CN111285882A

CN111285882A - Fused ring compound, pharmaceutical composition containing same, and preparation method and application thereof

Info

Publication number: CN111285882A
Application number: CN201811500391.8A
Authority: CN
Inventors: 孙启正; 李桂英; 陈忠辉; 韩润丰; 王太津; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-12-07
Filing date: 2018-12-07
Publication date: 2020-06-16
Anticipated expiration: 2038-12-07
Also published as: CN111285882B

Description

Fused ring compound, pharmaceutical composition containing same, and preparation method and application thereof

Technical Field

The present invention relates to fused ring compounds, pharmaceutical compositions comprising the same, methods of making the same, and their use for preventing or treating diseases or conditions associated with RET activity.

Background

Protein kinase is an enzyme that catalyzes protein phosphorylation reactions. By mediating cell signaling processes, protein phosphorylation regulates cell physiological activities 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, diabetes and the like.

RET (recovered reduced transfection) is a proto-oncogene, and the encoded RET protein is a transmembrane receptor type tyrosine protein kinase and is composed of three parts, namely a cysteine-rich cadherin-like extracellular region (for binding a ligand), a transmembrane region and an intracellular structural region with tyrosine kinase activity. The activated RET protein can activate multiple downstream signaling pathways, including the RAS/RAF/ERK pathway, PI3K/Akt pathway, JNK pathway, leading to cell proliferation, migration and differentiation. RET gene alteration (mutation or fusion) and abnormal expression of wild-type RET gene lead to abnormal activation of RET protein, signaling pathway hyperactivity, which is one of the major mechanisms of carcinogenesis. The abnormally activated RET protein participates in the proliferation and invasion of different tumor cells through a plurality of signal paths, thereby influencing the occurrence and development of tumors. RET gene change has more obvious effect on downstream cascade reaction, wherein RET gene mutation is mainly related to medullary thyroid carcinoma and papillary thyroid carcinoma, and RET gene fusion is mainly related to non-small cell lung cancer and chronic myelocytic leukemia. Therefore, inhibition of RET activity is of great medical value (Naturereviews Cancer, 2014, 14 (3): 173-86).

RET inhibitors have great potential for the treatment and prevention of a variety of diseases (e.g., tumors, irritable bowel syndrome). At present, 2 compounds are in clinical stage, and compounds of multiple companies are in preclinical research stage, however, no inhibitor with RET as main target is on the market at present.

Disclosure of Invention

The present invention provides fused ring compounds having good inhibitory effect on RET, and having excellent properties such as good physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life and duration of action), improved safety (less toxicity and/or fewer side effects, wider therapeutic window), and the like.

Some aspects of the invention provide a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has a structure of formula (I-a) or formula (I-B):

wherein:

represents a single bond or a double bond;

ring A, ring B and ring C are each independently selected from C_6-12Aromatic rings, 4-10 membered heterocycles and 5-10 membered heteroaromatics;

X¹is CR⁵Or N;

X²is CR⁷Or N;

X³、X⁴and X⁸Each of which isIndependently selected from C and N;

X⁵is C, CR⁸Or N; when X is present⁵Is CR⁸Or N, which does not form a double bond with the adjacent C in the ring; when X is present⁵When C is C, it forms a double bond with an adjacent C in the ring;

X⁶is CR⁹Or N;

X⁷is CR¹⁰Or N;

R¹、R²and R⁴Each occurrence independently selected from hydroxy, halogen, CN, NO₂、C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-SR²¹、-S(＝O)R²²、-S(＝O)₂R²²、-S(＝O)NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25bWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with C_6-12Aryl or 5-10 membered heteroaryl fused;

R³each occurrence is independently selected from hydroxy, halogen, CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a When t is greater than 1, two R³Optionally together with the group to which they are attached form C_3-6Cycloalkyl or 4-10 membered heterocyclyl;

R⁵、R⁷and R¹⁰Each independently selected from H, hydroxy, halogen,CN、C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹；

R⁸And R⁹Each independently selected from H, hydroxy, halogen, CN, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹and-SR²¹；

R^20a、R^20b、R^23a、R^23b、R^24a、R^25aAnd R^25bEach independently selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl; or R^20aAnd R^20b、R^23aAnd R^23bAnd/or R^25aAnd R^25bTogether with the group to which they are attached form a 3-8 membered heterocyclyl;

R²¹selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl;

R²²selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl;

l is selected from C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene radical, C_2-6Alkynylene group,

R^6a、R^6bAnd R^6cEach independently selected from H, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl;

R^6dselected from H, hydroxy, amino, CN, C_1-6Alkyl radical, C_1-6Haloalkyl, C_1-6Heteroalkyl group, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl;

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3;

t is 0, 1, 2 or 3;

z is 0, 1 or 2

m is 0 or 1;

n is 0 or 1;

the above alkyl, alkylene, heteroalkyl, heteroalkylene, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, heterocycle, heterocyclyl, aryl, heteroaryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^30aR^30b、-OR³¹、-SR³¹、-S(＝O)R³²、-S(＝O)₂R³²、-S(＝O)NR^30aR^30b、-S(＝O)₂NR^30aR^30b、-NR^30aS(＝O)R^30b、-NR^30aS(＝O)₂R^30b、-C(＝O)NR^33aR^33b、-NR^33aC(＝O)R^33b、-OC(＝O)NR^33aR^33b、-NR^34aC(＝O)NR^35aR^35bWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with C_6-12Aryl or 5-10 membered heteroaryl fused; and R is^30a、R^30b、R³¹、R³²、R^33a、R^33b、R^34a、R^35aAnd R^35bEach independently selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.

Another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RET activity.

Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of a disease or condition associated with RET activity.

Another aspect of the present invention provides a method of preventing or treating a disease or condition associated with RET activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

Another aspect of the invention provides a process for preparing a compound of the invention.

Definition of

Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C_1-8Alkyl group "," C_1-6Alkyl "and" C_1-4Alkyl "refers to a linear or branched group having 1 to 8 carbon atoms, 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), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents such as halogen (when the group is referred to as" haloalkyl ") (e.g., CH)₂F、CHF₂、CF₃、CCl₃、C₂F₅、C₂Cl₅、CH₂CF₃、CH₂Cl or-CH₂CH₂CF₃Etc.). The term "C_1-4Alkyl "refers to a linear 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). The term "alkylene" denotes a corresponding divalent radical, including, for example, "C_1-8Alkylene group "," C_1-6An alkylene group "-,“C_1-4Alkylene "and the like, specific examples include, but are not limited to: methylene (-CH)₂-) ethylene (-CH₂CH₂-) propylene (-CH)₂CH₂CH₂-) isopropylidene (-CH (CH)₃)CH₂-), butylene, pentylene, hexylene, and the like. The alkylene group is optionally substituted with one or more (such as 1 to 3) substituents which may be the same or different.

As used herein, the term "heteroalkyl" refers to an optionally substituted alkyl having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Can give a range of values (e.g. C)_1-6Heteroalkyl) refers to the number of carbons in the chain, including from 1 to 6 carbon atoms in this example. For example, -CH₂OCH₂CH₃The radical being designated C₃A heteroalkyl group. The attachment to the rest of the molecule may be through a heteroatom or carbon in the heteroalkyl chain.

As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, the term "C_1-8Haloalkyl "," C_1-6Haloalkyl "and" C₁₄Haloalkyl "refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, e.g., -CF₃、-C₂F₅、-CHF₂、-CH₂F、-CH₂CF₃、-CH₂Cl or-CH₂CH₂CF₃And the like.

As used herein, the term "hydroxyalkyl" refers to a group formed by replacement of a hydrogen atom in an alkyl group with one or more hydroxyl groups, e.g., C_1-4Hydroxyalkyl or C_1-3Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH₃And the like.

As used herein, the term "alkoxy" means a group, preferably C, that has an oxygen atom inserted at any reasonable position in the alkyl group (as defined above), and is preferably_1-8Alkoxy radical, C_1-6Alkoxy radical, C_1-4Alkoxy or C_1-3An alkoxy group. C_1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH₂-OCH₃Etc., said alkoxy being optionally substituted with one or more (such as 1 to 3) same or different substituents.

As used herein, the term "alkyleneoxy" refers to a divalent alkoxy group, such as-OCH₂-、-OCH(CH₃)CH₂-、-OCH₂CH₂O-、-CH₂CH₂O-, etc., said alkyleneoxy groups being optionally substituted with one or more (such as 1 to 3) same or different substituents.

As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having from 2 to 6 carbon atoms ("C)_2-6Alkenyl "). Said alkenyl is, for example, -CH ═ CH₂、-CH₂CH＝CH₂、-C(CH₃)＝CH₂、-CH₂-CH＝CH-CH₃2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the invention contain an alkenyl group, the compounds may be present in pure E (entgegen) form, in pure Z (ipsilateral (zusammen)) form or in any mixture thereof. The term "alkenylene" is a corresponding divalent radical, including, for example, "C_2-6Alkenylene group and C_2-4Alkenylene "and the like, specific examples of which include, but are not limited to: -CH ═ CH-, -CH₂CH＝CH-、-C(CH₃) CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene, and the like.

As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. The alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents which may be the same or different. The term "alkynylene group"is a corresponding divalent radical, including, for example," C_2-8Alkynylene group and C_2-6Alkynylene group and C_2-4Alkynylene "and the like. Examples include, but are not limited to

Etc., said alkynylene group being optionally substituted with one or more (such as 1 to 3) same or different substituents.

As used herein, the term "fused ring" refers to a ring system formed from two or more ring structures that share two adjacent atoms with each other.

As used herein, the term "spiro" refers to a ring system formed from two or more cyclic structures that share a ring atom with each other.

As used herein, the term "bridged ring" refers to a ring system formed from two or more cyclic structures that share two atoms not directly attached to each other.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including, but not limited to, monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicycloalkyl, including spirocyclic, fused (fused) or bridged ring systems (i.e., spirocycloalkyl, fused (fused) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1]Pentyl, bicyclo [2.2.1]Heptyl, etc.). In the present invention, cycloalkyl is optionally substituted with one or more (such as 1 to 3) same or different substituents. The carbon atom on the cycloalkyl group is optionally oxo (i.e., forming C ═ O). The term "C_3-8Cycloalkyl "refers to a cycloalkyl group having 3 to 8 ring-forming carbon atoms, e.g. C_3-6Cycloalkyl, which may be monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), and bicycloalkyl, such as C_5-8Spiro cycloalkyl, C_5-8Bridged cycloalkyl radical, C_5-8Condensed ring alkyl, C_5-6SpirocycloalkanesBase, C_5-6Bridged cycloalkyl radical, C_5-6A fused ring alkyl group.

As used herein, the term "heterocyclyl" or "heterocycle" refers to a monocyclic or polycyclic (e.g., bicyclic, spirocyclic, or bridged) group having 2 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, sulfur atoms, optionally oxo (oxo) groups (e.g., forming C O, S (═ O) or S (═ O)₂)。

As used herein, the term "3-14 membered heterocyclyl" means a heterocyclyl containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, said "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl", "sulfur-containing heterocyclyl" optionally also containing one or more other heteroatoms selected from oxygen, nitrogen, sulfur. Examples of 3-14 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl (dithianyl), thiomorpholinyl, piperazinyl, trithianyl (trithianyl), triazolyl, thiazolyl, triazolyl, and triazolyl,

And the like.

