2-oxide (1.4g, 8.8mmol) was added to Ac2The solution in O (20mL) was refluxed for 3 hours. The mixture was concentrated in vacuo and the residue dissolved in MeOH (20 mL). To the reaction mixture was added aqueous NaOH (20mL, 1M). The mixture was refluxed for 1 hour and stirred at room temperature for 10 hours. Vacuum concentrationThe mixture is condensed. The residue was diluted with water (20mL) and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 10mL) and Na2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 8-methylisoquinolin-1 (2H) -one (76a, 1g, 71%) as a yellow solid.
A mixture of 8-methylisoquinolin-1 (2H) -one (76a, 1g, 6.29mmol) and 10% Pd/C (0.5g) in MeOH (20mL) at 80 deg.C in H2Hydrogenation was carried out under an atmosphere (60psi) for 48 hours. The reaction mixture was filtered, solid washed with MeOH (2X 20mL), and the filtrate was concentrated in vacuo to give 8-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (76b, 1g, 100%) as a gray solid.
To cooled dense H2SO4(10mL) was added 8-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (76b, 1g, 6.21mmol) and the reaction mixture was stirred for 10 min. NBS (1.1g, 6.21mmol) was added and the reaction mixture was stirred at 60 ℃ for 2 h. The mixture was cooled to room temperature and poured into ice-water (30mL) while stirring. The suspension was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with water (20mL) and brine (20mL), and Na2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 1:1) to give 7-bromo-8-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (76c, 0.63g, 42%) as a white solid.
7-bromo-8-methyl-3, 4-dihydroisoquinolin-1 (2H) -one (76c, 0.6g, 2.5mmol), DIPEA (2mL) and PdCl2A mixture of (dppf) (0.12g) in MeOH (20mL) was stirred under an atmosphere of CO (4MPa) at 120 ℃ for 48 h in a 50mL autoclave. The mixture was filtered and the solid was washed with MeOH (2X 10 mL). The filtrate was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 1:1) to give methyl 8-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxylate (76d, 0.41g, 75%) as a white solid.
At 0 ℃ in N2Stirring methyl 8-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxylate (76d, 100mg, 0.46mmol) in DMF (5 d, 100mg, 0.46mmol) under an atmospheremL) was added NaH (0.032g, 1.32mmol, 60% solution in oil). After stirring for 30 min at 0 ℃ 1- (benzyloxy) -2- (chloromethyl) -3, 5-dimethylbenzyl 2- (chloromethyl) -3, 5-dimethylphenyl ether (Cpd Z, 180mg, 0.69mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixer was poured into ice-water (20 mL). The reaction mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 10mL) and Na2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 1:1) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxylic acid (76e, 120mg, 61%) as a yellow gum.
In N2To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl in an atmosphere]Methyl } -8-methyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxylic acid (76e, 120mg, 0.28mmol), (CH)3)2To a solution of NH. HCl (34mg, 0.42mmol) and DIPEA (181mg, 1.4mmol) in DMF (5mL) was added HATU (214mg, 0.56 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (10mL) and extracted with EtOAc (3X 10 mL). By H 2The combined organic layers were washed with O (10mL), brine (2X 10mL), and Na2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 1:1) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -N, N, 8-trimethyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxamide (76f, 80mg, 63%) as a colorless gum.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -N, N, 8-trimethyl-1-oxo-1, 2,3, 4-tetrahydroisoquinoline-7-carboxamide (76f, 80mg, 0.175mmol) and a mixture of 10% Pd/C (10mg) in MeOH (10mL) in H2Hydrogenation was carried out in a balloon atmosphere at room temperature for 20 hours. The mixture was filtered and the solid was washed with MeOH (2X 10 mL). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (EtOAc/MeOH ═ 5:1) to give the title compound (example 76, 32mg, 49.7%) as a white solid.1H NMR (400MHz, methanol-d 4)7.22-7.2(d, 1H), 7.17-7.15(d,1H)，6.11(s，1H)，4.77(s，2H)，3.45-3.43(m，2H)，3.13(s，3H)，2.9-2.85(m，5H)，2.28(s，3H)，2.25(s，3H)；MS 367.9[M+H]。
method F
Example 77: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -5- [6- (piperazin-1-yl) pyridin-3-yl ] -7- (propan-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one
To a solution of methyl 1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate (Cpd E, 1.00g, 3.80mmol) in MeOH (20mL) was added NaOH (3.00mL, 12.0 mmol). The reaction mixture was stirred at 50 ℃ for 3 hours. Volatiles were removed in vacuo and the resulting residue was dissolved in MeOH (30mL) and neutralized with 1M HCl to pH 2-3. A precipitate formed, collected by filtration, washed with water, and dried in an oven at 60 ℃ under vacuum to give 1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid (77a, 918mg, 97%) as a white solid.
To a solution of 1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid (77a, 1.76g, 7.06mmol) in anhydrous dioxane (100mL) was added CDI (1.43g, 8.83 mmol). The resulting mixture was stirred at room temperature for 30 minutes, and then at 100 ℃ for 30 minutes. After cooling to room temperature, TMSA (1.50mL, 10.8mmol) was added. After the reaction mixture was stirred for 2 hours, t-butanol (25.0mL) was added. The resulting mixture was stirred at 100 ℃ overnight. After cooling to room temperature and concentration in vacuo, the resulting residue was purified by column chromatography (0-100% EtOAc/heptane) to give tert-butyl [ 1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl ] carbamate (77b, 958mg, 42%) as a solid.
A solution of tert-butyl [ 1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl ] carbamate (77b, 875mg, 2.73mmol) and NCS (401mg, 3.00mmol) in MeCN (80mL) was stirred at 75 ℃ for 2 hours. After cooling to room temperature and concentration in vacuo, the resulting residue was purified by column chromatography (0-100% EtOAc/heptane) to give tert-butyl [ 8-chloro-1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl ] carbamate (77c, 893mg, 92%) as a solid.
To [ 8-chloro-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl]To a solution of tert-butyl carbamate (77c, 500mg, 0.282mmol) in THF (20mL) was added HBr (10.0mL, 88.4mmol, 48% aq). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0 deg.C, CuBr (303mg, 2.11mmol) was added, followed by NaNO addition2(1.07mL, 1.55mmol, 100mg/mL solution). The resulting reaction mixture was stirred at 0 ℃ for 1.5 hours. With NaHCO3The reaction mixture was neutralized and extracted with ethyl acetate (2X 50 mL). The combined organic phases were washed with brine (1 × 100mL), dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (0-100% EtOAc/heptane) to give 5-bromo-8-chloro-7- (propan-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (77d, 188mg, 42% in 2 steps) as a solid.
To a solution of 5-bromo-8-chloro-7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (77d, 188mg, 0.590mmol) in anhydrous 1, 4-dioxane (10mL) was added KHMDS (2.00mL, 2.00 mmol). Upon addition, a dark red paste formed. After stirring at room temperature for 30 min, 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 170mg, 0.649mmol) was added. The resulting reaction mixture was stirred at 100 ℃ for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (2X 50 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (0-40% EtOAc/heptane) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -5-bromo-8-chloro-7- (propan-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (77e, 140mg, 44%).
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -5-bromo-8-chloro-7- (prop-2-yloxy)-3, 4-dihydroisoquinolin-1 (2H) -one (77e, 60mg, 0.110mmol), 4- [5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-yl]Piperazine-1-carboxylic acid tert-butyl ester (64mg, 0.164mmol), Na2CO3(200. mu.L, 0.400mmol, 2M solution), PdCl2A mixture of (dppf) -DCM (9mg, 0.011mmol) and 1, 4-dioxane (2mL) was stirred in a microwave at 120 ℃ for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20mL) and water (20 mL). The organic phase was separated, washed with brine (1X 20mL), dried over sodium sulfate, concentrated in vacuo, and purified by column chromatography (0-100% EtOAc/heptane) to give 4- {5- [2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl]Pyridin-2-yl } piperazine-1-carboxylic acid tert-butyl ester (77f, 46mg, 58% yield) as a solid.
4- {5- [2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl]A mixture of tert-butyl pyridin-2-yl } piperazine-1-carboxylate (77f, 46mg, 0.063mmol) in TFA (2mL) was stirred at room temperature for 3 hours. After concentrating the volatiles in vacuo, the resulting residue was partitioned between ethyl acetate (30mL) and sodium bicarbonate (30 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (1X 30 mL). The combined organic phases were dried over sodium sulfate, concentrated in vacuo, and purified by preparative HPLC to give the title compound (example 77, 5.0mg, 15% yield) as a solid. 1H NMR (400MHz, methanol-d 4)8.09(d, J ═ 2.27Hz, 1H), 7.56(dd, J ═ 8.59, 2.53Hz, 1H), 7.09(s, 1H), 6.88(d, J ═ 8.84Hz, 1H), 6.10(s, 1H), 4.77(s, 2H), 4.60-4.70(m, 1H), 3.55-3.63(m, 4H), 3.35(t, J ═ 6.06Hz, 2H), 2.92-3.02(m, 4H), 2.75(t, J ═ 6.06Hz, 2H), 2.30(s, 3H), 2.24(s, 3H), 1.36(d, J ═ 5.81, 6H); MS 536.3[ M + H ]]。
Method G
Example 90: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -N, N-dimethyl-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide
To a mixture of methyl 8-chloro-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylate (Cpd F, 92.0mg, 0.310mmol) and 2- (benzyloxy) -3- (chloromethyl) -4, 6-lutidine (Cpd Z, 97.1mg, 0.371mmol) in 1, 4-dioxane (3mL) was added KHMDS (308mg, 1.54 mmol). The reaction mixture was heated at 100 ℃ for 1 hour. The solvent was removed in vacuo and the residue diluted with EtOAc (10mL) and water (10 mL). The pH of the aqueous layer was adjusted to 3-4 using 1N HCl. The aqueous layer was extracted with EtOAc (25mL) and the organic layer was concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -8-chloro-1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid (90a, 52mg, 33% yield) as an oil.
To 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]To a solution of methyl } -8-chloro-1-oxo-7- (propan-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxylic acid (90a, 17mg, 0.033mmol) in DMF (1mL) were added triethylamine (0.023mL, 0.165mmol) and HATU (14mg, 0.035 mmol). The reaction mixture was stirred for 5 minutes, then dimethylamine-HCl (4.10mg, 0.050mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. By H2The reaction mixture was diluted with O (5mL), and the precipitated solid was collected by filtration and dried in vacuo to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-N, N-dimethyl-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide (90b, 16mg, 89% yield) as a white solid.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A solution of methyl } -8-chloro-N, N-dimethyl-1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinoline-5-carboxamide (90b, 16mg, 89% yield) and TFA (1.5mL) was stirred at room temperature for 24 h. Volatiles were removed in vacuo, the residue was purified by preparative HPLC,the title compound (example 90, 11mg, 85% yield) was obtained as a white solid.1H NMR(700MHz，DMSO-d6)7.15(s，1H)5.90(s，1H)4.65-4.71(m，1H)4.56(br.s.，2H)2.98(s，3H)2.76(s，3H)2.57(br.s，2H)2.17(s，3H)2.13(s，3H)1.28(s，3H)1.28(s，3H)；MS：446.1[M+1]。
Improvement of method G
Example 143.N- ({ 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -1-oxo-7- (prop-2-yloxy) -1,2,3, 4-tetrahydroisoquinolin-5-yl } methyl) -2- (pyrrolidin-1-yl) acetamide
Reduction of Cpd F using lithium borohydride under standard conditions gives primary alcohol intermediate 143a which is reacted with Cpd Z under the conditions of method G to give N-alkylated lactam 143 b. The free hydroxyl group on 143b is converted to the mesylate 143c under standard conditions, followed by nucleophilic displacement with potassium phthalimide to afford the protected amine 143 d. Deprotection of the phthalimide with hydrazine affords the primary amine 143e, which is coupled with 1-pyrrolidineacetic acid using HATU to afford the amide 143 f. Treatment of 143f with TFA under the conditions of method G to remove the benzyl ether moiety afforded the compound of example 143:1H NMR(600MHz，DMSO-17mm)d ppm8.34(br.s.，1H)8.24(t，J＝5.87Hz，1H)7.12(s，1H)5.91(s，1H)4.56(s，2H)4.50-4.55(m，1H)4.24(d，J＝5.87Hz，2H)3.33-3.36(m，2H)3.09(s，2H)2.71(t，J＝6.05Hz，2H)2.50(br.s.，4H)2.15(s，3H)2.13(s，2H)1.69(br.s.，4H)1.28(d，J＝6.05Hz，6H)；MS：515[M+1]。
examples 94, 95, 96 and 144 were prepared in a similar manner to example 143 by amide bond coupling of amine intermediate 143e with the appropriate carboxylic acid followed by removal of the benzyl ether with TFA as in method G.
