WO2024032782A1 - Vaccine adjuvants and uses thereof - Google Patents
Vaccine adjuvants and uses thereof Download PDFInfo
- Publication number
- WO2024032782A1 WO2024032782A1 PCT/CN2023/112638 CN2023112638W WO2024032782A1 WO 2024032782 A1 WO2024032782 A1 WO 2024032782A1 CN 2023112638 W CN2023112638 W CN 2023112638W WO 2024032782 A1 WO2024032782 A1 WO 2024032782A1
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- WIPO (PCT)
- Prior art keywords
- alkyl
- independently selected
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- vaccine
- deuterium
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
- A61K2039/55511—Organic adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to vaccine adjuvants, compositions comprising such vaccine adjuvants, processes for the synthesis thereof, and uses thereof.
- the immune system has evolved to recognize and neutralize different types of threats in order to maintain the homeostasis of the host, and it is generally broken down into two arms: adaptive and innate.
- the adaptive immune system is specialized to recognize as foreign those antigens not naturally expressed in the host and to mount an anti-antigen response through the coordinated actions of many leukocyte subsets.
- the hallmark of adaptive immune responses is their ability to provide "memory" or long-lasting immunity against the encountered antigen. While this specific and long-lasting effect is critical to host health and survival, the adaptive immune response requires time to generate a full-blown response.
- the innate immune system compensates for this time delay and is specialized to act quickly against different insults or danger signals. It provides the first line of defense against bacteria, viruses, parasites and other infectious threats, but it also responds strongly to certain danger signals associated with cellular or tissue damage.
- the innate immune system has no antigen specificity but does respond to a variety of effector mechanisms. Opsonization, phagocytosis, activation of the complement system, and production of soluble bioactive molecules such as cytokines or chemokines are all mechanisms by which the innate immune system mediates its response. By responding to these damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) described above, the innate immune system is able to provide broad protection against a wide range of threats to the host.
- DAMPs damage-associated molecular patterns
- PAMPs pathogen-associated molecular patterns
- cytosolic DNA and RNA are among these PAMPs and DAMPs. It has recently been demonstrated that the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase) . Upon recognition of cytosolic DNA, cGAS catalyzes the generation of the cyclic-dinucleotide 2'3'-cGAMP, an atypical second messenger that strongly binds to the ER-transmembrane adaptor protein STING. A conformational change is undergone by cGAMP-bound STING, which translocates to a perinuclear compartment and induces the activation of critical transcription factors IRF-3 and NF- ⁇ . This leads to a strong induction of type I interferons and production of pro-inflammatory cytokines such as IL-6, TNF- ⁇ and IFN- ⁇ .
- pro-inflammatory cytokines such as IL-6, TNF- ⁇ and IFN- ⁇ .
- type I interferons and pro-inflammatory cytokines on various cells of the immune system has been very well established.
- these molecules strongly potentiate T-cell activation by enhancing the ability of dendritic cells and macrophages to uptake, process, present and cross-present antigens to T-cells.
- the T-cell stimulatory capacity of these antigen-presenting cells is augmented by the up-regulation of critical co-stimulatory molecules, such as CD80 or CD86.
- type I interferons can rapidly engage their cognate receptors and trigger the activation of interferon-responsive genes that can significantly contribute to adaptive immune cell activation.
- type I interferons are shown to have antiviral activities by directly inhibiting human hepatitis B virus and hepatitis C virus replication, and by stimulating immune responses to virally infected cells.
- Compounds that can induce type I interferon production are used in vaccines, where they act as adjuvants, enhancing specific immune responses to antigens and minimizing side effects by reducing dosage and broadening the immune response.
- interferons and compounds that can induce interferon production, have potential use in the treatment of human cancers. Such molecules are potentially useful as anti-cancer agents with multiple pathways of activity. Interferons can inhibit human tumor cell proliferation directly and may be synergistic with various approved chemotherapeutic agents. Type I interferons can significantly enhance anti-tumor immune responses by inducing activation of both the adaptive and innate immune cells. Finally, tumor invasiveness may be inhibited by interferons by modulating enzyme expression related to tissue remodeling.
- Vaccination is the most effective and cost-effective medical treatment for common infectious diseases.
- Vaccines usually refer to modified attenuated or inactivated pathogenic microorganisms or synthetic products containing their components, which are equivalent to a stimulating antigen relative to the human immune system.
- Vaccination of the human body can make the body produce an effective immune response against the pathogen and generate an immune memory, prompting the body to quickly activate the immune system when the relevant pathogenic microorganism invades, allowing the body to develop resistance to the pathogenic microorganism, eliminating or weakening the pathogen. Health hazards of microorganisms.
- adjuvants can assist vaccines to more effectively stimulate the body's immune system to respond, including humoral immunity and cellular immunity.
- An effective adjuvant can have both quantitative and qualitative effects on the action of the vaccine.
- the addition of adjuvants can not only enhance the strength of the immune response, reduce the amount of vaccine required and the number of immunizations, but also change the type and direction of the immune response by selecting different adjuvants, so that the protective effect of the vaccine is maximized and optimal.
- the present disclosure relates to vaccine adjuvants and/or vaccine compositions thereof, use of the sting agonist in the preparation of the vaccine adjuvant or the vaccine compositon, as well as these vaccine adjuvants and compositions comprising the sting agonist, which may be useful as agents to induce immune responses, to induce STING-dependent type I interferon production, to enhance or prolong an immune response, and/or to prevent/treat a cell proliferation disorder (eg. Tumor) or infectious diseases.
- a cell proliferation disorder eg. Tumor
- the present invention relates to a vaccine adjuvant including a sting agonist.
- the sting agonist is a compound of Formula Y-1, Y-2, Y-3, or an ester, stereoisomer, tautomer, isotopic derivative, prodrug or pharmaceutically acceptable salt:
- each W is independently selected from CR 1 , C (R 1 ) 2 , N, NR 1 , O or S;
- each W 1 is independently selected from C, CR 1 , or N;
- each W 2 is independently selected from C, CR 1 , or N;
- each Z 1 is independently selected from CR 1 , C (R 1 ) 2 , N, NR 1 , O or S;
- each Z 2 is independently selected from CR 1 , C or N;
- each Z 3 is independently selected from CR 1 , C (R 1 ) 2 , N, NR 1 , O or S;
- each Z 4 is independently selected from C, CR 1 or N;
- each Z 5 is independently selected from C, CR 1 or N;
- each R 1 is independently selected from H, deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 , CN or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 ;
- R 2 and R 3 are independently selected from the group consisting of O- (C 1 -C 4 alkylene or haloalkylene) , C 1 -C 5 alkylene or haloalkylene, N (R 6 ) - (C 1 -C 4 alkylene or haloalkylene) , -T a -C 1 -C 6 alkyl-T b -, -T a -N (Rs) -T b , -T a -O-T b , -T a -PEG n -O-T b , -T a -S-S-T b , -T a -S-S-S-T b , -T a -N (Rs) -T b -, -T a -C 2 -C 6 alkenyl-T b -, -T a -C 2 -C 6 alkenyl-T
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and
- each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen;
- each R 4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR 6 , N (R 6 ) 2 , COOR 6 , C (O) N (R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R 6 ) ;
- each X 2 is independently selected from (C (R 8 ) 2 ) (1-3) , NR 8 (C (R 8 ) 2 ) (1-3) , -NH (C (R 8 ) 2 ) (1-3) , –N (C 1-6 alkyl) (C (R 8 ) 2 ) (1-3) or –N (haloC 1-6 alkyl) (C (R 8 ) 2 ) (1-3) ; wherein each R 8 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N (R 6 ) 2 ; optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached,
- Y-1, Y-2 or Y-3 is independently selected from
- Y-1, Y-2 or Y-3 is independently selected from
- the sting agonist is a compound of Formula (A) , (B) , (C) , or a pharmaceutically acceptable salt:
- each W is independently selected from CR 1 or N;
- each R 1 is independently selected from H, deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 , CN or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 ;
- R 2 and R 3 are independently selected from the group consisting of O- (C 1 -C 4 alkylene or haloalkylene) , C 1 -C 5 alkylene or haloalkylene, N (R 6 ) - (C 1 -C 4 alkylene or haloalkylene) , -T a -C 1 -C 6 alkyl-T b -, -T a -N (Rs) -T b , -T a -O-T b , -T a -PEG n -O-T b , -T a -S-S-T b , -T a -S-S-S-T b , -T a -N (Rs) -T b -, -T a -C 2 -C 6 alkenyl-T b -, -T a -C 2 -C 6 alkenyl-T
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and
- each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen;
- each R 4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR 6 , N (R 6 ) 2 , COOR 6 , C (O) N (R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R 6 ) ;
- each X 2 is independently selected from (C (R 8 ) 2 ) (1-3) , NR 8 (C (R 8 ) 2 ) (1-3) , -NH (C (R 8 ) 2 ) (1-3) , –N (C 1-6 alkyl) (C (R 8 ) 2 ) (1-3) or –N (haloC 1-6 alkyl) (C (R 8 ) 2 ) (1-3) ; wherein each R 8 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N (R 6 ) 2 ; optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached,
- Formula (A) is independently selected from the group consisting of
- the compound is of Formula (A-1) :
- Formula (C) is independently selected from the group consisting of
- each W is independently CR 1 .
- each W is independently is CH or CF.
- each W is independently N.
- each R 1 is independently selected from H, deuterium, halogen, OR 6 , N (R 6 ) 2 , CN or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 .
- each R 1 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 3 alkyl, CN and C 1 -C 3 haloalkyl.
- each R 1 is independently selected from the group consisting of H, deuterium, halogen, CN and C 1 -C 3 alkyl.
- each R 1 is independently selected from the group consisting of H, deuterium, F, Cl , Br, CN and methyl.
- each R 1 independently is hydrogen or halogen.
- each R 1 independently is hydrogen or F.
- each R 1 independently is hydrogen or CN.
- each R 1 independently is deuterium.
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H , deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- R 2 and R 3 are independently selected from O- (C 1 -C 4 alkylene or haloalkylene) -C 2 -C 6 alkenyl, C 1 -C 5 alkylene or haloalkylene, (C 1 -C 4 alkylene or haloalkylene) -N (R 6 ) , and N (R 6 ) - (C 1 -C 4 alkylene or haloalkylene) -C 2 -C 6 alkenyl, -C 0-6 alkyl-NH-C 0-6 alkyl-, -C 0-6 alkyl-N (C 1-6 alkyl) -C 0-6 alkyl-, -C 0-6 alkyl-O-C 0-6 alkyl-, -C 0-6 alkyl-PEG n -O-C 0-6 alkyl, -C 0-6 alkyl, -C 0-6 alkyl-PEG n -O-C
- T a and T b each independently are -N (Rs) -, -O-, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl it optionally substituted with one or more halogen; each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- each R 5 is independently -OR 7 , NR 7 or -C (O) OR 7 ;
- each R 7 is independently hydrogen, deuterium or C 1-2 alkyl
- each R 10 is independently hydrogen, deuterium, C 1-2 alkyl or halogen.
- each R 7 is independently hydrogen, deuterium, or methyl.
- each R 10 is independently hydrogen, deuterium, methyl or fluorine.
- one R 10 is hydrogen, and the other R 10 is methyl or fluorine.
- one R 10 is deuterium, and the other R 10 is methyl or fluorine.
- R 2 -R 3 is selected from the group consisting of - (CH 2 ) 2-8 -, -O (CH 2 ) 1-7 -, -O (CH 2 ) 1-6 O-, -OCH 2 CH (CH 3 ) CH 2 O-, -OCH (CH 3 ) CH 2 CH (CH 3 ) O-, -NH (CH 2 ) 1-7 -, - (CH 2 ) 1- 6 NH (CH 2 ) 1-6 -, - (CH 2 ) 1-6 N (CH 3 ) (CH 2 ) 1-6 -, -NH (CH 2 ) 1-6 O-, -NH-CO-NH-, -N (CH 3 ) CO-NH-,
- R 2 -R 3 is selected from the group consisting of - (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) 5 -, -O (CH 2 ) 2 -, -O (CH 2 ) 3 -, -O (CH 2 ) 4 -, -O (CH 2 ) 2 O-, -O (CH 2 ) 3 O-, -O (CH 2 ) 4 O-, -OCH 2 CH (CH 3 ) CH 2 O-, -OCH (CH 3 ) CH 2 CH (CH 3 ) O-, -O (CH 2 ) 4 O-, -O (CH 2 ) 5 O-, -NH (CH 2 ) 2 -, -NH (CH 2 ) 3 -, -NH (CH 2 ) 4 -,
- each R 4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR 6 , N (R 6 ) 2 , COOR 6 , C (O) N (R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and
- each R 4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, and N (R 6 ) 2 .
- each R 6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1- C 3 alkyl, C 1- C 3 alkoxy, C 2- C 4 alkenyl, C 2- C 4 alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 7-membered carbocyclic ring, 7-member
- each R 6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -NO 2 , carbony
- each R 6 is independently selected from the group consisting of H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH 2 F, -CHF 2 , -CF 3 and
- each X 2 is independently selected from (C (R 8 ) 2 ) (1-3) , wherein each R 8 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N (R 6 ) 2 ; optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R 8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 2 independently is - (C (R 8 ) 2 ) 1-3 -, wherein each R 8 independently is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , or C 3 -C 6 cycloalkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen, OR 6 , or N (R 6 ) 2.
- each X 2 independently is - (C (R 8 ) 2 ) 1 - 3 -, wherein at least two R 8 , together with the one or more atoms to which they are attached, form C 3 -C 6 cycloalkyl or 3-to 6-membered heterocycloalkyl.
- each X 2 independently is -C (R 8 ) 1-3 -.
- each X 2 independently is - (CH 2 ) 1-3 -.
- each X 2 independently is -C (R 8 ) 2 -.
- each X 2 independently is -CH 2 -.
- each X 2 independently is -C (R 8 ) 2 C (R 8 ) 2 -.
- each X 2 independently is -CH 2 CH 2 -.
- each X 2 independently is -C (R 8 ) 2C (R 8 ) 2 C (R 8 ) 2 -.
- each X 2 independently is -CH 2 CH 2 CH 2 -.
- each X 2 is CH 2 CHR 8 , where R 8 is selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl.
- each X 2 is CH 2 CHR 8 , wherein R 8 is selected from the group consisting of H, deuterium, CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.
- each X 2 is CHR 8 CHR 8 , where each R 8 is independently selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, and optionally the 2 R 8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
- each X 2 is CHR 8 CHR 8 , where each R 8 is independently selected from the group consisting of H, deuterium and C 1 -C 3 alkyl, and optionally the 2 R 8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
- each X 2 is CH 2 C (R 8 ) 2 , where each R 8 is independently selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, and optionally the 2 R 8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 2 is CH 2 C (R 8 ) 2 , where each R 8 is independently selected from the group consisting of H, deuterium and C 1 -C 3 alkyl, and optionally the 2 R 8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 3 is independently selected from the group consisting of COOR 6 , C (O) SR 6 , C (S) OR 6 , SO 2 R 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOR 6 , SO 2 R 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOR 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOH, COOCH 3 , CONH 2 , and CN.
- each R 9 is independently selected from the group consisting of H, deuterium, COOR 6 , and SO 2 R 6 .
- each R 9 is independently H or deuterium, . preferably H.
- the compound is of Formula (Aa) , (Ba) , or (Ca) :
- the compound is of Formula (Ab) , or (Bb) :
- the compound is of Formula (Ac) , (Bc) , or (Cc) :
- each heterocyclic ring group and each carbocyclic ring group includes single ring, spiral ring, bridge ring, fused ring and various combinations of spiral ring, bridge ring and/or fused ring.
- the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
- the compound is the compounds described in Table 1.
- the sting agonist is a compound of Formula I, II, III, IV or V, or an ester, stereoisomer, tautomer, isotopic derivative, prodrug or pharmaceutically acceptable salt thereof:
- each W is independently selected from CR 1 or N;
- each R 1 is independently selected from H, deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 , CN or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 ;
- R 2 and R 3 are independently selected from O- (C 1 -C 4 alkylene or haloalkylene) , C 1 -C 5 alkylene or haloalkylene, N (R 6 ) - (C 1 -C 4 alkylene or haloalkylene) , -T a -C 1 -C 6 alkyl-T b -, -T a -N (Rs) -T b , -T a -O-T b , -T a -PEG n -O-T b , -T a -S-S-T b , -T a -S-S-S-T b , -T a -N (Rs) -T b -, -T a -C 2 -C 6 alkenyl-T b -, -T a -C 2 -C 6 alkyn
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and
- each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen;
- each R 4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR 6 , N (R 6 ) 2 , COOR 6 , C (O) N (R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R 6 ) ;
- each X 2 is independently selected from (C (R 8 ) 2 ) (1-3) , -NR 8 (C (R 8 ) 2 ) (1-3) , -NH (C (R 8 ) 2 ) (1-3) , –N (C 1-6 alkyl) (C (R 8 ) 2 ) (1-3) or –N (haloC 1-6 alkyl) (C (R 8 ) 2 ) (1-3) ; wherein each R 8 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N (R 6 ) 2 ; optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached
- the compound is of Formula I-1:
- each W is independently is CR 1 .
- each W is independently is CH or CF.
- each W is independently is N.
- each R 1 is independently selected from H, deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 , CN or C 1 -C 6 alkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more deuterium, halogen, OR 6 , N (R 6 ) 2 , COOR 6 , or C (O) N (R 6 ) 2 .
- each R 1 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 3 alkyl, CN and C 1 -C 3 haloalkyl.
- each R 1 is independently selected from the group consisting of H, deuterium, halogen, CN and C 1 -C 3 alkyl.
- each R 1 is independently selected from the group consisting of H, deuterium, F, Cl , Br, CN and methyl.
- each R 1 independently is hydrogen or halogen.
- each R 1 independently is hydrogen or F.
- each R 1 independently is hydrogen or CN.
- each R 1 independently is deuterium.
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- T a and T b each independently are absent, -N (Rs) -, -O-, C 1 -C 6 alkyl, -N (Rs) - (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -N (Rs) -, -N (R S ) - (C 1 -C 6 alkyl) -N (Rs) -, -O- (C 1 -C 6 alkyl) -, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- R 2 and R 3 are independently selected from O- (C 1 -C 4 alkylene or haloalkylene) -C 2 -C 6 alkenyl, C 1 -C 5 alkylene or haloalkylene, (C 1 -C 4 alkylene or haloalkylene) -N (R 6 ) , and N (R 6 ) - (C 1 -C 4 alkylene or haloalkylene) -C 2 -C 6 alkenyl, -C 0-6 alkyl-NH-C 0-6 alkyl-, -C 0-6 alkyl-N (C 1-6 alkyl) -C 0-6 alkyl-, -C 0-6 alkyl-O-C 0-6 alkyl-, -C 0-6 alkyl-PEG n -O-C 0-6 alkyl, -C 0-6 alkyl-S
- T a and T b each independently are -N (Rs) -, -O-, - (C 1 -C 6 alkyl) -O-, or -O- (C 1 -C 6 alkyl) -O-; wherein the C 1 -C 6 alkyl it optionally substituted with one or more halogen; each Rs independently is H, deuterium or C 1 -C 6 alkyl optionally substituted with one or more halogen.
- R 2 -R 3 is selected from
- each R 5 is independently -OR 7 , NR 7 or -C (O) OR 7 ;
- each R 7 is independently hydrogen, deuterium or C 1-2 alkyl
- each R 10 is independently hydrogen, deuterium, C 1-2 alkyl or halogen.
- each R 7 is independently hydrogen, deuterium or methyl.
- each R 10 is independently hydrogen, deuterium, methyl or fluorine.
- one R 10 is hydrogen, and the other R 10 is methyl or fluorine.
- one R 10 is deuterium, and the other R 10 is methyl or fluorine.
- R 2 -R 3 is selected from the group consisting of - (CH 2 ) 2-8 -, -O (CH 2 ) 1-7 -, -O (CH 2 ) 1-6 O-, -OCH 2 CH (CH 3 ) CH 2 O-, -OCH (CH 3 ) CH 2 CH (CH 3 ) O-, -NH (CH 2 ) 1-7 -, - (CH 2 ) 1- 6 NH (CH 2 ) 1-6 -, - (CH 2 ) 1-6 N (CH 3 ) (CH 2 ) 1-6 -, -NH (CH 2 ) 1-6 O-, -NH-CO-NH-, -N (CH 3 ) CO-NH-,
- R 2 -R 3 is selected from the group consisting of - (CH 2 ) 2 -, - (CH 2 ) 3 -, - (CH 2 ) 4 -, - (CH 2 ) 5 -, -O (CH 2 ) 2 -, -O (CH 2 ) 3 -, -O (CH 2 ) 4 -, -O (CH 2 ) 2 O-, -O (CH 2 ) 3 O-, -O (CH 2 ) 4 O-, -OCH 2 CH (CH 3 ) CH 2 O-, -OCH (CH 3 ) CH 2 CH (CH 3 ) O-, -O (CH 2 ) 4 O-, -O (CH 2 ) 5 O-, -NH (CH 2 ) 2 -, -NH (CH 2 ) 3 -, -NH (CH 2 ) 4 -, - (CH 2 ) 2 ) 2
- each R 4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, OR 6 , N (R 6 ) 2 , COOR 6 , C (O) N (R 6 ) 2 , SO 2 R 6 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl substituted by OR 6 , C 2 -C 6 alkenyl, C 2 -C 6 haloalkenyl, C 2 -C 6 alkenyl substituted by OR 6 , C 2 -C 6 alkynyl, C 2 -C 6 haloalkynyl, C 2 -C 6 alkynyl substituted by OR 6 , C 3 -C 6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and
- each R 4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, OC 1 -C 3 alkyl, OC 1 -C 3 haloalkyl, C 2 -C 3 alkenyl, C 2 -C 3 alkynyl, and N (R 6 ) 2 .
- each R 6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, -N 3 , -NO 2 , carboxyl, C 1- C 3 alkyl, C 1- C 3 alkoxy, C 2- C 4 alkenyl, C 2- C 4 alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, 8-membered heterocyclic ring, 5-membered
- each R 6 is independently selected from the group consisting of H, deuterium, -F, -Cl, -Br, -I, -NH 2 , -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH2F, -CHF2, and -CF3.
- each X 2 is independently selected from (C (R 8 ) 2 ) (1-3) , wherein each R 8 is independently selected from the group consisting of H, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by OR 6 , and C 1 -C 6 alkyl substituted by N (R 6 ) 2 ; optionally 2 R 8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R 8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 2 independently is - (C (R 8 ) 2 ) 1-3 -, wherein each R 8 independently is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, CN, OR 6 , N (R 6 ) 2 , or C 3 -C 6 cycloalkyl; wherein the C 1 -C 6 alkyl is optionally substituted with one or more halogen, OR 6 , or N (R 6 ) 2.
- each X 2 independently is - (C (R 8 ) 2 ) 1 - 3 -, wherein at least two R 8 , together with the one or more atoms to which they are attached, form C 3 -C 6 cycloalkyl or 3-to 6-membered heterocycloalkyl.
- each X 2 independently is -C (R 8 ) 1-3 -.
- each X 2 independently is - (CH 2 ) 1-3 -.
- each X 2 independently is -C (R 8 ) 2 -.
- each X 2 independently is -CH 2 -.
- each X 2 independently is -C (R 8 ) 2 C (R 8 ) 2 -.
- each X 2 independently is -CH 2 CH 2 -.
- each X 2 independently is -C (R 8 ) 2C (R 8 ) 2 C (R 8 ) 2 -.
- each X 2 independently is -CH 2 CH 2 CH 2 -.
- each X 2 is CH 2 CHR 8 , where R 8 is selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl.
- each X 2 is CH 2 CHR 8 , wherein R 8 is selected from the group consisting of H, deuterium, CH 3 , CH 2 OH, CH 2 CH 3 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 OCH 3 , and cyclopropyl.
- each X 2 is CHR 8 CHR 8 , where each R 8 is independently selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, and optionally the 2 R 8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
- each X 2 is CHR 8 CHR 8 , where each R 8 is independently selected from the group consisting of H, deuterium and C 1 -C 3 alkyl, and optionally the 2 R 8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
- each X 2 is CH 2 C (R 8 ) 2 , where each R 8 is independently selected from the group consisting of H, deuterium, C 1 -C 3 alkyl, C 1 -C 3 alkyl substituted by OH, C 1 -C 3 alkyl substituted by OC 1 -C 3 alkyl, and C 3 -C 6 cycloalkyl, and optionally the 2 R 8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 2 is CH 2 C (R 8 ) 2 , where each R 8 is independently selected from the group consisting of H, deuterium and C 1 -C 3 alkyl, and optionally the 2 R 8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
- each X 3 is independently selected from the group consisting of COOR 6 , C (O) SR 6 , C (S) OR 6 , SO 2 R 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOR 6 , SO 2 R 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOR 6 , C (O) N (R 9 ) 2 , and CN.
- each X 3 is independently selected from the group consisting of COOH, COOCH 3 , CONH 2 , CONH-SO 2 -N (CH 3 ) 2 , CONH-SO 2 -CH 3 , and CN.
- each R 9 is independently selected from the group consisting of H, deuterium, COOR 6 , and SO 2 R 6 .
- each R 9 is independently H or deuterium, preferably H.
- the compound is of Formula Ia, IIa, IIIa, IVa or Va:
- the compound is of Formula Ib, IIb, IIIb, or IVb:
- the compound is of Formula Ic, IIc, IIIc, IVc or Vc:
- each heterocyclic ring group and each carbocyclic ring group includes single ring, spiral ring, bridge ring, fused ring and various combinations of spiral ring, bridge ring and/or fused ring.
- the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
- the compound is the compounds described in Table 2.
- the compound is an isotopic derivative of any one of the compounds described in the two tables above and prodrugs and pharmaceutically acceptable salts thereof.
- the compound is an isotopic derivative of any one of the compounds described in the two tables above and pharmaceutically acceptable salts thereof.
- the compound is an isotopic derivative of any one of prodrugs of the compounds described in the two tables above and pharmaceutically acceptable salts thereof.
- the sting agonist is a compound described in the two tables.
- any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
- the present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
- stereoisomer refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers.
- the configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers.
- the invention includes all possible stereoisomers of the compound.
- any of the compound of formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V is intended to include its isotopic derivative.
- the isotopic derivatives have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope.
- isotopes include and are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 35 S, 36 Cl, respectively.
- the isotopic derivative is a deuterated derivative, wherein one or more hydrogen atoms in one or more substituents are replaced with deuterium, e.g. all hydrogens in one or more alkyl substituents are replaced with deuterium (the respective moiety/moieties are then perdeuterated) .
- Substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index.
- the concentration of such a heavier isotope, specifically deuterium may be defined by the isotopic enrichment factor.
- isotopic enrichment factor as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
- the vaccine adjuvant in the present disclosure, wherein the vaccine adjuvant further includes a solvent.
- the present disclosure provides a vaccine adjuvant composition, comprising a sting agonist described herein and at least one pharmaceutically acceptable excipient.
- the sting agonist is in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
- the present invention also provides a vaccine composition comprising a vaccine adjuvant described herein and a vaccine.
- the vaccine is selected from pathogenic bacteria or viruses that produce T-lymphocyte-independent antibody immune responses and T-lymphocyte-dependent antibody immune responses; the vaccine is a tumor vaccine.
- the vaccine is selected from live attenuated vaccines, inactivated vaccines, antitoxins, subunit vaccines (including peptide vaccines) , vector vaccines, nucleic acid vaccines, etc.
- the vaccine is selected from capsular polysaccharide vaccine, cholera vaccine or novel coronavirus vaccine.
- the vaccine is selected from Streptococcus pneumoniae vaccines.
- the vaccine comprises at least one antigen, and the antigen is selected from the group consisting of viral antigen, protozoal antigen, bacterial antigen, fungal antigen, cancer antigen and allergen.
- the viral antigen may be derived from viruses including but not limited to: Epstein-Barr virus (EBV) , hepatitis A virus (HAV) , hepatitis B virus (HBV) , hepatitis C virus (HCV) , hepatitis D virus (HDV) , hepatitis E virus (HEV) , Hantaan virus, cytomegalovirus (CMV) , human immunodeficiency virus (HIV) , influenza virus, human papillomavirus (HPV) , poliovirus, ebola virus, rotavirus, dengue virus, West Nile virus, yellow fever virus, adenovirus, Japanese encephalitis virus, BK virus, smallpox virus, Zika virus, severe fever with thrombocytopenia syndrome (SFTS) virus, herpes simplex virus (HSV) or Severe Acute Respirator Syndrome Coronavirus 2 (SARS-CoV-2) , such as COVI
- the protozoal antigens include, but are not limited to, antigens from Plasmodium spp. or Toxoplasma spp., schistosomae antigens, leishmania major and other leishmaniae antigens, Trypanosoma cruzi antigens, antigens from Entamoeba spp., Babesia spp., Trypanosoma spp., Giardia spp., leishmania spp., Pneumocystis spp., Trichomonas spp., Schisostoma spp..
- the bacterial antigen may be antigens from Neisseria spp.; antigens from Streptococcus spp.; antigens from Streptococcus agalactiae, Streptococcus mutans, Haemophilus ducreyi, Moraxella spp.; antigens from Bordetella spp.; antigens from Mycobacterium spp.; antigens from Escherichia spp.; antigens from Vibrio spp.; antigens from Shigella spp., Yersinia spp.; antigens from Y. pestis, Y.
- pseudotuberculosis Campylobacter spp.; antigens from Salmonella spp., Listeria spp., Helicobacter spp.; antigens from Pseudomonas spp.; Staphylococcus spp., Enterococcus spp., Clostridium spp.; antigens from C. botulinum; antigens from C. difficile; antigens from Bacillus spp., Corynebacterium spp.; antigens from Borrelia spp.; antigens from B. garinii, B. afzelii; antigens from B. andersonfi; antigens from B.
- hermsii antigens from Ehrlichia spp., Rickettsia spp.; Chlamydia spp.; antigens from Chlamydia pneumoniae; antigens from C. psittaci, Leptospira spp., Treponema spp.; antigens from T. denticola, T. hyodysenteriae; antigens from M. tuberculosis; antigens from Chlamydia; antigens from Streptococcus spp.; antigens from Haemophilus spp.; antigens from non typeable H. influenzae.
- the fungal antigen include, but are not limited to, e.g., antigens from Candida spp.; histoplasma fungal antigens such as heat shock protein 60 (HSP60) ; antigens from Cryptococcus spp.; coccidiodes fungal antigens; and tinea fungal antigens.
- HSP60 heat shock protein 60
- the cancer antigen is an antigen specially expressed on a cancer cell and recognized/attacked by the immune system as a foreign body.
- the cancer antigen may be expressed on cancer cells of all types and a specific type of cancer.
- As the cancer antigen a protein having strong immunogenicity and never be expressed in normal cells, is preferable.
- cancer antigen includes, but is not limited to: WT1, MUC1, LMP2, HPVE6, HPVE7, EGFRv III, HER-2/neu, MAGE-A3, p53nonmutant, HSP70, GPC3, MUC1, Casp8, CDAM1, cMyb, EVC1, EVC2, Helios, Fas, NY-ESO-1, PSMA, GD2, CEA, MelanA/MART1, Ras mutant, gp100, p53 mutant, Proteinase3 (PR1) , bcr-abl, Tyrosinase, Survivin, PSA, hTERT, Sarcoma translocation breakpoints, EphA2, PAP, ML-IAP, AFP, EpCAM, ERG, NA17, PAX3, ALK, Androgen receptor, Cyclin B1, Polysialic acid, MYCN, PhoC, TRP-2, GD3, Fucosyl GM1, Mesothelin, PSCA, MAGE A1, sLe,
- the cancer antigen derived peptide is also within the scope of the present disclosure.
- the cancer antigen derived peptide is a peptide having addition, substitution or deletion of 1 or 2 amino acids, or a peptide having a sequence identity with the above amino acid sequence of 90%or more, 95%or more, 98%or more, or 99%or more and maitaining at least part of the function of the cancer antigen.
- the cancer antigen may be a human papillomavirus (HPV) -derived antigen, a carcinoembryonic antigen, a prostate-specific membrane antigen (PSMA) , Her2/neu, MUC-1, BCR/ABL, ⁇ -fetoprotein (AFP) , an Epstein-Barr virus (EBV) -derived antigen, a human hepatitis B virus (HBV) -derived antigen, a human hepatitis C virus (HCV) -derived antigen, cancer antigen-125 (CA-125) , cancer antigen-72-4 (CA-72-4) , cancer antigen-15-3 (CA-15-3) , or cancer antigen-19-9 (CA-19-9) .
- HPV human papillomavirus
- PSMA prostate-specific membrane antigen
- AFP ⁇ -fetoprotein
- EBV Epstein-Barr virus
- HBV human hepatitis B virus
- HCV human hepatitis C virus
- the allergen may be pollen allergens (tree-, herb, weed-, and grass pollen allergens) , insect allergens (inhalant, saliva and venom allergens) , animal hair and dandruff allergens, and food allergens.
- pollen allergens tree-, herb, weed-, and grass pollen allergens
- insect allergens insect, saliva and venom allergens
- animal hair and dandruff allergens and food allergens.
- Other allergen antigens that may be used include allergens from house dust mites of the genus Dermatophagoides and Euroglyphus, storage mite e.g Lepidoglyphys, Glycyphagus and Tyrophagus, those from cockroaches, midges and fleas e.g.
- Blatella, Periplaneta, Chironomus and Ctenocepphalides those from mammals such as cat, dog and horse, birds, venom allergens including such originating from stinging or biting insects such as those from the taxonomic order of Hymenoptera including bees (superfamily Apidae) , wasps and ants (superfamily Formicoidae) .
- venom allergens including such originating from stinging or biting insects such as those from the taxonomic order of Hymenoptera including bees (superfamily Apidae) , wasps and ants (superfamily Formicoidae) .
- Still other allergen antigens that may be used include inhalation allergens from fungi such as from the genus Alternaria and Cladosporium.
- the present disclosure provides a method of preparing an antibody, comprise:
- the vaccine adjuvant or vaccine composition containing the sting agonist can effectively help the vaccine to play a better role, activate B lymphocytes, and enhance the T lymphocyte-independent antibody immune response. Therefore, after contacting the animal with the vaccine adjuvant or vaccine composition, an immune response is activated to produce corresponding antibodies.
- the present disclosure provides a use of a sting agonist as a vaccine adjuvant, preferably the sting agonist is defined herein.
- the present disclosure provides a use of a sting agonist in manufacture of a vaccine adjuvant, a vaccine adjuvant composition and/or a vaccine composition, preferably the sting agonist is defined herein.
- the present disclosure further provides a use of a vaccine adjuvant, a vaccine adjuvant composition, and/or a vaccine composition described herein.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used to active B lymphocytes.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for enhancing T lymphocyte-independent antibody immune response and T lymphocyte-dependent antibody immune response.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for preventing or treating diseases caused by pathogenic bacteria carrying capsular polysaccharide, cholera or novel coronavirus, the pathogenic bacteria Selected from Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic Escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and/or Streptococcus pneumoniae.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for preventing or treating diseases caused by Streptococcus pneumoniae, Solitary cholerae or novel coronavirus.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a disease or disorder in a subject in need thereof.
- the disease may be an infectious disease, a cell proliferation disorder such as tumor or cancer, or an immune disorder.
- the infectious disease is bacterial, viral, or fungal infection.
- the immune disorder such as autoimmune disease or immunodeficiency disease.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a STING-mediated disease or disorder in a subject.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a cancer in a subject in need thereof.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing an immune response in a subject.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing STING-dependent type I interferon production in a subject.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing a STING-dependent cytokine production in a subject.
- the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a cell proliferation disorder in a subject.
- the cell proliferation disorder is cancer.
- the vaccine adjuvant, vaccine adjuvant composition or vaccine composition of the disclosure are useful in methods for treating or ameliorating a viral infection, disease, a syndrome, a condition or a disorder that is affected by the agonism of STING.
- Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a vaccine adjuvant or a vaccine composition.
- the vaccine adjuvant, vaccine adjuvant composition or vaccine composition is useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, fibrosarcoma, and hepatitis B.
- the present invention provides a method of enhancing or prolonging an immune response in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition disclosed herein.
- the immune response is T lymphocyte-independent antibody immune response or T lymphocyte-dependent antibody immune response.
- the vaccine composition is capable of inducing STING-dependent type I interferon production, or inducing a STING-dependent cytokine production in a subject
- the present invention provides a method for preventing or treating diseases caused by pathogenic bacteria that produce T lymphocyte-independent antibody immune responses or T lymphocyte-dependent immune responses in the body type antibody immune response.
- the method comprises: applying the aforementioned vaccine composition, the aforementioned antibody or the aforementioned artificial antibody to the body.
- sting agonists can effectively activate B lymphocytes, enhance T lymphocyte-independent antibody immune responses and T lymphocyte-dependent antibody immune responses, and thus can play a better preventive and therapeutic purpose.
- the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of vaccine composition disclosed herein.
- the disease may be an infectious disease, a cell proliferation disorder such as tumor or cancer, or an immune disorder.
- the infectious disease is bacterial, viral, or fungal infection.
- the immune disorder such as autoimmune disease or immunodeficiency disease.
- the cell proliferation disorder is cancer, or cancer metastasis.
- the disease may be cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
- the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition disclosed herein.
- the present disclosure provides a method of inducing an immune response in a subject, said method comprising administering a therapeutically effective amount of the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
- the present disclosure provides a method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
- the present disclosure provides a method of inducing a STING-dependent cytokine production in a subject, said method comprising administering a therapeutically effective the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
- the disclosure provides methods of treatment or prevention of STING mediated diseases and disorders, comprising applying the aforementioned vaccine adjuvant or vaccine composition.
- diseases/disorders include, but are not limited to, cancer, infectious disease (e.g., HIV, HBV, HCV, HPV, and influenza infectious diseases) .
- the disease or disorder is an infectious disease or a cancer.
- These vaccine adjuvants or vaccine compositions are potentially useful in treating diseases or disorders including, but not limited to, cell proliferation disorders, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, infectious diseases or an ocular disorder.
- infectious diseases include, but are not limited to, a disease is caused by pathogenic bacteria carrying capsular polysaccharide, cholera or novel coronavirus, the pathogenic bacteria Selected from Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic Escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and/or Streptococcus pneumoniae, HIV, HBV, HCV, HPV, or influenza.
- Cell-proliferation disorders include, but are not limited to, cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.
- the disease or disorder to be treated is a cell proliferation disorder.
- the cell proliferation disorder is cancer.
- the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (i.e., cancers in which a metastasized cancer is found but the original cancer site is not known) .
- the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient.
- the cancer is AIDS-related.
- the cancer is selected from brain and spinal cancers.
- the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (also known as olfactory blastomas) .
- the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma) , oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma) , oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma) , ependymoma (e.g., myxopapillary ependymoma), e
- the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sP ET) .
- the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas) , lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas) , and cancers of the eye or ocular cancers.
- the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
- the cancer is selected from leukemia and cancers of the blood.
- the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML) , myelodysplastic syndrome (MDS) , chronic myelogenous leukemia (CML) , myeloproliferative neoplasm (MPN) , post-MPN AML, post-MDS AML, del (5q) -associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas.
- the cancer is selected from skin cancers.
- the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
- the cancer is selected from cancers of the reproductive system.
- the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers.
- the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors.
- the breast cancer may be male breast cancer or female breast cancer.
- the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas.
- the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.
- the cancer is selected from cancers of the gastrointestinal system.
- the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers) , gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer.
- the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
- the cancer is selected from liver and bile duct cancers.
- the cancer is liver cancer (also known as hepatocellular carcinoma) .
- the cancer is bile duct cancer (also known as cholangiocarcinoma) ; in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
- the cancer is selected from kidney and bladder cancers.
- the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers.
- the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma) , squamous cell carcinomas, and adenocarcinomas.
- the cancer is selected from bone cancers.
- the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, chordoma (cancer of the bone along the spine) .
- the cancer is selected from lung cancers.
- the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
- the cancer is selected from malignant mesothelioma.
- the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
- the cancer is selected from sarcomas.
- the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
- the cancer is selected from lymphomas.
- the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Sternberg cells) , non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma) , cutaneous T-cell lymphomas, primary central nervous system lymphomas.
- Hodgkin lymphoma e.g., Reed-Sternberg cells
- non-Hodgkin lymphoma e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma
- cutaneous T-cell lymphomas e.g., cutaneous T-cell lymphomas, primary central nervous system lymphomas.
- the cancer is selected from glandular cancers.
- the cancer is selected from the group consisting of adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma) , pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
- the cancer is selected from thyroid cancers.
- the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
- the cancer is selected from germ cell tumors.
- the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors.
- the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
- the cancer is selected from heart tumors.
- the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
- the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases.
- the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma.
- the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental -site trophoblastic tumors, and epithelioid trophoblastic tumors) .
- the disease or disorder is a neurodegenerative diseases.
- exemplary neurodegenerative diseases include, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) .
- ALS amyotrophic lateral sclerosis
- treatment and “treating” refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.
- the present disclosure relates to a kit, comprising the vaccine adjuvant, the vaccine adjuvant composition, and/or the vaccine composition described herein.
- the present disclosure also relates to a kit, comprising:
- administering should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and compositions of the foregoing to a subject.
- the amount of a vaccine adjuvant or vaccine composition administered to a subject is an amount sufficient to induce an immune response and/or to induce STING-dependent type I interferon production in the subject.
- the amount of a adjuvant/composition can be an "effective amount” or "therapeutically effective amount, " such that the subject adjuvant/composition is administered in an amount that will elicit, respectively, a biological or medical (i.e., intended to treat) response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.
- An effective amount does not necessarily include considerations of toxicity and safety related to the administration of an adjuvant/composition.
- an effective amount of an adjuvant/composition will vary with the particular compound chosen (e.g., considering the potency, efficacy, and/or half-life of the compound) ; the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of a concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.
- subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
- immune response relates to any one or more of the following: specific immune response, non-specific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.
- a compound of general formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V, or a pharmaceutically acceptable salt of the foregoing is administered in conjunction with one or more additional therapeutic agents including anti -viral compounds, vaccines intended to stimulate an immune response to one or more predetermined antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulatory agents, lipids, liposomes, peptides, anti-cancer agents, and chemotherapeutic agents, etc.
- the administration mode of the vaccine adjuvant or the vaccine composition includes intramuscular injection or oral administration, wherein the intramuscular injection dosage is 8 mg-2.5 g/kg/rat, and the oral administration dosage is 100mg ⁇ 200mg/kg/mouse.
- the administration mode of the vaccine adjuvant or the vaccine composition includes intramuscular injection or oral administration, wherein the administration dosage of intramuscular injection is 0.67 mg-178 mg/kg/person, and the oral administration dosage is 0.2mg ⁇ 200mg/kg/person.
- a vaccine refers to a biological product that provides effective acquired immunity against a specific infectious disease.
- Vaccines can be made of bacteria, viruses, tumor cells and metabolites, etc., which can make the body produce specific immunity. Vaccination confers immunity to the recipient.
- the vaccine includes, but is not limited to, attenuated vaccine, inactivated vaccine, toxoid vaccine, subunit vaccines, conjugate vaccine, vector vaccine, viral vector vaccines, nucleic acid vaccine, multiplex vaccines, or polyvalent Vaccines.
- the attenuated vaccines are vaccines that reduce the virulence of a pathogen while maintaining its activity, for example the following vaccines: 1) Viruses vaccines: Measles vaccine, mumps vaccine, rubella vaccine, attenuated influenza vaccine (seasonal flu nasal spray and nasal spray for 2009 H1N1 flu) , chickenpox vaccine, oral polio vaccine (Sabin) , rotavirus vaccine and yellow fever vaccine; 2) Bacteria vaccines: BCG, typhoid and epidemic typhus vaccines.
- the inactivated vaccine is a vaccine made by inactivating pathogenic microorganisms and retaining the whole microorganism.
- the subunit vaccines are types of vaccines prepared by using effective antigens on the surface of pathogenic microorganisms such as pneumococcal vaccine, meningococcal vaccine, Haemophilus influenzae vaccine, influenza (split or subunit) vaccine, cholera vaccine, typhoid vaccine, etc.
- Vaccine carriers many types have been developed and progressed to nanoparticle carriers, including artificial particles (gold, polymers, lipid micelles) , biological particles (nucleic acids, proteins, viruses) .
- Nucleic acid vaccine for example mRNA vaccine or DNA vaccines.
- mRNA vaccines send instructions for the manufacture of specific proteins to the cell's ribosomes for production, such as some COVID-19 vaccines.
- DTaP diphtheria pertussis vaccine
- D diphtheria toxoid
- T tetanus toxoid
- Streptococcus pneumoniae vaccines are now multivalent vaccines, the common ones are 13-valent conjugate vaccine (PCV13) and 23-valent polysaccharide vaccine (PPSV23) .
- STING agonists can effectively enhance or prolong the immune effect of the above vaccines.
- Vaccine adjuvants containing STING agonists can effectively help vaccines work better, activate B lymphocytes, and enhance T lymphocyte-independent antibody immune responses and T-lymphocyte-dependent antibody immune responses to help the body produce sufficiently strong immune response.
- Vaccine adjuvants are a class of substances that can nonspecifically alter or enhance the body's specific immune response to antigens and play adjuvant roles. Adjuvants can induce long-term and highly effective specific immune response, improve the body's protection ability, reduce the amount of immune substances, and reduce the cost of vaccine production.
- Adjuvants mainly include several modes of action, such as immune regulation, induction of cytotoxic T lymphocytes, antigen presentation, antigen targeting and storage. Through the above modes, the purpose of use is:
- adjuvants can increase infiltration into cells, prevent antigen degradation, transport antigens to specific antigen-presenting cells, enhance antigen presentation or induce cytokine release.
- STING agonist refers to a compound or moiety which is capable of interacting with STING, e.g., by binding to STING and/or inducing downstream signal transduction (e.g., characterized by activation of the molecules associated with STING function) .
- STING pathway activation results in increased production of type 1 interferons (mainly IFN-a and IFN-b) and/or expression of interferon-stimulated genes.
- halogen means fluoro, chloro, bromo or iodo.
- the preferred halogen groups include F, Cl and Br.
- haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
- the preferred halogen groups include F, Cl and Br.
- haloC 1-6 alkyl means fluoro, chloro, bromo or iodo.
- the preferred halogen groups include F, Cl and Br.
- haloC 1-6 alkyl , “haloC 2-6 alkenyl” , “haloC 2-6 alkynyl” and “haloC 1-6 alkoxy” mean a C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy in which one or more (in particular, 1, 2 or 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
- fluoroC 1-6 alkyl, fluoroC 2-6 alkenyl, fluoroC 2-6 alkynyl and fluoroC 1-6 alkoxy groups in particular fluoroC 1-3 alkyl, for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
- fluoroC 1-3 alkyl for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 and fluoroC 1-3 alkoxy groups, for example, OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH
- alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties.
- alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
- C 1-8 as in C 1-8 alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
- Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
- methylene i.e., -CH 2 -
- ethylene i.e., -CH 2 -CH 2 -or –CH (CH 3 ) -
- propylene i.e., -CH 2 -CH 2 -CH 2 -, -CH (-CH 2 -CH 3 ) -or –CH 2 -CH (CH 3 ) -
- alkenyl refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bonds.
- alkenylene refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bonds.
- alkynyl refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bonds.
- alkynylene refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bonds.
- alkoxy as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom.
- alkoxy also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them.
- suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether' ) , and methoxy ethane (also referred to as 'ethyl methyl ether' ) .
- aryl as used herein, unless otherwise indicated, by itself or as part of another substituent refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
- heterocyclic refers to unsubstituted and substituted mono-or polycyclic non-aromatic, partially unsaturated or fully saturated ring system containing one or more heteroatoms.
- Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides.
- the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
- heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
- heteroaryl refers to an aromatic ring system containing carbon (s) and at least one heteroatom.
- Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
- a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
- a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl.
- Bicyclic heteroaryl rings may contain from 8 to 12 member atoms.
- Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) .
- heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
- carbocyclic refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system onle containing carbon atoms.
- Examplary “carbocyclic” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
- cycloalkyl as used herein, unless otherwise indicated, by itself or as part of another substituent refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsatureated hydrocarbon group, which optionally includes an alkylene linker through which the cycloalkyl may be attached.
- Examplary "cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
- alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) , unless otherwise indicated, by itself or as part of another substituent, it shall be interpreted as including those limitations given above for “alkyl” and “aryl” .
- Designated numbers of carbon atoms e.g., C l - 6 ) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
- fused ring refers to a cyclic group formed by substituents on separate atoms in a straight or branched alkane, or to a cyclic group formed by substituents on separate atoms in another ring.
- spirocycle or "spirocyclic ring” refers to a pendant cyclic group formed by substituents on a single atom.
- one or more item includes a single item selected from the list as well as mixtures of two or more items selected from the list.
- a group such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group
- ring or moiety may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent (s) .
