Preparation and application of RET inhibitors

Abstract

The present invention discloses the preparation and use of Ret inhibitors. Specifically, the present invention provides a compound represented by formula (I) and its pharmaceutically acceptable salts, a pharmaceutical composition containing the compound or its pharmaceutically acceptable salts, and the use of the compound or its pharmaceutically acceptable salts in a medicament for treating or preventing Ret kinase-related disorders, particularly tumors. This is a class of heterocyclic compounds. Also disclosed is a method for preparing pharmaceutical compositions of the compound or its pharmaceutically acceptable salts. The substituents in general formula (I) have the same definitions as in the specification. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of drug synthesis, and specifically relates to a novel RET inhibitor and a preparation method and use thereof. Background Art

[0002] The present invention generally relates to novel compounds and methods for their preparation and use as RET inhibitors, for example for the treatment of cancer.

[0003] The RET gene was discovered by Takahashi et al. (Takahashi M, Ritz J, Cooper GM. Activation of novel human transforming gene, ret, by DNA rearrangement. Cell, 1985, 42(2): 581-588) in transformed cultured mouse NTH3T3 cells and was named the RET gene. The RET gene is a proto-oncogene located on the long arm of chromosome 10 (10q11.2). The encoded RET protein is a tyrosine kinase receptor composed of a cysteine-rich cadherin-like extracellular region, a transmembrane region, and an intracellular domain with tyrosine kinase activity. It shares 37% amino acid identity with the ALK kinase domain. RET protein stimulates receptor dimerization through the binding of ligand to receptor, and the intracellular region undergoes autophosphorylation and intracellular substrate phosphorylation, thereby activating various downstream pathways, such as RAS / RAF / MEK / ERK, PI3K / AKT and STAT pathways, playing an important role in cell proliferation, migration and differentiation (J Clin Oncol, 2012, 30(2): 200-202).

[0004] With the gradual progress of research, it has been found that the occurrence of many diseases is closely related to RET gene mutations, including papillary thyroid carcinoma, medullary thyroid carcinoma, multiple endocrine neoplasia type 2, congenital medullary colon, lung adenocarcinoma, etc. Currently, only four RET fusion genes, KIF5B-RET, CCDC6-RET, TRIM33-RET, and NCOA4-RET, have been reported in non-small cell lung cancer, and KIF5B-RET is the most common RET fusion gene in non-small cell lung cancer (Cancer, 2013, 119(8): 1486-1494). KIF5B-RET is a fusion gene formed by chromosomal inversion (p11;q11) of the KIF5B (kinesin family member 5B) gene and the RET gene. It was first confirmed in adenocarcinoma of non-smoking Koreans through whole-genome and transcriptome sequencing. KIF5B-RET is present at a very low rate in lung cancer and is more common in non-smokers and adenocarcinoma patients. It is also exclusive of other mutations, such as EGFR, KRAS, BRAF, ErbB2, and EML4-ALK (Genome Res, 2012, 22(3): 436-445). The KIF5B-RET fusion protein contains a motor domain and a coiled-coil domain of KIF5B. Through dimerization of the coiled-coil domain, the RET tyrosine kinase activity of the fusion protein can be abnormally activated, thereby promoting lung tumorigenesis (Cancer, 2011, 117(12): 2709-2718). In a study by Qian et al. (Mol Cancer, 2014, 13:176), the KIF5B-RET fusion kinase was shown to possess significant oncogenic activity both in vitro and in vivo, and the STAT3 signaling pathway may be a major downstream mediator of tumorigenesis. Evidence suggests that KIF5B-RET regulates the sustained activation of STAT3. The KIF5B-RET fusion kinase can bind to STAT3, directly phosphorylating and activating STAT3 at Tyr705. It can also mediate activation of STAT3 at Tyr705 through a JAK / STAT3-dependent pathway, triggering phosphorylation of Ser727 via the RAS / RAF / MEK / ERK1 pathway. Currently, some small molecule kinase inhibitors targeting multiple kinases have inhibitory activity against RET kinase. For example, Vandetinib and Cabozantinib have been approved by the FDA for the treatment of thyroid cancer. Others such as Ponatinib, Nintedanib, and Lenvatinib are also undergoing clinical research on tumors with abnormal RET signaling activation. However, due to the lack of selectivity for the RET protein, the above-mentioned multi-kinase inhibitors have different problems in efficacy and safety, which limits their further research and application in RET-abnormal tumors.Therefore, there is an urgent need for small molecule kinase inhibitory compounds that highly selectively target the RET protein in clinical practice.

[0005] Recently, the RET selective inhibitors Selpercatinib and Pralsetinib have been approved for marketing, with indications for thyroid cancer and non-small cell lung cancer (Selpercatinib and Pralsetinib drug instructions, FDA). Not all patients with RET rearrangement / mutation respond to these drugs, so it is necessary to develop inhibitors with high activity, few side effects, strong specificity, and effective against RET mutations and rearrangements. Summary of the Invention

[0006] A compound represented by general formula (I), its stereoisomers, pharmaceutically acceptable salts, polymorphs or isomers, wherein the compound represented by general formula (I) has the following structure:

[0007]

[0008] in,

[0009] Each L1 is independently selected at each occurrence from a bond, an OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 alkyl;

[0010] Each L2 is independently selected at each occurrence from a key, OC 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 alkyl;

[0011] Each L3 at each occurrence is independently selected from a bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 alkyl;

[0012] Each L4 at each occurrence is independently selected from a bond, C 0-3 Alkyl, NHC 0-6 Alkyl, C 1-3 Alkyl, COC 0-3 Alkyl or SC 0-3 alkyl;

[0013] Each X1, at each occurrence, is independently selected from N or CR9;

[0014] Each R1 at each occurrence is independently selected from H, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene-(halogen)1-3, C 1-6 Heteroalkyl, -CN, -OR6, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-(OR6) 1-3 、-OC 1-6 Alkylene-(halogen)1-3, -SR6, -SC 1-6 Alkylene-(halogen)1-3, -NR6R7, -C1-6alkylene-NR6R7, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7, -S(O)2NR6R7 or -C 3-6 Carbocyclic group; each R1 is independently optionally substituted by 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C(=O)C 1-6 Alkyl or -S(O)2NC 1-6 Alkyl C 1-6 The substituents of the alkyl group may be substituted or unsubstituted;

