Uses and methods of heterocyclic compounds for treating diseases associated with kinase drug resistance mutations - Patents.com

Abstract

TIFF2024511389000047.tif6334 The present invention relates to the use of heterocyclic compounds of formula I in the manufacture of a medicament for treating or aiding in the treatment of a disease or condition associated with a Rearranged during transfection (RET) drug resistance mutation in an individual, and to methods of treatment using said heterocyclic compounds.

Description

[Technical field]

[0001] The present invention relates to the use of heterocyclic compounds in the manufacture of a medicament for treating or aiding in the treatment of a disease or condition associated with a Rearranged during transfection (RET) drug resistance mutation in an individual, and to methods of treatment using said heterocyclic compounds. [Background technology]

[0002] Protein kinases are enzymes that catalyze the phosphorylation of proteins. Protein phosphorylation mediates the process of cell signaling, thereby regulating the physiological activities of cells, such as cell survival, proliferation, differentiation, apoptosis, and metabolism. Dysfunction of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, and diabetes.

[0003] RET is a proto-oncogene, and the RET protein it encodes is a transmembrane receptor tyrosine protein kinase, composed of three parts: a cysteine-rich cadherin-like extracellular domain (used to bind to ligands), a transmembrane domain, and an intracellular domain with tyrosine kinase activity. Activated RET protein can activate multiple downstream signaling pathways, including the RAS / RAF / ERK pathway, the PI3K / Akt pathway, and the JNK pathway, thereby resulting in cell proliferation, migration, and differentiation. Alterations (mutations or fusions) in the RET gene and abnormal expression of the wild-type RET gene lead to abnormal activation of the RET protein, resulting in excessive activation of signaling pathways, which is one of the main mechanisms of carcinogenesis. Abnormally activated RET protein is involved in the proliferation and invasion of various tumor cells through multiple signaling pathways, affecting the development and progression of tumors. RET gene alterations are more prominent in downstream cascade reactions, of which RET gene mutations are mainly associated with medullary thyroid cancer and papillary thyroid cancer, and RET gene fusions are mainly associated with non-small cell lung cancer and chronic myeloid leukemia. Therefore, inhibition of RET activity is of great medical value (Nature Reviews Cancer, 2014, 14(3):173-186).

[0004] RET inhibitors have great potential for treating and preventing various diseases (e.g., tumors, irritable bowel syndrome, etc.). Currently, two compounds (selpercatinib (also known as LOXO-292) and pralsetinib (also known as BLU-667)) have been approved and are on the market, and several compounds are in clinical trials. However, clinical studies have found that RET drug resistance mutations (G810R, G810S, G810C, Y806C, Y806N, and V738A, etc.) occur after long-term administration of RET inhibitors, which leads to poor conditions such as reduced therapeutic efficacy, recurrence, and poor prognosis (Journal of Thoracic Oncology, 2020, 15(4), 541-549; Annals of oncology: official journal of the European Society for Medical Oncology, 2021,32(2),261-268; Annals of oncology: official journal of the European Society for Medical Oncology,2020,31(12),1599-1600; Annals of oncology: official journal of the European Society for Medical Oncology,2020,31(12),1725-1733, etc.), therefore, the development of compounds effective against diseases associated with RET drug resistance mutations has good application prospects. Summary of the Invention

[0005] In one aspect, the invention provides the use of a compound of formula I, a stereoisomer, tautomer or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, in the manufacture of a medicament for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual, [ka] Where: R 1 is selected from a 4- to 10-membered heterocyclyl group and a 5- to 10-membered heteroaryl group, and the heterocyclyl group and the heteroaryl group are each independently selected from a hydroxy group, a halogen, CN, NO2, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Haloalkoxy group, C 1-4 Heteroalkyl groups, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups; R 2 is halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a heteroalkyl group, a 4- to 10-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group, wherein the alkyl group, the heteroalkyl group, the heterocyclyl group, and the heteroaryl group are each independently selected from a hydroxy group, a halogen, CN, NO2, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Haloalkoxy group, C 1-4 Heteroalkyl groups, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups; R 3 H, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Heteroalkyl groups and C 3-6 cycloalkyl groups, and X 1 , X 2 and X 3 are each independently selected from CH and N.

[0006] In some preferred embodiments, the present invention provides the use of compound 1, a stereoisomer, tautomer or mixture thereof of compound 1, an N-oxide of compound 1, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of compound 1, or a stable isotope derivative, metabolite, or prodrug of compound 1, in the manufacture of a medicament for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual, wherein compound 1 is [ka] The structure is For example, a pharma- ceutically acceptable salt of Compound 1 is the fumarate salt of Compound 1.

[0007] In another aspect, the present invention provides a compound of formula I, a stereoisomer, tautomer or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual.

[0008] In another aspect, the present invention provides a method for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual, comprising administering to the individual an effective amount of a compound of formula I, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound.

[0009] In another aspect, the present invention provides the use of a compound of formula I, a stereoisomer, a tautomer or a mixture thereof of the compound, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound in the manufacture of a medicament for modulating (e.g., decreasing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).

[0010] In another aspect, the present invention provides a compound of formula I, a stereoisomer, a tautomer or a mixture thereof of the compound, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, for modulating (e.g., decreasing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).

[0011] In another aspect, the present invention provides a method for regulating (e.g., reducing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A), comprising administering an effective amount of a compound of formula I, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound.

[0012] The compound has a good inhibitory effect on RET drug resistance mutations, and also has good pharmacokinetics, safety and other properties. [Brief description of the drawings]

[0013] [Figure 1]In vivo efficacy of compound 1-A and control compounds in the Ba / F3 KIF5B-RETG810R subcutaneously transplanted tumor model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition Unless otherwise defined below, all technical and scientific terms used herein shall have the same meaning as commonly understood by those of ordinary skill in the art of this application. References to technology used herein are intended to be references to technology as commonly understood in the art, including modifications to the technology or substitutions of equivalent technology that are obvious to those of ordinary skill in the art. Although the following terms are believed to be well understood by those of ordinary skill in the art, the following definitions are provided to better explain the present invention.

[0015] The terms "comprising," "including," "having," "containing," or "relating to," and other similar terms used herein, are inclusive or open-ended and do not necessarily mean that other unrecited elements or method steps are present, but do not exclude them (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of").

[0016] As used herein, the term "alkyl group" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, an alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, "C 1-6 Alkyl group" and "C 1-4The term "alkyl group" refers to straight or branched chain groups having 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as halogens (in which case the group is referred to as a "haloalkyl group") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or -CH2CH2CF3, etc.). 1-4 "Alkyl group" refers to a straight or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0017] As used herein, a "heteroalkyl group" refers to an optionally substituted alkyl group having one or more skeletal atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. 1-6 The heteroalkyl group can indicate the number of carbons in the chain, which in this example includes 1 to 6 carbon atoms. For example, the group -CH2OCH2CH3 is referred to as a C3 heteroalkyl group. Attachment to the remainder of the molecule can be through either a heteroatom or a carbon atom in the heteroalkyl chain.

[0018] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more (e.g., 1 to 3) of the same or different halogen atoms, and includes "C 1-6 Haloalkyl group" and "C 1-4 The term "haloalkyl group" refers to haloalkyl groups having 1 to 6 carbon atoms and 1 to 4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0019] As used herein, the term "hydroxyalkyl group" refers to a group formed by replacing a hydrogen atom in an alkyl group with one or more hydroxy groups, such as C 1-4 Hydroxyalkyl group or C 1-3 Hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, -C(CH3)2OH, and the like.

[0020] As used herein, the term "alkoxy group" refers to an alkyl group (as defined above) having an oxygen atom inserted at any reasonable position, e.g., C 1-6 Alkoxy group, C 1-4 Alkoxy group or C 1-3 Refers to an alkoxy group. 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, -CH2-OCH3, and the like, which are optionally substituted with one or more (e.g., 1 to 3) of the same or different substituents.

[0021] As used herein, the term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures which share two adjacent atoms with each other.

[0022] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures which share one ring atom with each other.

[0023] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures that share two atoms that are not directly bonded to each other.