- substituents may be selected from a number of alternative groups, the selected groups may be the same or different.
- Suitable substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino) , acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido) , amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarbox
- substituted refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent (s) .
- the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C (OCH 3 ) , cyano, nitro, CF 3 , -OCF 3 , amino, dimethylamino, methyl thio, sulfonyl and acetyl.
- Particularly preferred substituent (s) is -F, -Cl or -Br.
- the substituents the two “R 1 ” of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be the same or different. Similar to “R 1 ” , and the two “R4” , “X1” , “X2” , or “X3” of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be the same or different.
- substituents and substitution patterns on the compound as a sting agonist drug moiety [D] of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
- Compounds described herein such as certain compounds of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration.
- the present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
- enriched R-or S-designated isomer can be substantially free (e.g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center.
- the enriched R-or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R-or S-tert-butylsulfinamide in the synthetic process.
- chiral HPLC purifications of a stereoisomeric mixture such as a racemic mixture.
- General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art.
- Agonists described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature.
- Isotopes can be radioactive or non-radioactive isotopes.
- Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 I.
- Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention.
- one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
- ring systems include but not limitation to a carbocyclic ring, a heterocyclic ring, a heteroaromatic ring, etc., may also include only a heterocyclic ring, and/or a heteroaromatic ring, and the like, specifically includes which rings need to be determined according to the context, but anyway the “ring systems” do not include the cycloalkyl based on a C 1-6 alkyl or C 1-3 alkyl ogroup, and do not include the cycloalkoxy based on a C 1-6 alkoxy or C 1-3 alkoxy group.
- compositions containing vaccine adjuvants of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
- Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the conjugates into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the conjugates of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention.
- compositions of the present invention comprise a vaccine adjuvant (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of conjugates can be calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
- the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the conjugates and the particular therapeutic effect to be achieved.
- the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- oral liquid preparations such as suspensions, elixirs and solutions
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques.
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered conjugates moistened with an inert liquid diluent.
- Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
- a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active conjugates in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a conjugate of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the conjugate, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration and the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient.
- dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day.
- inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.01 to 50mg of the conjugate per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
- compositions can be included in a container, pack, or dispenser together with instructions for administration.
- Step a Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and Triethylamine (4.73 g, 46.7440 mmol) in Ethanol (200 mL) at 20 °C. The reaction mixture was stirred for 1 h at 20 °C. SOCl 2 (20 mL) was added to the solution above at 0 °C. The reaction mixture was stirred for 3 h at 20 °C. The reaction mixture was evaporated under reduced pressure.
- Step b NBS (10.51 g, 59.0503 mmol) was added to ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate in Tetrahydrofuran (100 mL) and Acetonitrile (100 mL) at 20 °C. The reaction mixture was stirred overnight at 20 °C. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step c Potassium Acetate (3.74 g, 38.1080 mmol) was added to Pd (dppf) Cl 2 (0.72 g, 984.0050 ⁇ mol) , ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.84 g, 15.1218 mmol) in 1, 4-Dioxane (100 mL) at 20 °C.
- the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo.
- Step d Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol) in Tetrahydrofuran (20 mL) and Water (20 mL) at 20 °C. The reaction mixture was stirred for 1 h at 20 °C. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq.
- DCM 500 mL
- Step e To a solution of ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.72 g, 2.4547 mmol) in N, N-Dimethylformamide (10 mL) was added 1, 3-Dibromopropane (0.73 g, 3.6159 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) 2. This mixture was stirred for 16 hours at 50 °C. The reaction mixture was diluted with Ethyl acetate (100 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (1 x 100 mL) .
- Step a 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
- Step b 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
- Step c ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 20°C. The reaction mixture was quenched with adding of water (50 mL) at 20°C, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) .
- Step d ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 2 h at 20°C. The reaction mixture was quenched with adding to EtOH (100 mL) at 20°C, The reaction mixture was evaporated under reduced pressure and diluted with H 2 O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) .
- Step e ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0°C under N 2 atmosphere.
- the reaction mixture was stirred for 2 h and warmed up to 20°C naturally.
- the precipitate was collected by filtration.
- the filter cake was dried under vacuo.
- Step f ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
- Step g ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
- the reaction mixture was heated to 100°C and stirred for 12 h.
- the reaction mixture was quenched with adding of water (150 mL) at 20°C, extracted with EA (3 x 150 mL) and washed with brine (50 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Sodium perborate (0.91g, 5.9145 mmol) was added to a solution of the residue in THF (10 mL) and H 2 O (10 mL) at 20°C under N 2 atmosphere.
- the reaction mixture was stirred for 1 h at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- the residue was purified on C18 column ACN/H 2 O (0.1%FA) (0-38%) .
- Step h ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Methyl Iodidle (0.345 g, 2.4306 mmol) was added to a mixture of Potassium carbonate (0.448 g, 3.2415 mmol) and ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.328 g, 960.9441 ⁇ mol) in DMF (10 mL) at 20°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 20°C. The reaction mixture was quenched with adding of water (50 mL) at 20°C, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) .
- Step a Potassium carbonate (0.240 g, 1.7365 mmol) was added to a solution of INT A3 (0.240 g, 579.3045 ⁇ mol) and INT A2 (0.169 g, 576.1737 ⁇ mol) in N, N-Dimethylformamide (10 mL) at 20°C. The reaction mixture was heated to 50 °C and stirred overnight. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) . The organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step a 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
- Step b 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
- Step c ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 20°C. The reaction mixture was quenched with adding of water (50 mL) at 20°C, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) .
- Step d ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 2 h at 20°C. The reaction mixture was quenched with adding to EtOH (100 mL) at 20°C, The reaction mixture was evaporated under reduced pressure and diluted with H 2 O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) .
- Step e ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0°C under N 2 atmosphere.
- the reaction mixture was stirred for 2 h and warmed up to 20°C naturally.
- the precipitate was collected by filtration.
- the filter cake was dried under vacuo.
- Step f ethyl 4- (6-bromo-4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Methyl Iodidle (0.477 g, 3.3606 mmol) was added to a mixture of ethyl 4- (6-bromo-4-fluoro-5-hydroxyisoindolin-2-yl) -4-oxobutanoate (0.463 g, 1.2855 mmol) and Potassium carbonate (0.779 g, 5.6365 mmol) in DMF (5 mL) at 20°C under N 2 atmosphere. The reaction mixture was stirred for 2 h at 25°C. The mixture was purified on C18 column ACN/H 2 O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo.
- Step g [2- (4-ethoxy-4-oxo-butanoyl) -7-fluoro-6-methoxy-isoindolin-5-yl] boronic acid
- Step h ethyl 4- (4-fluoro-6-hydroxy-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Step i ethyl 4- (6- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate
- Step j 4- (6- (3- ( (2- (3-carboxypropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-xobutanoic acid
- Step a methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate
- NMI (7.96 g, 96.9507 mmol) was added to a solution of TCFH (8.11 g, 28.9045 mmol) and (S) -4-methoxy-3-methyl-4-oxobutanoic acid (2.81 g, 19.2280 mmol) in DMF (100 mL) at 25°C.
- the reaction mixture was stirred for 10 min at 20°C.
- 5-methoxyisoindoline hydrochloride (4.99 g, 26.8785 mmol) was added to the solution at 25°C.
- the reaction mixture was stirred 2 h at 25°C.
- Step b methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate
- NBS (3.717 g, 20.8839 mmol) was added to a solution of methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.426 g, 12.3542 mmol) in THF (30 mL) and MeCN (30 mL) at 0°C.
- the reaction mixture was stirred for 3 h at 25°C.
- the reaction mixture was concentrated and diluted with DCM (200 mL) , washed with H 2 O (100 mL) , KHCO 3 (aq. ) (2 x 100 mL) and brine (100 mL) .
- Step c methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate
- the reaction mixture was heated to 100°C and stirred overnight.
- the reaction mixture was diluted with EA (200 mL) ,
- the precipitate was collected by filtration, washed with EA (1 x 100 mL) .
- the filtrate was evaporated under reduced pressure.
- the residue was purified on silica gel column EA/n-Hexane (0-50%) .
- the pure fractions was concentrated and dried under vacuo.
- Step e methyl (2R) -4- [5- (3-bromopropoxy) -6-methoxy-isoindolin-2-yl] -2-methyl-4-oxo-butanoate
- Step f methyl (S) -4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
- Step g sodium (S) -4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
- Step a ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
- reaction mixture was quenched with adding of water (50 mL) at 25°C, washed with EA (3 x 50 mL) and brine (50 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure obtained as a brown oil.
- the residue was purified on on C18 column ACN/H 2 O (0.1%FA) (0-60%) .
- the pure fractions was concentrated and dried by lyophilization.
- Step b 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
- Step a 5-bromo-2, 3-bis (bromomethyl) pyridine
- NBS 129.49 g, 727.5373 mmol
- 5-bromo-2, 3-dimethylpyridine 65.61 g, 352.6494 mmol
- AIBN 0.98 g, 5.9681 mmol
- CCl 4 1000 mL
- the reaction mixture was heated to 80°C and stirred for 2 h.
- the reaction mixture was cooled down to 25°C.
- the reaction mixture was filtered through a short silica column, washed with DCM (3 x 400 mL) . The filtrate was concentrated and dried under vacuo at 35°C.
- Step b 3-bromo-6-trityl-5, 7-dihydropyrrolo [3, 4-b] pyridine
- N, N-Diisopropylethylamine (78.2000 g, 605.0646 mmol) was added to a solution of triphenylmethanamine (93.77 g, 361.5657 mmol) and 5-bromo-2, 3-bis (bromomethyl) pyridine (125.17 g, 182.0173 mmol) in DMF (800 mL) at 25°C.
- the reaction mixture was heated to 60°C and stirred for overnight.
- the reaction mixture was evaporated under reduced pressure.
- the reaction mixture was diluted with EA (800 mL) , washed with water (500 mL) and brine (300 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step c benzyl 3-bromo-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate
- Trifluoroacetic acid (100 mL, 1.3462 mol) was added to a solution of 3-bromo-6-trityl-5, 7-dihydropyrrolo [3, 4-b] pyridine (20.63 g, 46.7417 mmol) in DCM (100 mL) at 0°C.
- the reaction mixture was stirred overnight at 25°C.
- the reaction mixture was evaporated under reduced pressure.
- the reaction mixture was diluted with HCl (1 M, 150 mL) , washed with EA (3 x 200 mL) .
- the aqueous was neutralized to pH 7-8 by adding of NaOH (4 M) at 0°C.
- Step e methyl 3-methoxy-1-oxido-5, 7-dihydropyrrolo [3, 4-b] pyridin-1-ium-6-carboxylate
- Step f methyl 2-chloro-3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate
- Phosphorus oxychloride 32.90 g, 214.5668 mmol was added to a solution of methyl 3-methoxy-1-oxido-5, 7-dihydropyrrolo [3, 4-b] pyridin-1-ium-6-carboxylate (6.31 g, 23.1065 mmol) in DCE (100 mL) at 25°C.
- the reaction mixture was heated to 80°C and stirred for 2 h.
- the reaction mixture was evaporated under reduced pressure.
- the reaction mixture was concentrated and diluted with DCM (1000 mL) , washed with water (500 mL) and brine (500 mL) .
- Step j 3- ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol
- Step k 1, 3-bis ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane
- the reaction mixture was heated to 100°C and stirred for 1 h.
- the reaction mixture was quenched with adding of water (10 mL) at 0°C.
- the resulting mixture was extracted with EA (2 x 300 mL) , washed with water (100 mL) and brine (100 mL) .
- the organics dried over Na 2 SO4, filtered and evaporated under reduced pressure.
- the residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo.
- Step l 1, 3-bis ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane
- Step m dimethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoate)
- Methyl 4-chloro-4-oxobutanoate (0.061 g, 405.1541 ⁇ mol) was added to a solution of 1, 3-bis ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane (0.037 g, 99.3510 ⁇ mol) and TEA (0.076 g, 751.0668 ⁇ mol) in DCM (3 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 25°C. The reaction mixture was quenched with adding of water (50 mL) at 25°C.
- reaction mixture was extracted with EA (3 x 50 mL) , washed with brine (50 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified on C18 column ACN/H 2 O (0.1%FA) (0-40%) .
- the pure fractions was concentrated and dried under vacuo.
- Step n 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoic acid)
- Step a tert-butyl 5-methoxyisoindoline-2-carboxylate
- TEA (33.12 g, 327.3070 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (20.01 g, 107.7833 mmol) and Di-tert-butyl dicarbonate (35.28 g, 161.6523 mmol) in DCM (500 mL) at 20°C.
- the reaction mixture was stirred overnight at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- the residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo.
- Step b tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate
- NBS 43.64 g, 245.1906 mmol
- tert-butyl 5-methoxyisoindoline-2-carboxylate 30.40 g, 121.9390 mmol
- Tetrahydrofuran 300 mL
- Acetonitrile 300 mL
- the reaction mixture was stirred overnight at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- the reaction mixture was concentrated and diluted with EA (1000 mL) , washed with NaHCO 3 (aq. ) (3 x 200 mL) and brine (300 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step c tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate
- reaction mixture was heated to 100°C and stirred overnight under N 2 atmosphere.
- the reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (200 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified on silica gel column EA/n-Hexane (0-50%) .
- the pure fractions was concentrated and dried under vacuo.
- Step d tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate
- Step e tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate
- Step f 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
- Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate (0.088 g, 146.9896 ⁇ mol) in DCM (3 mL) at 20°C .
- the reaction mixture was stirred for 1 h at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- dihydrofuran-2, 5-dione (0.050 g, 499.6373 ⁇ mol) was added to a solution of the residue and TEA (0.209 g, 2.0654 mmol) in DCM (5 mL) at 0°C under N 2 atmosphere.
- the reaction mixture was stirred and warmed up to 20°C naturally.
- the reaction mixture was stirred for 3 h at 20°C under N 2 atmosphere.
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step a ethyl 4- (5-methoxy-6-vinyl-isoindolin-2-yl) -4-oxo-butanoate
- reaction mixture was stirred overnight at 80°C under nitrogen atmosphere.
- the reaction mixture was concentrated and diluted with EA (100 mL) , washed with NaHCO 3 (aq. ) (2 x 50 mL) and brine (50 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified on silica gel column EA/n-Hexane (0-70%) .
- the pure fractions was concentrated and dried under vacuo.
- Step b ethyl 4- (5-formyl-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Step c ethyl 4- [5- (hydroxymethyl) -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
- Step d diethyl 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
- N, N-Diisopropylethylamine (0.113 ml, 683.7230 ⁇ mol) was added to a solution of 4- [5- (hydroxymethyl) -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.067 g, 217.9990 ⁇ mol) and Methylamine hydrochloride (0.018 g, 266.5964 ⁇ mol) in N, N-Dimethylformamide (2 mL) at 20°C. The reaction mixture was stirred overnight at 20°C. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/Water (0-60%) . The pure fractions was concentrated and dried under vacuo.
- Step e 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
- Step a ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- NCS (0.105 g, 786.3231 ⁇ mol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.205 g, 698.9090 ⁇ mol) in DMF (10 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 12 h and warmed up to 20°C naturally. The reaction mixture was purified on C18 column ACN/H 2 O (0-25%) . The pure fractions was concentrated and dried under vacuo.
- Step b ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
- Step c 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
- Step b diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
- Step c 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
- Step a diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
- Step b 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
- Step a ethyl 4- [4-chloro-5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
- Step b diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
- Step c 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
- Step a ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
- Step b diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
- Step c 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
- Step c tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate
- Step d tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate
- NBS (2.20 g, 12.3607 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL) at 0°C.
- the reaction mixture was stirred for 2.5 h at 20°C.
- the reaction mixture was concentrated under reduced pressure.
- the residue was dissloved with EA/MeOH (200 mL/10 mL) , and washed with H 2 O (200 mL) .
- the organic layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo.
- Step e tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate
- Step f tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate
- the reaction mixture was diluted with EA (100 mL) and filtered through a celite. The filtrate was evaporated under reduced pressure.
- H 2 O 2 (88.1974 mmol, 10 mL, 30%aqueous solution) was added to a mixture of the residue and NaHCO 3 (11.9038 mmol, 20 mL, 5%aqueous solution) in THF (80 mL) at 0°C.
- the reaction mixture was stirred for 2 h at 20°C.
- the resulting reaction mixture was diluted with brine (150 mL) and saturated NaHSO 3 (100 mL) , and extracted with EA (200 mL) . The organic layer was collected and dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step g tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate
- Step h tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
- Step i tert-butyl 4-chloro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
- NCS (10.92 g, 81.7776 mmol) was added to a solution of tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (20.21 g, 76.1767 mmol) in DMF (200 mL) at 0°C.
- the reaction mixture was stirred for 3 h at 60°C.
- the reaction mixture was quenched with adding of water (500 mL) , extracted with EA (3 x 500 mL) and washed with brine (250 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-2%) .
- Step j tert-butyl 5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindoline-2-carboxylate
- Step k tert-butyl 5- [3- (2-tert-butoxycarbonyl-4-chloro-6-methoxy-isoindolin-5-yl) oxypropoxy] -4-fluoro-6-methoxy-isoindoline-2-carboxylate
- Potassium carbonate (0.115 g, 832.0942 ⁇ mol) was added to a mixture of tert-butyl 4-fluoro-5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.090 g, 317.6904 ⁇ mol) and tert-butyl 5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindoline-2-carboxylate (0.093 g, 221.0471 ⁇ mol) in DMF (5 mL) at 20°C under N 2 atmosphere. The reaction mixture was stirred for 3 h at 50°C. The reaction mixture was purified on C18 column ACN/H 2 O (0.1%FA) (0-50%) .
- Step l 4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline dihydrochloride
- Step m 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
- Step a ethyl 4- (5-methoxy-6- (3- ( (6-methoxyisoindolin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate
- the reaction mixture was diluted with Ethyl acetate (100 mL) , washed sequentially with water (100 mL) and brine (100 mL) . The organic layer was dried over Na 2 SO 4 , filtered and evaporated to afford crude product.
- HCl (4 M) in Ethyl acetate (10 mL) was added to a solution of the crude product in Ethyl acetate (10 mL) .
- the reaction mixture was stirred for 1 hour at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- the residue was purified on C-18 column MeCN/water (0-100%) .
- the pure fractions was concentrated and dried under vacuo.
- Step b (4-nitrophenyl) 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate
- reaction mixture was diluted with Ethyl acetate (100 mL) , washed sequentially with water (100 mL) and brine (100 mL) .
- the organic layer was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified on silica gel column EA/Heptane (0-100%) .
- the pure fractions was concentrated and dried under vacuo.
- Step c ethyl 4- (5- (3- ( (2- ( (3-ethoxy-3-oxopropyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
- Step d 4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
- Cisbio Bioassays human STING WT binding assay (#64BDSTGPEG &64BDSTGPEH, Cisbio) is for quantitative measurement of human STING WT ligand using technology.
- Negative control Dispense 5 ⁇ L of diluent into each negative control well.
- Standard Dispense 5 ⁇ L of each Human STING WT Standard 2’3’-cGAMP (Std 0 -Std 7) into each standard well.
- Compound Dispense 5 ⁇ L of compound into each compound well.
- Negative control Add 5 ⁇ L of detection buffer to all wells.
- Other wells Add 5 ⁇ L of human STING WT protein 6His-tagged protein to all wells.
- Y is HTRF Ratio and X is compound concentration.
- Step a Bromomethyl methyl ether, (3.15 g, 25.2073 mmol) was added to a solution of DIEA (4.10 g, 46.5111 mmol) and 2-Bromoisovanillin (4.98 g, 21.5544 mmol) in Dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 2 h. The resulting solution was quenched by water (10 mL) and washed with water (100 mL) and brine (100 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step b Methyl thioglycolate (2.30 g, 21.6688 mmol) was added to a solution of 2-bromo-4-methoxy-5- (methoxymethoxy) benzaldehyde (5.83 g, 21.1926 mmol) and Cs 2 CO 3 (13.99 g, 42.9380 mmol) in N, N-Dimethylformamide (100 mL) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 16 h. The reaction mixture was cooled to 20 °C, and Methyl Iodide (1.81 g, 12.7520 mmol) was added to the reaction solution, and stirred for 2 h at 20 °C.
- Step d To a stirred solution of 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol) in N, N-Dimethylformamide (20 mL) was added 1, 1'-Carbonyldiimidazole (2.84 g, 17.5148 mmol) at 20 °C. The resulting mixture was stirred for 1 h at 20 °C under nitrogen atmosphere. To the mixture above was added 3-tert-Butoxy-3-oxopropanoic acid and Magnesium chloride (1.31 g, 13.7589 mmol) . The reaction mixture was stirred at 20 °C for 16 h.
- Step e To a stirred solution of tert-butyl 3- [6-methoxy-5- (methoxymethoxy) benzothiophen-2-yl] -3-oxo-propanoate (2.62 g, 7.1501 mmol) in N, N-Dimethylformamide (20 mL) was added Potassium carbonate (2.0621 g, 14.9207 mmol) and Ethyl bromoacetate (1.3648 g, 8.1724 mmol) at 20 °C . The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere.
- Step f TFA (5 mL) was added to O1-tert-butyl O4-ethyl 2- [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] butanedioate (2.82 g, 6.2318 mmol) in Toluene (25 mL) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step a To a solution of 6-bromothieno [3, 2-b] pyridine (30.0 g, 140.1 mmol) in DMF (300 mL) was added a solution of 25%MeONa in MeOH (605.6 g, 2802.6 mmol) and CuI (26.7 g, 140.1 mmol) . The reaction mixture was heated to 100 °C and stirred for 2 h. Then the reaction mixture was cooled to room temperature, poured into ice water (900 mL) and filtered. The filtrate was diluted with NH 3 . H 2 O (300 mL) , extracted with EtOAc (1.0 L x 2) and washed with brine (1.0 L) .
- Step d To a solution of 5-chloro-6-methoxythieno [3, 2-b] pyridine (8.0 g, 40.1 mmol) in THF (80 mL) was added LDA (2.0 M, 80 mL) dropwise at -78 °C under nitrogen. After 15 min, a solution of dihydrofuran-2, 5-dione (22.0 g, 220.4 mmol) in THF (240 mL) was added to the mixture dropwise at -40 °C under nitrogen. Then the reaction mixture was warmed to room temperature and stirred for 2 h. After that the reaction was quenched with 2N HCl (100 mL) and extracted with EtOAc (300 mL x 2) .
- Step b To a solution of cis -2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (3.0 g, 8.4 mmol) in MeOH (30 mL) was added 50%aq. NaOH (45 mL) at room temperature. Then the reaction mixture was heated to 40 °C and stirred for 24 h. After the reaction completed analysis by HPLC, the solvent was removed by concentrated. The residue was diluted with water (30 mL) and was adjustd pH ⁇ 2 with 6 N HCl. The white solid was collected by filtration.
- Step c To a solution of trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (2.5 g, 7.0 mmol) in DMF (25 mL) was added K 2 CO 3 (2.4 g, 17.5 mmol) and MeI (2.0 g, 14.1 mmol) at room temperature. The reaction mixture was stirred for 16 h. Then the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) . The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2) .
- Step a Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and Triethylamine (4.73 g, 46.7440 mmol) in Ethanol (200 mL) at 20 °C. The reaction mixture was stirred for 1 h at 20 °C. SOCl 2 (20 mL) was added to the solution above at 0 °C. The reaction mixture was stirred for 3 h at 20 °C. The reaction mixture was evaporated under reduced pressure.
- Step b NBS (10.51 g, 59.0503 mmol) was added to ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate in Tetrahydrofuran (100 mL) and Acetonitrile (100 mL) at 20 °C. The reaction mixture was stirred overnight at 20 °C. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Step c Potassium Acetate (3.74 g, 38.1080 mmol) was added to Pd (dppf) Cl 2 (0.72 g, 984.0050 ⁇ mol) , ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.84 g, 15.1218 mmol) in 1, 4-Dioxane (100 mL) at 20 °C.
- the reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo.
- Step d Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol) in Tetrahydrofuran (20 mL) and Water (20 mL) at 20 °C. The reaction mixture was stirred for 1 h at 20 °C. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO 3 aq.
- DCM 500 mL
- Step e To a solution of ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.72 g, 2.4547 mmol) in N, N-Dimethylformamide (10 mL) was added 1, 3-Dibromopropane (0.73 g, 3.6159 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) 2. This mixture was stirred for 16 hours at 50 °C. The reaction mixture was diluted with Ethyl acetate (100 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (1 x 100 mL) .
- Titanium tetrachloride 38.06 g, 200.6548 mmol was added dropwise to a solution of 2-Bromo-3-fluoroanisole (10.17 g, 49.6039 mmol) in Dichloromethane (250 mL) at 0°C for 1 h.
- the reaction mixture was stirred for 3 h at 20°C.
- the reaction mixture was quenched with adding of ice-water (200 mL) at 0°C.
- the reaction mixture was extracted with DCM (2 x 100 mL) , washed with NaHCO 3 (1 x 200 mL) and brine (100 mL) .
- the organics dried over Na 2 SO 4, filtered and evaporated under reduced pressure.
- Step b (5E) -5- [ (3-bromo-2-fluoro-4-methoxy-phenyl) methylene] -2-thioxo-thiazolidin-4-one
- Step c (Z) -3- (3-bromo-2-fluoro-4-methoxy-phenyl) -2-sulfanyl-prop-2-enoic acid
- Step e tert-butyl 3- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -3-oxo-propanoate
- the reaction mixture was stirred overnight at 20°C.
- the reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO 3 aq (2 x 500 mL) and brine (100 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo.
- Step c tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate
- Step d tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate
- NBS (2.20 g, 12.3607 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL) at 0°C.
- the reaction mixture was stirred for 2.5 h at 20°C.
- the reaction mixture was concentrated under reduced pressure.
- the residue was dissloved with EA/MeOH (200 mL/10 mL) , and washed with H 2 O (200 mL) .
- the organic layer was dried over Na 2 SO 4 , filtered and evaporated in vacuo.
- Step e tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate
- Step f tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate
- Step g tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate
- Step h tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
- Step a 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
- Step b 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
- Step c ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 20°C. The reaction mixture was quenched with adding of water (50 mL) at 20°C, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) .
- Step d ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0°C under N 2 atmosphere. The reaction mixture was stirred for 2 h at 20°C. The reaction mixture was quenched with adding to EtOH (100 mL) at 20°C, The reaction mixture was evaporated under reduced pressure and diluted with H 2 O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) .
- Step e ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
- NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0°C under N 2 atmosphere.
- the reaction mixture was stirred for 2 h and warmed up to 20°C naturally.
- the precipitate was collected by filtration.
- the filter cake was dried under vacuo.
- Step f ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
- Step g ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
- the reaction mixture was heated to 100°C and stirred for 12 h.
- the reaction mixture was quenched with adding of water (150 mL) at 20°C, extracted with EA (3 x 150 mL) and washed with brine (50 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- Sodium perborate (0.91g, 5.9145 mmol) was added to a solution of the residue in THF (10 mL) and H 2 O (10 mL) at 20°C under N 2 atmosphere.
- the reaction mixture was stirred for 1 h at 20°C.
- the reaction mixture was evaporated under reduced pressure.
- the residue was purified on C18 column ACN/H 2 O (0.1%FA) (0-38%) .
- Step h ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- Methyl Iodidle (0.345 g, 2.4306 mmol) was added to a mixture of Potassium carbonate (0.448 g, 3.2415 mmol) and ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.328 g, 960.9441 ⁇ mol) in DMF (10 mL) at 20°C under N 2 atmosphere. The reaction mixture was stirred for 1 h at 20°C. The reaction mixture was quenched with adding of water (50 mL) at 20°C, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) .
- Step b 6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carboxylic acid
- Step c tert-butyl 3- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -3-oxopropanoate
- Step d 1- (tert-butyl) 4-ethyl 2- (6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carbonyl) succinate
- Step e ethyl 4- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
- Step f (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) boronic acid
- Step g ethyl 4- (6-hydroxy-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
- Step a Potassium carbonate (0.240 g, 1.7365 mmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.240 g, 579.3045 ⁇ mol) and ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.169 g, 576.1737 ⁇ mol) in N, N-Dimethylformamide (10 mL) at 20 °C. The reaction mixture was heated to 50 °C and stirred for 3 h. The reaction mixture was evaporated under reduced pressure.
- reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO 3 aq. (2 x 300 mL) and brine (200 mL) .
- the organics was dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified on silica gel column EA/Hept (0-100%) .
- the pure fractions was concentrated and dried under vacuo.
- Step a O1-tert-butyl O4-ethyl 2- (5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) butanedioate
- Step b ethyl 4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate
- Trifluoroacetic acid (2 mL) was added to a solution of O1-tert-butyl O4-ethyl 2- (5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) butanedioate (1.85 g, 3.7805 mmol) in Toluene (10 mL) at 20°C. The reaction mixture was stirred at 60°C for 2 h . The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with DCM (200 mL) , washed with NaHCO 3 aq (2 x 100 mL) and brine (100 mL) .
- Step c ethyl 4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate
- Pd (dppf) Cl 2 (0.15 g, 205.0010 ⁇ mol) was added to a mixture of Potassium Acetate (0.60 g, 6.1136 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (0.97 g, 3.8198 mmol) and ethyl 4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate (0.72 g, 1.8498 mmol) in 1, 4-Dioxane (30 mL) at 20°C.
- the reaction mixture was stirred at 100°C for 20 h under N 2 atmosphere.
- the reaction mixture was evaporated under reduced pressure.
- the residue was concentrated and diluted with EA (200 mL) , washed with NaHCO 3 aq (2 x 100 mL) and brine (100 mL) .
- the organics dried over Na 2 SO 4 , filtered and evaporated under reduced pressure.
- the residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo.
- Step d ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate
- Step e ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
- NCS (0.105 g, 786.3231 ⁇ mol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.205 g, 698.9090 ⁇ mol) in DMF (10 mL) at 0°C under N 2 atmosphere.
- the reaction mixture was stirred for 12 h and warmed up to 20°Cnaturally.
- the reaction mixture was purified on C18 column ACN/H 2 O (0-25%) . The pure fractions was concentrated and dried under vacuo.
- Step f ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
- Step g ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
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Abstract
Provided is a vaccine adjuvant containing a STING agonist and a use thereof. The vaccine adjuvant containing a STING agonist provided by the present invention can enhance an immune response, and is especially suitable for the prevention and treatment of diseases or disorders.
Description
The present invention relates to vaccine adjuvants, compositions comprising such vaccine adjuvants, processes for the synthesis thereof, and uses thereof.
The immune system has evolved to recognize and neutralize different types of threats in order to maintain the homeostasis of the host, and it is generally broken down into two arms: adaptive and innate. The adaptive immune system is specialized to recognize as foreign those antigens not naturally expressed in the host and to mount an anti-antigen response through the coordinated actions of many leukocyte subsets. The hallmark of adaptive immune responses is their ability to provide "memory" or long-lasting immunity against the encountered antigen. While this specific and long-lasting effect is critical to host health and survival, the adaptive immune response requires time to generate a full-blown response.
The innate immune system compensates for this time delay and is specialized to act quickly against different insults or danger signals. It provides the first line of defense against bacteria, viruses, parasites and other infectious threats, but it also responds strongly to certain danger signals associated with cellular or tissue damage. The innate immune system has no antigen specificity but does respond to a variety of effector mechanisms. Opsonization, phagocytosis, activation of the complement system, and production of soluble bioactive molecules such as cytokines or chemokines are all mechanisms by which the innate immune system mediates its response. By responding to these damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs) described above, the innate immune system is able to provide broad protection against a wide range of threats to the host.
Free cytosolic DNA and RNA are among these PAMPs and DAMPs. It has recently been demonstrated that the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase) . Upon recognition of cytosolic DNA, cGAS catalyzes the generation of the cyclic-dinucleotide 2'3'-cGAMP, an atypical second messenger that strongly binds to the ER-transmembrane adaptor protein STING. A conformational change is undergone by cGAMP-bound STING, which translocates to a perinuclear compartment and induces the activation of critical transcription factors IRF-3 and NF-κΒ. This leads to a strong induction of type I interferons and production of pro-inflammatory cytokines such as IL-6, TNF-α and IFN-γ.
The importance of type I interferons and pro-inflammatory cytokines on various cells of the immune system has been very well established. In particular, these molecules strongly potentiate T-cell activation by enhancing the ability of dendritic cells and macrophages to uptake, process, present and cross-present antigens to T-cells. The T-cell stimulatory capacity of these antigen-presenting cells is augmented by the up-regulation of critical co-stimulatory molecules, such as CD80 or CD86. Finally, type I interferons can rapidly engage their cognate receptors and trigger the activation of interferon-responsive genes that can significantly contribute to adaptive immune cell activation.
From a therapeutic perspective, type I interferons are shown to have antiviral activities by directly inhibiting human hepatitis B virus and hepatitis C virus replication, and by stimulating immune responses to virally infected cells. Compounds that can induce type I interferon production are used in vaccines, where they act as adjuvants, enhancing specific immune responses to antigens and minimizing side effects by reducing dosage and broadening the immune response.
In addition, interferons, and compounds that can induce interferon production, have potential use in the treatment of human cancers. Such molecules are potentially useful as anti-cancer agents with multiple pathways of activity. Interferons can inhibit human tumor cell proliferation directly and may be synergistic with various approved chemotherapeutic agents. Type I interferons can significantly enhance anti-tumor immune responses by inducing activation of both the adaptive and innate immune cells. Finally, tumor invasiveness may be inhibited by interferons by modulating enzyme expression related to tissue remodeling.
Vaccination is the most effective and cost-effective medical treatment for common infectious diseases. Vaccines usually refer to modified attenuated or inactivated pathogenic microorganisms or synthetic products containing their components, which are equivalent to a stimulating antigen relative to the human immune system. Vaccination of the human body can make the body produce an effective immune response against the pathogen and generate an immune memory, prompting the body to quickly activate the immune system when the relevant pathogenic microorganism invades, allowing the body to develop resistance to the pathogenic microorganism, eliminating or weakening the pathogen. Health hazards of microorganisms. However, in the immunization process, vaccine antigens alone are often not enough (especially purified protein subunit vaccines) , and a powerful substance similar to "accelerant" is also needed, and the technical term for this substance is called adjuvant. Adjuvants can assist vaccines to more effectively stimulate the body's immune system to respond, including humoral immunity and cellular immunity. An effective adjuvant can have both quantitative and qualitative effects on the action of the vaccine. The addition of adjuvants can not only enhance the strength of the immune response, reduce the amount of vaccine required and the number of
immunizations, but also change the type and direction of the immune response by selecting different adjuvants, so that the protective effect of the vaccine is maximized and optimal.
In recent years, the importance of the cGAS-STING pathway in innate and adaptive immune responses has been gradually revealed, leading to the exploration of using agonists of the cGAS-STING pathway as vaccine adjuvants. Stimulation of the cGAS-STING pathway by cytoplasmic DNA activates the transcription factors IRF3 and NF-kB and promotes the expression of type I interferons and other proinflammatory factors, thereby enhancing antigen presentation and adaptive immune responses. Therefore, STING agonists are promising vaccine adjuvants.
The present disclosure relates to vaccine adjuvants and/or vaccine compositions thereof, use of the sting agonist in the preparation of the vaccine adjuvant or the vaccine compositon, as well as these vaccine adjuvants and compositions comprising the sting agonist, which may be useful as agents to induce immune responses, to induce STING-dependent type I interferon production, to enhance or prolong an immune response, and/or to prevent/treat a cell proliferation disorder (eg. Tumor) or infectious diseases.
In one aspect, the present invention relates to a vaccine adjuvant including a sting agonist.
In some embodiments, the sting agonist is a compound of Formula Y-1, Y-2, Y-3, or an ester, stereoisomer, tautomer, isotopic derivative, prodrug or pharmaceutically acceptable salt:
or pharmaceutically acceptable salts thereof, wherein,
represents a single bond or a double bond;
each W is independently selected from CR1, C (R1) 2, N, NR1, O or S;
each W1 is independently selected from C, CR1, or N;
each W2 is independently selected from C, CR1, or N;
each Z1 is independently selected from CR1, C (R1) 2, N, NR1, O or S;
each Z2 is independently selected from CR1, C or N;
each Z3 is independently selected from CR1, C (R1) 2, N, NR1, O or S;
each Z4 is independently selected from C, CR1 or N;
each Z5 is independently selected from C, CR1 or N;
each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2;
R2 and R3 are independently selected from the group consisting of O- (C1-C4 alkylene or haloalkylene) , C1-C5 alkylene or haloalkylene, N (R6) - (C1-C4 alkylene or haloalkylene) , -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and
each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen;
each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) ;
each R6 is independently selected from the group consisting of -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-10heterocyclic ring or C3-10carbocyclic ring; and each of which is independently optionally substituted with deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, or C1-6alkyl; and each of the heteroaryl and heterocyclic ring contains at least one heteroatoms selected from N, O or S;
each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-;
each X2 is independently selected from (C (R8) 2) (1-3) , NR8 (C (R8) 2) (1-3) , -NH (C (R8) 2) (1-3) , –N (C1-6alkyl) (C (R8) 2) (1-3) or –N (haloC1-6alkyl) (C (R8) 2) (1-3) ; wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle;
each X3 is independently selected from the group consisting of H, CN, COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, OR6, SR6, N (R6) 2, OCOR6, NR6COR6, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-
10heterocyclic ring or C3-10carbocyclic ring; and each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2) 1-3-C (=O) OR6, OR6, SR6, NH2, NH (C1-C6 alkyl) , N (C1-C6 alkyl) 2, O (C1-C6 alkyl) , O (C6-C10 aryl) , O (C1-C6 alkyl) -OR6, S (C1-C6alkyl) , S (C6-C10 aryl) , S (=O) 2R6, S (=O) 2OR6, P (=O) (R6) 2, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl.
In some embodiment of formula Y-1, Y-2 or Y-3, is independently selected from
In some embodiment of formula Y-1, Y-2 or Y-3, is independently selected from
In some embodiment of formula Y-2, is independently selected from
In some embodiment of formula Y-2, is independently selected from
In some embodiments, the sting agonist is a compound of Formula (A) , (B) , (C) , or a pharmaceutically acceptable salt:
wherein,
each W is independently selected from CR1 or N;
each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2;
R2 and R3 are independently selected from the group consisting of O- (C1-C4 alkylene or haloalkylene) , C1-C5 alkylene or haloalkylene, N (R6) - (C1-C4 alkylene or haloalkylene) , -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and
each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen;
each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) ;
each R6 is independently selected from the group consisting of -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-10heterocyclic ring or C3-10carbocyclic ring; and each of which is independently optionally substituted with deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, or C1-6alkyl; and each of the heteroaryl and heterocyclic ring contains at least one heteroatoms selected from N, O or S;
each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-;
each X2 is independently selected from (C (R8) 2) (1-3) , NR8 (C (R8) 2) (1-3) , -NH (C (R8) 2) (1-3) , –N (C1-6alkyl) (C (R8) 2) (1-3) or –N (haloC1-6alkyl) (C (R8) 2) (1-3) ; wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle;
each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN; and each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2) 1-3-C (=O) OR6, OR6, SR6, NH2, NH (C1-C6 alkyl) , N (C1-C6 alkyl) 2, O (C1-C6 alkyl) , O (C6-C10 aryl) , O (C1-C6 alkyl) -OR6, S (C1-C6alkyl) , S (C6-C10 aryl) , S (=O) 2R6, S (=O) 2OR6, P (=O) (R6) 2, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl.
In some embodiments of Formula (A) , is independently selected from the group consisting of
In some embodiments of Formula (A) , is independently selected from
In some embodiments of Formula (A) , the compound is of Formula (A-1) :
In some embodiments of Formula (B) , is independently selected from the group consisting of is independently selected from the group consisting of
In some embodiments of Formula (B) , is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula (C) , is independently selected from the group consisting of
In some embodiments of Formula (C) , is independently selected from
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each W is independently CR1.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each W is independently is CH or CF.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each W is independently N.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R1 is independently selected from the group consisting of H, deuterium, halogen, C1-C3 alkyl, CN and C1-C3 haloalkyl.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , wherein each R1 is independently selected from the group consisting of H, deuterium, halogen, CN and C1-C3 alkyl.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R1 is independently selected from the group consisting of H, deuterium, F, Cl , Br, CN and methyl.
In some embodiments, each R1 independently is hydrogen or halogen.
In some embodiments, each R1 independently is hydrogen or F.
In some embodiments, each R1 independently is hydrogen or CN.
In some embodiments, each R1 independently is deuterium.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally
substituted with one or more halo, -ORs, -N (Rs) 2, or -C (=O) ORs. Wherein in -Ta- (C3-C12 cycloalkyl) -Tb-or -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl is attached to Ta and Tb respectively via two different atoms of the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more halo, -ORs, -N (Rs) 2, or -C (=O) ORs; and wherein the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl is attached to Ta and Tb respectively via two different atoms of the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H , deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from O- (C1-C4 alkylene or haloalkylene) -C2-C6alkenyl, C1-C5 alkylene or haloalkylene, (C1-C4 alkylene or haloalkylene) -N (R6) , and N (R6) - (C1-C4 alkylene or haloalkylene) -C2-C6alkenyl, -C0-6alkyl-NH-C0-6alkyl-, -C0-6alkyl-N (C1-6alkyl) -C0-6alkyl-, -C0-6alkyl-O-C0-6alkyl-, -C0-6alkyl-PEGn-O-C0-6alkyl, -C0-6alkyl-S-S-C0-6alkyl, -C0-6alkyl-S-S-S-C0-6alkyl, -C0-6 alkyl-C2-C6alkenyl-C0-6 alkyl-, -C0-6 alkyl-C2-C6alkynyl-C0-6 alkyl-, -C0-6 alkyl-C (=O) -C0-6 alkyl-, -C0-6 alkyl-C (=CH2) -C0-6alkyl-, -C0-6 alkyl-C (=O) -C (=O) -C0-6alkyl-, -C0-6 alkyl-C (=S) -C0-6alkyl-, -C0-6 alkyl-S (=O) 2-C0-6alkyl-, -C0-6alkyl-S (=O) -C0-6alkyl-, -C0-6 alkyl-P (=O) (-OH) -C0-6alkyl-, -C0-6 alkyl-C3-C12 cycloalkyl-C0-6alkyl-, -C0-6 alkyl-C6-C12 aryl-C0-6alkyl-, -C0-6 alkyl- (3-to 12-membered heterocyclyl) -C0-6 alkyl-, -C0-6 alkyl- (5-to 12-membered heteroaryl) -C0-6 alkyl-, -C0-6alkyl-O- (5-to 12-membered heteroaryl) -O-C0-6alkyl-, -C0-6alkyl-O-C (=O) -NH-C0-6alkyl-, -C0-6alkyl-O-C (=O) -C0-6alkyl-, -C0-6alkyl-NH-C (=O) -C0-6alkyl-, -OC (=O) -O-, -NH-C (=O) -NH-, or -NH-C (=S) -NH-; wherein the C2-C6 alkenyl, C2-C6alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , R2 and R3 are independently selected from -Ta-C2-C6 alkenyl-Tb-, -Ta-C (=O) -Tb-, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-C (=CH2) -Tb-, or -Ta- (C6-C12 aryl) -Tb-, wherein the C2-C6alkenyl or C6-C12 aryl is optionally substituted with one or more halo, -ORs, -N (Rs) 2, or -C (=O) ORs;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are -N (Rs) -, -O-, - (C1-C6 alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6alkyl it optionally substituted with one or more halogen; each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , wherein R2-R3 is selected from
wherein:
each R5 is independently -OR7, NR7 or -C (O) OR7;
each R7 is independently hydrogen, deuterium or C1-2 alkyl; and
each R10 is independently hydrogen, deuterium, C1-2 alkyl or halogen.
In some embodiments, each R7 is independently hydrogen, deuterium, or methyl.
In some embodiments, each R10 is independently hydrogen, deuterium, methyl or fluorine.
In some embodiments, one R10 is hydrogen, and the other R10 is methyl or fluorine.
In some embodiments, one R10 is deuterium, and the other R10 is methyl or fluorine.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , wherein R2-R3 is selected from the group consisting of - (CH2) 2-8-, -O (CH2) 1-7-, -O (CH2) 1-6O-, -OCH2CH (CH3) CH2O-, -OCH (CH3) CH2CH (CH3) O-, -NH (CH2) 1-7-, - (CH2) 1-
6NH (CH2) 1-6-, - (CH2) 1-6N (CH3) (CH2) 1-6-, -NH (CH2) 1-6O-, -NH-CO-NH-, -N (CH3) CO-NH-,
In some embodiments of Formula (A) , (A-1) , (B) or (C) , wherein R2-R3 is selected from the group consisting of - (CH2) 2-, - (CH2) 3-, - (CH2) 4-, - (CH2) 5-, -O (CH2) 2-, -O (CH2) 3-, -O (CH2) 4-, -O (CH2) 2O-, -O (CH2) 3O-, -O (CH2) 4O-, -OCH2CH (CH3) CH2O-, -OCH (CH3) CH2CH (CH3) O-, -O (CH2) 4O-, -O (CH2) 5O-, -NH (CH2) 2-, -NH (CH2) 3-, -NH (CH2) 4-, - (CH2) 2NH-, - (CH2) 3NH-, - (CH2) 4NH-, -CH2NHCH2-, -CH2N (CH3) CH2-, -NH (CH2) 3O-, -NH-CO-NH-,
or -N (CH3) CONH-.
In some embodiments of Formula (A) , (A-1) or (B) , each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) .
In some embodiments of Formula (A) , (A-1) or (B) , each R4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl, C2-C3 alkenyl, C2-C3alkynyl, and N (R6) 2.
In some embodiments of Formula (A) , (A-1) or (B) , each R4 independently is selected from the group consisting of H, deuterium, Br, Cl, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, OCFH2, OCF2H, OCF3, and N (R6) 2.
In some embodiments of Formula (A) , (A-1) or (B) , each R4 independently is selected from the group consisting of H, deuterium, Br, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, NH2 and NHCH3.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-C3alkyl, C1-C3alkoxy, C2-C4alkenyl, C2-C4alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, or 8-membered carbocyclic ring; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-C3alkoxy, or C1-C3alkyl; and each of the heteroaryl and heterocyclic ring contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and each of the heteroaryl and heterocyclic ring contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R6 is independently selected from the group consisting of H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH2F, -CHF2, -CF3 and
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X1 is selected from the group consisting of C=O and -CH2-.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X1 is C=O.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is independently selected from (C (R8) 2) (1-3) , wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments, each X2 independently is - (C (R8) 2) 1-3-, wherein each R8 independently is hydrogen, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, or C3-C6 cycloalkyl; wherein the C1-C6 alkyl is optionally substituted with one or more halogen, OR6, or N (R6) 2.
In some embodiments, each X2 independently is - (C (R8) 2) 1-3-, wherein at least two R8, together with the one or more atoms to which they are attached, form C3-C6 cycloalkyl or 3-to 6-membered heterocycloalkyl.
In some embodiments, each X2 independently is -C (R8) 1-3-.
In some embodiments, each X2 independently is - (CH2) 1-3-.
In some embodiments, each X2 independently is -C (R8) 2-.
In some embodiments, each X2 independently is -CH2-.
In some embodiments, each X2 independently is -C (R8) 2C (R8) 2-.
In some embodiments, each X2 independently is -CH2CH2-.
In some embodiments, each X2 independently is -C (R8) 2C (R8) 2C (R8) 2-.
In some embodiments, each X2 independently is -CH2CH2CH2-.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CH2CHR8, where R8 is selected from the group consisting of H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CH2CHR8, wherein R8 is selected from the group consisting of H, deuterium, CH3, CH2OH, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2OCH3, and cyclopropyl.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CHR8CHR8, where each R8 is independently selected from the group consisting of H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally the 2 R8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CHR8CHR8, where each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl, and optionally the 2 R8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CH2C (R8) 2, where each R8 is independently selected from the group consisting of H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally the 2 R8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X2 is CH2C (R8) 2, where each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl, and optionally the 2 R8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X3 is independently selected from the group consisting of COOR6, SO2R6, C (O) N (R9) 2, and CN.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X3 is independently selected from the group consisting of COOR6, C (O) N (R9) 2, and CN.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each X3 is independently selected from the group consisting of COOH, COOCH3, CONH2, and CN.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R9 is independently selected from the group consisting of H, deuterium, COOR6, and SO2R6.
In some embodiments of Formula (A) , (A-1) , (B) or (C) , each R9 is independently H or deuterium, . preferably H.
In some embodiments of Formula (A) , (B) , or (C) , the compound is of Formula (Aa) , (Ba) , or (Ca) :
or a pharmaceutically acceptable salt thereof .
In some embodiments of Formula (A) or (B) , the compound is of Formula (Ab) , or (Bb) :
or a pharmaceutically acceptable salt thereof .