In the present invention, the heterocyclic group may form a heterocyclic group with a heterocyclic group or a cycloalkyl group, and the point of attachment of the heterocyclic group to other groups may be on any of the heterocyclic groups or the cycloalkyl group, and therefore, the heterocyclic group of the present invention also includes, but is not limited to, heterocyclo-heterocyclic groups, heterocyclo-cycloalkyl groups, mono-heterocyclo-mono-heterocyclic groups, mono-heterocyclo-mono-cycloalkyl groups, such as 3-7-membered (mono) heterocyclo-3-7-membered (mono) heterocyclic groups, 3-7-membered (mono) heterocyclo-mono-cycloalkyl groupsRadical, 3-7 membered (mono) heterocyclo C_4-6(mono) cycloalkyl, examples of which include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopent-aziridinyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinylpiperidinyl, pyrrolidinylpiperazinyl, piperidino-morpholinyl, pyrrolidinyl-piperazinyl, piperidinyl-piperidinyl, pyrrolidinyl-piperidinyl, piperidinyl,

In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.

As used herein, the term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed by two saturated rings sharing two ring atoms not directly connected, including, but not limited to, 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g.

And the like. The "nitrogen-containing bridged heterocyclic ring", "oxygen-containing bridged heterocyclic ring", "sulfur-containing bridged heterocyclic ring" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur.

As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur atoms) formed from two or more saturated rings sharing a ring atom, including, but not limited to, 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g.

Said "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-to 10-membered nitrogen-containing spiroheterocyclic group" means a spiroheterocyclic group containing a total of 6 to 10 ring atoms and in which at least one ring atom is a nitrogen atom.

Examples of the group obtained by fusing a heterocyclic group with an aryl group include, but are not limited to:

as used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C_6-12Aryl (aromatic ring) "means an aryl (aromatic ring) group containing 6 to 12 carbon atoms, preferably C_6-10Aryl (aromatic ring), preferably, phenyl or naphthyl. Aryl is optionally substituted by one or more (such as 1 to 3) identical or different substituents (e.g. halogen, OH, CN, NO)₂、C₁-C₆Alkyl, etc.).

As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more of the same or different heteroatoms, including monocyclic heteroaryl and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 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. The carbon and heteroatom of the heteroaryl group are optionally oxo (oxo) (e.g., to form C ═ O, S (═ O) or S (═ O)₂)。

As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaryl ring" means a heteroaryl (heteroaryl ring) group containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered monoheteroaryl, 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing monoheteroaryl, 5-6 membered oxygen-containing monoheteroaryl, 5-6 membered sulfur-containing monoheteroaryl. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", "sulfur-containing heteroaryl", "nitrogen-containing monoheteroaryl", "oxygen-containing monoheteroaryl", "sulfur-containing monoheteroaryl" are optionally substituted with one or more other heteroatoms selected from oxygen, nitrogen, sulfur. Examples thereof include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and 5-to 10-membered heterocyclic groups containing these groups.

In the present invention, a heteroaryl group (e.g., a monoheteroaryl group) may form a ring-merged structure with an aryl group (e.g., a monocyclic aryl group such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group), or another heteroaryl group (e.g., another monoheteroaryl group) sharing two adjacent atoms with each other, the point of attachment may be on any heteroaromatic ring or other ring, including but not limited to (mono) heteroarylo (mono) heteroaryl, (mono) heteroarylo (monocyclic) aryl, (mono) heteroarylo (mono) heterocyclyl, and (mono) heteroarylo (mono) cycloalkyl, for example, 5-6 membered (mono) heteroarylo 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylophenyl, 5-6 membered (mono) heteroarylo 5-6 membered (mono) heterocyclyl, or 5-6 membered (mono) heteroarylo C._4-6(Mono) cycloalkyl (e.g., 5-6 membered heteroarylbenzocyclobutyl, 5-6 membered heteroarylbenzocyclopentyl, 5-6 membered heteroarylbenzocyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, cyclohexyl, and the like,

And the like.

As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the current circumstances is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected optional substituent. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen is present) may each be replaced with an independently selected optional substituent.

If a substituent is described as being "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.

Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

The invention also includes all pharmaceutically acceptable isotopically-labeled compounds, which are identical to those 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 prevailing in nature. Adapted for inclusion in the present inventionExamples of isotopes in compounds include, but are not limited to, isotopes of hydrogen (e.g., deuterium (g), (b), (c), (d), (²H) Tritium (a)³H) ); isotopes of carbon (e.g. of¹¹C、¹³C and¹⁴C) (ii) a Isotopes of chlorine (e.g. of chlorine)³⁶Cl); isotopes of fluorine (e.g. of fluorine)¹⁸F) (ii) a Isotopes of iodine (e.g. of iodine)¹²³I and¹²⁵I) (ii) a Isotopes of nitrogen (e.g. of¹³N and¹⁵n); isotopes of oxygen (e.g. of¹⁵O、¹⁷O and¹⁸o); isotopes of phosphorus (e.g. of phosphorus)³²P); and isotopes of sulfur (e.g. of³⁵S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium³H) And carbon-14 (i.e.¹⁴C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type¹¹C、¹⁸F、¹⁵O and¹³n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D₂O, acetone-d₆Or DMSO-d₆。

The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) 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, a nitroso-oxime may exist in solution in equilibrium with the following tautomeric forms:

it is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

Solid lines may be used herein

Solid wedge shape

Or virtual wedge shape

Chemical bonds of the compounds of the present invention are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers (e.g., particular enantiomers, racemic mixtures, etc.) at that carbon atom are included. The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown are present. When present in a racemic mixture, solid and dotted wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerization and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

Cocrystals refer to pharmaceutically active molecules bound to other physiologically acceptable acid, base, salt, nonionic compound molecules in the same crystal lattice by hydrogen bonding, pi-pi stacking, van der waals forces, and other non-covalent bonds.

It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, meglumine salts and the like. For a review of suitable salts see Stahl and Wermuth, "Handbook of pharmaceutical salts: properties, Selection, and Use "(Wiley-VCH, 2002).

As used herein, the term "ester" means an ester derived from a compound of the respective general formula in the present application, including physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the compound of the invention in free acid or alcohol form). The compounds of the invention may themselves also be esters.

The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.

Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair is required for oxidation of the nitrogen to the oxide; one skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L.Gilchrist, Comprehensive organic Synthesis, vol.7, pp 748-; a.r.katitzky and a.j.boulton, eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-.

Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.

The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (t.higuchi and v.stella). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of Prodrugs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.

The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting Groups, such as those described in T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The term "about" means within. + -. 10%, preferably within. + -. 5%, more preferably within. + -. 2% of the stated value.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I-a) or formula (I-B):

wherein:

represents a single bond or a double bond;

X¹is CR⁵Or N;

X²is CR⁷Or N;

X³、X⁴and X⁸Each of which isIndependently selected from C and N;

X⁵is C, CR⁸Or N; with the proviso that when X⁵Is CR⁸Or N, which does not form a double bond with the adjacent C in the ring; when X is present⁵When C is C, it forms a double bond with an adjacent C in the ring;

X⁶is CR⁹Or N;

X⁷is CR¹⁰Or N;

R⁵、R⁷and R¹⁰Each independently selected from H, hydroxy,Halogen, CN, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹；

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3;

t is 0, 1, 2 or 3;

z is 0, 1 or 2

m is 0 or 1;

n is 0 or 1;

the above alkyl, alkylene, heteroalkyl, heteroalkylene, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, heterocycle, heterocyclyl, aryl, heteroaryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1.4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^30aR^30b、-OR³¹、-SR³¹、-S(＝O)R³²、-S(＝O)₂R³²、-S(＝O)NR^30aR^30b、-S(＝O)₂NR^30aR^30b、-NR^30aS(＝O)R^30b、-NR^30aS(＝O)₂R^30b、-C(＝O)NR^33aR^33b、-NR^33aC(＝O)R^33b、-OC(＝O)NR^33aR^33b、-NR^34aC(＝O)NR^35aR^35bWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with C_6-12Aryl or 5-10 membered heteroaryl fused; and is

R^30a、R^30b、R³¹、R³²、R^33a、R^33b、R^34a、R^35aAnd R^35bEach independently selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C₁-₆Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring a is a phenyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;

preferably, ring a is a benzene ring, a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, or a pyridine ring.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring B is a phenyl ring, a 6-membered heterocyclic ring, or a 6-membered heteroaromatic ring;

preferably, ring B is a benzene ring, a piperidine ring, an isoxazole ring, a pyridine ring, a pyrazine ring or a pyrimidine ring.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring C is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

preferably, ring C is a thiophene ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring or a pyridine ring.

In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, or pharmaceutically acceptable salt thereof,A solvate, N-oxide, isotopically-labelled compound, metabolite or prodrug, wherein X¹、X²、X⁶And X⁷Each independently CH, C-OMe or N.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein X is⁵C, CH or N.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein L is selected from the group consisting of

L is preferably

(e.g., -C (═ O) NH-),

(preferred is

)、

)；

L is more preferably

And is

L is most preferably

In some embodiments, R¹Selected from hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-SR²¹、-S(＝O)R²²、-S(＝O)₂R²²、-S(＝O)NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, heteroalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Heteroalkyl group, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R¹Selected from hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a It is composed ofWherein said alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Heteroalkyl group, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R¹Selected from halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy and C_1-3A haloalkoxy group.

In some embodiments, R¹Selected from F, Cl, CN and C_1-3Alkyl (e.g., methyl).

In some embodiments, R²Selected from hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Heteroalkyl group, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-SR²¹、-S(＝O)R²²、-S(＝O)₂R²²、-S(＝O)NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R²Selected from hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Heteroalkyl group, C_3-6Cycloalkyl, -NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, alkoxy, heteroalkyl, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R²Selected from halogen, CN, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Heteroalkyl group, C_3-6Cycloalkyl, -NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, alkoxy, heteroalkyl and ringEach alkyl group is optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy and C_1-3A haloalkoxy group;

in some embodiments, R²Selected from F, Cl, CN and C_1-3Alkyl (e.g., methyl).

In some embodiments, R³Selected from hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹。

In some embodiments, R³Is F, Cl, CN, OH, C_1-3Alkyl or C_1-3An alkoxy group.

In some embodiments, R⁴Selected from hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-SR²¹、-S(＝O)R²²、-S(＝O)₂R²²、-S(＝O)NR^20aR^20b、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6CycloalkanesA group, a 4-to 10-membered heterocyclic group, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R⁴Selected from hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R⁴Is selected from C_1-4Alkyl radical, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^20aR^20b、-OR²¹、-S(＝O)₂NR^20aR^20b、-NR^20aS(＝O)R^20b、-NR^20aS(＝O)₂R^20b、-C(＝O)NR^23aR^23b、-NR^23aC(＝O)R^23b、-OC(＝O)NR^23aR^23band-NR^24aC(＝O)NR^25aR^25b(ii) a Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R⁴Is C_1-4Alkyl radical, C_3-6Cycloalkyl (e.g., cyclopropyl), 4-10 membered heterocyclyl (e.g., oxetanyl, pyrrolidinyl), 5-6 membered heteroaryl (e.g., pyrazolyl, oxazolyl, imidazolyl, thiazolyl), -OR²¹(e.g. -OMe) or-NR^23aC(＝O)R^23b(e.g., -NHC (═ O) CH₃) Said alkyl, cycloalkyl, heterocyclyl and heteroaryl groups each being optionally substituted with one or more substituents selected from the group consisting of: F. cl, CN, C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy and C_1-3A haloalkoxy group.

In some embodiments, R⁵Selected from H, hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R⁵Selected from H, hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_3-6A cycloalkyl group.

In some embodiments, R⁵Selected from H, hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group;wherein said alkyl and alkoxy groups are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group.

In some embodiments, R⁵Is H, F, Cl, CN or C_1-3An alkoxy group.

In some embodiments, R⁷Selected from H, hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Heteroalkyl group, C_1-4Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

In some embodiments, R⁷Selected from H, hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_3-6A cycloalkyl group.

In some embodiments, R⁷Selected from H, hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group; wherein said alkyl and alkoxy groups are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group.

In some embodiments, R⁷Is H, F, Cl, CN or C_1-3An alkoxy group.

In some embodiments of the present invention, the substrate is,R⁸selected from H, hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_3-6A cycloalkyl group.