[0015] Each R9, at each occurrence, is independently selected from H, deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkylene-(halogen)1-3, C 1-6 Heteroalkyl, C 3-6 Heterocycloalkyl, C 3-6 Cycloalkyl, -CN, -OR6, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-(OR6) 1-3 、-OC 1-6 Alkylene-(halogen)1-3, -SR6, -SC 1-6Alkylene-(halogen)1-3, -NR6R7, -C1-6alkylene-NR6R7, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7, -S(O)2NR6R7 or phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl; each R9 is independently optionally replaced by 1, 2, 3, 4, 5 or 6 atoms selected from deuterium, halogen, -C1-6alkylene-NR6R7, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7, -S(O)2NR6R7 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C(=O)C 1-6 Alkyl or -S(O)2NC 1-6 Alkyl C 1-6 The substituents of the alkyl group may be substituted or unsubstituted;

[0016] Each R2, at each occurrence, is independently selected from H, deuterium, -CN, -C 1-6 Alkyl, -C 1-6 Alkylene-(halogen)1-3, C 1-6 Heteroalkyl, C 3-12 Cycloalkyl, C 7-12 Spiroalkyl, C 7-12 Heterospirocycloalkyl, C 3-12 heterocycloalkyl, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -C 1-6 Alkylene-(OR6) 1-3 、-OC 1-6 Alkylene-(halogen)1-3, -SR6, -SC 1-6 Alkylene-(halogen)1-3, -NR6R7, -C1-6alkylene-NR6R7, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7, -S(O)2NR6R7 or -C 3-6 Carbocyclic group; each R2 is independently optionally substituted by 1, 2, 3, 4, 5 or 6 groups selected from deuterium, halogen, -C 1-6 Alkyl, -C1-6 Alkoxy, oxo, -OC 1-6 Alkyl, -NC 1-6 Alkyl C 1-6 Alkyl, -CN, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C(=O)C 1-6 Alkyl or -S(O)2NC 1-6 Alkyl C 1-6 The substituents of the alkyl group may be substituted or unsubstituted;

[0017] Each Ar1 is independently selected at each occurrence from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, each heteroaryl independently containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; each R1 is independently selected at each occurrence from 1, 2, 3, 4, 5 or 6 R 10 to replace or not to replace;

[0018] Each Ar2 is independently selected at each occurrence from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl, or 10-membered heteroaryl, each heteroaryl independently containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each R1 is independently optionally replaced by 1, 2, 3, 4, 5, or 6 R 10 to replace or not to replace;

[0019] Each R 10 is independently selected at each occurrence from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene-(halogen)1-3, C 1-6 Heteroalkyl, -CN, -OR6, -C 1-6 Alkylene-(OR6) 1-3 、-OC 1-6 Alkylene-(halogen)1-3, -SR6, -SC 1-6 Alkylene-(halogen)1-3, -NR6R7, -C1-6alkylene-NR6R7, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7, -S(O)2NR6R7 or -C 3-6 Carbocyclic group; each R 20independently optionally substituted by 1, 2, 3, 4, 5 or 6 atoms selected from deuterium, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, oxo, -OR6, -NR6R7, -CN, -C(=O)R6, -C(=O)OR6, -OC(=O)R6, -C(=O)NR6R7, -NR6C(=O)R7 or -S(O)2NR6R7 may be substituted;

[0020] Each R6 and R7 at each occurrence is independently selected from hydrogen or -C 1-6 Alkyl, each R6 and R7 is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R8 or not; or R7 and R7 together with the nitrogen atom to which they are commonly attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further contain 1, 2, 3 or 4 heteroatoms selected from N, O, S, S(=O) or S(=O)2, and said 3-10 membered heterocyclic ring is independently optionally substituted by 1, 2, 3, 4, 5 or 6 R8 or not;

[0021] Each R8, at each occurrence, is independently selected from deuterium, halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkylene-(halogen)1-3, C 1-6 Heteroalkyl, -CN, -OC 1-6 Alkylene-(halogen)1-3, -SC 1-6 Alkyl, -SC 1-6 Alkylene-(halogen)1-3, -NC 1- 6C 1-6 、-C 1-6 Alkylene-NC 1-6 Alkyl C 1-6 Alkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -C(=O)NC 1-6 Alkyl C 1-6 Alkyl, -NC 1-6 Alkyl C(=O)C 1-6 Alkyl, -S(O)2NC 1-6 Alkyl C 1-6 Alkyl or -C 3-6 Carbocyclic group;

[0022] In some embodiments, the compound of formula (I) or its isomer, solvate or precursor, or pharmaceutically acceptable salt thereof is selected from the following compounds, its isomer, solvate or precursor, or pharmaceutically acceptable salt thereof:

[0023]

[0024]

[0025]

[0026]

[0027] The present invention also provides a drug

[0028] 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.

[0029] 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 drug for treating a disease mediated by RET.

[0030] 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 a disease mediated by RET. The RET includes wild-type RET, mutant RET, and RET fusion, wherein the mutant RET includes but is not limited to G810R mutant RET, M918T mutant RET, V804L mutant RET, 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 disease includes cancer and irritable bowel syndrome.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] The present invention also provides use of the above compound or its pharmaceutically acceptable salt or its pharmaceutical composition in preparing a drug for treating irritable bowel syndrome.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] Some chemical terms

[0042] Unless stated to the contrary, the following terms are used in the specification and claims.

[0043] The notation "C" used in this document has the following meanings: x-y " represents the range of carbon atoms, where x and y are both integers, for example, C 3-8 Cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, i.e. a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also understood that “C 3-8 " also includes any sub-ranges therein, such as C 3-7 、C 3-6 、C 4-7 、C 4-6 、C 5-6 wait.

[0044] "Alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl and 2-ethylbutyl. The alkyl group can be substituted or unsubstituted.

[0045] "Alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1,4-pentadienyl, and 1,4-butadienyl. The alkenyl group can be substituted or unsubstituted.