In some embodiments of Formula (A) , (B) , or (C) , the compound is of Formula (Ac) , (Bc) , or (Cc) :
or a pharmaceutically acceptable salt thereof .
In some embodiments of the preceding Formulae defined herein, each heterocyclic ring group and each carbocyclic ring group includes single ring, spiral ring, bridge ring, fused ring and various combinations of spiral ring, bridge ring and/or fused ring.
In some embodiments of the preceding Formulae defined herein, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
In some embodiments of the preceding Formulae defined herein, the compound is the compounds described in Table 1.
Table 1
In some embodiments, the sting agonist is a compound of Formula I, II, III, IV or V, or an ester, stereoisomer, tautomer, isotopic derivative, prodrug or pharmaceutically acceptable salt thereof:
wherein
each W is independently selected from CR1 or N;
each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2;
R2 and R3 are independently selected from O- (C1-C4 alkylene or haloalkylene) , C1-C5 alkylene or haloalkylene, N (R6) - (C1-C4 alkylene or haloalkylene) , -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and
each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen;
each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) ;
each R6 is independently selected from the group consisting of -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-10heterocyclic ring or C3-10carbocyclic ring; and each of which is independently optionally substituted with deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, or C1-6alkyl; and each of the heteroaryl and heterocyclic ring contains at least one heteroatoms selected from N, O or S;
each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-;
each X2 is independently selected from (C (R8) 2) (1-3) , -NR8 (C (R8) 2) (1-3) , -NH (C (R8) 2) (1-3) , –N (C1-6alkyl) (C (R8) 2) (1-3) or –N (haloC1-6alkyl) (C (R8) 2) (1-3) ; wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle;
each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN; and each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2) 1-3-C (=O) OR6, OR6, SR6, NH2, NH (C1-C6 alkyl) , N (C1-C6 alkyl) 2, O (C1-C6 alkyl) , O (C6-C10 aryl) , O (C1-C6 alkyl) -OR6, S (C1-
C6alkyl) , S (C6-C10 aryl) , S (=O) 2R6, S (=O) 2OR6, P (=O) (R6) 2, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl.
In some embodiments of Formula I, is independently selected from the group consisting of is independently selected from the group consisting of
In some embodiments of Formula I, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula I, the compound is of Formula I-1:
In some embodiments of Formula II, is independently selected from the group consisting of is independently selected from the group consisting of
In some embodiments of Formula II, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula III, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula III, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula IV, is independently selected from the group consisting of is independently selected from the group consisting of
In some embodiments of Formula IV, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula V, is independently selected from the group consisting of is independently selected from the group consisting of
In some embodiments of Formula V, is independently selected from the group consisting of
is independently selected from the group consisting of
In some embodiments of Formula I, I-1, II, III, IV or V, each W is independently is CR1.
In some embodiments of Formula I, I-1, II, III, IV or V, each W is independently is CH or CF.
In some embodiments of Formula I, I-1, II, III, IV or V, each W is independently is N.
In some embodiments of Formula I, I-1, II, III, IV or V, each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2.
In some embodiments of Formula I, I-1, II, III, IV or V, each R1 is independently selected from the group consisting of H, deuterium, halogen, C1-C3 alkyl, CN and C1-C3 haloalkyl.
In some embodiments of Formula I, I-1, II, III, IV or V, wherein each R1 is independently selected from the group consisting of H, deuterium, halogen, CN and C1-C3 alkyl.
In some embodiments of Formula I, I-1, II, III, IV or V, wherein each R1 is independently selected from the group consisting of H, deuterium, F, Cl , Br, CN and methyl.
In some embodiments, each R1 independently is hydrogen or halogen.
In some embodiments, each R1 independently is hydrogen or F.
In some embodiments, each R1 independently is hydrogen or CN.
In some embodiments, each R1 independently is deuterium.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs. wherein in -Ta- (C3-C12 cycloalkyl) -Tb-or -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl is attached to Ta and Tb respectively via two different atoms of the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and
each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs; and wherein the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl is attached to Ta and Tb respectively via two different atoms of the C3-C12 cycloalkyl or 3-to 12-membered heterocycloalkyl;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; and each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from O- (C1-C4 alkylene or haloalkylene) -C2-C6alkenyl, C1-C5 alkylene or haloalkylene, (C1-C4 alkylene or haloalkylene) -N (R6) , and N (R6) - (C1-C4 alkylene or haloalkylene) -C2-C6alkenyl, -C0-6alkyl-NH-C0-6alkyl-, -C0-6alkyl-N (C1-6alkyl) -C0-6alkyl-, -C0-6alkyl-O-C0-6alkyl-, -C0-6alkyl-PEGn-O-C0-6alkyl, -C0-6alkyl-S-S-C0-6alkyl, -C0-6alkyl-S-S-S-C0-6alkyl, -C0-6 alkyl-C2-C6alkenyl-C0-6 alkyl-, -C0-6 alkyl-C2-C6alkynyl-C0-6 alkyl-, -C0-6 alkyl-C (=O) -C0-6 alkyl-, -C0-6 alkyl-C (=CH2) -C0-6alkyl-, -C0-6 alkyl-C (=O) -C (=O) -C0-6alkyl-, -C0-6 alkyl-C (=S) -C0-6alkyl-, -C0-6 alkyl-S (=O) 2-C0-6alkyl-, -C0-6alkyl-S (=O) -C0-6alkyl-, -C0-6 alkyl-P (=O) (-OH) -C0-6alkyl-, -C0-6 alkyl-C3-C12 cycloalkyl-C0-6alkyl-, -C0-6 alkyl-C6-C12 aryl-C0-6alkyl-, -C0-6 alkyl- (3-to 12-membered heterocyclyl) -C0-6 alkyl-, -C0-6 alkyl- (5-to 12-membered heteroaryl) -C0-6 alkyl-, -C0-6alkyl-O- (5-to 12-membered heteroaryl) -O-C0-6alkyl-, -C0-6alkyl-O-C (=O) -NH-C0-6alkyl-, -C0-6alkyl-O-C (=O) -C0-6alkyl-, -C0-6alkyl-NH-C (=O) -C0-6alkyl-, -OC (=O) -O-, -NH-C (=O) -NH-, or -NH-C (=S) -NH-; wherein the C2-C6 alkenyl, C2-C6alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs.
In some embodiments of Formula I, I-1, II, III, IV or V, R2 and R3 are independently selected from -Ta-C2-C6 alkenyl-Tb-, -Ta-C (=O) -Tb-, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-C (=CH2) -Tb-, or -Ta- (C6-C12 aryl) -Tb-, wherein the C2-C6alkenyl or C6-C12 aryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;
PEGn is (-OCH2CH2-) n, n = 1-8;
Ta and Tb each independently are -N (Rs) -, -O-, - (C1-C6 alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6alkyl it optionally substituted with one or more halogen; each Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen.
In some embodiments of Formula I, I-1, II, III, IV or V, wherein R2-R3 is selected from
wherein:
each R5 is independently -OR7, NR7 or -C (O) OR7;
each R7 is independently hydrogen, deuterium or C1-2 alkyl; and
each R10 is independently hydrogen, deuterium, C1-2 alkyl or halogen.
In some embodiments of Formula I, I-1, II, III, IV or V, wherein each R7 is independently hydrogen, deuterium or methyl.
In some embodiments, each R10 is independently hydrogen, deuterium, methyl or fluorine.
In some embodiments, one R10 is hydrogen, and the other R10 is methyl or fluorine.
In some embodiments, one R10 is deuterium, and the other R10 is methyl or fluorine.
In some embodiments of Formula I, I-1, II, III, IV or V, wherein R2-R3 is selected from the group consisting of - (CH2) 2-8-, -O (CH2) 1-7-, -O (CH2) 1-6O-, -OCH2CH (CH3) CH2O-, -OCH (CH3) CH2CH (CH3) O-, -NH (CH2) 1-7-, - (CH2) 1-
6NH (CH2) 1-6-, - (CH2) 1-6N (CH3) (CH2) 1-6-, -NH (CH2) 1-6O-, -NH-CO-NH-, -N (CH3) CO-NH-,
In some embodiments of Formula I, I-1, II, III, IV or V, wherein R2-R3 is selected from the group consisting of - (CH2) 2-, - (CH2) 3-, - (CH2) 4-, - (CH2) 5-, -O (CH2) 2-, -O (CH2) 3-, -O (CH2) 4-, -O (CH2) 2O-, -O (CH2) 3O-, -O (CH2) 4O-, -OCH2CH (CH3) CH2O-, -OCH (CH3) CH2CH (CH3) O-, -O (CH2) 4O-, -O (CH2) 5O-, -NH (CH2) 2-, -NH (CH2) 3-, -NH (CH2) 4-, - (CH2) 2NH-, - (CH2) 3NH-, - (CH2) 4NH-, -CH2NHCH2-, -CH2N (CH3) CH2-, -NH (CH2) 3O-, -NH-CO-NH-,
or -N (CH3) CONH-.
In some embodiments of Formula I, I-1, II, III or IV, each R4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) .
In some embodiments of Formula I, I-1, II, III or IV, each R4 is independently selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, C1-C3 alkyl, C1-C3 haloalkyl, OC1-C3 alkyl, OC1-C3 haloalkyl, C2-C3 alkenyl, C2-C3alkynyl, and N (R6) 2.
In some embodiments of Formula I, I-1, II, III or IV, each R4 independently is selected from the group consisting of H, deuterium, Br, Cl, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, OCFH2, OCF2H, OCF3, and N (R6) 2.
In some embodiments of Formula I, I-1, II, III or IV, each R4 independently is selected from the group consisting of H, deuterium, Br, OH, CH3, CH2CH3, CH=CH2, C≡CH, OCH3, NH2 and NHCH3.
In some embodiments of Formula I, I-1, II, III, IV or V, each R6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-C3alkyl, C1-C3alkoxy, C2-C4alkenyl, C2-C4alkynyl, 6-membered aryl, 7-membered aryl, 8-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 7-membered heterocyclic ring, 8-membered heterocyclic ring, 5-membered carbocyclic ring, 6-membered carbocyclic ring, 7-membered carbocyclic ring, or 8-membered carbocyclic ring; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-C3alkoxy, or C1-C3alkyl; and each of the heteroaryl and heterocyclic ring contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of Formula I, I-1, II, III, IV or V, each R6 is independently selected from the group consisting of -H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -N3, -NO2, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, 6-membered aryl, 5-membered heteroaryl, 6-membered heteroaryl, 5-membered heterocyclic ring, 6-membered heterocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring; and each of which is independently optionally substituted with deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; and each of the heteroaryl and heterocyclic ring contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of Formula I, I-1, II, III, IV or V, each R6 is independently selected from the group consisting of H, deuterium, -F, -Cl, -Br, -I, -NH2, -CN, -OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, CH2F, -CHF2, and -CF3.
In some embodiments of Formula I, I-1, II, III, IV or V, each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-.
In some embodiments of Formula I, I-1, II, III, IV or V, each X1 is selected from the group consisting of C=O and -CH2-.
In some embodiments of Formula I, I-1, II, III, IV or V, each X1 is C=O.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is independently selected from (C (R8) 2) (1-3) , wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments, each X2 independently is - (C (R8) 2) 1-3-, wherein each R8 independently is hydrogen, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, or C3-C6 cycloalkyl; wherein the C1-C6 alkyl is optionally substituted with one or more halogen, OR6, or N (R6) 2.
In some embodiments, each X2 independently is - (C (R8) 2) 1-3-, wherein at least two R8, together with the one or more atoms to which they are attached, form C3-C6 cycloalkyl or 3-to 6-membered heterocycloalkyl.
In some embodiments, each X2 independently is -C (R8) 1-3-.
In some embodiments, each X2 independently is - (CH2) 1-3-.
In some embodiments, each X2 independently is -C (R8) 2-.
In some embodiments, each X2 independently is -CH2-.
In some embodiments, each X2 independently is -C (R8) 2C (R8) 2-.
In some embodiments, each X2 independently is -CH2CH2-.
In some embodiments, each X2 independently is -C (R8) 2C (R8) 2C (R8) 2-.
In some embodiments, each X2 independently is -CH2CH2CH2-.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CH2CHR8, where R8 is selected from the group consisting of H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CH2CHR8, wherein R8 is selected from the group consisting of H, deuterium, CH3, CH2OH, CH2CH3, CH2CH2CH3, CH (CH3) 2, CH2OCH3, and cyclopropyl.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CHR8CHR8, where each R8 is independently selected from the group consisting of H, deuterium, C1-C3 alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally the 2 R8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CHR8CHR8, where each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl, and optionally the 2 R8 on different carbon atoms are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CH2C (R8) 2, where each R8 is independently selected from the group consisting of H, deuterium, C1-C3alkyl, C1-C3 alkyl substituted by OH, C1-C3 alkyl substituted by OC1-C3 alkyl, and C3-C6 cycloalkyl, and optionally the 2 R8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments of Formula I, I-1, II, III, IV or V, each X2 is CH2C (R8) 2, where each R8 is independently selected from the group consisting of H, deuterium and C1-C3 alkyl, and optionally the 2 R8 on a single carbon atom are taken together, along with the atoms to which they are attached, to form a 3-to 6-membered spirocycle.
In some embodiments of Formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN.
In some embodiments of Formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of COOR6, SO2R6, C (O) N (R9) 2, and CN.
In some embodiments of Formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of COOR6, C (O) N (R9) 2, and CN.
In some embodiments of Formula I, I-1, II, III, IV or V, each X3 is independently selected from the group consisting of COOH, COOCH3, CONH2, CONH-SO2-N (CH3) 2, CONH-SO2-CH3, and CN.
In some embodiments of Formula I, I-1, II, III, IV or V, each R9 is independently selected from the group consisting of H, deuterium, COOR6, and SO2R6.
In some embodiments of Formula I, I-1, II, III, IV or V, each R9 is independently H or deuterium, preferably H.
In some embodiments, the compound is of Formula Ia, IIa, IIIa, IVa or Va:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is of Formula Ib, IIb, IIIb, or IVb:
or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is of Formula Ic, IIc, IIIc, IVc or Vc:
or a pharmaceutically acceptable salt thereof.
In some embodiments of the preceding Formulae defined herein, each heterocyclic ring group and each carbocyclic ring group includes single ring, spiral ring, bridge ring, fused ring and various combinations of spiral ring, bridge ring and/or fused ring.
In some embodiments of the preceding Formulae defined herein, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.
In some embodiments of the preceding Formulae defined herein, the compound is the compounds described in Table 2.
Table 2
In some embodiments, the compound is an isotopic derivative of any one of the compounds described in the two tables above and prodrugs and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is an isotopic derivative of any one of the compounds described in the two tables above and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in the two tables above and pharmaceutically acceptable salts thereof.
In some embodiments, the sting agonist is a compound described in the two tables.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the
art, the products of such procedures can be a mixture of stereoisomers. The term “stereoisomer” as used herein refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
Any of the compound of formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V is intended to include its isotopic derivative. The isotopic derivatives have structures depicted by the formulas given herein except that one or more atoms are replaced by an isotope. Examples of isotopes include and are not limited to isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 35S, 36Cl, respectively.
In some embodiments, the isotopic derivative is a deuterated derivative, wherein one or more hydrogen atoms in one or more substituents are replaced with deuterium, e.g. all hydrogens in one or more alkyl substituents are replaced with deuterium (the respective moiety/moieties are then perdeuterated) . Substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) , may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
In some embodiments of the vaccine adjuvant in the present disclosure, wherein the vaccine adjuvant further includes a solvent.
In another aspect, the present disclosure provides a vaccine adjuvant composition, comprising a sting agonist described herein and at least one pharmaceutically acceptable excipient.
In some embodiments of the vaccine adjuvant composition of the disclosure, wherein the sting agonist is in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
The present invention also provides a vaccine composition comprising a vaccine adjuvant described herein and a vaccine.
In some embodiments, the vaccine is selected from pathogenic bacteria or viruses that produce T-lymphocyte-independent antibody immune responses and T-lymphocyte-dependent antibody immune responses; the vaccine is a tumor vaccine.
In some embodiments, the vaccine is selected from live attenuated vaccines, inactivated vaccines, antitoxins, subunit vaccines (including peptide vaccines) , vector vaccines, nucleic acid vaccines, etc.
In some embodiments, the vaccine is selected from capsular polysaccharide vaccine, cholera vaccine or novel coronavirus vaccine.
In some embodiments, the vaccine is selected from Streptococcus pneumoniae vaccines.
In some embodiments, the vaccine comprises at least one antigen, and the antigen is selected from the group consisting of viral antigen, protozoal antigen, bacterial antigen, fungal antigen, cancer antigen and allergen.
In some embodiments, the viral antigen may be derived from viruses including but not limited to: Epstein-Barr virus (EBV) , hepatitis A virus (HAV) , hepatitis B virus (HBV) , hepatitis C virus (HCV) , hepatitis D virus (HDV) , hepatitis E virus (HEV) , Hantaan virus, cytomegalovirus (CMV) , human immunodeficiency virus (HIV) , influenza virus, human papillomavirus (HPV) , poliovirus, ebola virus, rotavirus, dengue virus, West Nile virus, yellow fever virus, adenovirus, Japanese encephalitis virus, BK virus, smallpox virus, Zika virus, severe fever with thrombocytopenia syndrome (SFTS) virus, herpes simplex virus (HSV) or Severe Acute Respirator Syndrome Coronavirus 2 (SARS-CoV-2) , such as COVID-19.
In some embodiments, the protozoal antigens include, but are not limited to, antigens from Plasmodium spp. or Toxoplasma spp., schistosomae antigens, leishmania major and other leishmaniae antigens, Trypanosoma cruzi antigens, antigens from Entamoeba spp., Babesia spp., Trypanosoma spp., Giardia spp., leishmania spp., Pneumocystis spp., Trichomonas spp., Schisostoma spp..
In some embodiments, the bacterial antigen may be antigens from Neisseria spp.; antigens from Streptococcus spp.; antigens from Streptococcus agalactiae, Streptococcus mutans, Haemophilus ducreyi, Moraxella spp.; antigens from Bordetella spp.; antigens from Mycobacterium spp.; antigens from Escherichia spp.; antigens from Vibrio spp.; antigens from Shigella spp., Yersinia spp.; antigens from Y. pestis, Y. pseudotuberculosis, Campylobacter spp.; antigens from Salmonella spp., Listeria spp., Helicobacter spp.; antigens from Pseudomonas spp.; Staphylococcus spp., Enterococcus spp., Clostridium spp.; antigens from C. botulinum; antigens from C. difficile; antigens from Bacillus spp., Corynebacterium spp.; antigens from Borrelia spp.; antigens from B. garinii, B. afzelii; antigens from B. andersonfi; antigens from B. hermsii; antigens from Ehrlichia spp., Rickettsia spp.; Chlamydia spp.; antigens from Chlamydia pneumoniae; antigens from C. psittaci, Leptospira spp., Treponema spp.; antigens from T. denticola, T. hyodysenteriae; antigens from M. tuberculosis; antigens from Chlamydia; antigens from Streptococcus spp.; antigens from Haemophilus spp.; antigens from non typeable H. influenzae.
In some embodiments, the fungal antigen include, but are not limited to, e.g., antigens from Candida spp.; histoplasma fungal antigens such as heat shock protein 60 (HSP60) ; antigens from Cryptococcus spp.; coccidiodes fungal antigens; and tinea fungal antigens.
In some embodiments, the cancer antigen is an antigen specially expressed on a cancer cell and recognized/attacked by the immune system as a foreign body. The cancer antigen may be expressed on cancer cells of all types and a specific type of cancer. As the cancer antigen, a protein having strong immunogenicity and never be expressed in normal cells, is preferable. Examples of the cancer antigen includes, but is not limited to: WT1, MUC1, LMP2, HPVE6, HPVE7, EGFRv III, HER-2/neu, MAGE-A3, p53nonmutant, HSP70, GPC3, MUC1, Casp8, CDAM1, cMyb, EVC1, EVC2, Helios, Fas, NY-ESO-1, PSMA, GD2, CEA, MelanA/MART1, Ras mutant, gp100, p53 mutant, Proteinase3 (PR1) , bcr-abl, Tyrosinase, Survivin, PSA, hTERT, Sarcoma translocation breakpoints, EphA2, PAP, ML-IAP, AFP, EpCAM, ERG, NA17, PAX3, ALK, Androgen receptor, Cyclin B1, Polysialic acid, MYCN, PhoC, TRP-2, GD3, Fucosyl GM1, Mesothelin, PSCA, MAGE A1, sLe, CYP1B1, PLAC1, GM3, BORIS, Tn, GloboH, ETV6-AML, NY-BR-1, RGS5, SART3, STn, Carbonic anhydrase IX, PAX5, OY-TES1, Sperm protein 17, LCK, HMWMAA, AKAP-4, SSX2, XAGE1, B7H3, Legumain, Tie2, Page4, VEGFR2, MAD-CT-1, FAP, PDGFR, MAD-CT-2 and Fos-related antigen 1.
The cancer antigen derived peptide is also within the scope of the present disclosure. The cancer antigen derived peptide is a peptide having addition, substitution or deletion of 1 or 2 amino acids, or a peptide having a sequence identity with the above amino acid sequence of 90%or more, 95%or more, 98%or more, or 99%or more and maitaining at least part of the function of the cancer antigen.
In some embodiments, the cancer antigen may be a human papillomavirus (HPV) -derived antigen, a carcinoembryonic antigen, a prostate-specific membrane antigen (PSMA) , Her2/neu, MUC-1, BCR/ABL, α-fetoprotein (AFP) , an Epstein-Barr virus (EBV) -derived antigen, a human hepatitis B virus (HBV) -derived antigen, a human hepatitis C virus (HCV) -derived antigen, cancer antigen-125 (CA-125) , cancer antigen-72-4 (CA-72-4) , cancer antigen-15-3 (CA-15-3) , or cancer antigen-19-9 (CA-19-9) .
In some embodiments, the allergen may be pollen allergens (tree-, herb, weed-, and grass pollen allergens) , insect allergens (inhalant, saliva and venom allergens) , animal hair and dandruff allergens, and food allergens. Other allergen antigens that may be used include allergens from house dust mites of the genus Dermatophagoides and Euroglyphus, storage mite e.g Lepidoglyphys, Glycyphagus and Tyrophagus, those from cockroaches, midges and fleas e.g. Blatella, Periplaneta, Chironomus and Ctenocepphalides, those from mammals such as cat, dog and horse, birds, venom allergens including such originating from stinging or biting insects such as those from the taxonomic order of Hymenoptera including bees (superfamily Apidae) , wasps and ants (superfamily Formicoidae) . Still other allergen antigens that may be used include inhalation allergens from fungi such as from the genus Alternaria and Cladosporium.
In another aspect, the present disclosure provides a method of preparing an antibody, comprise:
contacting an animal with the vaccine composition described herein; and isolating the antibody from the blood of the animal. The vaccine adjuvant or vaccine composition containing the sting agonist can effectively help the vaccine to play a better role, activate B lymphocytes, and enhance the T lymphocyte-independent antibody immune response. Therefore, after contacting the animal with the vaccine adjuvant or vaccine composition, an immune response is activated to produce corresponding antibodies. USES
The present disclosure provides a use of a sting agonist as a vaccine adjuvant, preferably the sting agonist is defined herein.
The present disclosure provides a use of a sting agonist in manufacture of a vaccine adjuvant, a vaccine adjuvant composition and/or a vaccine composition, preferably the sting agonist is defined herein.
The present disclosure further provides a use of a vaccine adjuvant, a vaccine adjuvant composition, and/or a vaccine composition described herein.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used to active B lymphocytes.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for enhancing T lymphocyte-independent antibody immune response and T lymphocyte-dependent antibody immune response.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for preventing or treating diseases caused by pathogenic bacteria carrying capsular polysaccharide, cholera or novel coronavirus, the pathogenic bacteria Selected from Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic Escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and/or Streptococcus pneumoniae.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for preventing or treating diseases caused by Streptococcus pneumoniae, Solitary cholerae or novel coronavirus.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a disease or disorder in a subject in need thereof. In some embodiments, the disease may be an infectious disease, a cell proliferation disorder such as tumor or cancer, or an immune disorder. In some embodiments, the infectious disease is bacterial, viral, or fungal infection. In some embodiments, the immune disorder such as autoimmune disease or immunodeficiency disease.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a STING-mediated disease or disorder in a subject.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a cancer in a subject in need thereof.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing an immune response in a subject.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing STING-dependent type I interferon production in a subject.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for inducing a STING-dependent cytokine production in a subject.
In some embodiments, the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition is used for treating or preventing a cell proliferation disorder in a subject. In some embodiments, wherein the cell proliferation disorder is cancer.
The vaccine adjuvant, vaccine adjuvant composition or vaccine composition of the disclosure are useful in methods for treating or ameliorating a viral infection, disease, a syndrome, a condition or a disorder that is affected by the agonism of STING. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and/or prevention, a therapeutically effective amount of a vaccine adjuvant or a vaccine composition.
In some embodiments, the vaccine adjuvant, vaccine adjuvant composition or vaccine composition is useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as melanoma, colon cancer, breast cancer, prostate cancer, lung cancer, fibrosarcoma, and hepatitis B.
METHODS
In yet another aspect of the present invention, the present invention provides a method of enhancing or prolonging an immune response in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition disclosed herein. In some embodiments, the immune response is T lymphocyte-independent antibody immune response or T lymphocyte-dependent antibody immune response. In some embodiments, the vaccine composition is capable of inducing STING-dependent type I interferon production, or inducing a STING-dependent cytokine production in a subject
In yet another aspect of the present invention, the present invention provides a method for preventing or treating diseases caused by pathogenic bacteria that produce T lymphocyte-independent antibody immune responses or T lymphocyte-dependent immune responses in the body type antibody immune response. According to an embodiment of the present invention, the method comprises: applying the aforementioned vaccine composition, the aforementioned antibody or the aforementioned artificial antibody to the body. As mentioned above, sting agonists can effectively activate B lymphocytes, enhance T lymphocyte-independent antibody immune responses and T lymphocyte-dependent antibody immune responses, and thus can play a better preventive and therapeutic purpose.
In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of vaccine composition disclosed herein. In some embodiments, the disease may be an infectious disease, a cell proliferation disorder such as tumor or cancer, or an immune disorder. In some embodiments, the infectious disease is bacterial, viral, or fungal infection. In some embodiments, the immune disorder such as autoimmune disease or immunodeficiency disease. In some embodiments, wherein the cell proliferation disorder is cancer, or cancer metastasis. In some embodiments, the disease may be cardiovascular disease, an immunological disorder, fibrosis, or an ocular disorder.
In some embodiments, the present disclosure relates to a method of treating a cancer in a subject in need thereof, comprising administering to the subject an effective amount of vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition disclosed herein.
In some aspects, the present disclosure provides a method of inducing an immune response in a subject, said method comprising administering a therapeutically effective amount of the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
In some aspects, the present disclosure provides a method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
In some aspects, the present disclosure provides a method of inducing a STING-dependent cytokine production in a subject, said method comprising administering a therapeutically effective the vaccine adjuvant, vaccine adjuvant comopsition, or vaccine composition described herein to the subject.
In some embodiments, the disclosure provides methods of treatment or prevention of STING mediated diseases and disorders, comprising applying the aforementioned vaccine adjuvant or vaccine composition. Exemplary diseases/disorders include, but are not limited to, cancer, infectious disease (e.g., HIV, HBV, HCV, HPV, and influenza infectious diseases) .
In some embodiments of the uses or methods above, the disease or disorder is an infectious disease or a cancer. These vaccine adjuvants or vaccine compositions are potentially useful in treating diseases or disorders including, but not limited to,
cell proliferation disorders, cancer metastasis, cardiovascular disease, an immunological disorder, fibrosis, infectious diseases or an ocular disorder. The infectious diseases include, but are not limited to, a disease is caused by pathogenic bacteria carrying capsular polysaccharide, cholera or novel coronavirus, the pathogenic bacteria Selected from Klebsiella pneumoniae, Acinetobacter baumannii, pathogenic Escherichia coli, Haemophilus influenzae type B, Neisseria meningitidis and/or Streptococcus pneumoniae, HIV, HBV, HCV, HPV, or influenza. Cell-proliferation disorders include, but are not limited to, cancers, benign papillomatosis, gestational trophoblastic diseases, and benign neoplastic diseases, such as skin papilloma (warts) and genital papilloma.
In specific embodiments of uses or methods, the disease or disorder to be treated is a cell proliferation disorder. In certain embodiments, the cell proliferation disorder is cancer. In particular embodiments, the cancer is selected from brain and spinal cancers, cancers of the head and neck, leukemia and cancers of the blood, skin cancers, cancers of the reproductive system, cancers of the gastrointestinal system, liver and bile duct cancers, kidney and bladder cancers, bone cancers, lung cancers, malignant mesothelioma, sarcomas, lymphomas, glandular cancers, thyroid cancers, heart tumors, germ cell tumors, malignant neuroendocrine (carcinoid) tumors, midline tract cancers, and cancers of unknown primary (i.e., cancers in which a metastasized cancer is found but the original cancer site is not known) . In particular embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In particular embodiments, the cancer is AIDS-related.
In specific embodiments of uses or methods, the cancer is selected from brain and spinal cancers. In particular embodiments, the cancer is selected from the group consisting of anaplastic astrocytomas, glioblastomas, astrocytomas, and estheosioneuroblastomas (also known as olfactory blastomas) . In particular embodiments, the brain cancer is selected from the group consisting of astrocytic tumor (e.g., pilocytic astrocytoma, subependymal giant-cell astrocytoma, diffuse astrocytoma, pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astrocytoma, giant cell glioblastoma, glioblastoma, secondary glioblastoma, primary adult glioblastoma, and primary pediatric glioblastoma) , oligodendroglial tumor (e.g., oligodendroglioma, and anaplastic oligodendroglioma) , oligoastrocytic tumor (e.g., oligoastrocytoma, and anaplastic oligoastrocytoma) , ependymoma (e.g., myxopapillary ependymoma, and anaplastic ependymoma) ; medulloblastoma, primitive neuroectodermal tumor, schwannoma, meningioma, atypical meningioma, anaplastic meningioma, pituitary adenoma, brain stem glioma, cerebellar astrocytoma, cerebral astorcytoma/malignant glioma, visual pathway and hypothalmic glioma, and primary central nervous system lymphoma. In specific instances of these embodiments, the brain cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, and suprantentorial primordial neuroectodermal tumors (sP ET) .
In specific embodiments of uses or methods, the cancer is selected from cancers of the head and neck, including nasopharyngeal cancers, nasal cavity and paranasal sinus cancers, hypopharyngeal cancers, oral cavity cancers (e.g., squamous cell carcinomas, lymphomas, and sarcomas) , lip cancers, oropharyngeal cancers, salivary gland tumors, cancers of the larynx (e.g., laryngeal squamous cell carcinomas, rhabdomyosarcomas) , and cancers of the eye or ocular cancers. In particular embodiments, the ocular cancer is selected from the group consisting of intraocular melanoma and retinoblastoma.
In specific embodiments of uses or methods, the cancer is selected from leukemia and cancers of the blood. In particular embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, acute myeloid leukemia (AML) , myelodysplastic syndrome (MDS) , chronic myelogenous leukemia (CML) , myeloproliferative neoplasm (MPN) , post-MPN AML, post-MDS AML, del (5q) -associated high risk MDS or AML, blast-phase chronic myelogenous leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myelomas. Leukemias referenced herein may be acute or chronic.
In specific embodiments of uses or methods, the cancer is selected from skin cancers. In particular embodiments, the skin cancer is selected from the group consisting of melanoma, squamous cell cancers, and basal cell cancers.
In specific embodiments of uses or methods, the cancer is selected from cancers of the reproductive system. In particular embodiments, the cancer is selected from the group consisting of breast cancers, cervical cancers, vaginal cancers, ovarian cancers, prostate cancers, penile cancers, and testicular cancers. In specific instances of these embodiments, the cancer is a breast cancer selected from the group consisting of ductal carcinomas and phyllodes tumors. In specific instances of these embodiments, the breast cancer may be male breast cancer or female breast cancer. In specific instances of these embodiments, the cancer is a cervical cancer selected from the group consisting of squamous cell carcinomas and adenocarcinomas. In specific instances of these embodiments, the cancer is an ovarian cancer selected from the group consisting of epithelial cancers.
In specific embodiments of uses or methods, the cancer is selected from cancers of the gastrointestinal system. In particular embodiments, the cancer is selected from the group consisting of esophageal cancers, gastric cancers (also known as stomach cancers) , gastrointestinal carcinoid tumors, pancreatic cancers, gallbladder cancers, colorectal cancers, and anal cancer. In instances of these embodiments, the cancer is selected from the group consisting of esophageal squamous cell carcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gastric lymphomas, gastrointestinal lymphomas, solid pseudopapillary tumors of the pancreas, pancreatoblastoma, islet cell tumors, pancreatic carcinomas including acinar cell carcinomas and ductal adenocarcinomas, gallbladder adenocarcinomas, colorectal adenocarcinomas, and anal squamous cell carcinomas.
In specific embodiments of uses or methods, the cancer is selected from liver and bile duct cancers. In particular embodiments, the cancer is liver cancer (also known as hepatocellular carcinoma) . In particular embodiments, the cancer is bile duct cancer (also known as cholangiocarcinoma) ; in instances of these embodiments, the bile duct cancer is selected from the group consisting of intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma.
In specific embodiments of uses or methods, the cancer is selected from kidney and bladder cancers. In particular embodiments, the cancer is a kidney cancer selected from the group consisting of renal cell cancer, Wilms tumors, and transitional cell cancers. In particular embodiments, the cancer is a bladder cancer selected from the group consisting of urethelial carcinoma (a transitional cell carcinoma) , squamous cell carcinomas, and adenocarcinomas.
In specific embodiments of uses or methods, the cancer is selected from bone cancers. In particular embodiments, the bone cancer is selected from the group consisting of osteosarcoma, malignant fibrous histiocytoma of bone, Ewing sarcoma, chordoma (cancer of the bone along the spine) .
In specific embodiments of uses or methods, the cancer is selected from lung cancers. In particular embodiments, the lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancers, bronchial tumors, and pleuropulmonary blastomas.
In specific embodiments of uses or methods, the cancer is selected from malignant mesothelioma. In particular embodiments, the cancer is selected from the group consisting of epithelial mesothelioma and sarcomatoids.
In specific embodiments of uses or methods, the cancer is selected from sarcomas. In particular embodiments, the sarcoma is selected from the group consisting of central chondrosarcoma, central and periosteal chondroma, fibrosarcoma, clear cell sarcoma of tendon sheaths, and Kaposi's sarcoma.
In specific embodiments of uses or methods, the cancer is selected from lymphomas. In particular embodiments, the cancer is selected from the group consisting of Hodgkin lymphoma (e.g., Reed-Sternberg cells) , non-Hodgkin lymphoma (e.g., diffuse large B-cell lymphoma, follicular lymphoma, mycosis fungoides, Sezary syndrome, primary central nervous system lymphoma) , cutaneous T-cell lymphomas, primary central nervous system lymphomas.
In specific embodiments of uses or methods, the cancer is selected from glandular cancers. In particular embodiment, the cancer is selected from the group consisting of adrenocortical cancer (also known as adrenocortical carcinoma or adrenal cortical carcinoma) , pheochromocytomas, paragangliomas, pituitary tumors, thymoma, and thymic carcinomas.
In specific embodiments of uses or methods, the cancer is selected from thyroid cancers. In particular embodiments, the thyroid cancer is selected from the group consisting of medullary thyroid carcinomas, papillary thyroid carcinomas, and follicular thyroid carcinomas.
In specific embodiments of uses or methods, the cancer is selected from germ cell tumors. In particular embodiments, the cancer is selected from the group consisting of malignant extracranial germ cell tumors and malignant extragonadal germ cell tumors. In specific instances of these embodiments, the malignant extragonadal germ cell tumors are selected from the group consisting of nonseminomas and seminomas.
In specific embodiments of uses or methods, the cancer is selected from heart tumors. In particular embodiments, the heart tumor is selected from the group consisting of malignant teratoma, lymphoma, rhabdomyosacroma, angiosarcoma, chondrosarcoma, infantile fibrosarcoma, and synovial sarcoma.
In specific embodiments of uses or methods, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In particular embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In particular embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental -site trophoblastic tumors, and epithelioid trophoblastic tumors) .
In some embodiments of uses or methods, the disease or disorder is a neurodegenerative diseases. Exemplary neurodegenerative diseases include, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) . The scope of the diseases would be readily recognized by a skilled artisan in the field.
As used herein, the terms "treatment" and "treating" refer to all processes in which there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of a disease or disorder described herein. The terms do not necessarily indicate a total elimination of all disease or disorder symptoms.
KITS
The present disclosure relates to a kit, comprising the vaccine adjuvant, the vaccine adjuvant composition, and/or the vaccine composition described herein.
The present disclosure also relates to a kit, comprising:
(1) the vaccine adjuvant, the vaccine adjuvant composition, and/or the vaccine composition described herein; and
(2) a vaccine.
The terms "administration of and or "administering" a compound should be understood to include providing a compound described herein, or a pharmaceutically acceptable salt thereof, and compositions of the foregoing to a subject.
The amount of a vaccine adjuvant or vaccine composition administered to a subject is an amount sufficient to induce an immune response and/or to induce STING-dependent type I interferon production in the subject. In an embodiment, the amount of a adjuvant/composition can be an "effective amount" or "therapeutically effective amount, " such that the subject adjuvant/composition is administered in an amount that will elicit, respectively, a biological or medical (i.e., intended to treat) response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician. An effective amount does not necessarily include considerations of toxicity and safety related to the administration of an adjuvant/composition.
An effective amount of an adjuvant/composition will vary with the particular compound chosen (e.g., considering the potency, efficacy, and/or half-life of the compound) ; the route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the subject being treated; the medical history of the subject being treated; the duration of the treatment; the nature of a concurrent therapy; the desired therapeutic effect; and like factors and can be routinely determined by the skilled artisan.
The term “subject” (alternatively referred to herein as “patient” ) as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression. In certain embodiments, a compound of general formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V, or a pharmaceutically acceptable salt of the foregoing, is administered in conjunction with one or more additional therapeutic agents including anti -viral compounds, vaccines intended to stimulate an immune response to one or more predetermined antigens, adjuvants, CTLA-4 and PD-1 pathway antagonists and other immunomodulatory agents, lipids, liposomes, peptides, anti-cancer agents, and chemotherapeutic agents, etc.
According to an embodiment of the present invention, the administration mode of the vaccine adjuvant or the vaccine composition includes intramuscular injection or oral administration, wherein the intramuscular injection dosage is 8 mg-2.5 g/kg/rat, and the oral administration dosage is 100mg~200mg/kg/mouse.
According to an embodiment of the present invention, the administration mode of the vaccine adjuvant or the vaccine composition includes intramuscular injection or oral administration, wherein the administration dosage of intramuscular injection is 0.67 mg-178 mg/kg/person, and the oral administration dosage is 0.2mg~200mg/kg/person.
VACCINE
A vaccine refers to a biological product that provides effective acquired immunity against a specific infectious disease. Vaccines can be made of bacteria, viruses, tumor cells and metabolites, etc., which can make the body produce specific immunity. Vaccination confers immunity to the recipient.
The vaccine includes, but is not limited to, attenuated vaccine, inactivated vaccine, toxoid vaccine, subunit vaccines, conjugate vaccine, vector vaccine, viral vector vaccines, nucleic acid vaccine, multiplex vaccines, or polyvalent Vaccines.
The attenuated vaccines are vaccines that reduce the virulence of a pathogen while maintaining its activity, for example the following vaccines: 1) Viruses vaccines: Measles vaccine, mumps vaccine, rubella vaccine, attenuated influenza vaccine (seasonal flu nasal spray and nasal spray for 2009 H1N1 flu) , chickenpox vaccine, oral polio vaccine (Sabin) , rotavirus vaccine and yellow fever vaccine; 2) Bacteria vaccines: BCG, typhoid and epidemic typhus vaccines.
The inactivated vaccine is a vaccine made by inactivating pathogenic microorganisms and retaining the whole microorganism. Such as inactivated hepatitis A vaccine, inactivated Japanese encephalitis vaccine, inactivated polio vaccine, influenza (whole virus) vaccine, COVID-19 vaccines, etc.
The subunit vaccines are types of vaccines prepared by using effective antigens on the surface of pathogenic microorganisms such as pneumococcal vaccine, meningococcal vaccine, Haemophilus influenzae vaccine, influenza (split or subunit) vaccine, cholera vaccine, typhoid vaccine, etc.
Vaccine carriers, many types have been developed and progressed to nanoparticle carriers, including artificial particles (gold, polymers, lipid micelles) , biological particles (nucleic acids, proteins, viruses) .
Nucleic acid vaccine, for example mRNA vaccine or DNA vaccines. mRNA vaccines send instructions for the manufacture of specific proteins to the cell's ribosomes for production, such as some COVID-19 vaccines.
Multiplex vaccine against multiple pathogens; one dose protects against several diseases at once. For example: "Diphtheria pertussis vaccine" (DTaP) is a mixed vaccine of pertussis antigen (aP) , diphtheria toxoid (D) and tetanus toxoid (T) .
Polyvalent vaccines against multiple types of a single pathogen (eg, multiple serotype antigens) ; a single dose provides broad protection against different strains or variants of the same pathogen. For example: Streptococcus pneumoniae vaccines are now multivalent vaccines, the common ones are 13-valent conjugate vaccine (PCV13) and 23-valent polysaccharide vaccine (PPSV23) .
The use of STING agonists can effectively enhance or prolong the immune effect of the above vaccines.
Those skilled in the art can understand that the features and advantages described above for the vaccine adjuvant are also applicable to the vaccine composition, and are not repeated here.
VACCINE ADJUVANT
Vaccine adjuvants containing STING agonists can effectively help vaccines work better, activate B lymphocytes, and enhance T lymphocyte-independent antibody immune responses and T-lymphocyte-dependent antibody immune responses to help the body produce sufficiently strong immune response.
Vaccine adjuvants are a class of substances that can nonspecifically alter or enhance the body's specific immune response to antigens and play adjuvant roles. Adjuvants can induce long-term and highly effective specific immune response, improve the body's protection ability, reduce the amount of immune substances, and reduce the cost of vaccine production.
Adjuvants mainly include several modes of action, such as immune regulation, induction of cytotoxic T lymphocytes, antigen presentation, antigen targeting and storage. Through the above modes, the purpose of use is:
(1) enhancing the immunogenicity, immune response speed and tolerance of purified or recombinant antigens;
(2) reducing the dosage of antigen or the vaccination dosage required for immune protection;
(3) improving the immune efficacy of the vaccine in infants, the elderly, or people with compromised immune systems;
(4) as an antigen delivery system for ingesting antigens through mucosa, it can promote the absorption of vaccines by gastrointestinal mucosa. The concept of adjuvant originates from ulcers formed at the inoculation site and promotes the production of high levels of specific antibodies, even ulcers produced by inoculation with unrelated substances are able to induce the production of highly specific antibodies;
(5) adjuvants can increase infiltration into cells, prevent antigen degradation, transport antigens to specific antigen-presenting cells, enhance antigen presentation or induce cytokine release.
The term “STING agonist” , as used herein, refers to a compound or moiety which is capable of interacting with STING, e.g., by binding to STING and/or inducing downstream signal transduction (e.g., characterized by activation of the molecules associated with STING function) . This includes direct phosphorylation of STING, IRF3 and/or NF-kB and could also include STAT6. In some embodiments, STING pathway activation results in increased production of type 1 interferons (mainly IFN-a and IFN-b) and/or expression of interferon-stimulated genes.
The term "halogen" , as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, Cl and Br. The terms "haloC1-6alkyl" , "haloC2-6alkenyl" , "haloC2-6alkynyl" and "haloC1-6alkoxy" mean a C1-
6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy in which one or more (in particular, 1, 2 or 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embiment, preferred are fluoroC1-6alkyl, fluoroC2-6alkenyl, fluoroC2-6alkynyl and fluoroC1-6alkoxy groups, in particular fluoroC1-3alkyl, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 and fluoroC1-3alkoxy groups, for example, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
As used herein, unless otherwise indicated, alkyl includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, cyclcopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, cyclcobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclcopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similary, C1-8, as in C1-8alkyl is defined to identify the group as having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms in a linear or branched arrangement.
Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., -CH2-) , ethylene (i.e., -CH2-CH2-or –CH (CH3) -) and propylene (i.e., -CH2-CH2-CH2-, -CH (-CH2-CH3) -or –CH2-CH (CH3) -) .
As used herein, the term "alkenyl" refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bonds.
As used herein, the term "alkenylene" refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more double bonds.
As used herein, the term "alkynyl" refers to a monovalent straight or branched chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bonds.
As used herein, the term "alkynylene" refers to a bivalent straight chain, unsaturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range and including one or more triple bonds.
As used herein, the term "alkoxy" as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom. The term "alkoxy" also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether' ) , and methoxy ethane (also referred to as 'ethyl methyl ether' ) .
The term "aryl" , as used herein, unless otherwise indicated, by itself or as part of another substituent refers to a monocyclic or polycyclic aromatic hydrocarbon. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
The term "heterocyclic" , "heterocyclyl" , or "heterocyclic" , as used herein, unless otherwise indicated, by itself or as part of another substituent refers to unsubstituted and substituted mono-or polycyclic non-aromatic, partially unsaturated or fully saturated ring system containing one or more heteroatoms. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to eight membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition.
Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term "heteroaryl" , as used herein, unless otherwise indicated, by itself or as part of another substituent refers to an aromatic ring system containing carbon (s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (cabons and heteroatoms) . Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term “carbocyclic” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring, sipiro ring non-aromatic ring system onle containing carbon atoms. Examplary “carbocyclic” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term "cycloalkyl" as used herein, unless otherwise indicated, by itself or as part of another substituent refers to a substituted or unsubstituted monocyclic, bicyclic or polycyclic non-aromatic saturated or partially unsatureated hydrocarbon group, which optionally includes an alkylene linker through which the cycloalkyl may be attached. Examplary "cycloalkyl" groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
The term "carbonyl" , "-C=O" , "C=O" , "-CO" , "-C (O) " , and "CO" refer to the group
The term "oxo" refers to the radical =O.
Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralky or dialkylamino) , unless otherwise indicated, by itself or as part of another substituent, it shall be interpreted as including those limitations given above for "alkyl" and "aryl" . Designated numbers of carbon atoms (e.g., Cl-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
As used herein, the term "fused ring" refers to a cyclic group formed by substituents on separate atoms in a straight or branched alkane, or to a cyclic group formed by substituents on separate atoms in another ring.
As used herein, the term "spirocycle" or "spirocyclic ring" refers to a pendant cyclic group formed by substituents on a single atom.
Unless expressly stated to the contrary, all ranges cited herein are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between. As an example, temperature ranges, percentages, ranges of equivalents, and the like described herein include the upper and lower limits of the range and any value in the continuum there between. Numerical values provided herein, and the use of the term "about" , may include variations of ± 1%, ± 2%, ±3%, ± 4%, ± 5%, ± 10%, ± 15%, and ± 20%and their numerical equivalents.
As used herein, the term "one or more" item includes a single item selected from the list as well as mixtures of two or more items selected from the list.
The term "optionally substituted" , as used herein, indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group) or ring or moiety may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent (s) . In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. Suitable substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino) , acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido) , amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.
The term "independently" , as used herein, means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
Wherein the term "substituted" refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent (s) . Typical substituents include, but are not limited to, X, Cl-6alkyl, Cl-6alkoxy, C3-20 cycloalkyl, -OR13, SR13, =O, =S, -C (O) R13, -C (S) R13, =NR13, -C (O) OR13, -C (S) OR13, -NR13R14, -C (O) NR13R14, cyano, nitro, -S (O) 2R13, -OS (O2) OR13, -OS (O) 2R13, or -OP (O) (OR13) (OR14) ; wherein each X is independently a halogen (F, Cl, Br or I) , and R13 and R14 is independently selected from -H, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, the substituent (s) is independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluromethoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, -SCH3 , -SC2H5 , formaldehyde group, -C (OCH3) , cyano, nitro, CF3 , -OCF3, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent (s) is -F, -Cl or -Br.
The substituents the two “R1” of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be the same or different. Similar to “R1” , and the two “R4” , “X1” , “X2” , or “X3” of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V can be the same or different.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compound as a sting agonist drug moiety [D] of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
Compounds described herein, such as certain compounds of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V may contain asymmetrically substituted carbon atoms (or chiral centers) in the R or S configuration. The present invention includes racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.
The compounds described herein, when specifically designated as the R-or S-isomer, either in a chemical name or in a drawing, should be understood as an enriched R-isomer or S-isomer, respectively. For example, in any of the embodiments described herein, such enriched R-or S-designated isomer can be substantially free (e.g., with less than 5%, less than 1%, or non-detectable, as determined by chiral HPLC) of the other isomer for the respective chiral center. The enriched R-or S-isomers can be prepared by methods exemplified in this application, such as by using a chiral auxiliary such as R-or S-tert-butylsulfinamide in the synthetic process. Other methods for prepaing the enriched R-or S-isomers herein include, but are not limited to, chiral HPLC purifications of a stereoisomeric mixture, such as a racemic mixture. General methods for separating stereoisomers (such as enantiomers and/or diastereomers) using HPLC are known in the art.