In some embodiments, R⁸Selected from H, hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group; wherein said alkyl and alkoxy groups are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group;

in some embodiments, R⁸Is H, F, Cl, CN, OH or C_1-3An alkoxy group.

In some embodiments, R⁹Selected from H, hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_3-6A cycloalkyl group.

In some embodiments, R⁹Is H, hydroxy, halogen, CN, C_1-3Alkyl or C_1-3An alkoxy group; wherein said alkyl and alkoxy groups are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group;

in some embodiments, R⁹Is H, F, Cl, CN, OH or C_1-3Alkoxy (e.g., methoxy).

In some embodiments, R¹⁰Selected from H, hydroxy, halogen, CN, C_1-3Alkyl radical, C_1-3Heteroalkyl group, C_1-3Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹(ii) a Wherein the alkyl, heteroalkyl, alkoxy, and cycloalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-3Alkyl radical, C_1-3Haloalkyl, C_1-3Alkoxy radical, C_1-3Haloalkoxy and C_3-6A cycloalkyl group.

In some embodiments, R¹⁰Is H, hydroxy, halogen, CN, C_1-3Alkyl or C_1-3An alkoxy group; wherein said alkyl and alkoxy groups are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-3Alkyl and C_1-3An alkoxy group;

in some embodiments, R¹⁰Is H, F, Cl, CN or C_1-3An alkoxy group.

In some embodiments, R^20a、R^20b、R^23a、R^23b、R^24a、R^25aAnd R^25bEach independently selected from H, C_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy and C_3-8A cycloalkyl group; or R^20aAnd R^20b、R^23aAnd R^23bAnd/or R^25aAnd R^25bTogether with the group to which they are attached form a 3-8 membered heterocyclyl; the alkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents selected from the group consisting of: OH, CN, halogen, NO₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Hydroxyalkyl radical, C_1-4Haloalkyl and C_1-4A haloalkoxy group.

In some embodiments, R^20a、R^20b、R^23a、R^23b、R^24a、R^25aAnd R^25bIs H or C_1-4An alkyl group.

In some embodiments, R²¹Selected from H, C_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl and 4-10 membered heterocyclyl; wherein said alkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents selected from the group consisting of: OH, halogen, CN, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy, C_3-6Cycloalkyl and 4-10 membered heterocyclyl.

In some embodiments, R²¹Is H or C_1-4An alkyl group.

In some embodiments, R²²Is selected from C_1-4Alkyl radical, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl and 4-10 membered heterocyclyl; wherein said alkyl, hydroxyalkyl, alkoxy, cycloalkyl and heterocyclyl are each optionally substituted with one or more substituents selected from the group consisting of: halogen, OH, CN, NO₂、C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl and C_1-4A haloalkoxy group.

In some embodiments, R²²Is C_1-4An alkyl group.

In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein R is a pharmaceutically acceptable salt of a pharmaceutically acceptable acid^6a、R^6bAnd R^6cEach independently selected from H, C_1-4Alkyl and C_1-4A heteroalkyl group; wherein the alkyl and heteroalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4A heteroalkyl group;

preferably, R^6a、R^6bAnd R^6cEach independently selected from H and C_1-4An alkyl group.

In some embodiments, the invention provides compoundsOr a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, wherein

Is selected from

Preferably, it is

Selected from:

in some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of any one of the following formulae:

wherein:

R^6ais H or C_1-4Alkyl, preferably H or Me;

R⁹is H OR-OR²¹(ii) a And is

R²¹Is C_1-4Alkyl, preferably Me.

Any combination of the above embodiments is encompassed by the present invention.

In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:

in some embodiments, the compounds of the invention are selected from:

preparation method

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 1):

wherein:

R^xis a carboxyl protecting group, preferably C_1-6Alkyl, more preferably methyl or ethyl;

R^yis C_1-4Haloalkylsulfonyl, preferably trifluoromethanesulfonyl;

r 'and R' are each independently H or C_1-6Alkyl, or R 'and R' together with the group to which they are attached form a 4-to 10-membered ring (e.g.

)；

Hal¹And Hal²Each independently is F, Cl, Br or I, preferably Cl;

the remaining groups are as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A1-1 with a bromine-containing reagent under alkaline conditions to generate a compound I-A1-2;

the bromine-containing reagent used is preferably CHBr₃Etc.; the alkali is inorganic alkali (NaOH or KOH) or organic alkali; the reaction solvent is MeOH, EtOH and the like; the reaction temperature is 0 ℃ to 80 ℃, preferably room temperature.

The second step is that: reacting the compound I-A1-2 under an acidic condition to generate a compound I-A1-3;

the acid is HCl or H₂SO₄P-toluenesulfonic acid, methanesulfonic acid, or the like; the reaction solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH₃CN, 1, 4-dioxane, toluene, etc.; the reaction temperature is 0 ℃ to 100 ℃.

The third step: reacting the compound I-A1-3 in the presence of a base and a sulfonylating agent to generate a compound I-A1-4;

the sulfonylating agent is, for example, PhNTf₂Or Tf₂O; the alkali is 2, 6-di-tert-butyl-4-methylpyridine, LiHMDS, LDA, NaHMDS, KHMDS,^tBuOK, NaH or NaOH, etc.; the reaction solvent is THF and CH₃CN, DCM, or DCE, etc.; the reaction temperature is-78 ℃ to 60 ℃.

The fourth step: reacting the compound I-A1-4 with a boron-containing reagent to generate a compound I-A1-5;

the boron-containing agent is, for example, B₂(pin)₂(ii) a The reaction is preferably carried out in the presence of a catalyst, Pd (PPh) as catalyst, and a base₃)₄、Pd(dppf)Cl₂、Pd(dppf)₂Cl₂DCM, etc., the base being Cs₂CO₃、K₃PO₄、Na₂CO₃、KOAc、NaHCO₃Or K₂CO₃Etc.; the reaction solvent is 1, 4-dioxane, DMF, DMSO or CH₃CN or any of the above solvents with H₂A mixed solvent of O, etc.; the reaction temperature is 20 ℃ to 120 ℃.

The fifth step: reacting the compound I-A1-6 with I-A1-7 in the presence of alkali to generate a compound I-A1-8;

the reaction is a substitution reaction or a coupling reaction;

the base used in the substitution reaction is^tBuONa、^tBuOK、^tBuOLi、Cs₂CO₃、DIPEA、LiHMDS、LDA、NaHMDS、KHMDS、K₃PO₄、Na₂CO₃、KOAc、NaHCO₃Or K₂CO₃Etc.; the reaction solvent is tert-butyl alcohol, toluene, xylene, THF, DME, dioxane, DMF, DMSO or NMP, etc.; the reaction temperature is 40 ℃ to 140 ℃.

The coupling reaction is preferably carried out in the presence of a catalyst, which is Pd (OAc), and a ligand₂、Pd2(dba)₃、Pd(dba)₂、PdCl₂、Pd(PPh₃)₄、Pd(dppf)Cl₂、Pd(acac)₂Or Pd (allyl)₂Etc., the ligand is PPh₃XPhos, SPhos, RuPhos, XantPhos, Dppf, BINOL, BINAP or Pcy₃Etc.; the base is^tBuONa、^tBuOK、^tBuOLi、Cs₂CO₃、LiHMDS、LDA、NaHMDS、KHMDS、K₃PO₄、Na₂CO₃、KOAc、NaHCO₃Or K₂CO₃Etc.; the reaction solvent is toluene, xylene, THF, DME, dioxane, DMF, DMSO or NMP, etc.; the reaction temperature is 40 ℃ to 140 ℃.

And a sixth step: carrying out coupling reaction on the compound I-A1-5 and the compound I-A1-8 to generate a compound I-A1-9;

such coupling reactions as the Suzuki reaction; the coupling reaction is preferably carried out in the presence of a catalyst, Pd (PPh) as catalyst, and a base₃)₄Or Pd (dppf) Cl₂Etc., the alkali is Cs₂CO₃、K₃PO₄、Na₂CO₃、KOAc、NaHCO₃Or K₂CO₃Etc.; the reaction solvent is 1, 4-dioxane, DMF, DMSO or CH₃CN or any of the above solvents with H₂A mixed solvent of O, etc.; the reaction temperature is 40 ℃ to 120 ℃.

The seventh step: reacting the compound I-A1-9 under alkaline or acidic conditions to generate a compound I-A1-10;

the acid used under acidic condition is HCl and H₂SO₄TFA, trifluoromethanesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like, and the base used under alkaline conditions is LiOH, NaOH, KOH or the like; the solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, CH₃CN, 1, 4-dioxane or toluene or any of the above solvents with H₂A mixed solvent of O, etc.; the reaction temperature is from 0 ℃ to 100 ℃, for example room temperature.

Eighth step: reacting the compound I-A1-10 with I-A1-11 to generate a compound shown as a formula (I-A1);

the reaction is preferably carried out in the presence of a condensing agent such as HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP and a base such as TEA, DIPEA, N-dimethylformamide,^tBuOK、^tBuONa、^tBuOLi、NaH、NaOH、Cs₂CO₃、K₃PO₄Or Na₂CO₃Etc.; the reaction solvent is THF, DCM, DCE, MeOH, EtOH, DMF, DMSO, acetone, CH₃CN, 1, 4-dioxane, toluene, etc.; the reaction temperature is from 0 ℃ to 120 ℃, for example room temperature.

Or compound I-A1-10 is first reacted with acylating reagent to produce acyl halide and then reacted with compound I-A1-11 optionally in the presence of base to produce compound of formula (I-A1);

the acylation reagent such as thionyl chloride, oxalyl chloride, etc. can be carried out with a small amount of DMF as a catalyst, or in a system not containing DMF. The alkali is TEA, DIPEA and the like; the reaction solvent is THF, DCM, DCE, CH₃CN, 1, 4-dioxane, toluene, etc.; the reaction temperature is 0 ℃ to 100 ℃.

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 2):

wherein each group is as defined above;

the reaction comprises the following steps:

the first step is as follows: reducing compound I-A1-10 to compound I-A2-1;

the reduction reaction is preferably carried out in the presence of a catalyst, which is Pd/C, PtO₂Or Pd (OH)₂C, etc.; the reaction is preferably carried out in the presence of hydrogen; the reaction is optionally carried out in the presence of an acid (e.g., acetic acid); the reaction solvent is MeOH or EtOH, etc.; the reaction temperature is 0 ℃ to 80 ℃.

The second step is that: reacting the compound I-A2-1 with I-A1-11 to generate a compound shown as a formula (I-A2);

the reaction conditions are as described in the eighth step of the process for preparing the compound of formula (I-A1).

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 3):

wherein:

Hal²is F, Cl, Br or I, preferably Gl;

the remaining groups are as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A1-8 with I-A3-1 in the presence of alkali to generate a compound I-A3-2;

the reaction conditions are as described in the fifth step of the process for preparing the compound of formula (I-A1).

The second step is that: reacting the compound I-A3-2 under alkaline or acidic conditions to generate a compound I-A3-3;

the reaction conditions are as described in the seventh step of the process for preparing the compound of formula (I-A1).