Examples 100, 102, 106 and 254 were prepared from mesylate intermediate 143c by nucleophilic displacement with the appropriate amine under standard conditions, followed by removal of the benzyl ether with TFA as in method G.
Example 92 was prepared by removing the benzyl ether in intermediate 143b with TFA as in method G.
Examples 97, 98, 99 and 103 were prepared by alkylating intermediate 143b O-with the appropriate alkyl halide and then removing the benzyl ether with TFA as in method G.
Examples 91 and 101 were prepared by oxidation of intermediate 143b to give intermediate formaldehyde, addition of the appropriate carbon-centered nucleophile and removal of the benzyl ether with TFA as in method G.
Method H
Example 107: 2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -8-methyl-7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one
With N2To methyl 6-bromo-2-methyl-3- (propan-2-yloxy) benzoate (Cpd PP, 154mg, 0.536mmol), {2- [ (tert-butoxycarbonyl) amino]A mixture of potassium ethyl (trifluoro) borate (269mg, 1.07mmol, 2 equiv.) and cesium carbonate (613mg, 1.88mmol) in 3:1 toluene: water (2.22mL) resulted in degassing of the mixture. Palladium acetate (7.2mg, 0.032mmol) and RuPhos (30.5mg, 0.064mmol) were added over N2The mixture was degassed and then heated at 95 ℃ for 19 hours. The reaction mixture was cooled to room temperature and then acidified to pH-6 with 10% aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (20mL), the organic layer was washed with brine (5mL), dried over sodium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (EtOAc/heptane, 0-100%). The substrate was dissolved in dichloromethane (2mL) and 4N hydrochloric acid in anhydrous dioxane (0.3mL), Stirred for 16 hours and then concentrated in vacuo to an oil. The residue was dissolved in 1, 4-dioxane (3mL) and diisopropylethylamine (25 μ L) was added. The mixture at 80 ℃ heating for 50 hours, vacuum concentration, by column chromatography purification residue (EtOAc/heptane, 0-100), 8-methyl-7- (propyl-2-methoxy) -3, 4-two hydrogen isoquinoline-1 (2H) -ketone (107a, 18.6mg, 15.8%), as a white solid.
To a 0 ℃ solution of 8-methyl-7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (107a, 30mg, 0.14mmol) in tetrahydrofuran (0.46mL) was added 60% sodium hydride (18mg, 0.45 mmol). After 30 min, 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 43mg, 0.16mmol) was added and the resulting mixture was heated at 50 ℃ for 16 h. The reaction mixture was quenched with water (1mL), then extracted with ethyl acetate (20mL), washed with brine (2mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/heptane, 0-100) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -8-methyl-7- (propan-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (107b, 46mg, 76%) as a colorless oil.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A mixture of methyl } -8-methyl-7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (107b, 46mg, 0.10mmol) and 10% palladium on carbon (10mg) in methanol (3mL) was hydrogenated using a balloon at 1 atmosphere for 26 hours. By passingThe reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (EtOAc/heptane, 50/50-100/0, then EtOAc/MeOH, 100/0-70/30) to give the title compound (example 107, 27mg, 74% yield) as a white solid.1H NMR(400MHz，DMSO-d6)11.52(br.s.，1H)，7.05-7.01(m，1H)，6.99(s，1H)，5.87(s，1H)，4.58(s，2H)，4.51(td，J＝5.9，12.1Hz，1H)，2.68(t，J＝6.0Hz，2H)，2.42(s，3H)，2.13(s，3H)，2.11(s，2H)，1.25(d，J＝5.9Hz，6H)；MS 355(M+H)。
Method I
Example 108: 2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one
To LiAlH at-5 DEG C4(1.90g, 50.2mmol) to a suspension in dry THF (60mL) was added dropwise methyl 5-bromo-2-methyl-3- (propan-2-yloxy) benzoate (Cpd PP, 17.0g, 65.6mmol) in THF (40 mL). After the addition, the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with 20% NaOH (10mL) at-5 ℃ and then stirred at room temperature for 30 min. The resulting mixture was filtered and the solid was washed with EtOAc (3X 30 mL). The filtrate was concentrated in vacuo to give [ 5-bromo-2-methyl-3- (prop-2-yloxy) phenyl ]Methanol (108a, 8g, 74%) as a yellow oil.
To [ 5-bromo-2-methyl-3- (prop-2-yloxy) phenyl]Methanol (108a, 25.0g, 96.5mmol) in CHCl3MnO was added to the solution (300mL)2(42.0g, 487 mmol). The mixture was stirred at room temperature for 18 hours. Filtering the mixture with CH2Cl2The solid was washed (2X 20 mL). The filtrate was concentrated in vacuo to give 5-bromo-2-methyl-3- (propan-2-yloxy) benzaldehyde (108b, 18g, 73%) as a colorless oil.
To a solution of 5-bromo-2-methyl-3- (prop-2-yloxy) benzaldehyde (108b, 4.5g, 18mmol) and 2, 2-dimethoxyethylamine (2.2g, 21mmol) in MeOH (50mL) at 0 deg.C was added NaBH3CN (1.4g, 22mmol) and HOAc (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL). The reaction mixture was concentrated in vacuo. The residue was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with brine (2X 30mL) and Na2SO4Drying, filtering, and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 5:1) to give N- [ 5-bromo-2-methyl-3- (propan-2-yloxy) benzyl]2, 2-Dimethoxyethylamine (108c, 3.5g, 58%) as a colorless oil.
To the N- [ 5-bromo-2-methyl-3- (prop-2-yloxy) benzyl group ]-2, 2-dimethoxy-ethylamine (108c, 3.5g, 10mmol) and Na2CO3(1.6g, 15mmol) in THF (40mL) and H2To the mixture in O (20mL) was added TsCl (2.0g, 11 mmol). The reaction mixture was stirred at room temperature for 5 hours, then extracted with EtOAc (4X 40 mL). By H2The combined organic layers were washed with O (2X 30mL) and brine (2X 100mL), and Na2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 5:1) to give N- [ 5-bromo-2-methyl-3- (propan-2-yloxy) benzyl]-N- (2, 2-dimethoxyethyl) -4-methylbenzene-sulfonamide (108d, 4.7g, 93%) as a colorless oil.
Reacting N- [ 5-bromo-2-methyl-3- (prop-2-yloxy) benzyl]A mixture of (e) -N- (2, 2-dimethoxyethyl) -4-methylbenzenesulfonamide (108d, 4.7g, 9.4mmol) in 6M HCl (75mL) and 1, 4-dioxane (75mL) was stirred in a sealed tube at 50 ℃ for 18 hours. Remove volatiles in vacuo and Na2CO3(s) basifying the aqueous solution to a pH of 8 to 9. The mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 40mL) and Na2SO4Drying, filtration and concentration in vacuo gave 5-bromo-8-methyl-7- (propan-2-yloxy) isoquinoline (108e, 1.6g, 61%) as a brown oil.
To a solution of 5-bromo-8-methyl-7- (prop-2-yloxy) isoquinoline (108e, 1.60g, 5.71mmol) in DCM (40mL) was added m-CPBA (1.47g, 8.56mmol), and the reaction mixture was stirred at room temperature for 10 h. With NaHSO 3The reaction mixture was washed (aqueous, 2X 20mL), 10% aqueous NaOH (2X 20mL) and brine (2X 10mL), and Na was added2SO4Drying and concentration in vacuo gave 5-bromo-8-methyl-7- (propan-2-yloxy) isoquinoline 2-oxide (108f, 1.3g, 77%) as a brown solid.
5-bromo-8-methyl-7- (prop-2-yloxy) isoquinoline 2-oxide (108f, 1.3g, 4.4mmol) is added to Ac2The solution in O (20mL) was refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). With NaHCO3The resulting solution was washed with aqueous solution (20mL) and brine (20mL), and Na was added2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 10:1) to give acetic acid 5-bromo-8-methyl-7- (propan-2-yloxy) isoquinolin-1-yl ester (108g, 0.28g, 17%).
To a solution of acetic acid 5-bromo-8-methyl-7- (prop-2-yloxy) isoquinolin-1-yl ester 108g, 0.28g, 0.83mmol) in MeOH (2mL) was added 1M NaOH (2 mL). The reaction mixture was refluxed for 1 hour and then concentrated in vacuo. The residue is diluted with water and the pH is adjusted to 4-5 with 1M HCl. The solution was extracted with EtOAc (3X 10 mL). The combined organic layers were washed with brine (2X 10mL) and Na2SO4Drying, filtration and concentration in vacuo gave 5-bromo-8-methyl-7- (propan-2-yloxy) isoquinolin-1 (2H) -one (108H, 0.21g, 86%) as a yellow solid.
With N25-bromo-8-methyl-7- (propan-2-yloxy) isoquinolin-1 (2H) -one (108H, 150mg, 0.507mmol), 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (210mg, 1.01mmol), and Pd (Ph)3P)4(29mg, 0.025mmol) in 1M Na2CO3The mixture in aqueous solution (1mL) and DME (5mL) was degassed for 3 minutes. The reaction mixture was stirred at 140 ℃ for 35 minutes in a microwave. With Na2SO4The reaction mixture was dried, filtered and concentrated in vacuo. The residue (EtOAc) was purified by column chromatography to give 8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (propan-2-yloxy) isoquinolin-1 (2H) -one (108i, 0.14g, 92.9%) as a white solid.
A mixture of 8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (propan-2-yloxy) isoquinolin-1 (2H) -one (108i, 0.14g, 0.47mmol) and 10% Pd/C (0.3g) in EtOH (20mL) in H2Hydrogenation was carried out in a 50mL autoclave at 80 ℃ for 48 hours under an atmosphere (1.6 MPa). The reaction mixture was filtered and the mixture was filtered,the solid was washed with EtOH (2X 10 mL). The filtrate was concentrated in vacuo to give 8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (propan-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (108j, 0.11g, 78.7%) as a white solid.
At 0 ℃ in N2To a stirred solution of 8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (108j, 60mg, 0.2mmol) in DMF (5mL) was added NaH (9.6mg, 0.4mmol, 60% solution in oil) under atmosphere. After 30 min, 1- (benzyloxy) -2- (chloromethyl) -3, 5-dimethylbenzylbenzyl 2- (chloromethyl) -3, 5-dimethylphenyl ether (Cpd Z, 115mg, 0.44mmol) was added and stirred at room temperature for 14 h. The reaction mixture was poured into ice-water (20mL) and then extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 10mL) and Na 2SO4Drying, filtering and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 1:1) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (108k, 40mg, 38%) as a white solid.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-methyl-5- (1-methyl-1H-pyrazol-4-yl) -7- (prop-2-yloxy) -3, 4-dihydroisoquinolin-1 (2H) -one (108k, 40mg, 0.076mmol) and a mixture of 10% Pd/C (20mg) in MeOH (10mL) in H2Hydrogenation was carried out in a balloon atmosphere at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative tlc (etoac) type to give the title compound (example 108, 19mg, 58%) as a white solid.1H NMR (400MHz, methanol-d 4)7.72(s, 1H), 7.56(s, 1H), 7.03(s, 1H), 6.11(s, 1H), 4.78(s, 3H), 4.6-4.57(m, 1H), 3.92(s, 3H), 3.92(s, 3H), 2.82-2.81(m,2H), 2.47(s, 3H), 2.28-2.24(m,5H), 1.34-1.32(d, 6H); MS 435.2[ M + H ]]。
Method J
Example 112: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one
Methyl 5-bromo-2-hydroxypyridine-4-carboxylate (3.00g, 12.9mmol), isopropyl iodide (3.30g, 19.4mmol) and Ag2CO3A solution of (4.66g, 16.8mmol) in toluene (40mL) was heated at 100 ℃ for 2 hours. Tong (Chinese character of 'tong')The solid was filtered, the filtrate concentrated in vacuo, and purified by column chromatography (0-20% ethyl acetate/heptane) to give methyl 5-bromo-2- (propan-2-yloxy) pyridine-4-carboxylate (112a, 3.5g, 99%) as a colorless oil.
