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CN117800969B - Tumor necrosis factor receptor complex inhibitors and uses thereof - Google Patents

Tumor necrosis factor receptor complex inhibitors and uses thereof Download PDF

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CN117800969B
CN117800969B CN202311212360.3A CN202311212360A CN117800969B CN 117800969 B CN117800969 B CN 117800969B CN 202311212360 A CN202311212360 A CN 202311212360A CN 117800969 B CN117800969 B CN 117800969B
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CN117800969A (en
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舒红兵
付玉志
杨清
李姝�
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Wuhan Houxian Biopharmaceutical Co ltd
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Wuhan Houxian Biopharmaceutical Co ltd
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Abstract

The invention discloses a compound which is a compound shown in a formula (I) or a stereoisomer, a tautomer, a solvate and a pharmaceutically acceptable salt of the compound shown in the formula (I). Compared with other inhibitors targeting other proteins at the downstream of the TNF receptor complex, the compound can avoid apoptosis induced by TNF alpha, can effectively inhibit inflammatory reaction and apoptosis induced by TNF alpha, and has the advantages of low cytotoxicity and the like. The compound can be used for preventing or treating diseases related to TNF signal paths (such as rheumatoid arthritis, autoimmune diseases and other inflammations), and has great market prospect.

Description

Tumor necrosis factor receptor complex inhibitors and uses thereof
Technical Field
The invention belongs to the technical field of biological pharmacy, in particular to a Tumor Necrosis Factor (TNF) receptor compound inhibitor and application thereof, and more particularly relates to a compound for inhibiting a TNF receptor compound, a TNF receptor compound inhibitor pharmaceutical composition and application thereof.
Background
Immune response is a protective mechanism against host defense against dangerous signals such as pathogenic infection, tissue damage and cellular variation. A modest immune response is able to eliminate pathogenic microorganisms or eliminate tumor cells. However, excessive or uncontrolled immune responses may trigger severe acute and chronic inflammation leading to death or autoimmune disease.
Inflammatory and autoimmune diseases such as rheumatoid arthritis, psoriasis, ankylosing spondylitis are serious diseases threatening human health. However, at present, no radical treatment medicine is available for the autoimmune diseases.
Tumor necrosis factor alpha (Tumor necrosis factor alpha, tnfalpha) is one of the members of the tumor necrosis factor family. It is an important pro-inflammatory factor, capable of inducing apoptosis of specific tumor cells. Tnfα can be secreted by a number of cells including adipocytes, activated monocytes, macrophages, B cells, T cells, and fibroblasts. Tnfα is cytotoxic to most tumor cells or normal cells. Tnfα plays a very important role in the induction of infectious shock, autoimmune diseases (e.g., rheumatoid arthritis), and diabetes. In addition, tnfα is also a key factor in inducing an inflammatory response against invasion by pathogenic microorganisms.
Tnfα binds to two classes of TNF receptors (TNFR), TNFR1 and TNFR2. TNFR1 plays a more important role in TNFα -induced signaling. After tnfα binds to TNFR1, TNFR1 forms a dimer or trimer, recruiting TRADD through its death domain, inducing the formation of two different classes of complexes (type I and type II), promoting NF- κb activation and apoptosis, respectively. Blocking the effect of TNFα or related inflammatory factors, and can be used for treating or delaying the progress of autoimmune diseases such as rheumatoid arthritis caused by TNFα.
Therefore, it is of great commercial interest to develop an inhibitor of TNF signaling pathway for the prevention or treatment of autoimmune diseases.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art to at least some extent. To this end, the present invention provides a compound that inhibits the TNF receptor complex, which can prevent or treat autoimmune diseases.
The present invention has been completed based on the following findings by the inventors:
The main process of TNFα -induced inflammatory response signaling is that after TNFα binds to the receptor, the receptor recruits TRADD, which in turn recruits TRAF2, TRAF5, cIAP1, cIAP2 and RIP1 to form a type I complex. RIP1 undergoes K63-linked polyubiquitination modification. The related chaperones TAB2 and TAB3 of TAK1 bind to the K63-linked polyubiquitin chain of RIP1, respectively, resulting in autophosphorylation and activation of TAK 1. TAK1 in turn phosphorylates ikkβ. Ikkβ phosphorylates iκbα, promoting degradation of iκbα by the proteasome pathway, leading to release and nucleation of NF- κb, ultimately inducing expression of inflammatory factors (see specifically fig. 10).
After the formation of type I complexes and activation of TAK1, IKK and NF-. Kappa.B, TRADD, RIP1 and TRAF2 dissociate from the receptor and form type II complexes with precursors of FADD and Caspase-8 in the cytoplasm. In the type II complex, a precursor of Caspase-8 is processed to mature Caspase-8, which in turn cleaves and activates Caspase-3, thereby inducing apoptosis. However, in most cells, tnfα does not induce apoptosis. This is because type I complex-mediated activation of NF-. Kappa.B induces synthesis of anti-apoptotic proteins, including cIAP and c-FLIP. c-FLIP binds to and blocks activation of Caspase-8 precursors (see FIG. 10 in particular). Furthermore, inhibition of polyubiquitination of RIP1 can promote degradation of cIAP. Meanwhile, the deubiquitination of RIP1 can also induce the activation of Caspase-8 and the generation of apoptosis.
In summary, inhibitors targeting the TNF receptor complex are effective in inhibiting tnfα -induced inflammatory responses and apoptosis, while inhibitors targeting other proteins downstream of the TNF receptor complex are effective in inhibiting tnfα -induced inflammatory responses while promoting tnfα -induced apoptosis, resulting in cytotoxicity. Thus, there is a need to develop an inhibitor against the tnfα signaling pathway, in particular an inhibitor targeting the TNF receptor complex.
However, most of the top twenty drugs currently marketed worldwide are directed to infections and immune diseases and tumors. The FDA in the united states approved drugs for the treatment of autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and the like are antibody drugs targeting TNF family members or upstream and downstream inflammatory factors and receptors. The antibody drug for resisting the tumor necrosis factor of rheumatoid arthritis is sold in about 200 hundred million dollars in the year of the Usmetic music, and the adalimumab is sold in more than 160 hundred million dollars in the year of the adalimumab 2016. At present, more than 20 enterprises in China are researching and developing TNFα inhibitors, which are all fusion proteins and monoclonal antibodies, for example, fully human anti-human TNFα monoclonal antibody injection (acceptance number: CXSL 1400074) applied by the institute of Wuhan biological products in Hubei province in 2015. The recombinant anti-TNFα fully human monoclonal antibody of the compound star medicine with faster progress has the tail sound in the three-stage clinic, and is expected to be obtained first. These antibodies are expensive, have limited efficacy and have certain side effects. The price is low, and small molecular medicines with similar action mechanism and better curative effect as those of the Ximei have not been developed successfully. The development of small molecule inhibitors against TNF is actively underway by large pharmaceutical companies worldwide. Thus, there is a need to develop a small molecule inhibitor against TNF signaling pathways, particularly against TNF receptor complexes.
In a first aspect of the present invention, the present invention provides a compound which is a compound of formula (I) or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt of a compound of formula (I):
wherein X 1 and X 2 are each independently selected from C or N;
Ring a is empty, 3-10 membered cycloalkylene optionally substituted with one or more R 1a, 3-10 membered heterocycloalkylene optionally substituted with one or more R 1a, 3-10 membered arylene optionally substituted with one or more R 1a, or 3-10 membered heteroarylene optionally substituted with one or more R 1a, wherein each R 1a is independently halogen, =o, -NH 2、-OH、-SH、-NO2, -CN, phenyl, -C 1～6 alkyl, -C 1～6 oxyalkyl, or-C 1～6 haloalkyl;
r 1 is null, H, -C 1～6 alkyl optionally substituted with one or more R 1b, -C 1～6 oxyalkyl optionally substituted with one or more R 1b, -C 1～6 alkenyl optionally substituted with one or more R 1b, or-C 1～6 oxyalkenyl optionally substituted with one or more R 1b, wherein each R 1b is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, -C 1～6 alkyl, or-C 1～6 oxyalkyl, said phenyl, -C 1～6 alkyl, or-C 1～6 oxyalkyl is independently substituted with one or more halogen, each R 1c is independently halogen, -C 1～6 alkyl, or-C 1～6 oxyalkyl;
R 2 is H, halogen, -N (R c)2, -C 1～6 alkyl optionally substituted by one or more R 1d), -C 1～6 oxyalkyl optionally substituted with one or more R 1d, -C 1～6 alkenyl optionally substituted with one or more R 1d, -C 1～6 oxy optionally substituted with one or more R 1d, -3-10 membered cycloalkyl optionally substituted with one or more R 1d, -3-10 membered heterocycloalkyl optionally substituted with one or more R 1d, 3-10 membered aryl optionally substituted with one or more R 1d, or 3-10 membered heteroaryl optionally substituted with one or more R 1d, wherein each R c is independently H, -C 1～6 alkyl or-C 1～6 oxyalkyl, each R 1d is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, -C 1～6 alkyl or-C 1～6 oxyalkyl;
R 3 is null, H, halogen, -C 1～6 alkyl optionally substituted by one or more R 1e, -C 1～6 oxyalkyl optionally substituted by one or more R 1e, -C 1～6 alkenyl optionally substituted with one or more R 1e, -C 1～6 oxyalkenyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered cycloalkyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1e, or-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1e, wherein each R 1e is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, -C 1～6 alkyl or-C 1～6 oxyalkyl;
R 4 is halogen, H, =O, -C 1～6 alkyl optionally substituted by one or more R 1f, -C 1～6 oxyalkyl optionally substituted by one or more R 1f, -C 1～6 alkenyl optionally substituted with one or more R 1f, -C 1～6 oxyalkenyl optionally substituted with one or more R 1f, -3-10 membered cycloalkyl optionally substituted with one or more R 1f, -3-10 membered heterocycloalkyl optionally substituted with one or more R 1f, -3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1f, -3-10 membered heterocycloalkyl optionally substituted by one or more R 1f, -3-10 membered aryl optionally substituted by one or more R 1f, or-3-10 membered heteroaryl optionally substituted by one or more R 1f, -C 0～6 alkylene-NH-C 1～10 alkyl optionally substituted by one or more R 1f, -C 0～6 alkylene-NH-C 1～10 alkylene-3-10 membered cycloalkyl optionally substituted with one or more R 1f, -C 0～6 alkylene-NH-C 1～10 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1f, -C 0～6 alkylene-NH-C 1～10 alkylene-3-10 membered aryl optionally substituted with one or more R 1f, -C 0～6 alkylene-NH-C 1～10 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1f, wherein each R 1f is independently of the others halogen, =o, -NH 2、-OH、-SH、-NO2, -CN, phenyl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl, said phenyl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl, or-C 2～6 oxyalkenyl optionally substituted with one or more-OH;
R 5 is null, -C (O) -, C 1～6 alkylene optionally substituted with one or more R 1g, -C 1～6 alkylene optionally substituted with one or more R 1g, -C 1～6 alkylene, -C 0～6 alkylene-NR d -, optionally substituted with one or more R 1g, -C 0～6 alkylene-NR d-C1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d -, optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d-C1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-S (O) 2-NRd -, optionally substituted with one or more R 1g, -C 0～6 alkylene-S (O) 2-NRd-C1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-S-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-S-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 1～6 alkylene-C (=ch) -3-10 membered heterocycloalkylene-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-3-15 membered cycloalkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-3-15 membered heterocycloalkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -3-10 membered cycloalkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -3-10 membered heterocycloalkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-3-10 membered cycloalkylene-C 1～6 alkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-3-10 membered cycloalkylene-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d-C1～6 alkylene-3-10 membered cycloalkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d-C1～6 alkylene-3-10 membered heterocycloalkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-S (O) 2-NRd-C1～6 alkylene-3-10 membered cycloalkylene optionally substituted with one or more R 1g, or-C 0～6 alkylene-S (O) 2-NRd-C1～6 alkylene-3-10 membered heterocycloalkyl-, optionally substituted with one or more R 1g, wherein each R d is independently H, -C 1～6 alkyl or-C 1～6 oxyalkyl, each R 1g being independently of the others halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl, said phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl optionally substituted with one or more-OH;
R 6 is null, H, C 1～6 alkyl optionally substituted with one or more R 1h, C 1～6 oxyalkyl optionally substituted with one or more R 1h, -N optionally substituted with one or more R 1h (R a)2, -C 0～6 alkylene-3-15 membered cycloalkyl optionally substituted with one or more R 1h), -C 0～6 alkylene-3-15 membered heterocycloalkyl optionally substituted by one or more R 1h, -C 0～6 alkylene-3-10 membered aryl optionally substituted by one or more R 1h, -C 0～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1h, -C 0～6 alkylene-3-10 membered cycloalkylene-C 0～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1h, -C 0～6 alkylene-3-10 membered heterocycloalkylene-C 0～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1h, -C 0～6 alkylene-3-10 membered cycloalkylene-C 0～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1h, -C 0～6 alkylene-3-10 membered heterocycloalkylene-C 0～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1h, -C (O) -3-10 membered cycloalkyl optionally substituted with one or more R 1h, -C (O) -3-10 membered heterocycloalkyl optionally substituted by one or more R 1h, -C (O) -3-10 membered aryl optionally substituted by one or more R 1h, -C (O) -3-10 membered heteroaryl optionally substituted by one or more R 1h, -C 0～6 Alkylene-N (R a)2、R1h substituted-C 0～6 Alkylene-N optionally substituted with one or more R 1h (R a)2), or-C (O) -N (R a)2) optionally substituted with one or more R 1h, wherein each R a is independently selected from H, C 1～6 alkyl optionally substituted with one or more R 1h, -C 1～6 oxyalkyl optionally substituted with one or more R 1h, -C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1h or-C (O) -N optionally substituted with one or more R 1h (R b)2, each R b is independently selected from-C 1～6 alkylene-3-10 membered cycloalkyl optionally substituted with one or more R 1h, -C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted by one or more R 1h, -C 1～6 alkylene-3-10 membered aryl optionally substituted by one or more R 1h, -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1h, -C (O) -3-10 membered cycloalkyl optionally substituted with one or more R 1h, -C (O) -3-10 membered heterocycloalkyl optionally substituted with one or more R 1h, -C (O) -3-10 membered aryl optionally substituted with one or more R 1h, or-C (O) -3-10 membered heteroaryl optionally substituted with one or more R 1h, each R 1h is independently halogen, =o, -NH 2、-OH、-SH、-NO2, -CN, phenyl, 3-to 10-membered cycloalkyl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl, said phenyl, 3-10 membered cycloalkyl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl optionally substituted with one or more halogens, -OH and/or-NH 2 substitutions;
n is 1 or 2.