The third step: reacting the compound I-A3-3 with I-A1-11 to generate a compound shown as a formula (I-A3);

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 4):

wherein each group is as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A3-3 with I-A4-1 to generate a compound shown as a formula (I-A4);

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 5):

wherein:

Hal¹and Hal²Each independently is F, Cl, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A5-1 with the compound I-A5-2 in the presence of alkali to generate a compound I-A5-3;

the used alkali is DIPEA, BuLi, LiHMDS, LDA,^tBuOK、NaH、Cs₂CO₃、K₂CO₃Or NaOH, etc., and the solvent is THF or CH₃CN, DCM, DMF, DMSO, DCE, acetone, etc., at-78 deg.C to 100 deg.C (e.g., 60 deg.C or 85 deg.C);

the second step is that: reacting the compound I-A5-3 under the condition of removing a protecting group PG to generate a compound I-A5-4;

depending on the particular PG group, one skilled in the art can select suitable reaction conditions. For example, when PG is Boc, the reaction is carried out under acidic conditions using HCl in 1, 4-dioxane, HCl in ethyl acetate, or TFA in DCM, etc.; the reaction temperature is from 0 ℃ to 80 ℃, e.g., room temperature; when PG is PMB, DMB, Bn or Cbz, the reaction can be carried out under catalytic hydrogenation conditions using Pd/C, PtO as a catalyst₂Or Pd (OH)₂C, and the like, wherein the solvent is MeOH, EtOH and the like, and the temperature is between room temperature and 80 ℃; when PG is PMB, DMB or Cbz, the reaction can be carried out under acidic conditions using HCl, TFA, H₂SO₄And the solvent is DCM, 1, 4-dioxane, MeOH, EtOH or the like, or the reaction is carried out under the condition of no solvent, and the reaction temperature is 0-80 ℃.

The third step: reacting the compound I-A5-4 with I-A1-8 in the presence of alkali to generate a compound I-A5-5;

The fourth step: reacting the compound I-A5-5 under alkaline or acidic conditions to generate a compound I-A5-6;

The fifth step: reacting the compound I-A5-6 with I-A4-1 to generate a compound shown as a formula (I-A5);

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 6):

wherein:

Hal¹、Hal²and Hal³Each independently is F, Cl, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A1-8 with I-A5-1 in the presence of alkali to generate a compound I-A6-1;

The second step is that: reacting the compound I-A6-1 under the condition of removing a protecting group PG to generate a compound I-A6-2;

the reaction conditions are as described in the second step of the process for preparing the compound of formula (I-A5).

The third step: reacting the compound I-A6-2 with the compound I-A6-3 in the presence of alkali to generate a compound I-A6-4;

the base is TEA or DIPEA, etc., and the reaction solvent is THF, DCM, DCE, CH₃CN, 1, 4-dioxane or toluene, etc. and the reaction temperature is 0-100 deg.c.

The fourth step: reacting the compound I-A6-4 with I-A4-1 in the presence of a base to generate a compound shown as a formula (I-A6);

the reaction conditions are as described in the first step of the process for preparing the compound of formula (I-A5).

In some embodiments, the present invention provides a method of preparing a compound of formula (I-a 7):

wherein:

Hal²is F, Cl, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined above;

the reaction comprises the following steps:

the first step is as follows: reacting the compound I-A1-8 with I-A7-1 in the presence of alkali to generate a compound I-A7-2;

The second step is that: reacting the compound I-A7-2 under the condition of removing a protecting group PG to generate a compound I-A7-3;

The third step: reacting the compound I-A7-3 with I-A4-1 to generate a compound shown as a formula (I-A6);

Pharmaceutical compositions, formulations and methods of treatment

In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers, preferably the pharmaceutical composition is in a solid, semi-solid, liquid, or gaseous formulation. In some embodiments, the pharmaceutical composition may further comprise one or more additional therapeutic agents. In a preferred embodiment, the pharmaceutical composition is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes.

In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RET activity.

In some embodiments, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention, in the manufacture of a medicament for modulating (e.g., reducing or inhibiting) the activity of RET.

In some embodiments, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a disease or condition associated with RET activity.

In some embodiments, the present invention provides a method of preventing or treating a disease or condition associated with RET activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of the present invention.

In some embodiments, the disease or condition associated with RET activity is preferably a cancer or tumor (e.g., brain tumor, lung cancer (e.g., non-small cell lung cancer), squamous cell cancer, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibroma, thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma), or irritable bowel syndrome.

By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's pharmaceutical sciences (1990).

The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

The term "effective amount" as used herein refers to an amount of a compound that, when administered, will alleviate one or more symptoms of the condition being treated to some extent.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

The compound of the invention may be present in the pharmaceutical composition in an amount or amount of about 0.01mg to about 1000 mg.

As used herein, unless otherwise specified, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.

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

In some embodiments, the pharmaceutical compositions of the invention may also comprise one or more additional therapeutic or prophylactic agents (e.g., other agents useful for treating cancer or neoplastic disease). In some embodiments, the methods of the invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other agents useful for treating cancer or neoplastic disease).

Detailed Description

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

The abbreviations in the present invention have the following meanings:

the structure of the compound of the invention is represented by (¹H NMR) and/or Mass Spectrometry (MS). The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS.

¹H NMR spectrum: bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400)MHz)。

LC/MS mass spectrometer: aglient 1260 Infinity/Aglient 6120 Quadrupole.

The thin layer chromatography adopts silica gel GF 254 as a stationary phase.

The compound can be separated and purified by a chromatography silica gel plate, a silica gel column chromatography, a preparative high performance liquid chromatograph (Prep-HPLC) and a Flash column chromatography (Flash column chromatography).

The column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as a stationary phase.

Flash column chromatography was performed using a Biotage flash column chromatograph.

Prep-HPLC was performed using Agilent 1260 chromatography.

The microwave reaction was performed using a BiotageInitiator microwave reactor.

In the following examples, the reaction temperature was room temperature (15-30 ℃ C.), unless otherwise specified.

Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Tereber Chemical, among others.

Example 1: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) piperidine-4-carboxamide (1)

The first step is as follows: 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [3, 2-d ] pyrimidin-4-amine (1c)

La (2.02g, 9.75mmol) and 1b (1.00g, 10.24mmol) were dissolved in DMSO (35mL) under nitrogen, followed by DIPEA (1.29g, 9.75mmol) and heated to 60 ℃ for 15 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 100mL of water, and a large amount of solid was precipitated, filtered and washed with methyl t-butyl ether, and the intermediate 1c (1.7g) was obtained as a filter cake. MS m/z (ESI): 266.0[ M + H]⁺。

The second step is that: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid ethyl ester (1e)

1c (300)mg, 1.02mmol), 1d (322.71mg, 2.03mmol) and K₂CO₃(212.46mg, 1.52mmol) was placed in a 10mL microwave reaction tube, 1, 4-dioxane (5mL) was added, and the reaction was carried out at 110 ℃ for 2h under microwave conditions. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into 100mL of water and extracted with EA (50mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated to dryness under reduced pressure and subjected to separation and purification by silica gel column chromatography (PE: EA ═ 1: 2 to 10: 1) to obtain intermediate 1e (391 mg). MS m/z (ESI): 387.2[ M + H]⁺。

The third step: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid (1f)

An aqueous solution of KOH (257.37mg, 4.54mmol) (4mL) was added to a solution of 1e (390mg, 908.22. mu. mol) in MeOH (10mL) under nitrogen and heated to 50 ℃ for 2 h. After the reaction was completed, the pH was adjusted to 5 with 2M hydrochloric acid, and concentrated to dryness under reduced pressure to obtain a crude product of 1f, which was used in the next reaction without further purification. MS m/z (ESI): 359.1[ M + H]⁺。

The fourth step: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) piperidine-4-carboxamide

1f (100mg, 251.10. mu. mol), 1g (85.67mg, 276.21. mu. mol) (see the synthesis of WO2016127074, pages 35-37), PyBOP (145.08mg, 276.21. mu. mol) and DIPEA (65.56mg, 502.21. mu. mol) were dissolved in DMF (5mL) under nitrogen protection, and the reaction was stirred at room temperature for 1 hour, after completion of the reaction, 30mL of water was added to dilute the solution, EA (30mLx3) was extracted, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and purified by Prep-HPLC to give the objective compound 1. MS m/z (ESI): 547.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.20(s，1H)，9.68(s，1H)，8.67(dd，J＝4.6，0.9Hz，1H)，8.44-8.35(m，2H)，7.95-7.84(m，4H)，7.07(d，J＝5.4Hz，1H)，6.29(s，1H)，5.01-4.94(m，1H)，4.65-4.70(m，2H)，2.87(t，J＝12.0Hz，2H)，2.48-2.53(m，1H)，2.23(s，3H)，1.73(t，J＝10.6Hz，2H)，1.62-1.44(m，2H)，1.40(d，J＝7.1Hz，3H).

Example 2: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) piperidine-4-carboxamide (2)

The first step is as follows: 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) quinazolin-4-amine (2b)

Dissolving 2a (2g, 9.95mmol) and 1b (1.02g, 10.45mmol) in DMSO (35mL) under the protection of nitrogen, adding DIPEA (1.95g, 14.92mmol), heating to 60 ℃, reacting for 15h, cooling to room temperature after the reaction is finished, adding 100mL of water for dilution, precipitating a large amount of solid, filtering and washing with methyl tert-butyl ether, and collecting a filter cake to obtain an intermediate 2b (1.7 g). MSm/z (ESI): 260.1[ M + H]⁺。

The second step is that: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) piperidine-4-carboxylic acid ethyl ester (2c)

2b (200mg, 693.12. mu. mol), 1d (220.13mg, 1.39mmol) and K₂CO₃(193.23mg, 1.39mmol) was placed in a 30mL microwave reaction tube, and 1.4-dioxane (15mL) was added and reacted at 110 ℃ for 2h under microwave conditions. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into 100mL of water, extracted with EA (50mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (PE: EA ═ 1: 2 to 10: 1) to obtain the objective product 2c (240 mg). MS m/z (ESI): 381.2[ M + H]⁺。

The third step: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) piperidine-4-carboxylic acid (2d)

An aqueous solution of KOH (160.87mg, 2.84mmol) (2mL) was added to a solution of 2c (240mg, 567.76. mu. mol) in MeOH (6mL) under nitrogen and heated to 50 ℃ for 2 h. After the reaction was completed, it was cooled to room temperature, adjusted to pH 5 with 2M hydrochloric acid, and concentrated to dryness under reduced pressure to give 2d crude product, which was directly subjected to the next reaction without further purification. MS m/z (ESI): 353.2[ M + H ]]⁺。

The fourth step: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) piperidine-4-carboxamide (2)

2d (60mg, 153.24. mu. mol), 1g (52.28mg, 168.56. mu. mol), PyBOP (88.54mg, 168.56. mu. mol) and DIPEA (40.01mg, 306.48. mu. mol) were dissolved in DMF (3mL) under nitrogen and reacted at room temperature for 1 h. After the reaction is finished, 30mL of water is added for dilution, EA (30mL x3) is used for extraction, organic phases are combined and washed by saturated saline solution, anhydrous sodium sulfate is used for drying, and after filtration, filtrate is decompressed and concentrated to be dry, and separation and purification are carried out by Prep-HPLC to obtain the target compound 2. MS m/z (ESI): 541.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.28(s，1H)，10.00(s，1H)，8.67(d，J＝4.4Hz，1H)，8.45-8.31(m，3H)，7.97-7.83(m，3H)，7.55(t，J＝7.4Hz，1H)，7.32(d，J＝8.2Hz，1H)，7.09(t，J＝7.2Hz，1H)，6.43(s，1H)，5.04-4.93(m，1H)，4.76(t，J＝8.6Hz，2H)，2.92(t，J＝13.2，2H)，2.48-2.53(m，1H)，2.26(s，3H)，1.78(t，J＝10.6Hz，2H)，1.57-1.47(m，2H)，1.40(d，J＝7.0Hz，3H).

Example 3: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (3)

The first step is as follows: 2-chloro-N- (5-methyl-1H-pyrazol-3-yl) thieno [2, 3-d ] pyrimidin-4-amine (3b)

Dissolving 3a (2.04g, 9.75mmoD) and 1b (1.06g, 10.73mmol) in DMSO (40mL) at room temperature, adding DIPEA (1.93g, 14.63mmol), heating to 60 ℃ for reaction for 12h, monitoring the complete conversion of the raw materials by LC-MS, cooling to room temperature after the reaction is finished, adding water to quench the reaction, filtering the precipitated solid, and collecting a filter cake to obtain an intermediate 3b (2.3 g).

