Pyrazole [1,5-a] pyridine compounds and their preparation methods and applications

Abstract

The present invention relates to pyrazolo[1,5-a]pyridine compounds represented by the following general formula (I), preparation methods, pharmaceutical compositions, and uses thereof, wherein R1, R2, R3, R4, R5, X, Y, and Z are as defined in the specification. The pyrazolo[1,5-a]pyridine compounds of the present invention can effectively inhibit wild-type RET, mutant RET, particularly the G810R mutant RET, and RET fusions such as KIF5B-RET and CCDC6-RET, and have good safety, and can be used to treat RET-mediated diseases, such as cancer and irritable bowel syndrome.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to pyrazolo[1,5-a]pyridine compounds that can be used as RET inhibitors, methods for preparing the compounds, pharmaceutical compositions containing the compounds, and uses of the compounds and pharmaceutical compositions thereof in treating diseases mediated by RET. Background Art

[0002] The rearranged during transfection gene, or RET (rearranged during transfection), is a proto-oncogene located on chromosome 10. The RET protein encoded by the RET gene is a cell membrane receptor tyrosine kinase (RTK) that belongs to the cadherin superfamily. RET's ligands are members of the glial cell line-derived neurotrophic factor family, including glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN). Binding of the ligand to the extracellular region of RET leads to RET dimerization and autophosphorylation of the intracellular kinase domain, thereby activating RET. This in turn activates multiple downstream signaling pathways, such as RAS / MAPK / ERK, PI3K / AKT, and JAK / STAT, which contribute to cell proliferation, migration, and differentiation.

[0003] Abnormalities in the RET gene (including fusions and point mutations) can lead to overactivation of the RET signaling pathway and uncontrolled cell growth, and are closely associated with the development and progression of various tumors. The incidence of RET gene fusion in patients with non-small cell lung cancer (NSCLC) is approximately 1% to 2%, and in patients with papillary thyroid carcinoma (PTC) it is 10% to 20%; the most common fusion partners include KIF5B, TRIM33, CCDC6, and NCOA4. The incidence of RET gene point mutations in patients with medullary thyroid carcinoma (MTC) is approximately 60%; common mutation sites include C634R, M918T, V804L, V804M, G810R, and others. In addition, low-frequency RET fusions have also been observed in colorectal cancer, breast cancer, pancreatic cancer, and other cancers; RET fusions have also been observed in NSCLC patients carrying EGFR mutations.

[0004] Currently, targeted drugs for the RET gene include (1) multi-kinase inhibitors targeting multiple targets, such as cabozantinib, vandetanib, and lenvatinib. Although they can inhibit the activity of RET, due to their low selectivity, off-target effects often occur, leading to serious toxic side effects, especially those related to VEGFR inhibition, which limits their clinical application; (2) drugs that selectively target the RET gene, such as BLU-667 and LOXO-292, which have good inhibitory activity against wild-type and mutant (such as M918T, V804L / M, etc.) RET, as well as common KIF5B-RET fusion and CCDC6-RET fusion, and have relatively low toxicity.

[0005] BLU-667, developed by Blueprint Medicines and disclosed in WO2017079140A1, has a structure shown below and has already submitted a rolling new drug application to the FDA. LOXO-292, developed by LoxoOncology and disclosed in WO2018071447A1, has a structure shown below and was approved by the FDA in May 2020. However, a report in the Journal of Thoracic Oncology, Volume 15, Issue 4, April 2020, Pages 541-549, suggests that patients with RET fusion NSCLC may develop the RET G810R resistance mutation, leading to LOXO-292 resistance.

[0006]

[0007] Furthermore, aberrant RET expression and / or activity has also been demonstrated in gastrointestinal disorders such as irritable bowel syndrome (IBS).

[0008] It is necessary to develop new, effective, low-toxic and selective RET small molecule inhibitors for the treatment of RET-mediated diseases. Summary of the Invention

[0009] The present invention provides a novel pyrazolo[1,5-a]pyridine compound or a pharmaceutically acceptable salt thereof, which is a class of selective RET inhibitors that can effectively inhibit wild-type RET, mutant RET, especially G810R mutant RET, and RET fusions such as KIF5B-RET and CCDC6-RET, and has good safety. It can be used to treat diseases mediated by RET, such as cancer and irritable bowel syndrome.

[0010] The present invention provides a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] in:

[0013] X is selected from CR6 or N;

[0014] Y is selected from CR6 or N;

[0015] Z is selected from CR6 or N;

[0016] Where 0, 1 or 2 of X, Y and Z are N;

[0017] R1 is selected from hydrogen, 6-10 membered aryl or 5-12 membered heteroaryl, wherein said 6-10 membered aryl or 5-12 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 groups each independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, 3-6 membered cycloalkyl, cyano, -NR7R8 or -O-(CH2) n -substituted by a substituent of NR7R8;

[0018] R2 is selected from hydrogen, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0019] R3 is selected from hydrogen, C 1-6 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl, wherein the C 1-6 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl or 5-12 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, cyano, hydroxy, hydroxy C 1-4 Alkyl, -C(=O)-NR7R8, -SO2-C 1-4 alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 3-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy-(CH2) m -or-C(=O)-C 1-4 substituted by an alkyl substituent;

[0020] R4 is selected from hydrogen, C 1-4Alkyl or halogenated C 1-4 alkyl;

[0021] R5 is selected from hydrogen, halogen, cyano, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0022] Each R6 is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogen;

[0023] Each R7 is independently selected from H, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0024] Each R8 is independently selected from H, C 1-4 Alkyl or halogenated C 1-4 alkyl;

[0025] n is selected from 1, 2 or 3;

[0026] m is selected from 0, 1, 2 or 3.

[0027] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above X is selected from CR6 or N, Y is selected from CR6 or N, and Z is selected from CR6 or N, wherein 0 or 1 of X, Y, and Z is N; wherein each R6 is independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or halogen.

[0028] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above X is CR6, Y is CR6, and Z is CR6; wherein each R6 is independently selected from H, C 1-4 Alkyl, halogenated C 1-4 Alkyl or halogen.

[0029] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, X is CR6, Y is CR6, and Z is CR6; wherein each R6 is independently selected from H, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-, CHF2CH2-, CH2FCH2-, F, Cl or Br.

[0030] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, X is CR6, Y is CR6, Z is CR6, and each R6 is H.

[0031] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 substituted by an alkoxy or cyano substituent.

[0032] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

[0033] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above-mentioned R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl or thiazolyl, wherein the phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl or thiazolyl are each optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

[0034] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl, wherein the phenyl group, Each optionally substituted by 1, 2 or 3 each independently selected from hydroxy, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

[0035] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl, wherein the phenyl group, Each is 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-.

[0036] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted by 1, 2 or 3 groups independently selected from hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

[0037] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from phenyl, wherein the phenyl group, Each is 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-.

[0038] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from

[0039] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R1 is selected from

[0040] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R2 is selected from hydrogen or C 1-4 alkyl.

[0041] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above-mentioned R2 is hydrogen.

[0042] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R4 is selected from hydrogen or C 1-4 alkyl.

[0043] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, R4 is hydrogen.

[0044] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above-mentioned R5 is selected from hydrogen, halogen or cyano.

[0045] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, R5 is cyano.

[0046] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R3 is selected from hydrogen, C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl are each optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, cyano, hydroxyl, -SO2-C 1-4 alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 3-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxyl or C 1-4 substituted by an alkyl substituent.

[0047] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R3 is selected from hydrogen, C 1-4 Alkyl, cyclopropyl, cyclobutyl or cyclopentyl, wherein the C 1-4 Alkyl, cyclopropyl, cyclobutyl or cyclopentyl are each optionally substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl, halogenated C 1-4 Alkoxy, cyano, hydroxyl, -SO2-C 1-4 alkyl, is substituted by a substituent, wherein Each optionally substituted by 1, 2 or 3 each independently selected from F, Cl, Br, hydroxyl or C 1-4 substituted by an alkyl substituent.

[0048] In another embodiment of the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above-mentioned R3 is selected 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 replaced by 1, 2 or 3 groups independently selected from F, Cl, Br, methyl, ethyl, methoxy, ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-, CHF2CH2-, CH2FCH2-, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-, CHF2CH2-O-, CH2FCH2-O-, cyano, hydroxyl, -SO2-CH3, -SO2-CH2CH3, is substituted by a substituent, wherein Each is optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy, methyl or ethyl.

[0049] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl,

[0050] In another embodiment of the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt thereof, the above R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl,

[0051] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof:

[0052]

[0053]

[0054]

[0055] The compound represented by formula (I) of the present invention can be prepared by various synthetic methods well known to those skilled in the art, without particular limitation. For example, it can be prepared by the method of the following scheme 1 or scheme 2 provided by the present invention. It should be understood that the synthetic method of the compound represented by formula (I) of the present invention is not limited to schemes 1 and 2, and those skilled in the art can make conventional substitutions and improvements.

[0056] Option 1:

[0057]

[0058] Wherein, R1, R2, R3, R4, R5, X, Y, and Z are as defined above; L is a leaving group, such as a halogen, preferably I; P is an amino protecting group, each P may be the same or different, and each P is independently preferably tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or benzyl (Bn).