The compound provided by the embodiment of the invention can effectively inhibit inflammatory reaction and apoptosis induced by TNF alpha by targeting the TNFR1-TRADD-RIP1-TRAF2 complex, so that the compound can be used for preventing or treating diseases related to the TNF signal path (such as autoimmune diseases such as rheumatoid arthritis and the like) and has a huge market prospect.
In addition, inhibitors targeting other proteins downstream of the TNF receptor complex, while effective in inhibiting tnfα -induced inflammatory responses, promote tnfα -induced apoptosis, resulting in cytotoxicity. However, the compound can avoid apoptosis induced by TNFR1-TRADD-RIP1-TRAF2 complex, and has the advantages of low cytotoxicity and the like.
According to an embodiment of the present invention, the above compound may further include at least one of the following technical features, that is, when the ring A is not empty, the compound of formula (I) has a structure of formula (II):
wherein, X 1 and X 2 are simultaneously C, or X 1 and X 2 are simultaneously N;
X 3 is C, N, S or O;
x 4 is C or N;
X 5 is C or N;
m is 0 or 1;
R 7 is null, H, C 1～6 alkyl optionally substituted with one or more R 1i, C 1～6 oxyalkyl optionally substituted with one or more R 1i, -3-10 membered aryl optionally substituted with one or more R 1i, -3-10 membered heteroaryl optionally substituted with one or more R 1i, -C 1～6 alkylene-C (O) -NR d-C1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1i, -C 1～6 alkylene-C (O) -NR d-C1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1i, or-C 1～6 alkylene-C (O) -NR d-C1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1i, wherein each R 1i is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl, said phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl optionally substituted with one or more-OH;
R 8 is null, H, -C 1～6 alkyl optionally substituted with one or more R 1j, -C 1～6 oxyalkyl optionally substituted with one or more R 1j, -3-10 membered aryl optionally substituted with one or more R 1j, or-3-10 membered heteroaryl optionally substituted with one or more R 1j, wherein each R 1j is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl, or-C 2～6 oxyalkenyl, said phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl, or-C 2～6 oxyalkenyl being optionally substituted with one or more-OH groups;
r 9 is H, =O, -C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1k, or-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1k, wherein each R 1k is independently halogen, -NH 2、-OH、-SH、-NO2, -CN, phenyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, 3-10 membered aryl, 3-10 membered heteroaryl, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 2～6 alkenyl, or-C 2～6 oxyalkenyl.
According to embodiments of the invention, R 1 is null, H, C 1～6 alkyl optionally substituted with one or more R 1b, or C 1～6 oxyalkyl optionally substituted with one or more R 1b.
According to an embodiment of the invention, each R 1b is independently halogen, -NH 2, -OH, or phenyl.
According to an embodiment of the invention, R 1 is null, H, -C 1～6 alkyl, or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 1 is null, H, -C 1～3 alkyl, or-C 1～3 oxyalkyl.
According to embodiments of the invention, R 2 is H, halogen, -N (R c)2, -C 1～6 alkyl optionally substituted with one or more R 1d, or-C 1～6 oxyalkyl optionally substituted with one or more R 1d).
According to an embodiment of the invention, R c is H.
According to an embodiment of the invention, each R 1d is independently halogen, -NH 2, -OH, or phenyl.
According to an embodiment of the invention, R 2 is H, halogen, -NH 2、-C1～6 alkyl, or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 2 is H, halogen, -NH 2、-C1～3 alkyl, or-C 1～3 oxyalkyl.
According to embodiments of the invention, R 3 is null, H, halogen, C 1～6 alkyl optionally substituted with one or more R 1e, -C 1～6 oxyalkyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered cycloalkyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1e, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1e, or-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1e.
According to embodiments of the invention, R 3 is null, H, halogen, C 1～6 alkyl optionally substituted with one or more R 1e, C 1～6 oxyalkyl optionally substituted with one or more R 1e, or C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1e.
According to an embodiment of the invention, each R 1e is independently halogen, -NH 2、-OH、-C1～6 alkyl or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 3 is null, H, halogen, -C 1～6 alkyl, -C 1～6 oxyalkyl, -C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more-C 1～6 alkyl.
According to an embodiment of the invention, R 3 is null, H, halogen, -C 1～3 alkyl, -C 1～3 oxyalkyl, -C 1～3 alkylene-C (O) -NH-C 2～4 alkylene-5-7 membered heterocycloalkyl optionally substituted with one or more-C 1～3 alkyl.
According to an embodiment of the invention, R 4 is H, =o, -C 1～6 alkyl optionally substituted with one or more R 1f, -C 1～6 oxyalkyl optionally substituted with one or more R 1f, -3-10 membered heterocycloalkyl optionally substituted with one or more R 1f, or-3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1f.
According to an embodiment of the invention, each R 1f is independently halogen, =o, -C 1～3 alkylene-OH, -C 1～3 alkyl, or-C 2～4 alkenyl.
According to an embodiment of the invention, R 4 is H, =o, -C 1～6 alkyl, -3-10 membered heterocycloalkyl, or-3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl, said-3-10 membered heterocycloalkyl being optionally substituted with =o and/or-C 1～3 alkyl, and 3-10 membered heterocycloalkyl of said-3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl being optionally substituted with-C 1～3 alkylene-OH and/or-C 2～4 alkenyl.
According to an embodiment of the invention, R 4 is H, =o, -C 1～6 alkyl, -5-7 membered heterocycloalkyl, or-5-7 membered heterocycloalkylene-5-7 membered heterocycloalkyl, said-5-7 membered heterocycloalkyl being optionally substituted with =o and/or-C 1～3 alkyl, and 5-7 membered heterocycloalkyl of said-5-7 membered heterocycloalkylene-3-10 membered heterocycloalkyl being optionally substituted with-C 1～3 alkylene-OH and/or-C 2～4 alkenyl.
According to embodiments of the invention, R 5 is null, -C (O) -, C 1～6 alkylene optionally substituted with one or more R 1g, -C 1～6 alkylene optionally substituted with one or more R 1g, -S-C 1～6 alkylene optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d -, optionally substituted with one or more R 1g, -C 0～6 alkylene-C (O) -NR d-C1～6 alkylene-, optionally substituted with one or more R 1g, -C 0～6 alkylene-3-15 membered heterocycloalkyl-, or-C 0～6 alkylene-C (O) -3-15 membered heterocycloalkyl-, optionally substituted with one or more R 1g.
According to an embodiment of the invention, each R d is independently H, -C 1～3 alkyl or-C 1～3 oxyalkyl.
According to an embodiment of the invention, each R d is independently H or-C 1～3 alkyl.
According to an embodiment of the invention, each R 1g is independently halogen, -OH, 3-10 membered cycloalkyl, 3-6 membered cycloalkyl, -C 1～6 alkyl, or-C 1～6 alkyl-OH.
According to embodiments of the invention, R 6 is null, H, C 1～6 oxyalkyl optionally substituted with one or more R 1h, -3-10 membered aryl optionally substituted with one or more R 1h, -C 1～6 oxyalkyl-3-10 membered heteroaryl optionally substituted with one or more R 1h, -3-10 membered cycloalkyl optionally substituted with one or more R 1h, -C 1～6 oxyalkyl-3-10 membered heterocycloalkyl optionally substituted with one or more R 1h, -C (O) -3-10 membered heteroaryl optionally substituted with one or more R 1h, -C 1～6 oxyalkyl-3-15 membered heterocycloalkyl optionally substituted with one or more R 1h, or-C 1～6 oxyalkyl-N (R e)2) optionally substituted with one or more R 1h.
According to an embodiment of the invention, each R e is independently H or-C 1～3 alkyl.
According to an embodiment of the invention, each R 1h is independently halogen, =o, -OH, -C 1～6 alkyl, -C 1～6 alkyl-OH, or-C 1～6 oxyalkyl.
According to an embodiment of the invention, -R 5-R6 is null, H, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C 1～6 oxyalkyl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-15 membered heterocycloalkyl optionally substituted by one or more R 1l, -S-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted by one or more R 1l, -S-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C (O) -3-10 membered aryl optionally substituted with one or more R 1l, -C (O) -3-10 membered heteroaryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, -C (O) -N (C 1～3 alkyl) -C (-C 1～3 alkylene-N (C 1～3 alkyl) 2) (3-10 membered aryl) optionally substituted with one or more R 1l, -C (O) -N (C 1～3 alkyl) -C 1～3 alkylene-N (C 1～3 alkyl) 2 optionally substituted with one or more R 1l, -C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C 1～6 oxyalkyl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -N (-C 1～6 alkyl) -C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -N (-C 1～6 alkyl) -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, -C (O) -3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, -C (O) -3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, -C (O) -3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -N (-C 1～6 alkyl) -C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1l, or-C (O) -3-10 membered heterocycloalkylene-C 1～6 alkylene-C (O) -N (-C 1～6 alkyl) -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1l, wherein each R 1l is independently halogen, or, =o, -OH, phenyl, -C 1～3 alkyl, -C 1～3 alkylene-OH, -C 1～3 oxyalkyl, or 3-5 membered cycloalkyl.
According to an embodiment of the invention, -R 5-R6 is null, H, -C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-C 1～6 oxyalkyl, -C 1～6 alkylene-3-15 membered heterocycloalkyl optionally substituted with one or more-C 1～3 alkyl groups and/or =o, -S-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more halogen, -S-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more halogen, -C (O) -3-10 membered aryl optionally substituted with one or more halo, -C (O) -3-10 membered heteroaryl optionally substituted with one or more halo, -C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more-C 1～3 alkyl, -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more-C 1～3 alkyl, -C (O) -N (C 1～3 alkyl) -C (-C 1～3 alkylene-N (C 1～3 alkyl) 2) (3-10 membered aryl) optionally substituted with one or more phenyl groups, -C (O) -N (C 1～3 alkyl) -C 1～3 alkylene-N (C 1～3 alkyl) 2 optionally substituted with one or more phenyl groups, -C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more 3-5 membered cycloalkyl and/or-C 1～3 alkyl, -C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more-OH and/or-C 1～3 alkylene-OH, -C 1～6 alkylene-3-10 membered aryl optionally substituted by one or more-C 1～3 alkyl, -C 1～3 oxyalkyl and/or-C 1～3 alkylene-OH, -C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more-C 1～3 alkyl, -C 1～3 oxyalkyl and/or-C 1～3 alkylene-OH.
According to an embodiment of the invention, -R 5-R6 is null, H,
According to embodiments of the invention, R 7 is null, H, C 1～6 alkyl optionally substituted with one or more R 1i, C 1～6 oxyalkyl optionally substituted with one or more R 1i, C3-10 membered aryl optionally substituted with one or more R 1i, or C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1i.
According to an embodiment of the invention, each R 1i is independently halogen, -NH 2, -OH, or phenyl.
According to embodiments of the invention, R 7 is null, H, -C 1～6 alkyl, a-3-10 membered aryl optionally substituted with one or more halogens, or-C 1～6 alkylene-C (O) -NH-C 1～6 alkylene-3-10 membered heteroaryl.
According to embodiments of the invention, R 7 is null, H, -C 1～3 alkyl, a-5-to 7-membered aryl optionally substituted with one or more halogens, or-C 2～4 alkylene-C (O) -NH-C 2～4 alkylene-5-to 7-membered heteroaryl.
According to an embodiment of the invention, R 7 is null, H, -C 1～3 alkyl, -5-7 membered aryl optionally substituted with one or more halogens, or-C 2～4 alkylene-C (O) -NH-C 2～4 alkylene-5-7 membered heteroaryl, wherein the 5-7 membered heteroaryl in-C 2～4 alkylene-C (O) -NH-C 2～4 alkylene-5-7 membered heteroaryl contains N and/or O.
According to embodiments of the invention, R 7 is null, H, -C 1～3 alkyl, -5-7 membered aryl optionally substituted with one or more halogens, or-C 2～4 alkylene-C (O) -NH-C 2～4 alkylene-5-7 membered heteroaryl, wherein the 5-7 membered heteroaryl in-C 2～4 alkylene-C (O) -NH-C 2～4 alkylene-5-7 membered heteroaryl is
According to an embodiment of the invention, R 7 is null, H, -C 1～3 alkyl,Or alternatively
According to embodiments of the invention, R 8 is null, H, C 1～6 alkyl optionally substituted with one or more R 1j, or-3-10 membered aryl optionally substituted with one or more R 1j.
According to an embodiment of the invention, each R 1j is independently halogen, -NH 2, -OH, phenyl, -C 1～3 alkyl, or-C 1～3 oxyalkyl.
According to embodiments of the invention, R 8 is null, H, -C 1～6 alkyl, -3-10 membered aryl, or-3-10 membered heteroaryl.
According to an embodiment of the invention, R 8 is null, H, -C 1～3 alkyl or-5-7 membered aryl.
According to an embodiment of the invention, R 9 is H, =o, -C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1k.
According to an embodiment of the invention, each R 1k is independently halogen, -NH 2, -OH, or-C 1～6 alkyl.
According to an embodiment of the invention, R 9 is H, =o, or-C (O) -NH-C 1～6 alkylene-5-7 membered heterocycloalkylene-C 1～6 alkylene-5-7 membered aryl optionally substituted with one or more-C 1～3 alkyl groups.
According to an embodiment of the invention, R 9 is H, =o, or-C (O) -NH-C 1～6 alkylene-5-7 membered heterocycloalkylene-C 1～6 alkylene-5-7 membered aryl optionally substituted with one or more-C 1～3 alkyl groups, wherein the 5-7 membered heterocycloalkylene in the-C (O) -NH-C 1～6 alkylene-5-7 membered heterocycloalkylene-C 1～6 alkylene-5-7 membered aryl contains N.
According to an embodiment of the invention, R 9 is H, =o, or-C (O) -NH-C 1～6 alkylene-5-7 membered heterocycloalkylene-C 1～6 alkylene-5-7 membered aryl optionally substituted with one or more-C 1～3 alkyl, wherein the 5-7 membered heterocycloalkylene in-C (O) -NH-C 1～6 alkylene-5-7 membered heterocycloalkylene-C 1～6 alkylene-5-7 membered aryl is
According to an embodiment of the invention, R 9 is H, =o, or
In accordance with an embodiment of the present invention,Is that
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIa):
According to an embodiment of the invention, R 8 is null, H or-C 1～6 alkyl.
According to an embodiment of the invention, R 8 is null, H or-C 1～3 alkyl.
According to an embodiment of the invention, R 3 is H, halogen or-C 1～6 alkyl.
According to an embodiment of the invention, R 3 is H, halogen or-C 1～3 alkyl.
According to an embodiment of the invention, R 7 is null, H or-C 1～6 alkyl.
According to an embodiment of the invention, R 7 is null, H or-C 1～3 alkyl.
According to an embodiment of the invention, R 7 is H or-C 1～3 alkyl.