[0024] As used herein, the term "cycloalkyl group" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring group, including, but not limited to, monocyclic alkyl groups (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), and polycyclic alkyl groups containing spiro rings, fused or bridged ring systems (i.e., spirocycloalkyl groups such as bicyclo[1.1.1]pentyl and bicyclo[2.2.1]heptyl, fused alkyl groups, and bridged cycloalkyl groups). In the present invention, cycloalkyl groups are optionally substituted with one or more (e.g., 1 to 3) of the same or different substituents. A carbon atom on a cycloalkyl group is optionally substituted with an oxo group (i.e., forming C=O). "C 3-6 The term "cycloalkyl group" refers to a cycloalkyl group having 3 to 6 ring carbon atoms, which may be a monocyclic alkyl group, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group, or a bicyclic alkyl group, such as a C 5-8 Spirocyclic alkyl groups, C 5-8 Bridged ring alkyl group, C 5-8 Fused ring alkyl group, C 5-6 Spirocyclic alkyl groups, C 5-6 Bridged ring alkyl group or C 5-6 It may be a condensed ring alkyl group.

[0025] As used herein, the term "cycloalkoxy group" refers to an -O-cycloalkyl group, where cycloalkyl is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0026] As used herein, the term "heterocyclyl group" or "heterocycle" refers to a monocyclic or polycyclic (e.g., fused, spiro or bridged ring) group having two or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms including, but not limited to, oxygen, nitrogen and sulfur atoms, wherein the carbon atoms and heteroatoms on the heterocyclyl group are optionally substituted with oxo groups (e.g., to form C=O, S(=O) or S(=O)2).

[0027] As used herein, the term "4- to 10-membered heterocyclyl group" refers to a heterocyclyl group containing 4 to 10 ring atoms, including, but not limited to, a 4- to 9-membered heterocyclyl group, a 4- to 8-membered heterocyclyl group, a 4- to 7-membered heterocyclyl group, a 5- to 6-membered heterocyclyl group, a 3- to 8-membered heterocyclyl group, a 3- to 7-membered heterocyclyl group, a 4- to 7-membered nitrogen-containing heterocyclyl group, a 4- to 7-membered oxygen-containing heterocyclyl group, a 4- to 7-membered sulfur-containing heterocyclyl group, a 5- to 6-membered nitrogen-containing heterocyclyl group, a 5- to 6-membered oxygen-containing heterocyclyl group, a 5- to 6-membered sulfur-containing heterocyclyl group, and the like, wherein said "nitrogen-containing heterocyclyl group", "oxygen-containing heterocyclyl group" and "sulfur-containing heterocyclyl group" each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. Examples of 4- to 10-membered heterocyclyl groups include oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, and pyrrolidonyl groups (e.g., [ka] ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, and trithianyl.

[0028] As used herein, the term "heteroaryl group" or "heteroaryl ring" refers to a monocyclic or polycyclic aromatic group containing one or more of the same or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaryl ring (aromatic ring system containing at least one heteroatom), and may contain 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example, 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. Carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (e.g., to form C=O, S(=O) or S(=O)2).

[0029] As used herein, the term "5- to 10-membered heteroaryl group" or "5- to 10-membered heteroaryl ring" refers to a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including a 5- to 10-membered nitrogen-containing heteroaryl group, a 5- to 10-membered oxygen-containing heteroaryl group, a 5- to 10-membered sulfur-containing heteroaryl group, a 5- to 6-membered nitrogen-containing heteroaryl group, a 5- to 6-membered oxygen-containing heteroaryl group, a 5- to 6-membered sulfur-containing heteroaryl group, etc. The terms "nitrogen-containing heteroaryl group", "oxygen-containing heteroaryl group" and "sulfur-containing heteroaryl group" each optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered fused ring groups containing these groups.

[0030] As used herein, the term "heteroaryl group" encompasses fused ring structures, and the point of attachment of the fused ring structure to other groups may be on any ring in the fused ring structure. Thus, heteroaryl groups of the present invention include (mono)heteroaryl group-(mono)heteroaryl group, (mono)heteroaryl group-(monocyclic)aryl group, (mono)heteroaryl group-(mono)heterocyclyl group and (mono)heteroaryl group-(mono)cycloalkyl group, such as 5-6 membered (mono)heteroaryl group-5-6 membered (mono)heteroaryl group, 5-6 membered (mono)heteroaryl group-phenyl group, 5-6 membered (mono)heteroaryl group-5-6 membered (mono)heterocyclyl group or 5-6 membered (mono)heteroaryl group-C 4-6 It may be, but is not limited to, a (mono)cycloalkyl group (for example, a 5- to 6-membered heteroaryl group-cyclobutyl group, a 5- to 6-membered heteroaryl group-cyclopentyl group, or a 5- to 6-membered heteroaryl group-cyclohexyl group), and examples thereof include an indolyl group, an isoindolyl group, an indazolyl group, a benzimidazole group, a quinolinyl group, an isoquinolinyl group, [ka] [ka] etc., but are not limited to these.

[0031] As used herein, the term "halogenated" or "halogen" group is defined to include F, Cl, Br, or I.

[0032] The term "substituted" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with the selection of a specified group, provided that the substitution results in a stable compound, but not in excess of the normal valence of the designated atom under the present circumstances. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0033] When a substituent is described as "optionally substituted...," the substituent may be (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be individually and / or together replaced by independently selected optional substituents. When a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced by an independently selected optional substituent.

[0034] When substituents are described as "independently selected," each substituent is selected independently of the others. Thus, each substituent can be the same or different from another (other) substituent.

[0035] As used herein, the term "one or more" refers to one, or more than one, such as two, three, four, five or ten, under reasonable conditions.

[0036] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be through any suitable position on the substituent.

[0037] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in that substitutable ring.

[0038] The present invention further includes all pharma- ceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention, except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, the following: Isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H), isotopes of carbon (e.g.11 C. 13 C and 14 C), isotopes of chlorine (e.g. 36 Cl), isotopes of fluorine (e.g. 18 F), isotopes of iodine (e.g. 123 I and 125 I), nitrogen isotopes (e.g. 13 N 15 N), isotopes of oxygen (e.g. 15 O. 17 O and 18 O), phosphorus isotopes (e.g. 32 P), and sulfur isotopes (e.g. 35 Certain isotopically labeled compounds of the invention (e.g., those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection. 11 C. 18 F, 15 O and 13 Substitution with 1,2-dichlorophenyl 1,4-difluorophenyl 2,5-difluorophenyl 1,6-difluorophenyl 2,7-difluorophenyl 1,8-difluorophenyl 2,9-difluorophenyl 1,9-difluorophenyl 2,10-difluorophenyl 1,5 ...1,5-difluorophenyl 2,10-difluorophenyl 1,5-difluorophenyl 2,10-difluorophenyl 1,5-difluorophenyl 1,5-difluorophenyl 2,10-difluorophenyl 1,5-difluorophenyl 1,5-difluorophenyl 2,10-difluorophenyl 1,5-difluorophenyl 1,5-difluorophenyl 2,1

[0039] The term "stereoisomer" refers to an isomer formed by at least one asymmetric center. In a compound having one or more (e.g., one, two, three or four) asymmetric centers, it can produce exo / meso mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly called tautomers) that are in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oxime may exist in equilibrium in solution in the following tautomeric forms: [ka]

[0040] The scope of the present application includes all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0041] In this specification, the solid line ( [ka] ), solid wedge ( [ka] ) or dashed wedge ( [ka] ) are used to depict chemical bonds in the compounds of the present invention. The use of solid lines to depict bonds to asymmetric carbon atoms indicates that all possible stereoisomers at that carbon atom (e.g., specific enantiomers, racemic mixtures, etc.) are included. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms represents the presence of the depicted stereoisomer. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry rather than absolute stereochemistry. Unless otherwise indicated, it is intended that the compounds of the present invention may exist in the form of stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention can exhibit one or more types of isomerism and are composed of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0042] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of two or more polymorphs in any ratio.

[0043] Cocrystals refer to pharma- ceutical active molecules bound in the same crystal lattice with other physiologically acceptable acids, bases, salts, and non-ionic compound molecules through hydrogen bonding, pi-pi stacking, van der Waals forces, and other non-covalent bonds.

[0044] It should be noted that certain compounds of the present invention may be present in free form for therapeutic use or, where appropriate, as their pharma- ceutically acceptable derivatives. In the present invention, pharma- ceutically acceptable derivatives include, but are not limited to, pharma- ceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which can directly or indirectly provide the compound of the present invention or its metabolites or residues after administration to a patient in need thereof. Thus, when referring to the "compound of the present invention" in this specification, it is intended to include each of the above-mentioned derivative forms of the compound.