[0059] Compound a-1 and compound a-2 are used as starting materials to undergo Suzuki coupling reaction to obtain compound a-3; compound a-3 and compound a-4 undergo substitution reaction to obtain intermediate 1; intermediate 1 is deprotected to obtain compound a-5; compound a-5 and compound a-6 undergo reductive amination reaction to obtain intermediate 2; intermediate 2 and A coupling reaction occurs to obtain the compound represented by formula (I).

[0060] Alternatively, when preparing a compound of formula (I) in which R4 is H, intermediate 2 can also undergo a coupling reaction with P-NH2 to obtain compound a-7; compound a-7 can undergo a substitution reaction with R3-L to obtain compound a-8; and compound a-8 can be deprotected to obtain the compound represented by formula (I).

[0061] In the above scheme 1, 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, PdCl2, etc., and the base includes but is not limited to cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, etc.; the substitution reaction for preparing intermediate 1 and compound a-8 is carried out in the presence of a base, wherein the base includes but is not limited to cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, etc.; the deprotection reaction of intermediate 1 and compound a-8 is carried out under acidic conditions or in the presence of catalyst / H2, wherein the acidic conditions include but are not limited to HCl / MeOH, HCl / EA, trifluoroacetic acid, etc., and the catalyst includes but is not limited to Pd / C, PdCl2 / C, Pd(OH)2 / C, etc.; the reductive amination reaction for preparing intermediate 2 is carried out in the presence of a reducing agent, wherein the reducing agent includes but is not limited to NaBH(OAc)3, NaBH4, NaBH3CN, etc.; intermediate 2 and Or the coupling reaction of P-NH2 is carried out in the presence of a catalyst and a base, wherein the catalyst includes but is not limited to Pd2(dba)3 / Xantphos, Pd2(dba)3 / Brettphos, Pd(OAc)2 / Xantphos, etc., and the base includes but is not limited to cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, etc.

[0062] Option 2:

[0063]

[0064] Wherein, R1, R2, R3, R4, R5, X, Y, and Z are as defined above; L is a leaving group, such as a halogen, preferably I; P is an amino protecting group, each P may be the same or different, and each P is independently preferably tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or benzyl (Bn).

[0065] Intermediate 1 and A coupling reaction occurs to obtain compound b-1; compound b-1 is deprotected to obtain intermediate 3; intermediate 3 undergoes a reductive amination reaction with compound a-6 to obtain the compound represented by formula (I).

[0066] Alternatively, when preparing a compound of formula (I) in which R4 is H, intermediate 1 can also undergo a coupling reaction with P-NH2 to obtain compound b-2; compound b-2 can undergo a substitution reaction with R3-L to obtain compound b-3; compound b-3 can be deprotected to obtain intermediate 3; intermediate 3 can undergo a reductive amination reaction with compound a-6 to obtain the compound represented by formula (I).

[0067] In the above scheme 2, intermediate 1 and or P-NH2 coupling reaction is carried out in the presence of a catalyst and a base, the catalyst including but not limited to Pd2(dba)3 / Xantphos, Pd2(dba)3 / Brettphos, Pd(OAc)2 / Xantphos, etc., the base including but not limited to cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, potassium acetate, sodium acetate, potassium tert-butoxide, sodium tert-butoxide, etc.; the deprotection of compound b-1 and compound b-3 is carried out under acidic conditions or in the presence of catalyst / H2, the acidic conditions including but not limited to HCl / MeOH, HCl / EA, trifluoroacetic acid, etc., the catalyst including but not limited to Pd / C, PdCl2 / C, Pd(OH)2 / C, etc.; the reductive amination reaction of intermediate 3 with compound a-6 is carried out in the presence of a reducing agent, the reducing agent including but not limited to NaBH(OAc)3, NaBH4, NaBH3CN, etc.; the substitution reaction to prepare compound b-3 is carried out in the presence of a base, the base including but not limited to cesium carbonate, potassium carbonate, sodium carbonate, triethylamine, etc.

[0068] The present invention also provides intermediate compounds, including compound a-7, compound a-8, compound b-1, compound b-2, compound b-3, and intermediate 3 shown in the following structures:

[0069]

[0070] Wherein, R1, R2, R3, R4, R5, X, Y, and Z are as defined above; P is an amino protecting group, each P may be the same or different, and each P is independently preferably tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or benzyl (Bn).

[0071] The present invention further provides an intermediate compound having the following structure:

[0072]

[0073] The present invention also provides a pharmaceutical composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof and an optional pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention comprising an optional pharmaceutically acceptable carrier means that the composition may contain a pharmaceutically acceptable carrier or may not contain a pharmaceutically acceptable carrier.

[0074] The present invention also provides use of the above-mentioned compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of a drug for treating a disease mediated by RET.

[0075] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a disease mediated by RET. The RET includes wild-type RET, mutant RET, and RET fusions, wherein the mutant RET includes but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, and V804M mutant RET, preferably G810R mutant RET, and the RET fusion includes but is not limited to KIF5B-RET fusion and CCDC6-RET fusion, preferably KIF5B-RET fusion; and the diseases include cancer and irritable bowel syndrome.

[0076] The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a medicament for treating diseases mediated by wild-type RET, mutant RET, or 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; the RET fusion includes but is not limited to KIF5B-RET fusion and CCDC6-RET fusion, preferably KIF5B-RET fusion; the diseases include cancer and irritable bowel syndrome.

[0077] The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a medicament for treating cancer or irritable bowel syndrome mediated by RET. The RET includes wild-type RET, mutant RET, and RET fusion, and the mutant RET includes but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, and V804M mutant RET, preferably G810R mutant RET, and the RET fusion includes but is not limited to KIF5B-RET fusion and CCDC6-RET fusion, preferably KIF5B-RET fusion.

[0078] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating cancer or irritable bowel syndrome mediated by wild-type RET, mutant RET, or RET fusion. The mutant RET includes, but is not limited to, G810R mutant RET, M918T mutant RET, V804L mutant RET, and V804M mutant RET, preferably G810R mutant RET; and the RET fusion includes, but is not limited to, KIF5B-RET fusion and CCDC6-RET fusion, preferably KIF5B-RET fusion.

[0079] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a drug for treating cancer.

[0080] The present invention also provides the use of the above compound or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of a drug for treating irritable bowel syndrome.

[0081] The present invention also provides a method for treating a disease mediated by RET, comprising 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 RET comprises wild-type RET, mutant RET, and RET fusion, wherein the mutant RET comprises but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, and V804M mutant RET, and the RET fusion comprises but is not limited to KIF5B-RET fusion and CCDC6-RET fusion; and the disease comprises cancer and irritable bowel syndrome.

[0082] The present invention also provides a method for treating cancer, comprising administering an effective amount of the above compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient in need thereof.

[0083] The present invention also provides a method for treating irritable bowel syndrome, which comprises administering an effective amount of the above compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient in need.

[0084] The cancers described herein include, but are not limited to, small cell lung cancer, non-small cell lung cancer, papillary thyroid cancer, medullary thyroid cancer, follicular thyroid cancer, anaplastic thyroid cancer, recurrent thyroid cancer, multiple endocrine neoplasia type 2A or 2B (MEN2A 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.

[0085] The irritable bowel syndrome described in the present invention includes but is not limited to diarrhea-predominant type, constipation-predominant type or alternating bowel movement pattern, functional bloating, functional constipation, functional diarrhea, nonspecific functional bowel disease, functional abdominal pain syndrome, chronic idiopathic constipation, functional esophageal disease, functional gastroduodenal disease, functional anorectal pain and inflammatory bowel disease.

[0086] The present invention also includes pharmaceutically acceptable salts of the compounds shown in formula (I). The "pharmaceutically acceptable salt" refers to a relatively nontoxic acid addition salt or base addition salt of the compounds of the present invention. The acid addition salt is a salt formed by the compound shown in formula (I) of the present invention with a suitable inorganic acid or organic acid. These salts can be prepared by reacting the compound shown in formula (I) with a suitable organic acid or inorganic acid in a suitable solvent. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, nitrate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, malate, ascorbate, tannate, pamoate, alginate, naphthalenesulfonate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate and laurylsulfonate. The base addition salt is a salt formed by a compound shown in formula (I) and a suitable inorganic base or organic base, and these salts can be prepared by reacting the compound shown in formula (I) with a suitable inorganic base or organic base in a suitable solvent. Representative base addition salts include, for example, salts formed with alkali metals, alkaline earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.; amine salts include salts formed with ammonia (NH3), primary amines, secondary amines, or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, and ethylamine salts.

[0087] In addition to salt forms, the compounds provided herein also exist in prodrug form. Prodrugs described herein refer to compounds that can be converted into the biologically active compounds described herein (such as compounds of formula (I)) under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable precursor of a biologically active compound.

[0088] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium (D), tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0089] 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, and racemic mixtures 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 and mixtures thereof are encompassed within the scope of the present invention.

[0090] 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 enantiomer of a compound of the present 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 (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0091] In the present invention, "pharmaceutically acceptable" refers to those compounds, substances, compositions and dosage forms that are, within the scope of sound medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0092] In the present invention, a "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "Compatibility" as used herein refers to the ability of the components of the composition to blend with the compound of the present invention, and with each other, without significantly reducing the compound's efficacy. Examples of pharmacologically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxypropyl methylcellulose and its derivatives, cellulose acetate and its derivatives, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium / calcium stearate, hydrogenated vegetable oils, sodium stearyl fumarate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (e.g., sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, etc.

