CN112679472A - Isoquinoline compounds with IRAK4 inhibitor activity - Google Patents
Isoquinoline compounds with IRAK4 inhibitor activity Download PDFInfo
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- CN112679472A CN112679472A CN201910986634.1A CN201910986634A CN112679472A CN 112679472 A CN112679472 A CN 112679472A CN 201910986634 A CN201910986634 A CN 201910986634A CN 112679472 A CN112679472 A CN 112679472A
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Abstract
The invention discloses a compound with a structure shown in a formula I. The compounds and their tautomers, and salts with suitable acids have the effect of inhibiting IRAActivity of K4. Also discloses a preparation method of the corresponding compound.
Description
Technical Field
The present invention relates to compounds useful in the treatment of autoimmune and inflammatory diseases associated with the interleukin-1 receptor associated kinase IRAK, more particularly compounds that modulate the function of IRAK4, and is in the field of medicine.
Background
Chronic inflammatory and autoimmune diseases threaten the lives of millions of people worldwide and are associated with inflammation-mediated signal abnormalities. In addition, some diseases, such as type 2 diabetes and cardiovascular disease, are also associated with abnormal signals that mediate inflammation. Interleukin-1 receptor-associated kinase 4(IRAK-4) is one of the members of the IRAK family of intracellular serine/threonine kinases. Other members of the kinase family also include IRAK-2, IRAK-M and IRAK-3. IRAK-4 is capable of mediating signaling and activating the expression of downstream inflammatory factors when interleukin-1 receptor (IL-1R) or Toll-like receptor (TLR) binds to a ligand[1]. TLRs can receive ligand signals generated by the action of organisms and microorganisms or the stimulation of endogenous substances, and first wave inflammation signals and innate immune response signals triggered by the stimulation[2]. TLRs play a very important role in many diseases, including infections and auto-inflammatory diseases, as well as many other diseases in humans. Like cancer necrosis factor-alpha (TNF-alpha) and other major cytokines, interleukin-1 (IL-1) is a key factor in the inflammation-mediated pathway, capable of transmitting and amplifying signals. Because TLR, IL-1R and other cytokine receptor mediated signal pathways have mutual cross-linking effect, the key signal factor IRAK-4 of TLR and IL-1R inflammation pathway downstream has important effect in systemic inflammation reaction, and can be used as an effective potential target spot for treating various inflammation-related diseases.
Central to the innate response mechanism is the Pattern Recognition Receptor (PRR). The PRR can recognize pathogen-associated pattern (PAMP) molecules carried or released by pathogenic microorganisms, activate the innate immune system, induce local inflammatory cell infiltration and inflammatory factor release of tissues, and lead the tissues to be continuously in an inflammatory injury state. In contrast to PAMP molecules, endogenous substances with a modulating effect on immune activity are called Damage Associated Mode (DAMP) molecules. In the course of chronic inflammatory diseases such as rheumatoid arthritis and lupus erythematosus, PRRs are able to recognize DAMP molecules, which in turn trigger inflammation and disease. TLR is a very important molecular pattern receptor, and IL-1R plays a very important role in the cascade amplification process of inflammation. IL-1R and TLR (except TLR 3) mediated signaling pathways are quite similar, and activate downstream inflammatory pathways by using a myeloid differentiation factor 88(MyD88) as a regulatory molecule. Myeloid differentiation factor 88(MyD88) is essential for TLR signaling in humans (with the exception of TLR 3), and all Toll-like receptors in humans signal through this protein (TLR4 has two signaling pathways, independent and dependent on MyD 88). TLR and IL-1R binding to ligandsSubsequently, the MyD88 molecule was enriched, followed by MyD88 enriching for IRAK-4 by its N-terminal death domain. After IRAK-4 is phosphorylated, kinase activity is generated, and a substrate IRAK-1 is activated to be phosphorylated, so that IRAK-1 configuration is changed. The allosteric IRAK-1 is separated from the receptor complex due to reduced affinity, and binds to TNF receptor-related factor 6(TRAF-6) to oligomerize TRAF-6. Further, the