CN113880865A - Pyrazolo [1,5-a ] pyridine compound and preparation method and application thereof - Google Patents

Pyrazolo [1,5-a ] pyridine compound and preparation method and application thereof Download PDF

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CN113880865A
CN113880865A CN202010625119.3A CN202010625119A CN113880865A CN 113880865 A CN113880865 A CN 113880865A CN 202010625119 A CN202010625119 A CN 202010625119A CN 113880865 A CN113880865 A CN 113880865A
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alkyl
ret
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罗会兵
周华勇
李庆
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Shanghai Allist Medicine Polytron Technologies Inc
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Priority to PCT/CN2021/103358 priority patent/WO2022002097A1/en
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Abstract

The present invention relates to a pyrazole [1,5-a ] represented by the following general formula (I)]Pyridine compounds, preparation method, pharmaceutical composition and application thereof, wherein R in the formula1、R2、R3、R4、R5X, Y, Z are as defined in the specification. The pyrazole [1,5-a ] of the present invention]The pyridine compounds can effectively inhibit wild-type RET, mutant RET, especially G810R mutant RET, and RET fusion such as KIF5B-RET and CCDC6-RET, and have good safety, and can be used for treating diseases mediated by RET, such as cancer and irritable bowel syndrome.

Description

Pyrazolo [1,5-a ] pyridine compound and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pyrazolo [1,5-a ] pyridine compound serving as a RET inhibitor, a preparation method of the compound, a pharmaceutical composition containing the compound, and application of the compound and the pharmaceutical composition in treatment of RET-mediated diseases.
Background
The transfected rearranged gene, RET (rearranged along transforming transformation) gene, is a protooncogene and is located on chromosome 10. The RET protein encoded by the RET gene is a Receptor Tyrosine Kinase (RTK) present on cell membranes and belongs to a member of the cadherin superfamily. Ligands for RET are the glial-derived neurotrophic factor family, including glial cell-derived neurotrophic factor (GDNF), neurturin (nrtn), artemin (artn), and persephin (pspn). When ligand binds to the extracellular domain of RET, it leads to dimerization of RET and autophosphorylation of the intracellular kinase domain, thus activating RET, and then initiating multiple downstream signaling pathways such as RAS/MAPK/ERK, PI3K/AKT, JAK/STAT, etc. to play roles in cell proliferation, migration and differentiation.
Abnormalities in the RET gene (including fusion and point mutations) lead to overactivation of the RET signaling pathway and uncontrolled cell growth, and are closely associated with the development and progression of a variety of tumors. The incidence of RET gene fusion in non-small cell lung cancer (NSCLC) patients is about 1% -2%, and the incidence in Papillary Thyroid Cancer (PTC) patients is 10% -20%; the most common fusion partners include KIF5B, TRIM33, CCDC6, and NCOA 4. The incidence of RET gene point mutations in Medullary Thyroid Carcinoma (MTC) patients is around 60%; common mutation sites include C634R, M918T, V804L, V804M, G810R, and the like. Furthermore, in colorectal, breast, pancreatic and other cancers, low frequency RET fusions are also observed; RET fusion was also observed in NSCLC patients carrying EGFR mutations.
At present, targeting drugs aiming at RET genes comprise (1) multikinase inhibitor drugs targeting multiple targets, such as Cabozantinib (Cabozantinib), Vandetanib (Vandernib), Lenvatinib (Lenvatinib) and the like, although the activity of RET can be inhibited, due to low selectivity, especially serious toxic and side effects related to VEGFR inhibition generally occur due to off-target effect, and clinical application is limited; (2) the drugs for selectively targeting RET genes, such as BLU-667 and LOXO-292, have good inhibitory activity on wild type and mutant RET (such as M918T, V804L/M and the like), common KIF5B-RET fusion and CCDC6-RET fusion and the like, and have relatively low toxicity.
The BLU-667 is disclosed in WO2017079140A1 and developed by Blueprint pharmaceuticals, having the following structure, and has been filed to FDA for new drug marketing applications. LOXO-292 is disclosed in WO2018071447A1, developed by Loxo Oncology, and has the following structure, which was approved by the FDA to be marketed in 5 months of 2020; however, in the literature (Journal of clinical Oncology, Volume 15, Issue 4, April 2020, Pages 541 and 549), it is reported that RET fusion NSCLC patients develop RET G810R resistance mutation, resulting in LOXO-292 resistance.
Figure BDA0002565535740000021
In addition, abnormal RET expression and/or activity has also been demonstrated in gastrointestinal disorders such as Irritable Bowel Syndrome (IBS).
The development of new potent, low toxicity selective small molecule inhibitors of RET for the treatment of RET mediated diseases is a need in humans.
Disclosure of Invention
The invention provides a pyrazolo [1,5-a ] pyridine compound with a novel structure or a pharmaceutically acceptable salt thereof, which is a selective RET inhibitor, can effectively inhibit wild RET, mutant RET, particularly G810R mutant RET, and RET fusion such as KIF5B-RET and CCDC6-RET, has good safety, and can be used for treating diseases mediated by RET, such as cancer and irritable bowel syndrome.
The invention provides a compound shown in the following formula (I) or a pharmaceutically acceptable salt thereof,
Figure BDA0002565535740000031
wherein:
x is selected from CR6Or N;
y is selected from CR6Or N;
z is selected from CR6Or N;
wherein 0, 1 or 2 of X, Y, Z are N;
R1selected from hydrogen, 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said 6-10 membered aryl or 5-12 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, 3-6 membered cycloalkyl, cyano, -NR7R8or-O- (CH)2)n-NR7R8Substituted with the substituent(s);
R2selected from hydrogen, C1-4Alkyl or halo C1-4An alkyl group;
R3selected from hydrogen, C1-6Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl, wherein said C1-6Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy C1-4Alkyl, -C (═ O) -NR7R8、-SO2-C1-4Alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 3-6 membered heterocyclyl are each optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy- (CH)2)m-or-C (═ O) -C1-4Alkyl is substituted by a substituent;
R4selected from hydrogen, C1-4Alkyl or halo C1-4An alkyl group;
R5selected from hydrogen, halogen, cyano, C1-4Alkyl or halo C1-4An alkyl group;
each R6Independently selected from H, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halogen;
each R7Independently selected from H, C1-4Alkyl or halo C1-4An alkyl group;
each R8Independently selected from H, C1-4Alkyl or halo C1-4An alkyl group;
n is selected from 1, 2 or 3;
m is selected from 0, 1, 2 or 3.
In another embodiment of the compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention, X is selected from CR6Or N, Y is selected from CR6Or N, Z are selected from CR6Or N, wherein 0 or 1 of X, Y, Z is N; wherein each R6Independently selected from H, C1-4Alkyl, halo C1-4Alkyl or halogen.
In another embodiment of the compound of the formula (I) according to the invention or a pharmaceutically acceptable salt thereof, wherein X is CR6Y is CR6Z is CR6(ii) a Wherein each R6Independently selected from H, C1-4Alkyl, halo C1-4Alkyl or halogen.
In another embodiment of the compound of the formula (I) according to the invention or a pharmaceutically acceptable salt thereof, wherein X is CR6Y is CR6Z is CR6(ii) a Wherein each R6Independently selected from H, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-、CHF2CH2-、 CH2FCH2-, F, Cl or Br.
In another embodiment of the compound of the formula (I) according to the invention or a pharmaceutically acceptable salt thereof, wherein X is CR6Y is CR6Z is CR6Wherein each R is6Is H.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Selected from phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is each optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy or cyano.
The compound of formula (I) according to the invention or a pharmaceutical preparation thereofIn another embodiment of the above acceptable salts, the above R1Selected from phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is each optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl or thiazolyl, wherein said phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl or thiazolyl is each optionally substituted with 1, 2 or 3 groups each independently selected from hydroxy, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Selected from phenyl,
Figure BDA0002565535740000041
Figure BDA0002565535740000042
Wherein said phenyl group,
Figure BDA0002565535740000043
Figure BDA0002565535740000051
Each optionally substituted by 1, 2 or 3 groups each independently selected from hydroxy, F, Cl, Br, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Selected from phenyl,
Figure BDA0002565535740000052
Figure BDA0002565535740000053
Wherein said phenyl group,
Figure BDA0002565535740000054
Figure BDA0002565535740000055
Each optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-、CHF2CH2-、 CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-、 CHF2CH2-O-or CH2FCH2-O-is substituted.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Is selected from phenyl or pyridyl, wherein said phenyl or pyridyl is each optionally substituted with 1, 2 or 3 groups each independently selected from hydroxy, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Selected from phenyl,
Figure BDA0002565535740000056
Wherein said phenyl group,
Figure BDA0002565535740000057
Figure BDA0002565535740000058
Each optionally substituted by 1, 2 or 3 substituents each independently selected from hydroxy, F, Cl, Br, methyl, ethyl, n-propyl, iso-propylPropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-、CHF2CH2-、CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-、CHF2CH2-O-or CH2FCH2-O-is substituted.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Is selected from
Figure BDA0002565535740000061
Figure BDA0002565535740000062
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above1Is selected from
Figure BDA0002565535740000063
Figure BDA0002565535740000064
Figure BDA0002565535740000071
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above2Selected from hydrogen or C1-4An alkyl group.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above2Is hydrogen.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above4Selected from hydrogen or C1-4An alkyl group.
In another embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereofIn (1), the above R4Is hydrogen.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above5Selected from hydrogen, halogen or cyano.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above5Is cyano.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above3Selected from hydrogen, C1-6Alkyl or 3-6 membered cycloalkyl, wherein said C is1-6Alkyl or 3-6 membered cycloalkyl each optionally substituted by 1, 2 or 3 substituents each independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy, -SO2-C1-4Alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein each of said 5-6 membered heteroaryl or 3-6 membered heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxy or C1-4Alkyl substituents.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above3Selected from hydrogen, C1-4Alkyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein said C1-4Alkyl, cyclopropyl, cyclobutyl or cyclopentyl is each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, Br, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy, -SO2-C1-4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure BDA0002565535740000081
Figure BDA0002565535740000082
Figure BDA0002565535740000083
Wherein said substituent is substituted, wherein
Figure BDA0002565535740000084
Figure BDA0002565535740000085
Figure BDA0002565535740000086
Each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy or C1-4Alkyl substituents.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above3Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl are each optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF, and3CH2-、CHF2CH2-、 CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-、 CHF2CH2-O-、CH2FCH2-O-, cyano, hydroxy, -SO2-CH3、-SO2-CH2CH3、
Figure BDA0002565535740000087
Figure BDA0002565535740000088
Figure BDA0002565535740000089
Wherein said substituent is substituted, wherein
Figure BDA0002565535740000091
Figure BDA0002565535740000092
Each optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy, methyl or ethyl.
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above3Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl,
Figure BDA0002565535740000093
Figure BDA0002565535740000094
In another embodiment of the compounds of formula (I) or pharmaceutically acceptable salts thereof of the present invention, R as described above3Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl,
Figure BDA0002565535740000101
Figure BDA0002565535740000102
The present invention also provides a compound as shown below or a pharmaceutically acceptable salt thereof:
Figure BDA0002565535740000111
Figure BDA0002565535740000121
Figure BDA0002565535740000131
the compounds of formula (I) of the present invention may be prepared by various synthetic methods known to those skilled in the art, without particular limitation, for example, by the methods of scheme one or scheme two provided herein, it is to be understood that the synthetic methods of the compounds of formula (I) of the present invention are not limited to scheme one or scheme two, and that conventional substitutions and modifications may be made by those skilled in the art.
The first scheme is as follows:
Figure BDA0002565535740000141
wherein R is1、R2、R3、R4、R5X, Y, Z are as defined above; l is a leaving group, such as halogen, preferably I; p is an amino-protecting group, each P may be the same or different, and each P is independently preferably a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), or a benzyl group (Bn).
Taking a compound a-1 and a compound a-2 as initial raw materials, and carrying out Suzuki coupling reaction to obtain a compound a-3; carrying out substitution reaction on the compound a-3 and the compound a-4 to obtain an intermediate 1; deprotection of the intermediate 1 to obtain a compound a-5; carrying out reductive amination reaction on the compound a-5 and the compound a-6 to obtain an intermediate 2; intermediate 2 and
Figure BDA0002565535740000151
coupling reaction is carried out to obtain the compound shown in the formula (I).