[0093] As used herein, an "effective amount" with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or pharmacologically active agent sufficient to achieve the desired effect. The determination of an effective amount varies from person to person, depending on the patient's age, weight, and condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0094] As used herein, an "active ingredient," "active substance," or "active agent" refers to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0095] In the present invention, "patient", "individual" or "subject" includes humans, animals, vertebrates, mammals, rodents (e.g., guinea pigs, hamsters, rats, mice), murines (e.g., mice), canines (e.g., dogs), primates, great apes (e.g., monkeys or anurans), monkeys (e.g., marmosets, baboons), anurans (e.g., gorillas, chimpanzees, orangutans, gibbons). In some embodiments, the "patient" is a human.

[0096] In the present invention, "treatment" means administering the compound or formulation of the present invention to prevent, improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0097] (i) preventing a disease or disease state from occurring in a mammal, particularly where such mammal is susceptible to the disease or disease state but has not yet been diagnosed as having the disease or disease state;

[0098] (ii) inhibiting the disease or disease state, i.e., arresting its development;

[0099] (iii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0100] As used herein, "optional," "optionally," or "optionally" means that the subsequently described event or condition may or may not occur, and the description includes both cases where the event or condition occurs and those where it does not. For example, "optionally substituted with R" means that the group may or may not be substituted with R, and the description includes both cases where the group is substituted with R and those where it is not substituted with R.

[0101] In the present invention, "substituted" or "substituted" means that one or more hydrogen atoms in the group, preferably 1-5 hydrogen atoms, more preferably 1, 2, 3 or 4 hydrogen atoms are independently replaced by a corresponding number of substituents, as long as the substituted compound is stable.

[0102] In the present invention, "independently" or "independent" means that more than one substituent is selected from a large number of possible substituents, and those substituents may be the same or different. For example, "R xSelected from -OR or -N(R)2; each R is independently selected from H or C1-C4 alkyl", wherein each substituent R is independent and they may be the same or different.

[0103] In the present invention, "base" and "group" refer to a monovalent group or a divalent or higher group that meets the valence requirements as needed. For example, a "cycloalkyl" includes a monovalent group obtained by removing one hydrogen atom therefrom, and also includes a divalent or higher group obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms therein. When a "cycloalkyl" is used as a terminal group, it is naturally a monovalent group. When a cycloalkyl group is used as a connecting group in the structure, it is a divalent or higher group. In the present invention, a monovalent or higher group generally refers to a monovalent group or a divalent group, but as needed, the group can be a higher valence (for example, trivalent, tetravalent, pentavalent, hexavalent, etc.).

[0104] In the present invention, "C d-e "(d and e represent integers greater than 1, d<e) includes any specific case of d to e carbons, such as C 1-6 Including C1, C2, C3, C4, C5, C6, and any range from d to e, such as C 1-6 Including C 1-3 、C 1-4 、C 1-5 、C 2-5 、C 2-4 、C 3-6 etc.; similarly, "de member" (d and e represent integers greater than 1, d<e) means that the number of atoms in the ring is d to e, for example, 3-6 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, and also includes any range from d to e, for example, 3-6 membered ring includes 3-4 membered ring, 3-5 membered ring, 4-6 membered ring, 4-5 membered ring, etc.

[0105] In the present invention, "halogen" refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, and bromine, and more preferably fluorine and chlorine.

[0106] In the present invention, "C 1-6 "Alkyl" refers to a straight or branched chain alkyl group derived from an alkane containing 1 to 6 carbon atoms by removing one or more hydrogen atoms. 1-6Alkyl includes, but is 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, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like; the “C 1-4 "Alkyl" refers to a straight or branched chain alkyl group derived from an alkane containing 1 to 4 carbon atoms by removing one or more hydrogen atoms. 1-4 Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.

[0107] In the present invention, "C 1-6 "Alkoxy" refers to the above-defined "C 1-6 Alkyl" is a group connected to the rest of the molecule through an oxygen atom, i.e., "C 1-6 Alkyl-O-" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexyloxy, etc.; the "C 1-4 "Alkoxy" refers to the above-defined "C 1-4 Alkyl" is a group connected to the rest of the molecule through an oxygen atom, i.e., "C 1-4 "Alkyl-O-" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

[0108] In the present invention, "halogenated C 1-6 "Alkyl" refers to one or more (preferably 1-5, more preferably 1, 2 or 3) halogen atoms replacing the above defined "C 1-6 The group formed by the corresponding number of hydrogen atoms on the "alkyl", wherein when there are multiple halogen atoms substituted, each halogen atom can be the same or different, specifically, the halogenated C 1-6 Alkyl groups include, but are not limited to, monofluoromethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, monochloromethyl, CF3CH2-, CHF2CH2-, CH2FCH2-, CH3CHF-, CH2FCHCl-, CF3CH2CH2-, CF3CH2CH(CH3)CH2-, and the like; "halogenated C 1-4 "Alkyl" refers to one or more (preferably 1-5, more preferably 1, 2 or 3) halogen atoms replacing the above defined "C 1-4When substituted with multiple halogen atoms, the halogen atoms may be the same or different, specifically including but not limited to monofluoromethyl, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, monochloromethyl, CF3CH2-, CHF2CH2-, CH2FCH2-, CH3CHF-, CH2FCHCl-, etc.

[0109] In the present invention, "halogenated C 1-6 "Alkoxy" refers to one or more (preferably 1-5, more preferably 1, 2 or 3) halogen atoms replacing the above defined "C 1-6 "alkoxy" is a group formed by the corresponding number of hydrogen atoms on the halogen group, wherein when there are multiple halogen atoms substituted, the halogen atoms can be the same or different, specifically including but not limited to monofluoromethoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, monochloromethoxy, CF3CH2-O-, CHF2CH2-O-, CH2FCH2-O-, CF3CH2CH2-O-, etc.; "halogenated C 1-4 "Alkoxy" refers to one or more (preferably 1-5, more preferably 1, 2 or 3) halogen atoms replacing the above defined "C 1-4 "alkoxy" is a group formed by the corresponding number of hydrogen atoms on the "alkoxy", wherein when there are multiple halogen atoms substituted, the halogen atoms may be the same or different, specifically including but not limited to monofluoromethoxy, trifluoromethoxy, trichloromethoxy, difluoromethoxy, dichloromethoxy, monochloromethoxy, CF3CH2-O-, CHF2CH2-O-, CH2FCH2-O-, CF3CH2CH2-O-, etc.

[0110] In the present invention, "hydroxy C 1-6 "Alkyl" refers to one or more (preferably 1, 2 or 3) hydroxy groups substituted with the above-defined "C 1-6 The group formed by the corresponding number of hydrogen atoms on the "alkyl" includes but is not limited to hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxy-2-methylpropyl, 4-hydroxybutyl, 5-hydroxypentyl, 2-hydroxymethyl-1-hydroxypropyl; "hydroxy C 1-4 "Alkyl" refers to one or more (preferably 1, 2 or 3) hydroxy groups substituted with the above-defined "C 1-4 The groups formed by the corresponding number of hydrogen atoms on the "alkyl" include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-hydroxy-2-methylpropyl, and 4-hydroxybutyl.

[0111] In the present invention, "ring atoms" refer to atoms forming a ring, including but not limited to C, N, O, P and S; "ring carbon atoms" refer to ring atoms C; "ring heteroatoms" refer to ring atoms other than C atoms, including but not limited to ring atoms N, O, P and S.

[0112] In the present invention, "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon group, which can be a monovalent group or a group with a valence of more than two, including monocyclic cycloalkyl and polycyclic cycloalkyl. Polycyclic cycloalkyl includes spirocyclic cycloalkyl, condensed ring cycloalkyl and bridged ring cycloalkyl. The "spirocyclic cycloalkyl" refers to a polycyclic cycloalkyl in which the monocyclic rings share a ring carbon atom (called a spiro atom), the "condensed ring cycloalkyl" refers to a polycyclic cycloalkyl in which each ring in the group shares a pair of adjacent ring carbon atoms with other rings, and the "bridged ring cycloalkyl" refers to a polycyclic cycloalkyl in which any two rings share two ring carbon atoms that are not directly connected. In the present invention, "3-6 membered cycloalkyl" refers to a cycloalkyl group including 3 to 6 ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.