[0046] "Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl group can be substituted or unsubstituted.

[0047] "Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl group can be a single carbon ring, typically containing from 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. A cycloalkyl group can alternatively be a bicyclic or tricyclic ring fused together, such as decahydronaphthyl. The cycloalkyl group can be substituted or unsubstituted.

[0048] "Heterocyclyl," "heterocycloalkyl," and "heterocycle" refer to stable, 3- to 18-membered, monovalent, non-aromatic rings containing 2-12 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, heterocyclyl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused, spirocyclic, or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocyclyl group may be optionally oxidized, the nitrogen atom may be optionally quaternized, and the heterocyclyl group may be partially or fully saturated. The heterocyclyl group may be attached to the rest of the molecule through a single bond via a carbon or heteroatom in the ring. Heterocyclyl groups containing fused rings may contain one or more aromatic or heteroaromatic rings, as long as the attachment to the rest of the molecule is to an atom in a non-aromatic ring. For the purposes of the present application, the heterocyclic group is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclic groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, dihydroindolinyl, dioxolane, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

[0049] "Spiro heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein the single rings share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer 0 to 2) heteroatoms, and all the other ring atoms are carbon. These can contain one or more double bonds, but no ring has a completely conjugated electronic system that is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiral atoms between ring and ring, spiroalkyl is divided into single spiral heterocyclic radical, double spiral heterocyclic radical or multi-spiro heterocyclic radical, preferably single spiral alkyl and double spiral alkyl. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral alkyl. The non-limiting examples of spiro heterocyclic radical include:

[0050]

[0051] "Fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0052]

[0053] "Aryl" or "aromatic group" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring.

[0054] "Heteroaryl" or "heteroaromatic" refers to a 5- to 16-membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused or bridged ring systems, provided that the point of attachment to the rest of the molecule is an aromatic ring atom. Nitrogen atoms, carbon atoms, and sulfur atoms in the heteroaryl ring can be selectively oxidized, and nitrogen atoms can be selectively quaternized. For purposes of the present invention, a heteroaryl group is preferably a stable 4- to 11-membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and more preferably a stable 5- to 8-membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepine, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyrone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazinyl, etc. In the present application, heteroaryl is preferably a 5-8 membered heteroaryl group containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

[0055] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0056] "Hydroxy" refers to -OH, "amino" refers to -NH2, "amido" refers to -NHCO-, "cyano" refers to -CN, "nitro" refers to -CN, "isocyano" refers to -NC, and "trifluoromethyl" refers to -CF3.

[0057] The term "heteroatom" or "hetero" as used herein, alone or as part of another component, refers to atoms other than carbon and hydrogen, the heteroatoms being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium, and tin, but not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.

[0058]

[0046] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

[0059]

[00146] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

[0060] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycle group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocycle group is substituted with an alkyl group and instances where the heterocycle group is not substituted with an alkyl group.

[0061] "Substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms, in a group are independently substituted by a corresponding number of substituents. It goes without saying that the substituents are in their possible chemical positions and that those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, a free amino or hydroxyl group may be unstable when combined with a carbon atom having an unsaturated (such as an olefin) bond. The substituents include, but are not limited to, hydroxyl, amino, halogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, etc.

[0062] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert biological activity.

[0063] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or order of their atomic bonding or the spatial arrangement of their atoms. Isomers whose atoms are arranged differently in space are called "stereoisomers." Stereoisomers include optical isomers, geometric isomers, and conformational isomers. The compounds of the present invention may exist as optical isomers. Depending on the configuration of substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers. Methods for preparing and separating optical isomers are known in the art.

[0064] The compounds of the present invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups, or heterocyclic rings. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl groups or heterocyclic rings are designated as cis or trans configurations.

[0065] The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.

[0066] It is to be understood that the present invention encompasses any tautomeric or stereoisomeric forms and mixtures thereof and is not intended to be limited to any one tautomeric or stereoisomeric form used in the naming of the compounds or chemical formulas.

[0067] "Isotopes" are all isotopes of atoms that occur in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 31 P. 32 P. 35 S. 18 F and 36 Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using appropriate isotopically labeled reagents in place of non-isotopically labeled reagents. Such compounds have various potential uses, for example, as standards and reagents in assays for biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological, or pharmacokinetic properties.

[0068] "Prodrug" means that the compound of the present invention can be administered in the form of a prodrug. Prodrug refers to a derivative that is converted into a biologically active compound of the present invention under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc. (each of which is carried out using an enzyme or without the participation of an enzyme). Examples of prodrugs are compounds wherein the amine group in the compound of the present invention is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanylamide, pivaloyloxymethylamino, or wherein the hydroxyl group is acylated, alkylated, phosphorylated, or converted into a borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or wherein the carboxyl group is esterified or amidated, or wherein the sulfhydryl group forms a disulfide bridge with a carrier molecule that selectively delivers the drug to the target and / or to the cytosol of the cell, such as a peptide. These compounds can be prepared from the compounds of the present invention according to known methods.

[0069] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable" refers to salts prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the present invention contain one or more acidic or basic groups, the present invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups may exist in salt form and be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with amines or organic amines, such as primary amines, secondary amines, tertiary amines, cyclic amines, and the like, for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline, and caffeine. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compound of the present invention that contains basic group can exist in salt form and can be used according to the present invention with the form of addition of them and inorganic or organic acid.The example of suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acid well known to persons skilled in the art.If the compound of the present invention contains acidic and basic group simultaneously in molecule, the present invention also comprises inner salt or betaine except mentioned salt form.Each salt is obtained by conventional method well known to persons skilled in the art, for example, by making these and organic or inorganic acid or alkali contact or by with other salt anion exchange or cation exchange in solvent or dispersant.

[0070] Therefore, when referring to a "compound," "compound of the present invention," or "compound of the present invention" in this application, all forms of the compound, such as prodrugs, stable isotopic derivatives, pharmaceutically acceptable salts, isomers, meso- and racemates, enantiomers, diastereomers, and mixtures thereof, are included.

[0071] As used herein, the term "tumor" includes benign tumors and malignant tumors (eg, cancer).