Agonists described herein can exist in isotope-labeled or -enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur, fluorine, chlorine, and iodine include, but are not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. In some embodiments, one or more hydrogen atoms of any of the compounds described herein can be substituted with deuterium to provide the corresponding deterium-labeled or -enriched compounds.
The term "ring systems" as used herein, unless otherwise indicated, include but not limite to a carbocyclic ring, a heterocyclic ring, a heteroaromatic ring, etc., may also include only a heterocyclic ring, and/or a heteroaromatic ring, and the like, specifically includes which rings need to be determined according to the context, but anyway the "ring systems" do not include the cycloalkyl based on a C1-6 alkyl or C1-3 alkyl ogroup, and do not include the cycloalkoxy based on a C1-6 alkoxy or C1-3 alkoxy group.
Where the plural form (e.g. adjuvants, compositions, salts) is used, this includes the singular (e.g. a single adjuvant, a composition, a single salt) . The "a" merely representing the indefinite article. "A" can thus preferably be read as "one or more" , less preferably alternatively as "one" .
The pharmaceutical compositions containing vaccine adjuvants of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the conjugates into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.
The term "composition" , as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the conjugates of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention.
The pharmaceutical compositions of the present invention comprise a vaccine adjuvant (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular
host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of conjugates can be calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the conjugates and the particular therapeutic effect to be achieved.
The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered conjugates moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about lmg to about 2g of the active ingredient, typically 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg, or l000mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active conjugates in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a conjugate of this invention, or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 5wt%to about 10wt%of the conjugate, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration and the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a conjugate of the present invention or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.01mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) , may be effectively treated by the administration of from about 0.01 to 50mg of the conjugate per kilogram of body weight per day, or alternatively about 0.5mg to about 3.5g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
It is understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow.
These and other aspects will become apparent from the following written description of the invention.
The following Examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:
SERIES 1-COMPOUNDS OF FORMULA Y-1, Y-2, Y-3, (A) , (B) , OR (C)
INTERMEDIATES
INT A1, INT A2 AND INT A3:
Step a: Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and Triethylamine (4.73 g, 46.7440 mmol) in Ethanol (200 mL) at 20 ℃. The reaction mixture was stirred for 1 h at 20 ℃. SOCl2 (20 mL) was added to the solution above at 0 ℃. The reaction mixture was stirred for 3 h at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate (17.5 g, 31.5526 mmol, 119.7901%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.28 –7.21 (m, 1H) , 6.94 (s, 0.5H) , 6.92 (s, 0.5H) , 6.88 (s, 0.5H) , 6.86 (s, 0.5H) , 4.81 (s, 1H) , 4.76 (s, 1H) , 4.58 (s, 1H) , 4.54 (s, 1H) , 4.02 –3.95 (m, 2H) , 3.75 (s, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.54 (m, 2H) , 1.17 (t, J = 3.5 Hz, 3H) .
Step b: NBS (10.51 g, 59.0503 mmol) was added to ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate in Tetrahydrofuran (100 mL) and Acetonitrile (100 mL) at 20 ℃. The reaction mixture was stirred overnight at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (7.26 g, 20.3812 mmol, 64.5943%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 0.5H) , 7.57 (s, 0.5H) , 7.15 (s, 0.5H) , 7.12 (s, 0.5H) , 4.80 (s, 1H) , 4.77 (s, 1H) , 4.57 (s, 1H) , 4.54 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.84 (s, 3H) , 2.65 –2.59 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step c: Potassium Acetate (3.74 g, 38.1080 mmol) was added to Pd (dppf) Cl2 (0.72 g, 984.0050 μmol) , ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.84 g, 15.1218 mmol) in 1, 4-Dioxane (100 mL) at 20 ℃. The reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol, 59.7809%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H) , 7.48 (s, 0.5H) , 6.98 (s, 0.5H) , 6.95 (s, 0.5H) , 4.83 (s, 1H) , 4.74 (s, 1H) , 4.60 (s, 1H) , 4.53 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.74 (t, J = 6.2 Hz, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.52 (m, 2H) , 1.27 (s, 12H) , 1.21 –1.13 (m, 3H) .
Step d: Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol) in Tetrahydrofuran (20 mL) and Water (20 mL) at 20 ℃. The reaction mixture was stirred for 1 h at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (1.37 g, 4.6708 mmol, 76.8818%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 0.5H) , 8.96 (s, 0.5H) , 6.91 (s, 0.5H) , 6.89 (s, 0.5H) , 6.73 (s, 0.5H) , 6.73 (s, 0.5H) , 4.71 (s, 1H) , 4.69 (s, 1H) , 4.50 (s, 1H) , 4.47 (s, 1H) , 4.08 –4.00 (m, 2H) , 3.75 (s, 3H) , 2.64 –2.58 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step e: To a solution of ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.72 g, 2.4547 mmol) in N, N-Dimethylformamide (10 mL) was added 1, 3-Dibromopropane (0.73 g, 3.6159 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) 2. This mixture was stirred for 16 hours at 50 ℃. The reaction mixture was diluted with Ethyl acetate (100 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (1 x 100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. There was ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.43 g, 1.0379 mmol, 42.2829%yield) obtained as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 7.01 –6.93 (m, 2H) , 4.75 (s, 2H) , 4.53 (s, 2H) , 4.10 –4.00 (m, 4H) , 3.76 (s, 3H) , 3.71 –3.62 (m, 2H) , 2.65 –2.58 (m, 2H) , 2.58 –2.53 (m, 2H) , 2.28 –2.18 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
INT A4: ethyl 4- (4-fluoro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate
Step a: 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
4-Methoxybenzylchloride (4.141g, 26.4416 mmol) was added to a solution of NaH (1.000 g, 25.0024 mmol) and 7-fluoro-6-methoxyisoindolin-1-one (4.336 g, 23.9342 mmol) in DMF (100 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 3 h and warmed up to 20℃ naturally. The reaction mixture was quenched with adding to water (300 mL) at 20℃, extracted with EA (3 x 200 mL) and washed with brine (150 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one (6.51 g, 21.6055 mmol, 90.2706%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 302.110. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.9 Hz, 1H) , 7.27 (d, J = 8.2 Hz, 1H) , 7.22 (d, J = 8.2 Hz, 2H) , 6.91 (d, J = 8.3 Hz, 2H) , 4.60 (s, 2H) , 4.25 (s, 2H) , 3.87 (s, 3H) , 3.73 (s, 3H) .
Step b: 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
Borane-tetrahydrofuran complex (120 mL, 120 mmol) was added to a solution of 7-fluoro-6-methoxy-2- (4-methoxybenzyl) isoindolin-1-one (6.17 g, 20.4771 mmol) in THF (60 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 80℃ and stirred for 5 h. The reaction mixture was quenched with pouring into MeOH (300 mL) at 20℃ and evaporated under reduced pressure. The residue was diluted with MeOH (100 mL) . The precipitate was collected by filtration, washed with MeOH (50 mL) . The filter cake was dried under vacuo. There was 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline (3.854 g, 13.4132 mmol, 65.5036%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 288.130. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 8.0 Hz, 2H) , 7.06 –6.93 (m, 2H) , 6.88 (d, J = 8.0 Hz, 2H) , 4.53 –4.37 (m, 2H) , 4.22 –4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (s, 3H) .
Step c: ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Pd/C (2.17 g, 2.0391 mmol) was added to a solution of 4-fluoro-5-methoxy-2- (4-methoxybenzyl) isoindoline (3.36 g, 11.6940 mmol) in THF (20 mL) and MeOH (20 mL) at 20℃. The reaction mixture was stirred overnight at 20℃ under H2 atmosphere. The precipitate was collected by filtration, washed with MeOH (50 mL) . The filtrate was evaporated under reduced pressure. Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (2.619 g, 8.8688 mmol, 75.8406%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 296.120. 1H NMR (400 MHz, DMSO-d6) δ 7.16 –7.09 (m, 2H) , 4.91 (s, 1H) , 4.81 (s, 1H) , 4.64 (s, 1H) , 4.58 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.84 (s, 3H) , 2.73 –2.53 (m, 4H) , 1.18 (t, J =7.2 Hz, 3H) .
Step d: ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was quenched with adding to EtOH (100 mL) at 20℃, The reaction mixture was evaporated under reduced pressure and diluted with H2O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.408 g, 8.5609 mmol, 97.3461%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 282.110. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H) , 6.99 –6.85 (m, 2H) , 4.88 (s, 1H) , 4.77 (s, 1H) , 4.62 (s, 1H) , 4.54 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 2.66 –2.53 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step e: ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h and warmed up to 20℃ naturally. The precipitate was collected by filtration. The filter cake was dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.84 g, 7.8851 mmol, 105.3134%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 359.010. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H) , 7.36 (s, 0.5H) , 7.35 (s, 0.5H) , 4.87 (s, 1H) , 4.78 (s, 1H) , 4.60 (s, 1H) , 4.55 (s, 1H) , 4.14 –3.97 (q, J = 7.2 Hz, 2H) , 2.70 –2.52 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step f: ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
Bromomethyl methyl ether (1.20 g, 9.6028 mmol) was added to a solution of ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.23 g, 6.1914 mmol) and DIEA (2.55 g, 19.7304 mmol) in DCM (50 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h and warmed up to 20℃ naturally. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (1.809 g, 4.4752 mmol, 72.2806%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 403.140. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 0.5H) , 7.51 (s, 0.5H) , 5.16 (s, 2H) , 4.90 (s, 1H) , 4.85 (s, 1H) , 4.63 (s, 1H) , 4.61 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.54 (s, 3H) , 2.72 –2.53 (m, 4H) , 1.24 –1.12 (t, J = 7.2 Hz, 3H) .
Step g: ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
Pd (dppf) Cl2 (0.228 g, 311.6016 μmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.170 g, 4.6074 mmol) and Potassium Acetate (0.743 g, 7.5706 mmol) was added to a solution of ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.735 g, 1.8183 mmol) in 1, 4-Dioxane (20 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 100℃ and stirred for 12 h. The reaction mixture was quenched with adding of water (150 mL) at 20℃, extracted with EA (3 x 150 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. Sodium perborate (0.91g, 5.9145 mmol) was added to a solution of the residue in THF (10 mL) and H2O (10 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-38%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.365 g, 1.0693 mmol, 58.8%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =342.130. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H) , 6.68 (s, 1H) , 5.04 (s, 2H) , 4.80 (s, 1H) , 4.76 (s, 1H) , 4.55 (s, 1H) , 4.53 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.47 (s, 3H) , 2.67 –2.51 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step h: ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Methyl Iodidle (0.345 g, 2.4306 mmol) was added to a mixture of Potassium carbonate (0.448 g, 3.2415 mmol) and ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.328 g, 960.9441 μmol) in DMF (10 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. Trifluoroacetic acid (2 mL) was added to a solution of the residue (0.446 g, 1.2551 mmol) in DCM (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0-80%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.274 g, 880.1663 μmol, 91.6%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 312.12. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H) , 6.83 (s, 0.5H) , 6.80 (s, 0.5H) , 4.82 (s, 1H) , 4.77 (s, 1H) , 4.57 (s, 1H) , 4.54 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.80 (d, J = 2.0 Hz, 3H) , 2.68 –2.51 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
EXAMPLE I-1
4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
Step a: Potassium carbonate (0.240 g, 1.7365 mmol) was added to a solution of INT A3 (0.240 g, 579.3045 μmol) and INT A2 (0.169 g, 576.1737 μmol) in N, N-Dimethylformamide (10 mL) at 20℃. The reaction mixture was heated to 50 ℃ and stirred overnight. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was compound 1a (0.185 g, 295.2007 μmol, 50.9578%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.01 –6.93 (m, 4H) , 4.75 (s, 2H) , 4.73 (s, 2H) , 4.53 (s, 2H) , 4.51 (s, 2H) , 4.14 –4.08 (m, 4H) , 4.05 (q, J = 7.1 Hz, 4H) , 3.74 (t, J = 1.9 Hz, 6H) , 2.65 –2.58 (m, 4H) , 2.58 –2.53 (m, 4H) , 2.35 –2.30 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step b: A solution of LiOH (0.042 g, 1.7538 mmol) in Water (5 mL) was added to a solution of compound 1a (0.182 g, 290.4138 μmol) in Tetrahydrofura (20 mL) at 20 ℃. The reaction mixture was stirred at 20 ℃. The reaction mixture was adjusted pH=7 with adding of HCl (1 M) in water. The reaction mixture was concentrated under reduced pressure. The residue was purified on HPLC. The pure fractions was concentrated and dried under vacuo. There was compound 1 (0.104 g, 182.2687 μmol, 62.7617%yield) obtained as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 6.97 –6.89 (m, 3H) , 6.83 (s, 0.5H) , 6.81 (s, 0.5H) , 4.76 (s, 1H) , 4.73 (s, 1H) , 4.68 (s, 1H) , 4.56 (s, 1H) , 4.49 (s, 2H) , 4.45 (s, 1H) , 4.37 (s, 1H) , 4.16 –4.06 (m, 4H) , 3.74 (d, J = 5.4 Hz, 6H) , 2.49 –2.41 (m, 4H) , 2.40 –2.30 (m, 4H) , 2.16 –2.08 (m, 2H) .
Example I-2
4- (6- (3- ( (2- (3-carboxypropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
4-Methoxybenzylchloride (4.141g, 26.4416 mmol) was added to a solution of NaH (1.000 g, 25.0024 mmol) and 7-fluoro-6-methoxyisoindolin-1-one (4.336 g, 23.9342 mmol) in DMF (100 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 3 h and warmed up to 20℃ naturally. The reaction mixture was quenched with adding to water (300 mL) at 20℃, extracted with EA (3 x 200 mL) and washed with brine (150 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one (6.51 g, 21.6055 mmol, 90.2706%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 302.110. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.9 Hz, 1H) , 7.27 (d, J = 8.2 Hz, 1H) , 7.22 (d, J = 8.2 Hz, 2H) , 6.91 (d, J = 8.3 Hz, 2H) , 4.60 (s, 2H) , 4.25 (s, 2H) , 3.87 (s, 3H) , 3.73 (s, 3H) .
Step b: 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
Borane-tetrahydrofuran complex (120 mL, 120 mmol) was added to a solution of 7-fluoro-6-methoxy-2- (4-methoxybenzyl) isoindolin-1-one (6.17 g, 20.4771 mmol) in THF (60 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 80℃ and stirred for 5 h. The reaction mixture was quenched with pouring into MeOH (300 mL) at 20℃ and evaporated under reduced pressure. The residue was diluted with MeOH (100 mL) . The precipitate was collected by filtration, washed with MeOH (50 mL) . The filter cake was dried under vacuo. There was 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline (3.854 g, 13.4132 mmol, 65.5036%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 288.130. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 8.0 Hz, 2H) , 7.06 –6.93 (m, 2H) , 6.88 (d, J = 8.0 Hz, 2H) , 4.53 –4.37 (m, 2H) , 4.22 –4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (s, 3H) .
Step c: ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Pd/C (2.17 g, 2.0391 mmol) was added to a solution of 4-fluoro-5-methoxy-2- (4-methoxybenzyl) isoindoline (3.36 g, 11.6940 mmol) in THF (20 mL) and MeOH (20 mL) at 20℃ under H2 atmosphere. The reaction mixture was stirred overnight at 20℃. The precipitate was collected by filtration, washed with MeOH (50 mL) . The filtrate was evaporated under reduced pressure. Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (2.619 g, 8.8688 mmol, 75.8406%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 296.120. 1H NMR (400 MHz, DMSO-d6) δ 7.16 –7.09 (m, 2H) , 4.91 (s, 1H) , 4.81 (s, 1H) , 4.64 (s, 1H) , 4.58 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.84 (s, 3H) , 2.73 –2.53 (m, 4H) , 1.18 (t, J =7.2 Hz, 3H) .
Step d: ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was quenched with adding to EtOH (100 mL) at 20℃, The reaction mixture was evaporated under reduced pressure and diluted with H2O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.408 g, 8.5609 mmol, 97.3461%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 282.110. 1H NMR (400 MHz, DMSO-d6) δ 9.83 (s, 1H) , 6.99 –6.85 (m, 2H) , 4.88 (s, 1H) , 4.77 (s, 1H) , 4.62 (s, 1H) , 4.54 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 2.66 –2.53 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step e: ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h and warmed up to 20℃ naturally. The precipitate was collected by filtration. The filter cake was dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.84 g, 7.8851 mmol, 105.3134%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 359.010. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H) , 7.36 (s, 0.5H) , 7.35 (s, 0.5H) , 4.87 (s, 1H) , 4.78 (s, 1H) , 4.60 (s, 1H) , 4.55 (s, 1H) , 4.14 –3.97 (q, J = 7.2 Hz, 2H) , 2.70 –2.52 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step f: ethyl 4- (6-bromo-4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Methyl Iodidle (0.477 g, 3.3606 mmol) was added to a mixture of ethyl 4- (6-bromo-4-fluoro-5-hydroxyisoindolin-2-yl) -4-oxobutanoate (0.463 g, 1.2855 mmol) and Potassium carbonate (0.779 g, 5.6365 mmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 25℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.326 g, 871.1884 μmol, 67.7711%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 374.030. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 0.5H) , 7.49 (s, 0.5H) , 4.90 (s, 1H) , 4.84 (s, 1H) , 4.63 (s, 1H) , 4.61 (s, 1H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.86 (s, 3H) , 2.70 –2.59 (m, 2H) , 2.58 –2.52 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step g: [2- (4-ethoxy-4-oxo-butanoyl) -7-fluoro-6-methoxy-isoindolin-5-yl] boronic acid
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.137 g, 187.2343 μmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (0.648 g, 2.5518 mmol) and Potassium Acetate (0.362 g, 3.6885 mmol) was added to a solution of ethyl 4- (6-bromo-4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.331 g, 884.5502 μmol) in 1, 4-Dioxane (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 90℃ and stirred overnight. The reaction mixture was diluted with EA (100 mL) . The precipitate was collected by filtration, washed with EA (1 x 100mL) . The combined filtrate was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-35%) . The pure fractions was concentrated and dried under vacuo.
There was [2- (4-ethoxy-4-oxo-butanoyl) -7-fluoro-6-methoxy-isoindolin-5-yl] boronic acid (0.112 g, 330.2636 μmol, 37.3369%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + = 340.130.
Step h: ethyl 4- (4-fluoro-6-hydroxy-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Sodium perborate tetrahydrate (0.098 g, 636.9435 μmol) was added to a solution of [2- (4-ethoxy-4-oxo-butanoyl) -7-fluoro-6-methoxy-isoindolin-5-yl] boronic acid (0.105 g, 309.6221 μmol) in THF (5 mL) and H2O (5 mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-33%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-6-hydroxy-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.082 g, 263.4074 μmol, 85.0739%yield) exampleobtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 310.120. 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H) , 6.66 (s, 1H) , 4.79 (s, 1H) , 4.75 (s, 1H) , 4.54 (s, 1H) , 4.52 (s, 1H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.77 (s, 3H) , 2.65 –2.57 (m, 2H) , 2.56 –2.52 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step i: ethyl 4- (6- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate
Potassium carbonate (0.104 g, 752.5026 μmol) was added to a solution of ethyl 4- (4-fluoro-6-hydroxy-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.077 g, 247.3459 μmol) and ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.101 g, 243.7906 μmol) in DMF (4 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred overnight at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (6- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (0.069 g, 107.0293 μmol, 43.2711%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 645.270. 1H NMR (400 MHz, DMSO-d6) δ 7.05 –6.91 (m, 3H) , 4.84 (s, 1H) , 4.79 (s, 1H) , 4.75 (s, 1H) , 4.73 (s, 1H) , 4.58 (s, 1H) , 4.57 (s, 1H) , 4.53 (s, 1H) , 4.51 (s, 1H) , 4.19 (s, 2H) , 4.12 (t, J = 6.5 Hz, 2H) , 4.05 (q, J = 7.1 Hz, 4H) , 3.78 (s, 3H) , 3.74 (s, 3H) , 2.69 –2.58 (m, 4H) , 2.57 –2.52 (m, 4H) , 2.25 –2.14 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step j: 4- (6- (3- ( (2- (3-carboxypropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-xobutanoic acid
LiOH (0.050 g, 2.0878 mmol) was added to a solution of ethyl 4- (6- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (0.039 g, 60.4948 μmol) in THF (2 mL) , EtOH (2 mL) and Water (2 mL) at 20℃ . The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-42%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (6- (3- ( (2- (3-carboxypropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.025 g, 42.4753 μmol, 70.2131%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 589.210. 1H NMR (400 MHz, DMSO-d6) δ 7.03 –6.90 (m, 3H) , 4.85 –4.70 (m, 4H) , 4.59 –4.49 (m, 4H) , 4.22 –4.17 (m, 2H) , 4.13 (t, J = 6.2 Hz, 2H) , 3.78 (s, 3H) , 3.74 (s, 3H) , 2.61 –2.53 (m, 4H) , 2.48 –2.43 (m, 4H) , 2.24 –2.16 (m, 2H) .
Example I-3
sodium (S) -4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
Step a: methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate
NMI (7.96 g, 96.9507 mmol) was added to a solution of TCFH (8.11 g, 28.9045 mmol) and (S) -4-methoxy-3-methyl-4-oxobutanoic acid (2.81 g, 19.2280 mmol) in DMF (100 mL) at 25℃. The reaction mixture was stirred for 10 min at 20℃. 5-methoxyisoindoline hydrochloride (4.99 g, 26.8785 mmol) was added to the solution at 25℃. The reaction mixture was stirred 2 h at 25℃. The reaction mixture was concentrated and diluted with H2O (200 mL) , extracted with EA (2 x 200 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-55%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.49 g, 12.5850 mmol, 65.4512%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 278.130. 1H NMR (400 MHz, DMSO-d6) δ 7.23 (t, J = 8.0 Hz, 1H) , 6.95 –6.84 (m, 2H) , 4.78 (s, 1H) , 4.73 (s, 1H) , 4.56 (s, 1H) , 4.52 (s, 1H) , 3.75 (d, J = 1.8 Hz, 3H) , 3.60 (s, 3H) , 2.91 –2.81 (m, 1H) , 2.76 –2.66 (m, 1H) , 2.54 –2.51 (m, 0.5H) ,
2.49 –2.45 (m, 0.5H) , 1.18 –1.14 (m, 3H) .
Step b: methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate
NBS (3.717 g, 20.8839 mmol) was added to a solution of methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.426 g, 12.3542 mmol) in THF (30 mL) and MeCN (30 mL) at 0℃. The reaction mixture was stirred for 3 h at 25℃. The reaction mixture was concentrated and diluted with DCM (200 mL) , washed with H2O (100 mL) , KHCO3 (aq. ) (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-60%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.02 g, 8.4781 mmol, 68.6255%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 356.040. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 0.5H) , 7.55 (s, 0.5H) , 7.14 (s, 0.5H) , 7.09 (s, 0.5H) , 4.78 (s, 1H) , 4.75 (s, 1H) , 4.56 (s, 1H) , 4.53 (s, 1H) , 3.86 (s, 3H) , 3.59 (s, 3H) , 2.93 –2.79 (m, 1H) , 2.78 –2.64 (m, 1H) , 2.49 –2.46 (m, 1H) , 1.15 (d, J = 7.1 Hz, 3H) .
Step c: methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate
Potassium Acetate (2.81 g, 28.6319 mmol) was added to a mixture of methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.00 g, 8.4220 mmol) , [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.74 g, 1.0113 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.18 g, 12.5228 mmol) in 1, 4-Dioxane (100 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred overnight. The reaction mixture was diluted with EA (200 mL) , The precipitate was collected by filtration, washed with EA (1 x 100 mL) . The filtrate was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate (2.38 g, 5.9017 mmol, 70.0746%yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H] + = 404.222. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H) , 7.46 (s, 0.5H) , 6.97 (s, 0.5H) , 6.93 (s, 0.5H) , 4.81 (s, 1H) , 4.73 (s, 1H) , 4.59 (s, 1H) , 4.52 (s, 1H) , 3.73 (s, 3H) , 3.59 (s, 3H) , 2.90 –2.81 (m, 1H) , 2.76 –2.65 (m, 1H) , 2.54 –2.51 (m, 1H) , 1.27 (s, 12H) , 1.15 (d, J = 6.6 Hz, 3H) .
Step d: methyl (2S) -4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate
Sodium perborate tetrahydrate (0.80 g, 5.1995 mmol) was added to a solution of methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate (1.99 g, 4.9346 mmol) in THF (25 mL) and H2O (25 mL) at 25℃. The reaction mixture was stirred for 1 h at 25℃. The reaction mixture was concentrated and diluted with H2O (200 mL) , extracted with DCM (3 x 100 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0-40%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (1.23 g, 4.1935 mmol, 84.9809%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 294.130.
Step e: methyl (2R) -4- [5- (3-bromopropoxy) -6-methoxy-isoindolin-2-yl] -2-methyl-4-oxo-butanoate
Potassium carbonate (0.462 g, 3.3428 mmol) was added to a solution of methyl (2S) -4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (0.311 g, 1.0603 mmol) and 1, 3-Dibromopropane (1.158 g, 5.7359 mmol) in DMF (20 mL) at 25℃. The reaction mixture was stirred for 3 h at 25℃. The reaction mixture was purified on C18 column ACN/H2O (0-45%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2R) -4- [5- (3-bromopropoxy) -6-methoxy-isoindolin-2-yl] -2-methyl-4-oxo-butanoate (0.314 g, 757.9234 μmol, 71.4822%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + =414.080.
Step f: methyl (S) -4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
Potassium carbonate (0.106 g, 766.9738 μmol) was added to a solution of methyl (2R) -4- [5- (3-bromopropoxy) -6-methoxy-isoindolin-2-yl] -2-methyl-4-oxo-butanoate (0.110 g, 265.5146 μmol) and ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.075 g, 255.6987 μmol) in DMF (5 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was purified on C18 column ACN/H2O (0-40%) . The pure fractions was concentrated and dried under vacuo. There was methyl (S) -4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.09 g, 143.6111 μmol, 54.0879%yield ) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 627.280.
Step g: sodium (S) -4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
LiOH (0.011 g, 459.3228 μmol) was added to a mixture of methyl (S) -4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.089 g, 142.0155 μmol) in Water (2 mL) and THF (2 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The mixture was purified on C18 column ACN/H2O (0-30%) . The pure fractions was concentrated and dried under vacuo and dried by lyophilization to obtain the residue. NaHCO3 (0.012 g, 142.8459 μmol) was added to a mixture of the residue in Water (5 mL) and ACN (2 mL) at 25℃. The reaction mixture was stirred for 1 h at 25℃. The mixture was dried by lyophilization. There was sodium (S) -4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.047 g, 74.7721 μmol, 52.6507%yield ) obtained as a grey solid. LCMS: (ESI, m/z) : [M+H] + = 585.240. 1H NMR (400 MHz, DMSO-d6) δ 7.00 –6.90 (m, 4H) , 4.91 –4.61 (m, 4H) , 4.49 (d, J = 9.1 Hz, 4H) , 4.15 –4.05 (m, 4H) , 3.74 (s, 6H) , 2.46 –2.37 (m, 3H) , 2.72 –2.71 (m, 1H) , 2.20 –2.10 (m, 4H) , 2.08 –1.99 (m, 1H) , 1.00 (d, J = 7.0 Hz, 3H) .
Example I-4
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Potassium carbonate (0.111 g, 803.1518 μmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.068 g, 218.4354 μmol) and ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.109 g, 263.1008 μmol) in DMF (4 mL) at 25℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 50℃. The reaction mixture was quenched with adding of water (50 mL) at 25℃, washed with EA (3 x 50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure obtained as a brown oil. The residue was purified on on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.014 g, 21.7161 μmol, 9.9417%yield) obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.99 –6.88 (m, 3H) , 4.83 (s, 1H) , 4.81 (s, 1H) , 4.75 (s, 2H) , 4.57 (s, 2H) , 4.53 (s, 2H) , 4.13 (t, J = 6.3 Hz, 4H) , 4.05 (q, J = 7.0 Hz, 4H) , 3.76 (s, 3H) , 3.74 (s, 3H) , 2.64 –2.59 (m, 4H) , 2.57 –2.53 (m, 4H) , 2.12 –2.05 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step b: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.044 g, 1.8373 mmol) was added to a mixture of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.100 g, 155.1150 μmol) in THF (2 mL) and Water (2 mL) at 25℃ . The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried further in lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.041 g, 69.6595 μmol, 44.9083%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 589.210. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 2H) , 7.00 –6.88 (m, 3H) , 4.82 (s, 1H) , 4.80 (s, 1H) , 4.74 (s, 2H) , 4.58 (s, 2H) , 4.53 (s, 2H) , 4.13 (t, J = 6.2 Hz, 4H) , 3.77 (s, 3H) , 3.74 (s, 3H) , 2.62 –2.54 (m, 4H) , 2.53 –2.47 (m, 4H) , 2.13 –2.03 (m, 2H) .
Example I-5
4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoic acid)
Step a: 5-bromo-2, 3-bis (bromomethyl) pyridine
NBS (129.49 g, 727.5373 mmol) was added to the mixture of 5-bromo-2, 3-dimethylpyridine (65.61 g, 352.6494 mmol) and AIBN (0.98 g, 5.9681 mmol) in CCl4 (1000 mL) at 25℃. The reaction mixture was heated to 80℃ and stirred for 2 h. The reaction mixture was cooled down to 25℃. The reaction mixture was filtered through a short silica column, washed with DCM (3 x 400 mL) . The filtrate was concentrated and dried under vacuo at 35℃. There was 5-bromo-2, 3-bis (bromomethyl) pyridine (127.9 g, 185.9871 mmol, 52.7400%yield) obtained as a red oil. LCMS: (ESI, m/z) : [M+H] + = 341.805.
Step b: 3-bromo-6-trityl-5, 7-dihydropyrrolo [3, 4-b] pyridine
N, N-Diisopropylethylamine (78.2000 g, 605.0646 mmol) was added to a solution of triphenylmethanamine (93.77 g, 361.5657 mmol) and 5-bromo-2, 3-bis (bromomethyl) pyridine (125.17 g, 182.0173 mmol) in DMF (800 mL) at 25℃. The reaction mixture was heated to 60℃ and stirred for overnight. The reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with EA (800 mL) , washed with water (500 mL) and brine (300 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-10%) . The pure fractions was concentrated and dried under vacuo at 35℃. There was 3-bromo-6-trityl-5, 7-dihydropyrrolo [3, 4-b] pyridine (42.00 g, 95.1601 mmol) obtained as a yellow sem-solid. LCMS: (ESI, m/z) : [M+H] + = 441.089.
Step c: benzyl 3-bromo-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate
Trifluoroacetic acid (100 mL, 1.3462 mol) was added to a solution of 3-bromo-6-trityl-5, 7-dihydropyrrolo [3, 4-b] pyridine (20.63 g, 46.7417 mmol) in DCM (100 mL) at 0℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with HCl (1 M, 150 mL) , washed with EA (3 x 200 mL) . The aqueous was neutralized to pH 7-8 by adding of NaOH (4 M) at 0℃. Sodium carbonate (16.45 g, 155.2048 mmol) and 1, 4-Dioxane (100 mL) was added to aqueous above. Carbobenzyloxy chloride (16.9680 g, 99.4650 mmol) was added dropwise to the mixture at 0℃. The reaction mixture stirred for 1 h at 25℃. The reaction mixture was extracted with EA (600 mL) , washed with water (200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-20%) to remove impurities, and then EA/DCM (10%) . The pure fractions was concentrated and dried under vacuo. There was benzyl 3-bromo-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (8.49 g, 25.4818 mmol, 54.5161%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 333.016. 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H) , 8.08 (s, 0.5H) , 8.04 (s, 0.5H) , 7.45 –7.29 (m, 5H) , 5.16 (d, J = 2.9 Hz, 2H) , 4.74 (s, 1H) , 4.68 (s, 1H) , 4.65 (s, 1H) , 4.58 (s, 1H) .
Step d: 3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate
Sodium methanolate (160.63 g, 891.9991 mmol) and Cuprous iodide (8.17 g, 42.8984 mmol) was added to a solution of benzyl 3-bromo-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (16.21 g, 48.6525 mmol) in DMF (200 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred for 2 h at N2 atmosphere. The reaction mixture was concentrated and diluted with EA (1000 mL) , washed with water (500 mL) and brine (500 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was methyl 3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (5.16 g, 24.7823 mmol, 50.9373%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 209.085. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H) , 7.42 (s, 0.5H) , 7.38 (s, 0.5H) , 4.64 (s, 1H) , 4.61 (s, 1H) , 4.52 (s, 1H) , 4.50 (s, 1H) , 3.82 (s, 3H) , 3.68 (s, 3H) .
Step e: methyl 3-methoxy-1-oxido-5, 7-dihydropyrrolo [3, 4-b] pyridin-1-ium-6-carboxylate
M-Chloroperoxybenzoic acid (7.24 g, 33.5640 mmol) was added to a solution of methyl 3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (5.07 g, 24.3500 mmol) in DCM (100 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was diluted with DCM (500 mL) , washed with KHCO3 (aq) (2 x 200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . There was methyl 3-methoxy-1-oxido-5, 7-dihydropyrrolo [3, 4-b] pyridin-1-ium-6-carboxylate (3.39 g, 15.1196 mmol, 62.0926%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 225.080. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H) , 7.10 (s,
0.5H) , 7.07 (s, 0.5H) , 4.68 (s, 1H) , 4.65 (s, 1H) , 4.55 (d, J = 8.2 Hz, 1H) , 4.53 (s, 1H) , 3.81 (s, 3H) , 3.67 (s, 3H) .
Step f: methyl 2-chloro-3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate
Phosphorus oxychloride (32.90 g, 214.5668 mmol) was added to a solution of methyl 3-methoxy-1-oxido-5, 7-dihydropyrrolo [3, 4-b] pyridin-1-ium-6-carboxylate (6.31 g, 23.1065 mmol) in DCE (100 mL) at 25℃. The reaction mixture was heated to 80℃ and stirred for 2 h. The reaction mixture was evaporated under reduced pressure. The mixture was adjusted to pH=8 with saturated NaHCO3 (aq) . The reaction mixture was concentrated and diluted with DCM (1000 mL) , washed with water (500 mL) and brine (500 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/DCM (0-50%) . The pure fractions was concentrated and dried under vacuo. There was methyl 2-chloro-3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (6.30 g, 25.9624 mmol, 112.3596%yield) obtained as a off-white solid. LCMS: (ESI, m/z) : [M+H] + = 243.046. 1H NMR (400 MHz, CDCl3-d) δ 7.08 (s, 0.5H) , 7.03 (s, 0.5H) , 4.67 (s, 1H) , 4.61 (d, J = 3.2 Hz, 2H) , 4.55 (s, 1H) , 3.86 (s, 3H) , 3.73 (s, 3H) .
Step g: 2-chloro-3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine
To a solution of methyl 2-chloro-3-methoxy-5, 7-dihydropyrrolo [3, 4-b] pyridine-6-carboxylate (4.22 g, 17.3907 mmol) in hydrogen chloride (80 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred overnight. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in water (10 mL) and adjusted to pH=8 with NaOH (aq. ) (4 M) . The residue was purified on silica gel column MeCN/water (0-50%) . The pure fractions was concentrated and dried under vacuo. There was 2-chloro-3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.688 g, 9.1430 mmol, 52.5739%yield) obtained as a yellow semi-solid. LCMS: (ESI, m/z) : [M+H] + = 185.040.
Step h: 2-chloro-3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine
4-Methoxybenzylchloride (1.507 g, 9.6227 mmol) was added to a solution of 2-chloro-3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.781 g, 9.6467 mmol) and TEA (1.985 g, 19.6167 mmol) in DCM (40 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was concentrated and diluted with DCM (600 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/DCM (0-50%) . The pure fractions was concentrated and dried under vacuo. There was 2-chloro-3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.808 g, 5.9323 mmol, 61.4957%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 305.098. 1H NMR (400 MHz, DMSO-d6) δ 7.51 (s, 1H) , 7.28 (d, J = 8.3 Hz, 2H) , 6.91 (d, J = 8.3 Hz, 2H) , 3.94 (s, 1H) , 3.89 –3.78 (m, 7H) , 3.77 –3.73 (m, 4H) .
Step i: 3-methoxy-6- (4-methoxybenzyl) -2- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) propoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine
NaH (1.25 g, 31.2530 mmol) was added to a solution of 3- ( (tetrahydro-2H-pyran-2-yl) oxy) propan-1-ol (4.73 g, 29.5237 mmol) in DMF (30 mL) at 0℃. The reaction mixture was stirred for 30 min at 25℃. 2-chloro-3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.81 g, 5.9389 mmol) was added to the mixture at 25℃. The reaction mixture was heated to 80℃ and stirred for 2 h. The reaction mixture was concentrated and diluted with EA (600 mL) , washed with water (200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was 3-methoxy-6- (4-methoxybenzyl) -2- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) propoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (3.114 g, 5.8135 mmol, 97.8886%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 429.231.
Step j: 3- ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol
4-methylbenzenesulfonic acid (0.331 g, 1.2199 mmol) was added to a solution of 3-methoxy-6- (4-methoxybenzyl) -2- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) propoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (0.502 g, 1.1715 mmol) in MeOH (10 mL) at 25℃. The reaction mixture was stirred at 25℃ for 1 h. The mixture was adjusted to pH=8 with saturated NaHCO3 (aq) . The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with water (200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) .
The pure fractions was concentrated and dried under vacuo. There was 3- ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol (0.180 g, 522.6422 μmol, 44.6141%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 345.174. 1H NMR (400 MHz, DMSO-d6) δ 7.28 (d, J = 8.3 Hz, 2H) , 7.20 (s, 1H) , 6.90 (d, J = 8.3 Hz, 2H) , 4.50 (t, J = 4.7 Hz, 1H) , 4.26 (t, J = 6.5 Hz, 2H) , 3.80 –3.75 (m, 4H) , 3.74 (d, J = 3.7 Hz, 3H) , 3.73 (s, 3H) , 3.72 (s, 2H) , 3.58 –3.47 (m, 2H) , 1.90 –1.79 (m, 2H) .
Step k: 1, 3-bis ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane
NaH (0.142 g, 3.5503 mmol) was added to a solution of 3- ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol (0.176 g, 511.0277 μmol) in DMF (5 mL) at 0℃. The mixture was allowed to warm to 25℃ and stirred for 40 min. 2-chloro-3-methoxy-6- [ (4-methoxyphenyl) methyl] -5, 7-dihydropyrrolo [3, 4-b] pyridine (0.302 g, 990.9079 μmol) was added to the mixture. The reaction mixture was heated to 100℃ and stirred for 1 h. The reaction mixture was quenched with adding of water (10 mL) at 0℃. The resulting mixture was extracted with EA (2 x 300 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was 1, 3-bis ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane (0.234 g, 381.9076 μmol, 74.7332%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 613.295.
Step l: 1, 3-bis ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane
Pd/C (0.145 g, 136.2526 μmol) was added to a solution of 1, 3-bis ( (3-methoxy-6- (4-methoxybenzyl) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane (0.093 g, 151.7837 μmol) in Ethyl acetate (10 mL) at 25℃. The reaction mixture was stirred overnight at 25℃ under H2 atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM/MeOH=5: 1 (3 x 50 mL) . The filtrate was concentrated under reduced pressure. There was 1, 3-bis ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane (0.039 g, 104.7213 μmol, 68.9938%yield) obtained as a red solid. LCMS: (ESI, m/z) : [M+H] + = 373.180.
Step m: dimethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoate)
Methyl 4-chloro-4-oxobutanoate (0.061 g, 405.1541 μmol) was added to a solution of 1, 3-bis ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propane (0.037 g, 99.3510 μmol) and TEA (0.076 g, 751.0668 μmol) in DCM (3 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 25℃. The reaction mixture was quenched with adding of water (50 mL) at 25℃. The reaction mixture was extracted with EA (3 x 50 mL) , washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was dimethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoate) (0.017 g, 28.3043 μmol, 28.4892%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 601.240. 1H NMR (400 MHz, DMSO-d6) δ 7.37 –7.31 (m, 2H) , 4.76 (s, 2H) , 4.64 (s, 2H) , 4.52 (s, 2H) , 4.44 –4.35 (m, 6H) , 3.78 (s, 6H) , 3.59 (s, 6H) , 2.65 –2.60 (m, 4H) , 2.59 –2.55 (m, 4H) , 2.22 –2.16 (m, 2H) .
Step n: 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.049 g, 2.0461 mmol) was added to a solution of dimethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoate) (0.012 g, 19.9795 μmol) in THF (2 mL) and Water (2 mL) at 25℃ . The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0-40%) . The pure fractions was concentrated and dried under vacuo. There was 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridine-2, 6-diyl) ) bis (4-oxobutanoic acid) (7 mg, 12.2257 μmol, 61.1914%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 571.210. 1H NMR (400 MHz, DMSO-d6) δ 7.32 –7.27 (m, 2H) , 4.76 (s, 2H) , 4.68 (s, 2H) , 4.56 (s, 2H) , 4.49 –4.40 (m, 6H) , 3.78 –3.71 (m, 6H) , 2.44 –2.40 (m, 4H) , 2.38 –2.35 (m, 4H) , 2.18 –2.12 (m, 2H) .
Example I-6
4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: tert-butyl 5-methoxyisoindoline-2-carboxylate
TEA (33.12 g, 327.3070 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (20.01 g, 107.7833 mmol) and Di-tert-butyl dicarbonate (35.28 g, 161.6523 mmol) in DCM (500 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-methoxyisoindoline-2-carboxylate (30.66 g, 104.5347 mmol, 96.9859%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 235.136. 1H NMR (400 MHz, DMSO-d6) δ 7.24 –7.18 (m, 1H) , 6.90 (d, J = 4.5 Hz, 1H) , 6.85 (s, 0.5H) , 6.83 (s, 0.5H) , 4.58 –4.44 (m, 4H) , 3.74 (s, 3H) , 1.45 (s, 9H) .
Step b: tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate
NBS (43.64 g, 245.1906 mmol) was added to a solution of tert-butyl 5-methoxyisoindoline-2-carboxylate (30.40 g, 121.9390 mmol) in Tetrahydrofuran (300 mL) and Acetonitrile (300 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (1000 mL) , washed with NaHCO3 (aq. ) (3 x 200 mL) and brine (300 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (17.61 g, 53.6562 mmol, 44.0025%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 313.047. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.3 Hz, 1H) , 7.11 (d, J = 4.2 Hz, 1H) , 4.51 (t, J = 9.8 Hz, 4H) , 3.82 (d, J = 3.7 Hz, 3H) , 1.45 (s, 9H) .
Step c: tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (2.10 g, 2.8700 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (11.71 g, 46.1137 mmol) and Potassium Acetate (9.76 g, 99.4475 mmol) was added to a solution of tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (10.04 g, 30.5910 mmol) in 1, 4-Dioxane (200 mL) at 20℃. The reaction mixture was heated to 100℃ and stirred overnight under N2 atmosphere. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate (11.00 g, 29.3126 mmol, 95.8208%yield) obtained as a oil. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 361.222.
Step d: tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate
Sodium perborate tetrahydrate (6.28 g, 40.8164 mmol) was added to a solution of tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate (9.75 g, 25.9816 mmol) in Tetrahydrofura (150 mL) and Water (150 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was concentrated and diluted with EA (600 mL) , washed with water (300 mL) and brine (300 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/DCM (0-100%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate (6.58 g, 24.8017 mmol, 95.4589%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 251.131. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H) , 6.88 (d, J = 5.8 Hz, 1H) , 6.70 (d, J = 2.3 Hz, 1H) , 4.44 (t, J = 9.6 Hz, 4H) , 3.74 (d, J = 3.4 Hz, 3H) , 1.44 (s, 9H) .
Step e: tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate
Potassium carbonate (0.375 g, 2.7134 mmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.364 g, 878.6118 μmol) and tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.264 g, 995.0841 μmol) in DMF (8 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate (0.498 g, 831.8270 μmol, 94.6751%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 584.290. 1H NMR (400 MHz,
DMSO-d6) δ 7.06 –6.90 (m, 4H) , 4.74 (s, 1H) , 4.72 (s, 1H) , 4.60 –4.41 (m, 6H) , 4.19 –3.99 (m, 6H) , 3.81 –3.69 (m, 6H) , 2.65 –2.53 (m, 4H) , 2.21 –2.10 (m, 2H) , 1.45 (s, 9H) , 1.18 (t, J = 8.0 Hz, 3H) .
Step f: 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate (0.088 g, 146.9896 μmol) in DCM (3 mL) at 20℃ . The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. dihydrofuran-2, 5-dione (0.050 g, 499.6373 μmol) was added to a solution of the residue and TEA (0.209 g, 2.0654 mmol) in DCM (5 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred and warmed up to 20℃ naturally. The reaction mixture was stirred for 3 h at 20℃ under N2 atmosphere. The reaction mixture was quenched with adding of water (50 mL) at 20℃ and adjusted to pH=3 with HCl (1 mol/L) , extracted with EA (3 x 50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.061 g, 101.8978 μmol, 69.3231%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 597.250. 1H NMR (400 MHz, DMSO-d6) δ 7.02 –6.92 (m, 4H) , 4.75 (s, 2H) , 4.73 (s, 2H) , 4.53 (s, 2H) , 4.51 (s, 2H) , 4.11 (t, J = 6.0 Hz, 4H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.74 (s, 6H) , 2.65 –2.53 (m, 6H) , 2.52 –2.48 (m, 2H) , 2.20 –2.11 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Example I-7
4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
Step a: ethyl 4- (5-methoxy-6-vinyl-isoindolin-2-yl) -4-oxo-butanoate
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.223 g, 304.7682 μmol) and Potassium carbonate (2.271 g, 16.4321 mmol) was added to a solution of 2-ethenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (1.2349 g, 8.0180 mmol) and ethyl 4- (5-bromo-6-methoxyisoindolin-2-yl) -4-oxobutanoate (1.812 g, 5.0869 mmol) in 1, 4-Dioxane (18 mL) and Water (3 mL) at 20℃. The reaction mixture was stirred overnight at 80℃ under nitrogen atmosphere. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with NaHCO3 (aq. ) (2 x 50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-70%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6-vinyl-isoindolin-2-yl) -4-oxo-butanoate (1.371 g, 4.5195 mmol, 88.8463%yield) obtained as a red solid. LCMS: (ESI, m/z) : [M+H] + = 304.147. 1H NMR (400 MHz, DMSO-d6) δ 7.50 (s, 0.5H) , 7.48 (s, 0.5H) , 7.05 –6.90 (m, 2H) , 5.80 –5.72 (m, 1H) , 5.24 (d, J = 11.2 Hz, 1H) , 4.82 (s, 1H) , 4.77 (s, 1H) , 4.59 (s, 1H) , 4.55 (s, 1H) , 4.06 (q, J = 7.0 Hz, 2H) , 3.81 (s, 3H) , 2.65 –2.59 (m, 2H) , 2.59 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step b: ethyl 4- (5-formyl-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Potassium osmate (VI) dehydrate (0.085 g, 230.6933 μmol) in Water (6 mL) was added to a solution of ethyl 4- (5-methoxy-6-vinylisoindolin-2-yl) -4-oxobutanoate (1.295 g, 4.2690 mmol) and 4-Methylmorpholine N-oxide (1.062 g, 9.0656 mmol) in Tetrahydrofuran (26 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. Sodium periodate (1.026 g, 4.7968 mmol) was added to the mixture at 20℃. The resulting mixture was stirred overnight at 20℃. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with water (50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-formyl-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.522 g, 1.7097 mmol, 40.0484%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + =306.126. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H) , 7.67 (d, J = 6.2 Hz, 1H) , 7.28 (s, 0.5H) , 7.24 (s, 0.5H) , 4.90 (s, 1H) , 4.80 (s, 1H) , 4.66 (s, 1H) , 4.57 (s, 1H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.96 –3.90 (m, 3H) , 2.66 –2.59 (m, 2H) , 2.59 –2.52 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step c: ethyl 4- [5- (hydroxymethyl) -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
NaBH4 (0.044 g, 1.1630 mmol) was added to ethyl 4- (5-formyl-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.515 g, 1.6867 mmol) in methanol (10 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was concentrated and
diluted with EA (10 mL) , washed with water (10 mL) and brine (5 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- (hydroxymethyl) -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.327 g, 1.0640 mmol, 63.0787%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + =308.142. 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 6.4 Hz, 1H) , 6.95 (s, 0.5H) , 6.92 (s, 0.5H) , 5.07 –5.00 (m, 1H) , 4.81 (s, 1H) , 4.77 (s, 1H) , 4.59 (s, 1H) , 4.55 (s, 1H) , 4.48 (d, J = 5.6 Hz, 2H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.77 (s, 3H) , 2.67 –2.60 (m, 2H) , 2.60 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step d: diethyl 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
N, N-Diisopropylethylamine (0.113 ml, 683.7230 μmol) was added to a solution of 4- [5- (hydroxymethyl) -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.067 g, 217.9990 μmol) and Methylamine hydrochloride (0.018 g, 266.5964 μmol) in N, N-Dimethylformamide (2 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/Water (0-60%) . The pure fractions was concentrated and dried under vacuo. There was diethyl 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.071 g, 116.4492 μmol, 53.4173%yield) obtained as a off-white solid. LCMS: (ESI, m/z) : [M+H] + = 610.305. 1H NMR (400 MHz, DMSO-d6) δ 7.36 (s, 2H) , 6.98 (s, 1H) , 6.96 (s, 1H) , 4.81 (s, 2H) , 4.77 (s, 2H) , 4.59 (s, 2H) , 4.56 (s, 2H) , 4.13 –3.98 (m, 4H) , 3.77 (s, 6H) , 3.59 (s, 2H) , 3.55 (s, 4H) , 2.61 (d, J = 5.0 Hz, 3H) , 2.56 (d, J = 4.7 Hz, 3H) , 2.15 (s, 3H) , 1.25 –1.14 (m, 6H) .