[0113] In the present invention, "heterocyclic group" refers to 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. It can be a monovalent group or a divalent or higher group, including monocyclic heterocyclic groups and polycyclic heterocyclic groups. Polycyclic heterocyclic groups include spirocyclic heterocyclic groups, fused ring heterocyclic groups and bridged heterocyclic groups. The "spirocyclic heterocyclic group" refers to a polycyclic heterocyclic group in which the monocyclic rings share a ring atom (called a spiro atom), the "fused ring cycloalkyl" refers to a polycyclic heterocyclic group in which each ring in the group shares a pair of adjacent ring atoms with other rings, and the "bridged ring cycloalkyl" refers to a polycyclic heterocyclic group in which any two rings share two ring atoms that are not directly connected. In addition, the heterocyclic group also includes the case where the ring atoms C and S are oxo-substituted, such as the ring atoms C and S are replaced by C(=O), S(=O) or S(=O)2. In the present invention, "3-8 membered heterocyclic group" refers to a heterocyclic group including 3 to 8 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O or S. Specifically, the 3-8 membered heterocyclic group includes but is not limited to aziridine, oxirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrrolidonyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperidonyl, piperazinyl, morpholinyl, 1,4-dioxane, 1,4-oxathiacyclohexane, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc., preferably In the present invention, "3-6 membered heterocyclic group" refers to a heterocyclic group including 3 to 6 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O or S. Specifically, the 3-6 membered heterocyclic group includes but is not limited to aziridine, oxirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydropyrrolyl, pyrrolidonyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperidonyl, piperazinyl, morpholinyl, 1,4-dioxane, 1,4-oxazolidinyl, Thianyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc., preferably wait.

[0114] In the present invention, "aryl" refers to a cyclic hydrocarbon group with aromatic properties. It can be a monovalent group or a group with a valence of more than two, and includes monocyclic aryl groups and condensed-ring aryl groups. "Condensed-ring aryl" refers to an aryl group containing multiple rings (preferably two or three rings), in which each ring in the group shares a pair of adjacent ring carbon atoms with other rings. In the present invention, "6-10 membered aryl" refers to an aryl group containing 6 to 10 ring carbon atoms, including phenyl and naphthyl.

[0115] In the present invention, "heteroaryl" refers to an aromatic cyclic hydrocarbon group in which one or more (preferably 1-5, more preferably 1, 2, 3 or 4) ring atoms are ring heteroatoms selected from N, O or S. It can be a monovalent group or a divalent or higher group, including a monocyclic heteroaryl group and a condensed-ring heteroaryl group. The "condensed-ring heteroaryl group" refers to a heteroaryl group containing multiple rings (preferably 2 or 3 rings) in which each ring in the group shares a pair of adjacent ring atoms with other rings. In the present invention, "5-12 membered heteroaryl" refers to a heteroaryl group comprising 5 to 12 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S. Specifically, the 5-12 membered heteroaryl group 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, benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, purinyl, quinolyl, quinoxalinyl, thienopyridyl, etc., preferably In the present invention, "5-6 membered heteroaryl" refers to a heteroaryl group containing 5 to 6 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroatoms selected from N, O or S. Specifically, the 5-6 membered heteroaryl group includes but is not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, triazinyl, etc., preferably wait.

[0116] In the present invention, "-C(=O)-C 1-4 "Alkyl" refers to the above-defined "C 1-4 "alkyl" and -C (= O) - formed by the connection; "-SO2-C 1-4 "Alkyl" refers to the above-defined "C 1-4 "Alkyl" and -SO2- connected to form a group.

[0117] In the present invention, the term "more than one" means that the number of substituents can be the number of all chemically substitutable positions of the substituted group, preferably 1-6, more preferably 1-5, more preferably 1-3, more preferably 1-2, and more preferably 1.

[0118] In the present invention, "amino protecting group" refers to a chemical group attached to an amino group and easily removed under certain conditions, including but not limited to alkoxycarbonyl, acyl, and alkyl groups; for example, tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl, etc. Those skilled in the art can refer to Greene's Protective Groups in Organic Synthesis (4), a commonly used textbook in this field. th edition) to make appropriate selections and operations.

[0119] The pharmaceutical compositions of the present invention can be prepared by methods well known in the art, such as conventional mixing, dissolution, granulation, sugar-coated pill making, grinding, emulsification, and freeze-drying. The pharmaceutical compositions of the present invention can be administered to the subject by any convenient route of administration, including, but not limited to, oral, rectal, parenteral (e.g., injection, including subcutaneous, intradermal, intramuscular, and intravenous), topical (including, for example, transdermal, intranasal, ocular, oral, and sublingual), and pulmonary (e.g., oral or nasal inhalation or insufflation of aerosols), and the like.

[0120] Solid dosage forms suitable for oral administration include tablets, pills, capsules, powders, granules, etc. When preparing these solid dosage forms, in addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, one or more excipients, fillers or extenders, binders, disintegrants, stabilizers, wetting agents, adsorbents, lubricants or encapsulating materials conventionally used in the art may be added.

[0121] Liquid dosage forms suitable for oral administration include solutions, suspensions, emulsions, syrups, or tinctures. In addition to the compound of the present invention or a pharmaceutically acceptable salt thereof, the liquid dosage form may contain one or more diluents, solubilizers, emulsifiers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, or preservatives conventionally used in the art.

[0122] Dosage forms suitable for topical administration include ointments, powders, patches, drops, sprays, inhalants, etc., in which the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is mixed with a pharmaceutically acceptable carrier under sterile conditions.

[0123] Dosage forms suitable for rectal administration include suppositories comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a suitable base.

[0124] Dosage forms suitable for parenteral injection include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.

[0125] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient. The unit dosage form can be packaged into packages containing discrete amounts of the preparation, such as packaged tablets or capsules.

[0126] When 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, the therapeutically effective amount of the 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 exact dosage will depend on the route of administration, the form in which the compound is administered, the health condition of the subject (patient) to be treated, and the experience of the attending physician.

[0127] The compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition thereof can also be administered in combination with other anti-tumor drugs, such as chemotherapy drugs, or used in combination with other treatments such as radiotherapy or surgery as an adjuvant before or after surgery.

[0128] The abbreviations used in this invention have the following meanings:

[0129] Boc: tert-butyloxycarbonyl

[0130] Cbz: benzyloxycarbonyl

[0131] Bn: benzyl

[0132] Pd(dppf)Cl2: [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride

[0133] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium

[0134] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0135] Brettphos: dicyclohexyl[3,6-dimethoxy-2′,4′,6′-triisopropyl[1,1′-biphenyl]-2-yl]phosphine

[0136] PtO2: platinum dioxide

[0137] Pd(PPh3)4:Tetrakis(triphenylphosphine)palladium

[0138] PdCl2: Palladium dichloride

[0139] Pd(OH)2: Palladium hydroxide

[0140] Pd(OAc)2: Palladium acetate

[0141] Pd: Palladium

[0142] HCl: hydrogen chloride

[0143] HBr: Hydrogen bromide

[0144] NaBH(OAc)3: sodium triacetoxyborohydride

[0145] NaBH4: sodium borohydride

[0146] NaBH3CN: sodium cyanoborohydride

[0147] DCM: dichloromethane

[0148] MeOH: methanol

[0149] EA: ethyl acetate

[0150] CDCl3: deuterated chloroform

[0151] DMSO: dimethyl sulfoxide

[0152] TLC: Thin layer chromatography BRIEF DESCRIPTION OF THE DRAWINGS

[0153] Figure 1 Figure 2 is a curve showing the change in tumor volume of subcutaneous transplanted tumors in nude mice bearing stably transfected Ba / F3 KIF5B-RET cells when the compound of Example 12 and LOXO-292 were administered at a dose of 10 mg / kg twice a day.

[0154] Figure 2 Figure 2 is a curve showing the change in tumor volume of subcutaneous transplanted tumors in nude mice with stably transfected Ba / F3 KIF5B-RET-G810R cells when the compound of Example 12 and LOXO-292 were administered at a dose of 30 mg / kg twice a day. DETAILED DESCRIPTION

[0155] Below in conjunction with specific embodiment, the scheme of the present invention is explained.It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the invention.In the following examples, if no specific technology or conditions are indicated, they are carried out according to the technology or conditions described in the literature in this area or according to the product instructions. Reagents or instruments used that do not indicate the manufacturer are all conventional products that can be obtained by commercial purchase.

[0156] I. Preparation Examples of Compounds of the Invention

[0157] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, using deuterated dimethyl sulfoxide (DMSO-d6) and deuterated chloroform (CDCl3) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0158] Liquid chromatography-mass spectrometry (LC-MS) was performed using an Agilent 6410 Triple Quad LC / MS.

[0159] Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for TLC are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0160] Example 1: 6-(2,2-difluoroethylamine)-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

[0161]

[0162] Step 1: 6-Bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0163]

[0164] To a 500ml three-necked flask, add 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]palladium dichloride (2.7g, 3.70mmol), potassium fluoride dihydrate (31.0g, 0.33mmol), and 150ml of N,N-dimethylformamide. Under argon, react at 60°C overnight. After completion of the reaction, cool to room temperature and add 500ml of water. The reaction mixture is filtered, and the filter cake is rinsed with acetonitrile and ethyl acetate. Dry under reduced pressure to obtain 30g of 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. The yield is 86%.

[0165] 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).

[0166] Step 2: tert-Butyl 3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate

[0167]

[0168] To a 250 ml three-necked flask, add 6-bromo-4-(6-fluoropyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile (4.35 g, 13.7 mmol), 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (3.25 g, 16.3 mmol), potassium carbonate (5.67 g, 41.1 mmol), and 60 ml of dimethyl sulfoxide. The mixture was reacted at 100°C overnight. After completion of the reaction, the mixture was cooled to room temperature and 200 ml of water was added. The reaction mixture was filtered, and the filter cake was dissolved in a mixed solvent (DCM:MeOH=10:1) and then dried. The mixture was washed with water three times with acetonitrile. The mixture was then purified by silica gel column chromatography to obtain 3.4 g of tert-butyl 3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate. The yield was 50%.