[0072] As used herein, the term "cancer" includes various malignancies in which c-ret kinase is involved, including but not limited to non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyosarcoma, cell carcinoma, multiple myeloma, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular carcinoma), more specifically liver cancer, gastric cancer and bladder cancer.

[0073] As used herein, the terms "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" refer to an amount of at least one agent or compound sufficient to alleviate to some extent one or more symptoms of the disease or condition being treated. The result can be a reduction and / or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, a therapeutically effective amount is the amount of a composition comprising a compound disclosed herein that provides a clinically significant alleviation of symptoms. Techniques such as dose escalation studies can be used to determine the effective amount appropriate for any individual case.

[0074] The term "polymorph" or "polymorphism" used in the present invention refers to the compounds of the present invention having multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers all multiple forms or mixtures thereof.

[0075] Intermediate compounds of the compounds of the present invention and their polymorphs are also within the scope of the present invention.

[0076] Crystallization often produces solvates of the compounds of the present invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the present invention with one or more solvent molecules.

[0077] The solvent may be water, in which case the solvate is a hydrate. Alternatively, it may be an organic solvent. Thus, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, and the like, as well as the corresponding solvated forms. While the compounds of the present invention may be true solvates, in other cases, the compounds of the present invention may simply retain water or a mixture of water and some other solvent. The compounds of the present invention may react in a solvent or precipitate or crystallize in a solvent. Solvates of the compounds of the present invention are also encompassed within the scope of the present invention.

[0078] The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0079] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing an adverse biological response or interacting in an adverse manner with any components contained in the composition.

[0080] "Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.

[0081] As used herein, the terms "subject," "patient," "subject," or "individual" refer to individuals suffering from a disease, disorder, or condition, and include mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human.

[0082] The term "treatment" as used herein refers to the treatment of a disease or condition in a mammal, especially a human, including

[0083] (i) preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;

[0084] (ii) inhibiting the disease or condition, i.e., controlling its development;

[0085] (iii) alleviate the disease or condition, i.e., cause the disease or condition to regress;

[0086] (iv) Alleviate symptoms caused by a disease or condition.

[0087] As used herein, the terms "disease" and "disorder" are used interchangeably or may have different meanings because certain diseases or disorders do not yet have a known causative agent (and therefore the cause of the disease is unknown) and therefore cannot be considered diseases but rather are considered to be undesirable conditions or syndromes with more or less specific symptoms that have been confirmed by clinical researchers.

[0088] As used herein, the terms "administer," "administer," "administer," and the like refer to methods that enable a compound or composition to be delivered to the desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally. Specific implementation methods

[0089] The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the method described in the present invention can be used. The product obtained in each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature.

[0090] Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, Astatech Inc, or MacLean and were used without further purification unless otherwise stated.

[0091] Unless otherwise stated, the following reactions were performed at room temperature in anhydrous solvents under a positive pressure of nitrogen or CO or using a drying tube; glassware was oven-dried and / or heat-dried.

[0092] Unless otherwise specified, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin-layer chromatography silica gel precast plates (HSGF254) produced by Yantai Institute of Chemical Industry; and MS determination was performed using a ThernoLCD Fleet (ESI) liquid chromatography-mass spectrometer.

[0093] Nuclear magnetic resonance data (1H NMR) were obtained using a Bruker Avance-400 MHz or Varian Oxford-400 Hz NMR spectrometer. The solvents used for the NMR data included CDCl3, CD3OD, D2O, DMS-d6, etc., and the data were based on tetramethylsilane (0.000 ppm) or residual solvent (CDCl 3: When peak diversity is indicated, the following abbreviations are used to denote the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (double of doublets), dt (double of triplets). Coupling constants, if given, are in Hertz (Hz).

[0094] Preparation of intermediates

[0095] 5-Propynyl-2-methylthio-4,6-dichloropyrimidine

[0096]

[0097] 5-iodo-2-methylthiopyrimidine-4,6-dione (28.4 g, 0.1 mol) was dissolved in DMF (500 mL), followed by the addition of tributyl propynyl tin (49.35 mL, 0.15 mmol) and tetrakis triphenylphosphine palladium (23 g, 0.02 mmol). The reaction mixture was heated to 120 ° C with stirring and stirred for 2 h. The reaction mixture was diluted with EtOAc (1000 mL), washed with saturated NaHCO3 aqueous solution (300 mL) and water (300 mL), then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 50-100% DCM in cyclohexane to give 5-propynyl-2-methylthiopyrimidine-4,6-dione (10.4 g, 53%).

[0098] LC / MS (ESI): m / z = 197 [M+H] + .

[0099] 5-Propanyl-2-methylthiopyrimidine-4,6-dione (9.8 g, 0.05 mol) and POCl3 (50 mL) were mixed, the mixture was stirred and heated under reflux for 3 hours, then poured into stirred crushed ice, and then extracted with DCM and dissolved under reduced pressure to give 5-propynyl-2-methylthio-4,6-dichloropyrimidine (10.1 g, 87%) as a yellow solid.

[0100] LC / MS (ESI): m / z = 234 [M+H] + .

[0101] 5-Propynyl-2-(1-methyl-1H-pyrazol-3-yl)-4,6-dichloropyrimidine

[0102]

[0103] Bromine (24 g, 0.15 mol) was added dropwise to a solution of 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydroxypyrimidine (28.8 g, 0.15 mol) and sodium hydroxide (7 g, 0.175 mol) dissolved in 250 ml of water, and the mixture was cooled slightly to keep the temperature below 40°C. The mixture was then stirred for another half an hour, cooled, and then filtered to obtain 12 g (39.9 g, 98%) of 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydroxy-5-bromopyrimidine.

[0104] LC / MS (ESI): m / z = 272 [M+H] + .

[0105] 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydroxy-5-bromopyrimidine (27.1 g, 0.1 mol) was dissolved in DMF (500 mL), followed by the addition of tributyl propynyl tin (49.35 mL, 0.15 mmol) and tetrakis triphenylphosphine palladium (23 g, 0.02 mmol). The reaction mixture was heated to 120 ° C with stirring and stirred for 2 h. The reaction mixture was diluted with EtOAc (1000 mL), washed with saturated NaHCO3 aqueous solution (300 mL) and water (300 mL), then dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 50-100% DCM in cyclohexane to give 5-propynyl-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4,6-dione (11.78 g, 51%).