transforming growth factor beta activated kinase and NF-kB induced kinase (NIK) were activated by Trans-protein TAB. NIK activates the I κ B kinase (IKK) complex, which phosphorylates I κ B. The I kappa B is degraded after phosphorylation, thereby relieving the inhibition effect on NF-kappa B and activating the NF-kappa B. The activated NF-kB enters the nucleus of the cell and promotes the transcription and expression of proinflammatory cytokines[3]. TRAF-6 also activates mitogen-activated protein kinase in another way to activate transcription factors. Thus, MyD88 and TRAF-6 are key proteins in a common signaling pathway, while IRAK-4, as a mediator of signaling between the two, plays a central role in the TLR/IL-1R signaling pathway, making it a strong and powerful target for preventing inflammatory signaling. One of the characteristics of clinical IRAK-4 deficiency is an increased susceptibility of an individual to bacterial infection. Patients lacking MyD88 have similar clinical manifestations. Patients lacking IRAK-4, Peripheral Blood Mononuclear Cells (PBMCs) were unable to respond to TLR agonists (except TLR 3). Furthermore, lymphocytes from patients lacking IRAK-4 (B cells, T cells and NK cells) also do not respond to TLR agonists. In addition, fibroblasts in patients also do not respond to IL-1 β stimulation [10 ]]. Stimulation of IRAK-4 deficient or kinase knock-out (KDKI) mouse models with TLR2, TLR4 or TLR9 ligands with significantly reduced levels of cytokine expression in vivo[4]A range of diseases including atherosclerosis, rheumatoid arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease have been demonstrated to be associated with MyD 88-dependent TLRs. Therefore, it is reasonable to believe that IRAK-4 inhibitors are able to achieve better results in the treatment of these diseases. Mutation of MyD88 gene is found in many types of leukemia (FIG. 2 IRAK-4), including activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), chronic lymphocytic leukemia, etc. [16-17]. IRAK-4 inhibitors and B cell signalingThe blockade synergy enables the reduction of the ability to isolate cells from ABC-BLBCL patients and the inhibition of tumor growth in a mouse xenograft model. IRAK-4 is also expressed at high levels in melanoma cell lines and the combination of vinblastine and an IRAK-4 inhibitor (administered intratumorally) produces better results than either alone. These reports all show the potential of IRAK-4 inhibitors in combating cancer[5]。
Reference documents: [1] p Nati Acad Sci USA, 2002, 99 (8): 5567-: 10-18 [3] Trends Immunol, 2002, 23 (10): 503- & ltSUB & gt 4] Eur J Immunol, 2008, 38 (3): 870 and 876.[5] Central South pharmacy. October 2015, Vol.13 No.10
Disclosure of Invention
The present invention relates to compounds of formula (I).
Wherein:
a is S, SO2Or Se;
x, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; 3 to 6 membered cycloalkyl; a 3 to 7 membered heterocycloalkyl having one to three heteroatoms; a 5 to 10 membered heteroaryl having one to three heteroatoms; 6 to 10 membered aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, OR aryl is optionally substituted with one to five halogen, deuterium, -OR6、-SR6、-NR7aR7bCyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;
r2 is hydrogen, cyano, amide, alkyl ketone, aldehyde, carboxylic acid, or carboxylic ester;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aIndependently of each other areHydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one five deuterium, fluoro, methyl, methoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl, -OR63-to 6-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R6is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen;
R7aand R7bEach independently is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, or cyano; if C2-C6 alkyl, the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen or OH; or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
1. The compound of claim 1, A is S, SO or SO2(ii) a Or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
2. A compound of claim 1, R2Is cyano (-CN), amido (-CONH)2、-CONR3aR3b) Or a carboxyl group (-CO)2R3a)；R3aAnd R3bIs hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
3. A compound according to claims 1, 2 and 3 wherein X is N, Y and Z are C; x and Y are N, Z is C; x and Z are N, Y is C; x and Z are C, Y is N; x is C, Y and Z are N; x and Y are C, Z is N; x, Y and Z is C; or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