[0169] MS m / z:495.1 / 497.1[M+1] + .

[0170] 1 H NMR (400MHz, CDCl3) δ8.68 (d, J=1.3Hz, 1H), 8.36 (d, J=2.1Hz, 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).

[0171] Step 3: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0172]

[0173] To a 250 ml three-necked flask, add tert-butyl 3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate (3.4 g, 6.88 mmol) and 50 ml of 4.0 M methanolic hydrogen chloride solution. The mixture was allowed to react overnight at 25°C. MS monitored the reaction until complete. The reaction solution was drained and washed with water three times with acetonitrile to obtain 3.66 g of crude 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile. The yield was 99%.

[0174] MS m / z:395.0 / 397.0[M+1] + .

[0175] 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

[0176]

[0177] To a 250 ml three-necked flask, add crude 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile (3.66 g, 6.88 mmol), 6-methoxy-3-pyridinecarboxaldehyde (1.88 g, 13.76 mmol) and 100 ml of dichloroethane, and slowly add sodium triacetylborohydride (7.3 g, 34.4 mmol). React at room temperature overnight and monitor the completion of the reaction by TLC. The reaction was quenched with saturated sodium bicarbonate, washed with water, extracted with dichloromethane, and the organic phase dried, drained, and purified by silica gel column chromatography to obtain 2.8 g of 6-bromo-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 was 79%.

[0178] MS m / z:516.1 / 518.1[M+1] + .

[0179] 1H NMR (400MHz, CDCl3) δ8.70 (d, J=1.5Hz, 1H), 8.40 (d, J=2.2Hz, 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).

[0180] Step 5: 6-(2,2-difluoroethylamine)-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

[0181]

[0182] To a 50 ml single-necked bottle, 6-bromo-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 (103 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium (18.3 mg, 0.02 mmol), dicyclohexyl[3,6-dimethoxy-2′,4′,6′-triisopropyl[1,1′-biphenyl]-2-yl]phosphine (10.8 mg, 0.02 mmol), cesium carbonate (163 mg, 0.50 mmol), 2,2-difluoroethylamine (33 mg, 0.40 mmol) and 10 ml of dioxane were added and the reaction was carried out at 90° C. under argon protection overnight. The filtrate was filtered through celite, and the filtrate was evaporated to dryness under reduced pressure. The product was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain 77 mg of the product 6-(2,2-difluoroethylamine)-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 was 74%.

[0183] MS m / z: 517.2[M+1] + .

[0184] 1H NMR (400MHz, DMSO-d6) δ8.44 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 8.08 (s, 1H), 7.8 0 (d, J=8.0Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.15 (s, 1H), 6.79 (t, J=8.0Hz, 2H), 6.3 2(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).

[0185] Example 2: 6-(Ethylamine)-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

[0186]

[0187] The synthesis of this compound was the same as in Example 1. Using intermediate 2A and ethylamine as starting materials, the target compound, 6-(ethylamino)-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, was obtained in a 30% yield.

[0188] MS m / z:481.5[M+1] + .

[0189] 1 H 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).

[0190] Example 3: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(n-propylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0191]

[0192] The synthesis of this compound was the same as in Example 1. Intermediate 2A and n-propylamine were used as starting materials to obtain the target compound, 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(n-propylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile. The yield was 13%.

[0193] MS m / z: 495.3[M+1] + .

[0194] 1 H 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), 3.62-3.4 5 (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).

[0195] Example 4: 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2,2,2-trifluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0196]

[0197] The synthesis of this compound was similar to that of Example 1. Using intermediate 2A and trifluoroethylamine as starting materials, the target compound, 4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2,2,2-trifluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile, was obtained in a yield of 68%.

[0198] MS m / z: 535.4[M+1] + .

[0199] 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).

[0200] Example 5: 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

[0201]

[0202] The synthesis of this compound was the same as in Example 1. Using intermediate 2A and isobutylamine as starting materials, the 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, was obtained in a 60% yield.

[0203] MS m / z: 509.3[M+1] + .

[0204] 1 H 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).

[0205] Example 6: 6-(3,3-difluorocyclobutylamino)-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

[0206]

[0207] The synthesis of this compound was the same as in Example 1. Using intermediate 2A and 3,3-difluorocyclobutylamine as starting materials, the target compound, 6-(3,3-difluorocyclobutylamino)-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, was obtained in a 50% yield.

[0208] MS m / z: 543.2[M+1] + .

[0209] 1 H NMR (400MHz, DMSO-d6) δ8.45 (s, 1H), 8.36 (d, J=1.88Hz, 1H), 8.09 (br.s., 1H), 7.9 8 (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).

[0210] Example 7: 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

[0211]

[0212] The synthesis of this compound was the same as in Example 1. Using intermediate 2A and aminoacetonitrile as starting materials, the 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, was obtained in a 15% yield.

[0213] MS m / z:492.2[M+1] + .

[0214] Example 8: 6-(2-hydroxyethylamine)-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

[0215]

[0216] The synthesis of this compound was the same as in Example 1. Intermediate 2A and aminoethanol were used as starting materials to obtain the target compound, 6-(2-hydroxyethylamino)-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 was 15%.

[0217] MS m / z:497.4[M+1] + .

[0218] 1 H 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).

[0219] Example 9: 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)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0220]

[0221] The synthesis of this compound was the same as in Example 1. Using intermediate 2A and 1-amino-2-methyl-2-propanol as starting materials, the target compound, 6-(2-hydroxy-2-methylpropylamino)-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, was obtained in an 8% yield.

[0222] MS m / z: 525.3[M+1] + .

[0223] 1 H 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).

[0224] Example 10: 6-((3-fluoroazetidin-3-yl)methylamino)-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

[0225]

[0226] Step 1: 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

[0227]

[0228] The synthesis of this compound was the same as in Example 1. Using Intermediate 2A and tert-butyl 3-(aminomethyl)-3-fluoroazetidine-1-carboxylate as starting materials, the target compound, tert-butyl 3-((3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-ylamino)methyl)-3-fluoroazetidine-1-carboxylate, was obtained in a yield of 74%.

[0229] MS m / z: 640.2[M+1] + .

[0230] Step 2: 6-((3-fluoroazetidin-3-yl)methylamino)-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

[0231]

[0232] To a 25 ml single-necked flask, tert-butyl 3-((3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-ylamino)methyl)-3-fluoroazetidine-1-carboxylate (95 mg, 0.15 mmol), 4 ml of dichloromethane, and 4 ml of trifluoroacetic acid were added. The mixture was reacted at 25°C under argon for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and 20 ml of dichloromethane and 10 ml of saturated sodium bicarbonate were added. The mixture was stirred until no bubbles appeared, 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 36 mg of the product, 6-((3-fluoroazetidin-3-yl)methylamino)-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 was 44%.

[0233] MS m / z: 540.2[M+1] + .

[0234] 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), 3.7 6-3.73(m, 4H), 3.64-3.60(m, 5H), 2.64(d, J=18.9Hz, 1H), 1.65(s, 1H).

[0235] Example 11: 4-(6-(6-(3-fluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-((3-fluoroazetidin-3-yl)methylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0236]

[0237] Step 1: 4-(6-(6-(3-fluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-bromopyrazolo[1,5-a]pyridine-3-carbonitrile

[0238]

[0239] The synthesis of this compound is similar to that of Intermediate 2A. After deprotection, Intermediate 1 is subjected to reductive amination with 3-fluoro-4-methoxybenzaldehyde to afford Intermediate 2B in a 44% yield.

[0240] MS m / z: 533.0[M+1] + .

[0241] 1H NMR (400MHz, CDCl3) δ8.69 (d, J=1.5Hz, 1H), 8.40 (d, J=2.1Hz, 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=8.5Hz, 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).

[0242] Step 2: tert-Butyl 3-((4-(6-(6-(3-fluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-3-cyanopyrazolo[1,5-a]pyridin-6-ylamino)methyl)-3-fluoroazetidine-1-carboxylate

[0243]

[0244] The synthesis of this compound was the same as in Step 1 of Example 10. The yield was 34%.

[0245] MS m / z:657.3[M+1] + .

[0246] 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

[0247]

[0248] The synthesis of this compound was the same as in Step 2 of Example 10. The yield was 30%.

[0249] MS m / z: 557.0[M+1] + .

[0250] 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).

[0251] Example 12: 6-(2-fluoroethylamine)-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

[0252]

[0253] Step 1: 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

[0254]

[0255] The synthesis of this compound was the same as in Step 5 of Example 1, using Intermediate 2A and tert-butyl carbamate as starting materials. The yield was 68%.

[0256] MS m / z: 553.4[M+1] + .

[0257] Step 2: 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

[0258]

[0259] To a 25 ml single-necked flask was added tert-butyl 3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-ylcarbamate (55 mg, 0.10 mmol), cesium carbonate (66 mg, 0.20 mmol), 1-fluoro-2-iodoethane (35 mg, 0.20 mmol), and 5 ml of DMF. The mixture was reacted at 80°C under nitrogen for 4 hours. The reaction mixture was quenched by the addition of 15 ml of water and extracted three times with ethyl acetate (15 ml). The organic layer was evaporated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 60 mg of tert-butyl 3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl(2-fluoroethyl)carbamate. The yield was 99%.