Or, in the preparation of R4When the compound of formula (I) is H, the intermediate 2 may be reacted with P-NH2Carrying out coupling reaction to obtain a compound a-7; compounds a-7 and R3-L undergoes a substitution reaction to give a compound a-8; deprotection of the compound a-8 can obtain the compound shown in the formula (I).
In the first scheme, the Suzuki coupling reaction is carried out in the presence of a base and a catalyst, wherein the catalyst includes but is not limited to Pd (dppf) Cl2、Pd(PPh3)4、PdCl2And the like, the base includes, but is not limited to, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium t-butoxide, t-butanolSodium and the like; the substitution reaction to prepare intermediate 1 and compounds a-8 is carried out in the presence of a base including, but not limited to, cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, and the like; deprotection of intermediate 1 and Compounds a-8 is under acidic conditions or in catalyst/H2In the presence of acidic conditions including but not limited to HCl/MeOH, HCl/EA, trifluoroacetic acid and the like, and catalysts including but not limited to Pd/C, PdCl2/C、Pd(OH)2C, etc.; the reductive amination reaction to prepare intermediate 2 is carried out in the presence of a reducing agent including, but not limited to, NaBH (OAc)3、NaBH4、NaBH3CN and the like; intermediate 2 and
Figure BDA0002565535740000152
or P-NH2The coupling reaction takes place in the presence of a catalyst, including but not limited to Pd, a base2(dba)3/Xantphos、Pd2(dba)3/Brettphos、Pd(OAc)2Xanthphos, and the like, including but not limited to cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, and the like.
Scheme II:
Figure BDA0002565535740000161
wherein R is1、R2、R3、R4、R5X, Y, Z are as defined above; l is a leaving group, such as halogen, preferably I; p is an amino-protecting group, each P may be the same or different, and each P is independently preferably a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), or a benzyl group (Bn).
Intermediate 1 and
Figure BDA0002565535740000162
carrying out coupling reaction to obtain a compound b-1; deprotection of compound b-1 gives intermediate 3; and carrying out reductive amination reaction on the intermediate 3 and the compound a-6 to obtain the compound shown in the formula (I).
Or, in the preparation of R4When the compound of formula (I) is H, the intermediate 1 may be reacted with P-NH2Carrying out coupling reaction to obtain a compound b-2; compounds b-2 and R3-L undergoes a substitution reaction to give a compound b-3; deprotecting compound b-3 to obtain intermediate 3; and carrying out reductive amination reaction on the intermediate 3 and the compound a-6 to obtain the compound shown in the formula (I).
In scheme two above, intermediate 1 is reacted with
Figure BDA0002565535740000163
Or P-NH2The coupling reaction takes place in the presence of a catalyst, including but not limited to Pd, a base2(dba)3/Xantphos、 Pd2(dba)3/Brettphos、Pd(OAc)2Xanthphos, and the like, including but not limited to cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, and the like; deprotection of Compounds b-1 and b-3 is under acidic conditions or in catalyst/H2In the presence of acidic conditions including but not limited to HCl/MeOH, HCl/EA, trifluoroacetic acid and the like, and catalysts including but not limited to Pd/C, PdCl2/C、Pd(OH)2C, etc.; the reductive amination of intermediate 3 with compound a-6 is carried out in the presence of a reducing agent including, but not limited to, NaBH (OAc)3、NaBH4、NaBH3CN and the like; the substitution reaction to prepare compound b-3 is carried out in the presence of a base including, but not limited to, cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, and the like.
The invention also provides intermediate compounds which comprise a compound a-7, a compound a-8, a compound b-1, a compound b-2, a compound b-3 and an intermediate 3 shown in the following structures,
Figure BDA0002565535740000171
wherein R is1、R2、R3、R4、R5X, Y, Z are as defined above; p isThe amino-protecting group, each P, which may be the same or different, is preferably a tert-butyloxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), or a benzyl group (Bn), each independently.
The present invention still further provides intermediate compounds of the structure:
Figure BDA0002565535740000181
the invention also provides a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention includes an optional pharmaceutically acceptable carrier, which means that the composition may or may not include a pharmaceutically acceptable carrier.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for treating diseases mediated by RET.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for treating diseases mediated by RET. Wherein the RET comprises wild type RET, mutant RET, RET fusion, the mutant RET comprises but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET, the RET fusion comprises but is not limited to KIF5B-RET fusion, CCDC6-RET fusion, preferably KIF5B-RET fusion; the diseases include cancer and irritable bowel syndrome.
The invention also provides the application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing medicines for treating diseases mediated by wild type RET, mutant RET and RET fusion; wherein the mutant RET includes, but is not limited to, G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET, and the RET fusion includes, but is not limited to, KIF5B-RET fusion, CCDC6-RET fusion, preferably KIF5B-RET fusion; the diseases include cancer and irritable bowel syndrome.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing medicines for treating RET-mediated cancer and irritable bowel syndrome. Wherein the RET comprises wild type RET, mutant RET, RET fusion, the mutant RET comprises but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET, the RET fusion comprises but is not limited to KIF5B-RET fusion, CCDC6-RET fusion, preferably KIF5B-RET fusion.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing medicines for treating cancers mediated by wild-type RET, mutant RET and RET fusion and irritable bowel syndrome. Wherein the mutant RET includes, but is not limited to, G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, preferably G810R mutant RET; such RET fusions include, but are not limited to, KIF5B-RET fusion, CCDC6-RET fusion, and preferably KIF5B-RET fusion.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for treating cancer.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition thereof in preparing a medicament for treating irritable bowel syndrome.
The present invention also provides a method for treating a disease mediated by RET, which comprises administering to a patient in need thereof an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Wherein the RET comprises wild type RET, mutant RET, RET fusion, the mutant RET comprises but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, V804M mutant RET, the RET fusion comprises but is not limited to KIF5B-RET fusion, CCDC6-RET fusion; the diseases include cancer and irritable bowel syndrome.
The present invention also provides a method for treating cancer, which comprises administering an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient in need thereof.
The present invention also provides a method for treating irritable bowel syndrome, which comprises administering an effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient in need thereof.
The cancers of the present invention include, but are not limited to, small cell lung cancer, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, undifferentiated thyroid cancer, recurrent thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN 2A or MEN2B, respectively), hepatocellular carcinoma, lung cancer, head and neck cancer, glioma, neuroblastoma, pheochromocytoma, colorectal cancer, testicular cancer, prostate cancer, fallopian tube cancer, ovarian cancer, cervical cancer, breast cancer, and pancreatic cancer.
Irritable bowel syndrome according to the present invention, including but not limited to diarrhea predominant, constipation predominant or alternating pattern of bowel movements, functional bloating, functional constipation, functional diarrhea, non-specific functional bowel disorder, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disorder, functional gastroduodenal disorder, functional anorectal pain, and inflammatory bowel disease.
The invention also comprises pharmaceutically acceptable salts of the compounds shown in the formula (I). The term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts of the compounds of the present invention that are relatively non-toxic. The acid addition salts are salts of the compounds of formula (I) of the present invention with suitable inorganic or organic acids, which salts may be prepared by reacting a compound of formula (I) with a suitable organic or inorganic acid in a suitable solvent. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, metasilicate, borate, benzoate, lactate, nitrate, phosphate, biphosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, malate, ascorbate, tannate, pamoate, alginate, naphthalenesulfonate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, and the likeSulfonate, gluconate, lactobionate, laurylsulfonate, and the like. The base addition salts are salts of the compounds of formula (I) with suitable inorganic or organic bases, which salts may be prepared by reacting a compound of formula (I) with a suitable inorganic or organic base in a suitable solvent. Representative base addition salts include, for example, those formed with alkali metal, alkaline earth metal, quaternary ammonium cations such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium, and the like; amine salts, including with ammonia (NH)3) And salts of primary, secondary or tertiary amines, such as methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs described herein refer to compounds that can be converted under physiological conditions or by solvolysis to the biologically active compounds described herein, such as compounds of formula (I). Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active compound.
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, compounds may be labelled with radioactive isotopes, such as deuterium (D), tritium (I), (II), (III), (IV)3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
In the present invention, "pharmaceutically acceptable" refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
In the present invention, a "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel materials that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of being blended with the compounds of the present invention and with each other without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hypromellose and its derivatives, cellulose acetate and the like), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium/calcium stearate, hydrogenated vegetable oils, sodium fumarate stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil and the like), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol and the like), emulsifiers, wetting agents (e.g. sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives and the like.
In the present invention, an "effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or pharmacologically active agent that is non-toxic but achieves the desired effect. The effective amount to be determined varies from person to person, depending on the age, weight and condition of the patient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art in the light of routine tests.
As used herein, "active ingredient," "active substance," or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
In the context of the present invention, a "patient", "individual" or "subject" includes a human, animal, vertebrate, mammal, rodent (e.g., guinea pig, hamster, rat, mouse), murine (e.g., mouse), canine (e.g., dog), primate, ape (e.g., monkey or ape), monkey (e.g., marmoset, baboon), ape (e.g., gorilla, chimpanzee, orangutan, gibbon). In some embodiments, a "patient" is a human.
In the present invention, "treatment" means administration of a compound or formulation of the present invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) preventing the occurrence of a disease or condition in a mammal, particularly when such mammal is susceptible to the disease or condition, but has not yet been diagnosed as having the disease or condition;
(ii) inhibiting a disease or disease state, i.e., arresting its development;
(iii) alleviating the disease or condition, i.e., causing regression of the disease or condition.
As used herein, "optional," "optional," or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted with R" means that it may or may not be substituted with R, and the description includes both substitution with R and non-substitution with R.
In the present invention, "substituted" or "substituted" means that one or more hydrogen atoms, preferably 1 to 5 hydrogen atoms, more preferably 1, 2, 3 or 4 hydrogen atoms in the group are substituted independently of each other by a corresponding number of substituents, as long as the substituted compound is stable.
In the present invention, "independently" or "independent" refers to where more than one substituent is selected from a large number of possible substituents, which may be the same or different. For example, "RxSelected from-OR OR-N (R)2(ii) a Each R is independently selected from H or C1-C4Alkyl ", wherein each substituent R is independent, which may be the same or different.
In the present invention, "group" and "group" represent a monovalent group or a divalent or more group corresponding to the valence as required, and for example, "cycloalkyl" includes a monovalent group obtained by removing one hydrogen atom therefrom, and also includes a divalent or more group obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms therein. "cycloalkyl" is naturally a monovalent group when it is a terminal group, and is a divalent or higher group when it is a linking group in the structure. In the present invention, a monovalent or divalent or higher group generally means a monovalent group or a divalent group, but the group may be higher in valence (for example, trivalent, tetravalent, pentavalent, hexavalent, etc.) as required.
In the present invention, "Cd-e"(d and e represent integers of 1 or more, and d < e) includes any particular case of d to e carbons, e.g. C1-6Comprising C1、C2、C3、C4、C5、C6Also included are any ranges of d to e, e.g. C1-6Comprising C1-3、C1-4、C1-5、C2-5、C2-4、 C3-6Etc.; similarly, "d-e-membered" (d and e represent integers of 1 or more, d < e) means that the number of atoms on the ring is d to e, for example, 3-6 membered rings including 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, and any of d to eBy way of example, a 3-6 membered ring includes a 3-4 membered ring, a 3-5 membered ring, a 4-6 membered ring, a 4-5 membered ring, and the like.
In the present invention, "halogen" means fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, bromine, more preferably fluorine, chlorine.
In the present invention, "C1-6Alkyl "refers to a straight or branched chain alkyl derived from an alkane moiety containing 1 to 6 carbon atoms by removal of one or more hydrogen atoms, specifically, C1-6Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like; said "C1-4Alkyl "refers to a straight or branched chain alkyl derived from an alkane moiety containing 1 to 4 carbon atoms by removal of one or more hydrogen atoms, specifically, C1-4Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
In the present invention, "C1-6Alkoxy "means" C "as defined above1-6Alkyl "radicals attached to the rest of the molecule via an oxygen atom, i.e." C1-6alkyl-O- "groups including, but not limited to, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy, n-hexyloxy, and the like; said "C1-4Alkoxy "means" C "as defined above1-4Alkyl "radicals attached to the rest of the molecule via an oxygen atom, i.e." C1-4alkyl-O- "groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.