4. A compound of claim 1, 2, 3 or 4, wherein the tautomer is a compound of formula (Ia).
Wherein:
a is S, SO2Or Se;
x, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; 3 to 6 membered cycloalkyl; a 3 to 7 membered heterocycloalkyl having one to three heteroatoms; a 5 to 10 membered heteroaryl having one to three heteroatoms; 6 to 10 membered aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, OR aryl is optionally substituted with one to five halogen, deuterium, -OR6、-SR6、-NR7aR7bCyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;
r2 is hydrogen, cyano, amide, alkyl ketone, aldehyde, carboxylic acid, or carboxylic ester;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aEach independently is hydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one five deuterium, fluoro, methyl, methoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally being hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl-OR63-to 6-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R6is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen;
R7aand R7bEach independently is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, or cyano; if C2-C6 alkyl, the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen or OH;
or a pharmaceutically acceptable salt of said compound.
5. The compounds of claims 1, 2, 3, 4 and 5 as a single non-corresponding isomer of the compound of formula (Ib) or of formula (Ic) or as a mixture of the compounds of formula (Ib) and of formula (Ic) in any ratio.
6. A compound of formula (II):
wherein:
a is S, SO or SO2；
X, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; wherein said alkyl is optionally substituted with halogen, deuterium, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aEach independently is hydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one to five deuterium, fluoro, methyl, methoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl, -OR63-to 6-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
Detailed description of the invention
The starting materials and equipment used in the embodiment of the present invention are known products and are obtained by purchasing commercially available products.
Example 1: preparation of 1-chloro-7- (methyl) isoquinoline-6-carbonitrile (10)
The method comprises the following steps: synthesis of the Compound 4-iodo-3-mercaptobenzoic acid (2)
Compound 1(17g, 0.1mol) was added to a 6N hydrochloric acid solution (185mL), and a solution of sodium nitrite (7.6g, 0.11mol) in water (20mL) was added dropwise with stirring at-5 ℃. The mixture was stirred at 0 ℃ for 30 minutes, and then a solution of potassium iodide (50g, 0.3mol) in water (40mL) was added. The reaction mixture was stirred at 0-15 ℃ for 2 hours, poured into water (1L), and extracted three times with ethyl acetate (800 mL). The organic phases were combined and washed twice with saturated brine (800 mL). The organic phase was dried over anhydrous sodium sulfate, then filtered and concentrated to give crude compound (2) (25.2g, 90%).
Step two: synthesis of the Compound 4-iodo-3- (methylthio) benzoic acid methyl ester (3)
Compound (2) (20g, 0.089mol) was dissolved in DMF (100mL) and potassium carbonate (30.7g, 0.222mol) was added under nitrogen. Methyl iodide (31.6g, 0.222mol) was added at room temperature with stirring. The reaction solution was stirred at 50 ℃ for 4 hours and then cooled to room temperature. The reaction mixture was poured into water (500mL) and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed twice with saturated brine (500mL), and then dried over anhydrous sodium sulfate. Filtration and evaporation of the organic solvent under reduced pressure gave compound (3) (20.24g, 92%).
Step three: synthesis of the Compound (4-iodo-3- (methylthio) phenyl) methanol (4)
To a solution of compound (3) (20g, 0.065mol) in THF (100mL) was added sodium borohydride (12.3g, 0.325mol), under nitrogen, and heated at reflux for 4 hours. The reaction was cooled to room temperature, poured into cold 1N hydrochloric acid solution (500mL), and extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed twice with saturated brine (500mL), and then dried over anhydrous sodium sulfate. After filtration, the organic solvent was evaporated under reduced pressure to give compound (4) (16.18g, 89%).