[0260] MS m / z: 599.5[M+1] + .

[0261] Step 3: 6-(2-fluoroethylamino)-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

[0262]

[0263] To a 10 ml single-necked flask, add tert-butyl 3-cyano-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridin-6-yl(2-fluoroethyl)carbamate (60 mg, 0.10 mmol) and 5 ml of 4.0 M methanolic hydrogen chloride solution. Under argon, react at 25°C for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, and 20 ml of dichloromethane and 10 ml of saturated sodium bicarbonate were added. The mixture was stirred until no bubbles appeared. 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 20 mg of the product, 6-(2-fluoroethylamino)-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 was 40%.

[0264] MS m / z: 499.3[M+1] + .

[0265] 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).

[0266] Example 13: 4-(6-(6-(3-fluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0267]

[0268] Step 1: tert-Butyl 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-ylcarbamate

[0269]

[0270] The synthesis of this compound was the same as in step 5 of Example 1, using intermediate 2B and tert-butyl carbamate as starting materials.

[0271] MS m / z: 570.2[M+1] + .

[0272] Step 2: tert-Butyl 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)carbamate

[0273]

[0274] The synthesis of this compound was the same as in Step 2 of Example 12.

[0275] MS m / z:616.2[M+1] + .

[0276] 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

[0277]

[0278] The synthesis of this compound is similar to that of 6-(2-fluoroethylamino)-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 is 28%.

[0279] MS m / z: 516.2[M+1] + .

[0280] 1 H 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).

[0281] Example 14: 4-(6-(6-(2-fluoro-5-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2,2-difluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0282]

[0283] Step 1: 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

[0284]

[0285] The synthesis of this compound was the same as in Step 5 of Example 1, using Intermediate 1 and 2,2-difluoroethylamine as starting materials. The yield was 61%.

[0286] MS m / z: 496.2[M+1] + .

[0287] Step 2: 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

[0288]

[0289] To a 25 ml three-necked flask, add 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 (245 mg, 0.50 mmol) and 5 ml of 4.0 M methanolic hydrogen chloride solution. The reaction was allowed to react overnight at 25°C. MS monitored the reaction until complete. The reaction solution was drained and washed with water three times with acetonitrile to obtain 300 mg 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 was 99%.

[0290] MS m / z: 396.2[M+1] + .

[0291] Step 3: 4-(6-(6-(2-fluoro-5-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2,2-difluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0292]

[0293] The synthesis of this compound was carried out in the same manner as in Step 4 of Example 1, using Intermediate 3A and 2-fluoro-5-methoxybenzaldehyde. The yield was 23%.

[0294] MS m / z: 534.2[M+1] + .

[0295] 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).

[0296] Example 15: 4-(6-(6-(4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0297]

[0298] Step 1: tert-Butyl 3-(5-(6-((tert-Butoxycarbonyl)amino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate

[0299]

[0300] To a 100 ml single-necked bottle was added tert-butyl 3-(5-(6-bromo-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate (635 mg, 1.28 mmol), tris(dibenzylideneacetone)dipalladium (118 mg, 0.13 mmol), dicyclohexyl[3,6-dimethoxy-2′,4′,6′-triisopropyl[1,1′-biphenyl]-2-yl]phosphine (69 mg, 0.13 mmol), cesium carbonate (1.26 g, 3.84 mmol), tert-butyl carbamate (453 mg, 3.84 mmol) and 15 ml of dioxane. The mixture was reacted at 90° C. overnight under argon protection. The product was filtered through celite, and the filtrate was evaporated to dryness under reduced pressure. The product was then purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain 488 mg of tert-butyl 3-(5-(6-((tert-butoxycarbonyl)amino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate. The yield was 71%.

[0301] MS m / z: 532.3[M+1] + .

[0302] 1 H 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).

[0303] Step 2: tert-Butyl 3-(5-(6-((tert-Butoxycarbonyl)(2-fluoroethyl)amino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate

[0304]

[0305] To a 250 ml single-necked flask were added tert-butyl 3-(5-(6-((tert-butoxycarbonyl)amino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate (2900 mg, 5.46 mmol), cesium carbonate (5340 mg, 16.4 mmol), 1-fluoro-2-iodoethane (1430 mg, 8.17 mmol), and 100 ml of DMF. The mixture was reacted at 80°C under nitrogen for 12 hours. The reaction mixture was quenched by the addition of 150 ml of water and extracted three times with ethyl acetate (150 ml). The organic layer was evaporated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain 2820 mg of the product. The yield was 89%.

[0306] MS m / z: 578.3[M+1] + .

[0307] 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).

[0308] Step 3: 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0309]

[0310] To a 250 ml single-necked flask, tert-butyl 3-(5-(6-((tert-butoxycarbonyl)(2-fluoroethyl)amino)-3-cyanopyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carbamate (2820 mg, 4.88 mmol) and 50 ml of a 4.0 M solution of hydrogen chloride in ethyl acetate were added. The mixture was reacted at 25°C for 2 hours under argon. The reaction solution was evaporated to dryness under reduced pressure, and 200 ml of dichloromethane and 100 ml of saturated sodium bicarbonate were added. The mixture was stirred until no bubbles appeared. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was obtained by silica gel column chromatography (dichloromethane:methanol = 15:1). The yield was 80%.

[0311] MS m / z: 378.2[M+1] + .

[0312] 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

[0313]

[0314] To a 25 ml three-necked flask was added 4-(6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-cyano (60 mg, 0.16 mmol), 4-methoxybenzaldehyde (18 mg, 0.13 mmol) and 6 ml of dichloroethane, and sodium triacetylborohydride (140 mg, 0.66 mmol) was slowly added. The reaction was allowed to react overnight at room temperature and the completion of the reaction was monitored by TLC. The reaction was quenched with saturated sodium bicarbonate, washed with water, extracted with dichloromethane, and the organic phase was dried, drained, and purified by silica gel column chromatography to obtain 4-(6-(6-(4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-cyano.

[0315] MS m / z:498.2[M+1] + .

[0316] 1 H 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, 4.7Hz, 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).

[0317] Example 16: 4-(6-(6-((5-fluoro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamine)-pyrazolo[1,5-a]pyridine-3-carbonitrile

[0318]

[0319] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 5-fluoro-6-methoxynicotinaldehyde as raw materials.

[0320] MS m / z: 517.1[M+1] + .

[0321] 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).

[0322] Example 17: 4-(6-(6-(3,5-difluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0323]

[0324] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 3,5-difluoro-4-methoxybenzaldehyde as raw materials.

[0325] MS m / z: 534.2[M+1] + .

[0326] 1 H 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, 4.7Hz, 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).

[0327] Example 18: 4-(6-(6-(2-fluoro-4-methoxybenzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0328]

[0329] The synthesis of this compound was the same as in Example 15, using intermediate 3B and 2-fluoro-4-methoxybenzaldehyde as starting materials. The yield was 37%.

[0330] MS m / z: 516.2[M+1] + .

[0331] 1 H 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).

[0332] Example 19: 4-(6-(6-(4-(difluoromethoxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0333]

[0334] The synthesis of this compound was the same as in Example 15, using intermediate 3B and 4-(difluoromethoxy)benzaldehyde as starting materials. The yield was 24%.

[0335] MS m / z: 534.2[M+1] + .

[0336] 1 H 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).

[0337] Example 20: 4-(6-(6-((6-(difluoromethoxy)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0338]

[0339] The synthesis of this compound was the same as in Example 15, using intermediate 3B and 6-(difluoromethoxy)nicotinaldehyde as raw materials. The yield was 29%.

[0340] MS m / z: 535.2[M+1] + .

[0341] 1 H 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).

[0342] Example 21: 4-(6-(6-((3-fluoro-4-(difluoromethoxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0343]

[0344] The synthesis of this compound was the same as in Example 15. It was synthesized using intermediate 3B and 3-fluoro-4-(difluoromethoxy)benzaldehyde as starting materials. MS m / z: 552.2 [M+1] + .

[0345] 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), 6.7 8(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), 3.58-3.5 3(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).

[0346] Example 22: 4-(6-(6-((2,3-difluoro-4-(methyloxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0347]

[0348] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 2,3-difluoro-4-(methyloxy)benzaldehyde as raw materials.

[0349] MS m / z: 534.2[M+1] + .

[0350] Example 23: 4-(6-(6-((2,5-difluoro-4-(methyloxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0351]

[0352] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 2,5-difluoro-4-(methyloxy)benzaldehyde as raw materials.

[0353] MS m / z: 534.2[M+1] + .

[0354] 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 (d d, 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).

[0355] Example 24: 4-(6-(6-((3-chloro-4-(methyloxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0356]

[0357] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 3-chloro-4-(methyloxy)benzaldehyde as raw materials.

[0358] MS m / z: 532.2[M+1] + 、534.

[0359] 1 H 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).

[0360] Example 25: 4-(6-(6-((2-chloro-4-(methyloxy)benzyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0361]

[0362] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 2-chloro-4-(methyloxy)benzaldehyde as raw materials.

[0363] MS m / z: 532.2[M+1] + 、534.