According to an embodiment of the invention, R 5 is-C 1～6 alkylene-, optionally substituted with one or more R 1g, -C 1～6 alkylene-3-15 membered cycloalkylene-, optionally substituted with one or more R 1g, -C 1～6 alkylene-3-10 membered cycloalkylene-C 1～6 alkylene-, optionally substituted with one or more R 1g.
According to an embodiment of the invention, each R 1g is independently halogen, -OH, -C 1～3 alkyl, -C 1～3 oxyalkyl, or-C 1～3 alkyl-OH.
According to an embodiment of the invention, R 5 is-C 1～3 alkylene-, -C 1～3 alkylene-5-9 membered cycloalkylene-, -C 1～3 alkylene-4-7 membered cycloalkylene-C 1～3 alkylene-optionally substituted by one or more-C 1～3 alkyl-OH groups.
According to embodiments of the invention, R 6 is-3-15 membered cycloalkylene optionally substituted with one or more R 1h, -C (O) -3-10 membered heteroaryl optionally substituted with one or more R 1h, -C 1～6 alkylene-C 1～3 oxyalkyl optionally substituted with one or more R 1h, -3-10 membered aryl optionally substituted with one or more R 1h, or-C (O) -NH-C 1～3 alkylene-3-10 membered aryl optionally substituted with one or more R 1h.
According to an embodiment of the invention, each R 1h is independently halogen, =o, -OH, -C 1～3 alkyl, -C 1～3 oxyalkyl, or-C 1～3 alkyl-OH.
According to an embodiment of the invention, R 6 is-6-12 membered cycloalkylene optionally substituted by one or more-C 1～3 alkyl groups and/or =o, -C (O) -5-7 membered heteroaryl, -C 1～3 alkylene-C 1～3 oxyalkyl, -5-7 membered aryl optionally substituted by one or more-C 1～3 oxyalkyl groups and/or-C 1～3 alkyl groups, or-C (O) -NH-C 1～3 alkylene-5-7 membered aryl optionally substituted by one or more halogen groups.
According to an embodiment of the invention, -R 5-R6 is
According to an embodiment of the invention, X 3 is N and R 8 is H.
According to an embodiment of the invention, X 3 is not C.
According to an embodiment of the invention, X 4 is C.
According to an embodiment of the invention, X 5 is C.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIa 1):
according to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIa 2):
Wherein X 6 is C or N.
R 11 is-5-7 membered aryl optionally substituted by halogen or-C 1～3 alkyl or-5-7 membered heteroaryl optionally substituted by halogen or-C 1～3 alkyl.
According to an embodiment of the invention, R 11 is
According to an embodiment of the present invention, the compound represented by formula (II) has a structure represented by formula (IIb):
wherein X 3 and X 5 are not simultaneously N.
According to an embodiment of the invention, R 2 is H, -NH 2 or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 2 is H, -NH 2 or-C 1～3 oxyalkyl.
According to an embodiment of the invention, R 3 is null, H or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 3 is null, H or-C 1～3 oxyalkyl.
According to an embodiment of the invention, R 4 is H or-3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl optionally substituted by one or more R 1f.
According to an embodiment of the invention, each R 1f is independently =o or-C 1～3 alkyl.
According to an embodiment of the invention, R 4 is H or
According to an embodiment of the invention, R 8 is null, H or-5-7 membered aryl.
According to an embodiment of the invention, R 9 is H or-C (O) -NH-C 1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more-C 1～3 alkyl groups.
According to an embodiment of the invention, R 9 is H or
According to an embodiment of the invention, -R 5-R6 is-C 1～6 alkylene-3-10 membered aryl optionally substituted by one or more halogens or-C 1～6 alkylene-3-10 membered aryl optionally substituted by one or more halogens.
According to an embodiment of the invention, -R 5-R6 is-C 1～3 alkylene-5-7 membered aryl or-C 1～3 alkylene-5-7 membered aryl optionally substituted with one or more halogens.
According to an embodiment of the invention, R 4 is-3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1f, X 3 and X 5 are simultaneously C, -R 5-R6、R8 and R 9 are both H.
According to an embodiment of the present invention, when the ring a is not empty, the compound of formula (I) has a structure of formula (III):
Wherein R 10 is H, C 1～6 alkyl optionally substituted with one or more R 1m, C 1～6 oxyalkyl optionally substituted with one or more R 1m, C (O) -C 1～6 alkyl optionally substituted with one or more R 1m, or C (O) -C 1～6 oxyalkyl optionally substituted with one or more R 1m, wherein each R 1m is independently halogen, -NH 2、-OH、-SH、-NO2、-CN、-C1～6 alkyl or-C 1～6 oxyalkyl, -C 2～6 alkenyl or-C 2～6 oxyalkenyl.
According to an embodiment of the invention, X 1 is N and X 2 is not C.
According to an embodiment of the invention, X 1 is C or N.
According to an embodiment of the invention, X 2 is C, R 1 is H, or X 2 is N, R 1 is null.
According to embodiments of the invention, R 2 is H, -N (R c)2, 3-10 membered heterocycloalkyl optionally substituted with one or more R 1d, or 3-10 membered heteroaryl optionally substituted with one or more R 1d).
According to an embodiment of the invention, each R c is independently H or-C 1～3 alkyl.
According to an embodiment of the invention, each R 1d is independently halogen, -C 1～6 alkyl, or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 2 is H, -N (R c)2, 3-10 membered heterocycloalkyl optionally substituted with one or more-C 1～3 alkyl groups, or 3-10 membered heteroaryl optionally substituted with one or more-C 1～3 alkyl groups, wherein 3-10 membered heterocycloalkyl or 3-10 membered heteroaryl contains O and/or S.
According to an embodiment of the invention, R 2 is H, -NH 2、-N(CH3)2 or
According to an embodiment of the invention, R 2 is-NH 2 or-N (CH 3)2).
According to embodiments of the invention, R 4 is halogen, H, C 1～6 alkyl optionally substituted with one or more R 1f, C 1～6 oxyalkyl optionally substituted with one or more R 1f, 3-10 membered cycloalkyl optionally substituted with one or more R 1f, or 3-10 membered heterocycloalkyl optionally substituted with one or more R 1f.
According to an embodiment of the invention, each R 1f is independently halogen, -NH 2、-OH、-C1～6 alkyl or-C 1～6 oxyalkyl.
According to an embodiment of the invention, R 4 is halogen, H, -C 1～6 alkyl optionally substituted by one or more halogen or-3-6 membered cycloalkyl optionally substituted by one or more-NH 2.
According to an embodiment of the invention, R 4 is H, -C 1～3 alkyl, or-CF 3.
According to an embodiment of the invention, R 4 is halogen or-C 1～3 alkyl.
According to an embodiment of the invention, R 5 is-C 1～6 alkylene optionally substituted by one or more R 1g, -NR d-C1～6 alkylene optionally substituted by one or more R 1g, -3-10 membered heterocycloalkyl optionally substituted by one or more R 1g, -C 1～6 alkylene-C (=ch) -3-10 membered heterocycloalkyl-C 1～6 alkylene-, optionally substituted by one or more R 1g, or-S (O) 2-NRd-C1～6 alkylene-, optionally substituted by one or more R 1g.
According to an embodiment of the invention, R 5 is-C 1～3 alkylene-, optionally substituted with one or more R 1g, -NH-C 2～5 alkylene-, optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-, optionally substituted with one or more R 1g, -C 1～3 alkylene-C (=ch) -4-7 membered heterocycloalkylene-C 2～5 alkylene-, optionally substituted with one or more R 1g, -S (O) 2-NH-C1～3 alkylene-.
According to an embodiment of the invention, each R d is independently H or-C 1～3 alkyl.
According to an embodiment of the invention, each R 1g is independently halogen, phenyl, 3-to 5-membered cycloalkyl, -C 1～3 alkyl.
According to an embodiment of the invention, R 5 is-C 1～3 alkylene-, optionally-NH-C 2～5 alkylene substituted with one or more 3-to 5-membered cycloalkyl-, -4-to 7-membered heterocycloalkylene-, optionally-C 1～3 alkylene-C (=ch) -4-to 7-membered heterocycloalkylene-C 2～5 alkylene-, or-S (O) 2-NH-C1～3 alkylene-.
According to embodiments of the invention, R 6 is-C 1～6 oxyalkyl optionally substituted with one or more R 1h, 3-10 membered heterocycloalkyl optionally substituted with one or more R 1h, 3-10 membered heteroaryl optionally substituted with one or more R 1h, 3-10 membered aryl optionally substituted with one or more R 1h, N (R a)2, C (O) -N (R a)2, optionally substituted with one or more R 1h, or 3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1h) optionally substituted with one or more R 1h.
According to embodiments of the invention, R 6 is-C 1～3 oxyalkyl optionally substituted with one or more R 1h, 4-7 membered heterocycloalkyl optionally substituted with one or more R 1h, 4-7 membered heteroaryl optionally substituted with one or more R 1h, 4-7 membered aryl optionally substituted with one or more R 1h, N (R a)2, C (O) -NH (C 1～3 alkyl) optionally substituted with one or more R 1h, or 4-7 membered heterocycloalkylene-4-7 membered aryl optionally substituted with one or more R 1h.
According to an embodiment of the invention, each R a is independently H, -C 1～3 alkyl, selected from-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted by one or more R 1h, or-C (O) -N (R b)2).
According to an embodiment of the invention, each R b is independently selected from-C 1～3 alkylene-3-6 membered cycloalkyl, C (O) -4-7 membered aryl optionally substituted by one or more R 1h.
According to an embodiment of the invention, each R 1h is independently halogen, phenyl, -C 1～3 alkyl or-C 1～3 oxyalkyl.
According to an embodiment of the invention, each R a is independently selected from H, -C 1～3 alkyl, -C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted by one or more-C 1～3 alkyl, or-C (O) -N (R b)2).
According to an embodiment of the invention, each R a is independently selected from H or-C 1～3 alkyl.
According to an embodiment of the invention, each R a is independently selected from-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted by one or more-C 1～3 alkyl groups or-C (O) -N (R b)2).
According to an embodiment of the invention, each R b is independently selected from-C 1～3 alkylene-3-7 membered cycloalkyl, and-C (O) -4-7 membered aryl optionally substituted with one or more halogens.
According to an embodiment of the invention, R 6 is-N (CH 3)2、-C1～3 oxyalkyl or-C (O) -NH (CH 3).
According to an embodiment of the invention, -R 5-R6 is-NR d-C1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1g, -NR d-C1～6 alkylene-3-10 membered heteroaryl optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-N optionally substituted with one or more R 1g (R a)2, -3-10 membered heterocycloalkylene-C 1～6 alkylene-N optionally substituted with one or more R 1g (R a)2), -3-10 membered heterocycloalkylene-C 1～6 oxy alkyl optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-C (O) -N (R a)2) optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-3-10 membered heterocycloalkyl optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-3-10 membered heteroaryl optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-3-10 membered aryl optionally substituted with one or more R 1g, -3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered heterocycloalkyl optionally substituted by one or more R 1g, -C 1～6 alkylene-C (=ch) -3-10 membered heterocycloalkylene-C 1～6 alkylene-C 1～6 oxyalkyl optionally substituted with one or more R 1g, or-S (O) 2-NRd-C1～6 alkylene-3-10 membered heterocycloalkylene-C 1～6 alkylene-3-10 membered aryl optionally substituted with one or more R 1g, or-C 1～6 alkylene-N (R a)2) optionally substituted with one or more R 1g.
According to an embodiment of the invention, -R 5-R6 is-NH-C 2～5 alkylene-4-7 membered heterocycloalkyl optionally substituted with one or more R 1g, -NH-C 2～5 alkylene-4-7 membered heteroaryl optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-C 1～3 alkylene-NH 2 optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-N optionally substituted with one or more R 1g (CH 3)2), -4-7 membered heterocycloalkylene-C 1～3 oxy alkyl optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-C (O) -NH (CH 3) optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-4-7 membered heterocycloalkyl optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-4-7 membered heteroaryl optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-4-7 membered aryl optionally substituted with one or more R 1g, -4-7 membered heterocycloalkylene-C 1～3 alkylene-4-7 membered heterocycloalkyl optionally substituted with one or more R 1g, -C 1～3 alkylene-C (=ch) -4-7 membered heterocycloalkylene-C 2～5 alkylene-C 1～3 oxyalkyl optionally substituted with one or more R 1g, or-S (O) 2-NRd-C1～3 alkylene-4-7 membered heterocycloalkylene-C 1～3 alkylene-4-7 membered aryl optionally substituted with one or more R 1g, or-C 1～6 alkylene-N (R a)2) optionally substituted with one or more R 1g.
According to embodiments of the invention, -R 5-R6 is-NH-C 2～5 alkylene-4-7 membered heterocycloalkyl optionally substituted with one or more-C 1～3 alkyl, -4-7 membered heterocycloalkylene-N (CH 3)2, -4-7 membered heterocycloalkylene-C 1～3 oxyalkyl, -4-7 membered heterocycloalkylene-C (O) -NH (CH 3), -S (O) 2-NRd-C1～3 alkylene-4-7 membered heterocycloalkylene-C 1～3 alkylene-4-7 membered aryl optionally substituted with one or more-C 1～3 alkyl, or-C 1～6 alkylene-N (R a)2) optionally substituted with one or more R 1g.
According to an embodiment of the invention, -R 5-R6 is
According to an embodiment of the invention, -R 5-R6 is
According to an embodiment of the invention, R 10 is H, —c 1～6 alkyl optionally substituted with one or more halogens, or-C (O) -C 1～6 alkyl optionally substituted with one or more halogens.
According to an embodiment of the invention, R 10 is-C 1～6 alkyl or-C (O) -C 1～3 alkyl.
According to an embodiment of the invention, R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, -CH 3-CF3, -C (O) -methyl or-C (O) -ethyl.
According to an embodiment of the invention, R 10 is methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, -C (O) -methyl or-C (O) -ethyl.
According to an embodiment of the invention, R 10 is n-propyl, isopropyl, n-butyl or-CH 3-CF3.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIIa):
wherein R 12 is H or 3-7 membered cycloalkyl;
R 13 and R 14 are each independently selected from H or-C 1～3 alkyl.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIIa 1)
Wherein p1 is 2, 3, 4 or 5.
According to an embodiment of the present invention, the compound represented by formula (I) has a structure represented by formula (IIIb):
Wherein p2 is 0,1, 2 or 3.
According to an embodiment of the invention, p2 is 0.
According to an embodiment of the present invention, the heterocycloalkyl group is selected from heterocycloalkyl groups containing at least one of N, O and S.
According to an embodiment of the invention, the heterocycloalkyl is selected from the group consisting of N-containing heterocycloalkyl, O-containing heterocycloalkyl or S-containing heterocycloalkyl.