To a solution of methyl 5-bromo-2- (prop-2-yloxy) pyridine-4-carboxylate (112a, 3.40g, 12.4mmol) and N-vinylphthalimide (2.58g, 14.9mmol) in toluene (124mL) was added K2CO3(5.19g, 37.2mmol) followed by the addition of Pd (P (tBu)3)2(0.400g, 0.775 mmol). The reaction mixture was degassed and heated in a sealed tube at 110 ℃ for 18 hours. The reaction mixture was cooled to room temperature byAnd (5) filtering. Addition of H2O (100mL), the organic layer was separated, concentrated in vacuo, and the residue was purified by column chromatography (0-80%, ethyl acetate/heptane) to give 5- [ (E) -2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) vinyl]-methyl 2- (propan-2-yloxy) pyridine-4-carboxylate (112b, 1.56g, 34%) as a yellow solid.
A solution of methyl 5- [ (E) -2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) vinyl ] -2- (propan-2-yloxy) pyridine-4-carboxylate (112b, 1.56g, 4.26mmol) in THF/EtOH (25mL/5mL) was hydrogenated over H-Cube with Wilkinson's catalyst (10 bar, 75 ℃, 18H). The solvent was removed in vacuo and the resulting gum was purified by column chromatography (0-50% ethyl acetate/heptane) to give methyl 5- [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) ethyl ] -2- (propan-2-yloxy) pyridine-4-carboxylate (112c, 0.63g, 40%) as a white solid.
To 5- [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) ethyl in EtOH (50mL)]To methyl (112c, 0.630g, 1.71mmol) 2- (prop-2-yloxy) pyridine-4-carboxylate was added hydrazine monohydrate (0.850mL, 17.1 mmol). The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to room temperature and a white solid was collected by filtration and rinsed with EtOH. Concentrating the mother liquor, adding H2O (25mL), then the aqueous layer was extracted with EtOAc (3X 25 mL). The combined organic layers were concentrated in vacuo and purified by column chromatography (0-80% ethyl acetate/heptane) to give 7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112d, 337mg, 96%) as a white solid.
A solution of 7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112d, 75mg, 0.36mmol)) and NCS (498mg, 3.64mmol) in AcOH (3mL) was heated at 100 ℃ for 4.5 hours. The reaction mixture was cooled to room temperature, the AcOH was removed in vacuo, and the residue was purified by column chromatography (0-80% ethyl acetate/heptane) to give 8-chloro-7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112e, 60mg, 68%) as a white solid.
To a mixture of 8-chloro-7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112e, 60.0mg, 0.250mmol) and 2- (benzyloxy) -3- (chloromethyl) -4, 6-lutidine (CpdZ, 78mg, 0.3mmol) in 1, 4-dioxane (3mL) was added a THF solution of KHMDS (1.0M, 1.24mL, 1.24 mmol). The reaction mixture was heated at 100 ℃ for 1 hour and then cooled to room temperature. The reaction mixture was concentrated and H was added 2O (10mL), the aqueous layer was extracted with EtOAc (3X 10 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -8-chloro-7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112f, 22mg, 19% yield) as a white solid.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A solution of methyl } -8-chloro-7- (prop-2-yloxy) -3, 4-dihydro-2, 6-naphthyridin-1 (2H) -one (112f, 22mg, 0.05mmol) in TFA (2mL) was stirred at room temperature for 24H. Volatiles were removed in vacuo and the residue was diluted with MeOH (1 mL). With 7N NH3The solution was neutralized by preparative TLC (100% EtOAc) to give the title compound as a white solid (example 112, 8mg, 50%).1H NMR(400MHz，DMSO-d6)1.30(s，3H)1.32(s，3H)2.12(s，3H)2.15(s，3H)2.75(t，J＝6.17Hz，2H)3.43(t，J＝6.17Hz，2H)4.56(s，2H)5.21-5.30(m，1H)5.88(s，1H)8.02(s，1H)11.56(br.s.，1H)；MS 376.2[M+1]。
Method K
Example 114: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7-ethoxy-6-methyl-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one
To a solution of 3-hydroxy-2-methylbenzoic acid (3.80g, 25.0mmol) in methanol (3.0mL) was added thionyl chloride (3.00mL, 41.2mmol) dropwise at 0 ℃. The reaction was warmed to room temperature and then heated at 50 ℃ for 2 hours. The solvent was removed in vacuo and the resulting solid was dissolved in ethyl acetate and washed with NaHCO 3(saturated aqueous solution) washing. With Na2SO4The ethyl acetate layer was dried, filtered, and concentrated in vacuo to give methyl 3-hydroxy-2-methylbenzoate (114a, 3.49g, 84% yield) as a pale tan solid.
To a solution of methyl 3-hydroxy-2-methylbenzoate (114a, 3.557g, 21.40mmol) in dichloromethane (100mL) in a dry ice/acetonitrile bath (-45 ℃ C.) was added dropwise bromine (1.15mL, 22.5 mm)ol). The reaction was stirred at-45 ℃ for 2 hours, then Na was added2S2O3(saturated aqueous solution, 2 mL). The reaction mixture was warmed to room temperature. The reaction mixture was diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated in vacuo and the resulting crude product was purified by column chromatography (0-40% ethyl acetate/heptane) to give methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 4.8g, 92% yield) as a white solid.
To a solution of methyl 6-bromo-3-hydroxy-2-methylbenzoate (114b, 0.701g, 2.86mmol) in DMF (6mL) was added cesium carbonate (0.997g, 3.0mmol) followed by iodoethane (0.400mL, 5.00 mmol). The reaction was stirred at 65 ℃ for 30 minutes. The reaction mixture was poured into ethyl acetate and washed with water (× 2). The ethyl acetate layer was concentrated in vacuo to give methyl 6-bromo-3-ethoxy-2-methylbenzoate (114c, 0.75g, 96% yield) as a clear oil.
A solution of methyl 6-bromo-3-ethoxy-2-methylbenzoate (114c, 0.298g, 1.09mmol) in DMSO (4mL) was treated with 10M NaOH (1.0mL, 10mmol) and heated at 95 ℃. After 1 hour, the ester was hydrolyzed. The reaction mixture was cooled to room temperature and sodium bicarbonate (0.850g, 10.1mmol) and water (3mL) were added. The suspension was sonicated until homogeneous. Copper (II) sulfate (0.0348g, 0.218mmol) and a solution of trans-N, N' -dimethylcyclohexane-1, 2-diamine (0.071mL, 0.44mmol) in water (2.0mL) were added. The reaction mixture was heated at 95 ℃ for 1 hour. The reaction mixture was cooled to room temperature, poured into ethyl acetate and washed with 1N HCl and brine. With Na2SO4The organic layer was dried and concentrated in vacuo to give 3-ethoxy-6-hydroxy-2-methylbenzoic acid (114d, 0.168g, 79% yield) as a salmon color solid.
To a solution of 3-ethoxy-6-hydroxy-2-methylbenzoic acid (114d, 0.168g, 0.856mmol) in THF (4.0mL) was added 1,1' -carbonyldiimidazole (0.155g, 0.91mmol) and the reaction was stirred at 60 ℃ for 3 hours. The reaction mixture was cooled to room temperature and 2- ({ [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) was added]Methyl } amino) ethanol (CpdKK, 330mg, 1.10mmo l). Heating was then continued at 60 ℃ for 16 hours. The reaction mixture was cooled to room temperature and 10M NaOH (0.3mL) was added. The reaction mixture was stirred at room temperature for 1 hour, then poured into ethyl acetate and washed with 1M KH2PO4And water washing. The organic layer was concentrated and purified by column chromatography (0-80% ethyl acetate/dichloromethane) to give N- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -3-ethoxy-6-hydroxy-N- (2-hydroxyethyl) -2-methylbenzamide (114e, 0.274g, 69% yield) as a white solid.
A solution of triphenylphosphine (0.176g, 0.671mmol) in THF (5mL) was treated in an ice bath by dropwise addition of diisopropyl azodicarboxylate (0.140mL, 0.67 mmol). After 10 minutes, N- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) was added in one portion]Methyl } -3-ethoxy-6-hydroxy-N- (2-hydroxyethyl) -2-methylbenzamide (114e, 0.155g, 0.334 mmol). The reaction mixture was stirred in an ice bath overnight and the reaction mixture was gradually warmed to room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (0-40% ethyl acetate/heptane) to give 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -7-ethoxy-6-methyl-3, 4-dihydro-1, 4-benzoxazepine -5(2H) -one (114f, 0.087g, 58%) as a clear thick oil.
4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -7-ethoxy-6-methyl-3, 4-dihydro-1, 4-benzoxazepineA solution of-5 (2H) -one (114f, 0.085g, 0.19mmol) in 4N HCl in dioxane (5.0mL, 20mmol) was stirred at 45 ℃ for 16H. The reaction was concentrated in vacuo and the resulting yellow residue was dissolved in hot DMSO (1.5 mL). A small amount of MeOH (1mL) was added and a white solid began to precipitate from solution. The suspension was allowed to stand overnight. The precipitate was collected by filtration and washed with water to give the title compound (example 114, 0.061g, 90% yield) as a bright white powder.1H NMR(400MHz，DMSO-d6)11.59(s，1H)，6.96(d，J＝8.80Hz，1H)，6.81(d，J＝8.80Hz，1H)，5.92(s，1H)，4.63(s，2H)，4.00(q，J＝6.97Hz，2H)，3.91(t，J＝5.32Hz，2H)，3.33(t，J＝5.38Hz，2H)，2.21(s，3H)，2.15(s，3H)，2.13(s，3H)，1.33(t，J＝6.91Hz，3H)；MS357[M+H]+。
Method L
Example 116: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-6-methyl-5-oxo-7- (prop-2-yloxy) -2,3,4, 5-tetrahydro-1, 4-benzoxazepine-9-carbonitrile
To a solution of 3-hydroxy-2-methylbenzoic acid (2.0g, 13mmol) in anhydrous ethanol (20mL) was added sulfuric acid (2.0mL, 37 mmol). The resulting mixture was stirred at 90 ℃ for 16 hours. The reaction was cooled to room temperature and then diluted with water (20 mL). The mixture was extracted with dichloromethane (2X 50 mL). The combined organic layers were washed with brine (50mL), dried over magnesium sulfate, and concentrated in vacuo to give ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4g, 99% yield) as a yellow oil.
To a cooled (0 ℃ C.) solution of ethyl 3-hydroxy-2-methylbenzoate (116a, 2.4g, 13mmol) and N, N-diisopropylethylamine (5.8mL, 33mmol) in dichloromethane (50mL) was added dropwise methanesulfonyl chloride (1.4mL, 17 mmol). The reaction mixture was stirred at 0 ℃ for 30 minutes, then diluted with water (20mL) and extracted with dichloromethane (2X 25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (30% EtOAc/heptane) to give ethyl 2-methyl-3- [ (methylsulfonyl) oxy ] benzoate (116b, 3.0g, 88% yield) as a yellow oil.
To a solution of ethyl 2-methyl-3- [ (methylsulfonyl) oxy ] benzoate (116b, 3.0g, 12mmol) in trifluoroacetic acid (35mL) and trifluoroacetic anhydride (15mL) were added potassium persulfate (3.5g, 13mmol) and dichloro (p-cymene) ruthenium (II) dimer (0.36g, 0.59 mmol). The resulting mixture was stirred in a sealed tube at 90 ℃ for 22 hours. The reaction mixture was concentrated in vacuo, then diluted with water (50mL) and extracted with dichloromethane (2X 75 mL). The combined organic layers were washed with brine (50mL), dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (40% EtOAc/heptane) to give ethyl 6-hydroxy-2-methyl-3- [ (methylsulfonyl) oxy ] benzoate (116c, 1.3g, 41% yield) as a white solid.
To a solution of ethyl 6-hydroxy-2-methyl-3- ((methylsulfonyl) oxy) benzoate (116c, 1.3g, 4.8mmol) in acetonitrile (63mL) was added N-bromosuccinimide (1.1g, 6.2 mmol). The reaction was stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo, then diluted with water (30mL) and extracted with dichloromethane (2X 50 mL). The combined organic layers were washed with brine (30mL), dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (30% EtOAc/heptane) to give ethyl 3-bromo-2-hydroxy-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116d, 1.3g, 79% yield) as a yellow solid.