[0364] 1 H 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).

[0365] Example 26: 4-(6-(6-((5-chloro-6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-(2-fluoroethylamino)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0366]

[0367] The synthesis of this compound is the same as that of Example 15. It is synthesized using intermediate 3B and 5-chloro-6-methoxynicotinaldehyde as raw materials.

[0368] MS m / z: 532.2[M+1] + 、534.2.

[0369] Example 27: 6-(4,4,4-trifluorobutylamino)-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

[0370]

[0371] The synthesis of this compound is the same as that of Example 12. Intermediate 2A is coupled with tert-butyl carbamate, followed by nucleophilic substitution with 1,1,1-trifluoro-4-iodobutane and deprotection to obtain the compound.

[0372] MS m / z: 563.2[M+1] + .

[0373] 1 H 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).

[0374] Example 28: 6-(3-methanesulfonylpropylamine)-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

[0375]

[0376] The synthesis of this compound is the same as in Example 1. It is synthesized using intermediate 2A and 3-methanesulfonylpropylamine as raw materials.

[0377] MS m / z:573.2[M+1] + .

[0378] 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).

[0379] Example 29: 6-(3-fluoropropylamine)-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

[0380]

[0381] The synthesis of this compound is the same as that of Example 12. Intermediate 2A is coupled with tert-butyl carbamate, followed by nucleophilic substitution with 1-fluoro-3-iodopropane and deprotection to obtain the compound.

[0382] MS m / z: 513.2[M+1] + .

[0383] Example 30: 6-(3,3,3-trifluoropropylamine)-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

[0384]

[0385] The synthesis of this compound is the same as that of Example 1. It is synthesized using intermediate 2A and 3,3,3-trifluoropropylamine as raw materials.

[0386] MS m / z: 549.2[M+1] + .

[0387] Example 31: 6-(2,2,3,3,3-pentafluoropropylamine)-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

[0388]

[0389] The synthesis of this compound is the same as that of Example 1. It is synthesized using intermediate 2A and 2,2,3,3,3-pentafluoropropylamine as raw materials.

[0390] MS m / z: 585.2[M+1] + .

[0391] 1 H 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).

[0392] Example 32: 6-((2-(1H-imidazol-1-yl)ethylamino)-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

[0393]

[0394] The synthesis of this compound is the same as in Example 1. It is synthesized using intermediate 2A and 2-(1H-imidazol-1-yl)ethylamine as raw materials.

[0395] MS m / z: 547.2[M+1] + .

[0396] 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).

[0397] 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]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0398]

[0399] The synthesis of this compound is the same as that of Example 1. It is synthesized using intermediate 2A and 2-(1H-1,2,4-triazol-1-yl)ethylamine as raw materials.

[0400] MS m / z:548.2[M+1] + .

[0401] 1 H 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, 2 H), 3.83(s, 3H), 3.77-3.74(m, 4H), 3.60-3.56(m, 6H), 2.55(s, 1H), 1.61(s, 1H).

[0402] 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]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0403]

[0404] The synthesis of this compound is the same as that of Example 1. It is synthesized using intermediate 2A and 2-(1H-1,3,4-triazol-1-yl)ethylamine as raw materials.

[0405] MS m / z:548.2[M+1] + .

[0406] 1 H NMR (400MHz, DMSO) δ8.55 (s, 2H), 8.43 (s, 1H), 8.35 (d, J=2.3Hz, 1H), 8.17 (d, J=1.7 Hz, 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).

[0407] 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]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0408]

[0409] The synthesis of this compound is the same as that of Example 12. Intermediate 2A is coupled with tert-butyl carbamate, followed by nucleophilic substitution with 3-(2-iodoethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole and deprotection to obtain the compound.

[0410] MS m / z:548.2[M+1] + .

[0411] 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]heptane-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile

[0412]

[0413] The synthesis of this compound is the same as that of Example 12. Intermediate 2A is coupled with tert-butyl carbamate, followed by nucleophilic substitution with tert-butyl 3-(2-iodoethyl)-5-methyl-4H-1,2,4-triazole-4-carboxylate and deprotection to obtain the compound.

[0414] MS m / z: 562.2[M+1] + .

[0415] II. Biological Test Examples

[0416] Test Example 1: Inhibitory activity against RET kinase

[0417] The inhibitory effects of the compounds on RET kinase (purchased from Carna Biosciences, Inc., Catalog No. 08-159) were determined using the Caliper Mobility Shift Assay, a microfluidic chip-based assay developed by Caliper. The compounds of the present invention, BLU-667, and LOXO-292 were tested starting at 2 μM or 10 μM, with 10 three-fold dilutions. Using an Echo 550 dispenser, 250 nL of each compound at 100 times the final concentration was transferred to a 384-well reaction plate. 10 μL of kinase solution (RET kinase was diluted to a final concentration of 1 nM with buffer purchased from Sundia Medical Technology (Shanghai) Co., Ltd.) was added, and the plates were pre-incubated at room temperature for 10 minutes (negative control wells contained 10 μL of buffer and 250 nL of 100% DMSO; positive control wells contained 10 μL of kinase solution and 250 nL of 100% DMSO). The reaction was initiated by adding 15 μL of adenosine triphosphate (ATP) (final concentration: 16 μM) and 3 μM fluorescently labeled substrate peptide 2 (purchased from Gill Biochemical (Shanghai) Co., Ltd., Cat. No. 112394) to the 384-well reaction plate. The reaction was allowed to incubate at room temperature for 60 minutes. The kinase reaction was terminated by adding 30 μL of stop detection solution (ethylenediaminetetraacetic acid added to the buffer). The conversion rate was read using the Caliper EZ Reader platform and converted to inhibition rate.

[0418] Inhibition rate % = (positive control conversion rate mean % - each compound conversion rate mean %) / (positive control conversion rate mean % - negative control conversion rate mean %).

[0419] The log value of the concentration was used as the X-axis and the inhibition rate as the Y-axis. The log (inhibitor) vs. response-Variable slope analysis software GraphPad Prism 5 was used to fit the dose-effect curve to obtain the IC value of each compound on the enzyme activity. 50 The results are shown in Table 1.

[0420] Table 1

[0421]

[0422] Note: LOXO-292 was prepared according to the method of Example 163 of WO2018071447A1

[0423] BLU-667 was prepared according to the method of Example 130 of WO2017079140A1.

[0424] The test results show that the compound of the present invention has good inhibitory activity against RET kinase.

[0425] Test Example 2: Proliferation Inhibitory Activity on Stably Transfected Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET-G810R Cells

[0426] Used to determine the in vitro proliferation inhibitory activity of compounds against the Ba / F3 KIF5B-RET cell line, which stably expresses the KIF5B-RET fusion protein, and the Ba / F3 KIF5B-RET-G810R cell line, which stably expresses the KIF5B-RET fusion protein (with a G810R point mutation in the RET region).

[0427] Cell sources: Ba / F3 KIF5B-RET cells were purchased from Kangyuan Broad Biotechnology (Beijing) Co., Ltd., catalog number KC-1041; Ba / F3 KIF5B-RET-G810R cells were purchased from Kangyuan Broad Biotechnology (Beijing) Co., Ltd., catalog number KC-1448.

[0428] Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET cells in the logarithmic growth phase were seeded in 96-well plates (135 μl / well) and cultured in a 37°C incubator containing 5% CO2 for 24 hours. The compounds of the present invention, BLU-667, and LOXO-292 were previously dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution. For testing, these solutions were diluted to 10 times the target concentration in complete culture medium in another 96-well plate. Then, 15 μl / well of each compound was added to the 96-well plate seeded with cells to achieve the target concentration. Three replicates were set for each concentration, and a DMSO blank control was established. Culture was continued in a 37°C incubator containing 5% CO2 for 72 hours. The 96-well cell culture plate was taken out from the carbon dioxide constant temperature incubator, and 20 μl of thiazolyl blue (MTT) stock solution, which had been previously dissolved in 0.9% saline to 5 mg / ml and filtered and sterilized, was added to each well. The cells were then incubated in a constant temperature incubator at 37°C containing 5% CO2 for 4 hours. 100 μl of triple solution (10 g of sodium dodecyl sulfate (SDS), 5 ml of isobutanol, and 0.1 ml of 36%-38% hydrochloric acid were dissolved in purified water to make a 100 ml solution) was added to each well and incubated at 37°C until the precipitate was completely dissolved. The optical density value OD was detected at a wavelength of 570 nm and the data was sorted and the inhibition rate was calculated. The inhibition rate data were analyzed using GraphPad Prism 5.0 software, and the dose-effect curve was fitted using nonlinear S-curve regression, and the IC was calculated from this. 50 The results are shown in Table 2.

[0429] Inhibition rate % = [(OD 72小时含DMSO培养基对照组 -OD 72小时化合物组 ) / (OD 72小时含DMSO培养基对照组 -OD 0小时含DMSO培养基对照组 )]×100%.

[0430] Table 2

[0431]

[0432]

[0433] Note: ND means not determined

[0434] LOXO-292 was prepared according to the method of Example 163 of WO2018071447A1

[0435] BLU-667 was prepared according to the method of Example 130 of WO2017079140A1.