According to an embodiment of the invention, the heterocycloalkyl group is selected from the group consisting of one N-heterocycloalkyl group or two N-heterocycloalkyl groups.
According to an embodiment of the present invention, the heterocycloalkyl group is selected from 3-15 membered heterocycloalkyl group, 8-15 membered heterocycloalkyl group, 3-12 membered heterocycloalkyl group, 8-12 membered heterocycloalkyl group, 3-10 membered heterocycloalkyl group, 3-6 membered heterocycloalkyl group, 4-7 membered heterocycloalkyl group.
According to an embodiment of the present invention, the heterocycloalkylene group is selected from heterocycloalkylene groups containing at least one of N, O and S.
According to an embodiment of the invention, the heterocycloalkylene is selected from the group consisting of N-containing heterocycloalkylene, O-containing heterocycloalkylene, or S-containing heterocycloalkylene.
According to an embodiment of the invention, the heterocycloalkylene group is selected from one N-heterocycloalkylene group or two N-heterocycloalkylene groups.
According to an embodiment of the present invention, the heterocycloalkylene group is selected from a 3-15 membered heterocycloalkylene group, a 8-15 membered heterocycloalkylene group, a 3-12 membered heterocycloalkylene group, a 3-10 membered heterocycloalkylene group, a 3-6 membered heterocycloalkylene group, a 4-7 membered heterocycloalkylene group.
According to an embodiment of the invention, the heteroaryl group is selected from heteroaryl groups containing at least one of N, O and S.
According to an embodiment of the invention, the heteroaryl is selected from the group consisting of N-containing heteroaryl, O-containing heteroaryl or S-containing heteroaryl.
According to an embodiment of the invention, the heteroaryl group is selected from one N heteroaryl group or two N heteroaryl groups.
According to an embodiment of the invention, the heteroaryl group is selected from 3-15 membered heteroaryl, 8-15 membered heteroaryl, 3-12 membered heteroaryl, 8-12 membered heteroaryl, 3-10 membered heteroaryl, 3-6 membered heteroaryl, 4-7 membered heteroaryl.
According to an embodiment of the present invention, the heteroarylene is selected from heteroarylene groups containing at least one of N, O and S.
According to an embodiment of the invention, the heteroarylene is selected from the group consisting of N-containing heteroarylene, O-containing heteroarylene, or S-containing heteroarylene.
According to an embodiment of the invention, the heteroarylene is selected from the group consisting of one N heteroarylene group or two N heteroarylene groups.
According to an embodiment of the present invention, the heteroarylene group is selected from the group consisting of 3-15 membered heteroarylene, 8-15 membered heteroarylene, 3-12 membered heteroarylene, 8-12 membered heteroarylene, 3-10 membered heteroarylene, 3-6 membered heteroarylene, 4-7 membered heteroarylene.
In a second aspect of the invention, the invention provides a compound having the following structure or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt thereof:
in a third aspect of the invention, the invention provides the use of a compound according to the first or second aspect in the manufacture of a reagent for inhibiting TNF signalling pathways.
In a fourth aspect of the invention, the invention provides a TNF signaling pathway inhibitor comprising a compound of the first or second aspect. Thus, TNF signaling pathways can be effectively inhibited.
According to embodiments of the present invention, the TNF signaling pathway inhibitor may further comprise pharmaceutically acceptable carriers, adjuvants, vehicles.
In a fifth aspect, the invention provides a pharmaceutical composition comprising a compound according to the first or second aspect or an inhibitor of TNF signaling pathway according to the fourth aspect, and optionally a pharmaceutically acceptable carrier, adjuvant, vehicle.
According to the embodiment of the invention, pharmaceutically acceptable auxiliary materials refer to conventional pharmaceutical auxiliary materials in the pharmaceutical field, such as diluents, excipients, fillers (such as starch, sucrose, lactose, microcrystalline cellulose and the like), binders (such as cellulose derivatives, alginate, gelatin and polyvinylpyrrolidone), wetting agents (such as glycerin), disintegrating agents (such as sodium carboxymethyl starch, hydroxypropyl cellulose, crosslinked carboxymethyl cellulose, agar, calcium carbonate and sodium bicarbonate), absorption promoters (such as quaternary ammonium compounds), surfactants (such as cetyl alcohol, sodium dodecyl sulfate and the like, and other auxiliary materials such as flavoring agents, sweetening agents and the like can be added.
According to the embodiment of the invention, the pharmaceutically acceptable carrier refers to a conventional drug carrier in the pharmaceutical field, such as an adsorption carrier (such as kaolin and soap clay), a lubricant (such as talcum powder, calcium stearate and magnesium, micro-powder silica gel and polyethylene glycol) and the like.
Pharmaceutically acceptable vehicle means, according to embodiments of the present invention, pharmaceutical vehicles conventional in the pharmaceutical arts, such as creams, gels, emulsions, solutions (e.g., water) and liposomes.
Examples of suitable pharmaceutically acceptable carriers, adjuvants, vehicles are well known in the art. Pharmaceutical compositions comprising such carriers, excipients, vehicles may be formulated by well known conventional methods.
In some alternative embodiments, other therapeutically active ingredients may also be included in the pharmaceutical compositions of the present invention.
The pharmaceutical composition of the invention may be administered by different means, for example enterally, orally (e.g. pills, tablets, buccal, sublingual, disintegrants, capsules, films, liquid solutions or suspensions, powders, solid crystals or liquids), rectally (e.g. suppositories, enemas), via injection (e.g. intravenous, subcutaneous, intramuscular, intraperitoneal, intradermal), via inhalation (e.g. intrabronchial), topical, vaginal, dermal or intranasal. Preferably, the pharmaceutical composition of the present invention is in the form of a lyophilized formulation or an aqueous solution. The clinical dosage regimen will be determined by the attending physician and clinical factors. As is well known in the medical arts, the dosage for any one patient depends on many factors, including the patient's constitution, body surface area, age, the drug to be administered, sex, time and route of administration, general health, and other drugs administered simultaneously. The pharmaceutical compositions of the present invention may be administered topically or systemically. Preferably, administration may be performed intravenously or subcutaneously. The pharmaceutical compositions of the invention may also be administered directly to a target site, for example by targeted administration to an internal or external target site.
In a sixth aspect of the invention, the invention provides the use of a compound according to the first or second aspect, a TNF signaling pathway inhibitor according to the fourth aspect or a pharmaceutical composition according to the fifth aspect in the manufacture of a medicament for the prevention or treatment of a TNF signaling pathway related disorder.
According to embodiments of the invention, the TNF signaling pathway related diseases include diseases related to excessive activity and/or overexpression of tnfα.
According to embodiments of the invention, the TNF signaling pathway related diseases include, but are not limited to, inflammatory diseases, septic shock, or diabetes;
According to embodiments of the present invention, the inflammatory disease includes, but is not limited to, atherosclerosis, restenosis, autoimmune diseases, immune-mediated inflammatory diseases (IMID), or other diseases mediated by immune complexes.
According to embodiments of the invention, the immune-mediated inflammatory disease includes, but is not limited to, rheumatoid arthritis, psoriasis, uveitis (e.g., pediatric and seronegative), ulcerative colitis, hidradenitis suppurativa or lupus.
According to embodiments of the invention, the other diseases mediated by immune complexes include, but are not limited to, pemphigus and glomerulonephritis, congenital Hyperthyroidism (CH), delayed type hypersensitivity reactions (DTH) such as contact allergies, sarcoidosis, bei Dite's disease, chronic arthritis, psoriatic arthritis, polyarthritis juvenile idiopathic arthritis, ankylosing spondylitis, adult Shi Dier's disease, primary xerosis, scleroderma, psoriasis, plaque psoriasis (including childhood plaque psoriasis), giant cell arteritis, SAPHO syndrome, primary Biliary Cirrhosis (PBC), neoplasia, myelodysplastic syndrome, wegener's syndrome and other vasculitis, hematological tumors, cochlear vestibular disorders, macrophage activation syndrome, asthma, interstitial lung disease, hepatitis c, pulmonary fibrosis, induced ovulation, dysplasia syndrome, crohn's disease (including childhood plaque psoriasis), graft-versus-host reaction, cachexia, shock, multiple sclerosis, and the like.
In a seventh aspect of the invention, the invention provides a method of preventing or treating a disorder associated with a TNF signaling pathway comprising administering to a subject a pharmaceutically acceptable dose of a compound according to the first or second aspect, an inhibitor of a TNF signaling pathway according to the fourth aspect, or a pharmaceutical composition according to the fifth aspect.
According to embodiments of the present invention, the pharmaceutically acceptable dose may be selected from an effective dose (or an effective amount).
The effective amount of the compounds of the present invention may vary depending upon the mode of administration and the severity of the condition being treated, etc. The selection of the preferred effective amount can be determined by one of ordinary skill in the art based on a variety of factors (e.g., by clinical trials). Such factors include, but are not limited to, the pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc., the severity of the disease to be treated by the patient, the weight of the patient, the immune status of the patient, the route of administration, etc. For example, separate doses may be administered several times per day, or the dose may be proportionally reduced, as dictated by the urgent need for the treatment of the condition.
According to embodiments of the invention, the TNF signaling pathway related diseases include diseases related to excessive activity and/or overexpression of tnfα.
According to embodiments of the invention, the TNF signaling pathway related diseases include, but are not limited to, inflammatory diseases, septic shock, or diabetes;
According to embodiments of the present invention, the inflammatory disease includes, but is not limited to, atherosclerosis, restenosis, autoimmune diseases, immune-mediated inflammatory diseases (IMID), or other diseases mediated by immune complexes.
According to embodiments of the invention, the immune-mediated inflammatory disease includes, but is not limited to, rheumatoid arthritis, psoriasis, uveitis (e.g., pediatric and seronegative), ulcerative colitis, hidradenitis suppurativa or lupus.
According to embodiments of the invention, the other diseases mediated by immune complexes include, but are not limited to, pemphigus and glomerulonephritis, congenital Hyperthyroidism (CH), delayed type hypersensitivity reactions (DTH) such as contact allergies, sarcoidosis, bei Dite's disease, chronic arthritis, psoriatic arthritis, polyarthritis juvenile idiopathic arthritis, ankylosing spondylitis, adult Shi Dier's disease, primary xerosis, scleroderma, psoriasis, plaque psoriasis (including childhood plaque psoriasis), giant cell arteritis, SAPHO syndrome, primary Biliary Cirrhosis (PBC), neoplasia, myelodysplastic syndrome, wegener's syndrome and other vasculitis, hematological tumors, cochlear vestibular disorders, macrophage activation syndrome, asthma, interstitial lung disease, hepatitis c, pulmonary fibrosis, induced ovulation, dysplasia syndrome, crohn's disease (including childhood plaque psoriasis), graft-versus-host reaction, cachexia, shock, multiple sclerosis, and the like.
Additional aspects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Drawings
The foregoing and/or additional aspects and advantages of the invention will become apparent and may be better understood from the following description of embodiments taken in conjunction with the accompanying drawings in which:
FIG. 1 shows the results of a luciferase reporter assay for a portion of the compounds of test example 1 of the present invention;
FIG. 2 shows the inhibitory effect of various doses of compound Ti28 on TNFα -induced NF- κB activation in test example 1 according to the present invention;
FIG. 3 shows the inhibitory effect of different doses of the compounds Ti13 and Ti34 of test example 1 according to the invention on TNF alpha-induced NF- κB activation;
FIG. 4 shows the inhibitory effect of different doses of compound Ti20 on TNFα -induced NF- κB activation in test example 1 according to the present invention;
FIG. 5 shows the results of the detection of the specific inhibition of TNF-induced inflammatory response by the compound Ti2 of test example 2 according to the invention;
FIG. 6 shows the results of the detection of the specific inhibition of TNF-induced inflammatory response by the compound Ti11 of test example 2 according to the invention;
FIG. 7 shows the results of the detection of the specific inhibition of TNF-induced inflammatory response by the compound Ti13 of test example 2 according to the present invention;
FIG. 8 shows the results of the detection of a portion of the compounds (Ti 2, ti15, ti16, ti17, ti18, ti19 and Ti 20) of test example 2 according to the invention specifically inhibiting TNF-induced inflammatory responses;
FIG. 9 shows the results of detection of the inhibition of the TNF signal pathway by a portion of the compounds of test example 3 of the present invention (Ti 2, ti11 and Ti 13) by targeting the TNFR1-TRADD-RIP1-TRAF2 complex;
FIG. 10 is a diagram of TNF signaling pathways;
FIG. 11 is a graph showing the characterization of compound Ti2 in example 1;
FIG. 12 is a graph showing the characterization of the compound Ti35b in example 1.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention.
It should be noted that the terms "first," "second," and "second" are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implying a number of technical features being indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. Further, in the description of the present invention, unless otherwise indicated, the meaning of "a plurality" is two or more.
Description
Definitions and general terms
It should be noted that the application is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the application as defined by the appended claims with respect to the structural and chemical formulas in the examples or embodiments of the application. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments or implementations, may also be provided in combination in a single embodiment or implementation. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment or implementation, may also be provided separately or in any suitable subcombination.
Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise indicated, all patent publications cited throughout the disclosure of this invention are incorporated by reference in their entirety.
The invention will apply to the following definitions unless otherwise indicated. For the purposes of the present invention, chemical elements are defined according to the periodic Table of the elements, CAS version and chemical handbook, 75, thred, 1994. In addition, the general principles of organic chemistry are seen at "Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,and"March's Advanced Organic Chemistry",by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007, and the disclosure of the present invention is hereby incorporated by reference in its entirety.
In this document, the terms "comprise" or "include" are used in an open-ended fashion, i.e., to include what is indicated by the present invention, but not to exclude other aspects.
In this context, the compounds of the invention also include isotopically-labelled compounds of the invention which are identical to those recited in the invention except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H、3H、13C、14C、15N、16O、17O、31P、32P、36S、18F and 37 Cl.
Compounds of the invention that contain the aforementioned isotopes and/or other isotopes of other atoms, and pharmaceutically acceptable salts of such compounds, are included within the scope of the invention. Isotopically-labeled compounds of the present invention, for example, radioisotopes such as 3 H and 14 C, may be used in drug and/or substrate tissue distribution assays for incorporation into the compounds of the present invention. Isotopes of tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, are particularly preferred for ease of preparation and detection. In addition, substitution with heavy isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.
The stereochemical definition and convention used in the present invention is generally that the compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms according to S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994.. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomer) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefix D and L or R and S are used to denote the absolute configuration of the molecule in terms of chiral center (or chiral centers) in the molecule. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as mixtures of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and methods, the compounds according to the invention may be present in the form of one of the possible isomers or mixtures thereof, for example as pure optical isomers or as isomer mixtures, for example as racemic and non-corresponding isomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in E or Z configuration, and if the compound contains a disubstituted cycloalkyl, the substituent of the cycloalkyl may be in cis or trans (cis-or trans-) configuration.