Step e: 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.010 g, 417.5662 μmol) was added to a solution of diethyl 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.069 g, 113.1689 μmol) in Tetrahydrofuran (2 mL) and Water (2 mL) at 20℃. The reaction mixture was stirred overnight at 50℃. The reaction mixture was adjusted to pH=6 with HCl (1 M) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/Water (0-80%) . The pure fractions was concentrated and dried by lyohpilization. There was 4, 4'- ( ( (methylazanediyl) bis (methylene) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) (0.027 g, 48.7715 μmol, 43.0962%yield) obtained as a off-white solid. LCMS: (ESI, m/z) : [M-H] -=552.242. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (s, 2H) , 6.98 (s, 1H) , 6.96 (s, 1H) , 4.80 (s, 2H) , 4.77 (s, 2H) , 4.59 (s, 2H) , 4.56 (s, 2H) , 3.77 (s, 6H) , 3.50 (s, 4H) , 2.60 –2.54 (m, 4H) , 2.49 –2.45 (m, 4H) , 2.12 (s, 3H) .
Example I-8
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
NCS (0.105 g, 786.3231 μmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.205 g, 698.9090 μmol) in DMF (10 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 12 h and warmed up to 20℃ naturally. The reaction mixture was purified on C18 column ACN/H2O (0-25%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.148 g, 451.5507 μmol, 64.6079%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 328.100. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H) , 6.97 (s, 0.5H) , 6.95 (s, 0.5H) , 4.81 (s, 1H) , 4.76 (s, 1H) , 4.59 (s, 1H) , 4.51 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.82 (s, 3H) , 2.69 –2.53 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H)
Step b: ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.079 g, 241.0308 μmol) and Potassium carbonate (0.098 g, 709.0890 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.082 g, 197.9290 μmol) in DMF (2 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried under vacuo.
There was ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.096 g, 145.2043 μmol, 73.3618%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 661.240. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 0.5H) , 7.05 (s, 0.5H) , 7.01 –6.92 (m, 2H) , 4.85 (s, 1H) , 4.76 (d, J = 7.3 Hz, 3H) , 4.62 (s, 1H) , 4.52 (d, J = 6.5 Hz, 3H) , 4.16 (t, J = 7.0 Hz, 2H) , 4.11 (t, J = 6.1 Hz, 2H) , 4.05 (q, J = 7.0 Hz, 4H) , 3.78 (s, 3H) , 3.74 (s, 3H) , 2.69 –2.58 (m, 4H) , 2.58 –2.53 (m, 4H) , 2.18 –2.09 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step c: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.054 g, 2.2549 mmol) was added to a mixture of ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.060 g, 90.7527 μmol) in THF (2 mL) , EtOH (1 mL) and Water (2 mL) at 20℃ . The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.044 g, 72.7235 μmol, 80.1337%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 605.180. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 0.5H) , 7.05 (s, 0.5H) , 7.00 –6.93 (m, 2H) , 4.85 (s, 1H) , 4.75 (d, J =6.7 Hz, 3H) , 4.62 (s, 1H) , 4.53 (d, J = 4.9 Hz, 3H) , 4.17 (t, J = 6.4 Hz, 2H) , 4.12 (t, J = 6.1 Hz, 2H) , 3.78 (s, 3H) , 3.74 (s, 3H) , 2.61 –2.54 (m, 4H) , 2.53 –2.47 (m, 4H) , 2.17 –2.09 (m, 2H) .
Example I-9
4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) Step a: ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate
1, 3-dibromopropane (0.708 g, 3.5069 mmol) was added to a mixture of ethyl 4- (4-fluoro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.217 g, 697.0656 μmol) and Potassium carbonate (0.346 g, 2.5035 mmol) in DMF (5 mL) at 20℃. The reaction mixture was stirred for 8 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.211 g, 488.1091 μmol, 70.0234%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 432.070.
Step b: diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
Potassium carbonate (0.111 g, 803.1518 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.072 g, 166.5586 μmol) and ethyl 4- (4-fluoro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.051 g, 163.8266 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 8 h at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried by lyophilization. There was diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.085 g, 128.2683 μmol, 78.2952%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 663.270. 1H NMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H) , 6.90 (s, 1H) , 4.83 (s, 2H) , 4.81 (s, 2H) , 4.57 (s, 4H) , 4.16 (t, J = 6.0 Hz, 4H) , 4.05 (q, J = 7.2 Hz, 4H) , 3.83 –3.73 (m, 6H) , 2.67 –2.53 (m, 8H) , 2.06 –1.94 (m, 2H) , 1.18 (t, J = 7.2 Hz, 6H) .
Step c: 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.044 g, 1.8373 mmol) was added to a solution of diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.057 g, 86.0153 μmol) in THF (2 mL) , H2O (2 mL) and EtOH (1 mL) at 20℃ . The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-fluoro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) (0.042 g, 69.2421 μmol, 80.4998%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =607.200. 1H NMR (400 MHz, DMSO-d6) δ 6.92 (s, 1H) , 6.90 (s, 1H) , 4.82 (s, 2H) , 4.80 (s, 2H) , 4.58 –4.56 (m, 4H) , 4.16 (t, J = 6.2
Hz, 4H) , 3.78 (s, 6H) , 2.64 –2.54 (m, 4H) , 2.49 –2.44 (m, 4H) , 2.07 –1.94 (m, 2H) .
Example I-10
4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
Step a: diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
Potassium carbonate (0.151 g, 1.0926 mmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.099 g, 337.5219 μmol) and 3-Chloro-2- (chloromethyl) prop-1-ene (0.034 g, 151.7938 μmol) in N, N-Dimethylformamide (5 mL) at 20℃. The reaction mixture was stirred overnight at 60℃. The reaction mixture was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.10 g, 156.5673 μmol, 103.1447%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 639.284. 1H NMR (400 MHz, DMSO-d6) δ 7.13 –6.88 (m, 4H) , 5.33 (s, 2H) , 4.83 –4.58 (m, 8H) , 4.57 –4.40 (m, 4H) , 4.12 –3.96 (m, 4H) , 3.82 –3.69 (m, 6H) , 2.66 –2.53 (m, 8H) , 1.25 –1.11 (m, 6H) .
Step b: 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.014 g, 584.5926 μmol) was added to a solution of diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.08 g, 125.2538 μmol) in Tetrahydrofuran (10 mL) and Water (2.5 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) (0.028 g, 48.0607 μmol, 38.3706%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =583.221. 1H NMR (400 MHz, DMSO-d6) δ 7.01 –6.89 (m, 4H) , 5.32 (s, 2H) , 4.78 –4.59 (m, 8H) , 4.55 –4.43 (m, 4H) , 3.75 (s, 6H) , 2.56 (d, J = 5.5 Hz, 4H) , 2.47 –2.41 (m, 4H) .
Example I-11
4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
Step a: ethyl 4- [4-chloro-5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
3-Chloro-2- (chloromethyl) prop-1-ene (0.507 g, 2.2635 mmol) was added to a mixture of Potassium carbonate (0.202 g, 1.4616 mmol) and ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.154 g, 469.8574 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 4 h at 20℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [4-chloro-5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.151 g, 362.7238 μmol, 77.1987%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 328.090.
Step b: diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
Potassium carbonate (0.105 g, 759.7382 μmol) was added to a solution of ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.068 g, 207.4693 μmol) and ethyl 4- (4-chloro-5- ( (2- (chloromethyl) allyl) oxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.084 g, 187.1929 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried under vacuo. There was diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.083 g, 119.3245 μmol, 63.7441%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 707.210. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 1H) , 7.07 (s, 1H) , 5.36 (s, 2H) , 4.86 (s, 2H) , 4.77 (s, 2H) , 4.67 (s, 4H) , 4.64 (s, 2H) , 4.51 (d, J = 4.7 Hz, 2H) , 4.06 (q, J = 7.1 Hz, 4H) , 3.82 (s, 6H) , 2.71 –2.59 (m, 4H) , 2.59 –2.53 (m, 4H) , 1.19 (t, J = 7.1 Hz, 6H) .
Step c: 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.038 g, 1.5868 mmol) was added to a solution of diethyl 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.046 g, 65.0091 μmol) in THF (1.5 mL) and Water (1.5 mL) at 20℃ . The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried by lyophilization. There was 4, 4'- ( ( (2-methylenepropane-1, 3-diyl) bis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) (0.037 g, 56.7931 μmol, 87.3618%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 649.140. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 1H) , 7.07 (d, J = 3.1 Hz, 1H) , 5.36 (s, 2H) , 4.86 (s, 2H) , 4.77 (s, 2H) , 4.67 (s, 4H) , 4.63 (s, 2H) , 4.51 (d, J = 6.0 Hz, 2H) , 3.82 (s, 6H) , 2.65 –2.54 (m, 6H) , 2.50 –2.46 (m, 2H) .
Example I-12
4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
Step a: ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
1, 3-Dibromopropane (0.495 g, 2.4519 mmol) was added to a mixture of K2CO3 (0.199 g, 1.4399 mmol) , ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.149 g, 454.6023 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 4 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.163 g, 363.2433 μmol, 79.9035%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 448.040. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 0.5H) , 7.08 (s, 0.5H) , 4.87 (s, 1H) , 4.79 (s, 1H) , 4.64 (s, 1H) , 4.53 (s, 1H) , 4.06 –4.02 (m, 4H) , 3.83 (d, J = 2.4 Hz, 3H) , 3.78 –3.70 (m, 2H) , 2.71 –2.53 (m, 4H) , 2.23 –2.20 (m, 2H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step b: diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate)
Potassium carbonate (0.105 g, 759.7382 μmol) was added to a solution of ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.068 g, 207.4693 μmol) and ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.084 g, 187.1929 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 4 h at 50℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried under vacuo. There was diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.083 g, 119.3245 μmol, 63.7441%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 695.210. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H) , 7.06 (s, 1H) , 4.86 (s, 2H) , 4.77 (s, 2H) , 4.63 (s, 2H) , 4.52 (s, 2H) , 4.17 (t, J = 6.4 Hz, 4H) , 4.05 (q, J = 7.1 Hz, 4H) , 3.82 –3.76 (m, 6H) , 2.68 –2.59 (m, 4H) , 2.58 –2.53 (m, 4H) , 2.11 (d, J = 7.0 Hz, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step c: 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid)
LiOH (0.051 g, 2.1296 mmol) was added to a solution of diethyl 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoate) (0.053 g, 76.1951 μmol) in THF (2 mL) and Water (2 mL) at 20℃ . The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried by lyophilization. There was 4, 4'- ( (propane-1, 3-diylbis (oxy) ) bis (4-chloro-6-methoxyisoindoline-5, 2-diyl) ) bis (4-oxobutanoic acid) (0.044 g, 68.8063 μmol, 90.3028%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 637.140. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H) , 7.06 (s, 1H) , 4.85 (s, 2H) , 4.77 (s, 2H) , 4.63 (s, 2H) , 4.51 (d, J = 4.1 Hz, 2H) , 4.17 (t, J =6.3 Hz, 4H) , 3.80 (d, J = 2.6 Hz, 6H) , 2.63 –2.53 (m, 5H) , 2.50 –2.46 (m, 3H) , 2.16 –2.05 (m, 2H) .
Example I-13
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: 4-fluoro-5-methoxy-isoindoline
10%Pd/C (7.68 g, contain 55%H2O) was added to a solution of 4-fluoro-5-methoxy-2- [ (4-methoxyphenyl) methyl] isoindoline (7.18 g, 24.9889 mmol) in THF (70 mL) and MeOH (70 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The
reaction mixure was filtered and the filter cake was washed with MeOH (70 mL) . The filtrate was evaporated under reduced pressure. There was 4-fluoro-5-methoxy-isoindoline (4.88 g, 29.1901 mmol, 100%yield) obtained as a brown oil, which was used directly in the next step. LCMS: (ESI, m/z) : [M+H] + = 168.200.
Step b: 4-fluoroisoindolin-5-ol hydrobromate
4-fluoro-5-methoxy-isoindoline (4.5 g, 26.9171 mmol) was dissolved in Hydrobromic acid (120 mL, 48%aq) at 20℃. The reaction mixture was heated to 100℃ and stirred for 6 h. The resulting reaction mixture was evaporated under reduced pressure. The residue was treated with n-hexane/EA (1: 2) . The solid was collected by filtration, and dried under reduced pressure. There was 4-fluoroisoindolin-5-ol hydrobromate (4.70 g, 20.0799 mmol, 74.60%yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H] + =154.200. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H) , 9.58 (s, 2H) , 7.10 –6.93 (m, 2H) , 4.57 (s, 2H) , 4.44 (s, 2H) .
Step c: tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate
NaHCO3 (3.43 g, 40.8301 mmol) was added to a solution of 4-fluoroisoindolin-5-olhydrobromate (4.70 g, 20.0799 mmol) in Water (80 mL) at 0℃. After the reaction mixure was stirred for 20 min, THF (60 mL) was added to the reaction mixture, and Di-tert-butyl dicarbonate (4.45 g, 20.3898 mmol) in THF (20 mL) was added dropwise to the mixure at 0℃. After stirring for 20 min, the reaction mixure was warmed to 20℃ and stirred for 2 h. The resulting reaction mixture was diluted with EA (150 mL) and washed with brine (150 mL) . The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in n-hexane (0-40%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.14 g, 12.3979 mmol, 60.78%yield) obtained as a reddish brown solid. LCMS: (ESI, m/z) : [M-H] -= 252.000. 1H NMR (400 MHz, CDCl3-d) δ 7.00 –6.93 (m, 1H) , 6.93 –6.83 (m, 1H) , 4.72 (s, 2H) , 4.64 (s, 2H) , 1.54 (s, 9H) .
Step d: tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate
NBS (2.20 g, 12.3607 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL) at 0℃. The reaction mixture was stirred for 2.5 h at 20℃. The reaction mixture was concentrated under reduced pressure. The residue was dissloved with EA/MeOH (200 mL/10 mL) , and washed with H2O (200 mL) . The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, eluting with MeOH in DCM (0-5%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol, 66.34%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 331.950. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H) , 7.33 (s, 0.5H) , 7.32 (s, 0.5H) , 4.58 (s, 1H) , 4.55 (s, 1H) , 4.52 (s, 1H) , 4.50 (s, 1H) , 1.45 (s, 9H) .
Step e: tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate
K2CO3 (2.20 g, 15.9183 mmol) was added to a solution of tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol) in DMF (50 mL) at 0℃. After the reaction mixture was stirred for 0.5 h at 0℃, BnBr (1.90 g, 11.1089 mmol) was added to the reaction mixture. The reaction mixture was stirred for 9 h at 20℃. The reaction mixture was diluted with EA (150 mL) and washed with water (150 mL) and brine (2 x 150 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in n-hexane (0-10%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3.43 g, 8.1224 mmol, 99.93%yield) obtained as a white semi-solid. LCMS: (ESI, m/z) : [M-tBu+ACN] + = 407.050. 1H NMR (400 MHz, CDCl3-d) δ 7.54 (d, J = 7.3 Hz, 2H) , 7.45 –7.35 (m, 3H) , 7.27 (s, 0.5H) , 7.20 (s, 0.5H) , 5.13 (s, 2H) , 4.70 (s, 1H) , 4.65 (s, 2H) , 4.62 (s, 1H) , 1.54 (s, 9H) .
Step f: tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (1.12 g, 1.5307 mmol) was added to a solution of tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3.30 g, 7.8146 mmol) , bis (neopentylglycolato) diboron (5.46 g, 24.1716 mmol) and KOAc (2.32 g, 23.6392 mmol) in 1, 4-Dioxane (80 mL) at 20℃. The reaction mixture was heated to 90℃ and stirred overnight under nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL) and filtered through a celite. The filtrate was evaporated under reduced pressure. H2O2 (88.1974 mmol, 10 mL, 30%aqueous solution) was added to a mixture of the residue and NaHCO3 (11.9038 mmol, 20 mL, 5%aqueous solution) in THF (80 mL) at 0℃. The reaction mixture was stirred for 2 h at 20℃. The resulting reaction mixture was diluted with brine (150 mL) and saturated NaHSO3 (100 mL) , and extracted with EA (200 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-10%) . There was tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.93 g, 5.3702 mmol, 68.93%yield) obtained as an off-white solid. LCMS: (ESI, m/z) : [M-H] -=358.100. 1H NMR (400 MHz, CDCl3-d) δ 7.46 –7.36 (m, 5H) , 6.62 (s, 0.5H) , 6.58 (s, 0.5H) , 5.15 (s, 2H) , 4.68 (s, 1H) , 4.65 (s, 1H) , 4.61 (s, 1H) , 4.58 (s, 1H) , 1.54 (s, 9H) .
Step g: tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate
K2CO3 (1.18 g, 8.5380 mmol) was added to a solution of tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.9 g, 5.2867 mmol) in DMF (25 mL) at 0℃. After the mixture was stirred for 30 min at 0℃, CH3I (1.12 g, 7.8908 mmol) was added. The reaction mixture was stirred for 3 h at 20℃. The resulting reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL) . The organic layer was separated and washed with brine (2 x 150 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. There was tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.98 g, 5.3024 mmol, 100%yield) obtained as a colorless oil, which was directly used in the next step without purification. LCMS: (ESI, m/z) : [M-tBu+ACN] + = 359.150. 1H NMR (400 MHz, CDCl3-d) δ 7.39 (d, J = 7.4 Hz, 2H) , 7.31 –7.21 (m, 3H) , 6.51 (s, 1H) , 4.99 (s, 2H) , 4.55 (s, 4H) , 3.77 (s, 3H) , 1.44 (s, 9H) .
Step h: tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
10%Pd/C (1.98 g, contain 55%H2O) was added to a solution of tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.96 g, 5.2488 mmol) in MeOH (40 mL) and THF (10 mL) at 20℃. The reaction mixture was stirred for 5 h at 20℃under H2 atmosphere. The reaction mixture was diluted with EA (20 mL) and filtered through a celite. The filtrate was evaporated under reduced pressure. The residue was purified on silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-40%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (1.21 g, 4.2712 mmol, 80.67%yield) obtained as a brown semi-solid. LCMS: (ESI, m/z) : [M-H] -=282.100. 1H NMR (400 MHz, CDCl3-d) δ 6.58 (s, 1H) , 4.67 (s, 2H) , 4.63 (s, 2H) , 3.92 (s, 3H) , 1.53 (s, 9H) .
Step i: tert-butyl 4-chloro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
NCS (10.92 g, 81.7776 mmol) was added to a solution of tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (20.21 g, 76.1767 mmol) in DMF (200 mL) at 0℃. The reaction mixture was stirred for 3 h at 60℃. The reaction mixture was quenched with adding of water (500 mL) , extracted with EA (3 x 500 mL) and washed with brine (250 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-2%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 4-chloro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (11.19 g, 37.3312 mmol, 49.0061%yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 285.090.
Step j: tert-butyl 5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindoline-2-carboxylate
1, 3-Dibromopropane (0.498 g, 2.4667 mmol) was added to a mixture of Potassium carbonate (0.326 g, 2.3588 mmol) and tert-butyl 4-chloro-5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.116 g, 386.9901 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was purified on silica gel column MeCN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindoline-2-carboxylate (0.099 g, 235.3082 μmol, 60.8047%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 405.050.
Step k: tert-butyl 5- [3- (2-tert-butoxycarbonyl-4-chloro-6-methoxy-isoindolin-5-yl) oxypropoxy] -4-fluoro-6-methoxy-isoindoline-2-carboxylate
Potassium carbonate (0.115 g, 832.0942 μmol) was added to a mixture of tert-butyl 4-fluoro-5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.090 g, 317.6904 μmol) and tert-butyl 5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindoline-2-carboxylate (0.093 g, 221.0471 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5- [3- (2-tert-butoxycarbonyl-4-chloro-6-methoxy-isoindolin-5-yl) oxypropoxy] -4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.145 g, 232.7046 μmol, 105.2738%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H-Boc] + = 523.250. 1H NMR (400 MHz, DMSO-d6) δ 7.05 (d, J = 6.2 Hz, 1H) , 6.90 (d, J = 5.8 Hz, 1H) , 4.59 (d, J = 8.4 Hz, 2H) , 4.54 (d, J = 7.4 Hz, 4H) , 4.47 (d, J = 8.9 Hz, 2H) , 4.17 (t, J = 6.2 Hz, 2H) , 4.12 (t, J = 6.2 Hz, 2H) , 3.77 (t, J = 5.1 Hz, 6H) , 2.08 –1.99 (m, 2H) , 1.45 (s, 18H) .
Step l: 4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline dihydrochloride
HCl in EA (5 mL, 20 mmol) was added to a mixture of tert-butyl 5- [3- (2-tert-butoxycarbonyl-4-chloro-6-methoxy-isoindolin-5-yl) oxypropoxy] -4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.139 g, 223.0754 μmol) in EA (2 mL) at 20℃ . The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was evaporated under reduced pressure. There was 4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline dihydrochloride (0.148 g, 349.9838 μmol) obtained as a brown solid, which was used directly to the next step. LCMS: (ESI, m/z) : [M+H] + = 423.140.
Step m: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Dihydrofuran-2, 5-dione (0.097 g, 969.2963 μmol) was added to a mixture of 4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindoline dihydrochloride (0.070 g, 165.5329 μmol) and TEA (0.225 g, 2.2236 mmol) in DCM (4 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (47 mg, 75.4388 μmol, 45.5733%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 623.170. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 2H) , 7.08 (s, 0.5H) , 7.06 (s, 0.5H) , 6.93 (s, 0.5H) , 6.90 (d, J = 2.9 Hz, 0.5H) , 4.85 (s, 1H) , 4.83 (s, 1H) , 4.80 (s, 1H) , 4.76 (s, 1H) , 4.63 (s, 1H) , 4.57 (d, J = 5.5 Hz, 2H) , 4.51 (d, J = 5.2 Hz, 1H) , 4.19 (t, J = 6.2 Hz, 2H) , 4.13 (t, J = 6.1 Hz, 2H) , 3.85 –3.75 (m, 6H) , 2.65 –2.53 (m, 6H) , 2.49 –2.44 (m, 2H) , 2.13 –1.99 (m, 2H) .
Example I-14
4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5-methoxy-6- (3- ( (6-methoxyisoindolin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate
Tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.149 g, 561.6195 μmol) and Potassium carbonate (0.230 g, 1.6642 mmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.230 g, 555.1668 μmol) in N, N-Dimethylformamide (10 mL) at 20℃. The reaction mixture was stirred for 4 hours at 50℃. The reaction mixture was diluted with Ethyl acetate (100 mL) , washed sequentially with water (100 mL) and brine (100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. HCl (4 M) in Ethyl acetate (10 mL) was added to a solution of the crude product in Ethyl acetate (10 mL) . The reaction mixture was stirred for 1 hour at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6- (3- ( (6-methoxyisoindolin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate (0.23 g, 461.3224 μmol, 83.0962%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 499.237.
Step b: (4-nitrophenyl) 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate
Bis (4-nitrophenyl) carbonate (0.24 g, 788.9235 μmol) and Triethylamine (0.27 g, 2.6683 mmol) was added to a solution of ethyl 4- (5-methoxy-6- (3- ( (6-methoxyisoindolin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate (0.28 g, 561.6096 μmol) in N, N-Dimethylformamide (10 mL) at 20℃. The reaction mixture was stirred for 2 hours at 20℃. The reaction mixture was diluted with Ethyl acetate (100 mL) , washed sequentially with water (100 mL) and brine (100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Heptane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was (4-nitrophenyl) 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate (0.29 g, 436.9644 μmol, 77.8057%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 664.243.
Step c: ethyl 4- (5- (3- ( (2- ( (3-ethoxy-3-oxopropyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Ethyl 3-aminopropanoate hydrochloride (0.20 g, 1.3020 mmol) and N, N-Diisopropylethylamine (0.33 g, 2.5533 mmol) was added to a solution of (4-nitrophenyl) 5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-isoindoline-2-carboxylate (0.29 g, 436.9642 μmol) in N, N-Dimethylformamide (10 mL) at 20℃. The reaction mixture was stirred for 3 hours at 100℃. The reaction mixture was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (2- ( (3-ethoxy-3-oxopropyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.08 g, 124.6675 μmol, 28.5304%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 642.295.
Step d: 4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (7.8371 mg, 327.2522 μmol) was added to a solution of ethyl 4- (5- (3- ( (2- ( (3-ethoxy-3-oxopropyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.07 g, 109.0841 μmol) in Acetonitrile (10 mL) and Water (10 mL) . The reaction mixture was stirred for 1 hours at 50℃. The reaction mixture was evaporated under reduced pressure. The residue was acidified pH=4 with HCl (1 M) . The mixture was evaporated under reduced pressure. The residue was purified by Prep-HPLC. The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (6.2 mg, 10.5874 μmol, 9.7057%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 586.632. 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 2H) , 7.03 –6.88 (m, 4H) , 6.36 (s, 1H) , 4.70-4.75 (m, 2H) , 4.53 (s, 2H) , 4.46 (s, 4H) , 4.10 (s, 4H) , 3.74 (s, 6H) , 3.23-3.30 (m, 2H) , 2.57 (s, 2H) , 2.40-2.50 (m, 4H) , 2.15 (s, 2H) .
Compounds in the following example shown in table 1 were synthesized using the above procedure with the corresponding starting materials.
Table 1
TEXTING EXAMPLE I: Human STING WT binding assay
Cisbio Bioassays’ human STING WT binding assay (#64BDSTGPEG &64BDSTGPEH, Cisbio) is for quantitative measurement of human STING WT ligand using technology.
1. Adding compounds
Negative control: Dispense 5 μL of diluent into each negative control well. Standard: Dispense 5 μL of each Human STING WT Standard 2’3’-cGAMP (Std 0 -Std 7) into each standard well. Compound: Dispense 5 μL of compound into each compound well.
2. Adding proteins
Negative control: Add 5 μL of detection buffer to all wells. Other wells: Add 5 μL of human STING WT protein 6His-tagged protein to all wells.
3. Adding antibodies
Add 10 μL of premixed STING WT ligand d2 reagent and 6His Tb antibody working solution to all wells.
4. RT incubation
Seal the plate and incubate 3 hours at RT or at Over Night if necessary.
5. Reading plate
Remove the plate sealer and read on an compatible reader (PerkinElmer, USA) . Results were analyzed with a two-wavelength signal ratio: intensity (665 nm) /intensity (620 nm) .
6. Curve fitting
Calculate HTRF Ratio:
Fit the data in GraphPad to obtain IC50 values using equation (2)
Equation (2) : Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *Hill Slope) )
Y is HTRF Ratio and X is compound concentration.
IC50 value of binding assay for human STING WT:
SERIES 2 -COMPOUNDS OF FORMULA I, II, III, IV and V
INTERMEDIATES
INT A1: ethyl 4- (5-hydroxy-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate
Step a: Bromomethyl methyl ether, (3.15 g, 25.2073 mmol) was added to a solution of DIEA (4.10 g, 46.5111 mmol) and 2-Bromoisovanillin (4.98 g, 21.5544 mmol) in Dichloromethane (200 mL) at 0 ℃. The reaction mixture was stirred at 20 ℃ for 2 h. The resulting solution was quenched by water (10 mL) and washed with water (100 mL) and brine (100 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. There was 2-bromo-4-methoxy-5- (methoxymethoxy) benzaldehyde (5.83 g, 21.1926 mmol, 98.3216%yield) obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H) , 7.51 (s, 1H) , 7.39 (s, 1H) , 5.25 (s, 2H) , 3.93 (s, 3H) , 3.38 (d, J = 9.3 Hz, 3H) .
Step b: Methyl thioglycolate (2.30 g, 21.6688 mmol) was added to a solution of 2-bromo-4-methoxy-5- (methoxymethoxy) benzaldehyde (5.83 g, 21.1926 mmol) and Cs2CO3 (13.99 g, 42.9380 mmol) in N, N-Dimethylformamide (100 mL) at 20 ℃. The reaction mixture was heated to 50 ℃ and stirred for 16 h. The reaction mixture was cooled to 20 ℃, and Methyl Iodide (1.81 g, 12.7520 mmol) was added to the reaction solution, and stirred for 2 h at 20 ℃. The reaction mixture was diluted with
EA (500 mL) , washed with water (2 x 100 mL) and brine (100 mL) . The organics was evaporated under reduced pressure. The residue was purified on silica gel column EA/hept (0-50%) . The pure fractions was concentrated and dried under vacuo. There was methyl 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylate (2.98 g, 10.5557 mmol, 49.8084%yield) obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H) , 7.66 (s, 1H) , 7.63 (s, 1H) , 5.23 (s, 2H) , 3.87 (d, J = 9.2 Hz, 6H) , 3.42 (s, 3H) .
Step c: LiOH (0.37 g, 15.4499 mmol) was added to a solution of methyl 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylate (2.98 g, 10.5557 mmol) in Tetrahydrofuran (100 mL) and Water (25 mL) at 20 ℃. The reaction mixture was heated to 50 ℃ and stirred for 2 h. The reaction mixture was evaporated under reduced pressure and diluted with water and adjusted pH = 3 with HCl (1 M) . The precipitate was filtered. Filter cake was washed with water (20 mL) . There was 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol, 85.1008%yield) obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.22 (s, 1H) , 7.93 (s, 1H) , 7.62 (d, J = 10.5 Hz, 2H) , 5.24 (d, J = 14.6 Hz, 2H) , 3.87 (s, 3H) , 3.52 –3.35 (m, 3H) .
Step d: To a stirred solution of 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylic acid (2.41 g, 8.9830 mmol) in N, N-Dimethylformamide (20 mL) was added 1, 1'-Carbonyldiimidazole (2.84 g, 17.5148 mmol) at 20 ℃. The resulting mixture was stirred for 1 h at 20 ℃ under nitrogen atmosphere. To the mixture above was added 3-tert-Butoxy-3-oxopropanoic acid and Magnesium chloride (1.31 g, 13.7589 mmol) . The reaction mixture was stirred at 20 ℃ for 16 h. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/PE (0-80%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 3- [6-methoxy-5- (methoxymethoxy) benzothiophen-2-yl] -3-oxo-propanoate (2.63 g, 7.1774 mmol, 79.9000%yield) obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H) , 7.67 (s, 1H) , 7.62 (s, 1H) , 5.24 (s, 2H) , 4.03 (d, J = 9.8 Hz, 2H) , 3.89 (s, 3H) , 3.42 (s, 3H) , 1.41 (s, 9H) .
Step e: To a stirred solution of tert-butyl 3- [6-methoxy-5- (methoxymethoxy) benzothiophen-2-yl] -3-oxo-propanoate (2.62 g, 7.1501 mmol) in N, N-Dimethylformamide (20 mL) was added Potassium carbonate (2.0621 g, 14.9207 mmol) and Ethyl bromoacetate (1.3648 g, 8.1724 mmol) at 20 ℃ . The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction mixture was concentrated and diluted with EA (200 mL) , washed water with (100 mL) and brine (50 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/PE (0-80%) . The pure fractions was concentrated and dried under vacuo. There was O1-tert-butyl O4-ethyl 2- [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] butanedioate (2.82 g, 6.2318 mmol, 87.1569%yield) obtained as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H) , 7.67 (s, 2H) , 5.31 –5.20 (m, 2H) , 4.79 (t, J = 7.3 Hz, 1H) , 4.15 –3.96 (m, 2H) , 3.89 (d, J = 6.7 Hz, 3H) , 3.42 (d, J = 4.2 Hz, 3H) , 3.32 (s, 3H) , 2.98 –2.81 (m, 2H) , 1.31 (s, 9H) .
Step f: TFA (5 mL) was added to O1-tert-butyl O4-ethyl 2- [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] butanedioate (2.82 g, 6.2318 mmol) in Toluene (25 mL) at 20 ℃. The reaction mixture was heated to 50 ℃ and stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Heptane (0-100%) . The pure fractions was concentrated and dried under vacuo to afford crude product. The residue was purified on silica gel column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-hydroxy-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate (0.79 g, 2.5620 mmol, 41.1122%yield) obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H) , 8.17 (s, 1H) , 7.54 (s, 1H) , 7.32 (s, 1H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.87 (s, 3H) , 3.31 –3.26 (m, 2H) , 2.65 (t, J = 6.3 Hz, 2H) , 1.27 –1.05 (m, 3H) .
INT A2: methyl 4- (5-chloro-6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
Step a: To a solution of 6-bromothieno [3, 2-b] pyridine (30.0 g, 140.1 mmol) in DMF (300 mL) was added a solution of 25%MeONa in MeOH (605.6 g, 2802.6 mmol) and CuI (26.7 g, 140.1 mmol) . The reaction mixture was heated to 100 ℃ and stirred for 2 h. Then the reaction mixture was cooled to room temperature, poured into ice water (900 mL) and filtered. The filtrate was diluted with NH3. H2O (300 mL) , extracted with EtOAc (1.0 L x 2) and washed with brine (1.0 L) . The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to afford 6-methoxythieno [3, 2-b] pyridine (19.0 g, 82.3%) as a yellow solid which was used for next step without further purification. 1H NMR (300 MHz, CDCl3) : δ 8.43 (d, J = 2.7 Hz, 1H) , 7.62 (d, J = 2.4 Hz, 1H) , 7.53-7.51 (m, 1H) , 7.47-7.45 (m, 1H) , 3.91 (s, 3H) . LCMS: (ESI, m/z) : [M+H] + = 166.2.
Step b: To a solution of 6-methoxythieno [3, 2-b] pyridine (19.0 g, 115.0 mmol) in DCM (200 mL) was added m-CPBA (19.8 g, 115.0 mmol) . The reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was diluted with DCM/MeOH = 10: 1 (300 mL) and washed with saturated sodium bicarbonate solution (300 mL x 2) and brine (300 mL) . The organic layer was dried
over Na2SO4, filtered and the filtrate was concentrated to afford 6-methoxythieno [3, 2-b] pyridine 4-oxide (13.0 g, 57.7%) as a yellow solid which was used for next step without further purification. 1H NMR (300 MHz, CDCl3) : δ 8.14 (d, J = 2.1 Hz, 1H) , 7.74 (dd, J = 5.7 Hz, 0.6 Hz, 1H) , 7.48-7.46 (m, 1H) , 7.31-7.30 (m, 1H) , 3.91 (s, 3H) . LCMS: (ESI, m/z) : [M+H] + = 182.0.
Step c: Add 6-methoxythieno [3, 2-b] pyridine 4-oxide (15.5 g, 85.5 mmol) portion wise to POCl3 (200 mL) at room temperature. The reaction mixture was heated to 100 ℃ and stirred for 16 h. Then the reaction mixture was cooled to room temperature and concentrated. The residue was diluted with water (200 mL) , adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with DCM (300 mL x 2) . The organic layers were washed with brine (200 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to give the residue which was purified by column chromatography on silica gel (eluted with petroleum ether/EtOAc = 10: 1) to afford 5-chloro-6-methoxythieno [3, 2-b] pyridine (9.0 g, 52.6%) as a white solid. 1H NMR (300 MHz, CDCl3) : δ 7.65 (s, 1H) , 7.58-7.56 (m, 1H) , 7.42 (dd, J = 5.7 Hz, 0.6 Hz, 1H) , 3.99 (s, 3H) . LCMS: (ESI, m/z) : [M+H] + = 200.0.
Step d: To a solution of 5-chloro-6-methoxythieno [3, 2-b] pyridine (8.0 g, 40.1 mmol) in THF (80 mL) was added LDA (2.0 M, 80 mL) dropwise at -78 ℃ under nitrogen. After 15 min, a solution of dihydrofuran-2, 5-dione (22.0 g, 220.4 mmol) in THF (240 mL) was added to the mixture dropwise at -40 ℃ under nitrogen. Then the reaction mixture was warmed to room temperature and stirred for 2 h. After that the reaction was quenched with 2N HCl (100 mL) and extracted with EtOAc (300 mL x 2) . The organic layers were washed with brine (200 mL) , dried over Na2SO4, filtered and the filtrate was concentrated. The residue was triturated with petroleum ether/EtOAc = 1: 1 and filtered to afford 4- (5-chloro-6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoic acid (6.0 g, crude) as a white solid which was used for next step without further purification. LCMS: (ESI, m/z) : [M-H] -= 298.8.
Step e: To a solution of 4- (5-chloro-6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoic acid (6.0 g crude, 20.0 mmol) in MeOH (120 mL) was added SOCl2 (12.0 g, 100.1 mmol) dropwise at 0 ℃. Then the reaction mixture was warmed to room temperature and stirred for 2 h. After that the reaction was concentrated, diluted with water (100 mL) , adjusted to pH = 8 with saturated sodium bicarbonate solution and extracted with DCM/MeOH (200 mL x 2) . The organic layers were washed with brine (100 mL) , dried over Na2SO4, filtered. The filtrate was concentrated, white solid precipitated and filtered to afford methyl 4- (5-chloro-6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (1.1 g, 8.5%in total of d and e two steps) as a white solid 1H NMR (400 MHz, CDCl3) : δ 8.01 (s, 1H) , 7.59 (s, 1H) , 4.02 (s, 3H) , 3.71 (s, 3H) , 3.35 (t, J = 6.8 Hz, 2H) , 2.80 (t, J = 6.8 Hz, 2H) , LCMS: (ESI, m/z) : [M+H] + = 569.20.
INT A3: methyl trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylate
Step a: To a solution of 3-oxabicyclo [3.1.0] hexane-2, 4-dione (6.3 g, 56.1 mmol) and AlCl3 (12.3 g, 92.6 mmol) in DCE (150 mL) was added a solution of 5-bromo-6-methoxybenzo [b] thiophene (15.0 g, 61.7 mmol) in DCE (50 mL) at -10℃. After that the reaction mixture was heated to 45 ℃ and stirred for 16 h. Then the reaction mixture was poured into ice-water (200 mL) and extracted with DCM/MeOH=10: 1 (100 mL x 2) . The organic layer washed with brine (100 mL) , dried over Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was triturated with Petroleum ether/EtOAc = 1: 1 (50 mL) and filtered to afford cis-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (3.0 g, yield 15.1%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) : δ 8.32 (s, 1H) , 8.26 (s, 1H) , 7.80 (s, 1H) , 4.05 (s, 3H) , 3.01-3.09 (m, 1H) , 2.25-2.31 (m, 1H) , 1.65-1.68 (m, 1H) , 1.58-1.52 (m, 1H) .
Step b: To a solution of cis -2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (3.0 g, 8.4 mmol) in MeOH (30 mL) was added 50%aq. NaOH (45 mL) at room temperature. Then the reaction mixture was heated to 40 ℃ and stirred for 24 h. After the reaction completed analysis by HPLC, the solvent was removed by concentrated. The residue was diluted with water (30 mL) and was adjustd pH~2 with 6 N HCl. The white solid was collected by filtration. The solid was dryness under vacuum at 50℃ to afford trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (2.5 g, yield 83.3%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) : δ 8.52 (s, 1H) , 8.27 (s, 1H) , 7.80 (s, 1H) , 3.96 (s, 3H) , 3.27-3.23 (m, 1H) , 2.16-2.11 (m, 1H) , 1.54-1.49 (m, 2H) .
Step c: To a solution of trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (2.5 g, 7.0 mmol) in DMF (25 mL) was added K2CO3 (2.4 g, 17.5 mmol) and MeI (2.0 g, 14.1 mmol) at room temperature. The reaction mixture was stirred for 16 h. Then the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL x 2) . The organic layer was washed with water (50 mL x 2) and brine (50 mL x 2) . The organic layer was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness. The residue was triturated with Petroleum ether/EtOAc = 5: 1 (50 mL) and filtered to afford methyl trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylate (2 g, yield 77.5%) as a yellow solid. LCMS: (ESI, m/z) : [M+H] + =368.8, 370.8. 1H NMR (400 MHz, CDCl3) : δ 8.07 (s, 1H) , 7.96 (s, 1H) , 7.30 (s, 1H) , 3.99 (s, 3H) , 3.75 (s, 3H) ,
3.15-3.11 (m, 1H) , 2.45-2.40 (m, 1H) , 1.70-1.64 (m, 2H) .
INT A4: ethyl 4- (4-chloro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
To a solution of ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (300 mg, 0.97 mmol) in DMF (6 mL) was added NCS (156 mg, 1.14 mmol) portion wise at room temperature. After that the reaction mixture was stirred for 5 h. Then the reaction mixture was poured into ice-water (18 mL) . The mixture was filtered and the filter cake was dissolved with EtOAc (20 mL) . The organic layer was washed with sat. aq. NaHCO3 (15 mL) and brine (10 mL) , dried over Na2SO4 and concentrated to afford a crude product which was purified by HPLC to give ethyl 4- (4-chloro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (240 mg, yield 72%) as a white solid. 1H NMR (300 MHz, CDCl3) : δ 8.02 (s, 1H) , 7.17 (s, 1H) , 6.04 (brs, 1H) , 4.20-4.12 (m, 2H) , 4.02 (s, 3H) , 3.36 (t, J = 8.8 Hz, 2H) , 2.79 (t, J = 8.8 Hz, 2H) , 1.30-1.20 (m, 3H) . LCMS: (ESI, m/z) : [M+H] + = 342.9.
INT A5: ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate
INT A6: ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
INT A7: ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate
AND INT A8: ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Step a: Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and Triethylamine (4.73 g, 46.7440 mmol) in Ethanol (200 mL) at 20 ℃. The reaction mixture was stirred for 1 h at 20 ℃. SOCl2 (20 mL) was added to the solution above at 0 ℃. The reaction mixture was stirred for 3 h at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate (17.5 g, 31.5526 mmol, 119.7901%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.28 –7.21 (m, 1H) , 6.94 (s, 0.5H) , 6.92 (s, 0.5H) , 6.88 (s, 0.5H) , 6.86 (s, 0.5H) , 4.81 (s, 1H) , 4.76 (s, 1H) , 4.58 (s, 1H) , 4.54 (s, 1H) , 4.02 –3.95 (m, 2H) , 3.75 (s, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.54 (m, 2H) , 1.17 (t, J = 3.5 Hz, 3H) .
Step b: NBS (10.51 g, 59.0503 mmol) was added to ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate in Tetrahydrofuran (100 mL) and Acetonitrile (100 mL) at 20 ℃. The reaction mixture was stirred overnight at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (7.26 g, 20.3812 mmol, 64.5943%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 0.5H) , 7.57 (s, 0.5H) , 7.15 (s, 0.5H) , 7.12 (s, 0.5H) , 4.80 (s, 1H) , 4.77 (s, 1H) , 4.57 (s, 1H) , 4.54 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.84 (s, 3H) , 2.65 –2.59 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step c: Potassium Acetate (3.74 g, 38.1080 mmol) was added to Pd (dppf) Cl2 (0.72 g, 984.0050 μmol) , ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.84 g, 15.1218 mmol) in 1, 4-Dioxane (100 mL) at 20 ℃. The reaction mixture was stirred at 100 ℃ for 16 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol, 59.7809%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H) , 7.48 (s, 0.5H) , 6.98 (s, 0.5H) , 6.95 (s, 0.5H) , 4.83 (s, 1H) , 4.74 (s, 1H) , 4.60
(s, 1H) , 4.53 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.74 (t, J = 6.2 Hz, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.52 (m, 2H) , 1.27 (s, 12H) , 1.21 –1.13 (m, 3H) .
Step d: Sodium perborate tetrahydrate (1 g, 6.4994 mmol) was added to ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol) in Tetrahydrofuran (20 mL) and Water (20 mL) at 20 ℃. The reaction mixture was stirred for 1 h at 20 ℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (1.37 g, 4.6708 mmol, 76.8818%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 0.5H) , 8.96 (s, 0.5H) , 6.91 (s, 0.5H) , 6.89 (s, 0.5H) , 6.73 (s, 0.5H) , 6.73 (s, 0.5H) , 4.71 (s, 1H) , 4.69 (s, 1H) , 4.50 (s, 1H) , 4.47 (s, 1H) , 4.08 –4.00 (m, 2H) , 3.75 (s, 3H) , 2.64 –2.58 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step e: To a solution of ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.72 g, 2.4547 mmol) in N, N-Dimethylformamide (10 mL) was added 1, 3-Dibromopropane (0.73 g, 3.6159 mmol) and potassium carbonate (0.86 g, 6.2226 mmol) 2. This mixture was stirred for 16 hours at 50 ℃. The reaction mixture was diluted with Ethyl acetate (100 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (1 x 100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. There was ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.43 g, 1.0379 mmol, 42.2829%yield) obtained as a white solid.
1H NMR (400 MHz, DMSO-d6) δ 7.01 –6.93 (m, 2H) , 4.75 (s, 2H) , 4.53 (s, 2H) , 4.10 –4.00 (m, 4H) , 3.76 (s, 3H) , 3.71 –3.62 (m, 2H) , 2.65 –2.58 (m, 2H) , 2.58 –2.53 (m, 2H) , 2.28 –2.18 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
INT A9: tert-butyl 3- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -3-oxo-propanoate
Step a: 3-bromo-2-fluoro-4-methoxy-benzaldehyde
Titanium tetrachloride (38.06 g, 200.6548 mmol) was added dropwise to a solution of 2-Bromo-3-fluoroanisole (10.17 g, 49.6039 mmol) in Dichloromethane (250 mL) at 0℃ for 1 h. The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was quenched with adding of ice-water (200 mL) at 0℃. The reaction mixture was extracted with DCM (2 x 100 mL) , washed with NaHCO3 (1 x 200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was dried under vacuo at 60℃. There was 3-bromo-2-fluoro-4-methoxy-benzaldehyde (11.42 g, 49.0057 mmol, 98.7940%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 232.954. 1H NMR (400 MHz, CDCl3-d) δ 10.24 (s, 1H) , 7.87 (t, J =8.3 Hz, 1H) , 6.84 (d, J = 8.8 Hz, 1H) , 4.05 –3.99 (m, 3H) .
Step b: (5E) -5- [ (3-bromo-2-fluoro-4-methoxy-phenyl) methylene] -2-thioxo-thiazolidin-4-one
Potassium Acetate (12.67 g, 129.0984 mmol) was added to a mixture of 3-bromo-2-fluoro-4-methoxy-benzaldehyde (10.01 g, 42.9551 mmol) and Rhodanine (5.72 g, 42.9456 mmol) in Acetic acid (100 mL) at 20℃. The reaction mixture was heated to 140℃and stirred overnight. The reaction mixture was added to water (1000 mL) and stirred for 10 min. The precipitate was collected by filtration, washed with water (200 mL) . The filtrate cake was dried under vacuo at 60℃. There was (5E) -5- [ (3-bromo-2-fluoro-4-methoxy-phenyl) methylene] -2-thioxo-thiazolidin-4-one (9.21 g, 26.4495 mmol, 61.5748%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 347.909. 1H NMR (400 MHz, DMSO-d6) δ 13.87 (s, 1H) , 7.68 –7.32 (m, 2H) , 7.16 (d, J = 8.7 Hz, 1H) , 3.97 (s, 3H) .
Step c: (Z) -3- (3-bromo-2-fluoro-4-methoxy-phenyl) -2-sulfanyl-prop-2-enoic acid
To a stirred mixture of (5E) -5- [ (3-bromo-2-fluoro-4-methoxy-phenyl) methylene] -2-thioxo-thiazolidin-4-one (8.03 g, 23.0607 mmol) in Water (200 mL) was added NaOH (9.15 g, 228.7666 mmol) in water (80 mL) at 20℃. The reaction mixture was stirred at 60℃ for 1 h. After the reaction completed, adjusted to pH=3 with HCl. The precipitate was collected by filtration, washed with water (1 x 100 mL) . The filtrate cake was dried under vacuo at 60℃. There was (Z) -3- (3-bromo-2-fluoro-4-methoxy-phenyl) -2-sulfanyl-prop-2-enoic acid (7.37 g, 23.9959 mmol, 104.0552%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 306.936.