Step four: synthesis of the Compound 4-iodo-3- (methylthio) benzaldehyde (5)
Manganese dioxide (40.8g, 0.324mol) was added to a chloroform (150mL) solution of compound (4) (15g, 0.054mol), and the reaction mixture was refluxed for 12 hours under nitrogen. The reaction solution was cooled to room temperature, filtered through celite, and washed thoroughly with chloroform. The organic solvents were combined and evaporated to dryness under reduced pressure to give crude compound (5) (13.4g, 90%).
Step five: synthesis of the Compound (E) -3- (4-iodo-3- (methylthio) phenyl) acrylic acid (6)
Compound (5) (13g, 0.047mol) was dissolved in pyridine (50mL), and malonic acid (6.35g, 0.061mol) was added under nitrogen. The reaction was heated under reflux for 4 hours. The solvent was then evaporated under reduced pressure and the residue was acidified with dilute hydrochloric acid to adjust the pH to 2.0 by adding water (80 mL). The resulting solid was filtered and washed three times with water (20 mL). After drying in vacuo, product (6) (13.5g, 90%) was obtained.
Step six: synthesis of (E) -3- (4-iodo-3- (methylthio) phenyl) acryloyl azide (7)
Compound (6) (13g, 0.04mol) was dissolved in DMF (50mL), triethylamine (4.04g, 0.04mol) was added with stirring under nitrogen, and the mixture was cooled to 0 ℃. Ethyl chloroformate (5.64g, 0.052mol) was added dropwise while maintaining the temperature at 0 ℃. After the addition was complete, the mixture was stirred at 0 ℃ for 2 hours. A solution of sodium azide (5.2g, 0.08mol) in water (20mL) was added slowly at 0 ℃. After the addition was completed, the reaction solution was warmed to room temperature and stirred for 1 hour. The reaction mixture was added to water (300mL) and stirred for 30 minutes. The solid was filtered and washed twice with water (10mL) and dried under vacuum to give product (7) (12g, 85%).
Step seven: synthesis of 6-iodo-7- (methylthio) isoquinolin-1- (2H) -one (8)
To a solution of compound (7) (10g, 0.02mol) in diphenyl ether (100mL) was added tri-n-butylamine (3.64g, 0.02mol) under nitrogen blanket. The reaction solution was heated to 200 ℃ and reacted for 3 hours. The reaction mixture was cooled to room temperature, and n-hexane (300mL) was added thereto, followed by stirring to give a solid. The solid was filtered and washed with cold n-hexane (100 mL). The solid was dried under vacuum to give product (8) (2.47g, 39%).
Step eight: synthesis of 7- (methylthio) -1-oxo-1, 2-dihydroisoquinoline-6-carbonitrile (9)
To a solution of compound (8) (1g, 3.2mmol) in DMSO (20mL) was added cuprous cyanide (0.63g, 7.04mmol) and the mixture was heated to 150 ℃ under nitrogen for 1 hour. The reaction was then poured into ice water (100 mL). After filtration, the aqueous solution was extracted three times with ethyl acetate (200 mL). The organic solvents were combined, washed twice with saturated brine (200mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure by filtration to give product (9) (0.51g, 75%).