[0045] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition and base addition salts thereof, such as hexafluorophosphate, meglumine salt, etc. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002).

[0046] As used herein, the term "ester" refers to an ester derived from a compound of each formula of the present application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release a compound of the present invention in the free acid or alcohol form). The compounds of the present invention may themselves be esters.

[0047] The compounds of the present invention can exist in the form of solvates, preferably hydrates, which contain polar solvents, in particular, for example, water, methanol or ethanol, as components of the crystal lattice of the compounds. The amount of polar solvent, in particular water, can be present in a stoichiometric or non-stoichiometric ratio.

[0048] As will be appreciated by those skilled in the art, not all nitrogen-containing heterocycles can form N-oxides, since nitrogen requires an available lone pair of electrons to be oxidized to an oxide. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. Methods for synthesizing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, and include, but are not limited to, oxidizing heterocycles and tertiary amines with peracids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethylbisoxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see, for example, TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESG Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0049] Also within the scope of the invention are metabolic products of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Thus, the invention includes metabolic products of the compounds of the invention, including compounds obtained by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0050] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are specific derivatives of the compounds of the present invention that may have little or no pharmacological activity themselves, and which, when administered into or on the body, may be converted, for example, by hydrolytic cleavage, to the compounds of the present invention having the desired activity. In general, such prodrugs are functional derivatives of said compounds that are easily converted into the desired therapeutically active compound in the body. For further information regarding the use of prodrugs, see "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention may be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0051] The present invention also encompasses the compounds of the present invention that contain protective groups.In any process of preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any related molecules, thereby forming chemically protected forms of the compounds of the present invention.This can be achieved by conventional protective groups, for example, the protective groups described in TW Greene & PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.Protective groups can be removed at a later appropriate stage by using methods known in the art.

[0052] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0053] The term "pharmaceutically acceptable carrier" in this invention refers to a diluent, adjuvant, excipient, or vehicle that is suitable for administration with a therapeutic agent and for contact with the tissues of humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment.

[0054] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharma- ceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0055] The compounds of the present invention or pharmaceutical compositions containing them can act systemically and / or locally. To this end, they can be administered by an appropriate route.

[0056] For these administration routes, the compounds of the present invention or pharmaceutical compositions containing them can be administered in appropriate dosage forms.

[0057] As used herein, the term "effective amount" refers to that amount of a compound which, upon administration, relieves to some extent one or more of the symptoms of the condition being treated.

[0058] Dosage regimen can be adjusted to provide optimal desired response.For example, it can be administered as a single bolus, or several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of treatment.It should be noted that the dosage value can vary according to the type and severity of the condition to be alleviated, and can include single or multiple doses.Furthermore, for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0059] The amount of the compound of the present invention administered depends on the individual being treated, the severity of the condition or pathology, the rate of administration, the treatment of the compound, and the judgment of the prescribing physician. In general, an effective dose is about 0.0001 to about 50 mg / kg body weight / day. In some cases, a dosage level below the lower limit of the above range may be sufficient, while in other cases, a higher dose may be employed without causing any adverse side effects. Provided that the higher dose is first divided into several lower doses administered throughout the day.

[0060] The content or dose of the compound of the present invention in the pharmaceutical composition may be about 0.01 mg to about 1000 mg.

[0061] As used herein, unless otherwise explained, the term "treating" means reversing, alleviating, inhibiting the progression of the condition or medical condition to which the term applies, or one or more symptoms of such condition or medical condition, or preventing one or more symptoms of such condition or medical condition.

[0062] As used herein, an "individual" includes a human or a non-human animal. Exemplary human individuals include human individuals (referred to as patients) with a disease (e.g., a disease described herein) or normal individuals. "Non-human" in the present invention includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0063] In some embodiments, the compounds of the present invention can be administered in combination with one or more additional therapeutic or prophylactic agents, such as other medicines for treating cancer or neoplastic disease. In some embodiments, the methods of the present invention can further include administering one or more additional therapeutic or prophylactic agents, such as other medicines for treating cancer or neoplastic disease.

[0064] Pharmaceutical Uses and Treatment Methods In some embodiments, the invention provides use of a compound of formula I, a stereoisomer, tautomer or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound in the manufacture of a medicament for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual; [ka] Where: R 1 is selected from a 4- to 10-membered heterocyclyl group and a 5- to 10-membered heteroaryl group, and the heterocyclyl group and the heteroaryl group are each independently selected from a hydroxy group, a halogen, CN, NO2, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Haloalkoxy group, C 1-4 Heteroalkyl groups, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups; R 2 is halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a heteroalkyl group, a 4- to 10-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group, wherein the alkyl group, the heteroalkyl group, the heterocyclyl group, and the heteroaryl group are each independently selected from a hydroxy group, a halogen, CN, NO2, C 1-4 Alkyl group, C 1-4 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Haloalkoxy group, C 1-4 Heteroalkyl groups, C 3-6 Cycloalkyl groups and C 3-6Optionally substituted with one or more substituents selected from cycloalkoxy groups; R 3 H, halogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Heteroalkyl groups and C 3-6 cycloalkyl groups, and X 1 , X 2 and X 3 are each independently selected from CH and N.

[0065] In some preferred embodiments, in the compound of formula I, a stereoisomer, a tautomer or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, a co-crystal, a polymorph, or a solvate of the compound, or a stable isotope derivative, a metabolite, or a prodrug of the compound according to the present invention, the compound of formula I is Compound 1, [ka] and For example, a pharma- ceutically acceptable salt of the compound is the fumarate salt of Compound 1.

[0066] In some embodiments, the present invention provides a compound of formula I, a stereoisomer, tautomer or mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual.

[0067] In some embodiments, the present invention provides a method for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual, comprising administering to the individual an effective amount of the compound of formula I, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound.

[0068] In certain embodiments, the disease or condition associated with a drug-resistant mutation in RET is a drug-resistant disease, preferably a drug-resistant cancer or tumor or irritable bowel syndrome, wherein the cancer or tumor is, for example, an advanced cancer or tumor or a metastatic cancer or tumor, wherein the cancer or tumor is preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphatic cancer, thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), colon cancer, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.

[0069] In a particular embodiment, the drug-resistant disease is a disease that is drug-resistant to selpercatinib and / or pralsetinib.

[0070] In certain embodiments, the drug-resistant disease is non-small cell lung cancer (e.g., RET fusion-positive non-small cell lung cancer), medullary thyroid cancer (e.g., advanced or metastatic medullary thyroid cancer), or thyroid cancer (e.g., advanced or metastatic RET fusion-positive thyroid cancer) that is drug-resistant to selpercatinib and / or pralsetinib.

[0071] In certain embodiments, the present invention provides the use of a compound of formula I, a stereoisomer, a tautomer or a mixture thereof of the compound, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound in the manufacture of a medicament for modulating (e.g., reducing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).

[0072] In certain embodiments, the present invention provides a compound of formula I, a stereoisomer, a tautomer or a mixture thereof of the compound, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound for modulating (e.g., reducing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).

[0073] In certain embodiments, the present invention provides a method for regulating (e.g., reducing or inhibiting) aberrant RET activity associated with a RET drug resistance mutation (e.g., one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A), comprising administering an effective amount of a compound of formula I, a stereoisomer, a tautomer, or a mixture thereof, an N-oxide of the compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound.

[0074] In some embodiments, the RET drug resistance mutation is one or more mutations selected from G810R, G810S, and G810C.

[0075] In some embodiments, the RET drug resistance mutation is one or more mutations selected from a RET solvent front mutation and a RET hinge region mutation.

[0076] In some embodiments, the drug resistance mutation is a RET solvent front mutation.

[0077] In some embodiments, the RET drug resistance mutation is an 810 mutation, such as a G810 mutation.

[0078] In some preferred embodiments, the RET drug resistance mutation is one or more mutations selected from G810R, G810S, and G810C.

[0079] In some embodiments, the compound has the structure shown in formula IA: [ka] R 1 , R 2 , R 3 , X 1 and X 2 is as defined above for formula I.

[0080] In some embodiments, the compound has the structure shown in formula IB: [ka] R 1 , R 2 , R 3 , X 1 and X 2 is as defined above for formula I.

[0081] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 1 is a 5-10 membered heteroaryl group, the heteroaryl group being independently selected from hydroxy, halogen, CN, C 1-4 Alkyl group, C 1-4Haloalkyl group, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups.