In the present invention, "halogeno C1-6Alkyl "means one or more (preferably 1 to 5, more preferably)Optionally 1, 2 or 3) halogen atoms substituted for "C" as defined above1-6A group formed by a corresponding number of hydrogen atoms on the alkyl group "wherein each halogen atom may be the same or different when substituted with a plurality of halogen atoms, in particular, a halogenated C1-6Alkyl includes, but is not limited to, monofluoromethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, monochloromethyl, CF3CH2-、CHF2CH2-、CH2FCH2-、 CH3CHF-、CH2FCHCl-、CF3CH2CH2-、CF3CH2CH(CH3)CH2-and the like; "halo C1-4Alkyl "means that one or more (preferably 1 to 5, more preferably 1, 2 or 3) halogen atoms are substituted for" C "as defined above1-4The corresponding number of hydrogen atoms in the alkyl group "wherein each halogen atom may be the same or different when substituted with multiple halogen atoms, specifically, but not limited to, monofluoromethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, chloromethyl, CF3CH2-、CHF2CH2-、CH2FCH2-、CH3CHF-、CH2FCHCl-, etc.
In the present invention, "halogeno C1-6Alkoxy "means that one or more (preferably 1 to 5, more preferably 1, 2 or 3) halogen atoms are substituted for" C "as defined above1-6The corresponding number of hydrogen atoms in the alkoxy group "wherein each halogen atom may be the same or different when substituted with a plurality of halogen atoms, specifically, but not limited to, monofluoromethoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, monochloromethoxy, CF3CH2-O-、CHF2CH2-O-、 CH2FCH2-O-、CF3CH2CH2-O-and the like; "halo C1-4Alkoxy "means that one or more (preferably 1 to 5, more preferably 1, 2 or 3) halogen atoms are substituted for" C "as defined above1-4The corresponding number of hydrogen atoms on the alkoxy radical ", wherein when there is a plurality of halogen atoms substitutedEach halogen atom may be the same or different, and specifically includes, but is not limited to, monofluoromethoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, monochloromethoxy, CF3CH2-O-、CHF2CH2-O-、CH2FCH2-O-、CF3CH2CH2-O-, etc.
In the present invention, "hydroxy group C1-6Alkyl "means that one or more (preferably 1, 2 or 3) hydroxy groups are substituted for" C "as defined above1-6The radicals formed by the corresponding number of hydrogen atoms in an alkyl group "include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl, 5-hydroxypentyl, 2-hydroxymethyl-1-hydroxypropyl; "hydroxy group C1-4Alkyl "means that one or more (preferably 1, 2 or 3) hydroxy groups are substituted for" C "as defined above1-4The radicals formed by the corresponding number of hydrogen atoms in an alkyl group "include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2, 3-dihydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl.
In the present invention, "ring atom" means an atom forming a ring, including but not limited to C, N, O, P and S; "Ring carbon atom" means ring atom C; "Ring heteroatom" means a ring atom other than a C atom, including but not limited to ring atoms N, O, P and S.
In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group, which may be a monovalent group or a group more than divalent, and includes monocyclic cycloalkyl groups and polycyclic cycloalkyl groups, including spirocyclic cycloalkyl groups, fused-ring cycloalkyl groups, and bridged-ring cycloalkyl groups, wherein "spirocyclic cycloalkyl groups" refers to polycyclic cycloalkyl groups in which single rings share one ring carbon atom (referred to as a spiro atom) between them, wherein "fused-ring cycloalkyl groups" refers to polycyclic cycloalkyl groups in which each ring in the group shares an adjacent pair of ring carbon atoms with other rings, and wherein "bridged-ring cycloalkyl groups" refers to polycyclic cycloalkyl groups in which any two rings share two ring carbon atoms which are not directly connected. In the present invention, "3-6 membered cycloalkyl" refers to cycloalkyl groups comprising 3 to 6 ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and the like.
In the present invention, "heterocyclyl" means a saturated or partially unsaturated cyclic hydrocarbon group in which one or more (preferably 1, 2, 3 or 4) ring atoms are ring heteroatoms selected from N, O or S, which may be a monovalent group or a group more than divalent, and includes monocyclic heterocyclyl groups including spirocyclic heterocyclyl groups, fused ring heterocyclyl groups and bridged heterocyclyl groups, said "spirocyclic heterocyclyl groups" means polycyclic heterocyclyl groups in which one ring atom (referred to as spiro atom) is shared between monocyclic rings, said "fused ring cycloalkyl" means polycyclic heterocyclyl groups in which each ring in a group shares an adjacent pair of ring atoms with other rings, and said "bridged cycloalkyl" means polycyclic heterocyclyl groups in which any two rings share two ring atoms which are not directly connected. Heterocyclyl also includes the case where ring atom C, S is oxo, such as ring atom C, S is substituted with C (═ O), S (═ O)2And (4) replacing. In the present invention, "3-8 membered heterocyclic group" means a heterocyclic group comprising 3 to 8 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O or S, and specific 3-8 membered heterocyclic groups include, but are not limited to, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrrolidinonyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl, 1, 2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperidinonyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 4-oxathianyl, piperidinonyl, piperazinyl, morpholinyl, 1, 4-oxathianyl, thianyl, and the like, 4, 5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 3, 4-dihydro-2H-pyrrolyl, 2, 3-dihydro-1H-pyrrolyl, 2, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-pyrazolyl, 4, 5-dihydro-3H-pyrazolyl, 4, 5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2, 3, 4, 5-tetrahydropyridinyl, 1, 2-Isooxazinyl, 1, 4-isooxazinyl, or 6H-1, 3-oxazinyl, and the like, with preference given to
Figure BDA0002565535740000261
Figure BDA0002565535740000262
Figure BDA0002565535740000263
And the like. In the present invention, "3-6 membered heterocyclic group" means a heterocyclic group comprising 3 to 6 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O or S, and specific 3-6 membered heterocyclic groups include, but are not limited to, aziridinyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrrolidinonyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl, 1, 2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperidinonyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 4-oxathianyl, piperidinonyl, piperazinyl, morpholinyl, 1, 4-oxathianyl, thianyl, and the like, 4, 5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 3, 4-dihydro-2H-pyrrolyl, 2, 3-dihydro-1H-pyrrolyl, 2, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-pyrazolyl, 4, 5-dihydro-3H-pyrazolyl, 4, 5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2, 3, 4, 5-tetrahydropyridinyl, 1, 2-isoxazolyl, 2, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 2-dihydrooxazolyl, 4, 5-dihydropyranyl, 4, 5-thiazolyl, 2H-thiapyranyl, 4, 5-tetrahydropyridinyl, 1, 2-isoxazolyl, 2, 5-thiazolyl, 2-thiapyranyl, 2, and a, 1, 4-isoxazolyl or 6H-1, 3-oxazinyl, etc., preferably
Figure BDA0002565535740000271
Figure BDA0002565535740000272
And the like.
In the present invention, "aryl" means a cyclic hydrocarbon group having aromaticity, which may be a monovalent group or a group of two or more valences, and includes monocyclic aryl groups and condensed ring aryl groups, and "condensed ring aryl" means an aryl group containing a plurality of rings (preferably 2 or 3 rings) in which each ring of the group shares an adjacent pair of ring carbon atoms with other rings. In the present invention, "6-10 membered aryl" means an aryl group comprising 6 to 10 ring carbon atoms, including phenyl, naphthyl.
In the present invention, "heteroaryl" means a cyclic hydrocarbon group having aromaticity in which one or more (preferably 1 to 5, more preferably 1, 2, 3 or 4) ring atoms are ring heteroatoms selected from N, O or S, which may be a monovalent group or a group of more than two valences, including monocyclic heteroaryl and fused ring heteroaryl, and "fused ring heteroaryl" means a heteroaryl group containing a plurality of rings (preferably 2 or 3 rings) in which each ring of the group shares an adjacent pair of ring atoms with other rings. In the present invention, "5-12 membered heteroaryl" means a heteroaryl group comprising 5 to 12 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S, and specifically, 5-12 membered heteroaryl includes, but is not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, triazinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiadiazolyl, benzothiazolyl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, purinyl, quinolyl, quinoxalyl, thienopyridyl, and the like, preferably
Figure BDA0002565535740000273
Figure BDA0002565535740000274
Figure BDA0002565535740000281
Figure BDA0002565535740000282
And the like. In the present invention, "5-6 membered heteroaryl" means a heteroaryl group comprising 5 to 6 ring atoms, preferably containing 1, 2, 3 or4 ring heteroatoms selected from N, O or S, specific, 5-6 membered heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, triazinyl and the like, preferably
Figure BDA0002565535740000283
Figure BDA0002565535740000284
Figure BDA0002565535740000285
And the like.
In the present invention, "-C (═ O) -C1-4Alkyl "means" C "as defined above1-4Alkyl "is a group formed by the attachment of-C (═ O) -; "-SO2-C1-4Alkyl "means" C "as defined above1-4Alkyl "and-SO2-linking the formed groups.
In the present invention, the term "one or more" means that the number of the substituents may be the number of all chemically substitutable positions of the substituent, preferably 1 to 6, more preferably 1 to 5, more preferably 1 to 3, more preferably 1 to 2, and still more preferably 1.
In the present invention, the "amino protecting group" refers to a chemical group that is attached to an amino group and is easily removed under certain conditions, and includes, but is not limited to, alkoxycarbonyl groups, acyl groups, alkyl groups; for example, t-butoxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl and the like. Those skilled in the art can refer to the textbook Greene's Protective Groups in Organic Synthesis (4)thedition) to make appropriate selections and operations.
The pharmaceutical compositions of the present invention may be prepared by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, and lyophilizing processes. The pharmaceutical compositions of the present invention may be administered to a subject by any convenient route of administration, including, but not limited to, oral, rectal, parenteral (e.g., injection, including subcutaneous, intradermal, intramuscular, intravenous, etc.), topical (including, for example, transdermal, intranasal, ocular, buccal, and sublingual), pulmonary (e.g., oral or nasal inhalation or insufflation therapy using an aerosol), and the like.
Solid dosage forms suitable for oral administration include tablets, pills, capsules, powders, granules and the like. In preparing these solid dosage forms, one or more of excipients, fillers or compatibilizers, binders, disintegrants, stabilizers, wetting agents, adsorbents, lubricants, or encapsulating materials conventionally employed in the art may be added in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof.
Liquid dosage forms suitable for oral administration include solutions, suspensions, emulsions, syrups or tinctures and the like. In addition to the compounds of the present invention or pharmaceutically acceptable salts thereof, the liquid dosage forms may contain one or more of diluents, solubilizers, emulsifiers, wetting agents, suspending agents, sweeteners, flavorants, aromas, or preservatives conventionally employed in the art.
Dosage forms suitable for topical administration include ointments, powders, patches, drops, sprays, inhalants and the like, and the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is mixed together with a pharmaceutically acceptable carrier under sterile conditions.
Dosage forms suitable for rectal administration include suppositories comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a suitable base.
Dosage forms suitable for parenteral injection include sterile physiologically acceptable aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage forms can be packaged in packages containing discrete quantities of the agent, such as packaged tablets, capsules.
In treating a patient, an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered to a patient (e.g., a human) in need of treatment. In some embodiments, a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, is about 0.01 to 1000 mg/day, preferably about 0.1 to 500 mg/day. The precise dosage will depend upon, among other things, the route of administration, the form of the compound when administered, the health of the subject (patient) to be treated, and the experience of the attending physician.
The compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof may also be administered in combination with other antineoplastic agents, such as chemotherapeutic agents, or in combination with other therapies, such as radiation therapy or surgery, as a pre-or post-operative adjuvant.