Step d: 5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid
Palladium (II) acetate (4.0934 g, 18.2330 mmol) was added to a solution of (Z) -3- (3-bromo-2-fluoro-4-methoxy-phenyl) -2-sulfanyl-prop-2-enoic acid (7 g, 22.7912 mmol) in Methyl sulfoxide (50 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 100℃ and stirred for 1 h. The reaction mixture was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid (3.9 g, 12.7819 mmol, 56.0824%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 304.921. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H) , 7.70 (s, 1H) , 3.97 (s, 3H) .
Step e: tert-butyl 3- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -3-oxo-propanoate
To a stirred solution of 5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carboxylic acid (3.88 g, 12.7163 mmol) in DMF (50 mL) was added Carbonyl diimidazole (4.12 g, 25.4088 mmol) at 20℃. The resulting mixture was stirred for 1 h at 20℃under nitrogen atmosphere. To the mixture above was added Magnesium chloride (1.81 g, 19.0104 mmol) , 3-tert-Butoxy-3-oxopropanoic acid (3.13 g, 19.5421 mmol) and Triethylamine (3.91 g, 38.6404 mmol) . The reaction mixture was stirred overnight at 20℃. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO3 aq (2 x 500 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo. There was tert-butyl 3- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -3-oxo-propanoate (3.29 g, 8.1585 mmol, 64.1574%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 402.994. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.2 Hz, 1H) , 7.74 (d, J = 8.5 Hz, 1H) , 4.16 (s, 2H) , 3.97 (d, J = 8.2 Hz, 3H) , 1.41 (d, J = 1.6 Hz, 10H) .
INT A10: tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
Step a: 4-fluoro-5-methoxy-isoindoline
10%Pd/C (7.68 g, contain 55%H2O) was added to a solution of 4-fluoro-5-methoxy-2- [ (4-methoxyphenyl) methyl] isoindoline (7.18 g, 24.9889 mmol) in THF (70 mL) and MeOH (70 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixure was filtered and the filter cake was washed with MeOH (70 mL) . The filtrate was evaporated under reduced pressure. There was 4-fluoro-5-methoxy-isoindoline (4.88 g, 29.1901 mmol, 100%yield) obtained as a brown oil, which was used directly in the next step. LCMS: (ESI, m/z) : [M+H] + = 168.200.
Step b: 4-fluoroisoindolin-5-ol hydrobromate
4-fluoro-5-methoxy-isoindoline (4.5 g, 26.9171 mmol) was dissolved in Hydrobromic acid (120 mL, 48%aq) at 20℃. The reaction mixture was heated to 100℃ and stirred for 6 h. The resulting reaction mixture was evaporated under reduced pressure. The residue was treated with n-hexane/EA (1: 2) . The solid was collected by filtration, and dried under reduced pressure. There was 4-fluoroisoindolin-5-ol hydrobromate (4.70 g, 20.0799 mmol, 74.60%yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H] + =154.200. 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H) , 9.58 (s, 2H) , 7.10 –6.93 (m, 2H) , 4.57 (s, 2H) , 4.44 (s, 2H) .
Step c: tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate
NaHCO3 (3.43 g, 40.8301 mmol) was added to a solution of 4-fluoroisoindolin-5-olhydrobromate (4.70 g, 20.0799 mmol) in Water (80 mL) at 0℃. After the reaction mixure was stirred for 20 min, THF (60 mL) was added to the reaction mixture, and Di-tert-butyl dicarbonate (4.45 g, 20.3898 mmol) in THF (20 mL) was added dropwise to the mixure at 0℃. After stirring for 20 min, the
reaction mixure was warmed to 20℃ and stirred for 2 h. The resulting reaction mixture was diluted with EA (150 mL) and washed with brine (150 mL) . The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in n-hexane (0-40%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.14 g, 12.3979 mmol, 60.78%yield) obtained as a reddish brown solid. LCMS: (ESI, m/z) : [M-H] -= 252.000. 1H NMR (400 MHz, CDCl3-d) δ 7.00 –6.93 (m, 1H) , 6.93 –6.83 (m, 1H) , 4.72 (s, 2H) , 4.64 (s, 2H) , 1.54 (s, 9H) .
Step d: tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate
NBS (2.20 g, 12.3607 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-isoindoline-2-carboxylate (3.10 g, 12.2400 mmol) in ACN (40 mL) and THF (20 mL) at 0℃. The reaction mixture was stirred for 2.5 h at 20℃. The reaction mixture was concentrated under reduced pressure. The residue was dissloved with EA/MeOH (200 mL/10 mL) , and washed with H2O (200 mL) . The organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography, eluting with MeOH in DCM (0-5%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol, 66.34%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 331.950. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H) , 7.33 (s, 0.5H) , 7.32 (s, 0.5H) , 4.58 (s, 1H) , 4.55 (s, 1H) , 4.52 (s, 1H) , 4.50 (s, 1H) , 1.45 (s, 9H) .
Step e: tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate
K2CO3 (2.20 g, 15.9183 mmol) was added to a solution of tert-butyl 6-bromo-4-fluoro-5-hydroxy-isoindoline-2-carboxylate (2.70 g, 8.1285 mmol) in DMF (50 mL) at 0℃. After the reaction mixture was stirred for 0.5 h at 0℃, BnBr (1.90 g, 11.1089 mmol) was added to the reaction mixture. The reaction mixture was stirred for 9 h at 20℃. The reaction mixture was diluted with EA (150 mL) and washed with water (150 mL) and brine (2 x 150 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in n-hexane (0-10%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3.43 g, 8.1224 mmol, 99.93%yield) obtained as a white semi-solid. LCMS: (ESI, m/z) : [M-tBu+ACN] + = 407.050. 1H NMR (400 MHz, CDCl3-d) δ 7.54 (d, J = 7.3 Hz, 2H) , 7.45 –7.35 (m, 3H) , 7.27 (s, 0.5H) , 7.20 (s, 0.5H) , 5.13 (s, 2H) , 4.70 (s, 1H) , 4.65 (s, 2H) , 4.62 (s, 1H) , 1.54 (s, 9H) .
Step f: tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate
Pd (dppf) Cl2 (1.12 g, 1.5307 mmol) was added to a solution of tert-butyl 5-benzyloxy-6-bromo-4-fluoro-isoindoline-2-carboxylate (3.30 g, 7.8146 mmol) , bis (neopentylglycolato) diboron (5.46 g, 24.1716 mmol) and KOAc (2.32 g, 23.6392 mmol) in 1, 4-Dioxane (80 mL) at 20℃. The reaction mixture was heated to 90℃ and stirred overnight under nitrogen atmosphere. The reaction mixture was diluted with EA (100 mL) and filtered through a celite. The filtrate was evaporated under reduced pressure. H2O2 (88.1974 mmol, 10 mL, 30%aqueous solution) was added to a mixture of the residue and NaHCO3 (11.9038 mmol, 20 mL, 5%aqueous solution) in THF (80 mL) at 0℃. The reaction mixture was stirred for 2 h at 20℃. The resulting reaction mixture was diluted with brine (150 mL) and saturated NaHSO3 (100 mL) , and extracted with EA (200 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-10%) . There was tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.93 g, 5.3702 mmol, 68.93%yield) obtained as an off-white solid. LCMS: (ESI, m/z) : [M-H] -= 358.100. 1H NMR (400 MHz, CDCl3-d) δ7.46 –7.36 (m, 5H) , 6.62 (s, 0.5H) , 6.58 (s, 0.5H) , 5.15 (s, 2H) , 4.68 (s, 1H) , 4.65 (s, 1H) , 4.61 (s, 1H) , 4.58 (s, 1H) , 1.54 (s, 9H) .
Step g: tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate
K2CO3 (1.18 g, 8.5380 mmol) was added to a solution of tert-butyl 5-benzyloxy-4-fluoro-6-hydroxy-isoindoline-2-carboxylate (1.9 g, 5.2867 mmol) in DMF (25 mL) at 0℃. After the mixture was stirred for 30 min at 0℃, CH3I (1.12 g, 7.8908 mmol) was
added. The reaction mixture was stirred for 3 h at 20℃. The resulting reaction mixture was diluted with water (200 mL) and extracted with EA (200 mL) . The organic layer was separated and washed with brine (2 x 150 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. There was tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.98 g, 5.3024 mmol, 100%yield) obtained as a colorless oil, which was directly used in the next step without purification. LCMS: (ESI, m/z) : [M-tBu+ACN] + = 359.150. 1H NMR (400 MHz, CDCl3-d) δ 7.39 (d, J = 7.4 Hz, 2H) , 7.31 –7.21 (m, 3H) , 6.51 (s, 1H) , 4.99 (s, 2H) , 4.55 (s, 4H) , 3.77 (s, 3H) , 1.44 (s, 9H) .
Step h: tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate
10%Pd/C (1.98 g, contain 55%H2O) was added to a solution of tert-butyl 5-benzyloxy-4-fluoro-6-methoxy-isoindoline-2-carboxylate (1.96 g, 5.2488 mmol) in MeOH (40 mL) and THF (10 mL) at 20℃. The reaction mixture was stirred for 5 h at 20℃under H2 atmosphere. The reaction mixture was diluted with EA (20 mL) and filtered through a celite. The filtrate was evaporated under reduced pressure. The residue was purified on silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-40%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (1.21 g, 4.2712 mmol, 80.67%yield) obtained as a brown semi-solid. LCMS: (ESI, m/z) : [M-H] -=282.100. 1H NMR (400 MHz, CDCl3-d) δ 6.58 (s, 1H) , 4.67 (s, 2H) , 4.63 (s, 2H) , 3.92 (s, 3H) , 1.53 (s, 9H) .
INT A11: ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Step a: 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one
4-Methoxybenzylchloride (4.141g, 26.4416 mmol) was added to a solution of NaH (1.000 g, 25.0024 mmol) and 7-fluoro-6-methoxyisoindolin-1-one (4.336 g, 23.9342 mmol) in DMF (100 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 3 h and warmed up to 20℃ naturally. The reaction mixture was quenched with adding to water (300 mL) at 20℃, extracted with EA (3 x 200 mL) and washed with brine (150 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 7-fluoro-6-methoxy-2- [ (4methoxyphenyl) methyl] isoindolin-1-one (6.51 g, 21.6055 mmol, 90.2706%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 302.110. 1H NMR (400 MHz, DMSO-d6) δ 7.39 (t, J = 7.9 Hz, 1H) , 7.27 (d, J = 8.2 Hz, 1H) , 7.22 (d, J = 8.2 Hz, 2H) , 6.91 (d, J = 8.3 Hz, 2H) , 4.60 (s, 2H) , 4.25 (s, 2H) , 3.87 (s, 3H) , 3.73 (s, 3H) .
Step b: 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline
Borane-tetrahydrofuran complex (120 mL, 120 mmol) was added to a solution of 7-fluoro-6-methoxy-2- (4-methoxybenzyl) isoindolin-1-one (6.17 g, 20.4771 mmol) in THF (60 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 80℃ and stirred for 5 h. The reaction mixture was quenched with pouring into MeOH (300 mL) at 20℃ and evaporated under reduced pressure. The residue was diluted with MeOH (100 mL) . The precipitate was collected by filtration, washed with MeOH (50 mL) . The filter cake was dried under vacuo. There was 4-fluoro-5-methoxy-2 [ (4methoxyphenyl) methyl] isoindoline (3.854 g, 13.4132 mmol, 65.5036%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 288.130. 1H NMR (400 MHz, DMSO-d6) δ 7.41 (d, J = 8.0 Hz, 2H) , 7.06 –6.93 (m, 2H) , 6.88 (d, J = 8.0 Hz, 2H) , 4.53 –4.37 (m, 2H) , 4.22 –4.08 (m, 4H) , 3.79 (s, 3H) , 3.74 (s, 3H) .
Step c: ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Pd/C (2.17 g, 2.0391 mmol) was added to a solution of 4-fluoro-5-methoxy-2- (4-methoxybenzyl) isoindoline (3.36 g, 11.6940 mmol) in THF (20 mL) and MeOH (20 mL) at 20℃. The reaction mixture was stirred overnight at 20℃ under H2 atmosphere. The precipitate was collected by filtration, washed with MeOH (50 mL) . The filtrate was evaporated under reduced pressure. Ethyl Succinyl Chloride (5.05 g, 30.6830 mmol) was added to a solution of the residue and TEA (3.91 g, 38.6404 mmol) in DCM (50 mL)
at 0℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-methoxy-isoindolin-2-yl) -4-oxo-butanoate (2.619 g, 8.8688 mmol, 75.8406%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 296.120. 1H NMR (400 MHz, DMSO-d6) δ 7.16 –7.09 (m, 2H) , 4.91 (s, 1H) , 4.81 (s, 1H) , 4.64 (s, 1H) , 4.58 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.84 (s, 3H) , 2.73 –2.53 (m, 4H) , 1.18 (t, J =7.2 Hz, 3H) .
Step d: ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
Tribromoboron (20 mL, 20 mmol) was added to a solution of ethyl 4- (4-fluoro-5-methoxyisoindolin-2-yl) -4-oxobutanoate (2.597 g, 8.7943 mmol) in DCM (40 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was quenched with adding to EtOH (100 mL) at 20℃, The reaction mixture was evaporated under reduced pressure and diluted with H2O (200 mL) , extracted with EA (2 x 100 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.408 g, 8.5609 mmol, 97.3461%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 282.110. 1H NMR (400 MHz, DMSO-d6) δ9.83 (s, 1H) , 6.99 –6.85 (m, 2H) , 4.88 (s, 1H) , 4.77 (s, 1H) , 4.62 (s, 1H) , 4.54 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 2.66 –2.53 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step e: ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate
NBS (1.194 g, 6.7085 mmol) was added to a solution of ethyl 4- (4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.106 g, 7.4872 mmol) in MeCN (20 mL) and THF (20 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h and warmed up to 20℃ naturally. The precipitate was collected by filtration. The filter cake was dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.84 g, 7.8851 mmol, 105.3134%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 359.010. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H) , 7.36 (s, 0.5H) , 7.35 (s, 0.5H) , 4.87 (s, 1H) , 4.78 (s, 1H) , 4.60 (s, 1H) , 4.55 (s, 1H) , 4.14 –3.97 (q, J = 7.2 Hz, 2H) , 2.70 –2.52 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step f: ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
Bromomethyl methyl ether (1.20 g, 9.6028 mmol) was added to a solution of ethyl 4- (6-bromo-4-fluoro-5-hydroxy-isoindolin-2-yl) -4-oxo-butanoate (2.23 g, 6.1914 mmol) and DIEA (2.55 g, 19.7304 mmol) in DCM (50 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 2 h and warmed up to 20℃ naturally. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (1.809 g, 4.4752 mmol, 72.2806%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 403.140. 1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 0.5H) , 7.51 (s, 0.5H) , 5.16 (s, 2H) , 4.90 (s, 1H) , 4.85 (s, 1H) , 4.63 (s, 1H) , 4.61 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.54 (s, 3H) , 2.72 –2.53 (m, 4H) , 1.24 –1.12 (t, J = 7.2 Hz, 3H) .
Step g: ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate
Pd (dppf) Cl2 (0.228 g, 311.6016 μmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (1.170 g, 4.6074 mmol) and Potassium Acetate (0.743 g, 7.5706 mmol) was added to a solution of ethyl 4- (6-bromo-4-fluoro-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.735 g, 1.8183 mmol) in 1, 4-Dioxane (20 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 100℃ and stirred for 12 h. The reaction mixture was quenched with adding of water (150 mL) at 20℃, extracted with EA (3 x 150 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. Sodium perborate (0.91g, 5.9145 mmol) was added to a solution of the residue in THF (10 mL) and H2O (10 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. The
residue was purified on C18 column ACN/H2O (0.1%FA) (0-38%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.365 g, 1.0693 mmol, 58.8%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =342.130. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H) , 6.68 (s, 1H) , 5.04 (s, 2H) , 4.80 (s, 1H) , 4.76 (s, 1H) , 4.55 (s, 1H) , 4.53 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.47 (s, 3H) , 2.67 –2.51 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step h: ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Methyl Iodidle (0.345 g, 2.4306 mmol) was added to a mixture of Potassium carbonate (0.448 g, 3.2415 mmol) and ethyl 4- (4-fluoro-6-hydroxy-5- (methoxymethoxy) isoindolin-2-yl) -4-oxobutanoate (0.328 g, 960.9441 μmol) in DMF (10 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with DCM (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. Trifluoroacetic acid (2 mL) was added to a solution of the residue (0.446 g, 1.2551 mmol) in DCM (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0-80%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.274 g, 880.1663 μmol, 91.6%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 312.12. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H) , 6.83 (s, 0.5H) , 6.80 (s, 0.5H) , 4.82 (s, 1H) , 4.77 (s, 1H) , 4.57 (s, 1H) , 4.54 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.80 (d, J = 2.0 Hz, 3H) , 2.68 –2.51 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
INT A12: ethyl 4- (6-hydroxy-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
Step a: 6-bromo-5-methoxythieno [3, 2-b] pyridine
A solution of 6-bromo-5-chlorothieno [3, 2-b] pyridine (1.0 g, 4.0 mmol) and NaOMe (9.3 ml, 40 mmol) in MeOH (6 mL) was stirred at 100 ℃ for 1 h under N2 atmosphere in microwave irradiation reactor. 1 N citric acid (80 mL) was added, then extracted with EtOAc (70 mL x 3) . The combined organic solution was dried over Na2SO4, concentrated to give 6-bromo-5-methoxythieno [3, 2-b] pyridine (1.0 g, 4.0 mmol, 99%yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) : δ 8.75 (d, J = 0.5 Hz, 1H) , 8.08 (d, J = 5.5 Hz, 1H) , 7.42 (dd, J = 5.5, 0.5 Hz, 1H) , 3.98 (s, 3H) . LCMS: (ESI, m/z) : [M+H] + = 244.0.
Step b: 6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carboxylic acid
To a solution of 6-bromo-5-methoxythieno [3, 2-b] pyridine (5.0 g, 20.0 mmol) in THF (200 mL) was added LDA (20 ml, 40 mmol) at -80 ℃. The reaction mixture was stirred at -80 ℃ for 30 min under N2 atmosphere. Then the solution was poured onto CO2 solid. The reaction mixture was stirred for about 1 h. 1 N HCl (50 mL) and water (200 ml) was added, then extracted with EtOAc (70 mL x 3) . The combined organic solution was dried over Na2SO4, concentrated to give 6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carboxylic acid (4.9 g, 17.0 mmol, 85%yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) : δ 8.84 (s, 1H) , 7.92 (s, 1H) , 4.00 (s, 3H) . LCMS: (ESI, m/z) : [M+H] + = 287.9.
Step c: tert-butyl 3- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -3-oxopropanoate
To a solution of 6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carboxylic acid (4.9 g, 17.0 mmol) in DMF (147 mL) was added CDI (5.5 g, 34.0 mmol) . After stirring at RT for 2 h under N2 atmosphere, 3-tert-Butoxy-3-oxopropanoic acid (5.5 g, 34.0 mmol) , TEA (5.2 g, 51.0 mmol, 3.0 eq) and MgCl2 (3.3 g, 34.0 mmol) was added, then stirred at RT for overnight. Upon completion, sat. NaHCO3 solution (200 mL) was added, then extracted with EtOAc (200 mL x 3) . The combined organic solution was dried over Na2SO4, concentrated to give a residue, purified by column chromatography (Petroleum ether/Ethyl acetate = 20: 1) to give tert-butyl 3- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -3-oxopropanoate (5.0 g, 12.9 mmol, 62%yield) as a yellow solid.
1H NMR (300 MHz, DMSO-d6) : δ 8.87 (s, 1H) , 8.33 (s, 1H) , 4.17 (s, 2H) , 4.01 (s, 3H) , 1.40 (s, 9H) .
LCMS: (ESI, m/z) : [M+H] + = 386.0.
Step d: 1- (tert-butyl) 4-ethyl 2- (6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carbonyl) succinate
To a solution of tert-butyl 3- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -3-oxopropanoate (3.0 g, 7.8 mmol) in DMF (60 mL) was added K2CO3 (1.8 g, 12.5 mmol) and Ethyl bromoacetate (1.3 g, 78mmol) at 0 ℃. The reaction mixture was stirred at 0 ℃for 5 h under N2 atmosphere. NaHCO3 solution (100 mL) was added, then extracted with EtOAc (100 mL x 3) . The combined organic solution was dried over Na2SO4, concentrated to give a residue, purified by column chromatography (Petroleum ether/Ethyl acetate = 20: 1) to give 1- (tert-butyl) 4-ethyl 2- (6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carbonyl) succinate (3.3 g, 7.0 mmol, 89%yield) as a white solid.
1H NMR (300 MHz, DMSO-d6) : δ 8.89 (s, 1H) , 8.47 (s, 1H) , 5.00 (t, J = 7.3 Hz, 1H) , 4.12 –3.93 (m, 5H) , 2.94 (t, J = 7.3 Hz, 2H) , 1.31 (d, J = 4.5 Hz, 9H) , 1.13 (t, J = 7.1 Hz, 3H) .
LCMS: (ESI, m/z) : [M+H] + = 472.0.
Step e: ethyl 4- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
To a solution of 1- (tert-butyl) 4-ethyl 2- (6-bromo-5-methoxythieno [3, 2-b] pyridine-2-carbonyl) succinate (3.3 g, 7.0 mmol) in PhMe (66 mL) was added TFA (33 ml) . After stirring at 50 ℃ for 1.5 h under N2 atmosphere, the solution was concentrated to give a residue, and the obtained solid was triturated with Petroleum ether /ethyl acetate (10/1) to obtain crude compound ethyl 4- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (2.2 g, 5.9 mmol, 84%yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6) : δ 8.87 (s, 1H) , 8.37 (s, 1H) , 4.11 –3.98 (m, 5H) , 3.45 –3.36 (m, 2H) , 2.71 –2.63 (m, 2H) , 1.17 (t, J = 7.1 Hz, 3H) .
LCMS: (ESI, m/z) : [M+H] + = 372.0.
Step f: (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) boronic acid
Ethyl 4- (6-bromo-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (1.6 g, 4.3 mmol) , B2Pin2 (1.4 g, 5.3 mmol) , AcOK (688 mg, 6.9 mmol) , Pd2 (dba) 3 (112 mg, 0.1 mmol) and Tricyclohexyl phosphine (128 mg, 0.43 mmol) were placed in the reaction bottle. The bottle was evacuated and filled with argon for three times. Then dioxane (32 mL) was added at room temperature. The mixture was stirred at 80 ℃ for 1 h. Water (50 mL) was added to the reaction mixture, extracted with EtOAc (3 x 50 mL) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) boronic acid (3.2 g) a crude residue. It was used for next step without any further purification. LCMS: (ESI, m/z) : [M+H] + = 338.1.
Step g: ethyl 4- (6-hydroxy-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
To a solution of (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) boronic acid (3.2 g, 4.3 mmol, crude) in acetone (48 mL) was added OXONE (36 ml, 6.5 mmol) . After stirring at RT for 2 h. Sat. NaHSO3 solution (120 mL) was added, after stirring at RT for 1 h, the mixture was extracted with EtOAc (3 x 30 mL) , and the combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude residue, purified by column chromatography (Petroleum ether/Ethyl acetate = 10: 1 to 5: 1) to give ethyl 4- (6-hydroxy-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (340 mg, 1.1 mmol, 25%yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) : δ 10.44 (s, 1H) , 8.22 (s, 1H) , 7.65 (s, 1H) , 4.05 (q, J = 7.1 Hz, 2H) , 3.97 (s, 3H) , ~ 3.30-3.31 (br, 2 h) , 2.65 (t, J = 6.1 Hz, 2H) , 1.17 (t, J = 7.1 Hz, 3H) .
LCMS: (ESI, m/z) : [M+H] + = 310.1.
The following intermediates were synthesized with the above steps or improved procedure with the corresponding starting materials and intermediates.
EXAMPLE II-1
4- (5- (3- ( (2- (3-carboxypropanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: Potassium carbonate (0.240 g, 1.7365 mmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.240 g, 579.3045 μmol) and ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.169 g, 576.1737 μmol) in N, N-Dimethylformamide (10 mL) at 20 ℃. The reaction mixture was heated to 50 ℃ and stirred for 3 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO3 aq. (2 x 300 mL) and brine (200 mL) . The organics was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.147 g, 229.0694 μmol, 62.8484%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H) , 7.61 (d, J = 1.9 Hz, 1H) , 7.53 (s, 1H) , 6.98 (dd, J = 15.7, 11.9 Hz, 2H) , 4.73 (d, J = 9.4 Hz, 2H) , 4.52 (s, 2H) , 4.17 (dd, J = 30.4, 7.5 Hz, 4H) , 4.05 (qd, J = 7.1, 3.4 Hz, 4H) , 3.86 (d, J = 1.6 Hz, 3H) , 3.75 (d, J = 2.0 Hz, 3H) , 2.70 –2.53 (m, 6H) , 2.30 –2.15 (m, 2H) , 1.24 –1.11 (m, 6H) .
Step b: LiOH (0.022 g, 918.6456 μmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate in Tetrahydrofuran (10 mL) and Water (2 mL) at 20 ℃. The reaction mixture was stirred for 2 h. The reaction mixture was evaporated under reduced pressure and diluted with water and adjusted pH = 3 with HCl (1 M) . The precipitate was filtered. Filter cake was washed with water (20 mL) . The filtrate cake was dried under vacuo at 60 ℃. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.119 g, 203.2031 μmol, 90.5562%yield) obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 2H) , 8.17 (s, 1H) , 7.67 –7.55 (m, 1H) , 7.53 (s, 1H) , 6.98 (dd, J = 16.6, 12.5 Hz, 2H) , 4.73 (d, J = 8.2 Hz, 2H) , 4.53 (s, 2H) , 4.18 (ddd, J = 23.1, 13.6, 6.3 Hz, 4H) , 3.86 (d, J = 1.0 Hz, 3H) , 3.75 (d, J = 1.9 Hz, 3H) , 3.25 (d, J = 6.6 Hz, 2H) , 2.67 –2.53 (m, 4H) , 2.30 –2.11 (m, 2H) .
EXAMPLE II-2
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
Step a: O1-tert-butyl O4-ethyl 2- (5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) butanedioate
To a stirred solution of tert-butyl 3- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -3-oxo-propanoate (1.58 g, 3.9180 mmol) in N, N-Dimethylformamide (10 mL) was added K2CO3 (1.10 g, 7.9592 mmol) and ethyl bromoacetate (0.72 g, 4.3114 mmol) at 20℃. The resulting mixture was stirred for 2 h at 20℃ under nitrogen atmosphere. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo. There was O1-tert-butyl O4-ethyl 2- (5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) butanedioate (1.925 g, 3.9338 mmol, 100.4016%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 489.030.
Step b: ethyl 4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate
Trifluoroacetic acid (2 mL) was added to a solution of O1-tert-butyl O4-ethyl 2- (5-bromo-4-fluoro-6-methoxy-benzothiophene-2-carbonyl) butanedioate (1.85 g, 3.7805 mmol) in Toluene (10 mL) at 20℃. The reaction mixture was stirred at 60℃ for 2 h . The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with DCM (200 mL) , washed with NaHCO3 aq (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate (0.727 g, 1.8678 mmol, 49.4050%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 388.978. 1H NMR (400 MHz, DMSO-d6) δ8.39 (s, 1H) , 7.71 (s, 1H) , 4.06 (q, J = 6.9 Hz, 2H) , 3.98 (s, 3H) , 3.39 (d, J = 6.2 Hz, 2H) , 2.73 –2.62 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step c: ethyl 4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate
Pd (dppf) Cl2 (0.15 g, 205.0010 μmol) was added to a mixture of Potassium Acetate (0.60 g, 6.1136 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (0.97 g, 3.8198 mmol) and ethyl 4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate (0.72 g, 1.8498 mmol) in 1, 4-Dioxane (30 mL) at 20℃. The reaction mixture was stirred at 100℃ for 20 h under N2 atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with EA (200 mL) , washed with NaHCO3 aq (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.38 g, 870.9586 μmol, 47.0845%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 437.153.
Step d: ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate
Sodium perborate tetrahydrate (0.21 g, 1.3649 mmol) was added to a solution of ethyl 4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate in Tetrahydrofuran (10 mL) and water (10 mL) at 20℃. The reaction mixture was stirred at 20℃ for 1 h. The reaction mixture was concentrated and diluted with DCM (100 mL) , washed with NaHCO3 aq (2 x 500 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-5%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl) -4-oxo-butanoate (0.263 g, 805.9094 μmol, 92.5313%yield)
obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 327.062. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H) , 8.25 (s, 1H) , 7.47 (s, 1H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.88 (s, 3H) , 3.39 –3.34 (m, 2H) , 2.69 –2.60 (m, 2H) , 1.17 (t, J = 7.1 Hz, 3H) .
Step e: ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
NCS (0.105 g, 786.3231 μmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.205 g, 698.9090 μmol) in DMF (10 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 12 h and warmed up to 20℃naturally. The reaction mixture was purified on C18 column ACN/H2O (0-25%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (4-chloro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.148 g, 451.5507 μmol, 64.6079%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 328.100. 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H) , 6.97 (s, 0.5H) , 6.95 (s, 0.5H) , 4.81 (s, 1H) , 4.76 (s, 1H) , 4.59 (s, 1H) , 4.51 (s, 1H) , 4.05 (q, J = 7.2 Hz, 2H) , 3.82 (s, 3H) , 2.69 –2.53 (m, 4H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step f: ethyl 4- [5- (3-bromopropoxy) -4-chloro-6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
1, 3-Dibromopropane (0.495 g, 2.4519 mmol) was added to a mixture of K2CO3 (0.199 g, 1.4399 mmol) , ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.149 g, 454.6023 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 4 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3-bromopropoxy) -4-chloro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.163 g, 363.2433 μmol, 79.9035%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 448.040. 1H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 0.5H) , 7.08 (s, 0.5H) , 4.87 (s, 1H) , 4.79 (s, 1H) , 4.64 (s, 1H) , 4.53 (s, 1H) , 4.06 –4.02 (m, 4H) , 3.83 (d, J = 2.4 Hz, 3H) , 3.78 –3.70 (m, 2H) , 2.71 –2.53 (m, 4H) , 2.23 –2.20 (m, 2H) , 1.18 (t, J = 7.2 Hz, 3H) .
Step g: ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
K2CO3 (0.115 g, 832.0942 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -4-chloro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.068 g, 151.5371 μmol) , ethyl 4- (4-fluoro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.049 g, 150.1504 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 4 h at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.040 g, 57.6234 μmol, 38.0259%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 694.180. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 7.57 (s, 1H) , 7.07 (s, 0.5H) , 7.04 (s, 0.5H) , 4.84 (s, 1H) , 4.73 (s, 1H) , 4.62 (s, 1H) , 4.49 (s, 1H) , 4.29 (t, J = 6.0 Hz, 2H) , 4.17 (t, J = 6.0 Hz, 2H) , 4.10 –4.01 (m, 4H) , 3.89 (s, 3H) , 3.80 (d, J = 2.0 Hz, 3H) , 3.40 –3.34 (m, 2H) , 2.72 –2.53 (m, 6H) , 2.09 –2.06 (m, 2H) , 1.22 –1.15 (m, 6H) .
Step h: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoicacid
LiOH (0.048 g, 2.0043 mmol) was added to a solution of ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.027 g, 38.8958 μmol) in THF (1 mL) and Water (1 mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-52%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid (0.017 g, 26.6434 μmol, 69.6846%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 638.150. 1H NMR (400 MHz, DMSO-d6) δ 12.2 (s, 2H) , 8.29 (s, 1H) , 7.56 (s, 1H) , 7.07 (s, 0.5H) , 7.03 (s,
0.5H) , 4.83 (s, 1H) , 4.72 (s, 1H) , 4.62 (s, 1H) , 4.49 (s, 1H) , 4.32 –4.25 (m, 2H) , 4.17 (t, J = 6.1 Hz, 2H) , 3.89 (s, 3H) , 3.80 (d, J = 1.7 Hz, 3H) , 3.30 –3.27 (m, 2H) , 2.61 –2.55 (m, 4H) , 2.48 –2.46 (m, 2H) , 2.09 –2.06 (m, 2H) .
EXAMPLE II-3
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: tert-butyl 5- (3-bromopropoxy) -4-fluoro-6-methoxy-isoindoline-2-carboxylate
To a solution of tert-butyl 4-fluoro-5-hydroxy-6-methoxy-isoindoline-2-carboxylate (0.50 g, 1.7649 mmol) in DMF (10 mL) , was added 1, 3-Dibromopropane (2.48 g, 12.2841 mmol) and K2CO3 (0.71 g, 5.1373 mmol) . The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was diluted with Ethyl acetate (200 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified on flash silica chromatography, elution gradient 0%to 100%Ethyl acetate in heptane. There was tert-butyl 5- (3-bromopropoxy) -4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.637 g, 1.5757 mmol, 89.2763%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 331.100.
Step b: tert-butyl 5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindoline-2-carboxylate
K2CO3 (0.166 g, 1.2011 mmol) was added to a solution of ethyl 4- (4-chloro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.147 g, 428.8290 μmol) and tert-butyl 5- (3-bromopropoxy) -4-fluoro-6-methoxy-isoindoline-2-carboxylate (0.173 g, 427.9318 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-75%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindoline-2-carboxylate (0.138 g, 207.1598 μmol, 48.3083%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 666.190. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H) , 7.74 (s, 1H) , 6.89 (s, 0.5H) , 6.87 (s, 0.5H) , 4.53 (s, 4H) , 4.21 (d, J = 6.2, 4H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.90 (s, 3H) , 3.77 (d, J = 3.7 Hz, 3H) , 3.39 (t, J = 6.4 Hz, 2H) , 2.66 (t, J = 6.3 Hz, 2H) , 2.11 –2.09 (m, 2H) , 1.45 (s, 9H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step c: ethyl 4- (4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
HCl (5 mL, 20 mmol, 4 M in EA) was added to a solution of tert-butyl 5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindoline-2-carboxylate (0.117 g, 175.6356 μmol) in EA (5 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was evaporated under reduced pressure. There was ethyl 4- (4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.182 g, 321.5338 μmol, 183.0687%yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H] + = 566.130. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 2H) , 8.22 (s, 1H) , 7.75 (s, 1H) , 6.97 (s, 1H) , 4.49 (s, 2H) , 4.46 (s, 2H) , 4.23 –4.20 (m, 4H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.90 (s, 3H) , 3.79 (s, 3H) , 2.67 (t, J = 6.3 Hz, 2H) , 2.09 –2.11 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step d: ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate
Ethyl Succinyl Chloride (0.097 g, 589.3557 μmol) was added to a solution of ethyl 4- (4-chloro-5- (3- ( (4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.167 g, 295.0337 μmol) and TEA (0.164 g, 1.6207 mmol) in DCM (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure
fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.081 g, 116.6874 μmol, 39.5505%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 694.180. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H) , 7.74 (d, J = 2.2 Hz, 1H) , 6.91 (s, 0.5H) , 6.89 (s, 0.5H) , 4.81 (s, 1H) , 4.80 (s, 1H) , 4.57 (s, 2H) , 4.22 (q, J = 5.9 Hz, 4H) , 4.09 –4.03 (m, 4H) , 3.90 (d, J = 1.1 Hz, 3H) , 3.78 (d, J = 2.5 Hz, 3H) , 3.40 (s, 2H) , 2.70 –2.58 (m, 4H) , 2.57 –2.53 (m, 2H) , 2.15 –2.04 (m, 2H) , 1.26 –1.14 (m, 6H) .
Step e: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.045 g, 1.8790 mmol) was added to a solution of ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.044 g, 63.3858 μmol) in THF (2 mL) , H2O (2 mL) and Ethanol (1 mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-52%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.032 g, 50.1523 μmol, 79.1223%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 638.120. 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H) , 7.73 (s, 1H) , 6.91 (s, 0.5H) , 6.88 (s, 0.5H) , 4.79 (s, 2H) , 4.57 (s, 2H) , 4.25 –4.19 (m, 4H) , 3.90 (s, 3H) , 3.78 (d, J = 1.7 Hz, 3H) , 3.33 (t, J = 12.0 Hz, 2H) , 2.63 –2.54 (m, 4H) , 2.49 –2.45 (m, 2H) , 2.15 –2.04 (m, 2H) .
EXAMPLE II-4
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate
1, 3-Dibromopropane (0.708 g, 3.5069 mmol) was added to a mixture of ethyl 4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.217 g, 697.0656 μmol) and Potassium carbonate (0.346 g, 2.5035 mmol) in DMF (5 mL) at 20℃. The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.211 g, 488.1091 μmol, 70.0234%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 432.070.
Step b: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate
Potassium carbonate (0.079 g, 571.6126 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.070 g, 161.9319 μmol) and ethyl 4- (4-fluoro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.065 g, 199.1791 μmol) in N, N-Dimethylformamide (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred overnight at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-70%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.056 g, 82.6315 μmol, 51.0285%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 678.210. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 7.56 (s, 1H) , 6.89 (s, 0.5H) , 6.86 (s, 0.5H) , 4.78 (s, 2H) , 4.56 (s, 1H) , 4.54 (s, 1H) , 4.25 (t, J = 6.0 Hz, 2H) , 4.19 (t, J = 6.0 Hz, 2H) , 4.09 –4.02 (m, 4H) , 3.88 (s, 3H) , 3.77 (d, J = 2.0 Hz, 3H) , 3.36 (t, J = 6.4 Hz, 2H) , 2.70 –2.51 (m, 6H) , 2.10 –1.99 (m, 2H) , 1.22 –1.14 (m, 6H) .
Step c: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.043 g, 1.7955 mmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.039 g, 57.5469 μmol) in THF (2 mL) , H2O (2 mL) and Ethanol (1 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was adjusted to pH=3 with HCl (aq. 1 M) , The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.012 g, 19.3050 μmol, 33.5465%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 622.150. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 2H) , 8.29 (s, 1H) , 7.56 (s, 1H) , 6.90 (s, 0.5H) , 6.86 (s, 0.5H) , 4.77 (s, 2H) , 4.56 (s, 1H) , 4.55 (s, 1H) , 4.29 –4.15 (m, 4H) , 3.88 (s, 3H) , 3.77 (s, 3H) , 3.31 –3.29 (m, 2H) , 2.63 –2.53 (m, 4H) , 2.50 –2.46 (m, 2H) , 2.10 –1.99 (m, 2H) .
EXAMPLE II-5
sodium (S) -4- (5- (3- ( (2- ( (S) -3-carboxylatobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
Step a: Bromomethyl methyl ether (60.56 g, 484.6196 mmol) was added to a solution of N, N-Diisopropylethylamine (97.64 g, 755.4796 mmol) and 2-bromo-5-hydroxy-4-methoxybenzaldehyde (102.80 g, 444.9386 mmol) in DCM (1500 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred at 25℃ for 2 h. The resulting solution was quenched with adding of water (1000 mL) at 25℃. The resulting mixture was extracted with DCM (2 x 1000 mL) , washed with water (500 mL) and brine (500 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was 2-bromo-4-methoxy-5- (methoxymethoxy) benzaldehyde (115.25 g, 418.9454 mmol, 94.1580%yield) obtained as a light yellow soilid. LCMS: (ESI, m/z) : [M+H] + = 274.984. 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H) , 7.51 (s, 1H) , 7.39 (s, 1H) , 5.25 (s, 2H) , 3.93 (s, 3H) , 3.39 (s, 3H) .
Step b: Methyl thioglycolate (53.415 g, 503.2348 mmol) was added to a solution of 2-bromo-4-methoxy-5- (methoxymethoxy) benzaldehyde (115.11 g, 418.4365 mmol) and Caesium fluoride (130.32 g, 857.9136 mmol) in N, N-Dimethylformamide (1200 mL) at 25℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was pour into the water (10 L) and stirred for 1 h. The precipitate was collected by filtration, washed with water (3 x 200 mL) . The filter cake was dried under vacuo at 60℃ to obtain a crude product. The crude product was diluted with DCM (200 mL) . Pour the mixture into n-Hexane (2000 mL) and stirred for 1 h. The precipitate was collected by filtration, washed with n-Hexane (3 x 100 mL) . The filter cake was dried under vacuo at 60℃. There was methyl 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylate (65.50 g, 232.0131 mmol, 55.4476%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 284.056. 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H) , 7.69 (s, 1H) , 7.65 (s, 1H) , 5.25 (s, 2H) , 3.90 (s, 3H) , 3.88 (s, 3H) , 3.44 (s, 3H) .
Step c: LiOH (17.58 g, 734.0813 mmol) was added to a solution of methyl 6-methoxy-5- (methoxymethoxy) benzothiophene-2-
carboxylate (51.16 g, 181.2181 mmol) in THF (600 mL) and Water (200 mL) at 25℃. The reaction mixture was stirred for 4 h at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was diluded with water and adjusted to pH=4 with HCl (1 M) . The precipitate was collected by filtration, washed with water (2 x 50 mL) . The filtrate cake was dried under vacuo. There was 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylic acid (44.17 g, 164.6382 mmol, 90.8509%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M-H] -= 267.041. 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 1H) , 7.95 (s, 1H) , 7.64 (s, 1H) , 7.62 (s, 1H) , 5.23 (s, 2H) , 3.88 (s, 3H) , 3.43 (s, 3H) .
Step d: To a stirred solution of 6-methoxy-5- (methoxymethoxy) benzothiophene-2-carboxylic acid (53.21 g, 198.3337 mmol) in DMF (1000 mL) was added CDI (64.55 g, 398.0919 mmol) at 25℃. The reaction mixture was stirred for 2 h at 25℃. To the mixture above was added 3- (tert-butoxy) -3-oxopropanoic acid (49.03 g, 306.1174 mmol) , TEA (62.33 g, 615.9736 mmol) and Magnesium chloride (29.11 g, 305.7420 mmol) . The reaction mixture was stirred overnight at 25℃. The reaction mixture was concentrated and diluted with EA (3000 mL) , washed with water (2 x 3000 mL) and brine (3000 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 3- (6-methoxy-5- (methoxymethoxy) benzo [b] thiophen-2-yl) -3-oxopropanoate (36.19 g, 98.7643 mmol, 49.7971%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 367.114. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H) , 7.67 (s, 1H) , 7.62 (s, 1H) , 5.24 (s, 2H) , 4.05 (s, 2H) , 3.89 (s, 3H) , 3.42 (s, 3H) , 1.41 (s, 9H) .
Step e: LDA (7.9020 g, 73.7662 mmol) was added to a solution of tert-butyl 3- (6-methoxy-5- (methoxymethoxy) benzo [b] thiophen-2-yl) -3-oxopropanoate (18.02 g, 49.1775 mmol) in 2, 5-Dioxahexane (200 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 40 min at 0℃ under N2 atmosphere. Ethyl (S) -2- ( ( (trifluoromethyl) sulfonyl) oxy) propanoate (18.06 g, 72.1843 mmol) was added to the mixture at 0℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 0℃ under N2 atmosphere. The reaction mixture was quenched with adding of KHCO3 (100 mL) at 0℃. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 1- (tert-butyl) 4-ethyl (3S) -2- (6-methoxy-5- (methoxymethoxy) benzo [b] thiophene-2-carbonyl) -3-methylsuccinate (21.55 g, 46.1908 mmol, 93.9267%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 467.166.
Step f: TFA (101.31 g, 888.5026 mmol) was added to a solution of 1- (tert-butyl) 4-ethyl (3S) -2- (6-methoxy-5- (methoxymethoxy) benzo [b] thiophene-2-carbonyl) -3-methylsuccinate (21.52 g, 46.1265 mmol) in Toluene (198 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (2S) -4- (5-hydroxy-6-methoxy-benzothiophen-2-yl) -2-methyl-4-oxo-butanoate (6.78 g, 21.0314 mmol, 45.5950%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 323.087. 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H) , 8.17 (s, 1H) , 7.54 (s, 1H) , 7.31 (s, 1H) , 4.10 –3.98 (m, 2H) , 3.87 (s, 3H) , 3.44 –3.35 (m, 1H) , 3.19 –3.08 (m, 1H) , 2.98 –2.88 (m, 1H) , 1.21 –1.10 (m, 6H) .
Step g: NMI (7.96 g, 96.9507 mmol) was added to a solution of TCFH (8.11 g, 28.9045 mmol) and (S) -4-methoxy-3-methyl-4-oxobutanoic acid (2.81 g, 19.2280 mmol) in DMF (100 mL) at 25℃. The reaction mixture was stirred for 10 min at 20℃. 5-methoxyisoindoline hydrochloride (4.99 g, 26.8785 mmol) was added to the solution at 25℃. The reaction mixture was stirred 2 h at 25℃. The reaction mixture was concentrated and diluted with H2O (200 mL) , extracted with EA (2 x 200 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-55%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.49 g, 12.5850 mmol, 65.4512%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 278.130. 1H NMR (400 MHz, DMSO-d6) δ 7.23 (t, J = 8.0 Hz, 1H) , 6.95 –6.84 (m, 2H) , 4.78 (s, 1H) , 4.73 (s, 1H) , 4.56 (s, 1H) , 4.52 (s, 1H) , 3.75 (d, J = 1.8 Hz, 3H) , 3.60 (s, 3H) , 2.91 –2.81 (m, 1H) , 2.76 –2.66 (m, 1H) , 2.54 –2.51 (m, 0.5H) , 2.49 –2.45 (m, 0.5H) , 1.18 –1.14 (m, 3H) .
Step h: NBS (3.717 g, 20.8839 mmol) was added to a solution of methyl (2S) -4- (5-methoxyisoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.426 g, 12.3542 mmol) in THF (30 mL) and MeCN (30 mL) at 0℃. The reaction mixture was stirred for 3 h at 25℃. The reaction mixture was concentrated and diluted with DCM (200 mL) , washed with H2O (100 mL) , KHCO3 (aq) (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-60%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.02 g, 8.4781 mmol, 68.6255%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 356.040. 1H NMR (400 MHz, DMSO-d6) δ 7.57 (s, 0.5H) , 7.55 (s, 0.5H) , 7.14 (s, 0.5H) , 7.09 (s, 0.5H) , 4.78 (s, 1H) , 4.75 (s, 1H) , 4.56 (s, 1H) , 4.53 (s, 1H) , 3.86 (s, 3H) , 3.59 (s, 3H) , 2.93 –2.79 (m, 1H) , 2.78 –2.64 (m, 1H) , 2.49 –2.46 (m, 1H) , 1.15 (d, J = 7.1 Hz, 3H) .
Step i: Potassium Acetate (2.81 g, 28.6319 mmol) was added to a mixture of methyl (2S) -4- (5-bromo-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (3.00 g, 8.4220 mmol) , [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.74 g, 1.0113 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.18 g, 12.5228 mmol) in 1, 4-Dioxane (100 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred overnight. The reaction mixture was diluted with EA (200 mL) , The precipitate was collected by filtration, washed with EA (1 x 100 mL) . The filtrate was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate (2.38 g, 5.9017 mmol, 70.0746%
yield) obtained as a brown solid. LCMS: (ESI, m/z) : [M+H] + = 404.222. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H) , 7.46 (s, 0.5H) , 6.97 (s, 0.5H) , 6.93 (s, 0.5H) , 4.81 (s, 1H) , 4.73 (s, 1H) , 4.59 (s, 1H) , 4.52 (s, 1H) , 3.73 (s, 3H) , 3.59 (s, 3H) , 2.90 –2.81 (m, 1H) , 2.76 –2.65 (m, 1H) , 2.54 –2.51 (m, 1H) , 1.27 (s, 12H) , 1.15 (d, J = 6.6 Hz, 3H) .
Step j: Sodium perborate tetrahydrate (0.80 g, 5.1995 mmol) was added to a solution of methyl (2S) -4- [5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl] -2-methyl-4-oxo-butanoate (1.99 g, 4.9346 mmol) in THF (25 mL) and H2O (25 mL) at 25℃. The reaction mixture was stirred for 1 h at 25℃. The reaction mixture was concentrated and diluted with H2O (200 mL) , extracted with DCM (3 x 100 mL) and washed with brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0-40%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (1.23 g, 4.1935 mmol, 84.9809%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 294.130.
Step k: Potassium carbonate (0.462 g, 3.3428 mmol) was added to a solution of methyl (2S) -4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (0.311 g, 1.0603 mmol) and 1, 3-Dibromopropane (1.158 g, 5.7359 mmol) in DMF (20 mL) at 25℃. The reaction mixture was stirred for 3 h at 25℃. The reaction mixture was purified on C18 column ACN/H2O (0-45%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2R) -4- [5- (3-bromopropoxy) -6-methoxy-isoindolin-2-yl] -2-methyl-4-oxo-butanoate (0.314 g, 757.9234 μmol, 71.4822%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + =414.080.