[0082] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 1 is a 5-6 membered heteroaryl group, the heteroaryl group being independently selected from halogen, C 1-3 Alkyl group and C 3-6 Optionally substituted with one or more substituents selected from cycloalkyl groups.

[0083] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 1 is a pyrazolyl group, the pyrazolyl group being independently selected from halogen, C 1-3 Alkyl groups (e.g., methyl groups) and C 3-6 It is optionally substituted with one or more substituents selected from cycloalkyl groups (eg, cyclopropyl groups).

[0084] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 1 is a pyrazolyl group substituted with a methyl group (for example 5-methyl-1H-pyrazolyl-3-yl or 1-methyl-1H-pyrazolyl-4-yl) or a pyrazolyl group substituted with a cyclopropyl group (for example 5-cyclopropyl-1H-pyrazolyl-3-yl).

[0085] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 2 is halogen (e.g. Cl), C 1-6 and 5-6 membered heteroaryl groups, each of which is independently selected from the group consisting of alkyl groups (e.g., methyl groups), halogen, C 1-4 Alkyl group, C 1-4 Hydroxyalkyl group, C 1-4 Heteroalkyl groups, C 3-6Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups.

[0086] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 2 is a 5-6 membered heteroaryl group, the heteroaryl group being independently selected from halogen, C 1-4 Alkyl group, C 1-4 Hydroxyalkyl group, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups.

[0087] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 2 is a 5-membered heteroaryl group, the heteroaryl group being independently selected from halogen, C 1-4 Alkyl group, C 1-4 Hydroxyalkyl group, C 3-6 Cycloalkyl groups and C 3-6 Optionally substituted with one or more substituents selected from cycloalkoxy groups.

[0088] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 2 are pyrrolyl, pyrazolyl, imidazolyl, furyl or thiazolyl groups, each of which is independently F, Cl, a methyl group, [ka] , a cyclopropyl group, and an -O-cyclopropyl group.

[0089] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 3 is H, C 1-6 Alkyl group and C 3-6 The cycloalkyl group is selected from the group consisting of cycloalkyl groups.

[0090] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 3 H and C 1-6 The alkyl group is selected from the group consisting of aryl, ... and alkyl groups.

[0091] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein R 3 is H or a methyl group.

[0092] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein X 1 is CH or N, preferably X 1 is N.

[0093] In certain embodiments, the present invention provides compounds of formula I, formula IA, and formula IB, wherein X 2 is CH or N, preferably X 2 is CH.

[0094] In certain embodiments, the present invention provides a compound of formula I, 3 is CH or N, preferably X 3 is N.

[0095] The present invention encompasses any combination of the above embodiments.

[0096] In some embodiments, the compounds include, but are not limited to:

[0097] [ka]

[0098] In some embodiments, the compound is [ka] It is.

[0099] In some embodiments, the pharma- ceutically acceptable salt is a fumarate salt.

[0100] In some embodiments, the pharma- ceutically acceptable salt of the compound is [ka] It is.

[0101] In certain embodiments, the compounds of the invention are prepared by the methods described in WO 2020 / 168939 A1.

[0102] Working Example The present invention will now be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

[0103] The abbreviations used herein have the following meanings:

[0104] [Table 1] [Table 2] [Table 3]

[0105] The compounds of the present invention are isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography, and their structures are as follows: 1 The reaction was confirmed by 1 H NMR and / or MS. The reaction was monitored by TLC or LC-MS.

[0106] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model number AVACE III HD 400 MHz).

[0107] LC / MS was performed using an Aglient 1260 Infinity / Aglient 6120 Quadrupole.

[0108] TLC used silica gel GF 254 as the stationary phase.

[0109] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Haiyang) as the stationary phase.

[0110] Biotage flash column chromatography was used for flash column chromatography.

[0111] Prep-HPLC uses Agilent 1260 model, Waters 2489 model and GeLai 3500 model chromatographs.

[0112] Microwave reactions were carried out using a BiotageInitiator microwave reactor.

[0113] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15 to 30° C.).

[0114] The reagents used in this application are available from companies such as Acros Organics, Aldrich Chemical Company, or Tokkaku Chemical.

[0115] Example 1: 2-(6-(6-((6-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 9) [ka]

[0116] First step: tert-butyl 3-(5-bromopyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 1c) Compound 1a (1.50 g) and 1b (1.77 g) are added in a 100 mL one-neck flask in order, followed by DMSO (20.0 mL) and K2CO3 (5.83 g) in order, and the mixture is heated to 90°C under nitrogen protection and stirred for 20 h. After the reaction is completed, the reaction solution is cooled to room temperature, diluted with water (100 mL), and extracted with EA. The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel flash column chromatography (PE:EA=5:1) to obtain compound 1c (2.03 g). MS m / z (ESI): 354.1 [M+H] + It is.

[0117] Second step: tert-butyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 1d) Compound 1c (2.03 g), B2(pin)2 (4.01 g), KOAc (1.55 g), 1,4-dioxane (15.0 mL) and Pd(dppf)Cl2·DCM (644.67 mg) were added in sequence to a 100 mL one-neck flask, and the mixture was reacted by heating to 90 °C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with EA (40 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and purified by silica gel flash column chromatography (DCM:MeOH = 15:1) to obtain compound 1d (2.11 g). MS m / z (ESI): 402.3 [M + H] + It is.

[0118] Third step: tert-butyl 3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 1f) Compound 1e (950 mg) is dissolved in 1,4-dioxane (50.0 mL), and compound 1d (2.11 g), Cs2CO3 (3.15 g) and water (5.0 mL) are added in that order. Pd(dppf)Cl2·DCM (477.83 mg) is then added, and the mixture is heated to 90°C under nitrogen protection for 14 h. After completion of the reaction, the reaction solution is cooled to room temperature, diluted with water (100 mL), and extracted with EA (60 mL x 3). The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain compound 1f (587.0 mg). MS m / z (ESI): 463.3 [M+H] + It is.

[0119] Fourth step: 2-(6-(3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1g) Compound 1f (1.36 g) is dissolved in DCM (20.0 mL), TFA (20.0 mL) is added, and the mixture is reacted at room temperature under nitrogen protection. After the reaction is completed, the reaction solution is concentrated under reduced pressure until dry, and then separated and purified by Prep-HPLC to obtain the trifluoroacetate salt of compound 1g (587.0 mg). MS m / z (ESI): 363.3 [M+H] + It is.

[0120] Fifth step: 6-(4-chloro-1H-pyrazol-1-yl)nicotinaldehyde (1j) Compound 1h (150 mg), 1i (99 mg) and K2CO3 (334 mg) are added to DMF (4 mL), heated to 80 ° C and reacted for 14 h, and the product formation is detected by LC-MS. After the reaction is completed, it is cooled to room temperature, diluted with water, extracted with ethyl acetate (25 mL × 3), the organic layers are combined and washed three times with water, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure until dry, and separated and purified by silica gel plate chromatography (DCM: MeOH = 10: 1) to obtain the target compound 1j (23 mg). MS m / z (ESI): 208.0 [M + H] + It is.

[0121] Sixth step: 2-(6-(6-((6-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 9) The trifluoroacetate salt of compound 1g (30 mg) and compound 1j (23 mg) were dissolved in methanol (0.5 mL), and then Et3N (8 mg) and NaBH3CN (26 mg) were added in that order. The reaction was allowed to proceed at room temperature for 20 hours, after which the reaction solution was concentrated under reduced pressure until dry, and the solution was purified by Prep-HPLC to obtain compound 9 (5 mg). MS m / z (ESI): 554.2 [M+H] + It is.

[0122] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.65(s,1H),9.13(d,J=2.0Hz,1H),8.81-8. 74(m,1H),8.47-8.41(m,2H),8.03-7.97(m,1H),7.96-7.92(m,1H),7.86(d,J=8.4 Hz,1H),6.84(br,1H),6.78(d,J=8.8Hz,1H),6.32(br,1H),3.82-3.67(m,4H),3.6 6-3.51(m,4H),2.60-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H).