The abbreviations used in the present invention have the following meanings:
boc: tert-butyloxycarbonyl radical
Cbz: benzyloxycarbonyl group
Bn: benzyl radical
Pd(dPPi)Cl2: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd2(dba)3: tris (dibenzylideneacetone) dipalladium
Xantphos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene
Brettphos: dicyclohexyl [3, 6-dimethoxy-2 ', 4', 6 '-triisopropyl [1, 1' -biphenyl ] -2-yl ] phosphine
PtO2: platinum dioxide
Pd(PPh3)4: tetrakis (triphenylphosphine) palladium
PdCl2: palladium dichloride
Pd(OH)2: palladium hydroxide
Pd(OAc)2: palladium acetate
Pd: palladium (II)
HCl: hydrogen chloride
HBr: hydrogen bromide
NaBH(OAc)3: sodium triacetoxyborohydride
NaBH4: sodium borohydride
NaBH3CN: sodium cyanoborohydride
DCM: methylene dichloride
MeOH: methanol
EA: ethyl acetate
CDCl3: deuterated chloroform
DMSO, DMSO: dimethyl sulfoxide
TLC: thin layer chromatography
Description of the drawings:
FIG. 1 is a plot of the tumor volume change of subcutaneously transplanted tumors of transfected-cell Ba/F3 KIF5B-RET nude mice with the compound of example 12 and LOXO-292 at a dose of 10mg/kg twice daily.
FIG. 2 is a plot of the change in tumor volume of subcutaneous transplantable tumors of the compound of example 12 and LOXO-292 in nude mice at a dose of 30mg/kg twice daily, of stably transfected cells Ba/F3 KIF 5B-RET-G810R.
Detailed Description
The embodiments of the present invention will be explained below with reference to specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples do not specify particular techniques or conditions, according to techniques or conditions described in the literature in the field or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
I. Preparation examples of Compounds of the present invention
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) And deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
The LC-MS was measured by Agilent 6410 Triple Quad LC/MS.
The thin layer chromatography silica gel plate is prepared from HSGF254 of tobacco yellow sea or GF254 of Qingdao, TLC is 0.15-0.20 mm, and the thin layer chromatography separation and purification product is 0.4-0.5 mm. The column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a carrier.
Example 1: 6- (2, 2-difluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000311
Step 1: 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000312
To a 500ml three-necked flask were added 4, 6-dibromopyrazolo [1,5-a ] pyridine-3-carbonitrile (33.0g, 0.11mol), 2-fluoro-5-pyridineboronic acid (14.1g, 0.10mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (2.7g, 3.70mmol), potassium fluoride dihydrate (31.0g, 0.33 mmol) and 150ml of N, N-dimethylformamide, and reacted under argon at 60 ℃ overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and 500ml of water was added thereto. Filtering the reaction solution, and leaching a filter cake with acetonitrile and ethyl acetate. Vacuum drying to obtain 30g of 6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 86%.
1H NMR(400MHz，DMSO-d6)δ9.48(d，J＝1.6Hz，1H)，8.73(s，1H)， 8.51(d，J＝2.5Hz，1H)，8.27(td，J＝8.1，2.6Hz，1H)，7.86(d，J＝1.6Hz， 1H)，7.40(dd，J＝8.4，2.8Hz，1H).
Step 2: 3- (5- (6-bromo-3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamic acid tert-butyl ester
Figure BDA0002565535740000321
6-bromo-4- (6-fluoropyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (4.35g, 13.7mmol), 6- (tert-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane (3.25g, 16.3mmol), potassium carbonate (5.67g, 41.1mmol) and 60ml of dimethyl sulfoxide were added to a 250ml three-necked flask and reacted at 100 ℃ overnight. After the reaction was completed, the reaction mixture was cooled to room temperature, and 200ml of water was added thereto. The reaction mixture was filtered, and the filter cake was dissolved in a mixed solvent (DCM: MeOH: 10: 1) and then dried by suction, acetonitrile was taken with water three times, and silica gel column chromatography was carried out to give 3.4g of tert-butyl 3- (5- (6-bromo-3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate. The yield thereof was found to be 50%.
MS m/z：495.1/497.1[M+1]+。
1H NMR(400MHz，CDCl3)δ8.68(d，J＝1.3Hz，1H)，8.36(d，J＝2.1 Hz，1H)，8.25(s，1H)，7.72(dd，J＝8.8，2.3Hz，1H)，7.39(d，J＝1.3Hz， 1H)，6.66(d，J＝8.8Hz，1H)，4.31(d，J＝4.3Hz，2H)，4.15(s，2H)，3.55(s， 2H)，2.68(d，J＝7.6Hz，1H)，1.53(d，J＝8.7Hz，1H)，1.37(d，J＝5.2Hz， 9H).
And step 3: 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-bromopyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000331
To a 250ml three-necked flask were added tert-butyl 3- (5- (6-bromo-3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate (3.4g, 6.88mmol) and 50ml of a 4.0M solution of hydrogen chloride in methanol, and reacted at 25 ℃ overnight. And the MS monitors the completion of the reaction. The reaction solution was drained and acetonitrile was taken with water three times to obtain 3.66g of crude 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-bromopyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 99%.
MS m/z：395.0/397.0[M+1]+。
And 4, step 4: 6-bromo-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000332
To a 250ml three-necked flask was added crude 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-bromopyrazolo [1,5-a ] pyridine-3-carbonitrile (3.66g, 6.88mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.88g, 13.76mmol) and 100ml dichloroethane, sodium triacetoxyborohydride (7.3g, 34.4mmol) was slowly added, reacted at room temperature overnight, and TLC monitored for completion of the reaction. Quenching reaction by saturated sodium bicarbonate, washing with water, extracting by dichloromethane, drying an organic phase, draining, and carrying out silica gel column chromatography to obtain 2.8g of 6-bromo-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 79%.
MS m/z：516.1/518.1[M+1]+。
1H NMR(400MHz，CDCl3)δ8.70(d，J＝1.5Hz，1H)，8.40(d，J＝2.2 Hz，1H)，8.26(s，1H)，8.11(d，J＝2.0Hz，1H)，7.77(dd，J＝8.8，2.5Hz， 2H)，7.40(d，J＝1.5Hz，1H)，6.71(dd，J＝15.8，8.7Hz，2H)，3.90(d，J＝ 12.7Hz，7H)，3.68(d，J＝9.2Hz，4H)，2.84(s，1H)，1.71(d，J＝9.0Hz， 1H).
And 5: 6- (2, 2-difluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000341
To a 50ml single neck flask was added 6-bromo-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile (103 mg, 0.20mmol), tris (dibenzylideneacetone) dipalladium (18.3mg, 0.02mmol), dicyclohexyl [3, 6-dimethoxy-2 ', 4', 6 '-triisopropyl [1, 1' -biphenyl ] -2-yl ] phosphine (10.8mg, 0.02mmol), cesium carbonate (163mg, 0.50mmol), 2, 2-difluoroethylamine (33mg, 0.40mmol) and 10ml dioxane, under argon, and reacted overnight at 90 ℃. Kieselguhr for filtration assistance, evaporation of the filtrate under reduced pressure and chromatography on silica gel (dichloromethane: methanol 15: 1) to give 77mg of the product 6- (2, 2-difluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 74%.
MS m/z：517.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.44(s，1H)，8.36(s，1H)，8.25 (s，1H)，8.08(s，1H)，7.80(d，J＝8.0Hz，1H)，7.69(d，J＝8.0Hz， 1H)，7.15(s，1H)，6.79(t，J＝8.0Hz，2H)，6.32(t，J＝8.0Hz，1H)， 6.22(tt，J1＝56.0Hz，J2＝4.0Hz，1H)，3.83(s，3H)，3.79-3.61(m， 4H)，3.59-3.46(m，4H)，3.39-3.28(m，2H)，2.50(s，1H)，1.60(d，J＝ 8.0Hz，1H)。
Example 2: 6- (ethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000342
The compound was synthesized as in example 1. And taking the intermediate 2A and ethylamine as raw materials to obtain a target compound 6- (ethylamine) -4- (6- (6- ((6-methoxypyridine-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 30%.
MS m/z：481.5[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.39(s，1H)，8.34(s，1H)，8.09(s，1H)， 7.93(s，1H)，7.78(d，J＝8.7Hz，1H)，7.71(s，1H)，7.07(s，1H)，6.90-6.67 (m，2H)，6.01(s，1H)，3.82(s，3H)，3.72(s，4H)，3.53(s，4H)，3.14-2.98(m， 2H)，2.07(s，1H)，1.59(s，1H)，1.22(t，J＝6.9Hz，3H).
Example 3: 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (n-propylamine) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000351
The compound was synthesized as in example 1. The intermediate 2A and n-propylamine are used as raw materials to obtain a target compound 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3-yl) -6- (n-propylamine) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 13%.
MS m/z：495.3[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.40(s，1H)，8.35(d，J＝2.0Hz， 1H)，8.09(s，1H)，7.95(d，J＝2.0Hz，1H)，7.80(d，J＝8.0Hz，1H)， 7.70(d，J＝8.0Hz，1H)，7.07(d，J＝2.0Hz，1H)，6.85-6.74(m，2H)， 5.98(t，J＝8.0Hz，1H)，3.83(s，3H)，3.80-3.63(m，4H)，3.62-3.45 (m，4H)，3.10-2.98(m，2H)，2.50(s，1H)，1.68-1.54(m，3H)，0.99(t， J＝6.0Hz，3H)。
Example 4: 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2, 2, 2-trifluoroethylamine) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000352
The compound was synthesized as in example 1. The intermediate 2A and trifluoroethylamine are used as raw materials to obtain a target compound 4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3-yl) -6- (2, 2, 2-trifluoroethylamine) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 68%.
MS m/z：535.4[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.46(s，1H)，8.37(d，J＝2.0Hz， 2H)，8.09(s，1H)，7.81(d，J＝8.0Hz，1H)，7.74-7.66(m，1H)，7.18 (d，J＝2.0Hz，1H)，6.86-6.74(m，2H)，6.60(t，J＝8.0Hz，1H)，4.18-4.05 (m，2H)，3.83(s，3H)，3.80-3.63(m，4H)，3.62-3.40(m，4H)，2.50 (s，1H)，1.60(s，1H)。
Example 5: 6- (isobutylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000361
The compound was synthesized as in example 1. And taking the intermediate 2A and isobutylamine as raw materials to obtain a target compound 6- (isobutylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 60%.
MS m/z：509.3[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.40(s，1H)，8.36(s，1H)，8.09 (s，1H)，7.94(s，1H)，7.80(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz， 1H)，7.11(s，1H)，6.85-6.75(m，2H)，6.00(t，J＝8.0Hz，1H)，3.83 (s，3H)，3.79-3.63(m，4H)，3.62-3.42(m，4H)，2.89(t，J＝6.0Hz， 2H)，1.96-1.85(m，1H)，2.50(s，1H)，1.60(s，1H)，0.99(t，J＝6.4Hz， 6H)。
Example 6: 6- (3, 3-Difluorocyclobutylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000362
The compound was synthesized as in example 1. The intermediate 2A and the 3, 3-difluorocyclobutylamine are used as raw materials to obtain a target compound 6- (3, 3-difluorocyclobutylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 50%.
MS m/z：543.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.45(s，1H)，8.36(d，J＝1.88Hz，1H)， 8.09(br.s.，1H)，7.98(s，1H)，7.80(d，J＝7.52Hz，1H)，7.70(d，J＝5.91Hz， 1H)，7.02(s，1H)，6.73-6.86(m，2H)，6.56(d，J＝6.18Hz，1H)，3.88-3.86 (m，1H)，3.83(s，3H)，3.76-3.64(m，4H)，3.60-3.45(m，4H)，3.17(tt， J＝7.29，13.94Hz，2H)，2.61-2.49(m，3H)，1.60(s，1H).
Example 7: 6- (cyanomethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000371
The compound was synthesized as in example 1. And taking the intermediate 2A and aminoacetonitrile as raw materials to obtain a target compound 6- (cyanomethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 15%.
MS m/z：492.2[M+1]+。
Example 8: 6- (2-hydroxyethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000372
The compound was synthesized as in example 1. And taking the intermediate 2A and aminoethanol as raw materials to obtain a target compound 6- (2-hydroxyethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 15%.
MS m/z：497.4[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(s，1H)，8.10 (s，1H)，8.02(s，1H)，7.80(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz， 1H)，7.15(s，1H)，6.86-6.73(m，2H)，5.99(t，J＝8.0Hz，1H)，4.78(t， J＝5.2Hz，1H)，3.96-3.85(m，2H)，3.83(s，3H)，3.79-3.63(m，4H)， 3.61-3.44(m，4H)，3.30(s，2H)，3.21-3.10(m，2H)，2.50(s，1H)，1.60 (s，1H)。
Example 9: 6- (2-hydroxy-2-methylpropylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000381
The compound was synthesized as in example 1. The intermediate 2A and 1-amino 2-methyl 2-propanol are used as raw materials to obtain the target compound 6- (2-hydroxy-2-methylpropylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) pyrazole [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 8%.