[0106] LC / MS (ESI): m / z = 231 [M+H] + .

[0107] 5-Propynyl-2-(1-methyl-1H-pyrazol-3-yl)pyrimidine-4,6-dione (11.5 g, 0.05 mol) and POCl3 (50 mL) were mixed, the mixture was stirred and heated under reflux for 3 hours, then poured into stirred crushed ice, and then extracted with DCM and dissolved under reduced pressure to give a yellow solid 5-propynyl-2-(1-methyl-1H-pyrazol-3-yl)-4,6-dichloropyrimidine (10.95 g, 82%).

[0108] LC / MS (ESI): m / z = 268 [M+H] + .

[0109] 5-Cyano-2-(1-methyl-1H-pyrazol-3-yl)-4-chloropyrimidin-6-one

[0110]

[0111] At 0 ° C, a mixture of DMF (32 mL) and POCl3 (100 mL) was stirred for 1 h, and then the mixture was added to 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dihydroxypyrimidine (43 g, 223 mmol) and stirred at room temperature for 0.5 h. The mixture was then stirred at reflux for 3 hours and dissolved under reduced pressure. The residue was poured into ice water and extracted six times with DCM. The organic phase was washed with a NaHCO3 aqueous solution, dried with Na2SO4 and dissolved under reduced pressure to give a yellow solid 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dichloropyrimidine-5-carboxaldehyde (53.3 g, 93%).

[0112] LC / MS (ESI): m / z = 258 [M+H] + .

[0113] 2-(1-methyl-1H-pyrazol-3-yl)-4,6-dichloropyrimidine-5-carboxaldehyde (42.15 g, 164 mmol) and hydroxylamine hydrochloride were dissolved in AcOH (200 mL), stirred and refluxed for 0.5 hours, and then cooled to room temperature. The solvent was removed in vacuo. The resulting yellow solid was placed in H2O and the product was filtered off. The solid product was then dried under vacuum overnight to provide the oxime in the form of a yellow solid. A solution of oxime (6.6 g, 26.0 mmol) in thionyl chloride (104 mL) was refluxed and stirred for 3 hours. The reaction was cooled to room temperature and the solvent was removed in vacuo. The resulting yellow-brown solid was dried under vacuum overnight to give 5-cyano-2-(1-methyl-1H-pyrazol-3-yl)-4-chloropyrimidin-6-one (6.14 g, 95%).

[0114] LC / MS (ESI): m / z = 236 [M+H] + .

[0115] Example 1

[0116] 2-(2-Hydroxy-2-methylpropoxy)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0117] -3-yl)pyridin-3-yl)-5-(prop-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 1)

[0118]

[0119] Under nitrogen at room temperature, 5-propynyl-2-methylthio-4,6-dichloropyrimidine 1a (1.92 g, 9.8 mmol) and 3-(6-boc-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine-5-boronic acid pinacol ester (4.13 g, 10.3 mmol) were dissolved in 98 mL of DMF. Aqueous KCO (9.8 mL, 1.96 mmol) was then added, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (600 mg, 0.735 mmol). The reaction was stirred at room temperature for over 48 hours. Ethyl acetate and water were then added to the reaction. The layers were separated, and the organic layer was washed with water and brine, then dried over NaSO. The solution was dissolved under reduced pressure and then purified by column chromatography to give 5-propynyl-2-methylthio-4-chloro-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1b (2.87 g, 62%).

[0120] LC / MS (ESI): m / z = 473 [M+H] + .

[0121] 5-Propanyl-2-methylsulfanyl-4-chloro-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1b (1.89 g, 4 mmol) was dissolved in 25 mL of methanol, followed by the addition of lithium hydroxide (0.2912 mmol). The mixture was stirred at room temperature for 24 hours and dissolved under reduced pressure. The residue was poured into ice water and filtered to afford 5-propynyl-2-methylsulfanyl-4-chloro-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1c (1.75 g, 97%).

[0122] LC / MS (ESI): m / z = 454 [M+H] + .

[0123] To a solution of 5-propynyl-2-methylsulfanyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1c (1.58 g, 3.5 mmol) in DCM (25 mL) was added m-CPBA (2.4 g, 15 mmol) in an ice-water bath. The mixture was stirred overnight at room temperature, diluted with water, and extracted with 100 mL of DCM. The organic phase was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate dissolved under reduced pressure. The residue was purified by column chromatography to yield the desired product, 5-propynyl-2-methylsulfanyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1d (1.49 g, 88%) as a pale yellow product.

[0124] LC / MS (ESI): m / z = 486 [M+H] + .

[0125] 5-Propynyl-2-methylsulfonyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1d (1.455 g, 3 mmol), 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (0.522 g, 3 mmol) and potassium tert-butoxide (0.5 g, 4.5 mmol) were dissolved in DCE, and the mixture was stirred under reflux for 12 hours. The residue was poured into ice water, extracted twice with DCM, dried over Na2SO4 and dissolved under reduced pressure. The residue was dissolved in methanol, and then 1N 2-[[(tetrahydro-2H-pyran-2-yl)oxy]propan-1-ol] was added dropwise at 0-5°C. HCl (5 mL), then stirred at room temperature for 3 h, then dissolved under reduced pressure, dissolved in DCM, washed with saturated NaHCO3 solution and saturated NaCl water, dried over anhydrous sodium sulfate, and then dissolved under reduced pressure and separated by preparative column to obtain 5-propynyl-2-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1e (0.69 g, 48%).

[0126] LC / MS (ESI): m / z = 396 [M+H] + .

[0127] 5-Propynyl-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1e (20 mg, 0.05 mmol) was dissolved in DCE, and then 6-methoxy-3-pyridinecarboxaldehyde (7.59 mg, 0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg, 0. The reaction mixture was stirred at room temperature overnight, and then dissolved under reduced pressure and separated by preparative column to give 2-(2-hydroxy-2-methylpropoxy)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(prop-1-yn-1-yl)pyrimidin-4(3H)-one 1 (25 mg, 97%).