[0123] Example 2: 2-(6-(6-(4-(5-cyclopropyl-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 14) [ka]

[0124] First step: 1-(4-(1,3-dioxolan-2-yl)phenyl)-3-cyclopropyl-1H-pyrazole (14c) and 1-(4-(1,3-dioxolan-2-yl)phenyl)-5-cyclopropyl-1H-pyrazole (14d) A round-bottom flask was charged with 14a (472 mg), 14b (1 g), CuI (831 mg), N,N'-dimethyl-1,2-ethylenediamine (384 mg), Cs2CO3 (4.27 g) and DMF (10 mL) in sequence, and heated to 115 °C under N2 protection for 3 h. After the complete conversion of the raw materials was detected by LC-MS, it was cooled to room temperature, diluted with 20 mL of water, extracted with ethyl acetate (25 mL x 3), the organic layer was washed with water three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a mixture of compounds 14c and 14d (1.1 g), which was used directly in the next step reaction without further purification. ESI-MS (m / z): 257.1 [M+H] + It is.

[0125] Second step: 4-(5-cyclopropyl-1H-pyrazol-1-yl)benzaldehyde (14e) and 4-(3-cyclopropyl-1H-pyrazol-1-yl)benzaldehyde (14f) The mixture of 14c and 14d from the previous step (930 mg) was dissolved in a mixed solvent of THF (20 mL) and water (20 mL), and 37% HCl solution (15 mL) was added dropwise and reacted at room temperature for 18 h, and the complete conversion of the raw material was detected by LC-MS. Part of the solvent was removed under reduced pressure, the pH was adjusted to about 9 with saturated NaHCO3, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtration. Compounds 14e (TLC-low polarity compound) (400 mg) and 14f (TLC-high polarity compound) (20 mg) were obtained by separation and purification using silica gel plate chromatography (DCM:MeOH = 10:1). ESI-MS (m / z): 213.2 [M + H] + It is.

[0126] Third step: 2-(6-(6-(4-(3-cyclopropyl-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 14) Dissolve the trifluoroacetate salt of compound 1g (30 mg) and compound 14e (26 mg) in methanol (0.5 mL), then add Et3N (8 mg) and NaBH3CN (26 mg) in that order, and react at room temperature for 16 hours after addition. After the reaction is complete, concentrate the reaction solution under reduced pressure until dry, and separate and purify it by Prep-HPLC to obtain compound 14 (22 mg). MS m / z (ESI): 559.3 [M+H] + It is.

[0127] 1H NMR(400MHz,DMSO-d6)δ11.97(s,1H),9.65(s,1H),9.12(d,J=2.4Hz,1H),8.43(dd,J=9.2,2.4Hz,1H) ,8.28(d,J=2.4Hz,1H),7.68(d,J=8.4Hz,2H),7.41(d,J=8.4Hz,2H),6.84(br,1H),6.78(d,J=8.8Hz,1 H),6.30(br,1H),6.21(d,J=2.4Hz,1H),3.82-3.65(m,4H),3.64-3.47(m,4H),2.59-2.53(m,1H),2.3 3(s,3H),2.26(s,3H),2.00-1.92(m,1H),1.59(d,J=8.4Hz,1H),0.95-0.88(m,2H),0.75-0.69(m,2H).

[0128] Example 3: 2-(6-(6-(4-(3-cyclopropyl-1H-pyrazol-1-yl)benzyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 15) The trifluoroacetate salt of compound 1g (30 mg) and compound 14f (20 mg) are dissolved in methanol (0.5 mL), and then Et3N (8 mg) and NaBH3CN (26 mg) are added in that order. After the addition, the mixture is reacted at room temperature for 16 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure until dry, and then separated and purified by Prep-HPLC to obtain compound 15 (12 mg). MS m / z (ESI): 559.3 [M+H] + It is.

[0129] 1H NMR(400MHz,DMSO-d6)δ11.79(br,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),8.44(dd,J=8. 8,2.4Hz,1H),7.59-7.45(m,5H),6.83(br,1H),6.78(d,J=9.2Hz,1H),6.28(br,1H),6.09( d,J=1.6Hz,1H),3.85-3.72(m,4H),3.66-3.53(m,4H),2.62-2.52(m,1H),2.33(s,3H),2. 25(s,3H),1.88-1.77(m,1H),1.60(d,J=8.4Hz,1H),0.98-0.92(m,2H),0.75-0.69(m,2H).

[0130] Example 4: Fumarate salt of 2-(6-(6-((6-(4-fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 1-A) [ka] Compound 1 (5 g) was dissolved in 200 mL of THF, stirred, and after waiting for complete dissolution, 1.56 g of fumaric acid was gradually added and the mixture was stirred for 20 to 45 minutes. o The mixture was reacted under the conditions of C for 46 hours. After the reaction was completed, the mixture was filtered and washed with THF to obtain 7.06 g of a solid wet product. o C to obtain 4.78 g of a solid powder.

[0131] 1H NMR(400MHz,DMSO-d6)δ12.43(br,3H),9.66(s,1H),9.13(d,J=2.4Hz,1H),8.60(d,J=4.4Hz,1H), 8.44(dd,J=8.8,2.4Hz,1H),8.41(d,J=1.2Hz,1H),7.97(dd,J=8.4,2.0Hz,1H),7.91(d,J=4.4Hz,1 H),7.86(d,J=8.4Hz,1H),6.81(br,1H),6.76(d,J=8.8Hz,1H),6.62(s,2H),6.31(br,1H),3.79-3 .76(m,4H),3.68-3.58(m,4H),2.62-2.56(m,1H),2.33(s,3H),2.25(s,3H),1.61(d,J=8.4Hz,1H).

[0132] Example 5: 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 24) [ka]

[0133] First step: methyl 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazole-3-carboxylate (compound 24b) Compounds 16a (2.53 g) and 24a (1.52 g) were dissolved in DMF (10 mL), and then N,N'-dimethylethylenediamine (379.29 mg), Cs2CO3 (7.01 g), and CuI (409.74 mg) were added in that order. The mixture was stirred for 90 minutes under nitrogen protection. oHeat to C and react for 2h. After the reaction is completed, cool to room temperature, add water (60mL) to the reaction solution to stop the reaction, and extract with EA (30mLx3). The organic phases are combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate is purified by silica gel column chromatography (PE:EA=50:1-5:1) to obtain compound 24b (1.59g). MS m / z(ESI):276.0[M+H] + It is.

[0134] Second step: 2-(1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 24c) Compound 24b (200 mg) is added to dry THF (10 mL) and cooled in a dry ice-ethanol bath for 15 min. Then, a solution of MeMgBr in Et2O (3N, 0.65 mL) is added dropwise, and the reaction is continued for 15 min while maintaining the temperature, and then the temperature is raised to room temperature and the reaction is continued for 4 h. After the reaction is completed, the reaction solution is quenched by adding a saturated aqueous solution of ammonium chloride (1 mL), and further diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 24c (200 mg). MS m / z (ESI): 276.1 [M+H] + It is.

[0135] Third step: 6-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)nicotinaldehyde (compound 24d) Compound 24c (200 mg) is added to THF (5 mL), followed by hydrochloric acid (2N, 4.5 mL) and reacted at 25°C for 12 h. After completion of the reaction, the reaction solution is added with saturated aqueous NaHCO3 to adjust the pH to 7-8, and extracted with EA (30 mL x 3). The organic phases are combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 24d (165 mg). MS m / z (ESI): 232.1 [M+H] + It is.

[0136] Fourth step: Preparation of 2-(1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 24) The trifluoroacetate salt of compound 1g is purified by flash column chromatography under basic conditions (purification conditions: C18 reverse phase column, mobile phase is 0.5% aqueous ammonium bicarbonate and CH3CN, gradient elution with 0% CH3CN for 5 min, gradient elution with 0%-100% CH3CN for 25 min, product is received at 45%-65% CH3CN), concentrated and lyophilized to obtain the free amine 1g.

[0137] Compound 24d (50.5 mg) and compound 1g (30 mg) are then added to DMA (3 mL) and stirred at room temperature for 1 h under nitrogen gas protection. NaBH(OAc)3 (101 mg) is then added and the mixture is reacted overnight at room temperature. After the reaction is completed, water (60 mL) is added to the reaction solution to quench the reaction, and the mixture is extracted with EA (30 mL x 3). The organic phases are combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 24 (12 mg). MS m / z (ESI): 578.3 [M+H] + It is.

[0138] 1H NMR(400MHz,DMSO-d6)δ11.97(br,1H),9.67(s,1H),9.12(d,J=2.0Hz,1H),8.48-8.41(m,2H) ,8.37(d,J=1.6Hz,1H),7.94(dd,J=8.4,2.4Hz,1H),7.82(d,J=8.4Hz,1H),6.82(br,1H),6.79 (d,J=8.8Hz,1H),6.52(d,J=2.8Hz,1H),6.31(br,1H),5.10(s,1H),3.82-3.70(m,4H),3.68- 3.55(m,4H),2.61-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.49(s,6H).