Step l: Potassium carbonate (0.214 g, 1.5484 mmol) was added to a solution of methyl (S) -4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.206 g, 497.2362 μmol) and ethyl (2S) -4- (5-hydroxy-6-methoxy-benzothiophen-2-yl) -2-methyl-4-oxo-butanoate (0.243 g, 753.7805 μmol) in DMF (5 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (S) -4- (6-methoxy-5- (3- ( (6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) benzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.130 g, 198.2454 μmol, 39.8695%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 656.245.
Step m: LiOH (0.017 g, 709.8625 μmol) was added to a solution of ethyl (S) -4- (6-methoxy-5- (3- ( (6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) benzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.120 g, 182.9957 μmol) in THF (4 mL) and Water (1 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was adjusted to pH=7 with HCl (1 M) . The reaction mixture was evaporated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC with the following conditions: (CXTH LC6000, HPLC-P1) : Column, Agela Durashell C18, 30mm*250mm, 10um; mobile phase, Water (0.1%NH3. H2O) and MeCN- (5-20-20%B (2-32-60min) ) ; Detector, uv 210 nm) . The solvent was removed by lyophilization. NaHCO3 (0.019 g, 226.1727 μmol) was added to the lyophilized product in water, and stirred for 30 min at 25℃. The solvent was removed by lyophilization. There was sodium (S) -4- (5- (3- ( (2- ( (S) -3-carboxylatobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.064 g, 97.3180 μmol, 53.1805%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 614.198. 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 0.5H) , 8.05 (s, 0.5H) , 7.56 (s, 1H) , 7.51 (s, 0.5H) , 7.50 (s, 0.5H) , 7.02 –6.89 (m, 2H) , 4.90 –4.77 (m, 1H) , 4.73 –4.62 (m, 1H) , 4.50 (s, 2H) , 4.24 –4.16 (m, 2H) , 4.15 –4.05 (m, 2H) , 3.85 (s, 3H) , 3.74 (s, 3H) , 3.45 –3.38 (m, 2H) , 2.75 –2.57 (m, 2H) , 2.47 –2.39 (m, 1H) , 2.27 –2.14 (m, 2H) , 2.11 –1.97 (m, 1H) , 1.02 (t, J = 6.5 Hz, 6H) .
EXAMPLE II-6
sodium (S) -4- (5- (3- ( (2- ( (S) -3-carboxylatobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate
Step a: Lithium diisopropylamide, (552.5297 mg, 5.1579 mmol) was added to a solution of tert-butyl 3- (5-bromo-4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -3-oxopropanoate (1.6 g, 3.9676 mmol) in 2, 5-Dioxahexane (50 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred for 40 min at 0℃ under N2 atmosphere. Ethyl (S) -2- ( ( (trifluoromethyl) sulfonyl) oxy) propanoate (2.9780 g, 11.9029 mmol) was added to the mixture at 0℃ under N2 atmosphere. The reaction mixture was stirred overnight at 25℃under N2 atmosphere. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with NaHCO3 (aq) (2 x 500 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-20%) . The pure fractions was concentrated and dried under vacuo. There was 1- (tert-butyl) 4-ethyl (3S) -2- (5-bromo-4-fluoro-6-methoxybenzo [b] thiophene-2-carbonyl) -3-methylsuccinate (1.15 g, 2.2846 mmol, 57.5800%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + = 503.046. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 0.5H) , 8.46 (s, 0.5H) ,
7.73 (s, 1H) , 4.93 –4.77 (m, 1H) , 4.13 –4.02 (m, 2H) , 4.00 –3.94 (m, 3H) , 3.24 –3.11 (m, 1H) , 1.31 (d, J = 11.5 Hz, 9H) , 1.25 –1.16 (m, 3H) , 1.10 (t, J = 7.8 Hz, 3H) .
Step b: Trifluoroacetic acid (4 mL) was added to a solution of 1- (tert-butyl) 4-ethyl (3S) -2- (5-bromo-4-fluoro-6-methoxybenzo [b] thiophene-2-carbonyl) -3-methylsuccinate (1.02 g, 2.0263 mmol) in Toluene (20 mL) at 25℃. The reaction mixture was stirred at 50℃ for 2 h. The reaction mixture was concentrated and purified on C-18 column MeCN /water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (S) -4- (5-bromo-4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.76 g, 1.8846 mmol, 93.0079%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 402.994. 1H NMR (400 MHz, MeOD-d4) δ 8.14 (s, 1H) , 7.40 (s, 1H) , 4.19 –4.03 (m, 2H) , 3.98 (s, 3H) , 3.60 –3.39 (m, 1H) , 3.25 –2.97 (m, 2H) , 1.28 (d, J = 7.1 Hz, 3H) , 1.23 (t, J = 7.1 Hz, 3H) .
Step c: [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.13 g, 177.6676 μmol) was added to a mixture of Potassium Acetate (0.53 g, 5.4003 mmol) ethyl (2S) -4- (5-bromo-4-fluoro-6-methoxy-benzothiophen-2-yl) -2-methyl-4-oxo-butanoate (0.70 g, 1.7358 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (0.87 g, 3.4260 mmol) in 1, 4-Dioxane (30 mL) at 25℃. The reaction mixture was stirred overnight at 100℃ under N2 atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with EA (200 mL) , washed with NaHCO3 (aq) (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (S) -4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (452 mg, 1.0037 mmol, 57.8229%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 451.168. 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H) , 7.49 (s, 1H) , 4.15 –3.99 (m, 2H) , 3.86 (s, 3H) , 3.57 –3.40 (m, 2H) , 3.18 (s, 1H) , 1.41 –1.23 (m, 12H) , 1.19 –1.14 (m, 6H) .
Step d: Sodium perborate tetrahydrate (0.23 g, 1.4949 mmol) was added to a solution of ethyl (S) -4- (4-fluoro-6-methoxy-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.46 g, 1.0215 mmol) in Tetrahydrofuran (20 mL) and Water (20 mL) at 25℃. The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with DCM (200 mL) , washed with water (2 x 100 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl (2S) -4- (4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl) -2-methyl-4-oxo-butanoate (0.28 g, 822.6441 μmol, 80.5345%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 341.078. 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H) , 8.25 (s, 1H) , 7.46 (s, 1H) , 4.09 –4.00 (m, 2H) , 3.96 –3.88 (m, 3H) , 3.52 –3.41 (m, 1H) , 3.24 –3.16 (m, 1H) , 2.94 (s, 1H) , 1.22 –1.10 (m, 6H) .
Step e: Ethyl (2S) -4- (4-fluoro-5-hydroxy-6-methoxy-benzothiophen-2-yl) -2-methyl-4-oxo-butanoate (0.16 g, 470.0822 μmol) was added to a mixture of methyl (S) -4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.20 g, 482.7536 μmol) and Potassium carbonate (0.15 g, 1.0853 mmol) in N, N-Dimethylformamide (5 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixtire was purified on C18 column ACN/H2O (0-45%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (S) -4- (4-fluoro-6-methoxy-5- (3- ( (6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) benzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.268 g, 397.7772 μmol, 82.3976%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + = 674.236. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 7.57 (s, 0.5H) , 7.54 (s, 0.5H) , 7.03 –6.83 (m, 2H) , 4.72 (s, 2H) , 4.52 (s, 2H) , 4.31 –4.09 (m, 4H) , 4.09 –3.96 (m, 2H) , 3.87 (s, 3H) , 3.72 (s, 3H) , 3.59 (s, 3H) , 3.51 –3.41 (m, 1H) , 3.24 –3.15 (m, 1H) , 3.02 –2.65 (m, 4H) , 2.12 (s, 2H) , 1.32 –0.96 (m, 9H) .
Step f: LiOH (0.030 g, 1.2527 mmol) was added to a solution of ethyl (2S) -4- [4-fluoro-6-methoxy-5- [3- [6-methoxy-2- [ (3S) -4-methoxy-3-methyl-4-oxo-butanoyl] isoindolin-5-yl] oxypropoxy] benzothiophen-2-yl] -2-methyl-4-oxo-butanoate (0.258 g, 382.9348 μmol) in Tetrahydrofuran (10 mL) and Water (2 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was purified by HPLC. The pure fractions was concentrated and dried under vacuo to obtain the free acid. NaHCO3 (0.016 g, 190.4612 μmol) was added to the free acid in Acetonitrile (10 mL) and Water (10 mL) at 25℃. The mixture was stirred at 25℃ for 1 h. The solvent was removed by lyophilization. There was sodium (S) -4- (5- (3- ( (2- ( (S) -3-carboxylatobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoate (0.063 g, 93.2466 μmol, 24.3505%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 632.289. 1H NMR (400 MHz, DMSO-d6) δ 8.17 –8.05 (m, 1H) , 7.51 (s, 1H) , 6.96 –6.80 (m, 2H) , 4.92 –4.72 (m, 2H) , 4.74 –4.58 (m, 2H) , 4.48 (s, 2H) , 4.29 –4.08 (m, 5H) , 3.87 (s, 3H) , 3.74 –3.65 (m, 3H) , 2.80 –2.57 (m, 4H) , 2.10 (s, 3H) , 1.03 (d, J = 6.9 Hz, 6H) .
EXAMPLE II-7
sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Step a: 5-bromo-2-fluoro-4- (methoxymethoxy) benzaldehyde
Bromomethyl methyl ether (0.71 g, 5.6816 mmol) was added to a solution of DIEA (0.83 g, 6.4220 mmol) and 5-bromo-2-fluoro-4-hydroxybenzaldehyde (0.94 g, 4.2921 mmol) in DCM (20 mL) at 0℃. The reaction mixture was stirred for 1 h at 25℃. The reaction mixture was quenched with adding of water (10 mL) at 20℃. The resulted mixture was washed with water (20 mL) and brine (20 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was a crude 5-bromo-2-fluoro-4- (methoxymethoxy) benzaldehyde (1.16 g, 4.4096 mmol, 102.7388%yield) obtained as a white solid. LCMS: (ESI, m/z) :
[M+H] + = 262.950. 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H) , 8.02 (d, J = 7.5 Hz, 1H) , 7.28 (d, J = 12.6 Hz, 1H) , 5.45 (s, 2H) , 3.43 (s, 3H) .
Step b: methyl 5-bromo-6- (methoxymethox y) benzothiophene-2-carboxylate
Methyl thioglycolate (0.4 mL, 4.4732 mmol) was added to a solution of 5-bromo-2-fluoro-4- (methoxymethoxy) benzaldehyde (1.06 g, 4.0295 mmol) and Potassium carbonate (0.15 g, 1.0853 mmol) in DMF (10 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred for 2 h. The reaction mixture was quenched with adding of water (100 mL) at 20℃. The precipitate was collected by filtration, washed with water (3 x 20 mL) . The filtrate cake was dried under vacuo at 60℃. There was methyl 5-bromo-6-(methoxymethox y) benzothiophene-2-carboxylate (1.12 g, 3.3818 mmol, 83.9267%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 331.100.
Step c: 5-bromo-6- (methoxymethoxy) benzothiophene-2-carboxylic acid
LiOH (0.18 g, 7.5162 mmol) was added to a solution of methyl 5-bromo-6- (methoxymethoxy) benzothiophene-2-carboxylate (1.10 g, 3.3214 mmol) in THF (40 mL) and Water (10 mL) at 25℃. The reaction mixture was stirred for 2 h at 50℃. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and acidified pH=3 with HCl (aq., 1 M) . The precipitate was filtered and filtrate cake was washed with water (20 mL) . The filtrate cake was dried under vacuo at 60℃. There was 5-bromo-6- (methoxymethoxy) benzothiophene-2-carboxylic acid (1.04 g, 3.2791 mmol, 98.7268%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 314.900. 1H NMR (400 MHz, DMSO-d6) δ 13.49 (s, 1H) , 8.30 (s, 1H) , 7.99 (s, 1H) , 7.86 (s, 1H) , 5.39 (s, 2H) , 3.44 (s, 3H) .
Step d: tert-butyl 3- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -3-oxopropanoate
CDI (1.13 g, 6.9689 mmol) was added to a solution of 5-bromo-6- (methoxymethoxy) benzothiophene-2-carboxylic acid (1.01 g, 3.1846 mmol) in DMF (20 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃ under nitrogen atmosphere. Magnesium chloride (0.64 g, 6.7219 mmol) , 3-tert-Butoxy-3-oxopropanoic acid (0.81 g, 5.0572 mmol) and TEA (1.06 g, 10.4754 mmol) were added to the reaction mixture. The reaction mixture was stirred overnight at 25℃. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with saturated aqueous NaHCO3 solution (2 x 50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-20%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 3- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -3-oxopropanoate (1.12 g, 2.6969 mmol, 84.6855%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M-H] -= 412.950. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H) , 8.22 (s, 1H) , 7.87 (s, 1H) , 5.39 (d, J = 10.0 Hz, 2H) , 4.06 (d, J = 8.4 Hz, 2H) , 3.45 (s, 3H) , 1.40 (s, 9H) .
Step e: 1- (tert-butyl) 4-ethyl 2- (5-bromo-6- (methoxymethoxy) benzo [b] thiophene-2-carbonyl) succinate
Ethyl 2-bromoacetate (0.356 g, 2.1317 mmol) was added to a solution of tert-butyl 3- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -3-oxopropanoate (0.891 g, 2.1454 mmol) and Potassium carbonate (0.587 g, 4.2473 mmol) in DMF (10 mL) at 25℃. The reaction mixture was stirred overnight at 25℃ under nitrogen atmosphere. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was 1- (tert-butyl) 4-ethyl 2- (5-bromo-6- (methoxymethoxy) benzo [b] thiophene-2-carbonyl) succinate (0.771 g, 1.5377 mmol, 71.6743%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 501.050.
Step f: ethyl 4- (5-bromo-6-hydroxy-benzothiophen-2-yl) -4-oxo-butanoate
Trifluoroacetic acid (3 mL) was added to a solution of 1- (tert-butyl) 4-ethyl 2- (5-bromo-6- (methoxymethoxy) benzo [b] thiophene-2-carbonyl) succinate (0.750 g, 1.4959 mmol) in toluene (9 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/water (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-bromo-6-hydroxy-benzothiophen-2-yl) -4-oxo-butanoate (0.431 g, 1.2065 mmol, 80.6593%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 357.000.
Step g: ethyl 4- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -4-oxobutanoate
Bromomethyl methyl ether (0.198 g, 1.5845 mmol) was added to a solution of ethyl 4- (5-bromo-6-hydroxy-benzothiophen-2-yl) -4-oxo-butanoate (0.427 g, 1.1953 mmol) and DIEA (0.235 g, 1.8183 mmol) in DCM (10 mL) at 25℃. The reaction mixture was stirred for 1 h at 25℃. The reaction mixture was concentrated and diluted with DCM (100 mL) , washed with water (50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.503 g, 1.1282 mmol, 94.3798%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 401.100.
Step h: ethyl 4- (6- (methoxymethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate
A mixture of [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.110 g, 150.3341 μmol) , ethyl 4- (5-bromo-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.478 g, 1.1912 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (0.491 g, 1.9335 mmol) and Potassium Acetate (0.389 g, 3.9636 mmol) dissolve in 1, 4-Dioxane (10 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred for 4.5 h under N2 atmosphere. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (6- (methoxymethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.420 g, 936.7968 μmol, 78.6423%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 449.200.
Step i: ethyl 4- (5-hydroxy-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -4-oxobutanoate
Sodium perborate tetrahydrate (0.200 g, 1.2999 mmol) was added to a solution of ethyl 4- (6- (methoxymethoxy) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.407 g, 907.8013 μmol) in THF (5 mL) and Water (5 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/water (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-hydroxy-6- (methoxymethoxy) benzo [b] thiophen-2-yl) -4-oxobutanoate (0.250 g, 738.8257 μmol, 81.3863%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 339.100.
Step j: ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate
Succinic anhydride (4.40 g, 43.9681 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (4.89 g, 26.3399 mmol) and TEA (4.73 g, 46.7440 mmol) in Ethanol (200 mL) at 25℃. The reaction mixture was stirred for 1 h at 25℃. Thionyl chloride (20 mL) was added to the solution aboved at 0℃. The reaction mixture was stirred for 3 h at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was diluted with EA (200 mL) , washed with water (100 mL) and brine (50 mL) . The
organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate (17.50 g, 31.5526 mmol, 119.7901%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 278.150. 1H NMR (400 MHz, DMSO-d6) δ 7.28 –7.21 (m, 1H) , 6.94 (s, 0.5H) , 6.92 (s, 0.5H) , 6.88 (s, 0.5H) , 6.86 (s, 0.5H) , 4.81 (s, 1H) , 4.76 (s, 1H) , 4.58 (s, 1H) , 4.54 (s, 1H) , 4.02 –3.95 (m, 2H) , 3.75 (s, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.54 (m, 2H) , 1.17 (t, J = 3.5 Hz, 3H) .
Step k: ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
NBS (10.51 g, 59.0503 mmol) was added to a solution of ethyl 4- (5-methoxyisoindolin-2-yl) -4-oxo-butanoate (17.50 g, 31.5526 mmol) in THF (100 mL) and MeCN (100 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was diluted with DCM (500 mL) , washed with saturated aqueous NaHCO3 solution (2 x 300 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (7.26 g, 20.3812 mmol, 64.5943%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 356.000. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (s, 0.5H) , 7.57 (s, 0.5H) , 7.15 (s, 0.5H) , 7.12 (s, 0.5H) , 4.80 (s, 1H) , 4.77 (s, 1H) , 4.57 (s, 1H) , 4.54 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.84 (s, 3H) , 2.65 –2.59 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step l: ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate
A mixture of Potassium Acetate (3.74 g, 38.1080 mmol) , [1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.72 g, 984.0050 μmol) , ethyl 4- (5-bromo-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (3.64 g, 10.2187 mmol) and 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (3.84 g, 15.1218 mmol) dissolve in 1, 4-Dioxane (100 mL) at 25℃. The reaction mixture was heated to 100℃ and stirred overnight under N2 atmosphere. The reaction mixture was diluted with EA (400 mL) . The precipitate was filtrated by celite, the filtrate cake was washed with EA (1 x 100 mL) . The combined filtrate was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.70 g, 6.6952 mmol, 65.5190%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 404.200. 1H NMR (400 MHz, DMSO-d6) δ 7.49 (s, 0.5H) , 7.48 (s, 0.5H) , 6.98 (s, 0.5H) , 6.95 (s, 0.5H) , 4.83 (s, 1H) , 4.74 (s, 1H) , 4.60 (s, 1H) , 4.53 (s, 1H) , 4.09 –4.01 (m, 2H) , 3.74 (t, J = 6.2 Hz, 3H) , 2.65 –2.58 (m, 2H) , 2.58 –2.52 (m, 2H) , 1.27 (s, 12H) , 1.21 –1.13 (m, 3H) .
Step m: ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate
Sodium perborate tetrahydrate (1.00 g, 6.4994 mmol) was added to a solution of ethyl 4- (5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindolin-2-yl) -4-oxobutanoate (2.45 g, 6.0752 mmol) in THF (20 mL) and Water (20 mL) at 25℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with DCM (500 mL) , washed with saturated aqueous NaHCO3 solution (2 x 300 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (1.37 g, 4.6708 mmol, 76.8818%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + =294.100. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 0.5H) , 8.96 (s, 0.5H) , 6.91 (s, 0.5H) , 6.89 (s, 0.5H) , 6.73 (s, 0.5H) , 6.73 (s, 0.5H) , 4.71 (s, 1H) , 4.69 (s, 1H) , 4.50 (s, 1H) , 4.47 (s, 1H) , 4.08 –4.00 (m, 2H) , 3.75 (s, 3H) , 2.64 –2.58 (m, 2H) , 2.56 –2.53 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step n: ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
1, 3-Dibromopropane (0.73 g, 3.6159 mmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxy-isoindolin-2-yl) -4-oxo-butanoate (0.72 g, 2.4547 mmol) and Potassium carbonate (0.86 g, 6.2226 mmol) in DMF (10 mL) . The reaction mixture was stirred overnight at 50℃. The reaction mixture was diluted with EA (100 mL) , and washed sequentially with water (2 x 100 mL) and saturated brine (100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude
product was purified by flash silica chromatography, elution gradient 0 to 100%Ethyl acetate in heptane. There was ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.43 g, 1.0379 mmol, 42.2829%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 414.050. 1H NMR (400 MHz, DMSO-d6) δ 7.01 –6.93 (m, 2H) , 4.75 (s, 2H) , 4.53 (s, 2H) , 4.10 –4.00 (m, 4H) , 3.76 (s, 3H) , 3.71 –3.62 (m, 2H) , 2.65 –2.58 (m, 2H) , 2.58 –2.53 (m, 2H) , 2.28 –2.18 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step o: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6- (methoxymethoxy) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Ethyl 4- [5-hydroxy-6- (methoxymethoxy) benzothiophen-2-yl] -4-oxo-butanoate (0.101 g, 298.4856 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.127 g, 306.5486 μmol) and Potassium carbonate (0.142 g, 1.0275 mmol) in DMF (5 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with water (100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-(methoxymethoxy) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.055 g, 81.8754 μmol, 27.4303%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 672.250.
Step p: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Trifluoroacetic acid (1.0 mL, 13.4622 mmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6- (methoxymethoxy) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.054 g, 80.3867 μmol) in toluene (2 mL) at 25℃. The reaction mixture was heated to 50℃ and stirred for 30 min. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water and neutralized pH=8 with saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EA (100 mL) , washed with water (50 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.057 g, 77.1865 μmol, 96.0190%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H] + = 628.200.
Step q: sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
LiOH (0.023 g, 960.4022 μmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.055 g, 87.6215 μmol) in THF (4 mL) and Water (1 mL) at 25℃. The reaction mixture was stirred overnight at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was acidified pH=4 with HCl (1 M) . The reaction mixture was evaporated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC with the following conditions: (CXTH LC6000, HPLC-P1) : Column, Daisogel-C18, 50mm*250mm, 10um; mobile phase, Water (0.1%TFA) and MeCN- (15-40-60%B (2-30-60min) ; Detector, uv 216 nm) . The solvent was removed by lyophilization. NaHCO3 (0.004 g, 47.6153μmol) was added to the lyophilized product in water, and stirred for 30 min at 25℃. The solvent was removed by lyophilization. There was sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-hydroxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.012 g, 19.4945 μmol, 22.2485%yield) obtained as a light yellow solid. LCMS: (ESI, m/z) : [M+H] + = 572.150. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 0.5H) , 7.97 (s, 0.5H) , 7.39 (s, 0.5H) , 7.37 (s, 0.5H) , 7.30 (s, 0.5H) , 7.28 (s, 0.5H) , 6.99 –6.87 (m, 2H) , 4.74 (s, 1H) , 4.70 (s, 1H) , 4.49 (s, 1H) , 4.47 (s, 1H) , 4.20 –4.08 (m, 4H) , 3.73 (s, 3H) , 3.07 (t, J = 6.8 Hz, 2H) , 2.47 –2.40 (m, 2H) , 2.36 –2.16 (m, 6H) .
EXAMPLE II-8
sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate
Step a: (3-Bromopropoxy) -tert-butyldimethylsilane (518 mg, 2.0456 mmol) and K2CO3 (320 mg, 2.3154 mmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (200 mg, 681.8624 μmol) in N, N-Dimethylformamide (8 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. Tetrabutylammonium fluoride (178 mg, 681.8624 μmol) was added to the mixture. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with NaHCO3 (aq) (100 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column MeOH/DCM (0-10%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3-hydroxypropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (106 mg, 301.6564 μmol, 44.2401%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 352.168. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 6.95 (d, J =9.4 Hz, 2H) , 4.74 (s, 2H) , 4.53 (s, 2H) , 4.00 (t, J = 6.1 Hz, 2H) , 3.75 (s, 3H) , 3.20 –3.13 (m, 2H) , 2.63 –2.51 (m, 4H) , 1.57 (s, 2H) , 1.38 –1.21 (m, 2H) , 0.94 (t, J = 7.1 Hz, 3H) .
Step b: K3PO4 (151 mg, 711.3706 μmol) and RockPhos Palladacycle Gen. 3 (11 mg, 13.1041 μmol) was added to a solution of ethyl 4- (5- (3-hydroxypropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (50 mg, 142.2907 μmol) and methyl 4- (5-chloro-6-methoxy-thieno [3, 2-b] pyridin-2-yl) -4-oxo-butanoate (66 mg, 210.3544 μmol) in Toluene (10 mL) at 25℃. The reaction mixture was stirred at 130℃ for 16 h under N2 atmosphere. The reaction mixture was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5-methoxy-6- (3- ( (6-methoxy-2- (4-methoxy-4-oxobutanoyl) thieno [3, 2-b] pyridin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate (4.1 mg, 6.5215 μmol, 4.5832%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 629.209.
Step c: LiOH (0.006 g, 250.5397 μmol) was added to a solution of ethyl 4- (5-methoxy-6- (3- ( (6-methoxy-2- (4-methoxy-4-oxobutanoyl) thieno [3, 2-b] pyridin-5-yl) oxy) propoxy) isoindolin-2-yl) -4-oxobutanoate (0.013 g, 20.6780 μmol) in Tetrahydrofuran (4 mL) and Water (1 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with water (2 mL) . The resulting mixture was adjusted to pH=7 with HCl (1 M) at 25℃ and evaporated under reduced pressure. The residue was purified by HPLC. The pure fractions was concentrated and dried by lyophilization to obtain the free acid. NaHCO3 (0.001 g, 11.9038 μmol) was added to a mixture of the free acid in Acetonitrile (2 mL) and Water (1 mL) at 25℃. The mixture was stirred at 25℃ for 1 h and dried by lyophilization. There was sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (0.0043 g, 6.8192 μmol, 32.9781%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 587.162. 1H NMR (400 MHz, DMSO-d6) δ8.07 (s, 0.5H) , 8.03 (s, 0.5H) , 7.96 (s, 1H) , 7.02 –6.93 (m, 2H) , 4.80 –4.73 (m, 2H) , 4.50 (s, 4H) , 4.13 (s, 2H) , 3.88 (s, 3H) , 3.75 –3.73 (m, 3H) , 3.08 (s, 2H) , 2.43 (s, 2H) , 2.24 (s, 4H) , 2.15 (s, 2H) .
EXAMPLE II-9
4- (5- (3- ( (6-bromo-2- (3-carboxypropanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3- ( (6-bromo-2- (4-ethoxy-4-oxobutanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Potassium carbonate (0.080 g, 578.8482 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.075 g, 181.0327 μmol) and ethyl 4- (6-bromo-5-hydroxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.071 g, 198.7576 μmol) in DMF (2 mL) at 25℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (6-bromo-2- (4-ethoxy-4-oxobutanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.080 g, 115.8418 μmol, 63.9894%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 690.13. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H) , 8.26 (s, 1H) , 7.69 (s, 1H) , 7.05 –6.92 (m, 2H) , 4.73 (s, 1H) , 4.72 (s, 1H) , 4.51 (d, J = 3.6 Hz, 2H) , 4.29 (s, 2H) , 4.19 (t, J = 6.4 Hz, 2H) , 4.11 –4.00 (m, 4H) , 3.73 (d, J = 2.0 Hz, 3H) , 3.40 –3.34 (m, 2H) , 2.68 (t, J = 6.3 Hz, 2H) , 2.63 –2.53 (m, 4H) , 2.26 (t, J = 6.3 Hz, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step b: 4- (5- (3- ( (6-bromo-2- (3-carboxypropanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.050 g, 2.0878 mmol) was added to a solution of ethyl 4- (5- (3- ( (6-bromo-2- (4-ethoxy-4-oxobutanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.044 g, 63.7130 μmol) in THF (2 mL) , EtOH (1 mL) and Water (2 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-55%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (6-bromo-2- (3-carboxypropanoyl) benzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.012 g, 18.9128 μmol, 29.6844%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 634.07. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H) , 8.24 (d, J = 3.1 Hz, 1H) , 7.68 (d, J = 3.8 Hz, 1H) , 7.04 –6.92 (m, 2H) , 4.73 (s, 1H) , 4.71 (s, 1H) , 4.51 (d, J = 4.7 Hz, 2H) , 4.29 (s, 2H) , 4.23 –4.15 (m, 2H) , 3.73 (s, 3H) , 3.33 –3.25 (m, 2H) , 2.63 –2.54 (m, 4H) , 2.53 –2.50 (m, 2H) , 2.31 –2.20 (m, 2H) .
EXAMPLE II-10
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
Potassium carbonate (0.099 g, 716.3246 μmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.062 g, 201.0709 μmol) and ethyl 4- (5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.069 g, 159.6186 μmol) in DMF (3 mL) at 25℃ under N2 atmosphere. The reaction mixture was stirred overnight at 50℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried further in lyophilization. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.071 g, 107.6218 μmol, 67.4244%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 660.220. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H) , 7.59 (s, 1H) , 7.50 (d, J = 3.4 Hz, 1H) , 6.92 (s, 0.5H) , 6.88 (s, 0.5H) , 4.80 (s, 1H) , 4.78 (s, 1H) , 4.57 (s, 2H) , 4.27 –4.20 (m, 2H) , 4.17 (t, J = 6.0 Hz, 2H) , 4.10 –4.02 (m, 4H) , 3.85 (s, 3H) , 3.76 (s, 3H) , 3.31 –3.28 (m, 2H) , 2.69 –2.53 (m, 6H) , 2.20 –2.09 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step b: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
LiOH (0.044 g, 1.8373 mmol) was added to a mixture of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.100 g, 155.1150 μmol) in THF (2 mL) , EtOH (2 mL) and Water (2 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid (0.026 g, 43.0741 μmol, 66.0854%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 604.160. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H) , 7.59 (s, 1H) , 7.50 (d, J = 3.0 Hz, 1H) , 6.91 (s, 0.5H) , 6.88 (s, 0.5H) , 4.79 (s, 1H) , 4.77 (s, 1H) , 4.56 (s, 2H) , 4.27 –4.20 (m, 2H) , 4.17 (t, J = 6.0 Hz, 2H) , 3.85 (s, 3H) , 3.76 (s, 3H) , 3.26 –3.24 (m, 2H) , 2.63 –2.54 (m, 4H) , 2.48 –2.44 (m, 2H) , 2.19 –2.10 (m, 2H) .
EXAMPLE II-11
4- (5- (3- ( (6- (3-carboxypropanoyl) -3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propoxy) -6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoic acid
Step a: 3-methoxy-2- (3-tetrahydropyran-2-yloxypropoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine
Pd/C (2.553 g, 2.3990 mmol) was added to a solution of 3-methoxy-6- (4-methoxybenzyl) -2- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) propoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (2.464 g, 5.7500 mmol) in Ethyl acetate (60 mL) at 25℃. The reaction mixture was stirred overnight at 25℃ under H2 atmosphere. The resulting mixture was filtered. The filter cake was washed with EA
(3 x 100 mL) . The filtrate was concentrated under reduced pressure. There was 3-methoxy-2- (3-tetrahydropyran-2-yloxypropoxy) -6,7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.936 g, 4.3947 mmol, 76.4291%yield ) obtained as a yellow oli. LCMS: (ESI, m/z) : [M+H] + = 309.174.
Step b: 3- ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol
4-methylbenzenesulfonic acid (0.69 g, 2.5430 mmol) was added to a solution of 3-methoxy-2- (3-tetrahydropyran-2-yloxypropoxy) -6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridine (1.91 g, 4.3357 mmol) in MeOH (40 mL) at 25℃. The reaction mixture was stirred for 2 h at 25℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column MeCN/water (0-50%) . The pure fractions was concentrated and dried under vacuo. There was 3- ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol (0.814 g, 3.6298 mmol, 83.7191%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 225.116.
Step c: ethyl 4- (2- (3-hydroxypropoxy) -3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate
Ethyl Succinyl Chloride (0.232 g, 1.4096 mmol) was added to a solution of 3- ( (3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propan-1-ol (0.366 g, 1.6321 mmol) and Triethylamine (0.363 g, 3.5873 mmol) in Tetrahydrofuran (20 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred at 25℃ for 1 h. The reaction mixture was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (2- (3-hydroxypropoxy) -3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate (224 mg, 635.6750 μmol, 38.9491%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 353.163. 1H NMR (400 MHz, DMSO-d6) δ 7.38 –7.26 (m, 1H) , 4.81 –4.73 (m, 1H) , 4.68 (s, 1H) , 4.54 (s, 2H) , 4.42 (s, 1H) , 4.30 (t, J = 6.3 Hz, 2H) , 4.11 –3.99 (m, 2H) , 3.78 (s, 3H) , 3.57 –3.50 (m, 2H) , 2.66 –2.59 (m, 2H) , 2.58 –2.52 (m, 2H) , 1.91 –1.80 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step d: ethyl 4- (3-methoxy-2- (3- ( (6-methoxy-2- (4-methoxy-4-oxobutanoyl) thieno [3, 2-b] pyridin-5-yl) oxy) propoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate
Potassium phosphate tribasic (0.212 g, 998.7454 μmol) and RockPhos Palladacycle Gen. 3 (0.022 g, 26.2082 μmol) was added to a solution of ethyl 4- (2- (3-hydroxypropoxy) -3-methoxy-5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate (0.087 g, 246.8916 μmol) and methyl 4- (5-chloro-6-methoxy-thieno [3, 2-b] pyridin-2-yl) -4-oxo-butanoate (0.120 g, 382.4626 μmol) in Toluene (20 mL) at 25℃. The reaction mixture was stirred overnight at 25℃ under N2 atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN /water (0-100%) . The pure fractions was concentrated and dried under vacuo. The residue was purified by HPLC. The pure fractions was concentrated and lyophilization. There was ethyl 4- (3-methoxy-2- (3- ( (6-methoxy-2- (4-methoxy-4-oxobutanoyl) thieno [3, 2-b] pyridin-5-yl) oxy) propoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate (20 mg, 31.7623 μmol, 12.8649%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =630.204. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 3.6 Hz, 1H) , 7.97 (d, J = 4.8 Hz, 1H) , 7.37 –7.28 (m, 1H) , 4.73 (s, 1H) , 4.61 (s, 1H) , 4.55 –4.48 (m, 3H) , 4.47 –4.36 (m, 3H) , 4.09 –4.01 (m, 2H) , 3.89 (s, 3H) , 3.78 (s, 3H) , 3.61 (d, J = 5.6 Hz, 3H) , 2.68 (d, J = 6.5 Hz, 2H) , 2.62 –2.54 (m, 3H) , 2.25 (d, J = 4.2 Hz, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step e: 4- (5- (3- ( (6- (3-carboxypropanoyl) -3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propoxy) -6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoic acid
LiOH (0.004 g, 167.0265 μmol) was added to a solution of ethyl 4- (3-methoxy-2- (3- ( (6-methoxy-2- (4-methoxy-4-oxobutanoyl) thieno [3, 2-b] pyridin-5-yl) oxy) propoxy) -5, 7-dihydro-6H-pyrrolo [3, 4-b] pyridin-6-yl) -4-oxobutanoate (0.010 g, 15.8812 μmol) in Tetrahydrofuran (4 mL) and Water (1 mL) at 25℃. The reaction mixture was stirred at 25℃ for 2 h. The reaction mixture was evaporated under reduced pressure. The residue was concentrated and diluted with water (2 mL) . The resulting mixture was
adjusted to pH=7 with HCl (1 M) at 25℃ and evaporated under reduced pressure. The residue was purified by HPLC. The pure fractions was concentrated and lyophilization. There was 4- (5- (3- ( (6- (3-carboxypropanoyl) -3-methoxy-6, 7-dihydro-5H-pyrrolo [3, 4-b] pyridin-2-yl) oxy) propoxy) -6-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoic acid (2.6 mg, 4.4248 μmol, 27.8619%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 588.157. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H) , 7.97 (d, J =3.4 Hz, 1H) , 7.35 –7.28 (m, 1H) , 4.73 (s, 2H) , 4.61 (s, 2H) , 4.51 (s, 4H) , 4.47 –4.33 (m, 4H) , 3.88 (s, 3H) , 3.78 (s, 3H) , 2.71 –2.61 (m, 4H) , 2.26 (s, 2H) .
EXAMPLE II-12
4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: tert-butyl 5-methoxyisoindoline-2-carboxylate
TEA (33.12 g, 327.3070 mmol) was added to a solution of 5-Methoxyisoindoline hydrochloride (20.01 g, 107.7833 mmol) and Di-tert-butyl dicarbonate (35.28 g, 161.6523 mmol) in DCM (500 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-methoxyisoindoline-2-carboxylate (30.66 g, 104.5347 mmol, 96.9859%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 235.136. 1H NMR (400 MHz, DMSO-d6) δ 7.24 –7.18 (m, 1H) , 6.90 (d, J = 4.5 Hz, 1H) , 6.85 (s, 0.5H) , 6.83 (s, 0.5H) , 4.58 –4.44 (m, 4H) , 3.74 (s, 3H) , 1.45 (s, 9H) .
Step b: tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate
NBS (43.64 g, 245.1906 mmol) was added to a solution of tert-butyl 5-methoxyisoindoline-2-carboxylate (30.40 g, 121.9390 mmol) in Tetrahydrofuran (300 mL) and Acetonitrile (300 mL) at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (1000 mL) , washed with NaHCO3 (aq) (3 x 200 mL) and brine (300 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (17.61 g, 53.6562 mmol, 44.0025%yield) obtained as a yellow solid. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 313.047. 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 5.3 Hz, 1H) , 7.11 (d, J = 4.2 Hz, 1H) , 4.51 (t, J = 9.8 Hz, 4H) , 3.82 (d, J = 3.7 Hz, 3H) , 1.45 (s, 9H) .
Step c: tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (2.10 g, 2.8700 mmol) , 4, 4, 4', 4', 5, 5, 5', 5'-Octamethyl-2, 2'-bi (1, 3, 2-dioxaborolane) (11.71 g, 46.1137 mmol) and Potassium Acetate (9.76 g, 99.4475 mmol) was added to a solution of tert-butyl 5-bromo-6-methoxy-isoindoline-2-carboxylate (10.04 g, 30.5910 mmol) in 1, 4-Dioxane (200 mL) at 20℃. The reaction mixture was heated to 100℃ and stirred overnight under N2 atmosphere. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate (11.00 g, 29.3126 mmol, 95.8208%yield) obtained as a oil. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 361.222.
Step d: tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate
Sodium perborate tetrahydrate (6.28 g, 40.8164 mmol) was added to a solution of tert-butyl 5-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) isoindoline-2-carboxylate (9.75 g, 25.9816 mmol) in Tetrahydrofura (150 mL) and Water (150 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was concentrated and diluted with EA (600 mL) , washed with
water (300 mL) and brine (300 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/DCM (0-100%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5-hydroxy-6-methoxy-isoindoline-2-carboxylate (6.58 g, 24.8017 mmol, 95.4589%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H-tBu+ACN] + = 251.131. 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H) , 6.88 (d, J = 5.8 Hz, 1H) , 6.70 (d, J = 2.3 Hz, 1H) , 4.44 (t, J = 9.6 Hz, 4H) , 3.74 (d, J = 3.4 Hz, 3H) , 1.44 (s, 9H) .
Step e: tert-butyl 5- (3-bromopropoxy) -6-methoxy-isoindoline-2-carboxylate
1, 3-Dibromopropane (0.564 g, 2.7936 mmol) was added to a mixture of Potassium carbonate (0.286 g, 2.0694 mmol) and tert-butyl 5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.179 g, 674.6977 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 5 h at 20℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 5- (3-bromopropoxy) -6-methoxy-isoindoline-2-carboxylate (0.154 g, 398.6747 μmol, 59.0894%yield) obtained as a white oil. LCMS: (ESI, m/z) : [M+H] + = 386.090. 1H NMR (400 MHz, DMSO-d6) δ 6.96 (t, J = 5.8 Hz, 2H) , 4.50 (s, 2H) , 4.48 (s, 2H) , 4.03 (q, J = 5.5 Hz, 2H) , 3.74 (d, J = 3.4 Hz, 3H) , 3.66 (t, J = 6.5 Hz, 2H) , 2.27 –2.19 (m, 2H) , 1.45 (s, 9H) .
Step f: tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate
Potassium carbonate (0.079 g, 571.6126 μmol) was added to a solution of tert-butyl 5- (3-bromopropoxy) -6-methoxyisoindoline-2-carboxylate (0.079 g, 204.5150 μmol) and ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.064 g, 207.5571 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred overnight at 50℃. The reaction mixture was quenched with adding of water (50 mL) at 20℃, extracted with EA (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. There was a crude tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate (0.088 g, 143.3886 μmol, 70.1115%yield) obtained as a yellow oil which was used directly in the next step. LCMS: (ESI, m/z) : [M+H] + = 614.230.
Step g: 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindoline-2-carboxylate (0.084 g, 136.8709 μmol) in DCM (3mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was evaporated under reduced pressure. Dihydrofuran-2, 5-dione (0.050 g, 499.6373 μmol) and TEA (0.195 g, 1.9271 mmol) was added to a solution of the residue in DCM (5 mL) at 0℃ under N2 atmosphere. The reaction mixture was stirred and warmed up to 20℃ naturally. The reaction mixture was quenched with adding of water (50 mL) at 20℃ and adjusted to pH=3 with HCl (1 mol/L) , extracted with EA (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.038 g, 61.9221 μmol, 45.2413%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 614.200. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H) , 7.60 (s, 1H) , 7.53 (s, 1H) , 7.02 (s, 0.5H) , 6.98 (s, 0.5H) , 6.97 (s, 0.5H) , 6.95 (s, 0.5H) , 4.74 (s, 1H) , 4.72 (s, 1H) , 4.52 (s, 2H) , 4.20 (t, J = 6.3 Hz, 2H) , 4.14 (t, J = 6.3 Hz, 2H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.86 (s, 3H) , 3.75 (s, 3H) , 3.30 –3.28 (m, 2H) , 2.70 –2.64 (m, 2H) , 2.58 –2.52 (m, 4H) , 2.27 –2.18 (m, 2H) , 1.17 (t, J = 7.1 Hz, 3H) .
EXAMPLE II-13
sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Step a: 2, 3-dimethoxy-5-vinyl-pyridine
2-ethenyl-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (9.25 g, 60.0595 mmol) , Potassium carbonate (18.91 g, 136.8252 mmol) and Pd (dppf) Cl2 (1.97 g, 2.6923 mmol) was added to a solution of 5-Bromo-2, 3-dimethoxypyridine (9.88 g, 45.3112 mmol) in 1, 4-
Dioxane (100 mL) and Water (20 mL) at 20℃. The reaction mixture was stirred at 80℃ for 2 h under nitrogen atmosphere. The reaction mixture was concentrated and diluted with EA (100 mL) , washed with NaHCO3 (aq) (100 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column Ethyl acetate/Heptane (0-20%) . The pure fractions was concentrated and dried under vacuo. There was 2, 3-dimethoxy-5-vinyl-pyridine (5.22 g, 31.6002 mmol, 69.7404%yield) obtained as a colorless oil. LCMS: (ESI, m/z) : [M+H] + = 166.079. 1H NMR (400 MHz, DMSO-d6) δ 7.70 (d, J = 1.9 Hz, 1H) , 7.46 (t, J = 5.8 Hz, 1H) , 6.73 –6.63 (m, 1H) , 5.83 (dd, J = 17.6, 0.8 Hz, 1H) , 5.24 (dd, J = 11.0, 0.8 Hz, 1H) , 3.86 (s, 3H) , 3.82 (s, 3H) .
Step b: 5, 6-dimethoxypyridine-3-carbaldehyde
Potassium osmate (VI) dehydrate (0.55 g, 1.4927 mmol) in Water (25 mL) was added to a solution of 2, 3-dimethoxy-5-vinyl-pyridine (5.17 g, 31.2975 mmol) and 4-Methylmorpholine N-oxide (7.44 g, 63.5105 mmol) in Tetrahydrofuran (100 mL) at 20℃. The reaction mixture was stirred at 20℃ for 30 min. Sodium periodate (6.82 g, 31.8854 mmol) was added to the mixture at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-20%) . The pure fractions was concentrated and dried under vacuo. There was 5,6-dimethoxypyridine-3-carbaldehyde (3.51 g, 20.9976 mmol, 67.0904%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 168.058. 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H) , 8.34 (d, J = 1.9 Hz, 1H) , 7.53 (d, J = 1.8 Hz, 1H) , 3.99 (s, 3H) , 3.87 (s, 3H) .
Step c: (5, 6-dimethoxy-3-pyridyl) methanol
NaBH4 (0.4 g, 10.5729 mmol) was added to a solution of 5, 6-dimethoxypyridine-3-carbaldehyde (3.51 g, 20.9976 mmol) in methanol (100 mL) at 20℃. The reaction mixture was stirred at 20℃ for 1 h. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with water (200 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The pure fractions was concentrated and dried under vacuo. There was (5, 6-dimethoxy-3-pyridyl) methanol (3.33 g, 19.6835 mmol, 93.7418%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 170.074. 1H NMR (400 MHz, DMSO-d6) δ7.61 (d, J = 1.6 Hz, 1H) , 7.23 (t, J = 6.4 Hz, 1H) , 5.13 (t, J = 5.7 Hz, 1H) , 4.43 (d, J = 5.7 Hz, 2H) , 3.84 (s, 3H) , 3.77 (s, 3H) .
Step d: (2-bromo-5, 6-dimethoxy-3-pyridyl) methanol
NBS (4.26 g, 23.9347 mmol) and Acetic acid (0.5 mL) was added to a solution of (5, 6-dimethoxy-3-pyridyl) methanol (3.30 g, 19.5062 mmol) in Acetonitrile (100 mL) at 20℃. The reaction mixture was stirred at 20℃ for 2 h. The reaction mixture was evaporated under reduced pressure. The resdue was diluted with EA (200 mL) , washed with NaHCO3 (aq) (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo. There was (2-bromo-5, 6-dimethoxy-3-pyridyl) methanol (2.91 g, 11.7304 mmol, 60.1369%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 247.984. 1H NMR (400 MHz, DMSO-d6) δ 7.40 (s, 1H) , 5.45 (t, J = 5.4 Hz, 1H) , 4.42 (d, J = 5.5 Hz, 2H) , 3.85 (s, 3H) , 3.80 (s, 3H) .
Step e: 2-bromo-5, 6-dimethoxy-pyridine-3-carbaldehyde
Dess-Martin periodinane (7.3 g, 17.2113 mmol) was added to a solution of (2-bromo-5, 6-dimethoxy-3-pyridyl) methanol (2.91 g,11.7304 mmol) in DCM (100 mL) at 20℃. The reaction mixture was stirred at 20℃ for 1 h. The reaction mixture was evaporated under reduced pressure. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with NaHCO3 (aq) (2 x 100 mL) and brine (100 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/Hept (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 2-bromo-5, 6-dimethoxy-pyridine-3-carbaldehyde (2.7 g, 10.9730 mmol, 93.5437%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =245.969. 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H) , 7.52 (s, 1H) , 3.99 (s, 3H) , 3.87 (s, 3H) .
Step f: 5, 6-dimethoxythieno [2, 3-b] pyridine-2-carboxylic acid
Methyl thioglycolate (1.1870 g, 11.1830 mmol) was added to a mixture of 2-bromo-5, 6-dimethoxy-pyridine-3-carbaldehyde (2.68 g, 10.8918 mmol) and Potassium carbonate (4.65 g, 33.6455 mmol) in N, N-Dimethylformamide (50 mL) at 20℃. The reaction mixture was stirred overnight at 60℃ under N2 atmosphere. The reaction mixture was concentrated and diluted with water (500 mL) . The precipitate was collected by filtration, washed with water (100 mL) . LiOH (0.40 g, 16.7026 mmol) was added to a solution of the filtrate cake in Tetrahydrofuran (50 mL) and Water (10 mL) at 20℃. The reaction mixture was stirred at 20℃ for 2 h. The reaction mixture was concentrated and diluted with water (200 mL) . The mixture was adjusted to pH=3 with HCl (1 M) . The precipitate was collected by filtration, washed with water (100 mL) . The pure fractions was dried under vacuo. There was 5, 6-dimethoxythieno [2, 3-b] pyridine-2-carboxylic acid (2.32 g, 9.6971 mmol, 89.0313%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =240.065. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (s, 1H) , 7.80 (s, 1H) , 3.98 (s, 3H) , 3.85 (s, 3H) .