The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the invention, including but not limited to diastereomers, enantiomers and atropisomers (atropisomer) and geometric (or conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the invention.
Unless otherwise indicated, the structures described herein are also meant to include all isomeric (e.g., enantiomer, diastereomeric atropisomer (atropisomer) and geometric (or conformational) forms of such structures, e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. The substituents on the atoms having unsaturated double bonds may be present in cis- (Z) -or trans- (E) -form, if possible.
Thus, as described herein, the compounds of the present invention may exist as one of the possible isomers, rotamers, atropisomers, tautomers or as a mixture thereof, for example as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or as a mixture thereof.
Any of the resulting isomer mixtures may be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, based on the physicochemical differences of the components, for example by chromatography and/or fractional crystallization.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the resulting diastereomeric salts thereof, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Pressure Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis (e.g ,Jacques,et al.,Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981);Principles of Asymmetric Synthesis(2nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012);Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962);and Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972).
Herein, the term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be converted to each other by a low energy barrier (low energy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomer (protontautomer) (also known as proton transfer tautomer (prototropic tautomer)) includes interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valence tautomer) include interconversions by recombination of some of the bond-forming electrons. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
As used herein, the term "solvate" refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
Herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in document ：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66：1-19.. Pharmaceutically acceptable non-toxic acid-forming salts include, but are not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, perchlorate) formed by reaction with amino groups, and organic acid salts (e.g., acetate, oxalate, maleate, tartrate, citrate, succinate, malonate) or by other methods described in the literature such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulfate, borates, butyrates, camphorinates, camphorsulfonates, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodinates, 2-hydroxy-ethanesulfonate, lactobionic aldehyde, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with suitable bases include the alkali metal, alkaline earth metal, ammonium and N +(C1～4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1～8 sulphonates and aromatic sulphonates.
In this document, the terms "optionally," "optional," or "optionally" generally refer to the subsequently described event or condition may, but need not, occur, and the description includes instances in which the event or condition occurs, as well as instances in which the event or condition does not.
The terms "optionally substituted", "optionally substituted" and "substituted or unsubstituted" are used interchangeably herein. In general, the term "optionally" whether or not prior to the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. An optional substituent group may be substituted at each substitutable position of the group unless otherwise indicated. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, then the substituents may be the same or different at each position. Wherein the substituents may be, but are not limited to F, cl, br, CN, OH, NH 2、NO2 and the like.
The term "one or more" (e.g., in the definition of substituents of compounds of the general formula of the present invention) means "one, two, three, four or five, especially one, two, three or four, more especially one, two or three, more especially one or two".
In addition, unless explicitly stated otherwise, the description as used in this disclosure is "each..and". Independently "and". Independently "can be interchanged, and is to be understood broadly as meaning that specific items expressed between the same symbols in different groups do not affect each other, or that specific items expressed between the same symbols in the same groups do not affect each other.
In this context, the term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.
Herein, the minimum and maximum values of the carbon atom content in the hydrocarbon group are indicated by a prefix, for example, the prefix C a～b means that it contains "a" to "b" carbon atoms. Illustratively, "C 1～n" refers to a straight or branched saturated/unsaturated carbon chain containing 1, 2, 3, 4, 5, &..the term "or n carbon atoms," C 1～n "is further understood to be interpreted as including any subrange included therein, such as in C 1～6, inclusive C1～5、C1～4、C1～3、C1～2、C2～5、C2～4、C2～3、C3～5、C3～4、C4～5.
It is noted that the term "C 1～6" as used herein, for example, in the context of the definition of "C 1～6 alkyl" or "C 1～6 alkoxy", refers to an alkyl group having 1 to 6 limited numbers of carbon atoms, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is further understood that the term "C 1～6" is to be construed as including any subrange therein, such as C 1～6、C2～5、C3～4、C1～2、C1～3、C1～4、C1～5, especially C 1～2、C1～3、C1～4、C1～5、C1～6, more especially C 1～4.
Similarly, as used herein, the term "C 2～6" as used throughout this document, for example, in the context of the definition of "C 2～6 alkenyl" and "C 2～6 alkynyl", is understood to mean alkenyl groups having from 2 to 6 limited numbers of carbon atoms, i.e., 2,3,4,5, or 6 carbon atoms. It is further understood that the term "C 2～6" is to be construed as including any subrange therein, e.g., C 2～6、C3～5、C3～4、C2～3、C2～4、C2～5; especially C 2～3.
As used herein, the term "C 1～6 alkyl" refers to a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, e.g., C 1～5 alkyl, C 1～4 alkyl, C 1～3 alkyl, C 2～5 alkyl, C 2～4 alkyl, C 2～3 alkyl. Including but not limited to methyl, ethyl, n-propyl (n-Pr, -CH 2CH2CH3), isopropyl (i-Pr, -CH (CH 3)2), n-butyl (n-Bu, -CH 2CH2CH2CH3), isobutyl (i-Bu, -CH 2CH(CH3)2), Sec-butyl (s-Bu), -CH (CH 3)CH2CH3), tert-butyl (t-Bu), -C (CH 3)3), n-pentyl (-CH 2CH2CH2CH2CH3), 2-pentyl (-CH (CH 3)CH2CH2CH3), 3-pentyl (-CH (CH 2CH3)2), 2-methyl-2-butyl (-C (CH 3)2CH2CH3), 3-methyl-2-butyl (-CH (CH 3)CH(CH3)2), 3-methyl-1-butyl (-CH 2CH2CH(CH3)2), 2-methyl-1-butyl (-CH 2CH(CH3)CH2CH3), n-hexyl (-CH 2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH 3)CH2CH2CH2CH3), 3-hexyl (-CH (CH 2CH3)(CH2CH2CH3))), 2-methyl-2-pentyl (-C (CH 3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH 3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH (CH 3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C (CH 3)(CH2CH3)2)), a catalyst for the preparation of a pharmaceutical composition, 2-methyl-3-pentyl (-CH (CH 2CH3)CH(CH3)2), 2, 3-dimethyl-2-butyl (-C (CH 3)2CH(CH3)2), 3-dimethyl-2-butyl (-CH (CH 3)C(CH3)3)), wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
As used herein, the term "alkylene" refers to a group formed by the removal of one more hydrogen atom from an "alkyl" group, wherein "C 1～6 alkylene" includes methylene, ethylene, propylene, isopropylene (e.g) Butylene (e.g) Pentylene (e.g) Hexyl (e.g) Etc.
Herein, the term "C 2～6 alkenyl" refers to a straight or branched monovalent hydrocarbon radical having 2,3, 4,5, or 6 carbon atoms, wherein at least one position C-C is in an sp2 double bond unsaturated state, wherein the alkenyl groups may independently be unsubstituted or substituted with one or more substituents described herein, including the positioning of the groups with "cis", "trans" or "Z", "E", wherein specific examples include, but are not limited to, allyl (-ch=ch 2), allyl (-CH 2CH＝CH2), and the like. Such as C 2～5 alkenyl, C 2～4 alkenyl, C 2～3 alkenyl, C 3～6 alkenyl, C 3～5 alkenyl, C 3～4 alkenyl.
As used herein, the term "alkenylene" refers to a group formed by the removal of one more hydrogen atom from an "alkenyl" group.
Herein, the term "C 1～6 alkoxy" refers to a C 1～6 alkyl group containing the formula "-O-alkyl", wherein the term "alkyl" is as defined above. For example methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentoxy, isopentoxy and n-hexoxy, or isomers of the foregoing. In particular, the "C1-C6 alkoxy" may contain 1,2, 3, 4 or 5 carbon atoms ("C 1～5 alkoxy"), preferably 1,2, 3 or 4 carbon atoms ("C 1～4 alkoxy").
As used herein, the term "alkyleneoxy" refers to a group formed by the removal of one more hydrogen atom from an "alkoxy" group.
Herein, the term "C 3～15 cycloalkyl" or "3-15 membered cycloalkyl" refers to a saturated, unsaturated or partially saturated mono-, bi-or tricyclic ring containing 3, 4, 5, 6. For example, 3-to 10-membered cycloalkyl 4-7 membered cycloalkyl, 3-6 membered cycloalkyl.
As used herein, the term "cycloalkylene" refers to a group formed by the removal of one more hydrogen atom from a "cycloalkyl" group.
The terms "C 3～15 heterocycloalkyl", "C 3～15 heterocyclyl", "3-15 membered heterocyclyl" or "3-15 membered heterocycloalkyl" as used herein refer to a saturated, unsaturated or partially saturated mono-, bi-or tricyclic ring containing 3, 4, 5, 6..15 ring atoms, wherein the heteroatoms refer to nitrogen, oxygen, sulfur atoms, etc. Typically a monovalent saturated or partially unsaturated mono-or bicyclic ring system of multiple ring atoms comprising 1, 2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Unless otherwise indicated, heteroatoms may be attached through carbon or nitrogen, wherein the-CH 2- group is optionally replaced by-C (O) -and wherein, unless otherwise indicated, the ring nitrogen atom or ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or the ring nitrogen atom is optionally quaternized, wherein the-NH group in the ring is optionally substituted with acetyl, formyl, methyl or methylsulfonyl, and the ring is optionally substituted with one or more halogens. It will be appreciated that when the total number of S and O atoms in the heterocyclyl exceeds 1, these heteroatoms are not adjacent to one another. If the heterocyclyl is bicyclic or tricyclic, at least one ring may optionally be heteroaromatic or aromatic, provided that at least one ring is non-heteroaromatic. If the heterocyclyl is a single ring, it must not be aromatic. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methylsulfonylpiperazinyl, homopiperazinyl, piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolyl, tetrahydroquinolinyl, indolinyl, tetrahydropyranyl, dihydro-2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1, 1-dioxide, 1H-pyridin-2-one, and 2, 5-dioxoimidazolidinyl. For example, 3-to 10-membered heterocycloalkyl 4-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl.
The 4-7 membered heterocyclic ring in the invention refers to a 4-, 5-, 6-or 7-membered saturated or unsaturated heterocyclic ring, wherein the unsaturated heterocyclic ring refers to a group or molecule containing a carbon-carbon double bond, a carbon-carbon triple bond, a carbon-oxygen double bond, a carbon-sulfur double bond, a carbon-nitrogen triple bond and the like.
As used herein, the term "heterocycloalkylene" refers to a group formed by the removal of one more hydrogen atom from a "heterocycloalkyl" group.
Herein, the term "3-10 membered aryl" is understood to mean a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 3, 4, 5, 6. For example, a 4-to 7-membered aryl group 3-6 membered aryl.
As used herein, the term "arylene" refers to a group formed by the removal of one more hydrogen atom from an "aryl" group.
Herein, the term "3-10 membered heteroaryl" is understood to have 3, 4, 5, 6..10 ring atoms and comprises one or more monovalent monocyclic, bicyclic, or tricyclic aromatic ring groups independently selected from heteroatoms of N, O and S. Preferably 1 to 3 monovalent monocyclic, bicyclic or tricyclic aromatic ring groups independently selected from the heteroatoms of N, O and S, and additionally may be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and the like. For example, a 4-to 7-membered heteroaryl, a 3-to 6-membered heteroaryl.
As used herein, the term "heteroarylene" refers to a group formed by the removal of one more hydrogen atom from a "heteroaryl" group.
In this context, the terms "-NR-", "-N (R) 2", etc., refer to an R group attached singly to an oxygen or nitrogen atom.
In the description of the radicals according to the inventionAre used to describe the positions of substitution of groups.
As used herein, the term "pharmaceutically acceptable adjuvant" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, all of which are known to those of skill in the art (as described in Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1990,pp.1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
As used herein, the term "administering" refers to introducing a predetermined amount of a substance into a patient by some suitable means. The compound or pharmaceutical composition of the present invention may be administered by any common route, as long as it reaches the intended tissue. Various modes of administration are contemplated, including peritoneal, intravenous, intramuscular, subcutaneous, etc., but the invention is not limited to these illustrated modes of administration.
In this context, the term "treatment" refers to the use to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing the disease or symptoms thereof, and/or may be therapeutic in terms of partially or completely curing the disease and/or adverse effects caused by the disease. "treating" as used herein encompasses diseases in mammals, particularly humans, including (a) preventing the occurrence of a disease or disorder in an individual susceptible to the disease but not yet diagnosed with the disease, (b) inhibiting the disease, e.g., arresting the development of the disease, or (c) alleviating the disease, e.g., alleviating symptoms associated with the disease. As used herein, "treating" or "treatment" encompasses any administration of a drug or compound to an individual to treat, cure, alleviate, ameliorate, reduce or inhibit a disease in the individual, including, but not limited to, administration of a drug comprising a compound described herein to an individual in need thereof.
The scheme of the present invention will be explained below with reference to examples. It will be appreciated by those skilled in the art that the following examples are illustrative of the present invention and should not be construed as limiting the scope of the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The instruments and reagents employed in the examples or test cases of the present invention are as follows:
1. Luciferase reporter gene experimental instrument and reagent
Cell lysate: PASSIVE LYSIS buffer was purchased from Promega corporation;
single substrate kit Steady-Glo luciferases ASSAY SYSTEM # E2550 was purchased from Promega corporation.
RT-qPCR experimental instrument and reagent
Trizol RNAiso Plus #9109 is available from TAKARA company;
Reverse transcription kit 5X HISCRIPTIIQRT SUPERMIX was purchased from Nanjinopran company;
the fluorescence quantitative kit is iTaq Universal SYBR Green Supermix #1725124 purchased from BIO-RAD company;
The fluorescence quantitative PCR instrument CFX Connect is purchased from BIO-RAD company;
MTT kit #40201ES80 was purchased from Shanghai, a company of san Biotech Co., ltd;
CCK8 kit #C0005 available from Shanghai Tao Shu Biotechnology Co., ltd;
human TNF alpha cytokine #300-01A was purchased from PEPROTECH company;
Murine TNFα cytokine #315-01A was purchased from PEPROTECH;
human IL-1. Beta. Cytokine: #200-01B was purchased from PEPROTECH company;
human IFN beta cytokines #300-02bc were purchased from PEPROTECH company;
human IFN gamma cytokines #300-02 were purchased from PEPROTECH;
human IL-33 cytokines: #200-33 were purchased from PEPROTECH company;
Human IL-36 cytokine #200-36A was purchased from PEPROTECH company;
DMSO: #0231 was purchased from Amresco.
EXAMPLE 1 preparation or obtaining of Compounds
1. Compound Ti2
Synthetic roadmap for Ti 2:
Synthesis of ethyl 2-oxobutyrate diethyl oxalate (10 g,1.0 equiv.) was dissolved in Et 2 O (100 mL) and cooled to-78 ℃. Propyl magnesium chloride (1.0 mol/L THF;72mL;71.8mmol,1.05 equiv.) was slowly added via syringe. The dry ice/acetone bath was melted and heated to 10 ℃. The reaction was cooled to 0 ℃ and quenched with saturated NH 4 Cl. And extracted with ethyl acetate and H 2 O, the organic layer was dried over Na 2SO4, filtered and concentrated. 7.6g of a crude yellow oil was isolated in 86% yield.