MS m/z：525.3[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.39(s，1H)，8.36(s，1H)，8.10(s， 1H)，8.05(s，1H)，7.80(d，J＝8.0Hz，1H)，7.70(d，J＝8.0Hz，1H)，7.26 (s，1H)，6.84-6.74(m，2H)，5.83(t，J＝8.0Hz，1H)，4.56(s，1H)，3.82 (s，3H)，3.78-3.66(m，4H)，3.59-3.42(m，4H)，3.00(d，J＝6.0Hz，2H)， 2.50(s，1H)，1.60(s，1H)，1.21(s，6H)。
Example 10: 6- ((3-fluoroazetidin-3-yl) methylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000382
Step 1: 3- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylamino) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
Figure BDA0002565535740000383
The compound was synthesized as in example 1. Using the intermediate 2A and 3- (aminomethyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester as raw materials to obtain a target compound, namely 3- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylamino) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester. The yield thereof was found to be 74%.
MS m/z：640.2[M+1]+。
Step 2: 6- ((3-fluoroazetidin-3-yl) methylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000391
To a 25ml single neck flask was added tert-butyl 3- ((3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylamino) methyl) -3-fluoroazetidine-1-carboxylate (95mg, 0.15mmol), 4ml dichloromethane and 4ml trifluoroacetic acid for 2 hours under argon. The reaction solution was evaporated to dryness under reduced pressure, 20ml of dichloromethane and 10ml of saturated sodium bicarbonate were added, stirred until no air bubbles were present and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (dichloromethane: methanol ═ 15: 1) gives 36mg of the product 6- ((3-fluoroazetidin-3-yl) methylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 44%.
MS m/z：540.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.43(s，1H)，8.35(d，J＝2.2Hz，1H)， 8.26(s，1H)，8.14(s，1H)，7.79(dd，J＝8.8，2.4Hz，1H)，7.74(dd，J＝5.5， 3.5Hz，1H)，7.20(s，1H)，6.83-6.75(m，2H)，6.53(t，J＝5.9Hz，1H)，4.18 (d，J＝2.6Hz，1H)，4.13(s，1H)，3.83(s，3H)，3.82-3.79(m，4H)，3.76- 3.73(m，4H)，3.64-3.60(m，5H)，2.64(d，J＝18.9Hz，1H)，1.65(s，1H).
Example 11: 4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((3-fluoroazetidin-3-yl) methylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000401
Step 1: 4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6-bromopyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000402
The compound is synthesized with the intermediate 2A. And (3) after the protecting group of the intermediate 1 is removed, carrying out reductive amination with 3-fluoro-4-methoxybenzaldehyde to obtain an intermediate 2B. The yield thereof was found to be 44%.
MS m/z：533.0[M+1]+。
1H NMR(400MHz，CDCl3)δ8.69(d，J＝1.5Hz，1H)，8.40(d，J＝2.1 Hz，1H)，8.27(s，1H)，7.76(dd，J＝8.8，2.5Hz，1H)，7.40(d，J＝1.5Hz， 1H)，7.15(dd，J＝12.2，1.7Hz，1H)，7.06(d，J＝8.4Hz，1H)，6.89(t，J＝8.5 Hz，1H)，6.69(d，J＝8.8Hz，1H)，3.87(s，3H)，3.83(d，J＝6.1Hz，4H)， 3.59(d，J＝8.8Hz，4H)，2.74(d，J＝6.9Hz，1H)，1.66(d，J＝8.7Hz，1H).
Step 2: 3- ((4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -3-cyanopyrazole [1,5-a ] pyridin-6-ylamino) methyl) -3-fluoroazetidine-1-carboxylic acid tert-butyl ester
Figure BDA0002565535740000403
The compound was synthesized as in step 1 of example 10. The yield thereof was found to be 34%.
MS m/z：657.3[M+1]+。
And step 3: 4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- ((3-fluoroazetidin-3-yl) methylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000411
The compound was synthesized as in step 2 of example 10. The yield thereof was found to be 30%.
MS m/z：557.0[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.43(s，1H)，8.35(d，J＝2.2Hz，1H)， 8.26(d，J＝1.2Hz，1H)，7.79(dd，J＝8.8，2.3Hz，1H)，7.25-7.05(m，4H)， 6.78(d，J＝8.8Hz，1H)，6.53(t，J＝6.2Hz，1H)，4.17-4.12(m，1H)，4.11 (s，1H)，3.81(s，3H)，3.78-3.70(m，6H)，3.65-3.48(m，6H)，2.60(s，1H)， 1.62(d，J＝7.8Hz，1H).
Example 12: 6- (2-fluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000412
Step 1: 3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylcarbamic acid tert-butyl ester
Figure BDA0002565535740000413
The compound was synthesized as in step 5 of example 1. The intermediate 2A and the tert-butyl carbamate are taken as raw materials for synthesis. The yield thereof was found to be 68%.
MS m/z：553.4[M+1]+。
Step 2: 3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl (2-fluoroethyl) carbamic acid tert-butyl ester
Figure BDA0002565535740000421
To a 25ml single-neck flask was added tert-butyl 3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylcarbamate (55mg, 0.10mmol), cesium carbonate (66mg, 0.20mmol), 1-fluoro-2-iodoethane (35mg, 0.20mmol) and 5ml of DMF, and reacted at 80 ℃ for 4 hours under nitrogen. The reaction mixture was quenched by the addition of 15ml of water and extracted three times with ethyl acetate (15 ml). The organic layer was evaporated to dryness under reduced pressure and crude silica gel column chromatography (dichloromethane: methanol ═ 30: 1) afforded 60mg of the product tert-butyl 3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl (2-fluoroethyl) carbamate. The yield thereof was found to be 99%.
MS m/z：599.5[M+1]+。
And step 3: 6- (2-fluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000422
To a 10ml single-neck flask were added tert-butyl 3-cyano-4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl (2-fluoroethyl) carbamate (60mg, 0.10mmol) and 5ml of a 4.0M solution of hydrogen chloride in methanol under argon and reacted at 25 ℃ for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, 20ml of dichloromethane and 10ml of saturated sodium bicarbonate were added, stirred until no air bubbles were present and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Column chromatography on silica gel (dichloromethane: methanol ═ 15: 1) gives 20mg of the product 6- (2-fluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 40%.
MS m/z：499.3[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(d，J＝1.6Hz，1H)， 8.11(d，J＝1.4Hz，2H)，7.79(d，J＝7.5Hz，1H)，7.70(s，1H)，7.12(s，1H)， 6.80(d，J＝8.5Hz，2H)，6.25(t，J＝5.8Hz，1H)，4.62(dt，J＝47.8，4.7Hz， 2H)，3.83(s，3H)，3.80-3.61(m，4H)，3.60-3.50(m，4H)，3.43(ddd，J＝ 14.5，11.1，5.9Hz，2H)，2.50(s，1H)，1.62(s，1H).
Example 13: 4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000431
Step 1: 3-cyano-4- (6- (6- ((3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-ylcarbamic acid tert-butyl ester
Figure BDA0002565535740000432
The compound was synthesized as in step 5 of example 1. The intermediate 2B and the tert-butyl carbamate are taken as raw materials for synthesis.
MS m/z：570.2[M+1]+。
Step 2: 3-carbonitrile-4- (6- (6- ((3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridin-6-yl (2-fluoroethyl) carbamic acid tert-butyl ester
Figure BDA0002565535740000433
The compound was synthesized as in step 2 of example 12.
MS m/z：616.2[M+1]+。
And step 3: 4- (6- (6- (3-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000441
This compound was synthesized as described for 6- (2-fluoroethylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 28%.
MS m/z：516.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.42(s，1H)，8.35(d，J＝1.5Hz，1H)， 8.11(d，J＝1.5Hz，1H)，7.88-7.64(m，2H)，7.13(d，J＝1.7Hz，2H)，6.80 (d，J＝8.8Hz，1H)，6.27(t，J＝5.9Hz，1H)，4.63(dt，J＝47.8，4.8Hz，2H)， 3.83(s，3H)，3.78-3.66(m，4H)，3.63-3.50(m，4H)，3.44(ddd，J＝28.5， 10.1，5.1Hz，2H)，2.64-2.54(m，1H)，1.63(s，1H)。
Example 14: 4- (6- (6- (2-fluoro-5-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000442
Step 1: 3- (5- (3-cyano-6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamic acid tert-butyl ester
Figure BDA0002565535740000443
The compound was synthesized as in step 5 of example 1. The intermediate 1 and 2, 2-difluoroethylamine are used as raw materials for synthesis. The yield thereof was found to be 61%.
MS m/z：496.2[M+1]+。
Step 2: 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000451
To a 25ml three-necked flask were added tert-butyl 3- (5- (3-cyano-6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate (245mg, 0.50mmol) and 5ml of a 4.0M methanolic hydrogen chloride solution, and reacted at 25 ℃ overnight. And the MS monitors the completion of the reaction. The reaction solution was drained and acetonitrile was taken with water three times to obtain 300mg of crude 4- (6- (3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridin-3-yl) -6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile. The yield thereof was found to be 99%.
MS m/z：396.2[M+1]+。
And step 3: 4- (6- (6- (2-fluoro-5-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2, 2-difluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000452
The synthesis of this compound was the same as in step 4 of example 1. Synthesized from intermediate 3A and 2-fluoro-5-methoxybenzaldehyde. The yield thereof was found to be 23%.
MS m/z：534.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.43(s，1H)，8.35(d，J＝2.2，1H)， 8.24(d，J＝1.6，1H)，7.79(dd，J＝8.7，2.2，1H)，7.18(d，J＝1.8，1H)，7.06(d， J＝8.3，2H)，6.81(t，J＝8.1，2H)，6.41(t，J＝6.5，1H)，6.22(t，J＝3.7，1H)， 3.75(s，3H)，3.75-3.54(m，11H)，2.60(s，1H)，1.63(s，1H).
Example 15: 4- (6- (6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000453
Step 1: 3- (5- (6- ((tert-Butoxycarbonyl) amino) -3-cyanopyrazol [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamic acid tert-butyl ester
Figure BDA0002565535740000461
To a 100ml single neck flask was added tert-butyl 3- (5- (6-bromo-3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate (635mg, 1.28 mmol), tris (dibenzylideneacetone) dipalladium (118mg, 0.13mmol), dicyclohexyl [3, 6-dimethoxy-2 ', 4', 6 '-triisopropyl [1, 1' -biphenyl ] -2-yl ] phosphine (69mg, 0.13mmol), cesium carbonate (1.26g, 3.84mmol), tert-butyl carbamate (453mg, 3.84mmol) and 15ml dioxane, under argon protection, and reacted at 90 ℃ overnight. Kieselguhr for filtration, evaporation of the filtrate under reduced pressure and chromatography on silica gel (dichloromethane: methanol ═ 30: 1) to give 488mg of the product tert-butyl 3- (5- (6- ((tert-butoxycarbonyl) amino) -3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate. The yield thereof was found to be 71%.
MS m/z：532.3[M+1]+。
1H NMR(400MHz，CDCl3)δ9.12(s，1H)，8.36(s，1H)，8.23(s，1H)， 7.76(d，J＝7.3，1H)，7.10(s，1H)，6.67(t，J＝7.3，2H)，4.32(d，J＝4.5，2H)， 4.23-4.07(m，2H)，3.59-3.47(m，2H)，2.69(d，J＝6.5，1H)，1.55(s，9H)， 1.43(s，1H)，1.39(s，9H).