[0128] LC / MS (ESI): m / z = 517 [M+H] + .

[0129] Example 2

[0130] 2-(2-Hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0131] -3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 2)

[0132]

[0133] Compound 6-bromonicotinaldehyde 2a (18.6 g, 0.1 mol), 6-boc-3,6-diazabicyclo[3.1.1]heptane (19.8 g, 0.1 mol), and potassium carbonate (20.7 g, 0.15 mol) were dissolved in DMSO (280 mL) and stirred at 90°C overnight. After cooling, water was added and the mixture was extracted with EA. The organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The mixture was dissolved under reduced pressure. The mixture was slurried with n-hexane and ethyl acetate to yield compound 6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)nicotinaldehyde 2b (23.6 g, 78%).

[0134] LC / MS (ESI): m / z = 304 [M+H] + .

[0135] To a solution of S-methylisothiourea (4.5 g, 50 mmol), 6-(6-boc-3,6-diazabicyclo[3.1.1]heptan-3-yl)nicotinaldehyde (15.15 ml, 50 mmol), and ethyl cyanoacetate (5.65 g, 50 mmol) in ethanol (100 ml) was added KCO (6.9 g, 50 mmol). The reaction mixture was heated to 80°C for 5 hours, cooled, and filtered. Crystallization from ethanol gave 5-cyano-2-methylthio-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidine 2c (18.7 g, 85%).

[0136] LC / MS (ESI): m / z = 441 [M+H] + .

[0137] To a solution of 5-cyano-2-methylsulfanyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2c (1.54 g, 3.5 mmol) in DCM (25 mL) was added m-CPBA (2.4 g, 15 mmol) in an ice-water bath. The mixture was stirred overnight at room temperature, diluted with water, and extracted with 100 mL of DCM. The organic phase was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate dissolved under reduced pressure. The residue was purified by column chromatography to yield the desired product, 5-propynyl-2-methylsulfanyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 1d (1.47 g, 89%) as a pale yellow product.

[0138] LC / MS (ESI): m / z = 473 [M+H] + .

[0139] 5-Cyano-2-methylsulfonyl-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2d (1.41 g, 3 mmol), 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol (0.522 g, 3 mmol) and potassium tert-butoxide (0.5 g, 4.5 mmol) were dissolved in DCE, and the mixture was stirred under reflux for 12 hours. The residue was poured into ice water, extracted twice with DCM, dried over Na2SO4 and dissolved under reduced pressure. The residue was dissolved in methanol, and then 1N 2-[[(tetrahydro-2H-pyran-2-yl)oxy]propan-1-ol] was added dropwise at 0-5°C. HCl (5 mL), then stirred at room temperature for 3 h, then dissolved under reduced pressure, dissolved in DCM, washed with saturated NaHCO3 solution and saturated NaCl water, dried over anhydrous sodium sulfate, and then dissolved under reduced pressure and separated by preparative column to obtain 5-cyano-2-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2e (0.66 g, 58%)

[0140] LC / MS (ESI): m / z = 383 [M+H] + .

[0141] 5-Cyano-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2e (19 mg, 0.05 mmol) was dissolved in DCE, and then 6-methoxy-3-pyridinecarboxaldehyde (7.59 mg, 0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg, 0.0830 mmol) were added sequentially. The reaction was stirred at room temperature overnight, and then dissolved under reduced pressure and separated by preparative column to give 2-(2-hydroxy-2-methylpropoxy)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one 2 (24 mg, 96%).

[0142] LC / MS (ESI): m / z = 504 [M+H] + .

[0143] Example 3

[0144] 2-((1-hydroxycyclopropyl)methoxy)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0145] -3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 3)

[0146]

[0147] Compound 3 (25 mg, yield 97%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z = 515 [M+H] + .

[0148] Example 4

[0149] 2-((1-hydroxycyclopropyl)methoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane

[0150] -3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 4)

[0151]

[0152] Compound 4 (23 mg, yield 91%) was obtained using a method similar to Example 2. LC / MS (ESI): m / z = 502 [M+H] + .

[0153] Example 5

[0154] 6-(6-(6-((6-methoxypyridin-3-yl)methyl)-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-2-(1-methyl

[0155] -1H-pyrazol-4-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 5)

[0156]

[0157] Compound 4 (21 mg, yield 82%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z = 509 [M+H] + .

[0158] Example 6

[0159] 6-(6-(6-((6-methoxypyridin-3-yl)methyl)-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 6)

[0160]

[0161] Compound 6 (22 mg, yield 89%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z = 496 [M+H] + .

[0162] Example 7

[0163] 2-((2-Fluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 7)

[0164]

[0165] Compound 7 (20 mg, yield 83%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z = 491 [M+H] + .

[0166] Example 8

[0167] 2-((2-Fluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 8)

[0168]

[0169] Compound 8 (22 mg, 92% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z = 478 [M+H] + .

[0170] Example 9

[0171] 2-((2-Fluoroethylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 9)

[0172]

[0173] Compound 9 (21 mg, yield 87%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z = 490 [M+H] + .

[0174] Example 10

[0175] 2-((2-Fluoroethylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 10)

[0176]

[0177] Compound 10 (22 mg, 92% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0178] =477[M+H] + .

[0179] Example 11

[0180] 2-((2,2,2-trifluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-

[0181] 1-propyl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 11)

[0182]

[0183] Compound 11 (26 mg, 97% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0184] =527[M+H] + .

[0185] Example 12

[0186] 2-((2,2,2-trifluoroethoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 12)

[0187]

[0188] Compound 12 (23 mg, 91% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0189] =514[M+H] + .

[0190] Example 13

[0191] 2-((2,2,2-trifluoroethylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 13)

[0192]

[0193] Compound 13 (25 mg, 94% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0194] =526[M+H] + .

[0195] Example 14

[0196] 2-((2,2,2-trifluoroethylamino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 14)

[0197]

[0198] Compound 14 (24 mg, 48% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0199] =513[M+H] + .