Synthesis of methyl 1-Boc-pyrrolidine-3-carboxylate 1-Boc-pyrrolidine-3-carboxylic acid (2.15 g,1.0 equiv.) and CH 3 I (1.70 g,1.2 equiv.) are added to a DMF solution (20 mL) containing potassium carbonate (2.76, 2.0 equiv.) and extracted with ethyl acetate and H 2 O, the organic layer is dried over Na 2SO4, filtered and concentrated to give methyl 1-Boc-pyrrolidine-3-carboxylate 2.01g in 72.4% yield. Methyl 1-Boc-pyrrolidine-3-carboxylate (2.0 g,1.0 equiv.) is reacted with LiAlH 4 (2.4 g,1.2 equiv.) in anhydrous diethyl ether to give 1.4g of 1-Boc-3-hydroxymethylpyrrolidine.
Synthesis of 3-methoxymethyl-pyrrolidine-1H hydrochloride 1-Boc-3-hydroxymethylpyrrolidine (1.0 g,1.0 equiv.) was reacted overnight with CH 3 I (0.84 g,1.2 equiv.) in DMF solution (6 mL) containing potassium carbonate (1.38 g,2.0 equiv.) to give 3-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (or 3-methoxymethyl-pyrrolidine-1-Boc) in 60% yield. Thionyl chloride (1 mL,2.9 equiv.) is added dropwise to a solution of tert-butyl 3-methoxymethyl-pyrrolidine-1-carboxylate (1.03 g,1.0 equiv.) in methanol (25 mL) at room temperature under nitrogen. The reaction mixture was refluxed for 2 hours and cooled at room temperature. The reaction mixture was concentrated and the crude product was dissolved in dichloromethane. The solution was concentrated to give 0.79g (100%) of 3-methoxymethyl-pyrrolidine-1H hydrochloride as an off-white solid.
Synthesis of ethyl 2- (2- (4-chlorophenyl) hydrazino) butyrate to an ethanol mixture (10 additions) containing ethyl 2-oxobutyrate (1.78 g,1.0 equiv.) p-chlorophenylhydrazine hydrochloride (1.30 g,1.0 equiv.) was added, and a catalytic amount of acetic acid was added, and the reaction mixture was refluxed at 80℃for 3 hours. After completion of the TLC (mobile phase 8:2 ethyl acetate: hexane) the solvent was distilled off in vacuo at 50℃to give a residue, which was extracted with ethyl acetate and water. The pH of the reaction mixture was adjusted to 7-8 with sodium carbonate, then the ethyl acetate layer was separated, dried over sodium sulfate and distilled off under vacuum at 500℃to give ethyl 2- (2- (4-chlorophenyl) hydrazino) butyrate.
Synthesis of ethyl 5-chloro-3-methyl-1H-indole-2-carboxylate A concentrated solution of ethyl 2- (2- (4-chlorophenyl) hydrazono) butyrate (5.09 g,0.02 mol) in HCl (20 mL) was heated and then refluxed on a water bath (70-80 ℃ C.) for 4 hours, the crude product was filtered and the product was washed with water until the test result was neutral to litmus to give ethyl 5-chloro-3-methyl-1H-indole-2-carboxylate.
Synthesis of 5-chloro-3-methyl-1H-indole-2-carbonyl chloride 5-chloro-3-phenyl-1H-indole-2-carboxylic acid ethyl ester (697 mg,1.0 equiv.) and 6N NaOH (775. Mu.L, 2.0 equiv.) were added to 25ml EtOH and the resulting mixture stirred at 70℃for 3H until the reaction was complete, the mixture was acidified and almost completely evaporated. More water was added and the precipitate was collected by filtration and dried in a vacuum oven. To give 5-chloro-3-phenyl-1H-indole-2-carboxylic acid (620 mg,1.0equiv.,98% yield) as an orange solid. Subsequently, 5-chloro-3-phenyl-1H-indole-2-carboxylic acid (2.37 g) was reacted with SOCl 2 at room temperature to give 5-chloro-3-methyl-1H-indole-2-carbonyl chloride.
1.7 Synthesis of 5-chloro-2- ((3- (methoxymethyl) pyrrolidin-1-yl) methyl) -3-methyl-1H-indole 5-chloro-3-methyl-1H-indole-2-carbonyl chloride (2.28 g,3.0 equiv.) was added to a solution of 3- (methoxymethyl) pyrrolidine-1H hydrochloride (1.5 g,1.0 equiv.) obtained in this example in dry dichloromethane (10 mL), pyridine (3 mL,10.0 equiv.) was added and the reaction mixture was stirred at room temperature for 48 hours. Treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, meOH/CH 2Cl2) to give (5-chloro-3-methyl-1H-indol-2-yl) (3- (methoxymethyl) pyrrolidin-1-yl) methanone. Finally (5-chloro-3-methyl-1H-indol-2-yl) (3- (methoxymethyl) pyrrolidin-1-yl) methanone (2.93 g,1.0 equiv.) is reacted with diisobutylaluminum hydride (DIBAL-H, 0.76g,2.0 equiv.) under anhydrous and anaerobic conditions to give 5-chloro-2- ((3- (methoxymethyl) pyrrolidin-1-yl) methyl) -3-methyl-1H-indole at-78 ℃. See fig. 11 for characterization of compound Ti 2.
2. Compound Ti20
2.1 Synthesis of Compound Ti20
1) First step reaction-Synthesis of Compound 26
To a solution of 3- (1- (tert-butylcarbonyl) piperidin-4-yl) propionic acid (10 g,1.0 equiv.) and (4-fluorophenyl) methylamine (5 g,1.0 equiv.) in N, N-dimethylformamide (100 mL), dichloromethane (100 mL) were added hydroxybenzotriazole (HOBt) (5 g,1.0 equiv.) and triethylamine (10 mL,3.0 equiv.). Stirred under nitrogen for 15 minutes, then EDC.HCl (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, CAS:25952-53-8;10.6g,1.3 equiv.) was added. The reaction mixture was stirred overnight, and methylene chloride (200 ml) was added to dilute the mixture. Washed with saturated NH 4 Cl (3 x 300 mL) and brine (300 mL) and dried over MgSO 4. The solvent was evaporated and then flash chromatographed in dichloromethane with 0-1% methanol to give tert-butyl 4- (3- (4-fluorobenzylamine) -3-oxopropyl) piperidine-1-carboxylate (13 g, 92% yield). 2) Second reaction-Synthesis of Compound 27
Trifluoroacetic acid (25 mL) was added dropwise to a solution of 4- (3- (4-fluorobenzylamine) -3-oxypropyl) -piperidine-1-carboxylic acid tert-butyl (13 g,0.036 mmol) in dichloromethane (150 mL). The reaction mixture was stirred overnight. 500mL of water was added and the organic layer was separated. The aqueous phase was washed with diethyl ether (150 mL). NaOH solution was added at 0 ℃, adjusting ph=13. Extracted with dichloromethane (2X 250 mL). The combined organic layers were washed with brine and dried over Na 2SO4. Evaporation of the solvent gave N- (4-fluorophenyl) -3- (piperidin-4-yl) propanamide (7.2 g, 77% yield).
3) Third step reaction-Synthesis of Ti20
N- (4-fluorophenyl) -3- (piperidin-4-yl) propionamide (7.2 g,1.0 equiv.) was dissolved in 1, 2-dichloroethane (170 mL) at 40 ℃. The solution was then cooled in ice water. 1H-indole-2-carbaldehyde (6.37 g,1.6 equiv.) was added. To the above mixture was added sodium triacetoxyborohydride (8.7 g,1.5 equiv.) followed by acetic acid (2.2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0 ℃ again. NaOH (30 ml) was added to quench the reaction. The organic layer was separated, washed with brine, dried over MgSO 4, and then filtered to remove MgSO 4. 5g of activated carbon was added to the filtrate. Stir overnight. Filtering to remove the active carbon. The solvent was evaporated and flash chromatographed in dichloromethane using 1.5% -4.5% methanol to give the desired compound Ti20 (5.5 g, 58% yield) as a solid. The compound Ti20 is characterized as follows:
1HNMR(400MHz,CDCl3,ppm):δ8.79(s,1H),7.57(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.24-7.26(m,2H),7.17(t,J＝7.5Hz,1H),7.10(t,J＝7.5Hz,1H),7.03(t,J＝8.6Hz,2H),6.37(s,1H),5.76(s,1H),4.41(d,J＝5.7Hz,2H),3.70(s,2H),2.94(d,J＝11.1Hz,2H),2.24(t,J＝7.8Hz,2H),2.00-2.10(m,2H),1.60-1.75(m,4H),1.25-1.40(m,3H).
2.2 Synthesis of the Compounds Ti 36-Ti 39
The preparation of the compounds Ti36 to Ti39 is referred to the synthesis of the compound Ti20 in this example. The structural formula and the nuclear magnetic characterization result of the compounds Ti 36-Ti 39 are shown in the following table:
3. Compound Ti28
3.1 Synthesis of Compound Ti28
1) First step reaction-Synthesis of Compound 2
To 50mL of a toluene solution of ethyl trifluoroacetate (9.17 g,1.5 equiv.) at 0deg.C, naH (4.30 g,60% purity, 3.0 equiv.) was slowly added. Then stirred at 80 ℃ for 30min, 5mL of a toluene solution of ethyl butyrate (5.00 g,1.0 equiv.) was added dropwise. The resulting mixture was stirred at 110 ℃ for 6 hours. The reaction mixture was cooled and poured into 50mL of aqueous NH 4 Cl, the layers were separated and extracted with ethyl acetate (20.0 mL. Times.2). The organic layer was collected with 20ml of 2% hcl aqueous solution, dried over Na 2SO4, filtered and concentrated under reduced pressure to give compound 2 as a yellow oil which was used in the next step without further purification.
2) Second reaction-Synthesis of Compound 3 from Compound 2
Compound 2 (4.20 g,0.02 mmol) and guanidine hydrochloride (1.89 g,1.0 equiv.) are dissolved in 40mL of methanol, and potassium t-butoxide (4.44 g,2.0 equiv.) is added. The reaction was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a solid substance, which was then purified by column chromatography (silica gel column, dichloromethane: methanol=60:1 to 30:1) to obtain compound 3 (2-amino-5-ethyl-6- (trifluoromethyl) pyrimidin-4-ol, 1.2 g) as a pale yellow solid.
3) Third reaction-Synthesis of Compound 4 from Compound 3
POCl 3 (88 mg,0.005 mmol) was added to 10mL of a toluene solution (10 mL) of compound 3 (400 mg, 0.002mmol) at 25 ℃. The reaction was stirred at 110 ℃ for 4 hours. The reaction mixture was concentrated under reduced pressure to give compound 4 (300 mg) as a yellow solid, which was used in the next step without further purification.
4) Fourth step of synthesizing compound Ti28
To a solution of 3- (3-methyl-1H-pyrazol-1-yl) propylamine hydrochloride (350 mg,1.0 equiv.) in DMSO (5 mL) was added potassium tert-butoxide (895 mg,2.5 equiv.). After the addition, stirring was carried out at 100℃for 1 hour, and then compound 4 (300 mg,1.0 equiv.) was added. The resulting mixture was stirred at 100 ℃ for 12 hours. To the reaction mixture was added 20mL of water, extracted with ethyl acetate (10 ml×2), washed with NaCl solution (10 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure to give a solid substance. Purification by high performance liquid chromatography (column: waters xbridge X25 mm 10 μm; mobile phase: [ water (NH 4HCO3) -ACN ]; B%:28% -58%,8 min) afforded compound Ti28 (35 mg, yield 7.87%) as a pale yellow solid. The compound Ti28 is characterized as follows:
LCMS:EC2672-23-P1A,Rt=0.632min,m/z=329.2(M+1)+
1H NMR:EC2672-23-P1A(400MHz,DMSO-d6)
δ7.58(d,J＝2.0Hz,1H),6.97(br s,1H),6.21(s,2H),5.99(d,J＝2.0Hz,1H),4.04(t,J＝7.2Hz,2H),2.44(br d,J＝7.2Hz,2H),2.15(s,3H),2.08-1.98(m,2H),1.00(br t,J＝6.8Hz,3H).
3.2 Synthesis of Compounds Ti29 to Ti33, ti59
The preparation of the compounds Ti29 to Ti33 and Ti59 refers to the synthesis of the compound Ti28 in this example. The structural formulas and the nuclear magnetic characterization results of the compounds Ti 29-Ti 33 and Ti59 are shown in the following table:
4. Compound Ti34
4.1 Synthesis of Compound Ti34
1) First step reaction-Synthesis of Compound 17
Trifluoroethyl methanesulfonate (6.42 g,1.2 equiv.) was added to a solution of ethyl acetoacetate (3 g,1.0 equiv.) and sodium t-butoxide (1 m,25.4 mL) in THF (30 mL). Stirred at 50 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The solid was diluted with H 2 O (30 mL), extracted with ethyl acetate (30 mL. Times.3), dried over Na 2SO4, the organic layer was filtered and concentrated to a solid under reduced pressure. Purification by column chromatography (SiO 2, petroleum ether: ethyl acetate=20/1 to 4/1, petroleum ether: ethyl acetate=5:1, rf=0.70). Compound 17 (1.02 g) was obtained as a pale yellow liquid in 20.9% yield.
2) Second reaction-Synthesis of Compound 18
To a solution of compound 17 (1 g,1.0 equiv.) and guanidine hydrochloride (540 mg,1.2 equiv.) in MeOH (3 mL) was added sodium t-butoxide (906 mg,2.0 equiv.). The mixture was stirred at 50 ℃ for 2 hours and then concentrated under reduced pressure to remove the solvent. The solid was diluted with H 2 O (10 ml), extracted with ethyl acetate (10 ml. Times.3), dried over Na 2SO4, the organic layer was filtered and concentrated to a solid under reduced pressure. Purification by column chromatography (SiO 2, petroleum ether: ethyl acetate=2/1~0/1, petroleum ether: ethyl acetate=1:1, rf=0.2). Compound 18 (0.10 g) was obtained as a yellow solid in 10.2% yield.