The second step is that: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid ethyl ester (3c)

3b (222.22mg, 752.67. mu. mol)) and 1d (120.74mg, 752.67. mu. mol) were dissolved in 4ml of DMF at room temperature, and K was added₂CO₃(105.99mg, 752.67 μmol), heated to 100 ℃ for 3h, LC-MS monitored complete conversion of starting material, cooled to room temperature after reaction, quenched with water, extracted with EA, the combined organic phases dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure, and purified by silica gel column chromatography (DCM: MeOH ═ 40: 1-10: 1) to give intermediate 3c (185 mg). MS m/z (ESI): 387.5[ M + H ]]⁺

The third step: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid (3d)

Dissolve 3c (185mg, 478.69. mu. mol) in MeOH (15mL) and H at room temperature₂To O (5mL), NaOH (105.61mg, 2.59mmol) was then added, stirred at room temperature for 4h, LC-MS monitored for complete conversion of the starting material, pH adjusted to neutral with 1N hydrochloric acid, EA extracted, the combined organic phases dried over anhydrous sodium sulfate, filtered and the solvent evaporated under reduced pressure to give the crude compound 3d, which was used in the next reaction without further purification. MS m/z (ESI): 359.4[ M + H]⁺。

The fourth step: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (3)

After 3d (60mg, 150.66. mu. mol), HATU (70.10mg, 180.79. mu. mol) and DIPEA (59.61mg, 451.99. mu. mol) were dissolved in DMF (5mL) at room temperature and reacted for 10min, 1g (51.40mg, 165.73. mu. mol) was added, LC-MS was used to monitor the complete conversion of the starting material, and after the reaction was completed, the reaction mixture was diluted with EA, washed with water, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to obtain the objective compound 3(25 mg). MS m/z (ESI): 547.6[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.11(br，1H)，9.87(s，1H)，8.67(d，J＝8.0Hz，1H)，8.40-8.38(m，2H)，7.95-7.84(m，3H)，7.67(d，J＝6.0Hz，1H)，7.04(d，J＝6.0Hz，1H)，6.41(s，1H)，5.02-4.93(m，1H)，4.68-4.63(m，2H)，2.94-2.89(m，2H)，2.48-2.53(m，1H)，2.24(s，3H)，1.79-1.74(m，2H)，1.55-1.45(m，2H)，1.40(d，J＝6.8Hz，3H).

Example 4: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((3-methyl-1H-pyrazol-5-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (4)

The first step is as follows: 2-chloro-N- (3-methyl-1H-pyrazol-5-yl) -7H-pyrrolo [2, 3-d ] pyrimidin-4-amine (4b)

At room temperature, 4a (1.53g, 7.98mmol) and 1b (869.70mg, 8.78mmol) were dissolved in 10mL of tert-butanol, then DIPEA (3.16g, 23.93mmol) was added, the mixture was heated to 110 ℃ under microwave conditions for 12h, LC-MS monitored until the starting material was completely converted, the mixture was cooled to room temperature after the reaction was completed, water was added to quench the reaction, EA was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure after filtration, and the mixture was separated and purified by silica gel column (PE: EA ═ 5: 1-1: 1) to obtain intermediate 4b (650 mg). MS m/z (ESI): 249.6[ M + H ]]⁺。

The second step is that: 1- (4- ((3-methyl-1H-pyrazol-5-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid ethyl ester (4c)

4b (133.33mg, 482.57. mu. mol) and 1d (154.82mg, 965.13. mu. mol) were dissolved in 4ml of DMF at room temperature, and K was added₂CO₃(169.88mg, 1.21mmol), heated to 100 ℃ for 3h, monitored by LC-MS until complete conversion of the starting material, cooled to room temperature after completion of the reaction, quenched with water, extracted with EA, the combined organic phases dried over anhydrous sodium sulphate, filtered and the solvent evaporated under reduced pressure to give intermediate 4c (100mg) which is purified by silica gel column separation (DCM: MeOH ═ 40: 1 to 10: 1). MS m/z (ESI): 370.4[ M + H]⁺。

The third step: 1- (4- ((3-methyl-1H-pyrazol-5-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxylic acid (4d)

Dissolve 4c (100.00mg, 232.88. mu. mol) in MeOH (8mL) and H₂In O (4mL)Then NaOH (47.53mg, 1.16mmol) was added and the reaction was carried out at room temperature, LC-MS monitoring was carried out until complete conversion of the starting material, pH was adjusted to neutral with 1N HCl after the end of the reaction, EA extraction was carried out, the organic phases were combined and dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure to give the crude product of intermediate 4d which was used in the next reaction without further purification. MS m/z (ESI): 342.4[ M + H]⁺。

The fourth step: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((3-methyl-1H-pyrazol-5-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (4)

4d (80mg, 210.92 μmol), HATU (98.14mg, 253.10 μmol) and DIPEA (83.45mg, 632.75 μmol) were dissolved in DMF (5mL), reacted at room temperature for 10min, then 1g (57.99mg, 253.10 μmol) was added, LC-MS was monitored until the starting material was completely converted, diluted with EA after the reaction was completed, the organic phase was dried over anhydrous sodium sulfate after washing with water, filtered and the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel column chromatography (DCM: MeOH: 100: 0-80: 20) to obtain the objective compound 4(10 mg). MS m/z (ESI): 530.6[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.07(br，1H)，11.08(br，1H)，9.71(br，1H)，8.67(d，J＝4.4Hz，1H)，8.41-8.38(m，2H)，8.01-7.80(m，3H)，6.84(s，1H)，6.65(s，1H)，6.33(s，1H)，5.05-4.87(m，1H)，4.45-4.58(m，2H)，3.00-2.90(m，2H)，2.49-2.41(m，1H)，2.24(s，3H)，1.79-1.75(m，2H)，1.63-1.50(m，2H)，1.40(d，J＝4.4Hz，3H).

Example 5: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (5)

The first step is as follows: 8-methoxy-1, 4-dioxaspiro [4, 5] decane-8-carboxylic acid methyl ester (5b)

5a (10g, 64.03mmol) and tribromomethane (161.82g, 640.29mmol) were placed in a reaction flask at room temperatureCooled to 0c, a solution of KOH (28.7g, 511mmol) in methanol (100mL) was slowly added, stirred at room temperature for 14h, LC-MS monitored complete conversion of the starting material, filtered and washed with EtOAc, and the filtrate was purified by silica gel column chromatography (PE: EA ═ 25: 1 to 5: 1) after evaporation of the solvent under reduced pressure to give the title compound 5b (5.5 g). MS m/z (ESI): 231.2[ M + H]⁺。

The second step is that: 1-methoxy-4-oxocyclohexanecarboxylic acid methyl ester (5c)

Dissolving 5b (5.5g, 23.89mmol) in 1, 4-dioxane (150mL), cooling to 0 deg.C, slowly adding 40mL of 6M HCl aqueous solution, heating to room temperature, stirring for 1.5h, LC-MS monitoring for complete conversion of the raw materials, and reacting with saturated NaHCO₃The pH was adjusted to neutral, and the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 20: 1 to 5: 1) to give the objective compound 5c (3.1 g). MS m/z (ESI): 187.2[ M + H]⁺。

The third step: 1-methoxy-4- (((trifluoromethyl) sulfonyl) oxy) cyclohex-3-enecarboxylic acid methyl ester (5e)

5c (3.1g, 16.67mmol) and 5d (5.1g, 25.01mmol) were dissolved in DCM (50mL) and Tf was added slowly while cooling on ice₂O (7.1g, 25.01mmol), after the addition, was warmed to room temperature and stirred for 12 hours, after the reaction was completed, the solvent was evaporated under reduced pressure, and the product was purified by silica gel column chromatography (PE: EA ═ 20: 1 to 6: 1) to obtain the objective compound 5e (2.2 g). MS m/z (ESI): 319.3[ M + H]⁺。

The fourth step: 1-methoxy-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) cyclohex-3-enecarboxylic acid methyl ester (5f)

Under the protection of nitrogen, 5e (2.2g, 6.91mmol) and B₂(pin)₂(2.6g，10.37mmol)、Pd(dppf)₂Cl₂DCM (563mg, 0.69mmol) and KOAc (1.7g, 17.27mmol) were placed in a 250mL three-necked flask, followed by the addition of 1, 4-dioxane (80mL), heated to 110 deg.C for reaction, and monitored by TLC until complete conversion of the starting material. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered, washed with EtOAc, and subjected to separation and purification by silica gel column chromatography (PE: EA: 18: 1 to 5: 1) after evaporation of the solvent under reduced pressure to obtain the objective compound 5f (1.6 g). MS m/z (ESI): 297.2[ M + H]⁺。

The fifth step: methyl 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylate (5g)

5f (333.33mg, 1.01mmol), 3b (271.88mg, 920.86. mu. mol), Pd (dppf)₂Cl₂(76.68mg, 92.09. mu. mol) and K₂CO₃(324.18mg, 2.30mmol) was placed in a 100mL three-necked flask and 1, 4-dioxane (15mL) and H were added₂O (5mL) in a mixed solvent, heated to 110 ℃ for reaction, and monitored by TLC until complete conversion of the starting material. After completion of the reaction, it was cooled to room temperature, filtered and washed with EtOAc, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (DCM: MeOH: 30: 1-10: 1) to obtain 5g (310mg) of the objective compound. MS m/z (ESI): 400.5[ M + H]⁺。

And a sixth step: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylic acid (5H)

5g (310mg, 776.04. mu. mol) were dissolved in MeOH (15mL) and H₂O (5mL), then NaOH (145.36mg, 3.56mmol) is added, the reaction is stirred at room temperature, LC-MS monitors until the raw material is completely converted, pH is adjusted to neutral by 1N Cl after the reaction is finished, EA extraction is carried out, organic phases are combined and dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is concentrated under reduced pressure to obtain an intermediate 5h (265 mg). MS m/z (ESI): 386.4[ M + H]⁺。

The seventh step: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (5)

5h (100mg, 233.50 mu mol), PyBOP (148.68mg, 280.20 mu mol) and DIPEA (92.38mg, 700.50 mu mol) are dissolved in DMF (10mL) at room temperature, 1g (79.66mg, 256.85 mu mol) is added after stirring for 10min, the reaction is carried out at room temperature, LC-MS is used for monitoring until the raw materials are completely converted, EA is used for dilution after the reaction is finished, an organic phase after washing is dried by anhydrous sodium sulfate, filtering is carried out, filtrate is decompressed and concentrated to be dry, and separation and purification by Prep-HPLC are carried out to obtain the target compound 5(20 mg). MSm/z (ESI): 574.4[ M + H]⁺。

¹H NMR(400MHz，CD₃OD)δ8.49-8.47(t，J＝4.4Hz，1H)，8.45-5.41(dd，J＝6.8Hz，J＝2.0Hz，1H)，7.98-7.87(m，2H)，7.695-7.655(d，J＝4.0Hz，1H)，7.59-7.54(m，1H)，7.43(s，1H)，7.16-7.14(m，1H)，6.66(s，1H)，5.21-5.08(m，1H)，3.27(s，3H)，2.88-2.50(m，4H)，2.32(s，3H)，2.25-1.94(m，2H)，1.62(d，J＝7.2Hz，3H).