Step g: tert-butyl 3- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -3-oxo-propanoate
Carbonyl diimidazole (3.11 g, 19.1799 mmol) was added to a solution of 5, 6-dimethoxythieno [2, 3-b] pyridine-2-carboxylic acid (2.29 g, 9.5717 mmol) in N, N-Dimethylformamide (50 mL) at 20℃. The reaction mixture was stirred for 30 min at 20℃ under nitrogen atmosphere. 3-tert-Butoxy-3-oxopropanoic acid (3.16 g, 19.7294 mmol) , Magnesium chloride (1.87 g, 19.6406 mmol) and Triethylamine (2.96 g, 29.2521 mmol) were added to the mixture at 20℃. The reaction mixture was stirred overnight at 20℃. The reaction mixture was concentrated and diluted with EA (500 mL) , washed with NaHCO3 (aq) (2 x 300 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was tert-butyl 3- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -3-oxo-propanoate (2.37 g, 7.0245 mmol, 73.3885%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + =338.098. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 9.8 Hz, 1H) , 7.83 (d, J = 7.7 Hz, 1H) , 4.06 (d, J = 8.5 Hz, 2H) , 3.98 (s, 3H) , 3.88 (s, 3H) , 1.41 (s, 9H) .
Step h: O1-tert-butyl O4-ethyl 2- (5, 6-dimethoxythieno [2, 3-b] pyridine-2-carbonyl) butanedioate
Ethyl bromoacetate (0.63 g, 3.7724 mmol) was added to a mixture of tert-butyl 3- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -3-oxo-propanoate (1.2 g, 3.5567 mmol) and Potassium carbonate (0.80 g, 5.7885 mmol) in N, N-Dimethylformamide (20 mL) at 20℃. The reaction mixture was stirred for 6 h at 20℃. The reaction mixture was concentrated and diluted with EA (200 mL) , washed with NaHCO3 (aq) (200 mL) and brine (200 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hexane (0-50%) . The pure fractions was concentrated and dried under vacuo. There was O1-tert-butyl O4-ethyl 2- (5, 6-dimethoxythieno [2, 3-b] pyridine-2-carbonyl) butanedioate (1.72 g, 4.0616 mmol, 114.1951%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 424.135. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 7.86 (s, 1H) , 4.82 (t, J = 7.3 Hz, 1H) , 4.05 (m, 2H) , 4.00 (s, 3H) , 3.87 (s, 3H) , 2.92 (d, J = 7.2 Hz, 2H) , 1.32 (s, 9H) , 1.18 –1.06 (m, 3H) .
Step i: ethyl 4- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate
Trifluoroacetic acid (2 mL) was added to a solution of O1-tert-butyl O4-ethyl 2- (5, 6-dimethoxythieno [2, 3-b] pyridine-2-carbonyl) butanedioate (1.51 g, 3.5657 mmol) in Toluene (10 mL) at 20℃. The reaction mixture was stirred for 1 h at 50℃. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate (0.94 g, 2.9069 mmol, 81.5252%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 324.083. 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H) , 7.79 (s, 1H) , 4.00-4.08 (m, 2H) , 3.99 (s, 3H) , 3.87 (s, 3H) , 3.30-3.33 (m, 2H) , 2.67 (t, J = 6.1 Hz, 2H) , 1.18 (t, J = 7.0 Hz, 3H) .
Step j: ethyl 4- (6-chloro-5-methoxy-thieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate
Ethyl 4- (5, 6-dimethoxythieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate (0.308 g, 952.4899 μmol) was added to HCl (10 mL) at 20℃. The reaction mixture was stirred at 100℃ for 1 h. Cooled the reaction mixture to 20℃, POCl3 (1 mL) was added to the reaction mixture. The reaction mixture was stirred at 100℃ for 2 h under N2 atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (6-chloro-5-methoxy-thieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate (0.25 g, 762.7004 μmol, 80.0744%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 328.033. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H) , 8.14 (s, 1H) , 4.00-4.08 (m 2H) , 3.99 (s, 3H) , 3.44 –3.36 (m, 2H) , 2.70 (t, J = 6.2 Hz, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step k: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
RockPhos Palladacycle Gen. 3 (0.03 g, 35.7385 μmol) was added to a mixture of ethyl 4- (6-chloro-5-methoxy-thieno [2, 3-b] pyridin-2-yl) -4-oxo-butanoate (0.10 g, 305.0799 μmol) , ethyl 4- (5- (3-hydroxypropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.18 g, 512.2470 μmol) and Potassium phosphate (0.20 g, 942.2127 μmol) in Toluene (10 mL) at 20℃. The reaction mixture was stirred overnight at 130℃ under N2 atmosphere. The reaction mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.013 g, 20.2267 μmol, 6.6300%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 643.225.
Step l: sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
LiOH (3 mg, 125.2699 μmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.018 g, 28.0062 μmol) in Tetrahydrofuran (4 mL) and Water (1 mL) at 20℃. The reaction mixture was stirred at 20℃ for 1 h. The reaction mixture was purified by Prep-HPLC. The pure fractions was concentrated and dried by lyophilization. NaHCO3 (3.4 mg, 40.4730 μmol) was added to the lyophilized product in Water (5 mL) , and stirred at 20℃ for 1 h. The solvent was removed by lyophilization. There was sodium 4- (5- (3- ( (2- (3-carboxylatopropanoyl) -5-methoxythieno [2, 3-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (13 mg, 20.6162 μmol, 73.6129%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 587.162.
EXAMPLE II-14 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- [5- (3-bromopropoxy) -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate
Potassium carbonate (0.113 g, 817.6230 μmol) was added to a solution of ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.081 g, 262.6894 μmol) and 1, 3-dibromopropane (0.263 g, 1.3027 mmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred overnight at 20℃. The mixture was purified on C18 column ACN/H2O (0-60%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- (3-bromopropoxy) -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate (0.074 g, 172.3638 μmol, 65.6150%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 309.070. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H) , 7.62 (s, 1H) , 7.53 (s, 1H) , 4.14 (t, J = 6.0 Hz, 2H) , 4.06 (q, J = 7.1 Hz, 2H) , 3.87 (s, 3H) , 3.70 (t, J = 6.5 Hz, 2H) , 3.30 (t, J = 6.5 Hz, 2H) , 2.66 (t, J = 6.4 Hz, 2H) , 2.35 –2.26 (m, 2H) , 1.18 (t, J = 7.1 Hz, 3H) .
Step b: ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
Potassium carbonate (0.094 g, 680.1466 μmol) was added to a solution of ethyl 4- [5- (3-bromopropoxy) -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate (0.092 g, 214.2904 μmol) and ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.072 g, 219.6763 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.089 g, 131.6233 μmol, 61.4229%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 676.190. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H) , 7.60 (s, 1H) , 7.51 (d, J = 4.3 Hz, 1H) , 7.07 (s, 0.5H) , 7.04 (s, 0.5H) , 4.83 (s, 1H) , 4.75 (s, 1H) , 4.61 (s, 1H) , 4.50 (s, 1H) , 4.26 (s, 2H) , 4.15 (t, J = 6.0 Hz, 2H) , 4.10 –4.01 (m, 4H) , 3.86 (s, 3H) , 3.77 (s, 3H) , 3.31 –3.27 (m, 2H) , 2.70 –2.52 (m, 6H) , 2.24 –2.14 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step c: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
LiOH (0.051 g, 2.1296 mmol) was added to a solution of ethyl 4- (5- (3- ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.040 g, 59.1565 μmol) in THF (2 mL) and H2O (2 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid (0.025 g, 40.3183 μmol, 68.1552%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 620.130. 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H) , 7.59 (s, 1H) , 7.50 (d, J = 3.3 Hz, 1H) , 7.06 (s, 0.5H) , 7.03 (s, 0.5H) , 4.82 (s, 1H) , 4.74 (s, 1H) , 4.61 (s, 1H) , 4.50 (s, 1H) , 4.31 –4.22 (m, 2H) , 4.15 (t, J = 6.1 Hz, 2H) , 3.86 (s, 3H) , 3.77 (s, 3H) , 3.26 –3.24 (m, 2H) , 2.61 –2.55 (m, 4H) , 2.54 –2.44 (m, 2H) , 2.19 (t, J = 6.2 Hz, 2H) .
EXAMPLE II-15
4- (5- (3- ( (2- (3-carboxypropanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Potassium carbonate (0.089 g, 643.9686 μmol) was added to a solution of ethyl 4- (6-hydroxy-5-methoxythieno [3, 2-b] pyridin-2-yl) -4-oxobutanoate (0.069 g, 223.0577 μmol) and ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.079 g, 190.6877 μmol) in DMF (2 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred overnight. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-55%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.075 g, 116.6925 μmol, 61.1956%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 690.130. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H) , 8.03 (s, 1H) , 7.06 –6.89 (m, 2H) , 4.74 (s, 1H) , 4.72 (s, 1H) , 4.51 (s, 2H) , 4.27 (t, J = 6.2 Hz, 2H) , 4.12 (t, J = 6.7 Hz, 2H) , 4.09 –4.01 (m, 4H) , 3.96 (s, 3H) , 3.74 (d, J = 2.1 Hz, 3H) , 3.40 –3.34 (m, 2H) , 2.68 –2.54 (m, 6H) , 2.29 –2.19 (m, 2H) , 1.18 (t, J = 7.1 Hz, 6H) .
Step b: 4- (5- (3- ( (2- (3-carboxypropanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.050 g, 2.0878 mmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.051 g, 79.3509 μmol) in THF (2 mL) , H2O (2 mL) and Ethanol (1 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) , The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -5-methoxythieno [3, 2-b] pyridin-6-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.015 g, 25.5707 μmol, 32.2248%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 586.160. 1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H) , 8.02 (s, 1H) , 7.02 –6.92 (m, 2H) , 4.73 (s, 1H) , 4.71 (s, 1H) , 4.51 (s, 2H) , 4.27 (t, J = 6.2 Hz, 2H) , 4.12 (s, J = 4.0 Hz, 2H) , 3.96 (s, 3H) , 3.74 (s, 3H) , 3.40 –3.34 (m, 2H) , 2.63 –2.46 (m, 6H) , 2.24 (t, J = 6.2 Hz, 2H) .
EXAMPLE II-16
4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- [4-chloro-5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
3-Chloro-2- (chloromethyl) prop-1-ene (0.507 g, 2.2635 mmol) was added to a mixture of Potassium carbonate (0.202 g, 1.4616 mmol) and ethyl 4- (4-chloro-5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.154 g, 469.8574 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [4-chloro-5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.151 g, 362.7238 μmol, 77.1987%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 416.100.
Step b: ethyl 4- (5- ( (2- ( ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate
K2CO3 (0.092 g, 665.6754 μmol) was added to a mixture of ethyl 4- (4-chloro-5- ( (2- (chloromethyl) allyl) oxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.068 g, 163.3458 μmol) and ethyl 4- (4-fluoro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.049 g, 150.1504 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred overnight at 50℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-60%) . The pure fractions was concentrated and dried by lyophilization. There was ethyl 4- (5- ( (2- ( ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.022 g, 31.1538 μmol, 19.0723%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 706.180. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H) , 7.56 (s, 1H) , 7.07 (s, 0.5H) , 7.04 (s, 0.5H) , 5.34 (d, J = 10.9 Hz, 2H) , 4.83 (s, 1H) , 4.77 (s, 2H) , 4.70 (s, 1H) , 4.66 (s, 2H) , 4.61 (s, 1H) , 4.47 (s, 1H) , 4.06 (q, J = 7.1 Hz, 4H) , 3.89 (s, 3H) , 3.81 (s, 3H) , 3.40 –3.34 (m, 2H) , 2.69 –2.54 (m, 6H) , 1.21 –1.14 (m, 6H) .
Step c: 4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid
LiOH (0.037 g, 1.5450 mmol) was added to a solution of ethyl 4- (5- ( (2- ( ( (4-chloro-2- (4-ethoxy-4-oxobutanoyl) -6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.012 g, 16.9930 μmol) in THF (1 mL) and H2O (1 mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -4-chloro-6-methoxyisoindolin-5-yl) oxy) methyl) allyl) oxy) -4-fluoro-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoic acid (0.011 g, 16.9213 μmol, 99.5782%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M-H] -= 648.120. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J = 3.0 Hz, 1H) , 7.56 (s, 1H) , 7.06 (s, 0.5H) , 7.03 (s, 0.5H) , 5.34 (d, J = 10.8 Hz, 2H) , 4.82 (s, 1H) , 4.77 (d, J = 3.3 Hz, 2H) , 4.68 (s, 1H) , 4.66 (s, 2H) , 4.61 (s, 1H) , 4.46 (s, 1H) , 3.89 (s, 3H) , 3.81 (s, 3H) , 3.32 –3.26 (m, 2H) , 2.61 –2.53 (m, 4H) , 2.48 –2.44 (m, 2H) .
EXAMPLE II-17
(S) -4- (5- (3- ( (2- ( (S) -3-carboxybutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoic acid
Step a: 4-fluoro-6-methoxyisoindolin-5-ol hydrochloride
HCl in EA (3 mL, 12 mmol) was added to a solution of tert-butyl 4-fluoro-5-hydroxy-6-methoxyisoindoline-2-carboxylate (0.103 g, 363.5790 μmol) in EA (1 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was
evaporated under reduced pressure. There was 4-fluoro-6-methoxyisoindolin-5-ol hydrochloride (0.12 g, 655.0962 μmol, 180.1799%yield) obtained as a white solid, which was used directly to the next step. LCMS: (ESI, m/z) : [M+H] + = 184.070.
Step b: methyl (2S) -4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate
4-fluoro-6-methoxyisoindolin-5-ol hydrochloride (0.112 g, 611.4238 μmol) was added to a solution of (S) -4-methoxy-3-methyl-4-oxobutanoic acid (0.108 g, 739.0133 μmol) , HATU (0.197 g, 518.1084 μmol) and DIEA (0.450 g, 3.4818 mmol) in DMF (10 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-55%) . The pure fractions was concentrated and dried under vacuo. There was methyl (2S) -4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (0.061 g, 195.9494 μmol, 32.0481%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 312.120.
Step c: ethyl (2S) -4- [5- (3-bromopropoxy) -4-fluoro-6-methoxy-benzothiophen-2-yl] -2-methyl-4-oxo-butanoate
1, 3-Dibromopropane (0.255 g, 1.2631 mmol) was added to a mixture of ethyl (S) -4- (4-fluoro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.061 g, 179.2189 μmol) and Potassium carbonate (0.129 g, 933.3927 μmol) in DMF (3 mL) at 20℃ under N2 atmosphere. The reaction mixture was stirred for 3 h at 20℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-70%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (2S) -4- [5- (3-bromopropoxy) -4-fluoro-6-methoxy-benzothiophen-2-yl] -2-methyl-4-oxo-butanoate (0.66 g, 1.4306 mmol, 798.2476%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 461.040.
Step d: ethyl (S) -4- (4-fluoro-5- (3- ( (4-fluoro-6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate
Potassium carbonate (0.074 g, 535.4346 μmol) was added to a solution of ethyl (2S) -4- [5- (3-bromopropoxy) -4-fluoro-6-methoxy-benzothiophen-2-yl] -2-methyl-4-oxo-butanoate (0.071 g, 153.8990 μmol) and methyl (2S) -4- (4-fluoro-5-hydroxy-6-methoxy-isoindolin-2-yl) -2-methyl-4-oxo-butanoate (0.056 g, 179.8880 μmol) in DMF (3 mL) at 20℃. The reaction mixture was stirred overnight at 50℃ under N2 atmosphere. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl (S) -4- (4-fluoro-5- (3- ( (4-fluoro-6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (61 mg, 88.1841 μmol, 57.3000%yield ) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 692.230. 1H NMR (400 MHz, DMSO-d6) δ8.31 (s, 1H) , 7.56 (s, 1H) , 6.90 (s, 0.5H) , 6.85 (s, 0.5H) , 4.77 (s, 2H) , 4.56 (s, 1H) , 4.54 (s, 1H) , 4.25 (t, J = 6.1 Hz, 2H) , 4.19 (t, J =6.1 Hz, 2H) , 4.05 (q, J = 7.0 Hz, 2H) , 3.88 (s, 3H) , 3.77 (d, J = 2.1 Hz, 3H) , 3.59 (s, 3H) , 3.55 –3.43 (m, 1H) , 3.26 –3.15 (m, 1H) , 3.00 –2.90 (m, 1H) , 2.90 –2.79 (m, 1H) , 2.76 –2.66 (m, 1H) , 2.50 –2.44 (m, 1H) , 2.09 –1.99 (m, 2H) , 1.21 –1.10 (m, 9H) .
Step e: (S) -4- (5- (3- ( (2- ( (S) -3-carboxybutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -2-methyl-4-oxobutanoic acid
LiOH (0.038 g, 1.5868 mmol) was added to a mixture of ethyl (S) -4- (4-fluoro-5- (3- ( (4-fluoro-6-methoxy-2- ( (S) -4-methoxy-3-methyl-4-oxobutanoyl) isoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophen-2-yl) -2-methyl-4-oxobutanoate (0.038 g, 54.9344 μmol) in THF (2 mL) and H2O (2 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The reaction mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried by lyophilization. There was (S) -4- (5- (3- ( (2- ( (S) -3-carboxybutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -4-fluoro-6-methoxyisoindolin-2-yl) -2-methyl-4-
oxobutanoic acid (18 mg, 27.7070 μmol, 50.4365%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 650.18. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 2H) , 8.30 (s, 1H) , 7.56 (s, 1H) , 6.90 (s, 0.5H) , 6.85 (s, 0.5H) , 4.76 (s, 2H) , 4.56 (s, 1H) , 4.54 (s, 1H) , 4.26 (t, J = 6.5 Hz, 2H) , 4.19 (t, J = 6.1 Hz, 2H) , 3.88 (s, 3H) , 3.77 (s, 3H) , 3.53 –3.44 (m, 1H) , 3.17 –3.05 (m, 1H) , 2.93 –2.83 (m, 1H) , 2.79 –2.61 (m, 2H) , 2.45 –2.35 (m, 1H) , 2.11 –1.98 (m, 2H) , 1.22 –1.10 (m, 6H) .
EXAMPLE II-18
4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 3- [ [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] amino] propanoate
Ethyl 3-aminopropanoate hydrochloride (0.34 g, 2.2134 mmol) was added to a solution of HATU (0.85 g, 2.2355 mmol) , DIEA (0.77 g, 5.9578 mmol) and 6-methoxy-5- (methoxymethoxy) benzo [b] thiophene-2-carboxylic acid (0.29 g, 1.0809 mmol) in DMF (15 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-50%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 3- [ [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] amino] propanoate (0.35 g, 952.5987 μmol, 88.1269%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 368.110.
Step b: ethyl 3- [ (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) amino] propanoate
Ethyl 3- [ [6-methoxy-5- (methoxymethoxy) benzothiophene-2-carbonyl] amino] propanoate (0.29 g, 789.2963 μmol) was added to Acetic acid (10 mL) at 20℃. The reaction mixture was heated to 120℃ and stirred for 4 h. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-40%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 3- [ (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) amino] propanoate (0.23 g, 711.2738 μmol, 90.1149%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 324.080.
Step c: ethyl 4- [5- [3- [2- [ (3-ethoxy-3-oxo-propyl) carbamoyl] -6-methoxy-benzothiophen-5-yl] oxypropoxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoateethyl
Potassium carbonate (0.25 g, 1.8089 mmol) was added to a solution of ethyl 3- [ (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) amino] propanoate (0.21 g, 649.4249 μmol) and ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.21 g, 506.8913 μmol) in DMF (5 mL) at 20℃ under N2 atmosphere. The reaction mixture was heated to 50℃ and stirred for 8 h. The reaction mixture was purified on C18 column ACN/H2O (0.1%FA) (0-65%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- [3- [2- [ (3-ethoxy-3-oxo-propyl) carbamoyl] -6-methoxy-benzothiophen-5-yl] oxypropoxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.147 g, 223.8324 μmol, 34.4662%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 657.240.
Step d: 4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.101 g, 4.2174 mmol) was added to a solution of ethyl 4- [5- [3- [2- [ (3-ethoxy-3-oxo-propyl) carbamoyl] -6-methoxy-benzothiophen-5-yl] oxypropoxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.082 g, 124.8589 μmol) in THF (8 mL) and H2O (8 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- (3- ( (2- ( (2-carboxyethyl) carbamoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (49 mg, 81.5803 μmol, 65.3380%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 601.180. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 2H) , 8.69 (t, J = 5.5 Hz,
1H) , 7.88 (s, 1H) , 7.56 (s, 1H) , 7.44 (d, J = 2.4 Hz, 1H) , 7.08 –6.90 (m, 2H) , 4.74 (s, 1H) , 4.71 (s, 1H) , 4.53 (s, 2H) , 4.25 –4.16 (m, 2H) , 4.16 –4.09 (m, 2H) , 3.84 (d, J = 1.5 Hz, 3H) , 3.74 (d, J = 2.1 Hz, 3H) , 3.50 –3.42 (m, 2H) , 2.60 –2.52 (m, 4H) , 2.50 –2.47 (m, 2H) , 2.27 –2.17 (m, 2H) .
EXAMPLE II-19
4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) methyl) allyl) oxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- [5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate
3-Chloro-2- (chloromethyl) prop-1-ene (1.108 g, 8.8643 mmol) was added to a mixture of ethyl 4- (5-hydroxy-6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.507 g, 1.7285 mmol) and Potassium carbonate (0.816 g, 5.9043 mmol) in DMF (20 mL) at 20℃. The reaction mixture was stirred for 8 h at 20℃. The reaction mixture was quenched with adding of water (100 mL) at 20℃, extracted with EA (3 x 50 mL) and washed with brine (50 mL) . The organics dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on silica gel column EA/n-Hex (0-70%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.27 g, 707.0847 μmol, 40.9069%yield) obtained as a yellow oil. LCMS: (ESI, m/z) : [M+H] + = 382.130.
Step b: ethyl 4- [5- [2- [ [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxymethyl] allyloxy] -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate
Sodium iodide (0.179 g, 1.1942 mmol) was added to a mixture of ethyl 4- [5- [2- (chloromethyl) allyloxy] -6-methoxy-isoindolin-2-yl] -4-oxo-butanoate (0.216 g, 55.6671 μmol) , ethyl 4- (5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.186 g, 603.2128 μmol) and Potassium carbonate (0.238 g, 1.7221 mmol) in DMF (5 mL) at 20℃. The reaction mixture was stirred for 5 h at 20℃ under N2 atmosphere. The mixture was purified on C18 column ACN/H2O (0.1%FA) (0-70%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- [5- [2- [ [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxymethyl] allyloxy] -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate (0.169 g, 258.5135 μmol, 45.7006%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 654.230. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H) , 7.63 (d, J = 4.9 Hz, 1H) , 7.53 (s, 1H) , 7.05 –6.87 (m, 2H) , 5.45 –5.32 (m, 2H) , 4.81 –4.72 (m, 3H) , 4.66 (s, 3H) , 4.52 (s, 1H) , 4.50 (s, 1H) , 4.10 –4.00 (m, 4H) , 3.87 (d, J = 1.9 Hz, 3H) , 3.76 (d, J = 2.8 Hz, 3H) , 3.32 –3.26 (m, 2H) , 2.72 –2.52 (m, 6H) , 1.21 –1.13 (m, 6H) .
Step c: 4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) methyl) allyl) oxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.073 g, 3.0482 mmol) was added to a mixture of ethyl 4- [5- [2- [ [2- (4-ethoxy-4-oxo-butanoyl) -6-methoxy-isoindolin-5-yl] oxymethyl] allyloxy] -6-methoxy-benzothiophen-2-yl] -4-oxo-butanoate (0.075 g, 114.7249 μmol) in THF (4 mL) and H2O (2 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was adjusted to pH=3 with HCl (1 mol/L) . The mixture was evaporated under reduced pressure. The residue was purified on C18 column ACN/H2O (0.1%FA) (0-45%) . The pure fractions was concentrated and dried by lyophilization. There was 4- (5- ( (2- ( ( (2- (3-carboxypropanoyl) -6-methoxybenzo [b] thiophen-5-yl) oxy) methyl) allyl) oxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (0.0423 g, 70.7794 μmol, 61.6949%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 598.170. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 2H) , 8.15 (s, 1H) , 7.63 (d, J = 4.0 Hz, 1H) , 7.53 (s, 1H) , 7.06 –6.90 (m, 2H) , 5.45 –5.32 (m, 2H) , 4.78 –4.70 (m, 3H) , 4.66 (t, J = 3.3 Hz, 3H) , 4.53 (s, 1H) , 4.50 (s, 1H) , 3.87 (d, J = 1.6 Hz, 3H) , 3.76 (d, J = 2.6 Hz, 3H) , 3.29 –3.24 (m, 2H) , 2.65 –2.50 (m, 6H) .
EXAMPLE II-20
4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
Step a: ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate
Ethyl 4- (4-fluoro-5-hydroxy-6-methoxybenzo [b] thiophen-2-yl) -4-oxobutanoate (0.081 g, 248.2078 μmol) and Potassium carbonate (0.136 g, 984.0419 μmol) was added to a solution of ethyl 4- (5- (3-bromopropoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.103 g, 248.6182 μmol) in N, N-Dimethylformamide (10 mL) at 20℃. The reaction mixture was stirred overnight at 50℃. The reaction mixture was diluted with Ethyl acetate (100 mL) , washed sequentially with water (100 mL) and brine (100 mL) . The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (66 mg, 100.0428 μmol, 40.2396%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 432.070. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H) , 7.57 (d, J = 3.2 Hz, 1H) , 6.98 (s, 0.5H) , 6.95 (s, 1H) , 6.92 (s, 0.5H) , 4.74 (s, 2H) , 4.53 (s, 2H) , 4.31 –4.09 (m, 4H) , 4.09 –3.98 (m, 4H) , 3.87 (s, 3H) , 3.73 (s, 3H) , 3.41 –3.34 (m, 2H) , 2.70 –2.53 (m, 6H) , 2.17 –2.04 (m, 2H) , 1.21 –1.12 (m, 6H) .
Step b: 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid
LiOH (0.010 g, 417.5662 μmol) was added to a solution of ethyl 4- (5- (3- ( (2- (4-ethoxy-4-oxobutanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoate (0.052 g, 78.8217 μmol) in Tetrahydrofuran (10 mL) and Water (2 mL) . The reaction mixture was stirred for 2 hours at 50℃. The reaction mixture was acidified pH=4 with HCl (1 M) . The mixture was evaporated under reduced pressure. The residue was purified on C-18 column MeCN/water (0-100%) . The pure fractions was concentrated and dried under vacuo. There was 4- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxybenzo [b] thiophen-5-yl) oxy) propoxy) -6-methoxyisoindolin-2-yl) -4-oxobutanoic acid (22 mg, 36.4473 μmol, 46.2402%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 604.157. 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 2H) , 8.30 (s, 1H) , 7.57 (s, 1H) , 6.98 (s, 0.5H) , 6.95 (s, 1H) , 6.92 (s, 0.5H) , 4.74 (s, 2H) , 4.53 (s, 2H) , 4.33 –4.06 (m, 4H) , 3.91 (s, 3H) , 3.68 (s, 3H) , 3.30-3.38 (m, 2H) , 2.71 –2.53 (m, 6H) , 2.18 –2.10 (m, 2H) .
EXAMPLE II-21
trans-2- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid
Step a: methyl trans-2- [5- (5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl) -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate
[1, 1'-Bis (diphenylphosphino) ferrocene] dichloropalladium (II) (0.203 g, 277.4347 μmol) was added to a mixture of methyl trans-2- (5-bromo-6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylate (0.510 g, 1.3813 mmol) , bis (neopentyl glycolato) diboron (0.953 g, 4.2190 mmol) and KOAc (0.437 g, 4.4527 mmol) in 1, 4-Dioxane (20 mL) at 20℃. The reaction mixture was heated to 90℃ and stirred overnight under N2 atmosphere. The reaction mixture was filtered through a celite pad. The filtrate was evaporated under reduced pressure. There was a crude methyl trans-2- [5- (5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl) -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (1.61 g, 2.0012 mmol, 144.8795%yield) obtained as a black oil, which was directly used in the next step. LCMS: (ESI, m/z) : [M+H] + = 403.13.
Step b: methyl trans-2- (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) cyclopropanecarboxylate
H2O2 (3.0 mL, 24.7468 mmol, 30%aqueous solution) was added to a mixture of methyl trans-2- [5- (5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl) -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (1.56 g, 1.9390 mmol) and NaHCO3 (3.0 mL, 1.6722 mmol, 5%aqueous solution) in THF (30 mL) at 20℃. The reaction mixture was stirred for 1 h at 20℃. The resulting reaction
mixture was diluted with brine (150 mL) , extracted with EA (150 mL) and washed with brine (150 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-100%) . The pure fractions was concentrated and dried under reduced pressure. There was methyl trans-2- (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) cyclopropanecarboxylate (0.30 g, 979.3261 μmol, 71.43%yield) obtained as a reddish brown solid. LCMS: (ESI, m/z) : [M+H] + = 307.05. 1H NMR (400 MHz, CDCl3-d) δ 7.98 (s, 1H) , 7.38 (s, 1H) , 7.26 (s, 1H) , 4.02 (s, 3H) , 3.76 (s, 3H) , 3.23 –3.11 (m, 1H) , 2.49 –2.38 (m, 1H) , 1.73 –1.66 (m, 1H) , 1.65 –1.58 (m, 1H) .
Step c: tert-butyl 4-fluoro-6-methoxy-5- [3- [6-methoxy-2- [trans-2-methoxycarbonylcyclopropanecarbonyl] benzothiophen-5-yl] oxypropoxy] isoindoline-2-carboxylate
K2CO3 (0.501 g, 3.6250 mmol) was added to a solution of methyl trans-2- (5-hydroxy-6-methoxy-benzothiophene-2-carbonyl) cyclopropanecarboxylate (0.300 g, 979.3264 μmol) and tert-butyl 5- (3-bromopropoxy) -4-fluoro-6-methoxyisoindoline-2-carboxylate (0.406 g, 1.0043 mmol) in DMF (10 mL) at 20℃. The reaction mixture was heated to 60℃ and stirred overnight. The resulting reaction mixture was diluted with H2O (150 mL) , extracted with EA (150 mL) and washed with brine (2 x 150 mL) . The organic layer was collected and dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/n-hexane (0-50%) . The pure fractions was concentrated and dried under reduced pressure. There was tert-butyl 4-fluoro-6-methoxy-5- [3- [6-methoxy-2- [trans-2-methoxycarbonylcyclopropanecarbonyl] benzothiophen-5-yl] oxypropoxy] isoindoline-2-carboxylate (0.45 g, 714.6357 μmol, 72.9722%yield) obtained as a yellowish solid. LCMS: (ESI, m/z) : [M+H-Boc] + = 530.20. 1H NMR (400 MHz, CDCl3-d) δ 7.92 (s, 1H) , 7.29 (s, 1H) , 7.18 (s, 1H) , 6.50 (s, 1H) , 4.55 (s, 4H) , 4.28 (t, J = 6.4 Hz, 2H) , 4.20 (t, J = 5.8 Hz, 2H) , 3.87 (s, 3H) , 3.71 (s, 3H) , 3.67 (s, 3H) , 3.11 –3.04 (m, 1H) , 2.38 –2.31 (m, 1H) , 2.30 –2.20 (m, 2H) , 1.65 –1.58 (m, 1H) , 1.57 –1.50 (m, 1H) , 1.44 (s, 9H) .
Step d: methyl trans-2- [5- [3- (4-fluoro-6-methoxy-isoindolin-5-yl) oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate
HCl (4 N) in EA (15 mL, 60 mmol) was added to a solution of tert-butyl 4-fluoro-6-methoxy-5- [3- [6-methoxy-2- [trans-2-methoxycarbonylcyclopropanecarbonyl] benzothiophen-5-yl] oxypropoxy] isoindoline-2-carboxylate (0.45 g, 714.6351 μmol) in EA (5 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The resulting reaction mixture was concentrated under reduced pressure. There was methyl trans-2- [5- [3- (4-fluoro-6-methoxy-isoindolin-5-yl) oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (0.42 g, 667.8009 μmol, 93.4464%yield, HCl salt) obtained as a gray solid. LCMS: (ESI, m/z) : [M+H] + = 530.20. 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 2H) , 8.49 (s, 1H) , 7.63 (s, 1H) , 7.52 (s, 1H) , 6.98 (s, 1H) , 4.50 (s, 2H) , 4.46 (s, 2H) , 4.23 (t, J = 6.0 Hz, 2H) , 4.17 (t, J = 5.8 Hz, 2H) , 3.86 (s, 3H) , 3.77 (s, 3H) , 3.68 (s, 3H) , 3.30 –3.26 (m, 1H) , 2.27 –2.20 (m, 1H) , 2.19 –2.11 (m, 2H) , 1.54 (t, J = 7.1 Hz, 2H) .
Step e: methyl trans-2- [5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -4-fluoro-6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate
Ethyl 4-chloro-4-oxobutanoate (0.055 mL, 385.9673 μmol) in DCM (2 mL) was added dropwise to a solution of methyl trans-2- [5- [3- (4-fluoro-6-methoxy-isoindolin-5-yl) oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (0.202 g, 356.8671 μmol, HCl salt) and N, N-Diisopropylethylamine (0.185 mL, 1.0621 mmol) in THF (4 mL) and ACN (4 mL) at 0℃. The reaction mixture was stirred for 2 h at 20℃. The reaction mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC with the developing solvent of DCM/MeOH (25: 1) . There was methyl trans-2- [5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -4-fluoro-6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (0.221 g, 336.0184 μmol, 94.1579%yield) obtained as an off-white semi-solid. LCMS: (ESI, m/z) : [M+H] + = 658.25. 1H NMR (400 MHz, CDCl3-d) δ 7.93 (s, 1H) , 7.19 (s, 2H) , 6.54 (s, 0.5H) , 6.49 (s, 0.5H) , 4.74 (d, J = 7.7 Hz, 2H) , 4.68 (d, J = 5.6 Hz, 2H) , 4.29 (s, 2H) , 4.21 (s, 2H) ,
4.09 (q, J = 7.1 Hz, 2H) , 3.88 (s, 3H) , 3.73 (s, 3H) , 3.68 (s, 3H) , 3.15 –3.02 (m, 1H) , 2.72 –2.54 (m, 4H) , 2.40 –2.31 (m, 1H) , 2.30 –2.18 (m, 2H) , 1.65 –1.51 (m, 2H) , 1.20 (t, J = 7.0 Hz, 3H) .
Step f: trans-2- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid
LiOH (0.027 g, 1.1274 mmol) was added to a solution of methyl trans-2- [5- [3- [2- (4-ethoxy-4-oxo-butanoyl) -4-fluoro-6-methoxy-isoindolin-5-yl] oxypropoxy] -6-methoxy-benzothiophene-2-carbonyl] cyclopropanecarboxylate (0.165 g, 250.8735 μmol) in THF (6 mL) and H2O (2 mL) at 20℃. The reaction mixture was stirred for 2 h at 20℃. The resulting reaction mixture was adjusted to pH= 2~3 with HCl (6 N) and evaporated under reduced pressure. The residue was purified by reverse C18 column chromatography, eluting with the mobilie phase ACN/H2O (0.1%FA) (0-100%) . The pure fractions was concentrated and lyophilized overnight. There was trans-2- (5- (3- ( (2- (3-carboxypropanoyl) -4-fluoro-6-methoxyisoindolin-5-yl) oxy) propoxy) -6-methoxybenzo [b] thiophene-2-carbonyl) cyclopropane-1-carboxylic acid (0.052 g, 84.4674 μmol, 33.6693%yield) obtained as a white solid. LCMS: (ESI, m/z) : [M+H] + = 616.20. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 2H) , 8.48 (s, 1H) , 7.61 (s, 1H) , 7.51 (d, J = 2.2 Hz, 1H) , 6.91 (s, 0.5H) , 6.88 (s, 0.5H) , 4.78 (d, J = 5.5 Hz, 2H) , 4.56 (s, 2H) , 4.23 (t, J = 5.0 Hz, 2H) , 4.17 (t, J = 5.9 Hz, 2H) , 3.86 (s, 3H) , 3.76 (s, 3H) , 3.27 –3.19 (m, 1H) , 2.60 –2.53 (m, 2H) , 2.49 –2.44 (m, 2H) , 2.21 –2.07 (m, 3H) , 1.49 (t, J = 7.1 Hz, 2H) .
The compounds of the following example shown in table 2 were synthesized using the above procedure with the corresponding starting materials.
Table 2
TESTING EXAMPLE II: Human STING WT binding assay
Cisbio Bioassays’ human STING WT binding assay (#64BDSTGPEG &64BDSTGPEH, Cisbio) is for quantitative measurement of human STING WT ligand usingtechnology.
1. Adding compounds
Negative control: Dispense 5 μL of diluent into each negative control well. Standard: Dispense 5 μL of each Human STING WT Standard 2’3’-cGAMP (Std 0 -Std 7) into each standard well. Compound: Dispense 5 μL of compound into each compound well.
2. Adding proteins
Negative control: Add 5 μL of detection buffer to all wells. Other wells: Add 5 μL of human STING WT protein 6His-tagged protein to all wells.
3. Adding antibodies
Add 10 μL of premixed STING WT ligand d2 reagent and 6His Tb antibody working solution to all wells.
4.RT incubation
Seal the plate and incubate 3 hours at RT or at Over Night if necessary.
5. Reading plate
Remove the plate sealer and read on ancompatible reader (PerkinElmer, USA) . Results were analyzed with a two-wavelength signal ratio: intensity (665 nm) /intensity (620 nm) .
6. Curve fitting
Calculate HTRF Ratio:
Fit the data in GraphPad to obtain IC50 values using equation (2)
Equation (2) : Y=Bottom + (Top-Bottom) / (1+10^ ( (LogIC50-X) *Hill Slope) )
Y is HTRF Ratio and X is compound concentration.
IC50 value of binding assay for human STING WT:
The vaccine adjuvants or compositons of the present invention are preferably formulated as pharmaceutical compositions administered by a variety of routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and processes for preparing the same are well known in the art. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro, et al, eds., 19th ed., Mack Publishing Co., 1995) . The compounds of Formula (Y-1) , (Y-2) , (Y-3) , (A) , (B) , (C) , I, II, III, IV or V are generally effective over a wide dosage range.
For example, dosages per day normally fall within the range of about 0.2 mg to about 100 mg total daily dose, preferably 0.2 mg to 50 mg total daily dose, more preferably 0.2 mg to 20 mg total daily dose. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed. The above dosage range is not intended to limit the scope of the invention in any way. It will be understood that the amount of the vaccine adjuvant or vaccine composition actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual adjuvants or compositions administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.
Claims (35)
- A vaccine adjuvant, comprising a sting agonist.
- The vaccine adjuvant of claim 1, wherein the sting agonist is a compound of Formula (A) , (B) , (C) , or an ester, stereoisomer, tautomer, isotopic derivative, prodrug, or pharmaceutically acceptable salt thereof:
whereineach W is independently selected from CR1 or N;each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2;R2 and R3 are independently selected from the group consisting of O- (C1-C4 alkylene or haloalkylene) , C1-C5 alkylene or haloalkylene, N (R6) - (C1-C4 alkylene or haloalkylene) , -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;PEGn is (-OCH2CH2-) n, n = 1-8;Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; andeach Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen;each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) ;each R6 is independently selected from the group consisting of -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-10heterocyclic ring or C3- 10carbocyclic ring; and each of which is independently optionally substituted with deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, or C1-6alkyl; and each of the heteroaryl and heterocyclic ring contains at least one heteroatoms selected from N, O or S;each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-;each X2 is independently selected from (C (R8) 2) (1-3) , -NH (C (R8) 2) (1-3) , –N (C1-6alkyl) (C (R8) 2) (1-3) or –N (haloC1-6alkyl) (C (R8) 2) (1-3) ; wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle;each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN; and each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2) 1-3-C (=O) OR6, OR6, SR6, NH2, NH (C1-C6 alkyl) , N (C1-C6 alkyl) 2, O (C1-C6 alkyl) , O (C6-C10 aryl) , O (C1-C6 alkyl) -OR6, S (C1-C6alkyl) , S (C6-C10 aryl) , S (=O) 2R6, S (=O) 2OR6, P (=O) (R6) 2, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl. - The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is a compound of Formula I, II, III, IV, or V, or an ester, stereoisomer, tautomer, isotopic derivative, prodrug, or pharmaceutically acceptable salt thereof:
whereineach W is independently selected from CR1 or N;each R1 is independently selected from H, deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2, CN or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with one or more deuterium, halogen, OR6, N (R6) 2, COOR6, or C (O) N (R6) 2;R2 and R3 are independently selected from O- (C1-C4 alkylene or haloalkylene) , C1-C5 alkylene or haloalkylene, N (R6) - (C1-C4 alkylene or haloalkylene) , -Ta-C1-C6 alkyl-Tb-, -Ta-N (Rs) -Tb, -Ta-O-Tb, -Ta-PEGn-O-Tb, -Ta-S-S-Tb, -Ta-S-S-S-Tb, -Ta-N (Rs) -N (Rs) -Tb-, -Ta-C2-C6alkenyl-Tb-, -Ta-C2-C6alkynyl-Tb-, -Ta-C (=O) -Tb-, -Ta-C (=CH2) -Tb-, -Ta-C (=O) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (C3-C12cycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (C3-C12cycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=O) - (3-to 12-membered heterocycloalkyl) -C (=O) -Tb-, -Ta-C (=O) - (C1-C6alkyl) - (3-to 12-membered heterocycloalkyl) - (C1-C6alkyl) -C (=O) -Tb-, -Ta-C (=S) -Tb-, -Ta-S (=O) 2-Tb-, -Ta-S (=O) -Tb-, -Ta-P (=O) (-ORs) -Tb-, -Ta- (C3-C12cycloalkyl) -Tb-, -Ta- (C6-C12 aryl) -Tb-, -Ta- (3-to 12-membered heterocycloalkyl) -Tb-, or -Ta- (5-to 12-membered heteroaryl) -Tb-, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 3-to 12-membered heterocycloalkyl, or 5-to 12-membered heteroaryl is optionally substituted with one or more deuterium, halo, -ORs, -N (Rs) 2, or -C (=O) ORs;PEGn is (-OCH2CH2-) n, n = 1-8;Ta and Tb each independently are absent, -N (Rs) -, -O-, C1-C6 alkyl, -N (Rs) - (C1-C6alkyl) -, - (C1-C6 alkyl) -N (Rs) -, -N (RS) - (C1-C6alkyl) -N (Rs) -, -O- (C1-C6 alkyl) -, - (C1-C6alkyl) -O-, or -O- (C1-C6 alkyl) -O-; wherein the C1-C6 alkyl is optionally substituted with one or more halogen; andeach Rs independently is H, deuterium or C1-C6 alkyl optionally substituted with one or more halogen;each R4 is independently selected from the group consisting of H, deuterium, halogen, CN, OR6, N (R6) 2, COOR6, C (O) N (R6) 2, SO2R6, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl substituted by OR6, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkenyl substituted by OR6, C2-C6 alkynyl, C2-C6 haloalkynyl, C2-C6 alkynyl substituted by OR6, C3-C6 cycloalkyl, and a 3-to 6-membered heterocyclic ring including 1 to 2 ring members selected from the group consisting of O, S, and N (R6) ;each R6 is independently selected from the group consisting of -H, deuterium, halogen, -NH2, -CN, -OH, -N3, -NO2, carboxyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, C2-6alkynyl, -C6-10aryl, -C5-10heteroaryl, C3-10heterocyclic ring or C3- 10carbocyclic ring; and each of which is independently optionally substituted with deuterium, halogen, -NH2, -CN, -OH, -NO2, carbonyl, =O, oxo, carboxyl, C1-6alkoxy, or C1-6alkyl; and each of the heteroaryl and heterocyclic ring contains at least one heteroatoms selected from N, O or S;each X1 is independently selected from the group consisting of C=O, -CH2-, -CHF-, and -CF2-;each X2 is independently selected from (C (R8) 2) (1-3) , -NH (C (R8) 2) (1-3) , –N (C1-6alkyl) (C (R8) 2) (1-3) or –N (haloC1-6alkyl) (C (R8) 2) (1-3) ; wherein each R8 is independently selected from the group consisting of H, deuterium, halogen, C1-C6 alkyl, CN, OR6, N (R6) 2, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl substituted by OR6, and C1-C6 alkyl substituted by N (R6) 2; optionally 2 R8 on different carbon atoms may be taken together, along with the atoms to which they are attached, to form a 3-to 6-membered fused ring; and optionally 2 R8 on a single carbon atom may be taken together, along with the atom to which they are attached, to form a 3-to 6-membered spirocycle;each X3 is independently selected from the group consisting of COOR6, C (O) SR6, C (S) OR6, SO2R6, C (O) N (R9) 2, and CN; and each R9 is independently selected from H, deuterium, COOR6, SO2R6, (CH2) 1- 3-C (=O) OR6, OR6, SR6, NH2, NH (C1-C6 alkyl) , N (C1-C6 alkyl) 2, O (C1-C6 alkyl) , O (C6-C10 aryl) , O (C1-C6 alkyl) -OR6, S (C1- C6alkyl) , S (C6-C10 aryl) , S (=O) 2R6, S (=O) 2OR6, P (=O) (R6) 2, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10aryl, 3-8 membered heterocycloalkyl, or 3-10 membered heteroaryl. - The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula (A) , is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 2.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula (B) , is independently selected from the group consisting of is independently selected from the group consisting ofeach R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 2.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula (C) , is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 2.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula I, is independently selected from the group consisting of is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 3.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of of Formula II, is independently selected from the group consisting of is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 3.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula III, is independently selected from the group consisting of is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 3.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula IV, is independently selected from the group consisting of is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 3.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist is of Formula V, is independently selected from the group consisting of is independently selected from the group consisting of each R1, R2, R3, R4, X1, X2 and X3 are as defined in claim 3.
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist independently is:
- The vaccine adjuvant of any one of the preceding claims, wherein the sting agonist independently is any one of the following compounds:
- The vaccine adjuvant of any one of the preceding claims, wherein the vaccine adjuvant further includes a solvent.
- A vaccine adjuvant composition comprising a sting agonist of any one of the preceding claims and at least one pharmaceutically acceptable excipient.
- The vaccine adjuvant composition of claim 15, wherein the sting agonist is in a weight ratio to the said excipient within the range from about 0.0001 to about 10.
- A vaccine composition comprising the vaccine adjuvant of any one of the preceding claims and a vaccine.
- The vaccine composition of claim 17, wherein the vaccine comprises at least one antigen, and the antigen is selected from the group consisting of viral antigen, protozoal antigen, bacterial antigen, fungal antigen, cancer antigen and allergen.
- The vaccine composition of claim 17, wherein the vaccine is selected from the group consisting of Live attenuated vaccines, inactivated vaccines, antitoxins, subunit vaccines, vector vaccines, and nucleic acid vaccines.
- Use of a sting agonist as a vaccine adjuvant, preferably the sting agonist is defined as any one of claims 1-13.
- Use of a sting agonist in manufacture of a vaccine adjuvant, a vaccine adjuvant composition and/or a vaccine composition, preferably the sting agonist is defined as any one of claims 1-13.
- A method of enhancing or prolonging an immune response in a subject in need thereof, comprising:administering to the subject a therapeutically effective amount of the vaccine adjuvant of any one of claims 1-14, the vaccine adjuvant composition of claim 15 or 16, or the vaccine composition of any one of claims 17-19.
- The method of claim 22, wherein the immune response is T lymphocyte-independent antibody immune response or T lymphocyte-dependent antibody immune response.
- The method of claim 22, wherein the vaccine composition is capable of inducing STING-dependent type I interferon production in a subject.
- The method of claim 22, wherein the vaccine composition is capable of inducing a STING-dependent cytokine production in a subject.
- A method of preventing or treating a disease, comprising administering to a subject in need thereof a therapeutically effective amount of the vaccine composition of any one of claims 17-19, wherein the disease is an infectious disease, a cell proliferation disorder such as tumor or cancer, or an immune disorder.
- The method according to claim 26, the infectious disease is bacterial, viral, or fungal infection.
- The method according to claim 26, the cell proliferation disorder is a tumor or cancer.
- The method according to claim 26, the immune disorder such as autoimmune disease or immunodeficiency disease.
- The method according to any one of claims 26-29, the vaccine composition is administrated intravenously, intramuscularly or orally.
- The vaccine adjuvant of any one of claims 1-14, the vaccine adjuvant composition of claim 15 or 16, and/or the vaccine composition of any one of claims 17-19, for use in preventing or treating diseases.
- A method of inducing STING-dependent type I interferon production in a subject, said method comprising administering a therapeutically effective amount of vaccine adjuvant of any one of claims 1-14, the vaccine adjuvant composition of claim 15 or 16, and/or the vaccine composition of any one of claims 17-19 to the subject.
- A method of inducing a STING-dependent cytokine production in a subject, said method comprising administering a therapeutically effective amount of vaccine adjuvant of any one of the preceding claims, and/or the vaccine composition of any one of claims 17-19 to the subject.
- A kit, comprising the vaccine adjuvant of any one of claims 1-14, the vaccine adjuvant composition of claim 15 or 16, and/or the vaccine composition of any one of claims 17-19.
- A kit, comprising:(1) the vaccine adjuvant of any one of claims 1-14, the vaccine adjuvant composition of claim 15 or 16, and/or the vaccine composition of any one of claims 17-19; and(2) a vaccine.
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