2) Third reaction-Synthesis of Compound 19
Compound 18 (30 mg,1.5 equiv.) and pyridine (23.4 μl) were added to a dichloromethane (2L) solution, followed by trifluoromethanesulfonic anhydride (47.8 μl,1.0 equiv.). The reaction was stirred at 25 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. Compound 19 (120 mg) was obtained as a brown solid without further purification. 4) Fourth step reaction-Synthesis of Compound Ti34
3-Dimethylaminopyrrolidine (67.3 mg,1.1 equiv.) and K 2CO3 (61.11 mg,1.5 equiv.) are added to a solution of compound 19 (100 mg,1.0 equiv.) in CH 3 CN (2.00 mL). Stirred for 1 hour at 25℃and diluted with water (5.00 mL) and extracted with ethyl acetate (10 mL. Times.3). The organic layer was dried over Na 2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by high performance liquid chromatography (column: waters xbridge 150 X125 mm10 μm; mobile phase: [ water (ammonium hydroxide v/v) -ACN ]; B%:17% -47%,8 min) afforded compound Ti34 (7.67 mg, yield 8.37%) as a brown solid. The compound Ti34 is characterized as follows:
LCMS:Rt=1.902min,m/z=304.2,M+H+
HPLC:Rt=2.398min
1H NMR:(400MHz,CDCl3)
δ4.56(s,2H),3.55-3.64(m,3H),3.44-3.48(m,2H),3.40(t,J＝6.8Hz,1H),2.57-2.65(m,1H),2.25(s,3H),2.23(s,6H),2.04-2.10(m,1H),1.66-1.80(m,1H).
4.2 Synthesis of Compounds Ti13, ti35a and Ti35b
Preparation of the Compounds Ti13, ti35a and Ti35b reference is made to the synthesis of the compound Ti34 in this example. The structural formulas and the nuclear magnetic characterization results of the compounds Ti13, ti35a and Ti35b are shown in the following table:
5. synthesis of Compound Ti58
Synthetic roadmap for Ti 58:
Synthesis of Compound 12 to a solution of 2, 6-dichloro-4-methylnicotinic acid (5 g,1.0 equiv.) in dichloromethane (50 mL) were added thionyl chloride (4.60 g,1.5 equiv.) and DMF (17.7 mg). Stirring was carried out at 40℃for 4 hours, and then the mixture was concentrated under reduced pressure to give compound 12 (5.37 g, yield 98.6%) as a butter.
Synthesis of Compound 13 to a solution of Compound 12 (5.37 g,1.0 equiv.) in tetrahydrofuran (50 mL) was added dropwise methyl magnesium bromide (7.97 mL,2.5 equiv.) at 0deg.C, followed by stirring at 0deg.C for 1 hour. The reaction was quenched by the addition of 10mL of H 2 O, extracted with ethyl acetate (10 ml×3), dried over Na 2SO4, filtered, concentrated under reduced pressure and the product purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=2:1 to 3:1, petroleum ether: ethyl acetate=10:1, r f =0.40). Compound 13 (2.40 g, 49.2% yield) was obtained as a yellow oil.
Synthesis of Compound 14 sodium tert-butoxide (353 mg,2.0 equiv.) and Compound 13 (500 mg) were added to a DMSO (3 mL) solution containing 3- (3-methylpyrazol-1-yl) propylamine hydrochloride (375 mg,1.0 equiv.) and the resulting mixture was stirred at 120℃for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. Dilute with H 2 O (10 mL) and extract with ethyl acetate (10 mL x 3). Dried over Na 2SO4, filtered, concentrated under reduced pressure and the product purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=10:1 to 1:1, petroleum ether: ethyl acetate=3:1, r f =0.1). Compound 14 (125 mg, yield 22.2%) was obtained as a yellow oil.
Synthesis of Compound 15 Compound 14 (102.2 mg,1.0 equiv.), t-butyl carbamate (57.3 mg,1.5 equiv.), dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (Xphos, 46.6mg,1% equiv.), palladium acetate (14.6 mg,1% equiv.) and sodium t-butoxide (47 mg,1.5 equiv.) were dissolved in 1, 4-dioxane (2 mL). The mixture was degassed and aerated 3 times with N 2 and the resulting mixture was stirred under N 2 protection at 100 ℃ for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the product was purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=3:1 to 0:1, petroleum ether: ethyl acetate=3:1, r f =0.3) to give compound 15 (110 mg) as a brown oil.
Synthesis of Ti58 to a solution of Compound 15 (0.11 g) in ethyl acetate (10 mL) was added HCl/ethyl acetate (4M, 709. Mu.L). The resulting mixture was stirred at 50 ℃ for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H 2 O (10 mL) and extracted with ethyl acetate (10 mL. Times.3). Dried over Na 2SO4, filtered, concentrated under reduced pressure and the product purified by column chromatography (SiO 2, petroleum ether: ethyl acetate=3:1 to 1:1, petroleum ether: ethyl acetate=2:1, p1r f =0.3). Compound Ti58 (47 mg, yield 52.8%) was obtained as a yellow solid. The compound Ti58 is characterized as follows:
LCMS:,Rt=0.760min,m/z=288.3,M+H+
HPLC:,Rt=2.090min
1H NMR:(400MHz,CDCl3)
δ7.31(d,J＝2.0Hz,1H),5.99(d,J＝1.6Hz,1H)5.61(s,1H),4.58(s,1H),4.13(t,J＝6.8Hz,2H),3.43(q,J＝6.4Hz,2H),2.50(s,3H),2.42(s,3H),2.28(s,3H),3.14～2.17(m,2H).
6. Some of the compounds in this example are commercially available, see in particular the following table:
test example 1 inhibition of TNF alpha-induced NF- κB activation by Compounds
1. The following tests were carried out using the compound obtained in example 1 and the synthesized compound:
Each of the compounds (10. Mu.M) obtained in the above examples of the present invention was treated for 20 minutes with DMSO as a control, followed by cytokine TNFα (10 ng/mL) for 6 hours in HCT116-Nifty cells (2X 10 5 cells), the medium was discarded, cells were lysed for 15 minutes with 1X PASSIVE LYSIS buffer lysate (100. Mu.L/well), and luciferase reporter activity in the cell lysate was measured. The results of the assays demonstrate that the compounds of the invention each specifically inhibit tnfα -induced activation of NF- κb, wherein the assay example illustratively demonstrates the assay results for Ti1, ti2, ti3, ti5, ti7, ti8, ti9, ti10, ti11 and Ti13, see fig. 1.
FIG. 1 shows that Ti1, ti2, ti3, ti5, ti7, ti8, ti9, ti10, ti11 and Ti13 inhibit TNFα -induced NF- κB activation.
2. Further, the inhibition effect of the compounds Ti11, ti28, ti13 and Ti34 with different dosages on NF- κB activation induced by TNF alpha is tested, and the specific steps are as follows:
2.1 adding the compound Ti28, the compound Ti13 and the compound Ti34 obtained in the above examples of the present invention respectively to HCT116-Nifty cells (2X 10 5 cells) at the doses shown in the figures, then treating for 20 minutes, adding cytokine TNFα (10 ng/mL) for 6 hours, discarding the medium, adding 1X PASSIVE LYSIS buffer lysate (100. Mu.l/well) for lysing the cells for 15 minutes, and then detecting the luciferase reporter activity in the cell lysate, and the results are shown in FIG. 2A, FIG. 3A and FIG. 3B.
The compound Ti20 obtained in the above example of the present invention was added to HCT116-Nifty cells (2X 10 5 cells) at the indicated dose, treated for 20 minutes, treated with or without cytokine TNFα (10 ng/mL) for 6 hours, medium was discarded, cells were lysed for 15 minutes by adding 1X PASSIVE LYSIS buffer lysate (100. Mu.l/well), and luciferase reporter activity in the cell lysate was detected, as a result of which see FIG. 4.
2.2 Compounds Ti28 obtained in the above examples of the present invention were added to 293-Nifty cells (2X 10 5 cells) at the indicated dose, and then treated for 20 minutes, cytokine TNFα (10 ng/mL) was added for 6 hours, medium was discarded, cells were lysed by adding 1X PASSIVE LYSIS buffer lysate (100. Mu.l/well) for 15 minutes, and luciferase reporter activity in the cell lysate was detected, as a result of which see FIG. 2B.
2.3 Addition of the compound Ti28 obtained in the above example of the invention to HCT116-Nifty cells (5X 10 5 cells) at the indicated concentrations, the absorbance at 460nm was measured after 72 hours according to the CCK8 kit instructions and the results are shown in FIG. 2C.
From the results of fig. 2, 3 and 4 obtained in the above step 2 in the present test example, it can be seen that:
FIG. 2A shows that the small molecule compound Ti28 dose-dependently inhibited TNFα -induced NF- κB activation in HCT116 cells. FIG. 2B shows that the small molecule compound Ti28 dose-dependently inhibited TNFα -induced NF- κB activation in 293 cells. Fig. 2C shows that the small molecule compound Ti28 does not affect cell survival.
FIG. 3A shows that the small molecule compound Ti13 dose-dependently inhibited TNFα -induced NF- κB activation in HCT116 cells. FIG. 3B shows that the small molecule compound Ti34 dose-dependently inhibited TNFα -induced NF- κB activation in HCT116 cells.
FIG. 4 shows that the small molecule compound Ti20 dose-dependently inhibited TNFα -induced NF- κB activation.
Test example 2 specific inhibition of TNF-induced inflammatory response by Compounds
The following tests were carried out using the compound obtained in example 1 and the synthesized compound:
1.1 treatment of HCT116-Nifty cells (2X 10 5 cells) with the compounds obtained in the above examples of the invention at the indicated doses for 20 minutes, respectively with the cytokines TNFα (10 ng/mL) or IL-1β (2 ng/mL), after 6 hours, the medium was discarded, the cells were lysed with 1X PASSIVE LYSIS buffer lysate (100. Mu.l/well) for 15 minutes, and the luciferase reporter activity in the cell lysates was examined.
1.2 Treatment of HCT116 cells (5X 10 5 cells) with the compounds (10. Mu.M) obtained in the above examples of the invention for 20 minutes, respectively with the cytokines TNFα (10 ng/mL), IL-1β (2 ng/mL), IFNβ (20 ng/mL) or IFNγ (20 ng/mL), after 1 hour, the cells were harvested and lysed with Trizol, RNA was extracted and RT-qPCR detection was performed.
1.3 Treatment with the compounds obtained in the above examples of the invention (10. Mu.M) in HCT116 or HepG2 for 20 min, with the cytokine TNF. Alpha. (10 ng/mL) for 24 and 48 hours respectively, followed by MTT (0.5 mg/mL), the cells were further cultured for 4 hours, the medium was discarded and 150. Mu.L of DMSO was added, and the crystals were allowed to dissolve well by shaking at low speed on a shaker for 10min, and the absorbance of each well was measured at OD490 nm.
1.4 Treatment of L929 cells (5X 10 5 cells) with each of the compounds (10. Mu.M) obtained in the above examples of the present invention for 20 minutes followed by treatment with mouse cytokine mTNFα (10 ng/mL) for 1.5 hours or 3 hours, after which the cells were harvested and lysed with Trizol, RNA was extracted and subjected to RT-qPCR detection.
1.5 Treatment of HCT116 cells (5X 10 5 cells) with the respective compounds (10. Mu.M) obtained in the above examples of the invention for 20 minutes, cytokine TNFα (10 ng/mL) was added separately, and after 1 hour, the cells were harvested and immunoblotted with NP40 lysed cells.
1.6 Addition of the compounds (10. Mu.M) obtained in the above examples of the present invention to 293-IL-33R-Nifty cells (2X 10 5 cells) for 20 minutes, followed by addition of the cytokines IL33 (50 ng/mL) or IL36 (50 ng/mL), treatment for 6 hours, removal of the medium, lysis of the cells for 15 minutes by addition of 1X PASSIVE LYSIS buffer lysate (100. Mu.L/well), and detection of luciferase reporter activity in the cell lysate.
As can be seen from the detection results obtained in the experiments 1.1-1.6 in the test example, the compounds of the present invention can specifically inhibit inflammatory response induced by TNF. The test examples exemplarily show the detection results of Ti2, ti11, ti13, ti15, ti16, ti17, ti18, ti19 and Ti20, and specifically refer to fig. 5 to 8.
FIG. 5A shows that the small molecule compound Ti2 dose-dependently inhibited TNFα -induced NF- κB activation, but did not inhibit IL-1β -induced NF- κB activation. Fig. 5B shows that the small molecule compound Ti2 significantly inhibited tnfα -induced transcription of downstream genes, but did not inhibit IL-1β -induced transcription of downstream genes. Fig. 5C shows that the small molecule compound Ti2 does not affect cell growth.
FIG. 6A shows that the small molecule compound Ti11 dose-dependently inhibited TNFα -induced NF- κB activation, but did not inhibit IL-1β -induced NF- κB activation. Fig. 6B shows that the small molecule compound Ti11 significantly inhibited tnfα -induced transcription of downstream genes, but did not inhibit IL-1β -induced transcription of downstream genes in human cells. Fig. 6C shows that the small molecule compound Ti11 inhibits mtnfα -induced transcription of downstream genes in mouse cells. Fig. 6B and 6C together illustrate that Ti11 inhibits tnfα -induced inflammatory responses in both human and mouse cells. FIG. 6D shows that the small molecule compound Ti11 does not inhibit IFNbeta-induced transcription of ISG56 nor IFNgamma-induced transcription of IRF 1. Fig. 6E shows that small molecule compound Ti11 inhibits tnfα -induced phosphorylation of the induced key molecules ikkβ and p65, suggesting that Ti11 is a target for its action on ikkβ and its upstream proteins. Fig. 6F shows that the small molecule compound Ti11 does not affect cell growth.
FIG. 7A shows that the small molecule compound Ti13 dose-dependently inhibited TNFα -induced NF- κB activation, but did not inhibit IL-1β -induced NF- κB activation. Fig. 7B shows that the small molecule compound Ti13 significantly inhibited tnfα -induced transcription of downstream genes, but did not inhibit IL-1β -induced transcription of downstream genes in human cells. Fig. 7C shows that the small molecule compound Ti13 inhibited mtnfα -induced transcription of downstream genes in mouse cells. Fig. 7B and 7C together demonstrate that Ti13 inhibits tnfα -induced inflammatory responses, both in human and mouse cells. FIG. 7D shows that the small molecule compound Ti13 does not inhibit IFNbeta-induced transcription of ISG56 nor IFNgamma-induced transcription of IRF 1. Fig. 7E shows that the small molecule compound Ti13 inhibits tnfα -induced phosphorylation of the induced key molecules ikkβ and p65, suggesting that the Ti13 is targeted on ikkβ and its upstream proteins. Fig. 7F shows that the small molecule compound Ti13 does not affect cell growth.
FIG. 8A shows that small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 inhibit TNFα -induced NF- κB activation. FIG. 8B shows that the small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 do not inhibit IL-1β -induced activation of NF- κB. FIG. 8C shows that the small molecule compounds Ti17, ti18 and Ti20 do not inhibit IL-33 induced NF- κB activation. FIG. 8D shows that small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 do not inhibit IL-36 induced activation of NF- κB. The experimental results above together demonstrate that small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 specifically inhibit TNF alpha-induced activation of NF- κB.