Example 6: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (6)

The first step is as follows: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylic acid methyl ester (6a)

5f (292.58mg, 889.09. mu. mol) was dissolved in 1, 4-dioxane (15mL), and 1c (250mg, 846.75. mu. mol) and K were added in that order₂CO₃(295.51mg, 2.12mmol) and H₂O (3mL), followed by addition of Pd (dppf)₂Cl₂(69.79mg, 84.68. mu. mol), and heated to 110 ℃ under nitrogen for 40 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure and purified by silica gel column chromatography (PE: EA: 1: 2 to 10: 1) to obtain intermediate 6a (180 mg). MS m/z (ESI): 400.2[ M + H]⁺。

The second step is that: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylic acid (6b)

6a (179mg, 403.29. mu. mol) was dissolved in MeOH (6mL), KOH (114.29mg, 2.02mmol) was added in water (2mL), and the reaction was stirred at 50 ℃ for 2h under nitrogen. After the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was adjusted to pH 5 with 1M hydrochloric acid, and concentrated under reduced pressure to dryness to obtain a crude product of intermediate 6b, which was used in the next reaction without further purification. MSm/z (ESI): 386.2[ M + H]⁺。

The third step: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [3, 2-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (6)

6b (83.33mg, 194.58. mu. mol) was dissolved in DMF (5mL) under nitrogen, and PyBOP (112.43mg, 214.04. mu. mol), DIPEA (50.80mg, 389.17. mu. mol) and 1g (66.39mg, 214.04. mu. mol) were added in this order to react at room temperature for 1 hr. After the reaction, the reaction mixture was diluted with 30mL of water, EA (30mLx3) was extracted, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure and separated and purified by Prep-HPLC to obtain the objective compound 6. MS m/z (ESI): 574.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.15(s，1H)，9.96(s，1H)，8.68(d，J＝4.5Hz，1H)，8.60(dd，J＝8.3，5.0Hz，1H)，8.45(s，1H)，8.09(t，J＝4.6Hz，1H)，8.03-7.99(m，1H)，7.95-7.86(m，2H)，7.36(t，J＝5.3Hz，1H)，7.06(d，J＝13.6Hz，1H)，6.48(s，1H)，5.11-5.08(m，1H)，3.14(s，3H)，2.74-2.58(m，2H)，2.26(s，3H)，2.15-2.03(m，2H)，2.00-1.82(m，2H)，1.49(d，J＝5.9Hz，3H).

Example 7: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (7)

The first step is as follows: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylic acid methyl ester (7a)

Under nitrogen protection, 5f (416.15mg, 1.19mmol), 4b (300mg, 1.09mmol), Pd (dppf)₂Cl₂(90.41 mg, 108.58. mu. mol) and K₂CO₃(382.24mg, 2.71mmol) was placed in a 100mL three-necked flask, followed by the addition of 1, 4-dioxane (15mL) and H₂O (5mL), heated to 110 ℃ for reaction and monitored by TLC until complete conversion of starting material. After completion of the reaction, it was cooled to room temperature, filtered, washed with EtOAc, evaporated under reduced pressure and purified by silica gel column chromatography (DCM: MeOH ═ 30:1-10: 1) intermediate 7a (223mg) was obtained. MS m/z (ESI): 383.4[ M + H]⁺。

The second step is that: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxylic acid (7b)

7a (223mg, 583.14. mu. mol) was dissolved in MeOH (15mL) and H at room temperature₂O (5mL), then NaOH (145.36mg, 3.56mmol) was added and the reaction was allowed to proceed at room temperature for 4h after the addition was complete, LC-MS monitored for complete conversion of the starting material, pH adjusted to neutral with 1N HCl, EA extracted, combined organic phases and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to give the crude intermediate 7b which was used directly in the next reaction without further purification. MS m/z (ESI): 369.4[ M + H]⁺。

The third step: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohex-3-enecarboxamide (7)

7b (75mg, 173.05. mu. mol), PyBOP (101.01mg, 190.36. mu. mol) and DIPEA (68.46mg, 519.15. mu. mol) were dissolved in DMF (6mL), stirred for 10min, added with 1g (59.04mg, 190.36. mu. mol), reacted at room temperature, LC-MS monitored until complete conversion of the starting material, washed with water and extracted with EA after the reaction was complete, the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness under reduced pressure, and separated and purified by Prep-HPLC to give the objective compound 7(15 mg). MS m/z (ESI): 557.6[ M + H]⁺。

¹H NMR(400MHz，CD₃OD)δ8.58-8.32(m，2H)，8.03-7.84(m，2H)，7.67(d，J＝4.4Hz，1H)，7.15-6.97(m，2H)，6.64-6.52(m，1H)，5.84(br，1H)，5.18-5.15(m，1H)，3.27(d，J＝2.4Hz，3H)，2.95-2.46(m，4H)，2.33(s，3H)，2.00-1.84(m，5H)，1.58(d，J＝7.2Hz，3H).

Example 8: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) cyclohex-3-enecarboxamide (8)

The first step is as follows: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) cyclohex-3-enecarboxylic acid methyl ester (8a)

5f (313.62mg, 953.05. mu. mol) was dissolved in 1, 4-dioxane (15mL), and 2b (250mg, 866.40. mu. mol) and K were added in that order₂CO₃(301.93mg, 2.17mmol) and water (3mL), replaced with nitrogen, and Pd (dppf) added thereto₂Cl₂(71.41mg, 86.64. mu. mol), replaced with nitrogen gas three times, and then heated to 110 ℃ for reaction for 40 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (PE: EA: 1: 2 to 10: 1) to obtain the objective product 8a (205 mg). MS m/z (ESI): 394.2[ M + H]⁺。

The second step is that: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) cyclohex-3-enecarboxylic acid (8b)

8a (111.11mg, 252.87. mu. mol) was dissolved in MeOH (6mL) under nitrogen, KOH (71.66mg, 1.26mmol) was added in water (2mL), and the mixture was heated to 50 ℃ for 2 h. After the reaction, the reaction solution was cooled to room temperature, the reaction solution was adjusted to pH 5 with 1M hydrochloric acid, and concentrated to dryness under reduced pressure, and the obtained crude product was used in the next reaction without further purification. MS m/z (ESI): 380.2[ M + H]⁺。

The third step: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) quinazolin-2-yl) cyclohex-3-enecarboxamide (8)

8b (60mg, 142.33. mu. mol) was dissolved in DMF (5mL) under nitrogen, PyBOP (82.23mg, 156.56. mu. mol), DIPEA (27.87mg, 213.49. mu. mol) and 1g (48.56mg, 156.56. mu. mol) were added in this order, and the reaction was stirred at room temperature for 1 h. After the reaction, the reaction mixture was diluted with 30mL of water, extracted with EA (30mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure, and then separated and purified by Prep-HPLC to obtain the objective compound 8. MS m/z (ESI): 568.3[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ10.21(s，1H)，8.68(d，J＝3.6Hz，1H)，8.65-8.54(m，2H)，8.45(s，1H)，8.24(s，1H)，8.03-7.99(m，1H)，7.94-7.86(m，2H)，7.79-7.65(m，2H)，7.48-7.44(m，lH)，7.13(d，J＝12.8Hz，1H)，6.64(s，1H)，5.13-5.06(m，1H)，3.14(s，3H)，2.77-2.61(m，2H)，2.28(s，3H)，2.19-1.83(m，4H)，1.49(d，J＝5.8Hz，3H).

Example 9: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohexanecarboxamide (9) and isomers thereof, 9A and 9B

The first step is as follows: 1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohexanecarboxylic acid (9a)

Adding 7b (200mg, 0.54mmol) and PtO₂(30mg, 0.13mmol) and AcOH (64.8mg, 1.08mmol) were placed in a 100mL reaction flask followed by MeOH (15mL) in 1atm H₂Heating to 70 ℃ under the condition, stirring for 2h, and monitoring the complete conversion of the raw materials by LC-MS. After completion of the reaction, it was cooled to room temperature, filtered and washed with EtOAc, and the solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (DCM: MeOH ═ 20: 1 to 5: 1) to obtain the objective compound 9a (180 mg). MS m/z (ESI): 371.4[ M + H]⁺。

The second step is that: (S) -N- (1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1-methoxy-4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) -7H-pyrrolo [2, 3-d ] pyrimidin-2-yl) cyclohexanecarboxamide (9)

Dissolving 9A (180mg, 437.36 μmol), PyBOP (278.5mg, 524.83 μmol) and DIPEA (173.03mg, 1.31mmol) in DMF (10mL), stirring at room temperature for 10min, adding 1g (135.65mg, 437.36 μmol), LC-MS monitoring until the raw materials are completely converted, EA extracting, combining organic phases and drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain cis-isomer or trans-isomer of compound 9, 9A (peak 1, single stereo configuration, 10 mg); 9B (Peak 2, 10mg, single stereo configuration). MS m/z (ESI): 559.6[ M + H]⁺。

9A：¹H NMR(400MHz，DMSO-d₆)δ8.66(d，J＝5.2Hz，1H)，8.55-8.35(m，2H)，8.05-7.95(m，1H)，7.94-7.84(m，2H)，7.09(s，1H)，6.78(s，1H)，5.14-4.99(m，1H)，3.11(s，3H)，2.96-2.82(m，1H)，2.23(s，3H)，2.19-2.01(m，3H)，1.89-1.84(d，2H)，1.82-1.67(m，1H)，1.65-1.50(m，2H)，1.45(d，J＝6.8Hz，3H).

9B：¹H NMR(400MHz，DMSO-d₆)δ8.69(d，J＝4.8Hz，1H)，8.53(d，J＝4.8Hz，1H)，8.44(d，J＝1.6Hz，1H)，8.05-7.95(dd，J＝8.4Hz，J＝2.0Hz，1H)，7.95-7.83(m，2H)，7.31(br，1H)，6.83(br，1H)，5.10-5.02(m，1H)，3.16(s，3H)，2.85-2.80(m，1H)，2.28(s，3H)，2.05-1.69(m，8H)，1.48(d，J＝7.2Hz，3H).

Example 10: n- (2- (4-fluoro-1H-pyrazol-1-yl) pyrimidin-5-yl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (10)

The first step is as follows: 2- (4-fluoro-1H-pyrazol-1-yl) pyrimidin-5-amine (10c)

10a (200mg, 1.14mmol) and 10b (183.09mg, 1.48mmol) were dissolved in CH under nitrogen₃CN (20mL), followed by addition of Cu₂O (16.44mg, 113.79. mu. mol), salicylaldoxime (31.49mg, 227.59. mu. mol) and Cs₂CO₃(748.97mg, 2.28mmol) and heated to 100 ℃ for 15 h. After the reaction is finished, the mixture is cooled to room temperature, filtered and added with CH₃CN washing, concentrating the filtrate under reduced pressure to dryness, and separating and purifying by silica gel column chromatography (PE: EA is 100: 0-50: 50 to obtain 10c (70mg), MSm/z (ESI) 180.1[ M + H ]]⁺。

The second step is that: n- (2- (4-fluoro-1H-pyrazol-1-yl) pyrimidin-5-yl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidine-4-carboxamide (10)

3d (60mg, 153.24. mu. mol) was dissolved in DCM (6mL) under nitrogen, cooled to 0 ℃ and 5 drops of oxalyl chloride and 1 drop of DMF were added and stirred at room temperature for 1 h. After the reaction is finished, the reaction solutionConcentrated to dryness under reduced pressure, the resulting solid was dissolved in DCM (3mL) and slowly added to a solution of DIPEA (153.02mg, 1.17mmol) and 10c (77.78mg, 390.73. mu. mol) in DCM (5mL), after which it was reacted at room temperature for 1 h. After the reaction is finished, water is added to quench the reaction, DCM (30mL x3) is used for extraction, organic phases are combined and washed by saturated saline solution, anhydrous sodium sulfate is used for drying, the solvent is removed by evaporation under reduced pressure after filtration, and the target compound 10 is obtained by separation and purification through Prep-HPLC. MS m/z (ESI): 520.1[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.10(br，1H)，10.54(s，1H)，9.93(s，1H)，9.06(s，2H)，8.69(d，J＝4.7Hz，1H)，7.95(d，J＝4.3Hz，1H)，7.70(d，J＝6.0Hz，1H)，7.06(d，J＝6.0Hz，lH)，6.44(s，1H)，4.71(d，J＝13.0Hz，2H)，3.01(t，J＝11.8Hz，2H)，2.75-2.69(m，1H)，2.25(s，3H)，1.95-1.91(m，2H)，1.68-1.58(m，2H).