A solution of ethyl 3-bromo-2-hydroxy-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116d, 593mg, 1.5mmol), triphenylphosphine (0.50g, 1.9mmol) and tert-butyl ((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) (2-hydroxyethyl) carbamate (CpdLL, 0.54g, 1.5mmol) in tetrahydrofuran (12mL) was cooled to 0 deg.C and diisopropyl azodicarboxylate (0.40mL, 1.9mmol) was added dropwise. The reaction was slowly warmed to room temperature and stirred overnight. Water (15mL) was used to dilute the reaction and extracted with ethyl acetate (2X 15 mL). The combined organic layers were washed with brine (15mL), dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (20% EtOAc/heptane) to give ethyl 2- (2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) (tert-butoxycarbonyl) amino) ethoxy) -3-bromo-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116e, 0.58g, 52% yield) as a white solid.
To a solution of ethyl 2- (2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) (tert-butoxycarbonyl) amino) ethoxy) -3-bromo-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116e, 0.58g, 0.80mmol) in dichloromethane (8mL) was added 85% phosphoric acid (0.20mL, 2.8 mmol). The mixture was stirred at room temperature for 2 hours, then 85% phosphoric acid (0.20mL, 2.8mmol) was added and stirring continued for 2 hours. The reaction was carefully quenched with saturated aqueous sodium bicarbonate (10mL) and extracted with dichloromethane (2X 15 mL). The combined organic layers were washed with brine (15mL), dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography (20% EtOAc/heptane) to give ethyl 2- (2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) amino) ethoxy) -3-bromo-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116f, 0.25g, 50% yield) as a bright viscous solid.
To a solution of ethyl 2- (2- (((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) amino) -ethoxy) -3-bromo-6-methyl-5- ((methylsulfonyl) oxy) benzoate (116f, 0.54g, 0.86mmol) in methanol (2mL) was added sodium hydroxide solution (50% aqueous solution, 0.73g, 9.2 mmol). The reaction mixture was heated at 120 ℃ in a microwave for 1 hour, then diluted with water and acidified to pH-4 with concentrated hydrochloric acid. The resulting precipitate was collected by vacuum filtration and then dissolved in N, N-dimethylacetamide (5 mL). N, N-diisopropylethylamine (0.38mL, 2.2mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 0.39g, 1.0mmol) were added and the reaction was stirred at room temperature overnight. The crude reaction was diluted with water (10mL) and extracted with dichloromethane (2X 15 mL). The combined organic layers were washed with brine (15mL), dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in N, N-dimethylacetamide (5mL), and cesium carbonate (0.51g, 1.6mmol) and 2-iodopropane (0.12mL, 1.2mmol) were added. The mixture was heated at 75 ℃ for 1 hour, cooled to room temperature, then diluted with water (10mL) and extracted with ethyl acetate (2X 15 mL). The combined organic layers were washed with brine (15mL), dried over magnesium sulfate, concentrated in vacuo, and purified by column chromatography Method purification (30% EtOAc/heptane) to give 4- ((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) -9-bromo-7-isopropoxy-6-methyl-3, 4-dihydrobenzo [ f][1,4]Oxazazem-5(2H) -one (116g, 242mg, 48% yield) as a bright viscous solid.
To 4- ((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) -9-bromo-7-isopropoxy-6-methyl-3, 4-dihydrobenzo [ f][1,4]OxazazemTo a solution of (E) -5(2H) -one (116g, 98mg, 0.18mmol) in N, N-dimethylacetamide (2mL) was added cuprous cyanide (50mg, 0.55 mmol). The reaction mixture was heated at 120 ℃ in a sealed tube for 20 hours, cooled to room temperature, then heated to copper cyanide (25mg, 0.26mmol) and the reaction system was heated at 150 ℃ in a sealed tube for 5 hours. The reaction was cooled to room temperature, diluted with water (5mL) and extracted with methyl tert-butyl ether (2X 5 mL). The combined organic layers were washed with brine (5mL), dried over magnesium sulfate and concentrated in vacuo. The crude residue was dissolved in dichloromethane (0.5mL) and trifluoroacetic acid (0.5mL, 2mmol), stirred at room temperature overnight, then concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound (example 116, 13mg, 19% yield).1H NMR(700MHz，DMSO-d6)7.47(s，1H)，5.93(br.s.，1H)，4.58-4.69(m，3H)，4.12(br.s.，2H)，2.19(d，J＝12.91Hz，6H)，2.14(s，3H)，1.26(d，J＝6.02Hz，6H)：MS 396[M+H]。
Method M
Example 123: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-9- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one
Trifluoroacetic anhydride (42.0mL, 300mmol) was added dropwise to a cooled (-5 ℃ C.) solution of 2, 3-dihydroxybenzoic acid (8.30g, 53.9mmol) in trifluoroacetic acid (83mL) with stirring. Acetone (14.0mL, 190mmol) was then added dropwise over 27 minutes, the mixture was stirred and allowed to gradually warm to room temperature over 16.5 hours. The volatiles were concentrated in vacuo, the residue was dissolved in ethyl acetate (100mL), and the solution was slowly added to a rapidly stirred aqueous sodium bicarbonate solution (200 mL). After the evolution of gas had ceased, the mixture was extracted with ethyl acetate (3X 100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate/heptane) to give 8-hydroxy-2, 2-dimethyl-4H-1, 3-benzodioxin-4-one (123a, 3.55g, 34% yield) as a yellow-white solid.
Cesium carbonate (5.46g, 16.6mmol) was added to a solution of 8-hydroxy-2, 2-dimethyl-4H-1, 3-benzodioxin-4-one (123a, 1.50g, 7.73mmol) in N, N-dimethylformamide (31mL), the mixture was stirred at room temperature for 5 minutes, and then 2-iodopropane (1.00mL, 10.0mmol) was added. The mixture was stirred at room temperature for 80 minutes, then partitioned between deionized water (30mL) and ethyl acetate (2X 75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (ethyl acetate/heptane) to give 2, 2-dimethyl-8- (propan-2-yloxy) -4H-1, 3-benzodioxin-4-one (123b, 1.41g, 77% yield) as a colorless gel that slowly crystallized as a white solid.
A solution of 2, 2-dimethyl-8- (propan-2-yloxy) -4H-1, 3-benzodioxin-4-one (123b, 1.40g, 5.92mmol) in methanol (12mL) was treated with a solution of sodium methoxide in methanol (0.5M, 24mL, 12mmol) and stirred at room temperature for 3 hours and 40 minutes. The solvent was evaporated and the residue partitioned between ammonium chloride solution (saturated aqueous solution, 20mL) and ethyl acetate (2X 30 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give methyl 2-hydroxy-3- (propan-2-yloxy) benzoate (123c, 1.24g, 93% yield) as a colorless liquid.
Cesium carbonate (2.05g, 6.2mmol) was added to a solution of methyl 2-hydroxy-3- (prop-2-yloxy) benzoate (123c, 539mg, 2.40mmol) in N, N-dimethylformamide (9.6mL), resulting in the formation of a thick paste. Allyl bromide (0.25mL, 3.0mmol) was added and the mixture was stirred at room temperature for 1.5 h. Deionized water (15mL) was added and the solution was extracted with ethyl acetate (2X 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (ethyl acetate/heptane) to give methyl 3- (prop-2-yloxy) -2- (prop-2-en-1-yloxy) benzoate (123d, 474.5mg, 79% yield) as a colorless oil.
Ozone was bubbled through a cooled (-78 ℃) solution of methyl 3- (prop-2-yloxy) -2- (prop-2-en-1-yloxy) benzoate (123d, 438.1mg, 1.75mmol) in dichloromethane (17.5mL) until a persistent violet-blue color was obtained (about 5 minutes). Nitrogen was bubbled through the solution for 3 minutes, resulting in color fading, then dimethylsulfide (1.0mL, 13.5mmol) was added and the mixture warmed to room temperature for 1 hour. The solvent was evaporated and the residue partitioned between sodium carbonate (saturated aqueous solution, 10mL) and ethyl acetate (2X 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a crude residue. The crude aldehyde was dissolved in methanol (10.0mL), treated with 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one hydrochloride (Cpd V, 334mg, 1.87mmol) at room temperature for 5 minutes then sodium cyanoborohydride (332mg, 4.50mmol) was added and the mixture stirred at room temperature for 14.5 hours. The solvent was evaporated in vacuo and the residue partitioned between deionized water (10mL) and ethyl acetate (2X 20 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (EtOH + 5% NH)4OH in ethyl acetate) to give 2- (2- { [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ]Amino } ethoxy) -3- (propan-2-yloxy) benzoic acid methyl ester (123e, 76mg, 11% yield) as a colorless glass.
2- (2- { [ ((s))4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]A solution of methyl-amino } ethoxy) -3- (propan-2-yloxy) benzoate (123e, 76.2mg, 0.196mmol) in methanol (5.0mL) was stirred with sodium hydroxide (1.0M aqueous, 0.800mL, 0.800mmol) for 28 h, then 4.0M aqueous sodium hydroxide (0.5mL, 2.0mmol) was added and stirring continued at room temperature for 25 h. LCMS showed spontaneous cyclization of some material, while some non-cyclized material remained. The solvent was concentrated in vacuo and the residue was acidified to pH 2 with 1N aqueous hydrochloric acid. The resulting white precipitate was collected by suction filtration. The mother liquor was extracted with ethyl acetate (2 × 10mL), and the combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo, and combined with the precipitate. The aqueous layer was lyophilized and the residue suspended in N, N-dimethylformamide (6.0mL), passed through a 0.2 micron syringe filter to remove inorganic salts, then treated with triethylamine (0.08mL) and O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 87.0mg, 0.23mmol) at room temperature for 20 hours. The mixture was partitioned between deionized water (5mL) and ethyl acetate (3 × 15 mL); the combined organic layers were dried, filtered, and concentrated in vacuo. This batch was combined with the first batch and purified by reverse phase HPLC to give the title compound 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ]-9- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (example 123, 11mg, 16% yield) as a white solid.1H NMR(400MHz，DMSO-d6)11.58(br.s.，1H)，7.05-7.18(m，3H)，5.93(s，1H)，4.60(s，2H)，4.51(spt，J＝6.03Hz，1H)，4.01(t，J＝5.38Hz，2H)，3.43(t，J＝5.38Hz，2H)，2.19(s，3H)，2.14(s，3H)，1.23(d，J＝6.11Hz，6H)。MS：357[M+H]。
Method N
Example 124: 6-chloro-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7- (2,2, 2-trifluoroethoxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one
To a solution of 2-chloro-6-fluoro-3-methoxy-benzoic acid (1.00g, 4.89mmol) in anhydrous DMF (30mL) was added HATU (2.30g, 5.85mmol) and TEA (1.36mL, 9.76 mmol). The reaction mixture was stirred for 5 minutes, then 2- [ (2-benzyloxy-4, 6-dimethyl-pyridin-3-ylmethyl) -amino ] -ethanol (Cpd KK, 1.47g, 5.12mmol) was added as a solid in one portion. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (200mL) and water (200 mL). The organic phase was separated, washed with brine (2X 200mL), dried over sodium sulfate and concentrated in vacuo to give N- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -2-chloro-6-fluoro-N- (2-hydroxyethyl) -3-methoxybenzamide (124a, 2.31g, 100%) as a gum.
To a solution of N- (2-benzyloxy-4, 6-dimethyl-pyridin-3-ylmethyl) -2-chloro-6-fluoro-N- (2-hydroxy-ethyl) -3-methoxy-benzamide (124a, 2.31g, 4.88mmol) in anhydrous DMF (20mL) was added KOtBu (1M solution in THF, 12.2mL, 12.2 mmol). The reaction mixture was stirred at 100 ℃ for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200mL) and water (200 mL). The organic phase was separated, washed with brine (2X 200mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc) to give 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ]Methyl } -6-methyl-9- [2- (methylamino) pyrimidin-5-yl group]-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (124b, 668mg, 30% yield) as a solid.
4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-9- [2- (methylamino) pyrimidin-5-yl]-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepineA mixture of-5 (2H) -one (124b, 636mg, 1.40mmol) in TFA (10mL) was stirred at 60 ℃ for 3H. The solvent was removed in vacuo and the resulting residue partitioned between ether (100mL) and sodium bicarbonate (100 mL). The organic phase was separated, washed with brine (100mL), dried over sodium sulfate and concentrated in vacuo to give 6-chloro-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7-methoxy-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (124c, 503mg, 99% yield) as a white solid.