Step nine: synthesis of 1-chloro-7- (methyl) isoquinoline-6-carbonitrile (10)
Compound (9) (5g, 0.023mol) was added to phosphorus oxychloride (40mL), and the reaction solution was heated to 100 ℃ for 2 hours. Cooling the reaction solution to room temperature, and reducing the pressureConcentrating to near dryness. The residue was quenched with ice water (200mL) and the aqueous solution was adjusted to pH 7.0-8.0 with saturated sodium carbonate solution with stirring. The aqueous solution was extracted three times with ethyl acetate (300 mL). The organic phases were combined, washed twice with 10% aqueous sodium bicarbonate (100mL) and twice with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. Filtering, and evaporating to dryness under reduced pressure to obtain crude product. The crude product was purified by silica gel column (ethyl acetate) to give product (10) (4.24g, 78%). MS (m/z): 234, 236.1H NMR(400MHz，DMSO)：8.41(d，H)，8.20(s，1H)，7.87(s，1H)，7.23(d，1H)，2.4(s，3H)。
Example 2: preparation of 1- (((2S, 4S) -4-methyl-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (13)
The method comprises the following steps: synthesis of Compound (12)
Compound (10) (5g, 0.021mol) and compound (11) (3g, 0.023mol) were dissolved in DMF (50mL) and the reaction was cooled to 0 ℃. LiHMDS (46mL, 1M, 0.046mol) was added and the reaction was stirred at room temperature for 2 hours. Ice water (100mL) was added and the mixture was extracted three times with ethyl acetate (200 mL). The organic phases were combined and washed twice with saturated brine (200 mL). The organic solution was dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to give crude product (12) which was used directly in the next step.
Step two: synthesis of the Compound 1- (((2S, 4S) -4-methyl-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (13)
The crude compound (12) was added to 6N hydrochloric acid solution (20mL) under nitrogen and stirred at 60 ℃ for 3 hours. The reaction solution was poured into ice water (100mL), and the pH was adjusted to 8.0 with a saturated ammonium hydroxide solution. The aqueous solution was extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed twice with saturated brine (300 mL). And drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the solvent to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate: petroleum ether ═ 1: 2) to give product (13) (5.15 g)Two step yield 70%).1H NMR(400MHz，DMSO)：8.61(s，1H)，8.42(d，1H)，8.03(br，1H)，7.89(br，1H)，7.81(s，1H)，7.02(d，1H)，3.90(m，1H)，3.50-3.73(m，2H)，2.56(s，3H)2.34(m，1H)，2.04(m，2H)，1.09(d，3H)。
Example 3: preparation of 1- (((2S, 4S) -4-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (16)
The method comprises the following steps: synthesis of Compound (15)
Compound (14) (5.07g, 0.032mol) was dissolved in DMF (100mL) and NaH (60%, 3.2g, 0.08mol) was added in portions at 0 ℃ under nitrogen. The reaction solution was stirred for 30 minutes, and then a solution of compound (10) (5g, 0.021mol) in DMF (10mL) was added at 0 ℃. The reaction solution was heated to 50 ℃ and stirred for 3 hours. The reaction was also quenched by the addition of ice water (200mL) and the mixture was extracted three times with ethyl acetate (300 mL). The organic phases were combined, washed twice with saturated brine (300mL), and then dried over anhydrous sodium sulfate. The crude product was obtained by filtration and evaporation of the solvent under reduced pressure and used directly in the next step.
Step two: synthesis of 1- (((2S, 4S) -4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (16)
The crude compound (15) was added to 6N hydrochloric acid solution (20mL) under nitrogen and stirred at 60 ℃ for 3 hours. The reaction solution was poured into ice water (100mL), and the pH was adjusted to 8.0 with a saturated ammonium hydroxide solution. The aqueous solution was extracted three times with ethyl acetate (300 mL). The organic phases were combined and washed twice with saturated brine (300 mL). And drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the solvent to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate: petroleum ether ═ 1: 3) to give product (16) (5.87g, 73% yield over two steps).1H NMR(400MHz，DMSO)：8.59(s，1H)，8.47(d，1H)，8.23(br，1H)，7.87(br，1H)，7.67(s，1H)，6.99(d，1H)，3.90(m，1H)，3.55-3.75(m，2H)，2.51(s，3H)2.22(m，2H)，1.83(m，2H)，0.98(d，3H)。
Example 4: preparation of 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (19)
The method comprises the following steps: synthesis of Compound (18)
Compound (17) (5.07g, 0.032mol) was dissolved in DMF (100mL) and NaH (60%, 3g, 0.075mol) was added in portions at 0 ℃ under nitrogen. The reaction solution was stirred for 30 minutes, and then a solution of compound (10) (7g, 0.03mol) in DMF (20mL) was added at 0 ℃. The reaction solution was heated to 50 ℃ and stirred for 4 hours. The reaction was also quenched by the addition of ice water (300mL) and the mixture was extracted three times with ethyl acetate (500 mL). The organic phases were combined, washed twice with saturated brine (500mL), and then dried over anhydrous sodium sulfate. The crude product was obtained by filtration and evaporation of the solvent under reduced pressure and used directly in the next step.