[0139] Example 6: 2-(6-(6-((6-(3-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 28) [ka]

[0140] First step: 5-(1,3-dioxolan-2-yl)-2-(5-methyl-1H-pyrazol-1-yl)pyridine (compound 28b) Compound 28a (785 mg), 16a (2000 mg), N,N'-dimethylethylenediamine (766 mg), CuI (1660 mg) and Cs2CO3 (8500 mg) are added to DMF (50 mL) and heated to 110 °C under nitrogen protection for 12 h. After the reaction is completed, it is cooled to room temperature, water is added to the reaction liquid to stop the reaction, and it is extracted with EA. The organic phase is combined and washed with water, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA = 7:3) to obtain compound 28b (2010 mg). MS m / z (ESI): 232.1 [M + H] + It is.

[0141] Second step: 5-(1,3-dioxolan-2-yl)-2-(3-fluoro-5-methyl-1H-pyrazol-1-yl)pyridine (compound 28c) Compound 28b (600 mg) is added to anhydrous THF (30 mL), cooled to -70 ° C, and under nitrogen protection, 1.6 mL of 2.5 M n-butyllithium THF solution is added dropwise, and then reacted at -70 ° C for 1 h. Then, N-fluorobisbenzenesulfonamide THF solution (30 mL) is added dropwise, and after the addition is completed, the reaction is continued at -70 ° C for 12 h. After the reaction is completed, water is added to the reaction solution to stop the reaction, and the reaction is extracted with EA, the organic phase is combined and washed with water, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and separated and purified by silica gel column chromatography (PE:EA = 17:3) to obtain compound 28c (80 mg). MS m / z (ESI): 250.1 [M + H] + It is.

[0142] Third step: 6-(3-fluoro-5-methyl-1H-pyrazol-1-yl)nicotinaldehyde (compound 28d) Concentrated hydrochloric acid (12N, 2mL) was added dropwise to a mixture of compound 28c (80mg) in THF (2mL) and water (2mL), and the mixture was reacted at room temperature for 8h. The pH of the reaction solution was adjusted to 10 or less with saturated K2CO3 solution, and then the mixture was extracted with EA. The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH=9:1) to obtain compound 28d (55mg). MS m / z(ESI):206.1[M+H] + It is.

[0143] Fourth step: 2-(6-(6-((6-(3-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 28) Compound 1g (30 mg) and compound 28d (20 mg) are dissolved in DMAC (1 mL), reacted at room temperature for 1 h, then NaBH(OAc)3 (70 mg) is added and reacted at room temperature for 12 h. After the reaction is completed, the reaction solution is diluted with ethyl acetate, the organic phase is washed with an aqueous K2CO3 solution, the organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and separated and purified by flash column chromatography to obtain compound 28 (8 mg). MS m / z (ESI): 552.3 [M+H] + It is.

[0144] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),8.45-8.4 2(m,2H),7.97(dd,J=8.4,2.4Hz,1H),7.66(d,J=8.4Hz,1H),6.84(br,1H),6.78(d,J =9.2Hz,1H),6.32(br,1H),6.08(d,J=5.2Hz,1H),3.78-3.70(m,4H),3.65-3.56(m,4 H),2.60-2.54(m,1H),2.33(s,3H),2.25(s,3H),2.21(s,3H),1.59(d,J=8.4Hz,1H).

[0145] Example 7: 2-(6-(6-((6-(furan-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 29) [ka]

[0146] First step: 6-(furan-2-yl)nicotinaldehyde (29b) Add 29a (312 mg), 1h (200 mg), Na2CO3 (341 mg,), Pd(PPh3)4 (62 mg), 1,4-dioxane (10 mL) and water (2.5 mL) to a round-bottom flask, and heat to 95 °C under nitrogen protection for 2 h. After the reaction is complete, cool to room temperature and separate and purify by flash silica gel column chromatography (PE:EA = 87%:13%) to obtain compound 29b (150 mg). MS m / z (ESI): 174.2 [M + H] + It is.

[0147] Second step: Preparation of 2-(6-(6-((6-(furan-2-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 29) Compound 1g (30 mg) and compound 29b (21 mg) are added to DMA (1 mL) and reacted at room temperature for 2 hours, then NaBH(OAc)3 (70 mg) is added and reacted at room temperature for 16 hours. After the reaction is complete, the product is directly separated and purified by Prep-HPLC to obtain compound 29 (30 mg). MS m / z (ESI): 520.3 [M+H] + It is.

[0148] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),9.66(s,1H),9.12(d,J=2.0Hz,1H),8.52(d,J=1.6Hz,1H) ,8.44(dd,J=9.2,2.4Hz,1H),7.87-7.78(m,2H),7.67(d,J=8.0Hz,1H),7.07(dd,J=3.2,0.4Hz, 1H),6.83(br,1H),6.78(d,J=9.2Hz,1H),6.64(dd,J=3.2,2.0Hz,1H),6.31(br,1H),3.82‐3.69 (m,4H),3.65-3.47(m,4H),2.59-2.53(m,1H),2.33(s,3H),2.26(s,3H),1.59(d,J=8.4Hz,1H).

[0149] Example 8: Fumarate salt of 2-(4-fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (Compound 30-A) [ka]

[0150] First step: 4-fluoro-3-iodo-1H-pyrazole (30b) Compound 30a (3.0 g) is dissolved in chloroform (50 mL), NIS (8.36 g) is added, and the mixture is heated to 80° C. under nitrogen protection and reacted overnight. After the reaction is completed, the mixture is cooled to room temperature, water (60 mL) is added to the reaction solution to stop the reaction, and the mixture is extracted with EA (30 mL x 3). The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 7:1) to obtain compound 30b (720 mg). MS m / z (ESI): 213.0 [M + H] + It is.

[0151] Second step: 5-(1,3-dioxolan-2-yl)-2-(4-fluoro-3-iodo-1H-pyrazol-1-yl)pyridine (30c) Compound 16a (705 mg) and 30b (500 mg) are dissolved in DMF (10 mL), Cs2CO3 (1.75 g) is added, and the mixture is heated to 110°C under nitrogen protection for 16 h. After the reaction is completed, the mixture is cooled to room temperature, water (60 mL) is added to the reaction solution to quench the reaction, and the mixture is extracted with EA (30 mL x 3). The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 9:1) to obtain compound 30c (720 mg). MS m / z (ESI): 361.9 [M + H] + It is.

[0152] Third step: methyl 1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-4-fluoro-1H-pyrazole-3-carboxylate (30d) Compound 30c (250 mg) was dissolved in DCM (15 mL), MeONa (160 mg), methyl formate (721 mg) and Pd(PPh3)2Cl2 (83 mg) were added in that order, and the mixture was heated to 35°C under nitrogen protection for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated, and purified by silica gel column chromatography (PE:EA=5:1) to obtain compound 30d (150 mg). MS m / z (ESI): 294.1 [M+H] + It is.

[0153] Fourth step: 2-(1-(5-(1,3-dioxolan-2-yl)pyridin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-ol (30e) Compound 30d (180 mg) is added to dry THF (15 mL), cooled in a dry ice ethanol bath at -78 °C for 15 min, and then MeMgBr ether solution (3N, 0.95 mL) is slowly added dropwise. After the addition is completed, the mixture is kept warm for 15 min and then warmed to room temperature for 4 h. After the reaction is completed, the reaction solution is quenched by adding saturated aqueous ammonium chloride solution (1 mL), diluted with water (30 mL), and extracted with EA (30 mL x 3). The organic phases are combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain crude compound 30e (145 mg), which is used directly in the next step reaction without further purification. MS m / z (ESI): 294.2 [M + H] + It is.

[0154] Fifth step: 6-(4-fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)nicotinaldehyde (30f) Compound 30e (300 mg) was dissolved in THF (5 mL), hydrochloric acid (2N, 15 mL) was added, and the mixture was reacted in an ice bath for 2 h. Saturated aqueous NaHCO3 was added to the reaction mixture to adjust the pH to 7-8, and the mixture was extracted with EA (30 mL x 3). The organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (PE:EA = 3:1) to obtain compound 30f (200 mg). MS m / z (ESI): 250.1 [M + H] + It is.