Step 2: 3- (5- (6- ((tert-Butoxycarbonyl) (2-fluoroethyl) amino) -3-cyanopyrazol [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamic acid tert-butyl ester
Figure BDA0002565535740000462
To a 250ml single neck flask was added tert-butyl 3- (5- (6- ((tert-butoxycarbonyl) amino) -3-cyanopyrazole [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate (2900mg, 5.46mmol), cesium carbonate (5340mg, 16.4mmol), 1-fluoro-2-iodoethane (1430mg, 8.17mmol) and 100ml DMF, and reacted at 80 ℃ for 12 hours under nitrogen. The reaction mixture was quenched by addition of 150ml of water, and extracted three times with ethyl acetate (150 ml). The organic layer was evaporated to dryness under reduced pressure and chromatographed on crude silica gel (dichloromethane: methanol 30: 1) to give 2820mg of the product. The yield thereof was found to be 89%.
MS m/z：578.3[M+1]+。
1H NMR(400MHz，CDCl3)δ8.57(s，1H)，8.37(d，J＝1.8，1H)，8.28(s， 1H)，7.76(d，J＝8.2，1H)，7.30(s，1H)，6.68(d，J＝8.7，1H)，4.69(dt，J＝ 47.5，4.5Hz，2H)，4.32(d，J＝4.6，2H)，4.12(dd，J＝14.3，7.1，2H)，3.94(dt， J＝26.5，4.6Hz，2H)3.57(s，2H)，2.69(dd，J＝13.7，6.2，1H)，1.53(s，1H)， 1.48(s，9H)，1.39(s，9H).
And step 3: 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000471
To a 250ml single neck flask were added tert-butyl 3- (5- (6- ((tert-butoxycarbonyl) (2-fluoroethyl) amino) -3-cyanopyrazol [1,5-a ] pyridin-4-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carbamate (2820mg, 4.88mmol) and 50ml of a 4.0M ethyl hydrogen chloride solution in ethyl acetate, and reacted under argon at 25 ℃ for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure, 200ml of dichloromethane and 100ml of saturated sodium bicarbonate were added, stirred until no air bubbles were present and the organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Silica gel column chromatography (dichloromethane: methanol 15: 1) afforded the product. The yield thereof was found to be 80%.
MS m/z：378.2[M+1]+。
And 4, step 4: 4- (6- (6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000472
To a 25ml three-necked flask were added 4- (6- (3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-cyano (60mg, 0.16mmol), 4-methoxybenzaldehyde (18mg, 0.13mmol) and 6ml dichloroethane, and sodium triacetoxyborohydride (140mg, 0.66mmol) was slowly added, reacted at room temperature overnight with TLC monitoring of completion of the reaction. Quenching reaction by saturated sodium bicarbonate, washing by water, extracting by dichloromethane, drying an organic phase, draining, and carrying out silica gel column chromatography to obtain 4- (6- (6- (4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptane-3-yl) pyridine-3-yl) -6- (2-fluoroethylamino) pyrazole [1,5-a ] pyridine-3-cyano.
MS m/z：498.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(d，J＝1.9，1H)， 8.10(d，J＝1.2，1H)，7.80(d，J＝7.5，1H)，7.31(s，2H)，7.14(d，J＝1.4，1H)， 6.90(s，2H)，6.80(d，J＝8.8，1H)，6.30(t，J＝5.6，1H)，4.62(dt，J＝47.7，4.7 Hz，1H)，4.16-3.86(m，4H)，3.74(s，3H)，3.68-3.44(m，4H)，3.43-3.37 (m，2H)，2.61(s，1H)，1.66(s，1H).
Example 16: 4- (6- (6- ((5-fluoro-6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamine) -pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000481
The compound was synthesized as in example 15. The intermediate 3B and 5-fluoro-6-methoxy nicotinaldehyde are taken as raw materials for synthesis.
MS m/z：517.1[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.34(d，J＝2.5Hz，1H)， 8.10(d，J＝1.9Hz，1H)，7.93(s，1H)，7.78(dd，J＝8.8，2.5Hz，1H)，7.64(d，J＝11.5Hz，1H)，7.12(d，J＝2.0Hz，1H)，6.78(d，J＝8.8Hz，1H)，6.27(t， J＝5.9Hz，1H)，4.63(dt，J＝47.7，4.6Hz，2H)，3.92(s，3H)，3.71(s，4H)， 3.54(s，4H)，3.43(ddd，J＝28.5，9.9，5.0Hz，2H)，2.55(s，1H)，1.59(d，J＝ 8.0Hz，1H).
Example 17: 4- (6- (6- (3, 5-difluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000491
The compound was synthesized as in example 15. The intermediate 3B and the 3, 5-difluoro-4-methoxybenzaldehyde are used as raw materials for synthesis.
MS m/z：534.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.40(s，1H)，8.32(d，J＝2.3，1H)，8.08(d，J＝1.5，1H)，7.77(dd，J＝8.8，2.4，1H)，7.41-7.34(m，1H)，7.12(d， J＝8.2，2H)，6.77(d，J＝8.8，1H)，6.27(t，J＝5.8，1H)，4.62(dt，J＝47.7，4.7 Hz，2H)，3.87(s，3H)，3.72-3.65(m，4H)，3.69-3.50(m，6H)，2.56(dd， J＝12.9，6.6，1H)，1.64(s，1H).
Example 18: 4- (6- (6- (2-fluoro-4-methoxybenzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000492
The compound was synthesized as in example 15. The intermediate 3B and the 2-fluoro-4-methoxybenzaldehyde are used as raw materials for synthesis. The yield thereof was found to be 37%.
MS m/z：516.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(d，J＝2.2，1H)， 8.10(d，J＝1.7，1H)，7.79(dd，J＝8.7，1.9，1H)，7.40(s，1H)，7.14(d，J＝1.7， 1H)，6.78(t，J＝8.3，3H)，6.25(t，J＝5.8，1H)，4.69(t，J＝4.7，1H)，4.57(t， J＝4.7，1H)，3.73(s，3H)，3.73-3.37(m，10H)，2.59(s，1H)，1.62(s，1H).
Example 19: 4- (6- (6- (4- (difluoromethoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000501
The compound was synthesized as in example 15. The intermediate 3B and the 4- (difluoromethoxy) benzaldehyde are taken as raw materials for synthesis. The yield thereof was found to be 24%.
MS m/z：534.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(d，J＝2.1，1H)， 8.10(d，J＝1.5，1H)，7.79(d，J＝8.5，1H)，7.42(s，2H)，7.25-6.98(m，4H)， 6.77(t，J＝11.7，1H)，6.25(t，J＝5.8，1H)，4.69(t，J＝4.7，1H)，4.57(t，J＝4.7， 1H)，3.82-3.37(m，10H)，2.57(s，1H)，1.63(s，1H).
Example 20: 4- (6- (6- ((6- (difluoromethoxy) pyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000502
The compound was synthesized as in example 15. The intermediate 3B and the 6- (difluoromethoxy) nicotinaldehyde are taken as raw materials for synthesis. The yield thereof was found to be 29%.
MS m/z：535.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.35(d，J＝2.2，1H)， 8.21(s，1H)，8.10(d，J＝1.6，1H)，7.91(d，J＝7.8，1H)，7.79(dd，J＝8.8，2.4， 1H)，7.68(s，1H)，7.12(d，J＝1.7，1H)，7.04(d，J＝8.4，1H)，6.79(d，J＝8.8， 1H)，6.25(t，J＝5.8，1H)，4.69(t，J＝4.7，1H)，4.57(t，J＝4.7，1H)，3.82-3.37 (m，10H)，2.55(s，1H)，1.61(d，J＝7.7，1H).
Example 21: 4- (6- (6- ((3-fluoro-4- (difluoromethoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000503
The compound was synthesized as in example 15. The intermediate 3B and the 3-fluoro-4- (difluoromethoxy) benzaldehyde are taken as raw materials for synthesis. MS m/z: 552.2[ M + 1]]+。
1H NMR(400MHz，DMSO-d6)δ8.42(s，1H)，8.34(d，J＝2.2，1H)， 8.10(d，J＝1.5，1H)，7.78(dd，J＝8.8，2.4，1H)，7.38(d，J＝12.1，1H)，7.29(t， J＝8.2，1H)，7.23(d，J＝11.5，2H)，7.13(d，J＝1.6，1H)，6.78(d，J＝8.8，1H)， 6.30(t，J＝5.8，1H)，4.63(dt，J＝47.7，4.7Hz，2H)，3.72-3.68(m，4H)， 3.58-3.53(m，4H)，3.43(ddd，J＝27.3，9.5，4.5Hz，2H)，2.57(dd，J＝12.8， 6.6Hz，1H)，1.60(d，J＝8.4，1H).
Example 22: 4- (6- (6- ((2, 3-difluoro-4- (methoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000511
The compound was synthesized as in example 15. The intermediate 3B and the 2, 3-difluoro-4- (methoxyl) benzaldehyde are taken as raw materials for synthesis.
MS m/z：534.2[M+1]+。
Example 23: 4- (6- (6- ((2, 5-difluoro-4- (methoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000512
The compound was synthesized as in example 15. The intermediate 3B and the 2, 5-difluoro-4- (methoxyl) benzaldehyde are taken as raw materials for synthesis.
MS m/z：534.2[M+1]+。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.34(d，J＝2.3，1H)， 8.10(d，J＝1.7，1H)，7.78(dd，J＝8.8，2.5，1H)，7.28(dd，J＝12.0，7.0，1H)，7.13(d，J＝1.8，1H)，7.06(dd，J＝11.5，7.3，1H)，6.77(d，J＝8.8，1H)，6.27(t， J＝5.8，1H)，4.62(dt，J＝47.7，4.7Hz，2H)，3.82(s，3H)，3.74-3.68(m，4H)， 3.60-3.40(m，6H)，2.53(d，J＝7.3，1H)，1.58(d，J＝8.4，1H).
Example 24: 4- (6- (6- ((3-chloro-4- (methoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000521
The compound was synthesized as in example 15. The intermediate 3B and the 3-chloro-4- (methoxyl) benzaldehyde are taken as raw materials for synthesis.
MS m/z：532.2[M+1]+、534。
1H NMR(400MHz，DMSO-d6)δ＝8.42(s，1H)，8.34(d，J＝2.3，1H)， 8.11(d，J＝1.6，1H)，7.78(dd，J＝8.8，2.4，1H)，7.41(s，1H)，7.28(d，J＝8.2， 1H)，7.14(s，1H)，7.07(d，J＝8.5，1H)，6.78(d，J＝8.8，1H)，6.31(d，J＝4.1， 1H)，4.63(dt，J＝47.7，4.7Hz，2H)，3.83(s，3H)，3.69(s，4H)，3.56-3.45(m， 4H)，3.43-3.38(m，2H)，2.57(s，1H)，1.60(d，J＝8.1，1H).
Example 25: 4- (6- (6- ((2-chloro-4- (methoxy) benzyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000522
The compound was synthesized as in example 15. The intermediate 3B and 2-chloro-4- (methoxyl) benzaldehyde are taken as raw materials for synthesis.
MS m/z：532.2[M+1]+、534。
1H NMR(400MHz，DMSO-d6)δ8.41(s，1H)，8.34(d，J＝2.2，1H)， 8.11(d，J＝1.6，1H)，7.79(dd，J＝8.7，2.3，1H)，7.49(s，1H)，7.15(d，J＝1.0， 1H)，7.00(s，1H)，6.93(d，J＝7.7，1H)，6.79(d，J＝8.8，1H)，6.30(s，1H)， 4.63(dt，J＝47.7，4.7Hz，2H)，3.83(s，3H)，3.82-3.66(m，4H)，3.61-3.51 (m，4H)，3.49-3.38(m，2H)，2.58(s，1H)，1.62(s，1H).
Example 26: 4- (6- (6- ((5-chloro-6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) -6- (2-fluoroethylamino) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000523
The compound was synthesized as in example 15. The intermediate 3B and 5-chloro-6-methoxy nicotinaldehyde are taken as raw materials for synthesis.
MS m/z：532.2[M+1]+、534.2。
Example 27: 6- (4, 4, 4-Triflubutamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000531
The compound was synthesized as in example 12. Coupling the intermediate 2A with tert-butyl carbamate, carrying out nucleophilic substitution on the coupled intermediate and 1, 1, 1-trifluoro-4-iodobutane, and removing a protecting group to obtain the product.