Step two: synthesis of 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide (19)
The crude compound (18) was added to 6N hydrochloric acid solution (80mL) under nitrogen and stirred at 60 ℃ for 3.5 hours. The reaction solution was poured into ice water (300mL), and the pH was adjusted to 8.0 with a saturated ammonium hydroxide solution. The aqueous solution was extracted three times with ethyl acetate (500 mL). The organic phases were combined and washed twice with saturated brine (500 mL). And drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the solvent to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate: petroleum ether ═ 1: 3) to give product (19) (7.36g, 65% yield over two steps).1H NMR(400MHz，DMSO)：8.56(s，1H)，8.48(d，1H)，8.23(br，1H)，7.79(br，1H)，7.61(s，1H)，7.04(d，1H)，4.09(m，1H)，3.87(m，1H)，3.59-3.73(m，2H)，2.64(m，1H)，2.47(s，3H)，1.79(m，2H)，0.96(d，3H)。
Example 5: preparation of 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfinyl) isoquinoline-6-carboxamide (20)
The method comprises the following steps: compound (17) (1.0g, 2.65mmol) was dissolved in dichloromethane (50 mL). The solution was cooled to-40 ℃. A solution of mCPPBA (0.43g, 2.52mmol) in dichloromethane (10mL) was added dropwise with stirring. The reaction was stirred at-40 ℃ for 3 hours and then diluted with dichloromethane (100 mL). When the solution was warmed to room temperature, the organic solution was washed with 10% sodium thiosulfate (50mL), saturated brine (50mL), and water (50mL), respectively. The organic phase is dried by anhydrous sodium sulfate, filtered and dried under pressure to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate: petroleum ether ═ 1: 4) to give product (20) (0.55g, 53%).1H NMR(400MHz，DMSO)：9.21(s，1H)，8.45(d，1H)，8.23(s，1H)，8.11(br，1H)，7.79(br，1H)，7.09(d，1H)，4.05(m，1H)，3.94(m，1H)，3.69(m，2H)，2.76(s，3H)，2.57(m，1H)，1.58(m，2H)，0.99(d，3H)。
Example 6: preparation of 1- (((2S, 3S, 4S) -3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfonyl) isoquinoline-6-carboxamide (21)
The method comprises the following steps: compound (19) (1.0g, 2.65mmol) was dissolved in dichloromethane (50 mL). A solution of mCPPBA (0.43g, 2.52mmol) in dichloromethane (10mL) was added with stirring at room temperature. The reaction was stirred at-40 ℃ for 3 hours and then diluted with dichloromethane (100 mL). When the solution was warmed to room temperature, the organic solution was washed with 10% sodium thiosulfate (50mL), saturated brine (50mL), and water (50mL), respectively. The organic phase is dried by anhydrous sodium sulfate, filtered and dried under pressure to obtain a crude product. The crude product was purified by silica gel column (ethyl acetate: petroleum ether ═ 1: 4) to give product (20) (0.55g, 53%).1H NMR(400MHz，DMSO)：9.21(s，1H)，8.45(d，1H)，8.23(s，1H)，8.11(br，1H)，7.79(br，1H)，7.09(d，1H)，4.05(m，1H)，3.94(m，1H)，3.69(m，2H)，2.76(s，3H)，2.57(m，1H)，1.58(m，2H)，0.99(d，3H)。
Claims (14)