To 0 ℃ 6-chloro-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7-methoxy-3, 4-dihydro-1, 4-benzoxazepineTo a solution of (2H) -5 (124c, 500mg, 1.38mmol) in anhydrous DCM (10mL) was added BBr slowly3Solution (1M in DCM, 4.00mL, 4.00 mmol). The reaction mixture was stirred at 0 ℃ for 3 hours, then quenched with water and diluted to 100mL with water. The resulting mixture was extracted with DCM (3X 100 mL). The combined organic phases were dried over sodium sulfate and concentrated in vacuo to give 6-chloro-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ]-7-hydroxy-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (124d, 456mg, 95% yield) as a solid.
Reacting 6-chloro-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7-hydroxy-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (124d, 100mg, 0.287mmol), toluene-4-sulfonic acid 2,2, 2-trisA mixture of fluoro-ethyl ester (73.0mg, 0.287mmol), potassium carbonate (79.0mg, 0.574mmol) and anhydrous DMF (6mL) was heated in a microwave at 150 ℃ for 45 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50mL) and water (50 mL). The organic phase was separated, washed with water (50mL) and brine (50mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, MeOH/EtOAc) to give the title compound (example 124, 18mg, 16% yield) as a white solid.1H NMR(400MHz，DMSO-d6)11.62(br.s.，1H)，7.33(d，J＝8.93Hz，1H)，7.05(d，J＝8.93Hz，1H)，5.94(s，1H)，4.84(q，J＝8.60Hz，2H)，4.62(s，2H)，4.02(br.s.，2H)，3.41(br.s.，2H)，2.21(s，3H)，2.14(s，3H)；MS 431.1[M+1]。
Process O
Example 126: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7- (1, 4-dimethyl-1H-pyrazol-5-yl) -6-methyl-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one
Treatment of 3-bromo-2-methyl-6- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy with 6N HCl (0.2mL)]A solution of methyl benzoate (Cpd HH, 162mg, 0.434mmol) in MeOH (4mL) was stirred at room temperature for 30 min. The solvent was concentrated to 1mL in vacuo and the solution was partitioned between DCM (25mL) and NaHCO 3(saturated aqueous solution, 25 mL). The organic layer was concentrated in vacuo to give methyl 3-bromo-6- (2-hydroxyethoxy) -2-methylbenzoate (126a, 138mg, 110% yield) as a colorless oil.
To a solution of methyl 3-bromo-6- (2-hydroxyethoxy) -2-methylbenzoate (126a, 126mg, 0.436mmol) in DCM (5mL) was added Dess-Martin reagent (Dess-Martinperiodinane) (192mg, 0.429 mmol). The solution was stirred at room temperature for 2 hours. The solution was purified directly by column chromatography (silica gel, heptane/EtOAc) to give methyl 3-bromo-2-methyl-6- (2-oxoethoxy) benzoate (126b, 111mg, 90% yield) as a clear oil.
To a solution of methyl 3-bromo-2-methyl-6- (2-oxoethoxy) benzoate (126b, 109mg, 0.380mmol) in MeOH (5mL) was added Cpd V (122mg, 0.538 mmol). The suspension was sonicated until the reaction mixture was homogeneous. The solution was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (59mg, 0.800mmol) was added in one portion. The reaction mixture was stirred for 3 hours, then the solvent was concentrated in vacuo. The residue was dissolved in DCM (25mL) and the organic layer was washed with water (25 mL). The aqueous layer was extracted with DCM and the combined organic layers were concentrated in vacuo to give methyl 3-bromo-6- (2- { [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] amino } ethoxy) -2-methylbenzoate (126c, 161mg, 83%) as a white foam.
To 3-bromo-6- (2- { [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]To a solution of methyl amino } ethoxy) -2-methylbenzoate (126c, 134mg, 0.317mmol) in 1, 4-dioxane (1mL) was added trimethylaluminum (2.0M in heptane, 32.0mg, 0.440 mmol). The reaction mixture was stirred at room temperature for 30 minutes, heated at 55 ℃ for 2 hours, and then heated at 75 ℃ for 4 hours. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was stirred vigorously with EtOAc (25mL) and 10% aqueous rochelle brine. Once the mixture became homogeneous, the layers were separated and the organic layer was purified directly by column chromatography (silica gel, (7N NH)3MeOH solution) to give 7-bromo-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] ester]-6-methyl-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (126d, 36mg, 27% yield) as a light tan solid.
With N2Reacting 7-bromo-4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl)) Methyl radical]-6-methyl-3, 4-dihydro-1, 4-benzoxazepineA suspension of-5 (2H) -one (126d, 36mg), 1, 4-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (34mg, 0.092mmol) and sodium carbonate (2M aqueous solution, 32mg, 0.30mmol) in 1, 4-dioxane (3mL) was degassed for 10 minutes. With PdCl 2(DPPF) -DCM (8.2mg, 0.010mmol) was treated with the reaction mixture, heated in a microwave at 100 ℃ for 1 hour, and then heated in a microwave at 120 ℃ for another 1 hour. The reaction mixture was poured into DCM (25mL) and washed with water (3 × 25 mL). The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound (example 126, 7mg, 19% yield) as a white solid.1H NMR(400MHz，DMSO-d6)7.33(s，1H)，7.23(d，J＝8.07Hz，1H)，6.99(d，J＝8.19Hz，1H)，5.93(s，1H)，4.66(s，2H)，4.09(t，J＝5.44Hz，2H)，3.48(s，3H)，3.42-3.46(m，2H)，2.23(s，3H)，2.14(s，3H)，2.03(s，3H)，1.79(s，3H)；MS 407.1[M+1]。
Method P
Example 128: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-6-methyl-9- [2- (methylamino) pyrimidin-5-yl]-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one
4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -9-bromo-6-methyl-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (116)g, 121mg, 0.224mmol), N-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-amine (52.7mg, 0.224mmol) and a solution of sodium carbonate (2.0M, 71.2mg, 0.672mmol) in 1, 4-dioxane (2.0mL) was degassed (N.sub.2)5min, then adding PdCl2(dppf) -DCM (50.0mg, 0.0610 mmol). The reaction was heated at 100 ℃ for 1 hour. The reaction was diluted with water (25mL) and EtOAc (25 mL). The layers were separated and the organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc) to give 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ]Methyl } -6-methyl-9- [2- (methylamino) pyrimidin-5-yl group]-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (128a, 94mg, 74% yield) as a white solid.
To 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-9- [2- (methylamino) pyrimidin-5-yl group]-7- (prop-2-yloxy) -3, 4-dihydro-1, 4-benzoxazepineTo a solution of-5 (2H) -one (128a, 94mg, 0.17mmol) in DCM (1mL) was added 4M HCl in dioxane (1 mL). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (example 128, 40mg, 50% yield) as a white solid.1H NMR(400MHz，DMSO-d6)8.43(s，2H)，7.19(q，J＝4.63Hz，1H)，7.05(s，1H)，5.92(s，1H)，4.59-4.69(m，3H)，3.28(s，3H)，3.17(d，J＝5.31Hz，2H)，2.83(d，J＝4.80Hz，2H)，2.23(s，3H)，2.13(d，J＝2.27Hz，6H)，1.27(d，J＝6.06Hz，6H)；MS 478.2[M+1]。
Method Q
Example 130: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-N, 6-trimethyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoOxazazem-7-carboxamides
4-methoxybenzaldehyde (10g, 74mmol), 2-aminoethanol (4.9g, 81mmol) and NaHCO3A mixture of (9.3g, 110mmol) in MeOH (100mL) was refluxed for 3 hours. The reaction mixture was cooled to 15 ℃. To this mixture was added NaBH stepwise4(3.3g, 88 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2- [ (4-methoxybenzyl) amino group ]Ethanol (130a, 20g) as a brown oil.
To 3-bromo-6-fluoro-2-methylbenzoic acid (Cpd QQ, 4.8g, 2.4mmol), 2- [ (4-methoxybenzyl) amino]To a solution of ethanol (130a, 5.5g, 23mmol) and DIPEA (8g, 62mmol) in dry DMF (80mL) was added HATU (12g, 31 mmol). The mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (130 mL). The solution was washed with brine (4X 60mL), Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 2/1) to give 3-bromo-6-fluoro-N- (2-hydroxyethyl) -N- (4-methoxybenzyl) -2-methylbenzamide (130b, 4g, 48.8%) as a colorless oil.
3-bromo-6-fluoro-N- (2-hydroxyethyl) -N- (4-methoxybenzyl) -2-methyl-benzamide (130b, 5.00g, 12.6mmol) and Cs2CO3A mixture of (8.20g, 25.3mmol) in dry DMF (60mL) was stirred at 65 ℃ for 14 h. To the reaction mixture was added brine (100 mL). The mixture was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (4X 60mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 5/1) to give 7-bromo-4- (4-methoxybenzyl) -6-methyl-3, 4-dihydro-1, 4-benzoxazepine -5(2H) -one (130c, 2.8g, 59%) as a colorless oil.
Reacting 7-bromo-4- (4-methoxybenzyl) -6-methyl-3, 4-dihydro-1, 4-benzazepineA mixture of-5 (2H) -one (130c, 2.8g, 7.4mmol) in TFA (30mL) was refluxed for 14H. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 3/1) to give 7-bromo-6-methyl-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (7-bromo-6-methyl-3, 4-dihydro-1, 4-benzazepine-5(2H) -one (130d, 1.2g, 63%) as a brown solid.
Feeding 7-bromo-6-methyl-3, 4-dihydro-1, 4-benzoxazepine with CO-5(2H) -one (7-bromo-6-methyl-3, 4-dihydro-1, 4-benzoxazepine-5(2H) -one (130d, 0.80g, 3.1mmol), Pd (dppf) Cl2A mixture of (0.11g, 0.16mmol) and DIPEA (0.80g, 6.3mmol) in MeOH (40mL) was degassed and the mixture was stirred at 100 deg.C under 4MPa for 48 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petrol ether/EtOAc, 1/1) to give 6-methyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepineMethyl 7-carboxylate (130e, 0.34g, 46%) as an off-white solid.
To 6-methyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzene at 0 deg.COxazaTo a solution of methyl-7-carboxylate (130e, 0.10g, 0.45mmol) in DMF (8mL) was added NaH (54mg, 1.36mmol, 60% solution in oil). After stirring for 10 min at 0 ℃ 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 0.20g, 0.77mmol) was added. The mixture was stirred at room temperature overnight. Adding H to the reaction mixture 2O (30 mL). The mixture was extracted with EtOAc (2X 20 mL). The aqueous layer was acidified to pH 3 with concentrated HCl and extracted with EtOAc (2X 20 mL). The combined organic layers were washed with brine (4X 30mL) and Na2SO4Drying and concentration in vacuo afforded 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepine7-Carboxylic acid (130f, 0.17g, 84.7%) as an off-white solid.
To 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepineTo a solution of-7-carboxylic acid (130f, 0.17g, 0.38mmol), dimethylamine hydrochloride (47mg, 0.57mmol) and DIPEA (0.25g, 1.90mmol) in DMF (10mL) was added HATU (0.29g, 0.76 mmol). The mixture was heated at room temperature under N2Stirred under an atmosphere for 5 hours. Adding H to the reaction mixture2O (30 mL). The mixture was extracted with EtOAc (2X 20 mL). The combined organic layers were washed with brine (4X 30mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 1/1) to give 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -N, 6-dimethyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepine7-formamide (130g, 0.17g, 94.6%) as a white solid.
4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -N, 6-dimethyl-5-oxo-2, 3,4, 5-tetrahydro-1, 4-benzoxazepineMixture of-7-carboxamide (130g, 0.17g, 0.36mmol) and Pd/C (93mg) in MeOH (15mL) at room temperature in H2Stir for 2 hours in a balloon. The reaction mixture was concentrated in vacuo to give the title compound (example 130, 130mg, 94%) as a white solid.1H NMR (400MHz, chloroform-d): 11.34(s, 1H), 7.18-7.16(d, 1H), 6.88-6.86(d, 1H), 5.97(s, 1H), 4.90-4.86(d, 2H), 4.12(s, 1H), 3.93(s, 1H), 3.53(s, 2H), 3.13(s, 3H), 2.85(s, 3H), 2.36-2.35(d, 6H), 2.27(s, 3H); MS 256.8[ M + H ]]。
Process R
Example 131: 4- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-6-methyl-7- (prop-2-yloxy) -3, 4-dihydropyrido [4,3-f][1,4]Oxazazem-5(2H) -one
With N2Phenyl 5- (benzyloxy) -2-bromo-3-methylpyridine-4-carboxylate (2.4g, 6.0mmol) and Cs2CO3A suspension of (6.1g, 19mmol) in i-PrOH (36mL) was degassed for 2 minutes. Adding Pd to the reaction mixture2(dba)3(0.31g, 0.34mmol) and t-Bu-BippyPhos (0.34g, 0.66mmol, cas: 894086-00-1). The mixture was heated in a microwave at 115 ℃ for 1 hour. To the reaction mixture was added 4M NaOH (7mL) and MeOH (7mL), and the reaction mixture was stirred at 60 ℃ for 3 hours. The reaction mixture was concentrated in vacuo. To the residue were added EtOAc (60mL) and H 2O(80mL). The aqueous layer was acidified to pH 4 with concentrated HCl and extracted with EtOAc (2X 40 mL). The combined organic layers were washed with brine (60mL) and Na2SO4Drying and concentration in vacuo afforded 5- (benzyloxy) -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylic acid (131a, 1.1g, 60%) as a yellow solid.