[0200] Example 15

[0201] 2-((3-Fluorocyclobutane-1-oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 15)

[0202]

[0203] Compound 15 (23 mg, yield 89%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0204] =517[M+H] + .

[0205] Example 16

[0206] 2-((3-Fluorocyclobutane-1-oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one (Compound 16)

[0207]

[0208] Compound 16 (22 mg, yield 87%) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0209] =504[M+H] + .

[0210] Example 17

[0211] 2-((3-Fluorocyclobutane-1-amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 17)

[0212]

[0213] Compound 17 (20 mg, yield 79%) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0214] =516[M+H] + .

[0215] Example 18

[0216] 2-((3-Fluorocyclobutane-1-amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one (Compound 18)

[0217]

[0218] Compound 18 (22 mg, 87% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0219] =503[M+H] + .

[0220] Example 19

[0221] 2-((3,3-Difluorocyclobutane-1-oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 19)

[0222]

[0223] Compound 19 (24 mg, 92% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0224] =535[M+H] + .

[0225] Example 20

[0226] 2-(3,3-Difluorocyclobutane-1-oxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one (Compound 20)

[0227]

[0228] Compound 20 (23 mg, 89% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0229] =522[M+H] + .

[0230] Example 21

[0231] 2-((3,3-Difluorocyclobutane-1-amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 21)

[0232]

[0233] Compound 21 (23 mg, 87% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0234] =534[M+H] + .

[0235] Example 22

[0236] 2-((3,3-Difluorocyclobutane-1-amino)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one (Compound 22)

[0237]

[0238] Compound 22 (21 mg, 82% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0239] =521[M+H] + .

[0240] Example 23

[0241] 2-((2-Fluoroethoxy)-4-(6-(6-((6-trifluoromethoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 23)

[0242]

[0243] Compound 23 (24 mg, 88% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0244] =545[M+H] + .

[0245] Example 24

[0246] 2-((2-Fluoroethoxy)-4-(6-(6-((6-trifluoromethoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 24)

[0247]

[0248] Compound 24 (24 mg, 90% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0249] =532[M+H] + .

[0250] Example 25

[0251] 2-((2-Fluoroethylamino)-4-(6-(6-((6-trifluoromethoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 25)

[0252]

[0253] Compound 25 (25 mg, 92% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0254] =544[M+H] + .

[0255] Example 26

[0256] 2-((2-Fluoroethylamino)-4-(6-(6-((6-trifluoromethoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 26)

[0257]

[0258] Compound 26 (25 mg, 93% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0259] =531[M+H] + .

[0260] Example 27

[0261] 2-((2-Fluoroethoxy)-4-(6-(6-((5-methoxypyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 27)

[0262]

[0263] Compound 27 (22 mg, 89% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0264] =492[M+H] + .

[0265] Example 28

[0266] 2-((2-Fluoroethoxy)-4-(6-(6-((5-methoxypyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 28)

[0267]

[0268] Compound 28 (22 mg, 92% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0269] =478[M+H] + .

[0270] Example 29

[0271] 2-((2-Fluoroethylamino)-4-(6-(6-((5-methoxypyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-(propyl-1-yn-1-yl)pyrimidin-4(3H)-one (Compound 29)

[0272]

[0273] Compound 29 (23 mg, 95% yield) was obtained using a method similar to Example 1. LC / MS (ESI): m / z

[0274] =491[M+H] + .

[0275] Example 30

[0276] 2-((2-Fluoroethylamino)-4-(6-(6-((5-methoxypyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 30)

[0277]

[0278] Compound 30 (23 mg, 96% yield) was obtained using a method similar to Example 2. LC / MS (ESI): m / z

[0279] =478[M+H] + .

[0280] Similar to the synthetic route of Example 1-30, the following compound can be obtained

[0281]

[0282]

[0283]

[0284] Example 31

[0285] 2-(2-Fluoroethylmercapto)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridine

[0286] -3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 59)

[0287]

[0288] To a solution of thiourea (3.8 g, 50 mmol), 6-(6-boc-3,6-diazabicyclo[3.1.1]heptan-3-yl)nicotinaldehyde (15.15 ml, 50 mmol), and ethyl cyanoacetate (5.65 g, 50 mmol) in ethanol (100 ml) was added KCO (6.9 g, 50 mmol). The reaction mixture was heated to 80°C for 5 hours, cooled, and filtered. Crystallization from ethanol gave 5-cyano-2-thioxo-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrimidine (16.8 g, 79%).

[0289] LC / MS (ESI): m / z = 427 [M+H] + .

[0290] 5-Cyano-2-thioxo-4-hydroxy-6-(6-boc-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine (1.27 g, 3 mmol), 1-fluoro-2-iodoethane (0.57 g, 33 mmol) and potassium carbonate (0.5 g, 4.5 mmol) were dissolved in DCE, and the mixture was stirred under reflux for 12 hours. The residue was poured into ice water, extracted twice with DCM, dried over Na2SO4 and dissolved under reduced pressure. The residue was The product was dissolved in methanol, and then 1N HCl (5 mL) was added dropwise at 0-5 ° C. The reaction was stirred at room temperature for 3 h, then dissolved under reduced pressure, dissolved in DCM, washed with saturated NaHCO3 solution and saturated NaCl water, dried over anhydrous sodium sulfate, and then dissolved under reduced pressure. The product was separated by preparative column to obtain 5-cyano-2-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2e (0.88 g, 79%).

[0291] LC / MS (ESI): m / z = 373 [M+H] + .

[0292] 5-Cyano-2-(2-hydroxy-2-methylpropoxy)-4-hydroxy-6-(3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)pyrimidine 2e (19 mg, 0.05 mmol) was dissolved in DCE, and then 6-methoxy-3-pyridinecarboxaldehyde (7.59 mg, 0.0553 mmol) and sodium triacetoxyborohydride (17.6 mg, 0.0830 mmol) were added sequentially. The reaction was stirred at room temperature overnight, and then dissolved under reduced pressure and separated by preparative column to give 2-(2-hydroxy-2-methylpropoxy)-6-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-5-cyanopyrimidin-4(3H)-one 2 (22 mg, 91%).

[0293] LC / MS (ESI): m / z = 494 [M+H] + .