MS m/z：563.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.42(s，1H)，8.36(d，J＝2.3Hz，1H)， 8.09(s，1H)，8.03(d，J＝1.6Hz，1H)，7.79(dd，J＝8.8，2.4Hz，1H)，7.70(d， J＝7.8Hz，1H)，7.05(d，J＝1.7Hz，1H)，6.94-6.65(m，2H)，6.11(t，J＝ 5.6Hz，1H)，3.83(s，3H)，3.79-3.65(m，4H)，3.55(d，J＝18.8Hz，4H)， 3.16(dd，J＝12.7，6.5Hz，3H)，2.52(s，1H)，2.48-2.33(m，3H)，1.92- 1.74(m，2H)，1.60(d，J＝6.4Hz，1H).
Example 28: 6- (3-Methylsulfonylpropamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000532
The compound was synthesized as in example 1. The intermediate 2A and the 3-methylsulfonylpropylamine are taken as raw materials for synthesis.
MS m/z：573.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.42(s，1H)，8.35(d，J＝2.2Hz，1H)， 8.07(d，J＝11.5Hz，2H)，7.79(dd，J＝8.8，2.2Hz，1H)，7.69(d，J＝7.7Hz， 1H)，7.04(s，1H)，6.78(t，J＝7.6Hz，2H)，6.13(t，J＝5.6Hz，1H)，3.82(s， 3H)，3.78-3.65(m，4H)，3.51(s，4H)，3.31-3.18(m，4H)，3.00(s，3H)， 2.52(s，1H)，2.00(dd，J＝14.6，7.1Hz，2H)，1.59(d，J＝7.1Hz，1H).
Example 29: 6- (3-Fluoropropylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000541
The compound was synthesized as in example 12. Coupling the intermediate 2A with tert-butyl carbamate, carrying out nucleophilic substitution with 1-fluoro-3-iodopropane, and removing protecting groups.
MS m/z：513.2[M+1]+。
Example 30: 6- (3, 3, 3-Trifluoropropylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000542
The compound was synthesized as in example 1. The intermediate 2A and the 3, 3, 3-trifluoropropylamine are taken as raw materials for synthesis.
MS m/z：549.2[M+1]+。
Example 31: 6- (2, 2, 3, 3, 3-Pentafluoropropylamine) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000543
The compound was synthesized as in example 1. The intermediate 2A and the 2, 2, 3, 3, 3-pentafluoropropylamine are taken as raw materials for synthesis.
MS m/z：585.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.46(s，1H)，8.35(d，J＝5.7Hz，2H)， 8.08(s，1H)，7.80(d，J＝7.7Hz，1H)，7.69(d，J＝8.1Hz，1H)，7.20(d，J＝ 1.6Hz，1H)，6.78(t，J＝9.4Hz，2H)，6.53(t，J＝6.8Hz，1H)，4.17(td，J＝ 15.8，6.5Hz，2H)，3.82(s，3H)，3.78-3.62(m，4H)，3.57-3.51(m，4H)， 2.50(s，1H)，1.59(d，J＝8.0Hz，1H).
Example 32: 6- ((2- (1H-imidazol-1-yl) ethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000551
The compound was synthesized as in example 1. The intermediate 2A and 2- (1H-imidazole-1-yl) ethylamine are taken as raw materials for synthesis.
MS m/z：547.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.42(s，1H)，8.34(d，J＝1.9Hz，1H)， 8.10(s，2H)，7.78(dd，J＝8.7，2.2Hz，1H)，7.70(d，J＝8.1Hz，2H)，7.28(s， 1H)，7.07(s，1H)，6.91(s，1H)，6.78(dd，J＝8.6，4.2Hz，2H)，6.20(t，J＝ 5.7Hz，1H)，4.20(t，J＝5.7Hz，2H)，3.83(s，3H)，3.78-3.65(m，4H)，3.63 -3.51(m，4H)，3.50-3.46(m，2H)，2.56(s，1H)，1.61(d，J＝8.2Hz，1H).
Example 33: 6- ((2- (1H-1, 2, 4-triazol-1-yl) ethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000552
The compound was synthesized as in example 1. The intermediate 2A and 2- (1H-1, 2, 4-triazole-1-yl) ethylamine are taken as raw materials for synthesis.
MS m/z：548.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.54(s，1H)，8.43(s，1H)，8.35(d，J＝ 2.2Hz，1H)，8.11(s，2H)，8.01(s，1H)，7.78(dd，J＝8.7，2.1Hz，1H)，7.70 (d，J＝7.9Hz，1H)，7.05(d，J＝1.0Hz，1H)，6.79(dd，J＝8.5，3.3Hz，2H)， 6.17(t，J＝5.9Hz，1H)，4.42(t，J＝5.7Hz，2H)，3.83(s，3H)，3.77-3.74 (m，4H)，3.60-3.56(m，6H)，2.55(s，1H)，1.61(s，1H).
Example 34: 6- ((2- (1H-1, 3, 4-triazol-1-yl) ethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000553
The compound was synthesized as in example 1. The intermediate 2A and 2- (1H-1, 3, 4-triazole-1-yl) ethylamine are taken as raw materials for synthesis.
MS m/z：548.2[M+1]+。
1H NMR(400MHz，DMSO)δ8.55(s，2H)，8.43(s，1H)，8.35(d，J＝ 2.3Hz，1H)，8.17(d，J＝1.7Hz，1H)，8.08(s，1H)，7.78(dd，J＝8.8，2.5Hz， 1H)，7.68(dd，J＝8.4，2.2Hz，1H)，7.04(d，J＝1.8Hz，1H)，6.86-6.72(m， 2H)，6.17(t，J＝6.0Hz，1H)，4.26(t，J＝5.8Hz，2H)，3.82(s，3H)，3.74- 3.67(m，4H)，3.57-3.51(m，6H)，2.52(s，1H)，1.59(d，J＝8.3Hz，1H).
Example 35: 6- ((2- (4H-1, 2, 4-triazol-1-yl) ethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000561
The compound was synthesized as in example 12. Coupling the intermediate 2A with tert-butyl carbamate, carrying out nucleophilic substitution on the coupled intermediate and 3- (2-iodoethyl) -1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-1, 2, 4-triazole, and removing protective groups to obtain the product.
MS m/z：548.2[M+1]+。
Example 36: 6- ((2- (5-methyl-4H-1, 2, 4-triazol-3-yl) ethylamino) -4- (6- (6- ((6-methoxypyridin-3-yl) methyl) -3, 6-diazabicyclo [3.1.1] heptan-3-yl) pyridin-3-yl) pyrazolo [1,5-a ] pyridine-3-carbonitrile
Figure BDA0002565535740000562
The compound was synthesized as in example 12. Coupling the intermediate 2A and tert-butyl carbamate, carrying out nucleophilic substitution on the coupled intermediate and 3- (2-iodoethyl) -5-methyl-4H-1, 2, 4-triazole-4-tert-butyl carbamate, and removing a protecting group to obtain the product.
MS m/z：562.2[M+1]+。
Biological test example
Test example 1: inhibitory Activity on RET kinase
The inhibitory effect of compounds on RET kinase (purchased from Carna Biosciences, inc., cat # 08-159) was examined using the method of microfluidics chip technology-based Mobility Assay (Caliper Mobility Shift Assay) developed by Caliper corporation. The final concentrations tested for the compounds of the invention, BLU-667 and LOXO-292 were 2. mu.M or 10. mu.M starting, 10 concentrations at 3-fold dilution. 250nL of each compound at 100-fold final concentration was transferred to 384-well reaction plates using a dispenser Echo 550, 10. mu.L of kinase solution (RET kinase was diluted with buffer to a final concentration of 1 nM; buffer purchased from Sangyo pharmaceutical technology (Shanghai) Co., Ltd.) was added, and pre-incubation was performed at room temperature for 10 minutes (negative control wells contained 10. mu.L of buffer and 250nL of 100% DMSO; positive control wells contained 10. mu.L of kinase solution and 250nL of 100% DMSO). To the 384-well reaction plate, 15. mu.L of Adenosine Triphosphate (ATP) was added to a final concentration of 16. mu.M and 3. mu.M of peptide # 2 (purchased from Gill Biochemical (Shanghai) Co., Ltd., product No. 112394) as a fluorescent labeling substrate, and the reaction was initiated with the mixed solution. After 60 minutes of reaction at room temperature, 30. mu.L of a termination test solution (ethylenediaminetetraacetic acid was added to the buffer solution) was added to stop the kinase reaction. And reading the conversion rate by using an EZ Reader platform of a Caliper company, and converting the inhibition rate.
Percent inhibition (% mean of positive control conversion% -mean of each compound%)/(mean of positive control conversion% -mean of negative control conversion%).
The log value of the concentration is taken as an X axis, the inhibition rate% is taken as a Y axis, and a dose-effect curve is fitted by adopting the log (inhibitor) vs. stress-Variable slope of the GraphPad Prism 5 analysis software, so that the IC of each compound on the enzyme activity is obtained50The values, results are shown in Table 1.
TABLE 1
Figure BDA0002565535740000571
Note: LOXO-292 reference WO2018071447A1 example 163 preparation
BLU-667 reference WO2017079140A1 example 130 preparation
Test results show that the compound has good inhibitory activity on RET kinase.
Test example 2: proliferation inhibitory activity against transfected cells Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET-G810R
The compound is used for determining the proliferation inhibition activity of the compound on Ba/F3 KIF5B-RET cell strain of a mouse protoB cell Ba/F3 stably expressing KIF5B-RET fusion protein and Ba/F3 KIF5B-RET-G810R cell strain of a mouse protoB cell Ba/F3 stably expressing KIF5B-RET fusion protein (the RET region is subjected to G810R point mutation).
Cell source: Ba/F3 KIF5B-RET cells were purchased from Congyuan Bo Chuang Biotechnology (Beijing) Ltd, cat # KC-1041; Ba/F3 KIF5B-RET-G810R cells were purchased from Congyuan Bo Chuang Biotechnology (Beijing) Ltd, cat # KC-1448.
Ba/F3 KIF5B-RET and Ba/F3 KIF5B-RET cells in logarithmic growth phase were seeded in 96-well plates (135. mu.l/well) and placed at 37 ℃ with 5% CO2The culture was carried out in a constant temperature incubator for 24 hours. The compounds of the present invention, BLU-667 and LOXO-292, had been dissolved in dimethyl sulfoxide (DMSO) beforehand to prepare 10mM stock solutions, and when assayed, were diluted 10 times the desired concentration in another 96-well plate with complete medium, and then 15. mu.l/well of each compound was added to the 96-well plate seeded with cells to reach the desired concentration. 3 replicate wells were set for each concentration, and a DMSO blank was set. Continuing to contain 5% CO at 37 deg.C2The culture was carried out in a constant temperature incubator for 72 hours. The inoculated 96-well cell culture plate was taken out from the carbon dioxide incubator, 20. mu.l of thiazole blue (i.e., MTT) stock solution which had been previously dissolved in 0.9% physiological saline to prepare 5mg/ml and subjected to filtration sterilization was added to each well, and then 5% CO was contained at 37 ℃2Incubated in a constant temperature incubator for 4 hours. Mu.l of triple solution (100 ml of a prepared solution prepared by dissolving 10g of Sodium Dodecyl Sulfate (SDS), 5ml of isobutanol and 0.1ml of 36-38% hydrochloric acid in purified water) is added into each hole, the mixture is incubated at 37 ℃ until the precipitate is completely dissolved, and the optical density value OD is detected at the wavelength of 570nm and the inhibition ratio is calculated by data arrangement. Inhibition data were analyzed using GraphPad Prism 5.0 software, dose-effect curves were fitted using non-linear sigmoidal regression, and IC was calculated therefrom50The values and results are shown in Table 2.
Percent inhibition [ (% OD)Control group containing DMSO culture medium for 72 hours-OD72 hours Compound group)/(ODControl group containing DMSO culture medium for 72 hours-ODControl group containing DMSO culture medium at 0 hour)]×100％。
TABLE 2
Figure BDA0002565535740000581
Figure BDA0002565535740000591
Note: ND means not determined
LOXO-292 reference WO2018071447A1 example 163 preparation
BLU-667 reference WO2017079140A1 example 130 preparation
Test results show that the compound has good proliferation inhibition activity on stably transfected cells Ba/F3 KIF5B-RET and Ba/F3 KIF 5B-RET-G810R; compared with BLU-667 and LOXO-292, the compound of the invention has better proliferation inhibition activity on the stable cells Ba/F3 KIF 5B-RET-G810R.