At 0 ℃ in N2To 5- (benzyloxy) -3-methyl-2- (prop-2-yloxy) pyridine-4-carboxylic acid (131a, 1.4g, 4.7mmol) in dry CH under an atmosphere2Cl2TMSCHN dropwise added (50mL) in dry MeOH (5mL)2(2.6mL, 5.1mmol, 2M in hexanes). The reaction mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give methyl 5- (benzyloxy) -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131b, 1.1g, 75%) as a colorless oil.
A mixture of methyl 5- (benzyloxy) -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131b, 1.1g, 3.5mmol) and Pd/C (0.5g) in MeOH (60mL) in H2Hydrogenation in balloon for 2 hours at room temperature. By passingThe reaction mixture was filtered and the filtrate was concentrated in vacuo to give methyl 5-hydroxy-3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131c, 0.7g, 89%) as a yellow oil.
With N 2Methyl 5-hydroxy-3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131c, 0.70g, 3.1mmol), (tert-butyl 2-bromoethyl) carbamate (0.76g, 3.4mmol) and K2CO3(0.86g, 6.2mmol) in CH3The mixture in CN (24mL) was degassed and refluxed for 15 hours. To the reaction mixture was added brine (40mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (60mL) and Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 5- {2- [ (tert-butoxycarbonyl) amino group]Ethoxy } -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylic acid methyl ester (131d, 0.74g, 65%) as a yellow oilAnd (4) forming a substance.
To 5- {2- [ (tert-butoxycarbonyl) amino group at 5 deg.C]Ethoxy } -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylic acid methyl ester (131d, 0.74g, 2.0mmol) in dry CH2Cl2To the solution in (20mL) was added TFA (5 mL). The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuo to give methyl 5- (2-aminoethoxy) -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131e, 1.4g) as a brown oil.
A mixture of methyl 5- (2-aminoethoxy) -3-methyl-2- (propan-2-yloxy) pyridine-4-carboxylate (131e, 1.2g, 2.2mmol) and NaOEt (3.0g, 45mmol) in dry EtOH (60mL) was refluxed for 14 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in H 2O (30mL), extracted with EtOAc (2X 20 mL). The combined organic layers were washed with brine (30mL) and Na2SO4Drying and vacuum concentrating to obtain 6-methyl-7- (propyl-2-oxyl) -3, 4-dihydropyrido [4,3-f][1,4]Oxazazem-5(2H) -one (131f, 0.34g) as a brown solid.
To 6-methyl-7- (prop-2-yloxy) -3, 4-dihydropyrido [4,3-f ] at 0 deg.C][1,4]OxazazemTo a solution of-5 (2H) -one (131f, 70mg, 0.30mmol) in dry DMF (6mL) was added NaH (36mg, 0.90mmol, 60% in oil). The mixture was stirred at 0 ℃ for 10 minutes. To the mixture was added 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 155mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (20 mL). The solution was washed with brine (5X 15mL), Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-7- (prop-2-yloxy) -3, 4-dihydropyrido [4,3-f][1,4]Oxazazem-5(2H) -one (131g, 0.14g, 100%) as a colorless oil.
4- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]Methyl } -6-methyl-7- (prop-2-yloxy) -3, 4-dihydropyrido [4,3-f ][1,4]OxazazemMixture of-5 (2H) -one (131g, 140mg, 0.30mmol) and 10% Pd/C (80mg) in MeOH (15mL) in H2Stir for 3 hours in a balloon. By passingThe reaction mixture was filtered through a pad and the filtrate was concentrated in vacuo to give the title compound (example 131, 110mg, 98%) as a white solid.1H NMR (400MHz, chloroform-d): 11.45(s, 1H), 7.72(s, 1H), 5.97(s, 1H), 5.26-5.21(m, 1H), 4.87(s, 2H), 4.00-3.97(t, 2H), 3.56-3.53(t, 2H), 2.36(s, 3H), 2.28-2.26(d, 6H), 1.35-1.33(d, 6H); MS 372.2[ M + H]。
Method S
Example 132-A: 9-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepine-1-ketone and example 132-B: 7-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepine-1-ketones
Will 8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepineA solution of-1-one (25.0mg, 0154mmol) and n-chlorosuccinimide (20.6mg, 0.154mmol) in AcOH (3mL) was stirred at 100 ℃ for 4.5 h. The reaction mixture was partitioned between ethyl acetate (20mL) and water (20 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo to give 9-chloro-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepine -1-one (132a) and 7-chloro-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepineA mixture of-1-ketones (132b) (35mg, 100%) as a clear oil.
To 9-chloro-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepine-1-one (132a) and 7-chloro-8-methoxy-2, 3,4, 5-tetrahydro-1H-2-benzazepineTo a mixture of (E) -1-one (132b) (35.0mg, 0.150mmol) in DMF (5mL) was added 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 47.1mg, 0.180 mmol). The reaction mixture was heated at 80 ℃ for 24 hours. The reaction mixture was poured into NaOAc-HOAc buffer (5mL) and extracted with EtOAc (2X 10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting brown oil was dissolved in MeOH (1mL) and HCl (3M in n-butanol, 0.05mL) was added. The reaction mixture was heated at 70 ℃ for 24 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (example 132-a, first eluting product, 20mg, 36%);1h NMR (400MHz, methanol-d 4)7.09-7.14(m, 1H), 7.05-7.10(m, 1H), 6.13(s, 1H), 4.89(s, 1H), 4.71-4.79(m, 1H), 3.88(s, 3H), 3.38(dd, J ═ 5.93, 14.86Hz，1H)，2.92-3.01(m，1H)，2.57-2.73(m，2H)，2.35(s，3H)，2.25(s，3H)，2.06-2.14(m，1H)，1.53-1.64(m，1H)；MS 361.1[M+1](ii) a And (example 132-B, second elution of product, 4mg, 7%); 1H NMR (400MHz, methanol-d 4)7.26(s, 1H), 7.22(s, 1H), 6.13(s, 1H), 4.78(s, 2H), 3.91(s, 3H), 3.26-3.29(m, 2H), 2.63(t, J ═ 7.09Hz, 2H), 2.34(s, 3H), 2.26(s, 3H), 1.78(t, J ═ 6.66Hz, 2H); MS 361.1[ M +1 ]](ii) a As a white solid.
Method T
Example 133: 7-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -6- (prop-2-yloxy) -2, 3-dihydro-1H-isoindol-1-one
A mixture of 7-chloro-6-hydroxy-2, 3-dihydro-isoindol-1-one (500mg, 2.72mmol), 2-iodopropane (556mg, 3.27mmol), and cesium carbonate (1.33mg, 4.08mmol) in DMF (20mL) was stirred at 80 deg.C overnight. The solution was cooled to room temperature and the reaction mixture was partitioned between ethyl acetate (50mL) and water (50 mL). The organic phase was separated, washed with water (50mL) and brine (50mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc) to give 7-chloro-6-isopropoxy-2, 3-dihydro-isoindol-1-one (133a, 300mg, 65% yield) as a solid.
A mixture of 7-chloro-6-isopropoxy-2, 3-dihydro-isoindol-1-one (133a, 120mg, 0.532mmol), 2-benzyloxy-3-chloromethyl-4, 6-dimethyl-pyridine (Cpd Z, 139mg, 0.532mmol), cesium carbonate (260mg, 0.798mmol) and potassium iodide (132mg, 0.798mmol) in DMF (6mL) was stirred at 100 ℃ overnight. The solution was cooled to room temperature and the reaction mixture was partitioned between ethyl acetate (50mL) and water (50 mL). The organic phase was separated, washed with water (50mL) and brine (50mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc) and concentrated in vacuo. The residue was treated with TFA at room temperature overnight. Excess TFA was removed in vacuo and the resulting residue partitioned between ethyl acetate (50mL) and sodium bicarbonate (50 mL). The organic phase was separated, washed with brine (50mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, MeOH/EtOAc, 1/10) to give the title compound (example 133, 20mg, 12% in 2 steps) as a solid.1H NMR (400MHz, chloroform-d) 12.09(br.s., 1H), 7.08-7.13(m, 1H), 7.02-7.07(m, 1H), 5.94(s, 1H), 4.66(s, 2H), 4.44-4.55(m, 1H), 4.31(s, 2H), 2.37(s, 3H), 2.24(s, 3H), 1.36(d, J ═ 6.06Hz, 6H): MS 361[ M + H ]]。
Method U
Example 134: 2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -6-ethoxy-2, 3-dihydro-1H-isoindol-1-one
To a solution of methyl 5-amino-2-methylbenzoate (6.25g, 37.8mmol) at 0 ℃ in H2SO4(10mL) and H2NaNO was added to a solution in O (160mL)2(aqueous, 3.78N, 10 mL). The resulting mixture was stirred at 0 ℃ for 10 minutes. After 10 minutes, the mixture was added to refluxing CuSO 4To the solution (1N, 100mL), was refluxed for 1 hour. The mixture was cooled to room temperature and quenched with CH2Cl2(2X 200 mL). By H2The organic layer was washed with O (50mL) and brine (50mL), Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 5:1) to give methyl 5-hydroxy-2-methylbenzoate (134a, 4.2g, 67%) as a yellow solid.
To methyl 5-hydroxy-2-methylbenzoate (134a, 0.600g, 3.63mmol) and iodoethane (1) at room temperature13g, 7.26mmol) in CH3CN (10mL) solution was added K2CO3(1.00g, 7.26 mmol). The resulting mixture was heated at 100 ℃ for 12 hours. With EtOAc (25mL) and H2The reaction mixture was diluted with O (10 mL). The organic layer was separated, washed with NaOH (2N, 5mL), H2O (5mL) and brine (5mL), Na2SO4Drying and concentration in vacuo afforded methyl 5-ethoxy-2-methylbenzoate (134b, 0.7g, 99%) as a yellow liquid.
To methyl 5-ethoxy-2-methylbenzoate (134b, 0.700g, 3.61mmol) in CCl at room temperature4To a solution in (12mL) was added BPO (18.0mg, 0.0720mmol) and NBS (0.706g, 3.97 mmol). The resulting mixture was heated to 80 ℃ under N2Heating in an atmosphere for 12 hours. By CH2Cl2The mixture was diluted (10mL) and brine (3 mL). Separating the organic layer with NaHCO 3(2N，10mL)、H2O (5mL) and brine (5mL), Na2SO4Drying and vacuum concentrating. The residue was purified by column chromatography (petroleum ether/EtOAc ═ 5:1) to give methyl 2- (bromomethyl) -5-ethoxybenzoate (134c, 0.85g, 86%) as a yellow liquid.