FIG. 8E shows that small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 inhibit TNFα -induced transcription of downstream genes CXCL1 and CXCL 2. FIG. 8F shows that the small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 do not inhibit IL-1β -induced transcription of the downstream genes CXCL1 and CXCL 2. Together, the above experimental results demonstrate that small molecule compounds Ti2, ti15, ti16, ti17, ti18, ti19 and Ti20 specifically inhibit tnfα -induced transcription of downstream genes CXCL1 and CXCL 2.
Test example 3 Compounds inhibit TNF signaling pathway by targeting TNFR1-TRADD-RIP1-TRAF2 Complex
The following tests were carried out using the compound obtained in example 1 and the synthesized compound:
TNFR1, TRADD, RIP1, TRAF2, IKKK beta or p65 expression plasmid (0.5. Mu.g) was transfected into HCT116-Nifty cells (2X 10 5 cells), treated for 4 hours with each compound (40. Mu.M) obtained in the above examples of the present invention, and then the cells were lysed by removing the medium, adding 1X PASSIVE LYSIS buffer lysate (100. Mu.l/well) for 15 minutes, and then luciferase reporter gene activity in the cell lysate was examined. Wherein at least 2 parallel experimental groups are set for each compound. The results of the assays demonstrate that the compounds of the invention all inhibit the TNF signaling pathway by targeting the TNFR1-TRADD-RIP1-TRAF2 complex, wherein the assay example exemplarily demonstrates the results of Ti2, ti11 and Ti13 assays, see fig. 9, respectively.
FIG. 9A shows that small molecule compound Ti2 inhibits activation of NF-. Kappa.B mediated by the upstream proteins TNFR1, RIP1 and TRAF2, but does not inhibit activation of Nifty mediated by the downstream proteins IKKKβ and p 65. FIG. 9B shows that small molecule compound Ti11 inhibits upstream protein TNFR1 and TRADD mediated activation of NF- κB, but not downstream protein IKKKβ and p65 mediated activation of Nifty. FIG. 9C shows that the small molecule compound Ti13 inhibits the upstream protein TNFR 1-mediated activation of NF- κB, but does not inhibit the downstream proteins IKKKβ and p 65-mediated activation of NF- κB.
Thus, the above results may demonstrate that the compounds of the present invention all inhibit the TNF signaling pathway by targeting the TNFR1-TRADD-RIP1-TRAF2 complex.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (15)

1.化合物或其立体异构体、药学上可接受的盐在制备试剂中的用途，所述试剂用于抑制TNF信号通路；1. Use of a compound or its stereoisomers or pharmaceutically acceptable salts in the preparation of an agent for inhibiting TNF signaling pathway; 所述化合物具有如下(IIa2)、(IIIa1)或(IIIb)所示的结构：The compound has the structure shown below: 1）(IIa2)，1) (IIa2), 其中，X3为N、X4为C或N、X6为C或N，wherein X3 is N, X4 is C or N, X6 is C or N, R3为H、卤素、-C1~3烷基或者-C1~3氧烷基， R3 is H, halogen, -C1 ~3 alkyl or -C1 ~3 oxyalkyl, R7为H或者-C1~3烷基， R7 is H or -C1 ~3 alkyl, R8为H或者-C1~3烷基， R8 is H or -C1 ~3 alkyl, R11为任选被卤素或-C1~3烷基取代的-5~7元芳基；R 11 is a 5- to 7-membered aryl group optionally substituted by halogen or -C 1-3 alkyl; 2）(IIIa1)，2) (IIIa1), 其中，X1为N，Where X1 is N, p1为2、3、4或5，p1 is 2, 3, 4, or 5, R4为H、任选被一个或多个卤素取代的-C1~6烷基， R4 is H, -C1 ~6 alkyl optionally substituted by one or more halogens, R10为任选被一个或多个卤素取代的-C1~6烷基；R 10 is -C 1~6 alkyl optionally substituted by one or more halogens; 3）(IIIb)，3) (IIIb), 其中，p2为0、1、2或3，Where p2 is 0, 1, 2 or 3, R4为任选被一个或多个卤素取代的-C1~6烷基， R4 is a -C1 ~6 alkyl group optionally substituted by one or more halogens, R6为-N(CH3)2、-C1~3氧烷基或者-C(O)-NH(CH3)， R6 is -N( CH3 ) 2 , -C1 ~3oxyalkyl or -C(O)-NH( CH3 ), R10为任选被一个或多个卤素取代的-C1~6烷基。R 10 is -C 1~6 alkyl which is optionally substituted by one or more halogens. 2.根据权利要求1所述的用途，其特征在于，(IIa2)所示的化合物中，2. The use according to claim 1, characterized in that, in the compound represented by (IIa2), X4为C、R7为H，和/或 X4 is C, R7 is H, and/or R3为H，和/或 R3 is H, and/or R8为H，和/或 R8 is H, and/or R11为任选被卤素或-C1~3烷基取代的-6元芳基。R 11 is a 6-membered aryl group which is optionally substituted by halogen or -C 1~3 alkyl. 3.根据权利要求1所述的用途，其特征在于，(IIIa1)所示的化合物中，3. The use according to claim 1, characterized in that, in the compound represented by (IIIa1), p1为2、3或4，和/或p1 is 2, 3, or 4, and/or R4为-C1~3烷基，和/或 R4 is -C1~3 alkyl, and/or R10为-C1~6烷基。 R10 is -C1~6 alkyl. 4.根据权利要求1所述的用途，其特征在于，(IIIb)所示的化合物中，4. The use according to claim 1, characterized in that, in the compound shown in (IIIb), R4为-C1~3烷基，和/或 R4 is -C1~3 alkyl, and/or R6为-N(CH3)2，和/或R 6 is -N(CH 3 ) 2 , and/or R10为-C1~6烷基。R 10 is -C 1~6 alkyl. 5.化合物或其立体异构体、药学上可接受的盐在制备试剂中的用途，所述试剂用于抑制TNF信号通路；所述化合物具有如下结构：5. Use of a compound or its stereoisomers or pharmaceutically acceptable salts in the preparation of a reagent for inhibiting TNF signaling pathway; the compound has the following structure: Ti1、Ti2、Ti3、 Ti1, Ti2, Ti3, Ti4、Ti5、Ti7、 Ti4, Ti5, Ti7, Ti8、Ti9、Ti10、 Ti8, Ti9, Ti10, Ti11、Ti13、Ti19、 Ti11, Ti13, Ti19, Ti20、Ti25、Ti28、 Ti20, Ti25, Ti28, Ti30、Ti31、Ti32、 Ti30, Ti31, Ti32, Ti33、Ti34、Ti35a、 Ti33, Ti34, Ti35a, Ti35b、Ti36、Ti37、 Ti35b, Ti36, Ti37, Ti38、Ti39、Ti42、 Ti38, Ti39, Ti42, Ti44、Ti45、Ti47、 Ti44, Ti45, Ti47, Ti52、Ti53、Ti55、 Ti52, Ti53, Ti55, Ti57、Ti59。 Ti57, Ti59. 6.化合物或其立体异构体、药学上可接受的盐在制备药物中的用途，所述药物用于预防或治疗TNFα的活性过高和/或表达过量产生的相关疾病；6. Use of a compound or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases related to excessive activity and/or overproduction of TNFα; 所述化合物具有如下(IIa2)、(IIIa1)或(IIIb)所示的结构：The compound has the structure shown below: 1）(IIa2)，1) (IIa2), 其中，X3为N、X4为C或N、X6为C或N，wherein X3 is N, X4 is C or N, X6 is C or N, R3为H、卤素、-C1~3烷基或者-C1~3氧烷基， R3 is H, halogen, -C1 ~3 alkyl or -C1 ~3 oxyalkyl, R7为H或者-C1~3烷基， R7 is H or -C1 ~3 alkyl, R8为H或者-C1~3烷基， R8 is H or -C1 ~3 alkyl, R11为任选被卤素或-C1~3烷基取代的-5~7元芳基；R 11 is a 5- to 7-membered aryl group optionally substituted by halogen or -C 1-3 alkyl; 2）(IIIa1)，2) (IIIa1), 其中，X1为N，Where X1 is N, p1为2、3、4或5，p1 is 2, 3, 4, or 5, R4为H、任选被一个或多个卤素取代的-C1~6烷基， R4 is H, -C1 ~6 alkyl optionally substituted by one or more halogens, R10为任选被一个或多个卤素取代的-C1~6烷基；R 10 is -C 1~6 alkyl optionally substituted by one or more halogens; 3）(IIIb)，3) (IIIb), 其中，p2为0、1、2或3，Where p2 is 0, 1, 2 or 3, R4为任选被一个或多个卤素取代的-C1~6烷基， R4 is a -C1 ~6 alkyl group optionally substituted by one or more halogens, R6为-N(CH3)2、-C1~3氧烷基或者-C(O)-NH(CH3)， R6 is -N( CH3 ) 2 , -C1 ~3oxyalkyl or -C(O)-NH( CH3 ), R10为任选被一个或多个卤素取代的-C1~6烷基。R 10 is -C 1~6 alkyl which is optionally substituted by one or more halogens. 7.根据权利要求6所述的用途，其特征在于，(IIa2)所示的化合物中，7. The use according to claim 6, characterized in that, in the compound represented by (IIa2), X4为C、R7为H，和/或 X4 is C, R7 is H, and/or R3为H，和/或 R3 is H, and/or R8为H，和/或 R8 is H, and/or R11为任选被卤素或-C1~3烷基取代的-6元芳基。R 11 is a 6-membered aryl group which is optionally substituted by halogen or -C 1~3 alkyl. 8.根据权利要求6所述的用途，其特征在于，(IIIa1)所示的化合物中，8. The use according to claim 6, characterized in that, in the compound represented by (IIIa1), p1为2、3或4，和/或p1 is 2, 3, or 4, and/or R4为-C1~3烷基，和/或 R4 is -C1~3 alkyl, and/or R10为-C1~6烷基。 R10 is -C1~6 alkyl. 9.根据权利要求6所述的用途，其特征在于，(IIIb)所示的化合物中，9. The use according to claim 6, characterized in that, in the compound represented by (IIIb), R4为-C1~3烷基，和/或 R4 is -C1~3 alkyl, and/or R6为-N(CH3)2，和/或R 6 is -N(CH 3 ) 2 , and/or R10为-C1~6烷基。R 10 is -C 1~6 alkyl. 10.化合物或其立体异构体、药学上可接受的盐在制备药物中的用途，所述药物用于预防或治疗TNFα的活性过高和/或表达过量产生的相关疾病，所述化合物具有如下结构：10. Use of a compound or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating diseases related to excessive activity and/or excessive expression of TNFα, wherein the compound has the following structure: Ti1、Ti2、Ti3、 Ti1, Ti2, Ti3, Ti4、Ti5、Ti7、 Ti4, Ti5, Ti7, Ti8、Ti9、Ti10、 Ti8, Ti9, Ti10, Ti11、Ti13、Ti19、 Ti11, Ti13, Ti19, Ti20、Ti25、Ti28、 Ti20, Ti25, Ti28, Ti30、Ti31、Ti32、 Ti30, Ti31, Ti32, Ti33、Ti34、Ti35a、 Ti33, Ti34, Ti35a, Ti35b、Ti36、Ti37、 Ti35b, Ti36, Ti37, Ti38、Ti39、Ti42、 Ti38, Ti39, Ti42, Ti44、Ti45、Ti47、 Ti44, Ti45, Ti47, Ti52、Ti53、Ti55、 Ti52, Ti53, Ti55, Ti57、Ti59。 Ti57, Ti59. 11.根据权利要求7~10任一项所述的用途，其特征在于，所述TNFα的活性过高和/或表达过量产生的相关疾病包括炎性疾病、感染性休克或糖尿病。11. The use according to any one of claims 7 to 10, characterized in that the diseases related to excessive activity and/or overexpression of TNFα include inflammatory diseases, septic shock or diabetes. 12.根据权利要求11所述的用途，其特征在于，所述炎性疾病包括动脉粥样硬化、再狭窄、自身免疫性疾病、免疫介导的炎症性疾病。12. The use according to claim 11, characterized in that the inflammatory disease comprises atherosclerosis, restenosis, autoimmune disease, and immune-mediated inflammatory disease. 13.根据权利要求12所述的用途，其特征在于，所述免疫介导的炎症性疾病包括类风湿性关节炎、牛皮癣、葡萄膜炎、溃疡性结肠炎、化脓性汗腺炎或狼疮。13. The use according to claim 12, characterized in that the immune-mediated inflammatory disease comprises rheumatoid arthritis, psoriasis, uveitis, ulcerative colitis, hidradenitis suppurativa or lupus. 14.根据权利要求7~10任一项所述的用途，其特征在于，所述TNFα的活性过高和/或表达过量产生的相关疾病包括由免疫复合物介导的其它疾病。14. The use according to any one of claims 7 to 10, characterized in that the diseases related to the excessive activity and/or overexpression of TNFα include other diseases mediated by immune complexes. 15.根据权利要求14所述的用途，其特征在于，所述由免疫复合物介导的其它疾病包括天疱疮和肾小球肾炎、先天性甲状腺功能亢进、迟发型过敏反应、肉样瘤病、贝堤特氏病、慢性关节炎、银屑病关节炎、牛皮癣关节炎、多关节型幼年特发性关节炎、强直性脊柱炎、成人史提尔氏病、原发性干燥症、硬皮病、银屑病、斑块状银屑病、巨细胞动脉炎、SAPHO综合症、原发性胆汁性肝硬化、内样瘤病、骨髓发育不良症候群、Wegener综合症和其它血管炎、血液肿瘤、耳蜗前庭紊乱、巨噬细胞活化综合症、哮喘、间质性肺疾病、丙型肝炎、肺纤维症、诱导排卵、克罗恩病、移植物抗宿主反应、败血症休克、恶病质、厌食或多发性硬化。15. The method of claim 14, wherein the other diseases mediated by the immune complex include pemphigus and glomerulonephritis, congenital hyperthyroidism, delayed allergic reaction, sarcoidosis, Betty's disease, chronic arthritis, psoriatic arthritis, psoriatic arthritis, polyarticular juvenile idiopathic arthritis, ankylosing spondylitis, adult Still's disease, primary Sjögren's disease, scleroderma, psoriasis, plaque psoriasis, giant cell arteritis, SAPHO syndrome, primary biliary cirrhosis, endocytosis, myelodysplastic syndrome, Wegener syndrome and other vasculitis, hematological tumors, cochlear vestibular disorders, macrophage activation syndrome, asthma, interstitial lung disease, hepatitis C, pulmonary fibrosis, ovulation induction, Crohn's disease, graft versus host reaction, septic shock, cachexia, anorexia or multiple sclerosis.
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