Example 11: n- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) -2- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) acetamide (11)

The first step is as follows: 4- (2-ethoxy-2-oxoethyl) piperazine-1-carboxylic acid tert-butyl ester (11c)

Under the protection of nitrogen, 11a (1g, 5.26mmol) and 11b (789.58mg, 6.31mmol) are dissolved in DMSO (35mL), then DIPEA (1.04g, 7.89mmol) is added, the mixture is heated to 60 ℃ for reaction for 15h, after the reaction is finished, the mixture is cooled to room temperature, 100mL of water is added for dilution, EA (60mL x3) is extracted, organic phases are combined, the mixture is washed by clean water and saturated saline solution in sequence, anhydrous sodium sulfate is dried, and after filtration, the solvent is evaporated under reduced pressure to obtain intermediate 11c (1.4 g). MS m/z (ESI): 273.1[ M + H]⁺。

The second step is that: 2- (piperazin-1-yl) acetic acid ethyl ester (11d)

11c (1.4g, 4.63mmol) was dissolved in 20mL of 2M HCl in EtOAC and reacted at room temperature for 2h, after the reaction was complete the solvent was evaporated under reduced pressure to give the crude 11d which was used in the next step without further purification. MS m/z (ESI): 173.1[M+H]⁺。

the third step: ethyl 2- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) acetate (11e)

Mixing 11d (392.68mg, 1.69mmol), 3b (250mg, 846.75. mu. mol), K₂CO₃(354.10mg, 2.54mmol) was placed in a microwave reaction tube, DMF (5mL) was added, sealed and heated to 110 ℃ under microwave conditions for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into 100mL of water, extracted with EA (50mLx3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure and separated and purified by silica gel column chromatography (PE: EA ═ 1: 2 to 10: 1) to obtain the objective product 11e (230 mg). MS m/z (ESI): 402.2[ M + H]⁺。

The fourth step: 2- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) acetic acid (11f)

A solution of KOH (67.05mg, 1.18mmol) in water (4mL) was added to a solution of 11e (100mg, 236.62. mu. mol) in MeOH (10mL) at room temperature and heated to 50 ℃ under nitrogen for 2 h. After the reaction is finished, the reaction solution is cooled to room temperature, the pH value is adjusted to 5 by using 2M hydrochloric acid, the reaction solution is decompressed and concentrated to be dry, and the obtained crude product is directly used for the next reaction without further purification. MS m/z (ESI): 374.1[ M + H]⁺。

The fifth step: n- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) -2- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) acetamide (11)

11f (157.20mg, 378.86. mu. mol) was dissolved in DCM (6mL) under nitrogen, cooled to 0 ℃ and then 5 drops of oxalyl chloride and 1 drop of DMF were added and reacted at room temperature for 1h after the addition was complete. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, the obtained solid was dissolved in 3mL of DCM, slowly added to a solution of DIPEA (166.54mg, 1.26mmol) and 11g (50mg, 252.57. mu. mol) of DCM (5mL), reacted at room temperature for 1h, quenched after the reaction, extracted with DCM (30 mL. times.3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the solvent, and separated and purified by Prep-HPLC to obtain the target compound 11. MS m/z (ESI): 534.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.06(br，1H)，10.18(s，1H)，9.91(s，1H)，8.74(d，J＝2.5Hz，1H)，8.65(dd，J＝4.5，0.9Hz，1H)，8.33-8.23(m，1H)，7.94-7.85(m，2H)，7.70(d，J＝6.0Hz，1H)，7.06(d，J＝6.0Hz，1H)，6.43(s，1H)，3.82-3.87(m，4H)，3.25(s，2H)，2.68-2.56(m，4H)，2.24(s，3H).

Example 12: 2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) amino) -1- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) ethanone (12)

The first step is as follows: 4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazine-1-carboxylic acid tert-butyl ester (12a)

11a (643.71mg, 3.39mmol) and 3b (500mg, 1.69mmol) were dissolved in DMSO (20mL) followed by the addition of K₂CO₃(472.81mg, 3.39mmol), heating to 100 ℃ under microwave condition for reaction for 2h, cooling to room temperature after the reaction is finished, adding 100mL of water for dilution, EA (60mL x3) for extraction, combining organic phases, washing with clean water and saturated saline sequentially, drying with anhydrous sodium sulfate, filtering, decompressing, evaporating to remove the solvent, and separating and purifying by Flash column chromatography (PE: EA is 2: 1-1: 8) to obtain 12a (640 mg). MS m/z (ESI): 416.2[ M + H]⁺。

The second step is that: n- (5-methyl-1H-pyrazol-3-yl) -2- (piperazin-1-yl) thieno [2, 3-d ] pyrimidin-4-amine (12b)

12a (640mg, 1.39mmol) was dissolved in 2.0mL of 4M HCl in 1, 4-dioxane, stirred at room temperature for 2h, and after the reaction was complete the solvent was evaporated under reduced pressure to give crude 12b, which was used in the next step without further purification. MS m/z (ESI): 316.1[ M + H]⁺。

The third step: 2-chloro-1- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) ethanone (12c)

12b (450mg, 1.28mmol) and DIPEA (500).87mg, 3.84mmol) was dissolved in DCM (10mL), cooled in an ice-water bath, and chloroacetyl chloride (158.89mg, 1.41mmol) was slowly added dropwise. The reaction was monitored by LC-MS, and after completion of the reaction, the reaction solution was poured into 100mL of water, EA (50mL × 3) was extracted, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (PE: EA ═ 1: 4 to 9: 1) to obtain the objective product 12c (120 mg). MS m/z (ESI): 392.1[ M + H]⁺。

The fourth step: 2- ((6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) amino) -1- (4- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperazin-1-yl) ethanone (12)

12c (91.65mg, 222.17. mu. mol) and 11g (50mg, 266.61. mu. mol) were dissolved in DMSO (20mL), followed by DIPEA (29.00mg, 222.17. mu. mol) and heated to 85 ℃ under nitrogen for 5 h. After the reaction is finished, cooling to room temperature, adding 100mL of water for dilution, extracting by EA (60mL x3), combining organic phases, washing by clean water and saturated saline solution in sequence, drying by anhydrous sodium sulfate, filtering, decompressing, evaporating to remove the solvent, and separating and purifying by Prep-HPLC to obtain the target compound 12. MS m/z (ESI): 534.2[ M + H]⁺。

¹H NMR(400MHz，DMSO-d₆)δ12.16(s，1H)，9.95(s，1H)，8.48(dd，J＝4.6，0.8Hz，1H)，7.93(d，J＝2.7Hz，1H)，7.78-7.74(m，1H)，7.72(d，J＝6.0Hz，1H)，7.64(d，J＝8.8Hz，1H)，7.29(dd，J＝8.9，2.8Hz，1H)，7.09(d，J＝6.0Hz，1H)，6.45(s，1H)，6.15(t，J＝5.2Hz，1H)，4.09(d，J＝5.1Hz，2H)，3.84-3.77(m，2H)，3.65-3.58(m，4H)，2.28(s，3H).

Example 13: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) pyrrolidine-3-carboxamide (13)

The first step is as follows: pyrrolidine-3-carboxylic acid methyl ester (13b)

13a (1.5g, 4.96mmol) was dissolved under nitrogenThe reaction was carried out in 15mL of 4M HCl in 1, 4-dioxane at room temperature for 3 h. After the reaction was completed, the solvent was distilled off under reduced pressure to give a crude product (1.7g) of intermediate 13a, which was used in the next reaction without further purification. MS m/z (ESI): 130.2[ M + H]⁺。

The second step is that: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) pyrrolidine-3-carboxylic acid methyl ester (13c)

3b (300mg, 1.02mmol), 13b (322.71mg, 2.03mmol) and K₂CO₃(280.85mg, 2.03mmol) was placed in a 10mL microwave reaction tube, DMF (5mL) was added, and the reaction tube was heated to 100 ℃ under microwave conditions for 2 h. After the reaction was completed, the reaction solution was cooled to room temperature, poured into 100mL of water and extracted with EA (50mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated to dryness under reduced pressure and subjected to separation and purification by silica gel column chromatography (PE: EA ═ 1: 2 to 10: 1) to obtain intermediate 13c (180 mg). MS m/z (ESI): 359.1[ M + H]⁺。

The third step: 1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) pyrrolidine-3-carboxylic acid (13d)

An aqueous solution of KOH (113.85mg, 2.01mmol) (4mL) was added to a solution of 13c (180mg, 401.77. mu. mol) in MeOH (10mL) under nitrogen and heated to 50 ℃ for 2 h. After the reaction was completed, it was cooled to room temperature, adjusted to pH 5 with 2M hydrochloric acid, and concentrated to dryness under reduced pressure to give 13d of crude product, which was used in the next reaction without further purification. MSm/z (ESI): 345.1[ M + H]⁺。

The fourth step: n- ((S) -1- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) ethyl) -1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) pyrrolidine-3-carboxamide (13)

Dissolving 13d (60mg, 156.80 mu mol), 1g (53.50mg, 172.48 mu mol), PyBOP (91.52mg, 172.48 mu mol) and DIPEA (41.36mg, 313.60 mu mol) in DMF (5mL) under the protection of nitrogen, stirring at room temperature for reaction for 1h, adding 30mL of water for dilution after the reaction is finished, extracting EA (30mL x3), combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target productCompound No. 13. MS m/z (ESI): 533.2[ M + H]⁺。

1H NMR(400MHz，DMSO-d₆)δ12.01(s，1H)，9.88(s，1H)，8.74-8.52(m，2H)，8.41(s，1H)，8.01-7.82(m，3H)，7.70(d，J＝5.1Hz，1H)，6.99(d，J＝5.9Hz，1H)，6.63(s，1H)，5.06-4.99(m，1H)，3.85-3.80(m，1H)，3.74-3.40(m，3H)，3.20-3.07(m，1H)，2.15(s，3H)，2.08-1.97(m，1H)，1.44(d，J＝7.0Hz，3H).

Example 14: 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) -N- (1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidin-4-yl) acetamide (14)

The first step is as follows: 2- (6-iodopyridin-3-yl) acetic acid methyl ester (14b)

14a (315.79mg, 1.62mmol) was dissolved in acetonitrile (3mL), NaI (1.24g, 8.08mmol) and acetyl chloride (211.47mg, 2.42mmol) were added, and the mixture was heated to 80 ℃ under microwave conditions for 4h reaction. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 50mL of water and added with a sodium bisulfite solution until the color of the starch KI test paper did not change, extracted with EA (30mLx3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to remove the solvent, to give a crude product of 14b (130mg), which was used in the next reaction without further purification. MS m/z (ESI): 278.0[ M + H]⁺。

The second step is that: 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid methyl ester (14c)

14b (200mg, 714.65. mu. mol), 10b (93.19mg, 1.07mmol) and salicylaldoxime (19.58mg, 142.93. mu. mol) were dissolved in acetonitrile (30mL), followed by the addition of Cu₂O (10.22mg, 71.47. mu. mol) and Cs₂CO₃(204.39mg, 627.35. mu. mol), and the temperature is raised to 100 ℃ under the protection of nitrogen for reaction for 16 h. After the reaction, the reaction mixture was cooled to room temperature, poured into 100mL of water and extracted with EA (50mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and then purified by silica gel column chromatography (PE: EA ═ 1: EA2-10: 1) to give intermediate 14c (150 mg). MS m/z (ESI): 236.1[ M + H]⁺。

The third step: 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) acetic acid (14d)

An aqueous solution of KOH (162.65mg, 2.87mmol) (4mL) was added to a solution of 14c (150mg, 573.95. mu. mol) in MeOH (10mL) under nitrogen and heated to 50 ℃ for 2 h. After the reaction was completed, the pH was adjusted to 5 with 2M hydrochloric acid and concentrated to dryness under reduced pressure to give 14d of crude product which was used in the subsequent reaction without further purification. MS m/z (ESI): 222.1[ M + H]⁺。