To a solution of methyl 2- (bromomethyl) -5-ethoxybenzoate (134c, 0.636g, 2.33mmol) and 3- (aminomethyl) -4, 6-dimethylpyridin-2 (1H) -one (Cpd V, 0.390g, 2.56mmol) in MeOH (20mL) at room temperature was added TEA (0.258g, 2.56 mmol). The resulting mixture was heated at 80 ℃ for 12 hours. The reaction mixture was concentrated in vacuo to give the crude product, which was purified by column Chromatography (CH)2Cl2MeOH ═ 20:1), then recrystallized from MeOH (15mL) to give the title compound (example 134, 32.6mg, 4.4%) as a white solid.1H NMR (400MHz, methanol-d 4)7.39-7.37(m, 1H), 7.25(s, 1H), 7.24-7.14(m, 1H), 6.09(s, 1H), 4.73(s, 2H), 4.33(s, 2H), 4.09-4.07(q, 2H), 2.30(s, 3H), 2.24(s, 3H), 1.43-1.40(t, 3H); MS 313.0[ M +1 ]]。
Method V
Example 217: 8-chloro-2- (4, 6-dimethyl-2-oxo-1, 2-dihydro-pyridin-3-ylmethyl) -7-methoxy-4-methyl-3, 4-dihydro-2H-isoquinolin-1-one
Methyl 2-chloro-6-iodo-3-methoxy-benzoate (217a, 8.1g, 24.8mmol), tert-butyl cyanoacetate (7.0g, 49.6mmol), CuI (0.47g, 2.48mmol) and Cs 2CO3(12.1g, 37.2mmol) of the mixture was mixed in 82.7mL of LDMSO. The reaction mixture was degassed 3 times and heated in an oil bath at 120 ℃ overnight to give 217 b. Cooling the reaction system to room temperature; methyl iodide (3.59g, 24.8mmol) was added and stirred at room temperature overnight. To the reaction mixture was added 300mL of H2O, extracted with EtOAc (300mL, then 2X 150 mL). The combined organic extracts were washed with brine (2 × 100mL), dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by column chromatography using 30% EtOAc/heptane to give methyl 6- (1- (tert-butoxy) -2-cyano-1-oxoprop-2-yl) -2-chloro-3-methoxybenzoate, 217c, as a red oil (2.75g, 35% yield).1H NMR(400MHz，CDCl3)ppm 7.38(d，J＝8.93Hz，1H)7.00(d，J＝8.93Hz，1H)3.97(s，3H)3.95(s，3H)1.97(s，3H)1.49(s，9H)。
To a solution of 217c (2.66g, 7.52mmol) in 20mL DCM was added 20mL TFA. The reaction was stirred at room temperature for 4 h. To the reaction mixture was added 50mL of H2O, the layers were separated, the aqueous layer was extracted with EtOAc, the organic layers were combined, concentrated, and purified by column chromatography using 20% EtOAc/heptane to give methyl 2-chloro-6- (1-cyanoethyl) -3-methoxybenzoate 217d as a colorless oil (300mg, 15.7%).1H NMR(400MHz，CDCl3)ppm 7.46(d，J＝8.68Hz，1H)7.04(d，J＝8.68Hz，1H)3.99(s，3H)3.94(s，3H)3.89(q，J＝7.21Hz，1H)1.61(d，J＝7.21Hz，3H)。
The ester 217d (0.35g, 1.4mmol) and cobalt chloride hexahydrate (II) II) (0.98g, 4.1mmol) was dissolved in 15 mM LEOH and the purple solution was cooled with an ice bath. NaBH4(0.26g, 6.9mmol) was added stepwise and the reaction warmed to room temperature and heated at 50 ℃ for 36 h. Evaporating the solvent and adding H to the residue2O50 mL and EtOAc 50mL, pH adjusted to 3-4 by slow addition of concentrated HCl, sonication ensured all inorganic salts were dissolved, the aqueous layer was adjusted to pH 8-9 with 30% KOH, extracted with EtOAc 3X 75 mL. The combined organic layers were concentrated and purified by column chromatography using 30% EtOAc/heptane to give 8-chloro-7-methoxy-4-methyl-3, 4-dihydroisoquinolin-1 (2H) -one 217e as a white solid (0.18g, 62% yield).1H NMR(400MHz，CDCl3)ppm 7.18(br.s.，1H)7.10(d，J＝8.80Hz，1H)7.01(d，J＝8.44Hz，1H)3.89(s，3H)3.51(dt，J＝12.41，3.88Hz，1H)3.16(ddd，J＝12.56，6.14，4.40Hz，1H)2.93-3.04(m，1H)1.28(d，J＝6.97Hz，3H)。
To a mixture of 217e (50mg, 0.22mmol) and 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (Cpd Z, 61mg, 0.23mmol) in 3mL dioxane was added a THF solution of KHMDS (1.0M, 0.55 mL). The reaction mixture was heated at 100 ℃ for 1h and then cooled to room temperature. The reaction mixture was concentrated and 20mL of H was added2And O. The mixture was extracted with EtOAc 3X 20mL, then concentrated and purified by column chromatography using 100% EtOAc to give 2- ((2- (benzyloxy) -4, 6-dimethylpyridin-3-yl) methyl) -8-chloro-7-methoxy-4-methyl-3, 4-dihydroisoquinolin-1 (2H) -one 217f as a white solid (94mg, 94% yield). 1H NMR(400MHz，CDCl3)ppm 7.46(d，J＝6.85Hz，2H)7.28-7.39(m，3H)6.93-7.02(m，2H)6.63(s，1H)5.37-5.50(m，2H)4.97(d，J＝14.31Hz，1H)4.88(d，J＝14.31Hz，1H)3.90(s，3H)3.30(dd，J＝12.72，4.16Hz，1H)3.01(dd，J＝12.72，6.11Hz，1H)2.76(td，J＝6.54，4.28Hz，1H)2.43(s，3H)2.28-2.39(m，3H)1.00(d，J＝6.97Hz，3H)。
To 217f (90mg, 0.2mmol) was added 1mL TFA and the mixture was stirred at room temperature overnight. Excess TFA was removed under reduced pressure. To the residue was added 1mL MeOH, followed by 1.5mL 7N NH3Neutralizing the solution with MeOH. By means of preparativeThe product was purified by HPLC to give the compound of example 217 as a white solid (56mg, 77%).1H NMR(700MHz，DMSO-17mm)ppm 11.54(br.s.，1H)7.23(d，J＝8.36Hz，1H)7.20(d，J＝8.36Hz，1H)5.89(s，1H)4.64(d，J＝13.86Hz，1H)4.55(d，J＝13.65Hz，1H)3.85(s，3H)3.45(dd，J＝12.87，3.85Hz，1H)3.20(dd，J＝12.98，5.50Hz，1H)2.93(dd，J＝11.00，5.72Hz，1H)2.17(s，3H)2.13(s，3H)1.06(d，J＝6.82Hz，3H)；MS：361[M+1]
Method W
Example 145: 8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -4, 4-difluoro-7-methoxy-3, 4-dihydroisoquinolin-1 (2H) -one
To a solution of Cpd R (0.0370g, 0.149mmol) in DMF (4.0mL) in an ice bath was added potassium tert-butoxide (1.0M in THF, 0.145mL, 0.145 mmol). After 5 min, Cpd Z (0.0421g, 0.161mmol) was added and the reaction stirred in an ice bath for 0.5 h. The reaction was acidified with AcOH (1 drop), diluted with ethyl acetate, washed with water (2 ×) and brine, and concentrated in vacuo. The resulting oil was purified on silica gel (Biotage SNAP, 10g, gradient 0-50% ethyl acetate in heptane) to give 145a (0.059g, 84%) as a clear oil which solidified on standing.1H NMR(400MHz，CDCl3-d)7.51(d，J＝8.59Hz，1H)，7.42-7.47(m，2H)，7.28-7.38(m，3H)，7.12(d，J＝8.59Hz，1H)，6.65(s，1H)，5.44(s，2H)，4.94(s，2H)，3.97(s，3H)，3.59(t，J＝11.62Hz，2H)，2.44(s，3H)，2.31(s，3H)；MS 473[M+H]+。
To a solution of 145a (0.057g, 0.12mmol) in acetic acid (2.0mL) was added potassium iodide (0.062g, 0.37 mmol). The reaction was stirred at 50 ℃ for 1h, then thiourea (0.018g, 0.24mmol) was added to scavenge the benzyl iodide. At 50 ℃ and then 2 After 0 min, the benzyl iodide was consumed. The reaction mixture was cooled to room temperature and water (10mL) was added. The resulting precipitate was collected by filtration, washed with water, and dried under high vacuum to give the title compound of example 145 (0.042g, 91%) as a white powder.1H NMR(400MHz，DMSO-d6)11.63(br.s.，1H)，7.64(d，J＝8.56Hz，1H)，7.46(d，J＝8.68Hz，1H)，5.92(s，1H)，4.62(s，2H)，4.02(t，J＝12.17Hz，2H)，3.94(s，3H)，2.17(s，3H)，2.14(s，3H)；MS 383[M+H]+。
Method X
Example 293: 5-bromo-8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one
A solution of methyl 5-bromo-2-methyl-3-nitrobenzoate (29.0g, 106mmol) and N, N-dimethylformamide dimethyl acetal (42.0mL, 317mmol) in N, N-dimethylformamide (200mL) was stirred at 110 ℃ overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (300mL) and water (300mL) ester. The organic phase was separated, washed with water (2 × 300mL) and brine (1 × 300mL), concentrated to dryness in the presence of silica gel, and purified by silica gel chromatography (gradient elution with 0-80% ethyl acetate in heptane) to give 7-bromo-5-nitro-1H-isochromen-1-one (293a, 9.62g, 32% yield) as a solid.1H NMR(400MHz，CDCl3-d)8.76(d，J＝1.47Hz，1H)，8.60(d，J＝2.20Hz，1H)，7.46(d，J＝6.11Hz，1H)，7.34(d，J＝6.11Hz，1H)。MS：269[M+1]。
A sealed tube containing 7-bromo-5-nitro-1H-isochromen-1-one (293a, 9.20g, 34.1mmol) and 7N ammonia in methanol (100mL) was stirred at 60 ℃ overnight. After cooling in an ice bath, the precipitate was collected by filtration and washed with cold methanol Washing and air drying gave 7-bromo-5-nitroisoquinolin-1 (2H) -one (293b, 7.6g, 83% yield) as a yellow solid.1HNMR(400MHz，DMSO-d6)11.82(br.s.，1H)，8.56-8.64(m，2H)，7.48(d，J＝7.58Hz，1H)，6.89(d，J＝7.58Hz，1H)。MS：267/269[M-1]。
A mixture of 7-bromo-5-nitroisoquinolin-1 (2H) -one (293b, 4.00g, 14.9mmol), 1, 4-dimethyl-1H-1, 2, 3-triazole (2.17g, 22.3mmol), palladium acetate (334mg, 1.49mmol), CataXiUMA (butyldi-1-adamantylphosphine) (1.10g, 2.97mmol) and potassium acetate (7.30g, 74.3mmol) in 2-methyl-2-butanol (100mL) was degassed with nitrogen and heated in a sealed tube at 120 ℃ overnight. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (300mL) and water (300 mL). The organic phase was separated, washed with brine (1 × 300mL), dried over sodium sulfate, concentrated to dryness and purified by silica gel chromatography (gradient elution with 0% -10% methanol in ethyl acetate) to give 7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5-nitroisoquinolin-1 (2H) -one (293c, 2.55g, 60% yield) as a solid.1H NMR(400MHz，DMSO-d6)11.95(br.s.，1H)，8.57(s，2H)，7.55(d，J＝5.38Hz，1H)，6.98(d，J＝7.34Hz，1H)，4.00(s，3H)，2.29(s，3H)。MS：284[M-1]。
A solution of 7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -5-nitroisoquinolin-1 (2H) -one (293c, 1.0g, 3.5mmol) and Raney nickel (6g) in isopropanol (60mL) was heated in a sealed tube at 110-. 16 parts of a 1g batch (16 g 293c total) were prepared by this method and then combined for purification. The combined solution was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to-30 mL, resulting in the formation of a precipitate. The precipitate was collected by filtration to give 5-amino-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293d, 4.0g, 26% yield) as a white solid. The first cake containing Raney nickel was dissolved in methanol/dichloromethane (1:1, 400 mL. times.4), stirred for 30 min, filtered, and concentrated in vacuo to afford a second crop of 5-amino-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293d, 8.0g, 54% yield) as a gray solid.
N-iodosuccinimide (5.27g, 23.43mmol) was added portionwise to a solution of 5-amino-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293d, 5.5g, 21.3mmol) in glacial acetic acid (400mL), and the resulting mixture was stirred at room temperature for 3 days. A second portion of N-iodosuccinimide (2.6g, 12.7mmol) was then added and stirring continued at room temperature overnight. The mixture was concentrated in vacuo to remove acetic acid. The residue was dissolved in methanol (200mL), concentrated to dryness, and purified by silica gel chromatography (eluting with 1:1-1:2 petroleum ether/ethyl acetate, then using 100:1-50:1 dichloromethane/methanol) to give 5-amino-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6-iodo-3, 4-dihydroisoquinolin-1 (2H) -one (293e, 5.0g, 60% yield) as a yellow solid.