[0294] Example 32

[0295] 2-(2,2,2-Trifluoroethylmercapto)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 60)

[0296]

[0297] Compound 60 (24.5 mg, 93% yield) was obtained using a method similar to Example 31. LC / MS (ESI): m / z

[0298] =530[M+H] + .

[0299] Example 33

[0300] 2-(2,2,2-Trifluoroethylmercapto)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 61)

[0301]

[0302] Compound 61 (24 mg, 91% yield) was obtained using a method similar to Example 31. LC / MS (ESI): m / z

[0303] =532[M+H] + .

[0304] Example 34

[0305] 2-(2,2,2-Trifluoroethylmercapto)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-3-yl)pyridin-3-yl)-6-oxopyrimidine-5-carbonitrile (Compound 62)

[0306]

[0307] Compound 62 (23 mg, 88% yield) was obtained using a method similar to Example 31. LC / MS (ESI): m / z

[0308] =531[M+H] + .

[0309] Example 15 Biological Activity Test

[0310] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0311] Test Example 1: Determination of the inhibitory activity of the compounds of the present invention on RET enzyme

[0312] Test conditions:

[0313] Enzyme concentration: 2.5 nM

[0314] ATPKm:16uM

[0315] Preincubation: 10 min

[0316] Reaction time: 60 minutes

[0317] The starting concentration of the compound was 1 μM, and the assay was performed in duplicate with 3-fold dilutions and 10 concentrations.

[0318] Test method:

[0319] 1. Compound preparation: Dissolve the compound powder in 100% DMSO to prepare a 10 mM stock solution.

[0320] 2. Kinase reaction process

[0321] (1) Prepare 1× Kinase buffer.

[0322] (2) Preparation of compound concentration gradient: The compound test concentration is 1 μM. Dilute the compound to a 100% DMSO solution in a 384-well plate at 100x the final concentration. Then dilute the compound 3-fold to 10 concentrations. Use a dispenser to transfer 250 nL of the compound at 100x the final concentration to the target plate.

[0323] (3) Prepare a kinase solution with a final concentration of 2.5 times using 1× Kinase buffer.

[0324] (4) Add 10 μL of kinase solution at 2.5 times the final concentration to the compound wells and positive control wells respectively; add 10 μL of 1× Kinase buffer to the negative control wells.

[0325] (5) Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate to mix, and incubate at room temperature for 10 minutes.

[0326] (6) Prepare a mixed solution of ATP and Kinase substrate 2 at 5 / 3 times the final concentration using 1× Kinase buffer.

[0327] (7) Add 15 μL of a mixed solution of ATP and substrate at 5 / 3 times the final concentration to start the reaction.

[0328] (8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 60 minutes.

[0329] (9) Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and shake to mix.

[0330] (10) Read the conversion rate using CaliperEZ Reader.

[0331] 3. Data Analysis

[0332] Calculation formula: %Inhibition = (Conversion%_max - Conversion%_sample) / (Conversion%_max - Conversion%_min) × 100%

[0333] Where: Conversion%_sample is the conversion reading of the sample;

[0334] Conversion%_min: Mean value of negative control wells, representing the conversion rate reading of wells without enzyme activity;

[0335] Conversion%_max: The mean of the positive control wells, representing the conversion rate readings of wells without compound inhibition.

[0336] Fitting the dose-effect curve: The log value of the concentration was used as the X-axis and the percentage inhibition rate was used as the Y-axis. The 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 Value. “++++” means IC 50 ≤10nM; “+++” means 10nM <IC 50 ≤500nM; “++” means 500nM <IC 50 ≤2000nM; “+” indicates 2000nM <IC 50 .

[0337] The test results are shown in Table 1:

[0338] Table 1. In vitro enzymatic activity test data

[0339]

[0340]

[0341] Test Example 1: Inhibitory effect of the compounds of the present invention on the growth of Ba / F3KIF5B-RET cells

[0342] Ba / F3 KIF5B-RET, Ba / F3 KIF5B-RET-V804M, and Ba / F3 RET-M918T cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was assessed by trypan blue exclusion to ensure viability was above 90%. The cell concentration was adjusted and 90 μL of the cell suspension was added to each 96-well plate. The cells in the 96-well plate were incubated overnight at 37°C, 5% CO2, and 95% humidity. Each well of the 96-well plate seeded with cells was then incubated with 10 μL of the corresponding drug solution (maximum concentration: 1000 nM) in a gradient of concentrations. Each drug concentration was replicated in triplicate, with a final DMSO concentration of 0.1%. The cells in the drug-treated 96-well plate were incubated for an additional 72 hours at 37°C, 5% CO2, and 95% humidity. After the drug treatment, 100 μL of CellTiter-Glo reagent was added to each well and the cells were shaken on an orbital shaker for 5 minutes to lyse the cells. The cell plate was placed at room temperature for 20 minutes to stabilize the luminescence signal, and then the luminescence value was read. The data were analyzed using GraphPad Prism 5.0 software, and the data were fitted using nonlinear S-curve regression to obtain the dose-effect curve, from which the IC was calculated. 50 The results are shown in Table 2. “++++” indicates IC 50 ≤10nM; “+++” means 10nM <IC 50 ≤500nM; “++” means 500nM <IC 50 ≤2000nM; “+” indicates 2000nM <IC 50 .

[0343] Table 2. IC values of the compounds for inhibition of tumor cell proliferation 50 (nm).

[0344] Compound number Ba / F3KIF5B-RET Ba / F3KIF5B-RET-V804M Ba / F3RET-M918T 1 ++++ ++++ ++++ 2 ++++ ++++ +++ 3 ++++ ++++ ++++ 4 ++++ ND ND 59 ++++ +++ +++ 60 ++++ ND ND 61 ++++ ND ND 62 ++++ ND ND selpercatinib ++++ +++ +++

[0345] Although the present invention has been described in detail above, it will be appreciated by those skilled in the art that various modifications and variations may be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but rather to the claims.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating a disease mediated by RET.

4. The use according to claim 3, 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.

5. The use according to claim 3, wherein: The disease is selected from cancer and irritable bowel syndrome.

6. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 2 in the preparation of a medicament for treating cancer.

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