The fourth step: (1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidin-4-yl) carbamic acid tert-butyl ester (14f)

3b (360mg, 1.22mmol), 14e (503.51mg, 2.44mmol) and K₂CO₃(343.40mg, 2.44mmol) was placed in a 10mL microwave reaction tube, DMSO (5mL) was added, and the reaction tube was heated to 100 ℃ under microwave conditions for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into 100mL of water and extracted with EA (50mL × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated to dryness under reduced pressure and purified by silica gel column chromatography (PE: EA ═ 1: 2 to 10: 1) to obtain intermediate 14f (420 mg). MS m/z (ESI): 430.1[ M + H]⁺。

The fifth step: 2- (4-Aminopiperidin-1-yl) -N- (5-methyl-1H-pyrazol-3-yl) thieno [2, 3-d ] pyrimidin-4-amine hydrochloride (14g)

14f (425mg, 890.49. mu. mol) was dissolved in 15mL of 4M HCl in 1, 4-dioxane (15mL) under nitrogen and reacted at room temperature for 3 h. After the reaction was completed, the solvent was distilled off under reduced pressure to obtain 14g of a crude product (300mg) as an intermediate, which was used in the next reaction without further purification. MS m/z (ESI): 330.1[ M + H]⁺。

And a sixth step: 2- (6- (4-fluoro-1H-pyrazol-1-yl) pyridin-3-yl) -N- (1- (4- ((5-methyl-1H-pyrazol-3-yl) amino) thieno [2, 3-d ] pyrimidin-2-yl) piperidin-4-yl) acetamide (14)

14g (101.09mg, 248.66. mu. mol), 14d (55.56mg, 226.05. mu. mol), PyBOP (131.94mg, 248.66. mu. mol) and DIPEA (89. mu. mol) were placed under nitrogen atmosphere43mg, 678.16 μmol) in DMF (5mL), stirring at room temperature for reaction for 1h, after the reaction is finished, adding 30mL of water for dilution, EA (30mL x3) for extraction, combining organic phases and washing with saturated brine, drying over anhydrous sodium sulfate, filtering, evaporating the solvent under reduced pressure, and separating and purifying by Prep-HPLC to obtain the target compound 14. MS m/z (ESI): 533.2[ M + H]⁺。

1H NMR(400MHz，DMSO-d₆)δ10.19(s，1H)，8.68(d，J＝4.5Hz，1H)，8.33(s，1H)，8.16(d，J＝7.6Hz，1H)，7.92(d，J＝4.2Hz，1H)，7.88(s，2H)，7.72(d，J＝5.9Hz，1H)，7.16(d，J＝6.0Hz，1H)，6.41(s，1H)，4.45(d，J＝13.2Hz，2H)，3.93-3.78(m，1H)，3.15(t，J＝11.6Hz，2H)，2.25(s，3H)，1.84(d，J＝10.1Hz，2H)，1.44-1.34(m，2H).

The separation method comprises the following steps:

in the invention, the compounds 1-14 (except the compound 4) are separated and purified by using an active 1260 type HPLC, the column temperature is 25 ℃, and other separation conditions are shown in the following table:

biological evaluation

Experimental example 1: RET inhibition assay

The experimental method comprises the following steps: the inhibitory effect of compounds on different RET subtypes was determined using the HTRF KinEASE-TK (Cisbio) kit. Different isoforms of RET enzyme were preincubated with different concentrations of test compounds (3 concentration points for compounds 5, 13, 14, 8 concentration points for others) at room temperature for 30min before starting the reaction by adding substrate and Adenosine Triphosphate (ATP). And (3) incubating at room temperature for 40min, adding the TK antibody-cryptate and streptavidin-XL 665, and incubating at room temperature for 45min for detection. The reaction conditions for the different subtypes of RET enzymes are shown in the following table:

subtype RET	RET(nM)	ATP(μM)	TK-substrate (μ M)
				RET-WT	1	20	1
RET-CCDC6	0.5	20	1
				RET-M918T	0.2	10	1
RET-V804L	2.5	5	1
				RET-V804M	0.5	5	1

The percentage of relative inhibitory activity of the compounds at different concentrations was calculated according to the following formula, using the vehicle group (DMSO) as a negative control and the buffer group (without RET enzyme) as a blank control:

relative percent inhibitory activity was 1- (different concentration of compound group-blank)/(negative control-blank) 100%

The percent relative inhibitory activity of compounds at various concentrations was plotted against compound concentration, and the IC was calculated according to the following equation, fitting a curve to a four parameter model₅₀The value:

y＝min+(max-min)/(1+(x/IC₅₀)^(-Hillslope))

where y is the relative percent inhibitory activity, max and min are the maximum and minimum values of the fitted curve, respectively, x is the log concentration of the compound, and Hillslope is the slope of the curve.

The experimental results are as follows: the inhibitory effect of the compounds on RET activity was determined as described above and the results are as follows:

TABLE 1 inhibition of RET-CCDC6 enzymatic Activity IC by the Compounds of the invention₅₀

Compound numbering	CCDC6 IC₅₀(nM)
		l	2.31±0.29
2	3.89±0.55
		3	2.52±0.37
4	3.38±1.71
		5	14.24±3.58
6	7.45±2.55
		7	2.86±0.47
8	22.59±4.97
		9A	2.49±0.82

As can be seen from Table 1, the compounds of the present invention have significant inhibitory effects on the RET-CCDC6 enzyme.

TABLE 2 inhibition of RET-M918T enzymatic Activity IC by Compounds of the invention₅₀

Compound numbering	M918T IC₅₀(nM)
		1	0.65±0.13
2	0.99±0.67
		3	1.10±0.47
4	1.97±0.99
		5	20.06±12.11
6	5.65±1.93
		7	2.06±0.52
8	13.23±3.16
		9A	2.58±0.79
13	13.52±1.91
		14	10.19±0.37

As can be seen from Table 2, the compounds of the present invention have a significant inhibitory effect on the RET-M918T enzyme.

The above examples do not limit the scheme of the present application in any way. Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

1. A compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (I-a) or formula (I-B):

wherein:

represents a single bond or a double bond;

X¹is CR⁵Or N;

X²is CR⁷Or N;

X³、X⁴and X⁸Each independently selected from C and N;

X⁶is CR⁹Or N;

X⁷is CR¹⁰Or N;

R⁵、R⁷and R¹⁰Each independently selected from H, hydroxy, halogen, CN, C_1-6Alkyl radical, C_1-6Heteroalkyl group, C_1-6Alkoxy radical, C_3-6Cycloalkyl, -NR^20aR^20b、-OR²¹and-SR²¹；

r is 0, 1, 2 or 3;

s is 0, 1, 2 or 3;

t is 0, 1, 2 or 3;

z is 0, 1 or 2

m is 0 or 1;

n is 0 or 1;

the above alkyl, alkylene, heteroalkyl, heteroalkylene, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, heterocycle, heterocyclyl, aryl, heteroaryl, and heteroaryl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, NO₂、C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Hydroxyalkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkoxy, C_1-4Heteroalkyl group, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-6Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl, 5-10 membered heteroaryl, -NR^30aR^30b、-OR³¹、-SR³¹、-S(＝O)R³²、-S(＝O)₂R³²、-S(＝O)NR^30aR^30b、-S(＝O)₂NR^30aR^30b、-NR^30aS(＝O)R^30b、-NR^30aS(＝O)₂R^30b、-C(＝O)NR^33aR^33b、-NR^33aC(＝O)R^33b、-OC(＝O)NR^33aR^33b、-NR^34aC(＝O)NR^35aR^35bWherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with C_6-12Aryl or 5-10 membered heteroaryl fused; and is

R^30a、R^30b、R³¹、R³²、R^33a、R^33b、R^34a、R^35aAnd R^35bEach independently selected from H, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-8Cycloalkyl, 4-10 membered heterocyclyl, C_6-12Aryl and 5-10 membered heteroaryl.

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, cocrystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring a is a phenyl ring, a 5-membered heteroaryl ring, or a 6-membered heteroaryl ring;

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein ring B is a phenyl ring, a 6-membered heterocyclic ring, or a 6-membered heteroaromatic ring;

4. A compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically-labeled compound, metabolite, or prodrug thereof, wherein ring C is a 5-membered heteroaryl ring or a 6-membered heteroaryl ring;

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein X is¹、X²、X⁶And X⁷Each independently CH, C-OMe or N.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein X is⁵C, CH or N.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein L is selected from the group consisting of

L is preferably

(e.g., -C (═ O) NH-),

)；

L is more preferably

And is

L is most preferably

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein R is^6a、R^6bAnd R^6cEach independently selected from H, C_1-4Alkyl and C_1-4A heteroalkyl group; wherein the alkyl and heteroalkyl are each optionally substituted with one or more substituents selected from the group consisting of: hydroxy, halogen, CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4A heteroalkyl group;

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein

Is selected from

And

preferably, it is

Selected from:

10. the compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of any one of the following formulae:

11. the compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of any one of the following formulae:

wherein:

R^6ais H or C_1-4Alkyl, preferably H or Me;

R⁹is H OR-OR²¹(ii) a And is

R²¹Is C_1-4Alkyl, preferably Me.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:

13. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and a pharmaceutically acceptable carrier, preferably said pharmaceutical composition is in a solid, semi-solid, liquid or gaseous formulation, and said pharmaceutical composition is preferably administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular or transdermal route.

14. Use of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 13, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RET activity, wherein said disease or condition associated with RET activity is preferably a cancer or tumor (e.g., brain tumor, lung cancer (e.g., non-small cell lung cancer), squamous cell cancer, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell cancer, prostate cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibroma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, carcinoma, bladder, Thyroid cancer (e.g., medullary thyroid cancer or papillary thyroid cancer), bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma), or irritable bowel syndrome.

15. The preparation method comprises the steps of (1) preparing,

wherein the process is a process for preparing a compound of formula (I-A1):

wherein:

R^yis C_1-4Haloalkylsulfonyl, preferably trifluoromethanesulfonyl;

)；

Hal¹And Hal²Each independently F, Cl, Br or I, preferably C1;

the remaining groups are as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the seventh step: reacting the compound I-A1-9 under alkaline or acidic conditions to generate a compound I-A1-10; and

or a process for preparing a compound of formula (I-A2):

wherein each group is as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the first step is as follows: reducing compound I-A1-10 to compound I-A2-1; and

or a process for preparing a compound of formula (I-A3):

wherein:

Hal²is F, Cl, Br or I, preferably C1;

the remaining groups are as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the second step is that: reacting the compound I-A3-2 under alkaline or acidic conditions to generate a compound I-A3-3; and

or a process for preparing a compound of formula (I-A4):

wherein each group is as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

or a process for preparing a compound of formula (I-A5):

wherein:

Hal¹and Hal²Each independently is F, Cl, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the fourth step: reacting the compound I-A5-5 under alkaline or acidic conditions to generate a compound I-A5-6; and

or a process for preparing a compound of formula (I-A6):

wherein:

Hal¹、Hal²and Hal³Each independently is F, Cl, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the third step: reacting the compound I-A6-2 with the compound I-A6-3 in the presence of alkali to generate a compound I-A6-4; and

or a process for preparing a compound of formula (I-A7):

wherein:

Hal²f, C1, Br or I, preferably Cl;

PG is an amino protecting group such as Boc, PMB, DMB, Bn, Cbz;

the remaining groups are as defined in any one of claims 1 to 12;

the reaction comprises the following steps:

the second step is that: reacting the compound I-A7-2 under the condition of removing a protecting group PG to generate a compound I-A7-3; and

the third step: the compound I-A7-3 reacts with I-A4-1 to generate the compound of formula (I-A6).