Two batches of 5-amino-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6-iodo-3, 4-dihydroiso-quinolin-1 (2H) -one (293e, 2.5g/6.5mmol per batch, 5.0g/13mmol in total) in glacial acetic acid (100 mL per batch) were treated dropwise with sulfonyl chloride (1 g, 75mmol per batch) at 20-25 ℃. The mixture was stirred for 2 hours, then combined and concentrated in vacuo to remove volatiles. The residue was purified by silica gel chromatography (10:1 dichloromethane/methanol) to give 5-amino-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6-iodo-3, 4-dihydroisoquinolin-1 (2H) -one (293f, 5.5g, 90% purity, 90% yield) as a yellow solid.
Two batches were prepared by the following method: a mixture of 5-amino-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -6-iodo-3, 4-dihydroisoquinolin-1 (2H) -one (293f, 2.9g, 6.9mmol per batch) and palladium on carbon (2.9g) in glacial acetic acid (29mL) and methanol (290mL) was stirred in a hydrogen balloon at room temperature overnight. The combined reaction mixture was filtered through celite and the filter pad was washed with methanol (300 mL). The filtrate was concentrated, and the residue was purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5-amino-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293g, 3.6g, combined yield 65%) as a yellow solid.1H NMR(400MHz，DMSO-d6)：8.12(s，1H)，6.82(s，1H)，3.75(s，3H)，3.29-3.28(m，2H)，2.70-2.67(m，2H)，2.07(s，3H)。MS：292[M+1]。
To a solution of 5-amino-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293g, 300mg, 1.03mmol) in tetrahydrofuran (5mL) cooled in an ice bath was added 40% aqueous hydrobromic acid (6.86g, 33.93 mmol). The mixture was stirred at room temperature for 3 hours, then cooled to 0 ℃ again. Copper (I) bromide (295mg, 2.06mmol) was added followed by sodium nitrite (78mg, 1.13mmol) and the resulting mixture was stirred at 0 ℃ for 2 h. The mixture was neutralized with sodium hydroxide and extracted with ethyl acetate (2X 100 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography to give 5-bromo-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293H, 60mg, 16.5% yield) as a white solid.
Sodium hydride (60% dispersion in mineral oil, 18mg, 0.45mmol) was added to a solution of 5-bromo-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293H, 80mg, 0.225mmol) in anhydrous N, N-dimethylformamide (15mL) cooled in an ice bath, and the resulting mixture was stirred at 0 ℃ for 30 minutes. Solid 2- (benzyloxy) -3- (chloromethyl) -4, 6-dimethylpyridine (compound Z, 59mg, 0.225mmol) was added and stirring continued at 0 ℃ for 1 h. While still cold, the reaction was quenched with water (20 mL). The resulting solution was extracted with ethyl acetate (2X 50 mL). The combined organic extracts were washed with brine (5 × 50mL), dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 1:1 petroleum ether/ethyl acetate) to give 2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl ] methyl } -5-bromo-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293i, 76mg, 58% yield) as a light yellow oil.
2- { [2- (benzyloxy) -4, 6-dimethylpyridin-3-yl]A solution of methyl } -5-bromo-8-chloro-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (293i, 76mg, 0.13mmol) in dichloromethane (4mL) was cooled in an ice-water bath. Trifluoroacetic acid (6mL) was added and the mixture was stirred, warmed to room temperature And (4) at night. After removal of volatiles in vacuo, the residue was purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5-bromo-8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl]-7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one (example 293, 56.9mg, 90% yield) as a white solid.1H NMR (400MHZ, methanol-d 4): 7.79(s, 1H), 6.10(s, 1H), 4.75(s, 2H), 3.84(s, 3H), 3.59(t, J ═ 6.2Hz, 2H), 3.07(t, J ═ 6.2Hz, 2H), 2.30(s, 3H), 2.24(s, 3H), 2.16(s, 3H). MS: 492[ M +1 ]]。
Additional compounds of the invention are prepared by modifications of the methods exemplified herein. Selected compounds prepared and corresponding characterization data are shown in tables 1 and 2 below.
TABLE 1
TABLE 2
Biological assays and data
Purification of WT and mutant EZH2Y641N
WT and mutant EZH2 were purified using the same method. The genes for the EZH2, EED, SUZ12, and RBBP4 proteins were cloned into the pBacPAK9 vector (Clontech). RBBP4 was FLAG-tagged at the N-terminus. Baculovirus populations of these proteins were expressed for co-infection with SF9 insect cells. Insect cell pellets were lysed with a buffer containing 25mM Tris pH8.0, 300mM NaCl, 0.5mM TCEP, inhibitor completely free of EDTA (Roche), 0.1% NP-40. The supernatant from the lysate is combined with M2 antibody resin (Sigma) were incubated together. The resin was washed with a column and eluted with 0.2mg/ml FLAG peptide. The eluate was incubated with omngleave nuclease (Epicentre Technologies) overnight at 4 ℃ and then concentrated on a Superdex 200(GE Healthcare) column. Superdex 200 column was eluted with 25mM Tris pH 8.0, 150mM NaCl, 0.5mM TCEP. Fractions containing PRC2 complex were collected.
Nucleosome assay protocol:
the same protocol was used for WT and mutant EZH2Y6412N assays.
A. Preparation of compounds
1. Preparation of a stock solution of 10mM in 100% DMSO from solid Material
2. Serial dilutions of 10mM compound stock solutions 2 or 3-fold in 100% DMSO produced 11-point dose-responsive compounds
B. Preparation of reagents
1. Preparation of assay buffer containing 100mM Tris pH 8.5, 4mM DTT and 0.01% Tween-201 ×
2. Purified HeLA oligonucleosomes and recombinant histone H1(New England Biolabs) were diluted to 1.67X with assay buffer
3. PRC24 protein complex (EZH2, EED, SUZ12, RbAp48) was diluted 3.5X with assay buffer
4. Using 0.94 u Ci/hole radioactive SAM (Perkin Elmer) and enough unlabeled SAM (Sigma), with test buffer preparation 10x3H SAM solution at 1.5. mu.M final concentration
5. Dilute TCA to 20% with DI water
C. Enzyme reaction
1. When WT EZH2 was used, the final reaction conditions were 4nM of PRC 24-protein complex; or when using the Y641N mutant EZH2, the final reaction conditions were 6nM of the PRC 24-protein complex; 1.5 u M SAM, 25 u g/mL oligonucleosome, 50nM rH1 in 50 u l reaction volume
2. Mu.l of diluted compound was added to the assay plate (96-well V-bottom polypropylene plate) or 1. mu.l DMSO was used in the control well
3. Add 30. mu.l nucleosomes to the assay plate
4. Mu.l of WT or Y641N mutant PRC24 protein complex was added to the assay plate
5. Adding 5 μ l3H SAM to initiate the reaction
After 6.60 minutes the reaction was stopped by adding 100. mu.l of 20% TCA
7. 50 μ l of the quenched reaction was added to a prepared filter plate (Millipore # MSIPN4B10)
8. Vacuum was applied to the filter plate to filter the reaction mixture through the membrane
9. The filter plates were washed with 5X 200. mu.l PBS, blotted dry and oven dried for 30 minutes
10. Add 50. mu.l microscint-20 scintillation fluid (Perkin Elmer) to each well, wait 30 minutes and count with liquid scintillation counter
D. Data analysis
1. Data were correlated with 4-parameter IC using proprietary curve fitting software50Equation fitting to determine IC50The value is obtained.
Preparation of HeLA oligonucleosomes:
reagent
Cell pellet 15L HeLa S3(Accelgen) +6L HeLa S3 (in house)
-Mnase(Worthington Biochemicals)
Device
-SW-28 rotor
Dunn homogenizer/B pestle
Buffer solution
-lysis solution: 20mM Hepes pH7.5, 0.25M sucrose, 3mM MgCl20.5% Nonidet P-40, 0.5mMTCEP, 1Roche protease tablet
-B：20mM Hepes pH7.5，3mM MgCl20.5mM EDTA, 0.5mM TCEP, 1Roche protease tablet
-MSB: 20mM Hepes pH7.5, 0.4M NaCl, 1mM EDTA, 5% v/v glycerol, 0.5mM TCEP, 0.2mM PMSF
-LSB：20mM Hepes pH7.5，0.1M NaCl，1mM EDTA，0.5mM TCEP，0.2mM PMSF
-NG：20mM Hepes pH7.5，1mM EDTA，0.4m NaCl，0.2mM PMSF，0.5mM TCEP
-storing: 20mM Hepes pH7.5, 1mM EDTA, 10% glycerol, 0.2mM PMSF, 0.5mM TCEP
Scheme(s)
A. Core
1. Resuspend 10L of this in 2X 40mL of lysate Using a Dounce homogenizer
2.3000 Xg rotate 15'
3. Repeating for more than 2 times
4. Resuspend pellet in 2X 40mL B
5.3000 Xg rotate 15'
B. Nuclear resuspension
1. The pellet was resuspended in 2X 40mL MSB. 5000 Xg of 20 'rotating'
2. Resuspend pellet in 2X 15mL HSB
3. Collection and homogenization of 40 strokes to shear DNA
4.10000 Xg precipitate 20'
5. Dialysis with LSB for O/N4 ℃ except batch A, which was dialyzed with LSB in 50nM NaCl for 3h
Mnase digestion
Testing Mnase digestion (200ul)
1. Warmed to 37 ℃ of 5'
2. Adding CaCl2To 3mM and 10U Mnase added
30' at 3.37 deg.C, taking 25 μ L every 5
4. Method, with 1 μ L of 0.5M EDTA, 40 μ L H2O, 15. mu.L of 10% SDS, 10. mu.L of 5M NaCl and 100. mu.L of phenol-chloroform, each after addition, was vortexed
5. Rotation 5' 13k
6. Run 5. mu.L of aqueous phase on 1% agarose gel
7. The time taken to generate a 2kb fragment
8. 15 'for A & B and 20' for C & D for upscaling
NaCl was added to 0.6M
D. Sucrose gradient 1
1. A gradient of 6X 34mL of 5-35% sucrose in NG solution was poured in a 38.5mL pollyallomer tube using an AKTA purifier
2. 4.0mL was directed at the top of the MN1 digest
3. Rotate 26k 16h 4 DEG C
4. 2mL of the fraction was taken from the top
5. Run on Page gel
6. Dialyzing the fraction with 4L LSB 7-140/N4 ℃ except for the D batch having 2X 2h
7. Repeat 3X
E. Finally, the product is processed
1. All were collected and concentrated with Amicon (moderate turbidity)
2. Adding 10% glycerol
3. 5K 15 'of rotation'
4.1.8mg/mL, 80mL, total 144mg
Biological activity
The biological activity of selected examples in the EZH2 nucleosome assay is provided in table 3. Data are presented as WTEZH2 and mutant Y641N EZH2IC50Value (. mu.M).
TABLE 3
All publications and patent applications cited in this specification are herein incorporated by reference in their entirety. Although the foregoing invention has been described in some detail by way of illustration and example, it will be apparent to those of skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (7)

1. A compound of formula (II-A):
or a pharmaceutically acceptable salt thereof,
wherein:
R1is C1-C4Alkyl or halogen;
R2is a 5-6 membered heteroaryl selected from pyrazolyl, isoxazolyl or triazolyl, each of which isUnsubstituted or substituted by 1 to 3R32Substitution;
R3is H;
R4is H or halogen;
m is 0 and R5Is absent;
R32each independently selected from-Cl, -F, -OH, -CH3、-CH2CH3、-CF3、-CH2OH、-CH2OCH3、-OCH3、-OC2H5、-OCF3、-CN、-C(O)NH2、-C(O)NHCH3、-C(O)N(CH3)2、-NHC(O)CH3、-NH2、-NHCH3、-N(CH3)2Cyclopropyl, or phenyl, wherein said phenyl is optionally substituted with 1-3 independently selected halogens, C1-C4Alkyl or C1-C4Alkoxy substitution;
x and Z are independently C1-C4Alkyl or C1-C4An alkoxy group; and is
Y is H.
2. A compound or salt of claim 1, wherein R1Is chlorine.
3. A compound or salt of claim 1, wherein R32Each independently selected from-CH3and-CH2CH3。
4. A compound or salt of claim 1, wherein R4Is a halogen.
5. A compound which is 5-bromo-8-chloro-2- [ (4, 6-dimethyl-2-oxo-1, 2-dihydropyridin-3-yl) methyl ] -7- (1, 4-dimethyl-1H-1, 2, 3-triazol-5-yl) -3, 4-dihydroisoquinolin-1 (2H) -one, or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
7. Use of a compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.
HK15109626.6A 2012-12-21 2013-12-05 Aryl and heteroaryl fused lactams HK1208866B (en)

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