[0155] Sixth step: 2-(4-fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 30) Compound 1g (46 mg) and compound 30f (45 mg) are dissolved in DMA (1 mL), and reacted at room temperature for 1 h under nitrogen gas atmosphere, then NaBH(OAc)3 (101 mg) is added, and the reaction is continued overnight at room temperature. After the reaction is completed, water (60 mL) is added to the reaction solution to stop the reaction, and the reaction is extracted with EA (30 mL x 3). The organic phases are combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure, and separated and purified by Prep-HPLC to obtain compound 30 (10 mg). MS m / z (ESI): 596.3 [M + H] + It is.

[0156] Seventh step: Fumaric acid salt of 2-(4-fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl)propan-2-ol (compound 30-A) Compound 30 (117 mg, 0.19 mmol) was dissolved in THF (4.0 mL), and then fumaric acid (46 mg, 0.39 mmol) was added and stirred overnight at room temperature under nitrogen gas protection. After the reaction was completed, the mixture was filtered and washed with THF, and 115 mg of fumarate salt was obtained after vacuum drying.

[0157] 1 H NMR(400MHz,DMSO-d6)δ12.73(br,2H),9.66(br,1H),9.12(d,J=2.4Hz,1H),8.56(d,J=4.8Hz,1H), 8.44(dd,J=8.8,2.4Hz,1H),8.37(d,J=2.0Hz,1H),7.96(dd,J=8.4,2.4Hz,1H),7.81(d,J=8.4Hz,1H ),6.83(br,1H),6.78(d,J=8.8Hz,1H),6.62(s,2H),6.30(br,1H),5.24(s,1H),3.79-3.72(m,4H), 3.64-3.58(m,4H),2.59-2.54(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J=8.4Hz,1H),1.54(s,6H).

[0158] Example 9: 2-(6-(6-((5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 31) [ka]

[0159] First step: 2-(6-(6-((5-chloropyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (31b) Compound 1g (150 mg) and compound 31a (71 mg) were dissolved in DMAC (5 mL), and reacted at room temperature for 1 h, followed by addition of NaBH(OAc)3 (351 mg), and continued to react at room temperature for 12 h. After the reaction was completed, ethyl acetate was added to dilute the reaction solution, and the organic phase was washed with an aqueous K2CO3 solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by Prep-TLC (DCM:MeOH=15:1) to obtain compound 31b (110 mg). MS m / z (ESI): 489.2 [M+H] + It is.

[0160] Second step: 2-(6-(6-((5-(4-fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (compound 31) Compound 31b (30 mg) and compound 30a (106 mg) are dissolved in DMF (1.5 mL), Cs2CO3 (60 mg) is added, and the mixture is heated to 90°C and stirred for 1 h. After the reaction is completed, the mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, and the organic phase is dried over anhydrous sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure and separated and purified by Prep-HPLC to obtain compound 31 (30 mg). MS m / z (ESI): 539.3 [M+H] + It is.

[0161] 1H NMR(400MHz,DMSO-d6)δ11.99(s,1H),9.66(s,1H),9.12(d,J=2.4Hz,1H),9.09(d,J=1.6 Hz,1H),8.72(dd,J=4.8,0.8Hz,1H),8.56(d,J=1.2Hz,1H),8.44(dd,J=8.8,2.0Hz,1H),8 .03(d,J=4.0Hz,1H),6.85(br,1H),6.78(d,J=9.2Hz,1H),6.33(br,1H),3.87-3.75(m,6H ),3.65-3.52(m,2H),2.57-2.52(m,1H),2.33(s,3H),2.26(s,3H),1.61(d,J=8.4Hz,1H).

[0162] Separation method: Except for compound 28 in Example 6, which was separated and purified by Biotage MPLC, the prep-HPLC purification of the compounds in the other Examples was carried out by Aglient 1260 model, Waters 2489 model or GeLai 3500 model HPLC, the column temperature was 25°C, the detection wavelength was 214nm, 254nm or 280nm, and other separation conditions were as shown in the table below.

[0163] [Table 4]

[0164] Biological evaluation Experimental example 1: RET inhibition experiment Experimental method: According to the instructions of the HTRF KinEASE-TK kit (Cisbio), the inhibitory effect of the compounds of the present invention on the activity of drug-resistant mutant RET enzymes (RET-G810R, RET-G810S and RET-G810C) was measured. Three drug-resistant mutant RET enzymes and different concentrations of test compounds (in the compound inhibition rate test, the compound concentrations are 300 and 1000 nM for RET-G810R and RET-G810C, and 30 and 300 nM for RET-G810S. The IC 50In the test, the compound concentrations for RET-G810R and RET-G810C were 1-10000nM, and for RET-G810S, the compound concentrations were 0.1-10000nM, with 9 different concentrations in each case. ) was pre-incubated at room temperature for 30min, and then the substrate and adenosine triphosphate (ATP) were added to initiate the reaction. RET-G810R and RET-G810S were incubated at room temperature for 90min, and RET-G810C was incubated at room temperature for 120min. TK antibody-cryptate and streptavidin-XL665 were added, and detection was performed after incubation at room temperature for 60min. The solvent group (DMSO) was used as the negative control, and the buffer group (without RET enzyme) was used as the blank control, and the relative inhibitory activity percentage (i.e., inhibition rate) of the compounds at different concentrations was calculated according to the following formula:

[0165] Relative inhibitory activity percentage = 1-(different concentrations of compounds-blank control) / (negative control-blank control)*100% The percentage relative inhibitory activity of different concentrations of compounds was plotted against compound concentration and the curves were fitted according to a four-parameter model and the IC was calculated by the following equation: 50 values ​​were calculated.

[0166] y=min+(max-min) / (1+(x / IC 50 )^(-Hillslope)) In the formula, y is the percentage relative inhibitory activity, max and min are the maximum and minimum values ​​of the fitting curve, respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve.

[0167] The experimental results are shown in Tables 1 to 7.

[0168] [Table 5]

[0169] [Table 6] As is clear from Tables 1 and 2, the compounds of the present invention have a significant inhibitory effect on the RET-G810R enzyme.

[0170] [Table 7]

[0171] [Table 8] As is clear from Tables 3 and 4, the compounds of the present invention have a significant inhibitory effect on the RET-G810S enzyme.

[0172] [Table 9]

[0173] [Table 10]

[0174] As is clear from Tables 5 and 6, the compounds of the present invention have a significant inhibitory effect on the RET-G810C enzyme.

[0175] [Table 11]

[0176] As is clear from Table 7, compound 1-A of the present invention has a significant inhibitory effect on the RET-G810R enzyme, the RET-G810S enzyme and the RET-G810C enzyme.

[0177] Experimental Example 2: Growth inhibition of three compounds against RET(G810) mutant cells Objective of the experiment: Three BaF3 cell lines (Ba / F3 KIF5B-RET G810R , Ba / F3 KIF5B-RET G810S , Ba / F3 KIF5B-RET G810CThe in vitro growth inhibitory effects of compounds against .

[0178] Experimental method: Three Ba / F3 cells in logarithmic growth phase (Ba / F3 KIF5B-RET G810R , Ba / F3 KIF5B-RET G810S , Ba / F3 KIF5B-RET G810C ) are collected and inoculated into a 96-well plate at 2000 cells / 95μl / well. 5μl of BLU-667, Loxo-292 and compound 1-A solutions are added to the 96-well plate (final concentration: 1.52-10000nM), and negative control wells (no test compound added) and blank control wells (no cells added) are also set up. After culturing for 3 days at 37℃ and 5%CO2, 50μl / well of Cell Titer Glo reagent is added, the cells are dissolved, and the luminescence signal value is detected with a microplate reader to calculate the inhibition rate%.

[0179] Inhibition rate % = [1-(average detection signal of compound group-average signal of blank control) / (average signal of negative control-average signal of blank control)]*100%. The inhibition rate % was fitted using the four-parameter equation "log(agonist) vs response-variable slope(four parameters)" in GraphPad Prism 6.0, and the IC 50 was calculated.

[0180] Experimental results: As shown in Table 8, the results show that compound 1-A Ba / F3 KIF5B-RET G810R , Ba / F3 KIF5B-RET G810S , Ba / F3 KIF5B-RET G810C The cell proliferation inhibitory effects of both are superior to those of BLU-667 and Loxo-292.

[0181] [Table 12]

[0182] Experimental Example 3: Efficacy test of compounds in mice Purpose of the experiment: Ba / F3 KIF5B-RET G810R The in vivo efficacy of the compounds is studied in a subcutaneous tumor-bearing BALB / c nude mouse model.