1. A compound of formula (I).
Wherein:
a is S, SO2Or Se;
x, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; 3 to 6 membered cycloalkyl; a 3 to 7 membered heterocycloalkyl having one to three heteroatoms; a 5 to 10 membered heteroaryl having one to three heteroatoms; 6 to 10 membered aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, OR aryl is optionally substituted with one to five halogen, deuterium, -OR6、-SR6、-NR7aR7bCyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;
R2is hydrogen, cyano, amide, alkyl ketone, aldehyde group, carboxylic acid group and carboxylic ester group;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aEach independently and optionally being hydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one to five deuterium, fluoro, methyl, methoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl, -OR63-to 6-membered cycloalkyl or 3-to 7-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R6is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen;
R7aand R7bEach independently is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, or cyano; if C2-C6 alkyl, the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen or OH;
or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
2. The compound of claim 1, A is S, SO or SO2(ii) a Or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
3. A compound of claim 1, R2Is cyano (-CN), amido (-CONH)2、-CONR3aR3b) Or a carboxyl group (-CO)2R3a)；R3dAnd R3bIs hydrogen or C1-C6 alkyl; or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
4. A compound according to claims 1, 2 and 3 wherein X is N, Y and Z are C; x and Y are N, Z is C; x and Z are N, Y is C; x and Z are C, Y is N; x is C, Y and Z are N; x and Y are C, Z is N; x, Y and Z is C; or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
5. A compound of claim 1, 2, 3 or 4, wherein the tautomer is a compound of formula (Ia).
Wherein:
a is S, SO2Or Se;
x, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; 3 to 6 membered cycloalkyl; a 3 to 7 membered heterocycloalkyl having one to three heteroatoms; a 5 to 10 membered heteroaryl having one to three heteroatoms; 6 to 10 membered aryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, OR aryl is optionally substituted with one to five halogen, deuterium, -OR6、-SR6、-NR7aR7bCyano, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy;
r2 is hydrogen, cyano, amide, alkyl ketone, aldehyde, carboxylic acid, or carboxylic ester;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aEach independently is hydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one five deuterium, fluoro, methyl, methoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl, -OR63-to 6-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl groupCycloalkyl or heterocycloalkyl optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R6is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with halogen;
R7aand R7bEach independently is hydrogen or C1-C6 alkyl, wherein the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, or cyano; if C2-C6 alkyl, the alkyl is optionally substituted with deuterium, C1-C6 alkoxy, cyano, halogen or OH;
or a pharmaceutically acceptable salt of said compound.
6. The compounds of claims 1, 2, 3, 4 and 5 as a single non-corresponding isomer of the compound of formula (Ib) or of formula (Ic) or as a mixture of the compounds of formula (Ib) and of formula (Ic) in any ratio.
7. A compound of formula (II):
wherein:
a is S, SO or SO2；
X, Y and Z are each independently C or N, and at least one of X, Y and Z is not N.
R1Is C1-C6 alkyl; wherein said alkyl is optionally substituted with halogen, deuterium, -OH, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy;
R3aand R3bEach independently is hydrogen or C1-C6 alkyl;
R4aand R5aEach independently is hydrogen, deuterium, fluorine, OH, -OR6Methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with one to five deuterium, fluoro, methylMethoxy or OH; or R4aAnd R5aTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
R4band R5bEach independently and optionally hydrogen, halogen, hydroxy, deuterium, C1-C6 alkyl, C2-C6 alkenyl, -OR63-to 6-membered cycloalkyl or 4-to 6-membered heterocycloalkyl, wherein each of said groups is optionally and independently substituted with one to five deuterium, halogen, cyano, hydroxy or C1-C6 alkoxy; an amino group; or R4bAnd R5bTogether with the carbon to which they are attached form a 4 to 7 membered cycloalkyl or heterocycloalkyl group, wherein cycloalkyl or heterocycloalkyl group is optionally substituted with one to three fluoro, hydroxy, C1-C3 alkyl;
or a pharmaceutically acceptable salt of said compound, or a tautomer of said compound or said salt.