[0436] The test results show that the compounds of the present invention have good proliferation inhibitory activity on stably transfected cells Ba / F3 KIF5B-RET and Ba / F3KIF5B-RET-G810R; compared with BLU-667 and LOXO-292, the compounds of the present invention have better proliferation inhibitory activity on stably transfected cells Ba / F3 KIF5B-RET-G810R.

[0437] Test Example 3: Inhibitory effect on the growth of subcutaneous transplanted tumors in nude mice stably transfected with Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET-G810R cells

[0438] This experiment was used to study the growth inhibitory effect and safety of the compound on subcutaneous transplanted tumors in nude mice stably transfected with Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET-G810R cells.

[0439] Cell Culture: Stably transfected Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET-G810R cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum in a 37°C incubator with 5% CO2. Cells in the exponential growth phase were harvested and counted for plating.

[0440] Experimental animals: 30 5-week-old female BALB / c nude mice were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0441] Three experimental groups were set up for the stably transfected Ba / F3 KIF5B-RET cells and the stably transfected Ba / F3 KIF5B-RET-G810R cells, with 5 mice in each group; the three experimental groups were: a solvent control group containing 10% dimethylacetamide + 5% polyethylene glycol-15 hydroxystearate + 85% saline (i.e., the Vehicle group), a LOXO-292 group, and an Example 12 compound group.

[0442] Experimental plan 3A: Stably transfected Ba / F3 KIF5B-RET cell line (2×10 6 The tumor was inoculated subcutaneously on the right side of the back of BALB / cNude nude mice with a volume of 0.1 mL per mouse. The tumor growth was observed regularly. 3 At 4 hr, mice were randomly divided into groups based on tumor size. LOXO-292 and the compound of Example 12 were each administered orally at 10 mg / kg in a 10 μL / g volume. The vehicle control group received an equal volume of vehicle twice daily for 14 consecutive days. Throughout the experiment, mouse body weight and tumor size were measured twice weekly to monitor for toxicity.

[0443] Experimental plan 3B: Stably transfected Ba / F3 KIF5B-RET-G810R cell line (2×10 6 The tumor was inoculated subcutaneously on the right side of the back of BALB / c nude mice with a volume of 0.1 mL per mouse. The tumor growth was observed regularly. 3 At 4 hr, mice were randomly divided into groups based on tumor size. The LOXO-292 group and the Example 12 compound group were each administered 30 mg / kg via gavage in a 10 μL / g volume. The vehicle control group received an equal amount of vehicle twice daily for 14 consecutive days. Throughout the experiment, mouse body weight and tumor size were measured twice weekly to monitor for toxicity.

[0444] The calculation formula for tumor volume (TV) is: TV = 1 / 2 × a × b × b, where a and b represent the length and width of the tumor, respectively.

[0445] Results: All animals in the vehicle control group of Experimental Schemes 3A and 3B died after 7 days, while no animals in the LOXO-292 group and the Example 12 compound group died, and there was no significant weight loss during the administration period; the tumor volume change curves of the three experimental groups in Experimental Schemes 3A and 3B are shown in Figure 2. Figure 1 and Figure 2 .

[0446] The test results show that the compound of the present invention has a good inhibitory effect on the growth of subcutaneous transplanted tumors in nude mice with stably transfected Ba / F3 KIF5B-RET and Ba / F3 KIF5B-RET-G810R cells; compared with LOXO-292, the compound of the present invention has a better inhibitory effect on the growth of subcutaneous transplanted tumors in nude mice with Ba / F3 KIF5B-RET-G810R; the compound of the present invention has little effect on the body weight of nude mice, showing good safety.

[0447] All documents mentioned herein are incorporated by reference into this application. It should also be noted that after reading the above disclosure of this application, those skilled in the art may make various modifications, alterations or modifications to the present invention without departing from the spirit and scope of the present invention, but such variations should also fall within the scope of the claims attached hereto.

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, in: X is selected from CR6; Y is selected from CR6; Z is selected from CR6; R1 is selected from 6-10 membered aryl or 5-12 membered heteroaryl, wherein said 6-10 membered aryl or 5-12 membered heteroaryl are each optionally substituted by 1, 2, 3 or 4 groups each independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy or hydroxy C 1-6 substituted by an alkyl substituent; R2 is selected from hydrogen, or C 1-4 alkyl; R3 is selected from C 1-6 Alkyl, or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl, or 3-6 membered cycloalkyl are each optionally substituted by 1, 2, 3 or 4 groups independently selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, cyano, hydroxyl, hydroxyl C 1-4 Alkyl, -SO2-C 1-4 alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 3-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxyl, or C 1-4 substituted by an alkyl substituent; R4 is selected from hydrogen, or C 1-4 alkyl; R5 is selected from halogen, or cyano; Each R6 is independently selected from H or C 1-4 Alkyl, excluding the following compounds:

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R6 is H.

3. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl are each optionally substituted by 1, 2 or 3 groups independently selected from hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl or halogenated C 1-6 substituted by an alkoxy substituent.

4. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted by 1, 2 or 3 groups each independently selected from hydroxy, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

5. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from phenyl, wherein the phenyl group, Each optionally substituted by 1, 2 or 3 each independently selected from hydroxy, F, Cl, Br, C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkyl or halogenated C 1-4 substituted by an alkoxy substituent.

6. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from phenyl, wherein the phenyl group, Each is optionally substituted with 1, 2 or 3 substituents each independently selected from hydroxy, F, Cl, Br, methoxy, ethoxy, n-propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, CF3CH2-O-, CHF2CH2-O- or CH2FCH2-O-.

7. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from 8. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from hydrogen.

9. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R4 is selected from hydrogen.

10. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from cyano.

11. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from C 1-6 Alkyl or 3-6 membered cycloalkyl, wherein the C 1-6 Alkyl or 3-6 membered cycloalkyl are each optionally substituted by 1, 2 or 3 groups independently selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, cyano, hydroxyl, -SO2-C 1-4 alkyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, wherein the 5-6 membered heteroaryl or 3-6 membered heterocyclic group is optionally substituted by 1, 2 or 3 groups each independently selected from halogen, hydroxyl or C 1-4 substituted by an alkyl substituent.

12. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from C 1-4 Alkyl or cyclobutyl, wherein the C 1-4 Alkyl or cyclobutyl are each optionally substituted by 1, 2 or 3 groups independently selected from F, Cl, Br, C 1-4 Alkyl, halogenated C 1-4 Alkyl, cyano, hydroxyl, -SO2-C 1-4 alkyl, is substituted by a substituent, wherein Each optionally substituted by 1, 2 or 3 each independently selected from F, Cl, Br, hydroxyl or C 1-4 substituted by an alkyl substituent.

13. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or cyclobutyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or cyclobutyl is each optionally replaced by 1, 2 or 3 groups each independently selected from F, Cl, Br, methyl, ethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, CF3CH2-, CHF2CH2-, CH2FCH2-, cyano, hydroxyl, -SO2-CH3, -SO2-CH2CH3, is substituted by a substituent, wherein Each is optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, Br, hydroxy, methyl or ethyl.

14. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 15. The compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, which is a compound selected from the following structures:

16. A method for preparing a compound represented by formula (I), comprising: wherein R1, R2, R3, R4, R5, X, Y, and Z are 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 tert-butyloxycarbonyl, benzyloxycarbonyl, or benzyl; Compound a-1 and compound a-2 are used as starting materials to undergo Suzuki coupling reaction to obtain compound a-3; compound a-3 and compound a-4 undergo substitution reaction to obtain intermediate 1; intermediate 1 is deprotected to obtain compound a-5; compound a-5 and compound a-6 undergo reductive amination reaction to obtain intermediate 2; intermediate 2 and A coupling reaction occurs to obtain a compound represented by formula (I); Alternatively, intermediate 2 undergoes a coupling reaction with P-NH2 to obtain compound a-7; compound a-7 undergoes a substitution reaction with R3-L to obtain compound a-8; and compound a-8 is deprotected to obtain the compound represented by formula (I).

17. A method for preparing a compound represented by formula (I), comprising: wherein R1, R2, R3, R4, R5, X, Y, and Z are 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 tert-butyloxycarbonyl, benzyloxycarbonyl, or benzyl; Intermediate 1 and A coupling reaction occurs to obtain compound b-1; compound b-1 is deprotected to obtain intermediate 3; intermediate 3 undergoes a reductive amination reaction with compound a-6 to obtain a compound represented by formula (I); Alternatively, intermediate 1 undergoes a coupling reaction with P-NH2 to obtain compound b-2; compound b-2 undergoes a substitution reaction with R3-L to obtain compound b-3; compound b-3 is deprotected to obtain intermediate 3; intermediate 3 undergoes a reductive amination reaction with compound a-6 to obtain the compound represented by formula (I).

18. An intermediate compound selected from compound a-7, compound a-8, compound b-1, compound b-2, compound b-3 or intermediate 3 shown in the following structure, in, R1, R2, R3, R4, R5, X, Y, and Z are 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 each is independently selected from tert-butyloxycarbonyl, benzyloxycarbonyl, or benzyl, excluding the following compounds:

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

20. Use of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, in the preparation of a medicament for treating a disease mediated by RET.

21. The use according to claim 20, wherein: The RET is selected from wild-type RET, mutant RET, and RET fusion; 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 and irritable bowel syndrome.

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