[0183] Preparation of drugs: Compound 1-A, BLU-667, and Loxo-292 are prepared as homogeneous suspensions in 0.5% methylcellulose (MC) and administered PO (intragastric infusion) or BID.

[0184] Tumor measurements: Tumor diameters were measured twice weekly with a caliper. Tumor volume was calculated as V = 0.5 × a × b 2 where a and b indicate the long and short diameters of the tumor, respectively. The tumor-inhibiting therapeutic effect of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1-(mean tumor volume at the end of administration in the drug group-mean tumor volume at the start of administration in the drug group)) / (mean tumor volume at the end of treatment in the solvent control group-mean tumor volume at the start of treatment in the solvent control group)] x 100%. The results are shown in Table 9 and Figure 1.

[0185] Statistical analysis: Statistical analysis was performed using Prism Graphpad 8.0 software based on relative tumor volume at the end of the experiment. Comparisons between two groups and between groups were analyzed by two-way ANOVA, and p<0.05 was considered as significant.

[0186] Experimental results: No mice died in the experiment. Ba / F3 KIF5B-RET G810R In the model, at the equivalent dose of 30 mg / kg, the tumor growth inhibition rates (TGI (%)) of compound 1-A and the control compounds BLU-667 and Loxo-292 were 72.37%, 29.78% and 2.69%, respectively, indicating that the tumor inhibition effect of compound 1-A is superior to that of the control compounds BLU-667 and Loxo-292, with p<0.05 for both the control compounds BLU-667 and Loxo-292.

[0187] [Table 13]

[0188] The above examples do not limit the solution of the present application. In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the above description. Such modifications are also intended to be included within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. Formula I: 【Chemistry 1】 (where: R １ is selected from a 4- to 10-membered heterocyclyl group and a 5- to 10-membered heteroaryl group, each of the heterocyclyl and heteroaryl groups being independently selected from a hydroxy group, a halogen, CN, NO ２ , C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Hydroxyalkyl group, C １－４ Haloalkoxy group, C １－４ Heteroalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; R ２ is halogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ a heteroalkyl group, a 4- to 10-membered heterocyclyl group, and a 5- to 10-membered heteroaryl group, wherein the alkyl group, the heteroalkyl group, the heterocyclyl group, and the heteroaryl group are each independently selected from a hydroxy group, a halogen, CN, NO ２ , C １－４ Alkyl group, C １－４ Haloalkyl group, C １－４ Hydroxyalkyl group, C １－４ Haloalkoxy group, C １－４ Heteroalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; R ３ H, halogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－４ Hydroxyalkyl group, C １－４ Heteroalkyl group and C ３－６ cycloalkyl groups, and X １ , X ２ and X ３ are each independently selected from CH and N. or a stereoisomer, tautomer or mixture thereof, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotope derivative, metabolite, or prodrug of said compound, for treating or aiding in the treatment of a disease or condition associated with a RET drug resistance mutation in an individual.

2. The pharmaceutical composition described in claim 1, wherein the RET drug resistance mutation is one or more mutations selected from a RET solvent front mutation and a RET hinge region mutation.

3. The pharmaceutical composition described in claim 1 or 2, wherein the RET drug resistance mutation is one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A.

4. The disease or condition associated with drug-resistant mutation of RET is a drug-resistant disease, preferably a drug-resistant cancer or tumor or irritable bowel syndrome, the cancer or tumor is, for example, an advanced cancer or tumor or a metastatic cancer or tumor, the cancer or tumor is preferably lung cancer (e.g., non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphatic cancer, thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), colon cancer, multiple myeloma, melanoma, glioma, brain tumor or sarcoma; Preferably, the drug-resistant disease is a disease resistant to selpercatinib and / or pralsetinib, Preferably, the drug-resistant disease is non-small cell lung cancer (e.g., RET fusion-positive non-small cell lung cancer), medullary thyroid cancer, or the like that is drug-resistant to selpercatinib and / or pralsetinib. The pharmaceutical composition according to any one of claims 1 to 3, wherein the cancer is cancer (e.g., advanced or metastatic medullary thyroid cancer) or thyroid cancer (e.g., advanced or metastatic RET fusion-positive thyroid cancer).

5. A pharmaceutical composition for regulating (e.g. reducing or inhibiting) aberrant RET activity associated with RET drug resistance mutations (e.g. one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A), comprising a compound of formula I as defined in any one of claims 1 to 3, a stereoisomer, a tautomer or a mixture thereof of said compound, an N-oxide of said compound, a pharma- ceutically acceptable salt, co-crystal, polymorph or solvate of said compound, or a stable isotope derivative, metabolite or prodrug of said compound.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein said RET drug resistance mutation is a RET solvent front mutation, such as a 810 mutation, preferably a G810 mutation.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the RET drug resistance mutation is one or more mutations selected from G810R, G810S and G810C.

8. The pharmaceutical composition according to claim 7 , wherein the RET drug resistance mutation is a G810R mutation.

9. The pharmaceutical composition according to claim 7 , wherein the RET drug resistance mutation is a G810S mutation.

10. The pharmaceutical composition according to claim 7 , wherein the RET drug resistance mutation is a G810C mutation.

11. R １ is a 5-10 membered heteroaryl group, the heteroaryl group being independently selected from hydroxy, halogen, CN, C １－４ Alkyl group, C １－４ Haloalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; Preferably, R １ is a 5-6 membered heteroaryl group, the heteroaryl group being independently selected from halogen, C １－３ Alkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkyl groups; Preferably, R １ are pyrazolyl groups, each of which is independently selected from halogen, C １－３ Alkyl groups (e.g., methyl groups) and C ３－６ Optionally substituted with one or more substituents selected from cycloalkyl groups (e.g., cyclopropyl groups); Preferably, R １ is a pyrazolyl group substituted with a methyl group (e.g., 5-methyl-1H-pyrazolyl-3-yl or 1-methyl-1H-pyrazolyl-4-yl) or a pyrazolyl group substituted with a cyclopropyl group (e.g., 5-cyclopropyl-1H-pyrazolyl-3-yl).

12. R ２ is halogen (e.g. Cl), C １－６ alkyl groups (e.g., methyl groups) and 5-6 membered heteroaryl groups, each of which is independently selected from halogen, C １－４ Alkyl group, C １－４ Hydroxyalkyl group, C １－４ Heteroalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; Preferably, R ２ is a 5-6 membered heteroaryl group, the heteroaryl group being independently selected from halogen, C １－４ Alkyl group, C １－４ Hydroxyalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; Preferably, R ２ is a 5-membered heteroaryl group, the heteroaryl group being independently selected from halogen, C １－４ Alkyl group, C １－４ Hydroxyalkyl group, C ３－６ Cycloalkyl group and C ３－６ Optionally substituted with one or more substituents selected from cycloalkoxy groups; Preferably, R ２ are pyrrolyl, pyrazolyl, imidazolyl, furyl or thiazolyl groups, each of which is independently F, Cl, a methyl group, 【Chemistry 2】 12. The pharmaceutical composition according to any one of claims 1 to 11, optionally substituted with one or more substituents selected from: -, -cyclopropyl and -O-cyclopropyl groups.

13. R ３ is H, C １－６ Alkyl group and C ３－６ cycloalkyl groups, Preferably, R ３ is H and C １－６ alkyl groups, Preferably, R ３ The pharmaceutical composition according to any one of claims 1 to 12, wherein is H or a methyl group.

14. X １ is CH or N, preferably X １ is N, X ２ is CH or N, preferably X ２ is CH, and / or X ３ is CH or N, preferably X ３ The pharmaceutical composition according to any one of claims 1 to 13, wherein is N.

15. The compound has the structure shown in formula IA or IB, 【Chemistry 3】 R １ , R ２ , R ３ , X １ and X ２ The pharmaceutical composition according to any one of claims 1 to 14, wherein:

16. The compound is 【Chemistry 4】 【Chemistry 5】 The pharmaceutical composition according to any one of claims 1 to 15, wherein the pharmaceutical composition is selected from the group consisting of

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharma- ceutically acceptable salt is a fumarate salt.

18. The compound is 【Chemistry 6】 The pharmaceutical composition according to any one of claims 1 to 17,

19. Pharmaceutically acceptable salts of the compounds include 【Chemistry 7】 The pharmaceutical composition according to any one of claims 1 to 18,

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