Test example 3: growth inhibition effect on stable cell Ba/F3 KIF5B-RET, Ba/F3 KIF5B-RET-G810R nude mouse subcutaneous transplantation tumor
The experiment is used for researching the growth inhibition effect and the safety condition of the compound on the subcutaneous transplantation tumor of the nude mice with the stable cells of Ba/F3 KIF5B-RET, Ba/F3 KIF 5B-RET-G810R.
Cell culture: the transfected cells Ba/F3 KIF5B-RET and Ba/F3 KIF5B-RET-G810R were each cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum and placed at 37 ℃ in the presence of 5% CO2Culturing in a constant temperature incubator. Cells in the exponential growth phase were harvested and counted for inoculation.
Experimental animals: BALB/c Nude mice, female, 5 weeks old, 30, purchased from Experimental animals technologies, Inc., Wei Tong Li Hua, Beijing.
3 experimental groups are respectively arranged aiming at the stable transfected cell Ba/F3 KIF5B-RET and the stable transfected cell Ba/F3 KIF5B-RET-G810R, and each group comprises 5 cells; the 3 experimental groups were: vehicle control group (i.e., Vehicle group), LOXO-292 group and the compound of example 12 group containing 10% dimethylacetamide + 5% polyethylene glycol-15 hydroxystearate + 85% physiological saline.
Experimental protocol 3A: stable transfected cell Ba/F3 KIF5B-RET cell strain (2X 10)6One/only) inoculation in BALThe right dorsal part of B/c Nude mice was subcutaneously inoculated with 0.1mL of each mouse, and the growth of the tumor was observed periodically. When the tumor grows to be larger than 150mm3Time, groups were randomized according to tumor size. The LOXO-292 group and the compound group of example 12 were each administered at 10mg/kg by gavage at a volume of 10uL/g, and the vehicle control group was given an equivalent amount of vehicle twice daily for 14 consecutive days. Throughout the experiment, the body weight and tumor size of the mice were measured twice a week to see if a toxic reaction occurred.
Experimental protocol 3B: stable transfected cell Ba/F3 KIF5B-RET-G810R cell line (2X 10)6One by one) was inoculated subcutaneously into the right dorsal side of BALB/c Nude mice, each mouse was inoculated with 0.1mL, and the growth of tumors was observed periodically. When the tumor grows to be larger than 150mm3Time, groups were randomized according to tumor size. The LOXO-292 group and the compound group of example 12 were each administered at 30mg/kg by gavage at a volume of 10uL/g, and the vehicle control group was given an equivalent amount of vehicle twice daily for 14 consecutive days. Throughout the experiment, the body weight and tumor size of the mice were measured twice a week to see if a toxic reaction occurred.
The Tumor Volume (Tumor Volume, TV) is calculated as: TV is 1/2 × a × b × b, where a and b represent tumor length and width, respectively.
As a result: animals in both vehicle control groups in protocols 3A, 3B died after 7 days, whereas animals did not die in LOXO-292 and the example 12 compound groups and there was no significant weight loss during dosing; the tumor volume change curves of 3 experimental groups in experimental protocols 3A, 3B are shown in fig. 1 and fig. 2, respectively.
Test results show that the compound has good inhibition effect on the growth of subcutaneous transplantation tumor of nude mice with stable cells of Ba/F3 KIF5B-RET and Ba/F3 KIF 5B-RET-G810R; compared with LOXO-292, the compound has better inhibition effect on the growth of the subcutaneous transplantation tumor of the Ba/F3 KIF5B-RET-G810R nude mice; the compound has small influence on the body weight of a nude mouse and shows better safety.
All documents mentioned herein are incorporated by reference into this application. It should also be noted that various modifications, adaptations, and alternatives may occur to one skilled in the art without departing from the spirit and scope of the present invention after reading the foregoing disclosure of the present application, and such variations should fall within the scope of the present invention as set forth in the appended claims.

Claims (23)

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0002565535730000011
wherein:
x is selected from CR6Or N;
y is selected from CR6Or N;
z is selected from CR6Or N;
wherein 0, 1 or 2 of X, Y, Z are N;
R1selected from hydrogen, 6-10 membered aryl or 5-12 membered heteroaryl, wherein each of said 6-10 membered aryl or 5-12 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents each independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, hydroxy C1-6Alkyl, 3-6 membered cycloalkyl, cyano, -NR7R8or-O- (CH)2)n-NR7R8Substituted with the substituent(s);
R2selected from hydrogen, C1-4Alkyl or halo C1-4An alkyl group;
R3selected from hydrogen, C1-6Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl, wherein said C1-6Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl are each optionally substituted with 1, 2, 3 or 4 substituents each independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy C1-4Alkyl, -C (═ O) -NR7R8、-SO2-C1-4Alkyl, 5-6 membered heteroaromaticOr 3-6 membered heterocyclyl, wherein said 5-6 membered heteroaryl or 3-6 membered heterocyclyl are each optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy- (CH)2)m-or-C (═ O) -C1-4Alkyl is substituted by a substituent;
R4selected from hydrogen, C1-4Alkyl or halo C1-4An alkyl group;
R5selected from hydrogen, halogen, cyano, C1-4Alkyl or halo C1-4An alkyl group;
each R6Independently selected from H, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halogen;
each R7Independently selected from H, C1-4Alkyl or halo C1-4An alkyl group;
each R8Independently selected from H, C1-4Alkyl or halo C1-4An alkyl group;
n is selected from 1, 2 or 3;
m is selected from 0, 1, 2 or 3.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CR6Y is CR6Z is CR6Wherein each R is6Is H.
3. A compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R1Selected from phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is each optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy or cyano.
4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolylImidazolyl or thiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl or thiazolyl is each optionally substituted with 1, 2 or 3 each independently selected from hydroxy, halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R1Selected from phenyl,
Figure FDA0002565535730000021
Figure FDA0002565535730000022
Wherein said phenyl group,
Figure FDA0002565535730000023
Figure FDA0002565535730000024
Each optionally substituted by 1, 2 or 3 groups each independently selected from hydroxy, F, Cl, Br, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl or halo C1-4Substituted by a substituent of alkoxy.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R1Selected from phenyl,
Figure FDA0002565535730000025
Figure FDA0002565535730000026
Wherein said phenyl group,
Figure FDA0002565535730000027
Figure FDA0002565535730000028
Each optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-、CHF2CH2-、CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-、CHF2CH2-O-or CH2FCH2-O-is substituted.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R1Is selected from
Figure FDA0002565535730000031
Figure FDA0002565535730000032
8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R2Selected from hydrogen or C1-4An alkyl group.
9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R4Selected from hydrogen or C1-4An alkyl group.
10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R5Selected from hydrogen, halogen or cyano.
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen, C1-6Alkyl or 3-6 membered cycloalkyl, wherein said C is1-6Alkyl orEach 3-6 membered cycloalkyl is optionally substituted by 1, 2 or 3 substituents each independently selected from halogen, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy, -SO2-C1-4Alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclyl, wherein each of said 5-6 membered heteroaryl or 3-6 membered heterocyclyl is optionally substituted with 1, 2 or 3 substituents each independently selected from halogen, hydroxy or C1-4Alkyl substituents.
12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen, C1-4Alkyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein said C1-4Alkyl, cyclopropyl, cyclobutyl or cyclopentyl is each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, Br, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy, cyano, hydroxy, -SO2-C1-4Alkyl, aryl, heteroaryl, and heteroaryl,
Figure FDA0002565535730000041
Figure FDA0002565535730000042
Figure FDA0002565535730000043
Wherein said substituent is substituted, wherein
Figure FDA0002565535730000044
Figure FDA0002565535730000045
Figure FDA0002565535730000046
Each optionally substituted by 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy or C1-4Taking of alkyl groupsSubstituted by substituent groups.
13. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R3Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl or cyclopentyl are each optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF, and3CH2-、CHF2CH2-、CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-、CHF2CH2-O-、CH2FCH2-O-, cyano, hydroxy, -SO2-CH3、-SO2-CH2CH3、
Figure FDA0002565535730000051
Figure FDA0002565535730000052
Figure FDA0002565535730000053
Wherein said substituent is substituted, wherein
Figure FDA0002565535730000054
Figure FDA0002565535730000055
Each optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy, methyl or ethyl.
14. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein，R3Selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl,
Figure FDA0002565535730000056
Figure FDA0002565535730000057
Figure FDA0002565535730000061
15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, which is a compound selected from the structures:
Figure FDA0002565535730000062
Figure FDA0002565535730000071
Figure FDA0002565535730000081
16. a process for preparing a compound of formula (I) comprising:
Figure FDA0002565535730000082
Figure FDA0002565535730000091
wherein R is1、R2、R3、R4、R5X, Y, Z is as defined in any one of claims 1 to 14; l is a leaving group selected from halogen; p is an amino protecting group, each P may be the same or different and is independently selected from t-butyloxycarbonyl, benzyloxycarbonyl or benzyl;
taking a compound a-1 and a compound a-2 as initial raw materials, and carrying out Suzuki coupling reaction to obtain a compound a-3; carrying out substitution reaction on the compound a-3 and the compound a-4 to obtain an intermediate 1; deprotection of the intermediate 1 to obtain a compound a-5; carrying out reductive amination reaction on the compound a-5 and the compound a-6 to obtain an intermediate 2; intermediate 2 and
Figure FDA0002565535730000092
carrying out coupling reaction to obtain a compound shown as a formula (I);
or intermediate 2 with P-NH2Carrying out coupling reaction to obtain a compound a-7; compounds a-7 and R3-L undergoes a substitution reaction to give a compound a-8; deprotection of the compound a-8 can obtain the compound shown in the formula (I).
17. A process for preparing a compound of formula (I) comprising:
Figure FDA0002565535730000101
wherein R is1、R2、R3、R4、R5X, Y, Z is as defined in any one of claims 1 to 14; l is a leaving group selected from halogen; p is an amino protecting group, each P may be the same or different and is independently selected from t-butyloxycarbonyl, benzyloxycarbonyl or benzyl;
intermediate 1 and
Figure FDA0002565535730000102
carrying out coupling reaction to obtain a compound b-1; deprotection of compound b-1 gives intermediate 3; carrying out reductive amination reaction on the intermediate 3 and a compound a-6 to obtain a compound shown in a formula (I);
or,intermediate 1 and P-NH2Carrying out coupling reaction to obtain a compound b-2; compounds b-2 and R3-L undergoes a substitution reaction to give a compound b-3; deprotecting compound b-3 to obtain intermediate 3; and carrying out reductive amination reaction on the intermediate 3 and the compound a-6 to obtain the compound shown in the formula (I).
18. An intermediate compound selected from the group consisting of compound a-7, compound a-8, compound b-1, compound b-2, compound b-3, and intermediate 3, as shown in the following structures,
Figure FDA0002565535730000103
Figure FDA0002565535730000111
wherein R is1、R2、R3、R4、R5X, Y, Z is as defined in any one of claims 1 to 14; p is an amino protecting group, each P may be the same or different and is independently selected from t-butyloxycarbonyl, benzyloxycarbonyl or benzyl.
19. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
20. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment of a disease mediated by RET.
21. The use according to claim 20, wherein the RET is selected from wild-type RET, mutant RET, RET fusions; the mutant RET is selected from G810R mutant RET, M918T mutant RET, V804L mutant RET and V804M mutant RET, and the RET fusion is selected from KIF5B-RET fusion and CCDC6-RET fusion.
22. The use according to claim 20, wherein the disease is selected from cancer, irritable bowel syndrome.
23. Use of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19, in the manufacture of a medicament for the treatment of cancer.
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WO2023143486A1 (en) * 2022-01-29 2023-08-03 深圳众格生物科技有限公司 Salt, crystalline form, solvate and hydrate of compound

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TWI783057B (en) * 2017-10-10 2022-11-11 美商絡速藥業公司 Process for the preparation of 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile
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TWI844244B (en) * 2022-01-19 2024-06-01 大陸商深圳眾格生物科技有限公司 Salts, crystal forms, solvents and hydrates of compounds
WO2023143486A1 (en) * 2022-01-29 2023-08-03 深圳众格生物科技有限公司 Salt, crystalline form, solvate and hydrate of compound

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