8. The compound of claim 7 selected from, but not limited to, the following compounds:
5- (((2S, 4S) -4-methyl-5-oxopyrrolidin-2-yl) methoxy) -3- (methylthio) -2-naphthamide;
1- (((2S, 4S) -4-methyl-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 4S) -4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S) -4-hydroxy-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S) -4- (3-hydroxyoxetan-3-yl) -5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 4S) -4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 4R) -4-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
(S) -7- (methylthio) -1- ((4-oxo-5-azaspiro [2.4] heptan-6-yl) methoxy) isoquinoline-6-carboxamide;
1- (((2S, 3S) -3-ethyl-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 3R) -3-ethyl-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 3R, 4R) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 3S, 4R) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
1- (((2R, 3R, 4S) -3-ethyl-4-fluoro-3-hydroxy-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide;
7- (methylthio) -1- (((1S, 2S, 5R) -4-oxo-3-azabicyclo [3.1.0] hex-2-yl) methoxy) isoquinoline-6-carboxamide;
5- (((2S, 4S) -4-methyl-1-5-oxopyrrolidin-2-yl) methoxy) -3- (methylsulfinyl) -2-naphthamide;
5- (((2S, 4S) -4-methyl-1-5-oxopyrrolidin-2-yl) methoxy) -3- (methylsulfonyl) -2-naphthamide;
1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfinyl) isoquinoline-6-carboxamide;
1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfonyl) isoquinoline-6-carboxamide.
Or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or said salt.
9. A method of treating a disease or disorder mediated by or associated with an IRAK receptor, the method comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to one of the preceding claims.
10. A pharmaceutical combination comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof or a tautomer of said compound or said salt, and a pharmaceutically acceptable excipient, diluent or carrier.
11. The compound 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylthio) isoquinoline-6-carboxamide, or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or said salt.
12. The compound 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfinyl) isoquinoline-6-carboxamide, or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or said salt.
13. The compound 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylsulfonyl) isoquinoline-6-carboxamide, or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or said salt.
14. The compound 1- (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl) methoxy) -7- (methylseleno) isoquinoline-6-carboxamide, or a pharmaceutically acceptable salt thereof, or a tautomer of said compound or said salt.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106458912A (en) * | 2014-04-04 | 2017-02-22 | 辉瑞公司 | Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors |
| CN107949559A (en) * | 2015-08-27 | 2018-04-20 | 辉瑞公司 | Bicyclic condensed heteroaryl or aryl compound as IRAK4 conditioning agents |
| WO2019089422A1 (en) * | 2017-10-30 | 2019-05-09 | Synblia Therapeutics, Inc. | Irak4 inhibitors and uses thereof |
-
2019
- 2019-10-17 CN CN201910986634.1A patent/CN112679472A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106458912A (en) * | 2014-04-04 | 2017-02-22 | 辉瑞公司 | Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors |
| CN107949559A (en) * | 2015-08-27 | 2018-04-20 | 辉瑞公司 | Bicyclic condensed heteroaryl or aryl compound as IRAK4 conditioning agents |
| WO2019089422A1 (en) * | 2017-10-30 | 2019-05-09 | Synblia Therapeutics, Inc. | Irak4 inhibitors and uses thereof |
Non-Patent Citations (2)
| Title |
|---|
| KATHERINE L. LEE等: "Discovery of Clinical Candidate 1‑{[(2S,3S,4S)‑3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin‑1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| STEPHEN W. WRIGHT等: "Improvements to Enable the Large Scale Synthesis of 1‑{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833)", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
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